Immunoglobulin single variable domains targeting PD-1

Abstract

The present technology provides polypeptides that binds to PD-1. The present technology also provides nucleic acids, vectors and compositions.

Description

[0001] IMMUNOGLOBULIN SINGLE VARIABLE DOMAINS TARGETING PD-1

[0002] 1 Field of the present technology

[0003] The present technology relates to immunoglobulin single variable domains (ISVDs) targeting PD-1 and more in particular to polypeptides and constructs that comprise or essentially consist of one or more such ISVDs. It also relates to nucleic acid molecules encoding the ISVDs and polypeptides and vectors comprising the nucleic acids, and to compositions comprising the ISVD, polypeptide, nucleic acid or vector. The present technology further relates to these products for use in a method of treating a subject suffering from cancer. The present technology also relates to methods of producing these products.

[0004] 2 Technological background

[0005] The PD-1 (programmed cell death-1) receptor (CD279) is expressed on the surface of activated T cells. Its ligands, PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273), are transmembrane proteins of the B7 family that are commonly expressed on dendritic cells and macrophages. PD-1 and PD-L1 / PD-L2 belong to the family of immune checkpoint proteins that act as co-inhibitory factors that can halt or limit the development of the T-cell response. The PD-1 / PD-L1 interaction ensures that the immune system is activated only at the appropriate time to minimize the possibility of chronic autoimmune inflammation. The biology of PD-L1 and its role in cancer immunology and immunotherapy are described by Sun et al.

[0006] 2018 (Immunity 48: 434) and Salmaninejad et al. 2019 (J. Cell Physiol. 234: 16824).

[0007] A number of biological compounds aiming at blocking the PD-1 / PD-L1 interaction have already been approved for use in cancer. Pembrolizumab (Keytruda; Merck) and Nivolumab (Opdivo; Bristol-Myers Squibb) are monoclonal anti-PD-1 Ig4 antibodies, both of which were approved by the FDA in 2014 for the treatment of melanoma, followed by the approval for various other cancers including multiple melanoma, non-small cell lung cancer (NSCLC), liver cancer, and colorectal cancer. Cemiplimab (Libtayo; Regeneron Pharmaceuticals) is an immunoglobulin (lg)G4 monoclonal antibody (mAb) to the programmed cell death (PD)-1 which was the first FDA-approved treatment for advanced cutaneous squamous cell carcinoma and was later approved to be used in basal cell carcinoma and non-small cell lung cancer. Several other monoclonal anti-PD-1 antibodies have been approved since then.

[0008] The less efficient penetration of monoclonal antibodies because of their large size and the complexity of the tumor microenvironment has impelled the development of small-molecule biologies with superior penetration efficiencies. Envafolimab (KN035; 3D Medicines / Alphamab Oncology / Simcere Pharmaceutical Group) is an anti-PD-Ll single domain-Fc fusion protein and is currently marketed for the treatment of advanced biliary cancer and soft tissue sarcoma. Immunoglobulin single variable domains that target PD1 have been described in WO 2008 / 071447.

[0009] Hence there is a need for improved small-molecule biologies to PD-1. Such small-molecule biologies are also useful for combining with other (cancer)target binders in a single chain, while maintaining a relatively small size, high affinity, potency and / or efficacy, in addition to good manufacturing yields. Furthermore, the biological drug should show safety, convenience, patient compliance and improve patients' quality of life.

[0010] 3 Summary of the present technology

[0011] In some embodiments, the present technology relates to immunoglobulin single variable domains specifically targeting PD-1. In some embodiments, the present technology relates to high affinity immunoglobulin single variable domains specifically targeting PD-1. In some embodiments, the present technology relates to high potency immunoglobulin single variable domains specifically targeting PD-1. In some embodiments, the present technology relates to high efficacy immunoglobulin single variable domains specifically targeting PD-1.

[0012] Targeting PD-1 with a biologic that is small (in size), such as a monovalent or bivalent immunoglobulin single variable domain, and keeping a high affinity, potency and / or efficacy may be advantageous in certain applications where a very small binder is desired. Small binders may be advantageous, e.g. for penetration in the tumor environment, or when additional binders for other (tumor) targets are implicated in the same construct, facilitating manufacturing and further handling of the therapeutic compound.

[0013] The present technology provides immunoglobulin single variable domains specifically targeting PD-1 that block the interaction of PD1 and PD-L1 (with comparable or better EC50 than benchmark(s)). The present technology provides immunoglobulin single variable domains specifically targeting PD-1 that show potency in bioassays, such as binding of PD-1 and competition with PD-L1 in flow-cytometry, or functionality in a tetanus-toxoid autogenic antigen-specific co-culture assay (tetanus-toxoid (TT) assay) and NFAT PD1 / PD-L1 blocking assay.

[0014] The immunoglobulin single variable domains of the present technology and polypeptides and constructs comprising said immunoglobulin single variable domains showed a high potency in competition assays with PD-L1 and a high potency and efficacy in TT assay, and could be efficiently produced (e.g. in microbial hosts such as Pichia, e.g. P. pastoris). In one embodiment, the immunoglobulin single variable domain, polypeptide or construct of the present technology may further comprise one or more other groups, residues, moieties or binding units, optionally linked via one or more peptidic linkers, in which said one or more other groups, residues, moieties or binding units provide the ISVD, polypeptide or construct with increased half-life, compared to the corresponding ISVD, polypeptide or construct without said one or more other groups, residues, moieties or binding units. Said one or more other groups, residues, moieties or binding units that provide the ISVD, polypeptide or construct with increased half-life may be chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that can bind to serum proteins, an Fc portion, and small proteins or peptides that can bind to serum proteins. The binding units that provide the ISVD, polypeptide or construct with increased half-life may be chosen from the group consisting of binding units that can bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG), e.g., human serum albumin.

[0015] In one embodiment, the binding unit that can bind to serum albumin (such as human serum albumin) is an ISVD. In one embodiment, the ISVD binding to human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which CDR1 is SEQ ID NO: 2436, CDR2 is SEQ ID NO: 2438, CDR3 is SEQ ID NO: 2440. In one embodiment, the ISVD binding to human serum albumin comprises a sequence identity of more than 90% (such as 95%) with SEQ ID NO: 2416. In one embodiment, the ISVD binding to human serum albumin comprises or consists of the amino acid sequence of SEQ ID NO: 2416.

[0016] In one embodiment, the ISVD binding to human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 2401), ALB23 (SEQ ID NO: 2402), ALBX00001 (SEQ ID NO: 2415) and ALB23002 (SEQ ID NO: 2416). In one embodiment, the ISVD binding to human serum albumin is ALB23002 (SEQ ID NO: 2416).

[0017] Also provided is a nucleic acid molecule capable of expressing the immunoglobulin single variable domain or polypeptide of the present technology, a vector comprising the nucleic acid, and a composition comprising the polypeptide, nucleic acid or vector.

[0018] Also provided is a (non-human) host or host cell comprising such a nucleic acid.

[0019] Also provided is a method for producing an immunoglobulin single variable domain or polypeptide of the present technology, said method at least comprising the steps of: a) expressing, in a suitable host cell or (non-human) host organism or in another suitable expression system, a nucleic acid encoding the immunoglobulin single variable domain or polypeptide of the present technology; optionally followed by:

[0020] b) isolating and / or purifying the ISVD or polypeptide.

[0021] Also provided is a composition comprising at least one immunoglobulin single variable domain, polypeptide or construct of the present technology, or a nucleic acid encoding an immunoglobulin single variable or polypeptide of the present technology.

[0022] The composition of the present technology is for use as a medicament. The composition can be a pharmaceutical composition which further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

[0023] The immunoglobulin single variable domain, polypeptide or construct of the present technology, a composition comprising the immunoglobulin single variable domain, polypeptide or construct, and a composition comprising a nucleic acid comprising a nucleotide sequence that encodes the immunoglobulin single variable domain or polypeptide can be used as a medicament.

[0024] The immunoglobulin single variable domain, polypeptide, construct or composition of the present technology can be used in the treatment. More specifically, the immunoglobulin single variable, polypeptide, construct or composition can be used in the treatment of cancer.

[0025] Accordingly, the present technology also encompasses a method of treating cancer. In some embodiments, the present technology encompasses a method of treating cancer, wherein said method comprises administering, to a subject in need thereof, a pharmaceutically active amount of an immunoglobulin single variable domain, polypeptide or construct of the present technology, a nucleic acid encoding an ISVD or polypeptide of the present technology or a composition comprising the same.

[0026] Accordingly, the present technology also encompasses the use of an immunoglobulin single domain, polypeptide or construct of the present technology in the preparation of a pharmaceutical composition for treating cancer. 4 Brief description of the drawings

[0027] Figure 1. Crystal structure of A0294047E02 in complex with PD-1. (A) Whole complex of A0294047E02 with PD-1; (B) p-sheet formed by the interactions of CDR3 with a p-strand from hPDl.

[0028] Figure 2. Detailed view of sites in the interaction between the PD-1 and A0294047E02 of one of the complexes. (A) Key interacting residues of paratope on A0294047E02 (chain H) located at <4.00A distance from PD-1 (chain A). (B) Key interacting residues of epitope on PD-1 (chain A) located at < 4.0A distance from A0294047E02 (chain H).

[0029] Figure 3. Crystal structure of A02900073 in complex with PD-1.

[0030] Figure 4. Detailed view of sites in the interaction between the PD-1 and A02900073 of one of the complexes. (A) Key interacting residues of paratope on A02900073 (chain H) located at <4.00A distance from the PD-1 (chain A). (B) Key interacting residues of epitope on PD-1 (chain A) located at <4.0A distance from A02900073 (chain H).

[0031] Figure 5. Crystal structure of A02900072 in complex with PD-1. (A) Whole complex of A02900072 with PD-1; (B) Surface representation of the interaction between chain A and chain C.

[0032] Figure 6. Detailed view of sites in the interaction between the PD-1 and A02900072 of one of the complexes. (A) Key interacting residues of paratope on A02900072 (chain C) located at <4.00A distance from the hPD-1 (chain A). (B) Key interacting residues of epitope on hPD-1 (chain A) located at < 4.0A distance from A02900072 (chain C).

[0033] Figure 7. Binding mode comparison between A0294047E02, A029400073 and A029400072.

[0034] Figure 8. Comparison of the binding modes of the anti-PD-1 ISVDs to PD-1 (UniProt: Q15116; SEQ. ID NO: 4703). (A) Alignment of the epitopes bound on PD-1. Epitopes are indicated as bold underlined; (B) Alignment of the anti-PD-1 ISVDs. Paratopes are indicated as bold underlined.

[0035] Figure 9. Binding mode comparison of the anti-PD-1 ISVDs with PD-L1.

[0036] 5 Detailed description of the present technology

[0037] 5.1 Definitions

[0038] Unless indicated or defined otherwise, all terms used have their usual meaning in the art, which will be clear to the skilled person. Reference is for example made to the standard handbooks, such as Sambrook et al. (Molecular Cloning: A Laboratory Manual (2nd. Ed.) Vols. 1-3, Cold Spring Harbor Laboratory Press, 1989), F. Ausubel et al. (Current protocols in molecular biology, Green Publishing and Wiley Interscience, New York, 1987), Lewin (Genes II, John Wiley & Sons, New York, N. Y., 1985), Old et al. (Principles of Gene Manipulation: An Introduction to Genetic Engineering (2nd edition) University of California Press, Berkeley, CA, 1981); Roitt et al. (Immunology (6th. Ed.) Mosby / Elsevier, Edinburgh, 2001), Roitt et al. (Roitt's Essential Immunology (10th Ed.) Blackwell Publishing, UK, 2001), and Janeway et al. (Immunobiology (6th Ed.) Garland Science Publishing / Churchill Livingstone, New York, 2005), as well as to the general background art cited herein.

[0039] Unless indicated otherwise, all methods, steps, techniques and manipulations that are not specifically described in detail can be performed and have been performed in a manner known per se, as will be clear to the skilled person. Reference is for example again made to the standard handbooks and the general background art mentioned herein and to the further references cited therein; as well as to for example the following reviews Presta (Adv. Drug Deliv. Rev. 58 (5-6): 640-56, 2006), Levin and Weiss (Mol. Biosyst.

[0040] 2(1): 49-57, 2006), Irving et al. (J. Immunol. Methods 248(1-2): 31-45, 2001), Schmitz et al. (Placenta 21 Suppl. A: S106-12, 2000), Gonzales et al. (Tumour Biol. 26(1): 31-43, 2005), which describe techniques for protein engineering, such as affinity maturation and other techniques for improving the specificity and other desired properties of proteins such as immunoglobulins.

[0041] The term "sequence" as used herein (for example in terms like "immunoglobulin sequence", "antibody sequence", "variable domain sequence", " VHH sequence" or "protein sequence"), should generally be understood to include both the relevant amino acid sequence as well as nucleic acids or nucleotide sequences encoding the same, unless the context requires a more limited interpretation.

[0042] Amino acid residues will be indicated according to the standard three-letter or one-letter amino acid code. Reference is made to Table A-2 on page 48 of WO 08 / 020079.

[0043] A nucleic acid or amino acid is considered to be "(in) (essentially) isolated (form)" - for example, compared to the reaction medium or cultivation medium from which it has been obtained - when it has been separated from at least one other component with which it is usually associated in said source or medium, such as another nucleic acid, another protein / polypeptide, another biological component or macromolecule or at least one contaminant, impurity or minor component. In particular, a nucleic acid or amino acid is considered "(essentially) isolated" when it has been purified at least 2-fold, in particular at least 10-fold, more in particular at least 100-fold, and up to 1000-fold or more. A nucleic acid or amino acid that is "in (essentially) isolated form" is preferably essentially homogeneous, as determined using a suitable technique, such as a suitable chromatographical technique, such as polyacrylamide-gel electrophoresis.

[0044] When a nucleotide sequence or amino acid sequence is said to "comprise" another nucleotide sequence or amino acid sequence, respectively, or to "essentially consist of" another nucleotide sequence or amino acid sequence, this may mean that the latter nucleotide sequence or amino acid sequence has been incorporated into the first mentioned nucleotide sequence or amino acid sequence, respectively, but more usually this generally means that the first mentioned nucleotide sequence or amino acid sequence comprises within its sequence a stretch of nucleotides or amino acid residues, respectively, that has the same nucleotide sequence or amino acid sequence, respectively, as the latter sequence, irrespective of how the first mentioned sequence has actually been generated or obtained (which may for example be by any suitable method described herein). By means of a non-limiting example, when a polypeptide is said to comprise an immunoglobulin single variable domain, this may mean that said immunoglobulin single variable domain sequence has been incorporated into the sequence of the polypeptide, but more usually this generally means that the polypeptide contains within its sequence the sequence of the immunoglobulin single variable domains irrespective of how said polypeptide has been generated or obtained. Also, when a nucleic acid or nucleotide sequence is said to comprise another nucleotide sequence, the first mentioned nucleic acid or nucleotide sequence is preferably such that, when it is expressed into an expression product (e.g. a polypeptide), the amino acid sequence encoded by the latter nucleotide sequence forms part of said expression product (in other words, that the latter nucleotide sequence is in the same reading frame as the first mentioned, larger nucleic acid or nucleotide sequence).

[0045] By "(essentially) consist of" is meant that the later nucleic acid sequence or amino acid sequence, either is exactly the same as the polypeptide (e.g. the CDR region; the ISVD) or corresponds to the polypeptide (e.g. the CDR region; the ISVD) which has a limited number of amino acid residues, such as 1-20 amino acid residues, for example 1-10 amino acid residues and preferably 1-6 amino acid residues, such as 1, 2, 3, 4, 5 or 6 amino acid residues, added at the amino terminal end, at the carboxy terminal end, or at both the amino terminal end and the carboxy terminal end of the immunoglobulin single variable domain.

[0046] For the purposes of comparing two or more amino acid sequences, the percentage of "sequence identity" between a first amino acid sequence and a second amino acid sequence may be calculated by dividing [the number of amino acid residues in the first amino acid sequence that are identical to the amino acid residues at the corresponding positions in the second amino acid sequence] by [the total number of amino acid residues in the first amino acid sequence] and multiplying by [100%], in which each deletion, insertion, substitution or addition of an amino acid residue in the second amino acid sequence - compared to the first amino acid sequence - is considered as a difference at a single amino acid residue (i.e. at a single position). Usually, for the purpose of determining the percentage of "sequence identity" between two amino acid sequences in accordance with the calculation method outlined hereinabove, the amino acid sequence with the greatest number of amino acid residues will be taken as the "first" amino acid sequence, and the other amino acid sequence will be taken as the "second" amino acid sequence. An "amino acid difference" as used herein refers to a deletion, insertion or substitution of a single amino acid residue vis-a-vis a reference sequence. In one embodiment, an "amino acid difference" is a substitution. In one embodiment, amino acid substitutions are conservative substitutions. Such conservative substitutions are substitutions in which one amino acid within the following groups (a) - (e) is substituted by another amino acid residue within the same group: (a) small aliphatic, nonpolar or slightly polar residues: Ala, Ser, Thr, Pro and Gly; (b) polar, negatively charged residues and their (uncharged) amides: Asp, Asn, Glu and Gin; (c) polar, positively charged residues: His, Arg and Lys; (d) large aliphatic, nonpolar residues: Met, Leu, Ile, Val and Cys; and (e) aromatic residues: Phe, Tyr and Trp. In one embodiment, conservative substitutions are as follows: Ala into Gly or into Ser; Arg into Lys; Asn into Gin or into His; Asp into Glu; Cys into Ser; Gin into Asn; Glu into Asp; Gly into Ala or into Pro; His into Asn or into Gin; Ile into Leu or into Val; Leu into lie or into Vai; Lys into Arg, into Gin or into Glu; Met into Leu, into Tyr or into lie; Phe into Met, into Leu or into Tyr; Ser into Thr; Thr into Ser; Trp into Tyr; Tyr into Trp; and / or Phe into Vai, into lie or into Leu.

[0047] A " VHH family" as used in the present specification refers to a group of VHH sequences that have identical lengths (i.e. they have the same number of amino acids within their sequence) and of which the amino acid sequence between position 8 and position 106 (according to Kabat numbering) has an amino acid sequence identity of 89% or more.

[0048] The terms "epitope" and "antigenic determinant", which can be used interchangeably, refer to the part of a macromolecule, such as a polypeptide or protein that is recognized by antigen-binding molecules, such as immunoglobulins, conventional antibodies, or immunoglobulin single variable domains, and more particularly by the antigen-binding site of said molecules. Epitopes define the minimum binding site for an immunoglobulin, and thus represent the target of specificity of an immunoglobulin. Epitopes may be either conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different segments of the linear polypeptide chain. A linear epitope is one produced by adjacent amino acid residues in a polypeptide chain. As will be appreciated by one of skill in the art, practically anything to which an antibody can specifically bind could be an epitope. The definition of the term "paratope" is derived from the above definition of "epitope", by reversing the perspective. Thus, the term "paratope" refers to the area or region (i.e., the residues) of an antibody or fragment thereof involved in recognition of and binding to the epitope of an antigen.

[0049] The term "interact with" as used herein in the context of at least two polypeptides forming a complex (e.g. anti-PD-1 ISVD and PD-1) means that at least one (amino acid) residue of one polypeptide is in close proximity to at least one (amino acid) residue of the other polypeptide. The distance between two (amino acid) residues which are located within distinct polypeptides may be determined using methods known is the art. For example, the skilled person knows that structural information allowing to determine the distance between two (amino acids) residues may be obtained using standard methods such as X-ray crystallography, Cryogenic electron microscopy (cryo-EM), nuclear magnetic resonance, and subsequent molecular modelling. The skilled person is also aware that two (amino acid) residues are in close proximity and therefore interact with each other if the (shortest) distance between the two (amino acid) residues is less than 10 A, less than 8 A, less than 6 A, less than 5 A, less than 4 A, less than 3 A, less than 2 A, preferably less than 4 A, more preferably less than 4 A and more than 2 A.

[0050] The term "interaction site" as used herein refers to the area within a complex comprising at least two polypeptides which is formed by the (amino acid) residue(s) within each of the respective polypeptides that interact with each other as defined herein. For example, an ISVD specifically binding to PD-1 comprises at least one amino acid residue that interacts with at least one (amino acid) residue on PD-1. In this respect, the at least one amino acid residue of the anti-PD-1 ISVD and the at least one (amino acid) residue on PD-1 interacting with each other also form an interaction site. The skilled person is aware that interaction sites may for example be defined by reference to a specific amino acid residue of the polypeptide (e.g. E104 of PD-1).

[0051] Molecular interactions can have a different strength, bond length (A), interaction area (A2), depending on the type of amino acid residues that make up the interaction. Strong molecular interactions include hydrogen bonds (or H-bonds), that are electrostatic forces of attraction between a hydrogen (H) atom which is covalently bonded to a more electronegative donor atom or group, and another electronegative atom bearing a lone pair of electrons, the hydrogen bond acceptor. Such an interacting system is generally denoted "donor-H---acceptor", where the solid line denotes a polar covalent bond, and the dotted or dashed line indicates the hydrogen bond. The most frequent donor and acceptor atoms are the period 2 elements: nitrogen (N), oxygen (O), and fluorine (F). The hydrogen bonds have a length around 1.5-2.5 A and an interaction area around 10-50 A2. Typical amino acid residues that form a H-bond are Lys, Arg, Asn, Gin, Ser and Thr (donors), and Asp, Glu, Asn, Gin, Ser and Thr (acceptors).

[0052] Other strong molecular interactions include salt bridges, that are defined as electrostatic interactions between two oppositely charged groups: the anionic carboxylate of either glutamate (E) or aspartate (D), and the cationic ammonium from either arginine (R) or lysine (K). The salt bridges have a length around 2.8-4.0 A and an interaction area around 10-100 A2. Typical amino acid residues that form a salt bridge are Lys, Arg and His (positive), and Asp and Glu (negative). Weaker interactions include hydrophobic interactions, that are the non-covalent force where nonpolar species tend to cluster in water in order to decrease the overall interfacial area between the hydrophobic species and water. Hydrophobic interactions have a length around 3.5-4.5 A and an interaction area around 100-300 A2. Typical amino acid residues that form hydrophobic interactions are Ala, Vai, Leu, He, Met, Phe, Trp.

[0053] Van der Waals forces include attraction and repulsions between atoms, molecules, as well as other (weaker) intermolecular forces. They differ from covalent and ionic bonding in that they are caused by correlations in the fluctuating polarizations of nearby particles. The force results from a transient shift in electron density. Specifically, the electron density may temporarily shift to be greater on one side of the nucleus. This shift generates a transient charge which a nearby atom can be attracted to or repelled by. Van der Waals forces have a length around 3.5-4.5 A and an interaction area around 50-200 A2.

[0054] Molecular modelling of the interaction site can be performed by tools known in the art, such as e.g., PDBe-PISA. PDBe-PISA is an interactive tool for the exploration of macromolecular interfaces based on cryo-EM or X-ray structures (https: / / www.ebi.ac.uk / pdbe / pisa / ). PDBe-PISA represents a systematic approach to automatic identification of probable quaternary structures, based on physical-chemical models of macromolecular interactions and chemical thermodynamics. Amongst others, PDBe-PISA calculates buried surface area (BSA) according to cryoEM / Xray structures, which is the portion of molecular surfaces no longer exposed to solvent upon complex formation. Core interacting residues are deeply buried, have a high buried surface area (BSA) and low solvent exposure (ASA, Accessible Surface Area). Chemical stability of macromolecular complexes is estimated in Gibbs free energy terms (Interface free energy (AG)) which, when negative, indicates a thermodynamically stable interaction.

[0055] A polypeptide (such as an immunoglobulin, an antibody, an immunoglobulin single variable domain, or generally an antigen binding molecule or a fragment thereof) that can "bind to" or "specifically bind to", that "has affinity for" and / or that "has specificity for" a certain epitope, antigen or protein (or for at least one part, fragment or epitope thereof) is said to be "against" or "directed against" said epitope, antigen or protein or is a "binding" molecule with respect to such epitope, antigen or protein, or is said to be "anti"-epitope, "anti"-antigen or "anti"-protein (e.g., "anti"- PD-1).

[0056] The terms "specificity", "binding specifically" or "specific binding" refer to the number of different target molecules, such as antigens, from the same organism to which a particular binding unit, such as an ISVD, can bind with sufficiently high affinity (see below). " Specificity", "binding specifically" or "specific binding" are used interchangeably herein with "selectivity", "binding selectively" or "selective binding". Binding units, such as ISVDs, specifically bind to their designated targets. The specificity / selectivity of a binding unit can be determined based on affinity. The affinity denotes the strength or stability of a molecular interaction. The affinity is commonly given by the KD, or dissociation constant, which has units of mol / liter (or M). The affinity can also be expressed as an association constant, KA, which equals 1 / KD and has units of (mol / liter)1(or M1).

[0057] The affinity is a measure for the binding strength between a moiety and a binding site on the target molecule: the lower the value of the KD, the stronger the binding strength between a target molecule and a targeting moiety. Typically, binding units used in the present technology, such as ISVDs, will bind to their targets with a dissociation constant (KD) of 10-5to 1012moles / liter or less, 10-7to 1012moles / liter or less, or 10-8to 1012moles / liter (i.e. with an association constant (KA) of 105to 1012liter / moles or more, 107to 1012liter / moles or more, or 108to 1012liter / moles). Any KD value greater than 10-4mol / liter (or any KA value lower than 104liters / mol) is generally considered to indicate non-specific binding. The KD for biological interactions, such as the binding of immunoglobulin sequences to an antigen, which are considered specific are typically in the range of 10-5moles / liter (10000 nM or 10µM) to 1012moles / liter (0.001 nM or 1 pM) or less.

[0058] Accordingly, specific / selective binding may mean that -using the same measurement method, e.g. SPR- a binding unit (or polypeptide comprising the same) binds to PD-1 with a KD value of 10-5to 1012moles / liter or less and binds to related CD28 receptor family members with a KD value greater than 10-4moles / liter. An example of a related CD28 receptor family member is CD28, CTLA-4, ICOS, and BTLA. Thus, in an embodiment of the present technology, the ISVD binds to (human) PD-1 with a KD value of 10-5to 1012moles / liter or less and binds to CD28, CTLA-4, ICOS, and BTLA of the same species with a KD value greater than 10-4moles / liter.

[0059] Specific binding to a certain target from a certain species does not exclude that the binding unit can also specifically bind to the analogous target from a different species. For example, specific binding to human PD-1 does not exclude that the binding unit or a polypeptide comprising the same can also specifically bind to PD-1 from cynomolgus monkeys ("cyno").

[0060] Specific binding of a binding unit to its designated target can be determined in any suitable manner known per se, including, for example, Scatchard analysis and / or competitive binding assays, such as radioimmunoassays (RIA), enzyme immunoassays (EIA) and sandwich competition assays, and the different variants thereof known per se in the art; as well as the other techniques mentioned further herein. The dissociation constant may be the actual or apparent dissociation constant, as will be clear to the skilled person. Methods for determining the dissociation constant will be clear to the skilled person, and for example include the techniques mentioned herein. In this respect, it will also be clear that it may not be possible to measure dissociation constants of more than 10-4moles / liter or 10-3moles / liter (e.g. of 10-2moles / liter). Optionally, as will also be clear to the skilled person, the (actual or apparent) dissociation constant may be calculated on the basis of the (actual or apparent) association constant (KA), by means of the relationship [KD = 1 / KA],

[0061] An amino acid sequence is said to be "cross-reactive" for two different antigens or antigenic determinants (such as e.g., serum albumin from two different species of mammal, such as e.g., human serum albumin and cyno serum albumin, such as e.g., PD-1 from different species of mammal, such as e.g., human PD-1, cyno PD-1 and mouse PD-1) if it is specific for (as defined herein) these different antigens or antigenic determinants.

[0062] The terms "block", "antagonize", "compete", "competing" and "-competition" are used interchangeably herein to mean the ability of an immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent to interfere with the binding of another protein, polypeptides, ligand or binding agent to a given target. The extent to which an immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent is able to interfere with the binding of another ligand to the target, and therefore whether it can be said to "block", can be determined using competition binding assays. Particularly suitable quantitative competitive blocking assays are described in the Examples and include, e.g., a fluorescence-activated cell sorting (FACS) competition assay with PD-1 expressed on cells. The extent of blocking can be measured by the (reduced) channel fluorescence.

[0063] The following generally describes a suitable FACS assay for determining whether an immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent blocks or is capable of blocking. It will be appreciated that the assay can be used with any of the immunoglobulin single variable domains and polypeptides described herein. The FACS instrument (e.g. FACS Canto; Becton Dickinson) is operated in line with the manufacturer's recommendations.

[0064] To evaluate the "blocking" or "competition" between two binding agents (such as an immunoglobulin single variable domain and a natural ligand or another binding agent) for binding PD-1, a FACS competition experiment can be performed using cells (such as, e.g., Flp-ln™-293 cells) overexpressing human PD-1 and the parental cells as background cell line. Different detection reagents can be used including, e.g., monoclonal ANTI-FLAG® M2 antibody (Sigma-Aldrich, cat# F1804), monoclonal anti-C-myc antibody (Sigma-Aldrich, cat# WH0004609M2), monoclonal ANTI-HIS TAG antibody (Sigma-Aldrich, cat# SAB1305538), each labeled differently. A wide range of fluorophores can be used as labels in flow cytometry (such as, e.g., PE (R-Phycoerythrin), 7-aminoactinomycin D (7-AAD), Acridine Orange, various forms of Alexa Fluor, Allophycocyanin (APC), AmCyan, Aminocoumarin, APC Cy5, APC Cy7, APC-H7, APC / Alexa Fluor 750, AsRed2, Azami-Green, Azurite, B ODIPY FL C5-ceramide, BCECF-AM, Bis-oxonol DiBAC2(3), BODIPY-FL, Calcein, Calcein AM, Caroxy-H2DCFDA, Cascade Blue, Cascade Yellow, Cell Tracker Green, Cerulean, CFSE, Chromomycin A3, CM-H2DCFDA, Cy2, Cy3, Cy3.5, Cy3B, Cy5, Cy5.5, Cy7, CyPet, DAF-FM DAF-FM diacetate, DAPI, DCFH (2'7'Dichorodihydrofluorescein), DHR, Dihydrocalcein AM, Dihydrorhoadamine, Dihydrothidium, DiLCl(5), DiOC6(3), DiOC7(3), dKeima-Red, DRAQ5, Dronpa-Green, various forms of DsRed dTomato, various forms of DyLight, E.coli BioParticles AF488, E2-Crimson, E2-Orange, EBFP2, ECFP, various forms of eFluor, EGFP, EGFP*, Emerald, eqFP650, eqFP670, ER-Tracker Blue-White DPX, Ethidium Bromide, Express2, EYFP, Fc OxyBurst Green, Fc OxyBurst Green 123, FITC, Fluo-3, Fluo-4, Fluorescein, Fura-2, Fura-Red, GFPuv, H2DCFDA, HcRedl, Hoechst Blue (33258), Hoechst Red (33342), Hydroxycoumarin, HyPer, lndo-1, lndo-1 Blue (Low Ca2+), lndo-1 Violet (High Ca2+), iRFP, J-Red, JC-1, JC-9, Katushka (TurboFP635), Katushka2 Kusabira-Orange, LDS 751, Lissamine Rhodamine B, various forms of Live / Dead, Lucifer yellow, Lucifer Yellow CH, Lyso Tracker Blue, Lyso Tracker Green, Lyso Tracker Red, mAmertrine, Marina Blue, mBanana, mCFP, mCherry, mCitrine, Methoxycoumarin, mHoneyDew, Midoriishi-Cyan, Mithramycin, Mito Tracker Deep Red, Mito Tracker Green, Mito Tracker Orange, Mito Tracker Red, MitoFluor Green, mKate (TagFP635), mKate2, mKeima, mKeima-Red, mKO, mKOk, mNeptune, Monochlorobimane, mOrange, mOrange2, mRaspberry, mPlum, mRFPl, mStrawberry, mTangerine, mTarquoise, mTFPl, mTFPl (Teal), NBD, OxyBurst Green H2DCFDA, OxyBurst Green H2HFF BSA, Pacific Blue, PE (R-Phycoerythrin), PE Cy5, PE Cy5.5, PE Cy7, PE Texas Red, PE-Cy5 conjugates, PE-Cy7 conjugates, PerCP (Peridinin chlorphyll protein), PerCP Cy5.5, PhiYFP, PhiYFP-m, Propidium Iodide (PI), various forms of Qdot, Red 613, RFP Tomato, Rhod-2, S65A, S65C, S65L, S65T, Singlet Oxygen Sensor Green, Sirius, SNARF, Superfolder GFP, SYTOX Blue, SYTOX Green, SYTOX Orange, T-Sapphire, TagBFP, TagCFP, TagGFP, TagRFP, TagRFP657, TagYFP, tdTomato, Texas Red, Thiazole Orange, TMRE, TMRM, Topaz, TOTO-1, TO-PRO-1, TRITC, TRITC TruRed, TurboFP602, TurboFP635, TurboGFP, TurboRFP, TurboYFP, Venus, Vybrant CycleDye Violet, Wild Type GFP, X-Rhodamin, Y66F, Y66H, Y66W, YOYO-1, YPet, ZsGreenl, ZsYellowl, Zymosan A BioParticles AF488 (see more at: http: / / www.thefcn.org / flow-fluorochromes). Fluorophores, or simply "fluors", are typically attached to the antibody (e.g., the immunoglobulin single variable domain) that recognizes PD-1 or to the antibody that is used as detection reagent. Various conjugated antibodies are available, such as (without being limiting) for example antibodies conjugated to Alexa Fluor®, DyLight®, Rhodamine, PE, FITC, and Cy3. Each fluorophore has a characteristic peak excitation and emission wavelength. The combination of labels which can be used will depend on the wavelength of the lamp(s) or laser(s) used to excite the fluorophore and on the detectors available.

[0065] To evaluate the competition between two test binding agents (termed A and B) for binding to PD-1, a dilution series of cold (without any label) binding agent A is added to (e.g. 200 000) cells together with the labeled binding agent B*. The concentration of binding agent B* in the test mix should be high enough to readily saturate the binding sites on PD-1 expressed on the cells. The concentration of binding agent B* that saturates the binding sites for that binding agent on PD-1 expressed on the cells can be determined with a titration series of binding agent B* on the PD-1 cells and determination of the EC50 value for binding. In order to work at saturating concentration, binding agent B* can be used at lOOx the EC50 concentration.

[0066] After incubation of the cells with the mixture of binding agent A and binding agent B* and cells wash, read out can be performed on a FACS. First a gate is set on the intact cells as determined from the scatter profile and the total amount of channel fluorescence is recorded. A separate solution of binding agent B* is also prepared. Binding agent B* in this solution should be in the same buffer and at the same concentration as in the test mix (with binding agent A and B*). This separate solution is also added to the cells. After incubation and cells wash, read out can be performed on a FACS. First a gate is set on the intact cells as determined from the scatter profile and the total amount of channel fluorescence is recorded. A reduction of fluorescence for the cells incubated with the mixture of binding agent A and B* compared to the fluorescence for the cells incubated with the separate solution of binding agent B* indicates that binding agent A blocks binding by binding agent B* to PD-1 expressed on the cells.

[0067] A cross-blocking immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent is one which will bind to the PD-1 in the above competition FACS such that during the assay and in the presence of the second binding agent the recorded fluorescence is between 80% and 0.1% (e.g.

[0068] 80% to 4%) of the maximum fluorescence (measured for the separate labelled immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent), specifically between 75% and 0.1% (e.g. 75% to 4%) of the maximum fluorescence, and more specifically between 70% and 0.1% (e.g. 70% to 4%) of maximum fluorescence (as just defined above).

[0069] The competition between two test binding agents (termed A* and B*) for binding to PD-1 can also be evaluated by adding both binding agents, each labeled with a different fluorophore, to the PD-1 expressing cells. After incubation and cells wash, read out can be performed on a FACS. A gate is set for each fluorophore and the total amount of channel fluorescence is recorded. Reduction and / or absence of fluorescence of one of the fluorophores indicates blocking by the binding agents for binding to PD-1 expressed on the cells.

[0070] Other methods for determining whether an immunoglobulin, antibody, immunoglobulin single variable domain, polypeptide or other binding agent directed against a target blocks, is capable of blocking, competitively binds or is competitive as defined herein are described e.g. in Xiao-Chi Jia et al. (Journal of Immunological Methods 288: 91-98, 2004), Miller et al. (Journal of Immunological Methods 365: 118-125, 2011).

[0071] As used herein, the term "potency" is a measure of the biological activity of an agent, such as an ISVD or polypeptide. Potency of an agent can be determined by any suitable method known in the art, such as for instance as described in the experimental section. Cell culture-based potency assays are often the preferred format for determining biological activity since they measure the physiological response elicited by the agent and can generate results within a relatively short period of time. Various types of cell-based assays, based on the mechanism of action of the product, can be used, such as e.g. a Tetanus-toxoid autogenic antigen-specific co-culture assay or the NFAT reporter assay (as further described in the Example section).

[0072] In contrast, the "efficacy" of an agent, such as an ISVD or polypeptide, measures the maximum strength of the effect itself, at saturating agent concentrations. Efficacy indicates the maximum response achievable from the agent. It refers to the ability of the agent to produce the desired (therapeutic) effect. The efficacy of an agent can be evaluated using in vitro functional assays or in vivo models.

[0073] 5.2 Immunoglobulin single variable domains

[0074] The present technology aims at providing a novel type of drug for treating diseases associated with PD-1. The present inventors have surprisingly found that an immunoglobulin single variable domain comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 2394 (such as SEQ ID NO: 493), a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 2395 (such as SEQ ID NO: 526), and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 2396 (such as SEQ ID NO: 691); or comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 4691 (such as SEQ ID NO: 1957), a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 4692 (such as SEQ ID NO: 2127), and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 4693 (such as SEQ ID NO: 2337); or comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 4608, a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 4609, and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 4610; or comprising a CDR1 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 4696 (such as SEQ ID NO: 4611), a CDR2 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO: 4697 (such as SEQ ID NO: 4481), and a CDR3 (AbM numbering) consisting of the amino acid sequence of SEQ ID NO; 4698 (such as SEQ ID NO: 4612); can be used for more potent and efficient blocking of the PD-1 / PD-L1 interaction and treatment of diseases associated with PD-1.

[0075] The term "immunoglobulin single variable domain" (ISVD), interchangeably used with "single variable domain", defines immunoglobulin molecules wherein the antigen binding site is present on, and formed by, a single immunoglobulin domain. This sets immunoglobulin single variable domains apart from "conventional" immunoglobulins (e.g. monoclonal antibodies) or their fragments (such as Fab, Fab', F(ab')2, scFv, di-scFv), wherein two immunoglobulin domains, in particular two variable domains, interact to form an antigen binding site. Typically, in conventional immunoglobulins, a heavy chain variable domain (VH) and a light chain variable domain (VL) interact to form an antigen binding site. In this case, the complementarity determining regions (CDRs) of both VH and VL will contribute to the antigen binding site, i.e. a total of 6 CDRs will be involved in antigen binding site formation.

[0076] In view of the above definition, the antigen-binding domain of a conventional 4-chain antibody (such as an IgG, IgM, IgA, IgD or IgE molecule; known in the art) or of a Fab fragment, a F(ab')2 fragment, an Fv fragment such as a disulfide linked Fv or a scFv fragment, or a diabody (all known in the art) derived from such conventional 4-chain antibody, would normally not be regarded as an immunoglobulin single variable domain, as, in these cases, binding to the respective epitope of an antigen would normally not occur by one (single) immunoglobulin domain but by a pair of (associating) immunoglobulin domains such as light and heavy chain variable domains, i.e., by a VH-VL pair of immunoglobulin domains, which jointly bind to an epitope of the respective antigen.

[0077] In contrast, immunoglobulin single variable domains are capable of specifically binding to an epitope of the antigen without pairing with an additional immunoglobulin variable domain. The binding site of an immunoglobulin single variable domain is formed by a single VH, a single VHH or single VL domain.

[0078] As such, the single variable domain may be a light chain variable domain sequence (e.g., a VL-sequence) or a suitable fragment thereof; or a heavy chain variable domain sequence (e.g., a VH-sequence or VHH sequence) or a suitable fragment thereof; as long as it is capable of forming a single antigen binding unit (i.e., a functional antigen binding unit that essentially consists of the single variable domain, such that the single antigen binding domain does not need to interact with another variable domain to form a functional antigen binding unit). An immunoglobulin single variable domain (ISVD) can for example be a heavy-chain ISVD, such as a VHH, including a humanized VHH, a VH, including a camelized VH and a human VH. In one embodiment, it is a VHH, a camelized VH or humanized VHH. Heavy chain ISVDs can be derived from a conventional four-chain antibody or from a heavy chain antibody.

[0079] For example, the immunoglobulin single variable domain may be a single domain antibody (or an amino acid sequence that is suitable for use as a single domain antibody), a "dAb" or dAb (or an amino acid sequence that is suitable for use as a dAb) or a NANOBODY® ISVD (as defined herein, and including but not limited to a VHH); other single variable domains, or any suitable fragment of any one thereof.

[0080] In particular, the immunoglobulin single variable domain may be a NANOBODY® ISVD (such as a VHH, including a humanized VHH or camelized VH) or a suitable fragment thereof. [Note: NANOBODY ® and NANOBODIES® are registered trademarks of Ablynx N. V.]

[0081] " VHH domains", also known as VHHs, VHH antibody fragments, have originally been described as the antigen binding immunoglobulin variable domain of "heavy chain antibodies" (i.e., of "antibodies devoid of light chains"; Hamers-Casterman et al. Nature 363: 446-448, 1993). The term " VHH domain" has been chosen in order to distinguish these variable domains from the heavy chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as " VH domains") and from the light chain variable domains that are present in conventional 4-chain antibodies (which are referred to herein as " VL domains"). For a further description of VHH's, reference is made to the review article by Muyldermans (Reviews in Molecular Biotechnology 74: 277-302, 2001).

[0082] The generation of immunoglobulin sequences, such as VHHs, has been described extensively in various publications, among which WO 94 / 04678, Hamers-Casterman et al. 1993 and Muyldermans et al. 2001 (Reviews in Molecular Biotechnology 74: 277-302, 2001). In these methods, camelids are immunized with the target antigen in order to induce an immune response against said target antigen. The repertoire of VHHs obtained from said immunization is further screened for VHHs that bind the target antigen.

[0083] In these instances, the generation of antibodies requires purified antigen for immunization and / or screening. Antigens can be purified from natural sources, or in the course of recombinant production. Immunization and / or screening for immunoglobulin sequences can be performed using peptide fragments of such antigens. Immunoglobulin sequences of different origin, comprising mouse, rat, rabbit, donkey, human and camelid immunoglobulin sequences can be used in the present technology. Also, fully human, humanized or chimeric sequences can be used. For example, camelid immunoglobulin sequences and humanized camelid immunoglobulin sequences, or camelized domain antibodies, e.g. camelized dAb as described by Ward et al (see for example WO 94 / 04678 and Riechmann, Febs Lett., 339:285-290, 1994 and Prot. Eng., 9:531-537, 1996) can be used herein. The ISVDs can be fused forming a multivalent and / or multispecific construct (for multivalent and multispecific polypeptides containing one or more VHH domains and their preparation, reference is also made to Conrath et al. 2001 (J. Biol. Chem., Vol. 276, 10. 7346-7350), as well as to for example WO 96 / 34103 and WO 99 / 23221).

[0084] However, it should be noted that the ISVD comprised in the present technology is not limited as to the origin of the ISVD sequence (or of the nucleotide sequence used to express it), nor as to the way that the ISVD sequence or nucleotide sequence is (or has been) generated or obtained. Thus, the ISVD sequences may be naturally occurring sequences (from any suitable species) or synthetic or semi-synthetic sequences. In a specific but non-limiting aspect, the ISVD sequence is a naturally occurring sequence (from any suitable species) or a synthetic or semi-synthetic sequence, including but not limited to "humanized" (as defined herein) immunoglobulin sequences (such as partially or fully humanized camelid, mouse or rabbit immunoglobulin sequences, and in particular partially or fully humanized VHH sequences), "camelized" (as defined herein) immunoglobulin sequences (and in particular camelized VH sequences), as well as ISVDs that have been obtained by techniques such as affinity maturation (for example, starting from synthetic, random or naturally occurring immunoglobulin sequences), CDR grafting, veneering, combining fragments derived from different immunoglobulin sequences, PCR assembly using overlapping primers, and similar techniques for engineering immunoglobulin sequences well known to the skilled person; or any suitable combination of any of the foregoing.

[0085] Similarly, nucleotide sequences may be naturally occurring nucleotide sequences or synthetic or semisynthetic sequences, and may for example be sequences that are isolated by PCR from a suitable naturally occurring template (e.g. DNA or RNA isolated from a cell), nucleotide sequences that have been isolated from a library (and in particular, an expression library), nucleotide sequences that have been prepared by introducing mutations into a naturally occurring nucleotide sequence (using any suitable technique known per se, such as mismatch PCR), nucleotide sequence that have been prepared by PCR using overlapping primers, or nucleotide sequences that have been prepared using techniques for DNA synthesis known per se. A "humanized VHH" comprises an amino acid sequence that corresponds to the amino acid sequence of a naturally occurring VHH domain, but that has been "humanized", i.e. by replacing one or more amino acid residues in the amino acid sequence of said naturally occurring VHH sequence (and in particular in the framework sequences) by one or more of the amino acid residues that occur at the corresponding position(s) in a VH domain from a conventional 4-chain antibody from a human being (e.g. indicated above). This can be performed in a manner known per se, which will be clear to the skilled person, for example on the basis of the prior art (e.g. WO 2008 / 020079). Again, it should be noted that such humanized VHHs can be obtained in any suitable manner known per se and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VHH domain as a starting material.

[0086] A "camelized VH" comprises an amino acid sequence that corresponds to the amino acid sequence of a naturally occurring VH domain, but that has been "camelized", i.e. by replacing one or more amino acid residues in the amino acid sequence of a naturally occurring VH domain from a conventional 4-chain antibody by one or more of the amino acid residues that occur at the corresponding position(s) in a VHH domain of a (camelid) heavy chain antibody. This can be performed in a manner known per se, which will be clear to the skilled person, for example on the basis of the description in the prior art (e.g. Davies and Riechman (1994 and 1996), supra). Such "camelizing" substitutions are inserted at amino acid positions that form and / or are present at the VH-VL interface, and / or at the so-called Camelidae hallmark residues, as defined herein (see for example WO 94 / 04678 and Davies and Riechmann (1994 and 1996), supra). In one embodiment, the VH sequence that is used as a starting material or starting point for generating or designing the camelized VH is a VH sequence from a mammal, such as the VH sequence of a human being, such as a VH3 sequence. However, it should be noted that such camelized VH can be obtained in any suitable manner known per se and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VH domain as a starting material.

[0087] The structure of an immunoglobulin single variable domain sequence can be considered to be comprised of four framework regions (" FRs"), which are referred to in the art and herein as " Framework region 1" (" FR1"); as " Framework region 2" (" FR2"); as " Framework region 3" (" FR3"); and as " Framework region 4" (" FR4"), respectively; which framework regions are interrupted by three complementary determining regions (" CDRs"), which are referred to in the art and herein as " Complementarity Determining Region 1" (" CDR1"); as " Complementarity Determining Region 2" (" CDR2"); and as " Complementarity Determining Region 3" (" CDR3"), respectively. As further described in paragraph q) on pages 58 and 59 of WO 08 / 020079, the amino acid residues of an ISVD can be numbered according to the general numbering for VHdomains given by Kabat et al. (" Sequence of proteins of immunological interest", US Public Health Services, NIH Bethesda, MD, Publication No. 91), as applied to VHH domains from Camelids in the article of Riechmann and Muyldermans, 2000 (J. Immunol. Methods 240 (1-2): 185-195; see for example Figure 2 of this publication). It should be noted that - as is well known in the art for VHdomains and for VHH domains - the total number of amino acid residues in each of the CDRs may vary and may not correspond to the total number of amino acid residues indicated by the Kabat numbering. That is, one or more positions according to the Kabat numbering may not be occupied in the actual sequence, or the actual sequence may contain more amino acid residues than the number allowed for by the Kabat numbering. This means that, generally, the numbering according to Kabat may or may not correspond to the actual numbering of the amino acid residues in the actual sequence. The total number of amino acid residues in a VHdomain and a VHH domain will usually be in the range of from 110 to 120, often between 112 and 115. It should however be noted that smaller and longer sequences may also be suitable for the purposes described herein.

[0088] In the present application, unless indicated otherwise, CDR sequences were determined according to the AbM numbering or Abm definition of CDRs (Abm numbering and Abm definition are used interchangeably) as described in Kontermann and Dübel (Eds. 2010, Antibody Engineering, vol 2, Springer Verlag Heidelberg Berlin, Martin, Chapter 3, pp. 33-51). According to this method, FR1 of an ISVD comprises the amino acid residues at positions 1-25, CDR1 of an ISVD comprises the amino acid residues at positions 26-35, FR2 of an ISVD comprises the amino acids at positions 36-49, CDR2 of an ISVD comprises the amino acid residues at positions 50-58, FR3 of an ISVD comprises the amino acid residues at positions 59-94, CDR3 of an ISVD comprises the amino acid residues at positions 95-102, and FR4 of an ISVD comprises the amino acid residues at positions 103-113.

[0089] Determination of CDR regions may also be done according to different methods, such as according to Kabat definition, Chothia definition, or IMGT definition (see Kontermann and Dübel, Eds. 2010, Antibody Engineering, vol 2, Springer Verlag Heidelberg Berlin, Martin, Chapter 3, pp. 33-51). In the CDR definition according to Kabat, FR1 of an ISVD comprises the amino acid residues at positions 1-30, CDR1 of an ISVD comprises the amino acid residues at positions 31-35, FR2 of an ISVD comprises the amino acids at positions 36-49, CDR2 of an ISVD comprises the amino acid residues at positions 50-65, FR3 of an ISVD comprises the amino acid residues at positions 66-94, CDR3 of an ISVD comprises the amino acid residues at positions 95-102, and FR4 of an ISVD comprises the amino acid residues at positions 103-113. The framework sequences are (a suitable combination of) immunoglobulin framework sequences or framework sequences that have been derived from immunoglobulin framework sequences (for example, by humanization or camelization). For example, the framework sequences may be framework sequences derived from a light chain variable domain (e.g. a VL-sequence) and / or from a heavy chain variable domain (e.g. a VH-sequence or VHH sequence). In one particular aspect, the framework sequences are either framework sequences that have been derived from a VHH-sequence (in which said framework sequences may optionally have been partially or fully humanized) or are conventional VH sequences that have been camelized (as defined herein).

[0090] In particular, the framework sequences present in the ISVD sequence used in the methods described herein may contain one or more of hallmark residues (as defined herein), such that the ISVD sequence is a NANOBODY® ISVD, such as e.g. a VHH, including a humanized VHH, or camelized VH. Non-limiting examples of (suitable combinations of) such framework sequences will become clear from the further disclosure herein.

[0091] Generally, NANOBODY® ISVDs (in particular VHH sequences, including (partially) humanized VHH sequences and camelized VH sequences) can be characterized by the presence of one or more " Hallmark residues" (as described herein) in one or more of the framework sequences (again as further described herein). Thus, generally, a NANOBODY® ISVD can be defined as an immunoglobulin sequence with the (general) structure

[0092] FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4

[0093] in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3, respectively, and in which one or more of the Hallmark residues are as further defined herein.

[0094] In particular, a NANOBODY® ISVD can be an immunoglobulin sequence with the (general) structure

[0095] FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4

[0096] in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3, respectively, and in which the framework sequences are as further defined herein. More in particular, a NANOBODY® ISVD can be an immunoglobulin sequence with the (general) structure

[0097] FR1 - CDR1 - FR2 - CDR2 - FR3 - CDR3 - FR4

[0098] in which FR1 to FR4 refer to framework regions 1 to 4, respectively, and in which CDR1 to CDR3 refer to the complementarity determining regions 1 to 3, respectively, and in which:

[0099] one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1 below.

[0100] Table 1: Hallmark Residues in NANOBODY® ISVDs

[0101] Position Human VH3 Hallmark Residues

[0102] 11 L, V; predominantly L L, S, V, M, W, F, T, Q, E, A, R, G, K, Y, N, P, 1; preferably L 37 V, 1, F; usually V F(1), Y, V, L, A, H, S, 1, W, C, N, G, D, T, P, preferably F(1)or Y

[0103] 44(8) G E(3), Q(3), G(2), D, A, K, R, L, P, S, V, H, T, N, W, M, 1;

[0104] preferably G(2), E(3)or Q(3);most preferably G(2)or Q(3).

[0105] 45(8) L L(2), R(3), P, H, F, G, Q, S, E, T, Y, C, 1, D, V; preferably L(2)or R(3)

[0106] 47(8) W, Y F(1), L(1)or W(2)G, 1, S, A, V, M, R, Y, E, P, T, C, H, K, Q, N, D; preferably W(2), L(1)or F(1)

[0107] 83 R or K; usually R R, K(5), T, E(5), Q, N, S, 1, V, G, M, L, A, D, Y, H; preferably K or R; most preferably K

[0108] 84 A, T, D; predominantly A P(5), S, H, L, A, V, 1, T, F, D, R, Y, N, Q, G, E; preferably P 103 W W(4), R(6), G, S, K, A, M, Y, L, F, T, N, V, Q, P(6), E, C;

[0109] preferably W

[0110] 104 G G, A, S, T, D, P, N, E, C, L; preferably G

[0111] 108 L, M orT; predominantly L Q, L(7), R, P, E, K, S, T, M, A, H; preferably Q. or L(7)Notes:

[0112] (1) In particular, but not exclusively, in combination with KERE or KQRE at positions 43-46.

[0113] (2) Usually as GLEW at positions 44-47.

[0114] (3) Usually as KERE or KQRE at positions 43-46, e.g. as KEREL, KEREF, KQREL, KQREF, KEREG, KQREW or KQREG at positions 43-47. Alternatively, also sequences such as TERE (for example TEREL), TQRE (for example TQREL), KECE (for example KECEL or KECER), KQCE (for example KQCEL), RERE (for example REREG), RQRE (for example RQREL, RQREF or RQREW), QERE (for example QEREG), QQRE, (for example QQREW, QQREL or QQREF), KGRE (for example KGREG), KDRE (for example KDREV) are possible. Some other possible, but less preferred sequences include for example DECKL and NVCEL.

[0115]

[0116] (4) With both GLEW at positions 44-47 and KERE or KQRE at positions 43-46.

[0117] (5) Often as KP or EP at positions 83-84 of naturally occurring VHH domains.

[0118] (6) In particular, but not exclusively, in combination with GLEW at positions 44-47.

[0119] (7) With the proviso that when positions 44-47 are GLEW, position 108 is always Qin (non-humanized) VHH sequences that also contain a W at 103.

[0120] (8) The GLEW group also contains GLEW-like sequences at positions 44-47, such as for example GVEW, EPEW, GLER, DQEW, DLEW, GIEW, ELEW, GPEW, EWLP, GPER, GLER and ELEW.

[0121]

[0122] The present technology relates to ISVDs that specifically bind to PD-1. Accordingly, the target molecules for the ISVDs is PD-1. Examples are mammalian PD-1. Besides human PD-1 (SEQ ID NO: 3922), the versions from other species are also amenable to the present technology, for example PD-1 from mice, rats, rabbits, cats, dogs, goats, sheep, horses, pigs, non-human primates, such as cynomolgus monkeys (also referred to herein as "cyno"), or camelids, such as llama or alpaca.

[0123] In some embodiments, the ISVDs of the present technology bind to human PD-1 (hPD-1; SEQ ID NO: 3922). In some embodiments, the ISVDs of the present technology bind to human PD-1 and cyno PD-1 (cPD-1; SEQ ID NO: 3923). Sequences of human, and cyno PD-1 are depicted in Table A-l.

[0124] The immunoglobulin single variable domains of the present technology show a highly affinity on PD-1 (e.g. as measured by Surface Plasmon Resonance) as a (monovalent) single variable domain. In some embodiments, the immunoglobulin single variable domains of the present technology show a highly potency on PD-1 (e.g. as measured in (FACS) competition assay, TT assay and / or NFAT reporter assay) as a (monovalent) single variable domain. In some embodiments, the immunoglobulin single variable domains of the present technology show a highly efficacy (e.g. as measured in (FACS) competition assay, TT assay and / or NFAT reporter assay) on PD-1 as a (monovalent) single variable domain. In some embodiments, the immunoglobulin single variable domains of the present technology are efficiently produced (e.g. in microbial hosts, such as Pichia, e.g. P. pastoris), even when encompassed with binders to other targets, and have good stability.

[0125] In some embodiments, the immunoglobulin single variable domains of the present technology show a highly affinity on PD-1 as a (monovalent) single variable domain. The affinity of a molecular interaction between two molecules can be measured via different techniques known per se, such as the well-known surface plasmon resonance (SPR) biosensor technique (see for example Ober et al. 2001, Intern. Immunology 13: 1551-1559). The term "surface plasmon resonance", as used herein, refers to an optical phenomenon that allows for the analysis of real-time biospecific interactions by detection of alterations in protein concentrations within a biosensor matrix, where one molecule is immobilized on the biosensor chip and the other molecule is passed over the immobilized molecule under flow conditions yielding kon, koff measurements and hence KD (or KA) values. This can for example be performed using the well-known BIAcore® system (BIAcore International AB, a GE Healthcare company, Uppsala, Sweden and Piscataway, NJ). For further descriptions, see Jonsson et al. 1993 (Ann. Biol. Clin. 51: 19-26), Jonsson et al. 1991 (Biotechniques 11: 620-627), Johnsson et al. 1995 (J. Mol. Recognit. 8: 125-131), and Johnsson et al. 1991 (Anal. Biochem. 198: 268-277).

[0126] Another well-known biosensor technique to determine affinities of biomolecular interactions is bio-layer interferometry (BLI) (see for example Abdiche et al. 2008, Anal. Biochem. 377: 209-217). The term "biolayer Interferometry" or " BLI", as used herein, refers to a label-free optical technique that analyzes the interference pattern of light reflected from two surfaces: an internal reference layer (reference beam) and a layer of immobilized protein on the biosensor tip (signal beam). A change in the number of molecules bound to the tip of the biosensor causes a shift in the interference pattern, reported as a wavelength shift (nm), the magnitude of which is a direct measure of the number of molecules bound to the biosensor tip surface. Since the interactions can be measured in real-time, association and dissociation rates and affinities can be determined. BLI can for example be performed using the well-known Octet® Systems (ForteBio, a division of Pall Life Sciences, Menlo Park, USA).

[0127] Alternatively, affinities can be measured in Kinetic Exclusion Assay (KinExA) (see for example Drake et al.

[0128] 2004, Anal. Biochem., 328: 35-43), using the KinExA® platform (Sapidyne Instruments Inc, Boise, USA). The term " KinExA", as used herein, refers to a solution-based method to measure true equilibrium binding affinity and kinetics of unmodified molecules. Equilibrated solutions of an antibody / antigen complex are passed over a column with beads precoated with antigen (or antibody), allowing the free antibody (or antigen) to bind to the coated molecule. Detection of the antibody (or antigen) thus captured is accomplished with a fluorescently labeled protein binding the antibody (or antigen).

[0129] The GYROLAB® immunoassay system provides a platform for automated bioanalysis and rapid sample turnaround (Fraley et al. 2013, Bioanalysis 5: 1765-74).

[0130] Because of their small size, (monovalent) immunoglobulin single variable domains are more efficient for the penetration of the tumor environment. In addition, they are easily combined with other (cancer)target binders in a single chain when the simultaneous targeting of multiple (cancer) targets is intended, e.g., as multivalent ISVD construct. The high production yields and better stability demonstrated for immunoglobulin single variable domains makes them ideally suited for subcutaneous administration. The interacting amino acid residues of the ISVD of the present technology (paratope) and the PD-1 protein (epitope) preferably have a distance of <4 A, wherein the distance between the amino acid residues is measured e.g., in X-ray crystallography or in Cryogenic-electron microscopy (cryo-EM). Thus, in an embodiment, two amino acid residues are considered to interact when the distance between them is 4.0 A or less.

[0131] The interacting amino acid residues of the ISVD of the present technology may be identified by a person skilled in the art, e.g., the skilled person knows that structural information allowing to determine the distance between two (amino acids) residues may be obtained using standard methods such as X-ray crystallography, Cryogenic electron microscopy (cryo-EM), nuclear magnetic resonance, and subsequent molecular modelling. Hence, the interacting amino acid residue(s) in the ISVD and in human PD-1 protein are identified by cryo-EM as described in the examples.

[0132] Based on the structural data provided herein, the skilled person understands that amino acid residues of an ISVD involved in the interaction with human PD-1 can be determined and that this interaction site is important for the binding of an ISVD to the epitope on human PD-1.

[0133] Specifically, the interaction site between an ISVD having SEQ ID NO: 402 and human PD-1 having SEQ ID NO: 3922 has been determined and provides clear technical guidance for the generation of further ISVDs having the binding specificity of the ISVD having SEQ ID NO: 402, e.g. binding to the same epitope on human PD-1.

[0134] In this respect, the skilled person understands that an ISVD of the present technology having the binding specificity of the ISVD having SEQ ID NO: 402, e.g. specifically binding to the same epitope on human PD-1 or blocking the binding to human PD-1 by an ISVD having SEQ ID NO: 402 is not limited to the specific amino acid sequence of the CDR region and / or the FR region of the ISVD having SEQ ID NO: 402, as long as the ISVD contains at least one or more amino acid residue(s) corresponding to the at least one or more amino acid residue(s) of the ISVD having SEQ ID NO: 402 that interact with human PD-1 as described herein.

[0135] In other words, an ISVD of the present technology having the binding specificity of the ISVD having SEQ ID NO: 402, e.g. specifically binding to the same epitope on human PD-1 or blocking the binding to human PD-1 by an ISVD having SEQ ID NO: 402, may contain, as compared to an ISVD having SEQ ID NO: 402, mutations and / or substitutions within the CDR region and / or within the FR region (such as conservative amino acid substitutions) whilst maintaining the amino acids of the ISVD that form the interaction site (i.e., the paratope on the ISVD) with human PD-1.

[0136] Another example of the ISVDs of the present technology specifically binding to PD-1 is an ISVD that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human PD-1, wherein the ISVD cross-blocks the binding to human PD-1 protein of a polypeptide with the amino acid sequence of SEQ ID Nos: 1-488 or wherein the ISVD is cross-blocked from binding to human PD-1 protein by a polypeptide with the amino acid sequence of SEQ ID Nos: 1-488.

[0137] In an embodiment, the ISVD competes with a polypeptide with the amino acid sequence of SEQ ID No: 1-488 for binding human PD-1 protein, as measured in a competition assay, such as a FACS competition assay.

[0138] 5.2.1 Embodiment 1, Family A0294047E02

[0139] There is provided an immunoglobulin single variable domain (ISVD) specifically binding to human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human PD-1 protein, wherein at least one amino acid residue in the ISVD is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following stretches (of the ectodomain) of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: V64-P83, and I126-E136, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

[0140] In some embodiments, the at least one amino acid residue in at least one, preferably in each stretch (of the ectodomain) of human PD-1 protein is selected from:

[0141] • For stretch V64-P83: V64, N66, Y68, S73, N74, Q75, T76, D77, K78, and P83;

[0142] • For stretch I126-E136: 1126, L128, A129, P130, K131, A132, 1134, and E136,

[0143] when numbered in accordance with SEQ ID NO: 4703.

[0144] In some embodiments, at least one amino acid residue located in the ISVD is capable of interacting with at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, or all of the following amino acid residues in stretch V64-P83 (of the ectodomain) of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: V64, N66, Y68, S73, N74, Q75, T76, D77, K78, and P83. In some embodiments, at least one amino acid residue located in the ISVD is capable of interacting with at least two, at least three, at least four, at least five, at least six, at least seven, or all of the following amino acid residues in stretch I126-E136 (of the ectodomain) of human PD-1 protein when numbered in accordance with SEQ ID NO: 4703: 1126, L128, A129, P130, K131, A132, 1134, and E136.

[0145] In some embodiments, at least one amino acid residue located in the ISVD is capable of forming salt bridges with at least the amino acid residue E136 of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

[0146] In some embodiments, at least one amino acid residue located in the ISVD is capable of forming hydrogen bonds with at least one, preferably all, of the following amino acid residues of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: N66, Y68, K78, A132, optionally wherein at least one amino acid residue located in the ISVD is further capable of forming hydrogen bonds with the amino acid residue N74 of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

[0147] In some embodiments, the least one amino acid residue located in the ISVD is capable of interacting with an (discontinuous) epitope on human PD-1 comprising at least one amino acid residue in each of the following stretches (of the ectodomain) of human PD-1 protein: V64-P83, and I126-E136, when numbered in accordance with SEQ ID NO: 4703.

[0148] In some embodiments, the at least one amino acid residue in each stretch (of the ectodomain) of human PD-1 protein is selected from:

[0149] • For stretch V64-P83: V64, N66, Y68, S73, N74, Q75, T76, D77, K78, and P83;

[0150] • For stretch I126-E136: 1126, L128, A129, P130, K131, A132, 1134, and E136,

[0151] when numbered in accordance with SEQ ID NO: 4703.

[0152] In some embodiments, at least one amino acid residue located in the ISVD is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least ten, at least fifteen, preferably all, of the following amino acid residues of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: V64, N66, Y68, S73, N74, Q75, T76, D77, K78, P83, 1126, L128, A129, P130, K131, A132, 1134, and E136, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

[0153] In some embodiments, the at least one amino acid residue located in the ISVD that is capable of interacting with amino acid residues of human PD-1 protein is located in CDR3.

[0154] In some embodiments, the amino acid at position 45 (Kabat numbering) is capable of interacting, preferably by forming a salt bridge, with E136 in PD-1, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

[0155] In some embodiments:

[0156] • the amino acid residue at position 100e (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with A132 in PD-1;

[0157] • the amino acid residue at position 100h (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with N66 in PD-1;

[0158] • the amino acid residue at position 100j (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with N66 in PD-1;

[0159] • the amino acid residue at position 100j (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Y68 in PD-1;

[0160] • the amino acid residue at position 100j (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with A132 in PD-1;

[0161] • the amino acid residue at position 101 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with N66 in PD-1; and / or

[0162] • the amino acid residue at position 101 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with K78 in PD-1;

[0163] preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

[0164] In some embodiments, two amino acids are considered to interact when the distance between them is 4.0 A or less.

[0165] In some embodiments, the interacting amino acid residue(s) in the ISVD and in human PD-1 protein are identified by X-ray crystallography by:

[0166] - Mixing human PD-1 protein, and the ISVD in PBS1X buffer; - Concentrating the protein complex to 10.6 mg / mL;

[0167] - Crystallizing by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C; - Collecting X-ray diffraction data;

[0168] - Processing the collected data,

[0169] preferably as described in Example 13.

[0170] In some embodiments, the (discontinuous) epitope comprises or consists of the following amino acid residues of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: V64, N66, Y68, T76, D77, K78, P83, 1126, L128, A129, P130, K131, A132, 1134, E136.

[0171] In some embodiments, the (discontinuous) epitope comprises or consists of the following amino acid residues of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: V64, N66, Y68, N74, T76, D77, K78, P83, 1126, L128, A129, P130, K131, A132, 1134, E136.

[0172] In some embodiments, the (discontinuous) epitope comprises or consists of the following amino acid residues of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: V64, N66, Y68, S73, Q75, T76, D77, K78, P83, 1126, L128, A129, P130, K131, A132, 1134, E136.

[0173] In some embodiments, the (discontinuous) epitope comprises or consists of the following amino acid residues of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: V64, N66, Y68, S73, N74, Q75, T76, D77, K78, P83, 1126, L128, A129, P130, K131, A132, 1134, E136.

[0174] In some embodiments, the ISVD cross-blocks the binding to human PD-1 protein of a polypeptide having an amino acid sequence selected from SEQ ID NOs: 1-488, preferably the ISVD cross-blocks the binding to human PD-1 protein of a polypeptide having an amino acid sequence selected from SEQ ID NO: 402, or the binding of the ISVD to human PD-1 protein is cross-blocked by a polypeptide having an amino acid sequence selected from SEQ ID NOs: 1-488, preferably SEQ ID NO: 402.

[0175] There is provided an immunoglobulin single variable domain (ISVD) specifically binding human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD comprises an amino acid residue capable of forming salt bridges at at least position 45 (Kabat numbering), preferably wherein the ISVD comprises at least the following amino acid residue: R45 (Kabat numbering). In some embodiments, the ISVD comprises an amino acid residue capable of forming hydrogen bonds at at least one, preferably at all, of the following positions: lOOe, lOOh, lOOj, and 101 (Kabat numbering) preferably wherein the ISVD comprises at least one, preferably all of the following amino acid residues at the following positions: I100e, Y100h, Y100j, and D101 (Kabat numbering).

[0176] In some embodiments, the ISVD comprises at least one, at least two, at least three, preferably all of the following amino acid residues at the following positions (Kabat numbering): T99, V100, I100e, M100g, Y100h, Y100j, D101, and Y102, preferably at least I100e, Y100h, Y100j, and D101.

[0177] In some embodiments, the CDR3 (AbM definition) consists of the following amino acid sequence X1X2STTVRX3X4CX5IIVIYX6YDY (SEQ ID NO: 4702), wherein:

[0178] • X1 is selected from any amino acid, preferably X1 is selected from A or G;

[0179] • X2 is selected from any amino acid, preferably X2 is selected T, A, E, G, F, I, D, H, K, S, P, R, Q, Y, V, or L;

[0180] • X3 is selected from any amino acid, preferably X3 is selected from D or G;

[0181] • X4is selected from any amino acid, preferably X4is selected from L, M, I, E, A, V, D, H, G, F, K, R, P, S, T, or Y;

[0182] • X5is selected from any amino acid, preferably X5is selected from G or F; and

[0183] • X6 is selected from any amino acid, preferably X6 is selected from L, V, or F.

[0184] In some embodiments, the following amino acid residue of the ISVD at the following position: R45 (Kabat numbering) is capable of forming salt bridges with at least one of the amino acid residues of human PD-1 protein, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

[0185] In some embodiments, at least one, preferably all of the following amino acid residues of the ISVD at the following positions: I100e, Y100h, Y100j, and D101 (Kabat numbering) are capable of forming hydrogen bonds with at least one of the amino acid residues of human PD-1 protein, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

[0186] In some embodiments, at least one, preferably all, of the following amino acid residues of the ISVD at the following positions: R45, I100e, Y100h, Y100j, and D101, and optionally Q105 (Kabat numbering) is capable of interacting with at least one, preferably all of the following amino acid residues of human PD- 1 protein, when numbered in accordance with SEQ. ID NO: 4703: N66, Y68, K78, A132, and E136, and optionally N74, preferably wherein:

[0187] R45 in the ISVD (Kabat numbering) interacts, preferably by forming a salt bridge, with E136 in human PD-1 protein;

[0188] I100e in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with A132 in human PD-1 protein;

[0189] Y100h in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with N66 in human PD-1 protein;

[0190] Y100j in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with N66 in human PD-1 protein;

[0191] Y100j in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with Y68 in human PD-1 protein;

[0192] Y100j in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with A132 in human PD-1 protein;

[0193] D101 in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with N66 in human PD-1 protein; and / or

[0194] D101 in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with K78 in human PD-1 protein;

[0195] preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

[0196] In one embodiment, Q105 in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with N74 in human PD-1 protein.

[0197] In some embodiments, the ISVD comprises at least one, at least two, at least three, preferably all of the following amino acid residues at the following positions (Kabat numbering): I100e, Y100h, Y100j, and D101.

[0198] In some embodiments, the ISVD comprises at least one, at least two, at least three, preferably all of the following amino acid residues at the following positions (Kabat numbering): R45, I100e, Y100h, Y100j, and D101.

[0199] In some embodiments, the ISVD comprises at least one, at least two, at least three, preferably all of the following amino acid residues at the following positions (Kabat numbering): R45, I100e, Y100h, Y100j, D101, and Q105. In some embodiments, the ISVD comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, preferably all of the following amino acid residues at the following positions (Kabat numbering): T99, V100, I100e, M100g, Y100h, Y100j, D101, and Y102.

[0200] In some embodiments, the ISVD comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, preferably all of the following amino acid residues at the following positions (Kabat numbering): R45, T99, V100, I100e, M100g, Y100h, Y100j, D101, and Y102.

[0201] In some embodiments, the ISVD essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which CDR3 (AbM definition) has an amino acid sequence selected from:

[0202] a) the amino acid sequence of SEQ ID NO: 691;

[0203] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 691;

[0204] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 691.

[0205] In some embodiments, the ISVD comprises V2, Q3, L4, R45, W103 and / or Q105 (Kabat numbering).

[0206] In some embodiments, the ISVD comprises R45 (Kabat numbering).

[0207] In some embodiments, the ISVD comprises:

[0208] R45 and Q105 (Kabat numbering);

[0209] R45 and W103 (Kabat numbering); or

[0210] R45, W103 and Q105 (Kabat numbering).

[0211] In some embodiments, the ISVD comprises at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, preferably all of the following amino acid residues at the following positions (Kabat numbering): V2, Q3, L4, R45, T99, V100, I100e, M100g, Y100h, Y100j, D101, Y102, W103, and Q105.

[0212] In some embodiments, R45, I100e, Y100h, Y100j, and D101, and optionally Q105 (Kabat numbering) of the ISVD are capable of interacting with at least one of the following amino acids of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: N66, Y68, K78, A132, E136, and optionally N74, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

[0213] In some embodiments, V2, Q3, L4, R45, I100e, Y100h, Y100j, D101, and Q105 (Kabat numbering) of the ISVD are capable of interacting with the following amino acids of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: N66, Y68, S73, N74, Q75, K78, A132, and E136, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

[0214] In some embodiments, wherein two amino acids are considered to interact when the distance between them is 4.0 A or less.

[0215] In some embodiments, the interacting amino acid residue(s) in the ISVD and in human PD-1 protein are identified by X-ray crystallography by:

[0216] Mixing human PD-1 protein, and the ISVD in PBS1X buffer;

[0217] Concentrating the protein complex to 10.6 mg / mL;

[0218] Crystallizing by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C; Collecting X-ray diffraction data;

[0219] Processing the collected data,

[0220] preferably as described in Example 13.

[0221] There is provided an immunoglobulin single variable domain (ISVD) specifically binding to human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD cross-blocks the binding to human PD-1 protein of a polypeptide having an amino acid sequence selected from SEQ ID NOs: 1-488, preferably wherein the ISVD cross-blocks the binding to human PD-1 protein of a polypeptide having an amino acid sequence selected from SEQ ID NO: 402, or wherein the binding of the ISVD to human PD-1 protein is cross-blocked by a polypeptide having an amino acid sequence selected from SEQ ID NOs: 1-488, preferably SEQ ID NO: 402.

[0222] In some embodiments, the ISVD competes with a polypeptide with an amino acid sequence selected from SEQ ID NO: 1-488, preferably SEQ ID NO: 402, for binding human PD-1 protein, as measured in a competition assay, such as a FACS competition assay. There is provided an immunoglobulin single variable domain (ISVD) specifically binding human PD-1, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR3 (AbM definition) consists of the amino acid sequence of one of SEQ ID NOs: 644-711, and wherein the amino acid residue of the ISVD at the following position: 45 (Kabat numbering) is capable of forming salt bridges with at least one of the amino acid residues of human PD-1 protein, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C, preferably wherein the ISVD comprises at least the following amino acid residue: R45 (Kabat numbering).

[0223] In some embodiments, R45 (Kabat numbering) of the ISVD is capable of forming salt bridges with the amino acid residue E136 of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703.

[0224] In some embodiments, the CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691.

[0225] Specific examples of ISVDs specifically binding to PD-1 are ISVDs that comprises 4 framework regions (FR1 to FR4, respectively) and three complementarity determining regions (CDR1 to CDR3, respectively), wherein:

[0226] - CDR1 (AbM numbering) consists of an amino acid sequence selected from:

[0227] a) the amino acid sequence of GFTLDX1YX2X3G (SEQ ID NO: 2394), wherein X1is selected from A, D, Q, P, S, G, T, V, I, R, K, E, L, H, F, or Y, X2is selected from V or F, and X3is selected from I, E, D, A, F, G, H, L, K, T, M, S, P, R, Y, V, or Q;

[0228] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GFTLDX1YX2X3G (SEQ ID NO: 2394), wherein X1is selected from A, D, Q, P, S, G, T, V, I, R, K, E, L, H, F, or Y, X2is selected from V or F, and X3is selected from I, E, D, A, F, G, H, L, K, T, M, S, P, R, Y, V, or Q;

[0229] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of GFTLDX1YX2X3G (SEQ ID NO: 2394), wherein X1is selected from A, D, Q, P, S, G, T, V, I, R, K, E, L, H, F, or Y, X2is selected from V or F, and X3is selected from I, E, D, A, F, G, H, L, K, T, M, S, P, R, Y, V, or Q;

[0230] and

[0231] - CDR2 (AbM numbering) consists of an amino acid sequence selected from:

[0232] a) the amino acid sequence of CX1SX2X3X4DRX5X6(SEQ ID NO: 2395), wherein X1is selected from L, G, H, K, P, R, S, or T, X2is selected from S, E, G, H, P, or Q, and X3is selected from N, E, A, D, F, G, H, I, K, L, P, Q, R, S, T, V, or Y, X4is selected from G, D, F, H, K, L, P, Q, R, S, T, V, A, or Y, X5is selected from I, A, E, G, H, K, P, R, S, or T, and X6 is selected from N, A, D, E, F, G, H, I, K, L, P, Q, R, S, T, V, or Y;

[0233] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of CX1SX2X3X4DRX5X6(SEQ ID NO: 2395), wherein X1is selected from L, G, H, K, P, R, S, or T, X2is selected from S, E, G, H, P, or Q, and X3is selected from N, E, A, D, F, G, H, I, K, L, P, Q, R, S, T, V, or Y, X4is selected from G, D, F, H, K, L, P, Q, R, S, T, V, A, or Y, X5is selected from I, A, E, G, H, K, P, R, S, or T, and X6is selected from N, A, D, E, F, G, H, I, K, L, P, Q, R, S, T, V, or Y;

[0234] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of CX1SX2X3X4DRX5X6(SEQ ID NO: 2395), wherein X1is selected from L, G, H, K, P, R, S, or T, X2is selected from S, E, G, H, P, or Q, and X3is selected from N, E, A, D, F, G, H, I, K, L, P, Q, R, S, T, V, or Y, X4is selected from G, D, F, H, K, L, P, Q, R, S, T, V, A, or Y, X5is selected from I, A, E, G, H, K, P, R, S, or T, and X6is selected from N, A, D, E, F, G, H, I, K, L, P, Q, R, S, T, V, or Y;

[0235] and

[0236] - CDR3 (AbM numbering) consists of an amino acid sequence selected from:

[0237] a) the amino acid sequence of X1X2STX3VRX4X5CX6IX7YX8YDX9(SEQ ID NO: 2396), wherein X1is selected from A or G, X2is selected from T, A, E, G, F, I, D, H, K, S, P, R, Q, Y, V, or L, X3is selected from T or I, X4is selected from D or G, X5is selected from L, M, I, E, A, V, D, H, G, F, K, R, P, S, T, or Y, X6is selected from G or F, X7is selected from I, M, F, Y, L, A, D, E, G, K, H, P, Q, S, T, V, or R, X8is selected from L, V, or F, and X9is selected from Y, E, I, L, or V; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence X1X2STX3VRX4X5CX6IX7YX8YDX9(SEQ ID NO: 2396), wherein X1is selected from A or G, X2is selected from T, A, E, G, F, I, D, H, K, S, P, R, Q, Y, V, or L, X3is selected from T or I, X4is selected from D or G, X5is selected from L, M, I, E, A, V, D, H, G, F, K, R, P, S, T, or Y, X6is selected from G or F, X7is selected from I, M, F, Y, L, A, D, E, G, K, H, P, Q, S, T, V, or R, X8is selected from L, V, or F, and X9is selected from Y, E, I, L, or V;

[0238] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1X2STX3VRX4X5CX6IX7YX8YDX9(SEQ ID NO: 2396), wherein X1is selected from A or G, X2is selected from T, A, E, G, F, I, D, H, K, S, P, R, Q, Y, V, or L, X3is selected T or I, X4is selected from D or G, X5is selected from L, M, I, E, A, V, D, H, G, F, K, R, P, S, T, V, or Y, X6is selected from G or F, X7is selected from I, M, F, Y, L, A, D, E, G, K, H, P, Q, S, T, V, or R, X8is selected from L, V, or F, and X9is selected from Y, E, I, L, or V. Preferably, the CDR sequences have at least 90% amino acid sequence identity, more preferably at least 95% amino acid sequence identity, such as 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the CDR sequences of SEQ ID NO: 2394, SEQ ID NO: 2395 or SEQ ID NO: 2396.

[0239] In one embodiment, the ISVD comprises CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-488.

[0240] In some embodiments, the ISVD essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[0241] - CDR1 (AbM numbering) consists of an amino acid sequence selected from:

[0242] a) the amino acid sequence of GFTLDYYVIG (SEQ ID NO: 493);

[0243] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GFTLDYYVIG (SEQ ID NO: 493);

[0244] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of GFTLDYYVIG (SEQ ID NO: 493);

[0245] and

[0246] - CDR2 (AbM numbering) consists of an amino acid sequence selected from:

[0247] a) the amino acid sequence of CLSSX1GDRX2N (SEQ ID NO: 4707), wherein X1is selected from N, E, S, and R, and X2is selected from I and T;

[0248] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of CLSSX1GDRX2N (SEQ ID NO: 4707), wherein X1is selected from N, E, S, and R, and X2is selected from I and T;

[0249] c) amino acid sequences that have 3, 2, or 1 amino acid sequence difference with the amino acid sequence of CLSSX1GDRX2N (SEQ ID NO: 4707), wherein X1is selected from N, E, S, and R, and X2is selected from I and T;

[0250] and

[0251] - CDR3 (AbM numbering) consists of an amino acid sequence selected from:

[0252] a) the amino acid sequence of GTSTTVRDXCGIMYLYDY (SEQ ID NO: 4708), wherein X is selected from M, L, V, and R;

[0253] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence GTSTTVRDXCGIMYLYDY (SEQ ID NO: 4708), wherein X is selected from M, L, V, and R; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence GTSTTVRDXCGIMYLYDY(SEQ ID NO: 4708), wherein X is selected from M, L, V, and R.

[0254] In some embodiments, the ISVD essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[0255] CDR1 (AbM definition) has an amino acid sequence selected from:

[0256] a) the amino acid sequence of SEQ ID NO: 493;

[0257] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 493; and

[0258] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 493;

[0259] and

[0260] CDR2 (AbM definition) has an amino acid sequence selected from:

[0261] a) the amino acid sequence of SEQ ID NO: 526;

[0262] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 526;

[0263] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 526;

[0264] and

[0265] CDR3 (AbM definition) has an amino acid sequence selected from:

[0266] a) the amino acid sequence of SEQ ID NO: 691;

[0267] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 691;

[0268] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 691.

[0269] In some embodiments, the ISVD essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[0270] CDR1 (AbM definition) has an amino acid sequence selected from:

[0271] a) the amino acid sequence of SEQ ID NO: 493;

[0272] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 493; and

[0273] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 493;

[0274] and CDR2 (AbM definition) has an amino acid sequence selected from:

[0275] a) the amino acid sequence of SEQ ID NO: 543;

[0276] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 543;

[0277] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 543;

[0278] and

[0279] CDR3 (AbM definition) has an amino acid sequence selected from:

[0280] a) the amino acid sequence of SEQ ID NOs: 680;

[0281] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 680;

[0282] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 680.

[0283] In some embodiments, the ISVD essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[0284] CDR1 (AbM definition) has an amino acid sequence selected from:

[0285] a) the amino acid sequence of SEQ ID NO: 493;

[0286] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 493; and

[0287] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 493;

[0288] and

[0289] CDR2 (AbM definition) has an amino acid sequence selected from:

[0290] a) the amino acid sequence of SEQ ID NO: 594;

[0291] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 594;

[0292] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 594;

[0293] and

[0294] CDR3 (AbM definition) has an amino acid sequence selected from:

[0295] a) the amino acid sequence of SEQ ID NO: 707;

[0296] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 707; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 707.

[0297] In some embodiments, the ISVD essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[0298] CDR1 (AbM definition) has an amino acid sequence selected from:

[0299] a) the amino acid sequence of SEQ ID NO: 493;

[0300] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 493; and

[0301] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 493;

[0302] and

[0303] CDR2 (AbM definition) has an amino acid sequence selected from:

[0304] a) the amino acid sequence of SEQ ID NO: 593;

[0305] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 593;

[0306] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 593;

[0307] and

[0308] CDR3 (AbM definition) has an amino acid sequence selected from:

[0309] a) the amino acid sequence of SEQ ID NO: 701;

[0310] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 701;

[0311] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 701.

[0312] In some embodiments, the ISVD essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

[0313] CDR1 (AbM definition) has an amino acid sequence selected from:

[0314] a) the amino acid sequence of SEQ ID NO: 493;

[0315] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 493; and

[0316] c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 493;

[0317] and CDR2 (AbM definition) has an amino acid sequence selected from:

[0318] a) the amino acid sequence of SEQ ID NO: 549;

[0319] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 549;

[0320] c) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 549;

[0321] and

[0322] CDR3 (AbM definition) has an amino acid sequence selected from:

[0323] a) the amino acid sequence of SEQ ID NO: 680;

[0324] b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 680;

[0325] c) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 680.

[0326] In one embodiment, the ISVD comprises CDRs (AbM numbering) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 402, 331, 332, 375, 212, 139, and 238.

[0327] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0328] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 546, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0329] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 547, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0330] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 547, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0331] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 547, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 547, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0332] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 541, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0333] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 541, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0334] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 541, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0335] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 541, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0336] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 549, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0337] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 549, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0338] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 549, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0339] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 548, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0340] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 549, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0341] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 547, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 540, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0342] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 542, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0343] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 544, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0344] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 530, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0345] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 604, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0346] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 604, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0347] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 604, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0348] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 603, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0349] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 603, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0350] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 603, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0351] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 603, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0352] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0353] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0354] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 604, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0355] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0356] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 547, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0357] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 535, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0358] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 547, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0359] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 541, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0360] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 531, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0361] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 531, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 534, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0362] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 534, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0363] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 534, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0364] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 531, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0365] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 531, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0366] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 531, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0367] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 531, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0368] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 531, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0369] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 529, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0370] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 602, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0371] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 527, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 528, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0372] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 601, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0373] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 532, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0374] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 534, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0375] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 531, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0376] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 534, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0377] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 534, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0378] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 541, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0379] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 541, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0380] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 541, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0381] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 549, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 549, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0382] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 549, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0383] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 547, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0384] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 549, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0385] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 534, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0386] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 534, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0387] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0388] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 578, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 707.

[0389] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 578, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 703.

[0390] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 578, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 672.

[0391] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 578, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 665. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 592, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 701.

[0392] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 592, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 703.

[0393] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 592, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 672.

[0394] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 592, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 665.

[0395] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 592, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 707.

[0396] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 593, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 701.

[0397] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 593, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 703.

[0398] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 593, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 672.

[0399] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 593, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 665.

[0400] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 593, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 707.

[0401] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 701. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 703.

[0402] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 537, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670.

[0403] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 593, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670.

[0404] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 559, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 645.

[0405] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 553, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670.

[0406] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 598, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 645.

[0407] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 593, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 644.

[0408] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 557, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 645.

[0409] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 550, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670.

[0410] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 595, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670.

[0411] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 555, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 559, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670.

[0412] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 550, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 645.

[0413] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 553, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 645.

[0414] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 591, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670.

[0415] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 578, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 701.

[0416] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 701.

[0417] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 703.

[0418] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 672.

[0419] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 665.

[0420] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 707.

[0421] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 672. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 603, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0422] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0423] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 539, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0424] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 678.

[0425] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 604, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0426] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 604, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0427] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 604, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0428] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 604, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0429] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 603, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0430] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 603, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0431] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0432] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 603, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 674.

[0433] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 707.

[0434] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 665.

[0435] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 595, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 701.

[0436] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 595, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 703.

[0437] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 595, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 672.

[0438] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 595, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 665.

[0439] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 595, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 707.

[0440] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0441] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 542, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 676.

[0442] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 677.

[0443] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 575, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0444] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 570, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0445] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 566, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0446] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 564, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0447] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 567, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0448] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 572, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0449] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 580, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0450] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 587, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0451] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 588, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 583, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0452] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 568, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0453] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 584, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0454] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 560, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0455] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 586, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0456] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2393, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0457] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 585, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0458] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 561, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0459] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 582, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0460] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 581, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0461] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 592, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 552, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0462] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 558, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0463] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 590, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0464] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 597, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0465] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 579, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0466] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 577, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0467] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 571, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0468] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 567, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 690.

[0469] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 702.

[0470] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 667.

[0471] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 673. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 663.

[0472] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0473] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 666.

[0474] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 661.

[0475] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 576, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0476] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 573, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0477] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 562, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0478] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 574, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0479] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 563, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0480] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 556, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0481] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 589, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 599, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0482] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 681.

[0483] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 662.

[0484] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0485] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0486] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 538, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0487] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 594, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0488] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 554, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0489] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 497, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0490] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 498, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0491] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 499, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 500, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0492] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 501, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0493] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 502, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0494] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 503, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0495] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 504, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0496] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 505, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0497] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 506, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0498] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 507, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0499] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 508, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0500] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 509, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0501] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 510, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 511, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0502] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 536, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0503] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 700.

[0504] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 569, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0505] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 565, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0506] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 675.

[0507] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 687.

[0508] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 706.

[0509] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 689.

[0510] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 669.

[0511] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 664. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 704.

[0512] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 684.

[0513] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 665.

[0514] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 707.

[0515] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 704.

[0516] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670.

[0517] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 664.

[0518] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 675.

[0519] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 649.

[0520] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 650.

[0521] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 660. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 648.

[0522] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 710.

[0523] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 711.

[0524] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 657.

[0525] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 705.

[0526] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 653.

[0527] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 647.

[0528] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 651.

[0529] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 679.

[0530] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 705.

[0531] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 706. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 680.

[0532] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 665.

[0533] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 707.

[0534] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 689.

[0535] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 687.

[0536] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 551, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 684.

[0537] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 655.

[0538] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 699.

[0539] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 543, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 671.

[0540] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 683.

[0541] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 2392, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 512, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0542] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 513, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0543] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 692.

[0544] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 694.

[0545] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 689.

[0546] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 688.

[0547] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 695.

[0548] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 682.

[0549] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 687.

[0550] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 600, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670.

[0551] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 696. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 685.

[0552] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 686.

[0553] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 697.

[0554] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 698.

[0555] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 684.

[0556] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 708.

[0557] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 709.

[0558] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 668.

[0559] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 557, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670.

[0560] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 514, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0561] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 693. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 496, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0562] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 646.

[0563] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 652.

[0564] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 659.

[0565] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 658.

[0566] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 656.

[0567] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 493, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 654.

[0568] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 515, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0569] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 516, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0570] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 517, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0571] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 518, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691. In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 519, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0572] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 520, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0573] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 495, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0574] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 521, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0575] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 522, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0576] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 523, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 526, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 691.

[0577] In one embodiment, the ISVD comprises a CDR1 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 494, a CDR2 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 596, and a CDR3 (AbM numbering) that is the amino acid sequence of SEQ ID NO: 670.

[0578] In some embodiments, the ISVD additionally comprises V2, Q3, L4, R45, W103 and / or Q105 (Kabat numbering). In some embodiments, the ISVD additionally comprises R45 (Kabat numbering). In some embodiments, the ISVD additionally comprises W103 (Kabat numbering). In some embodiments, the ISVD additionally comprises Q105 (Kabat numbering). In some embodiments, the ISVD additionally comprises R45 and Q105 (Kabat numbering). In some embodiments, the ISVD additionally comprises R45 and W103 (Kabat numbering). In some embodiments, the ISVD additionally comprises R45, W103 and Q105 (Kabat numbering). In some embodiments, the ISVD additionally comprises V2, Q3, L4, R45, W103 and Q105 (Kabat numbering).

[0579] In some embodiments, the ISVD comprises an amino acid sequence having 80% amino acid sequence identity with one of the amino acid sequences of SEQ ID NOs: 1-488, in which for the purposes of determining the degree of amino acid identity, the amino acid residues that form the CDR sequences are disregarded; and in which: preferably one or more of the amino acid residues at positions 11, 37, 44, 45, 47, 83, 84, 103, 104 and 108 according to the Kabat numbering are chosen from the Hallmark residues mentioned in Table 1. In some embodiments, the amino acid residue of the ISVD at the following position: 45 (Kabat numbering) is capable of forming salt bridges with at least one of the amino acid residues of human PD-1 protein, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C, preferably wherein the ISVD comprises at least the following amino acid residue: R45 (Kabat numbering).

[0580] In some embodiments, R45 (Kabat numbering) of the ISVD is capable of forming salt bridges with the amino acid residue E136 of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703, In some embodiments, the ISVD essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from a heavy chain antibody.

[0581] In some embodiments, the ISVD essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb.

[0582] In some embodiments, the ISVD is a humanized ISVD that is chosen from SEQ ID NO: 1-401, 403-488 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 1-488.

[0583] In some embodiments, the ISVD is a humanized ISVD that is chosen from SEQ ID NO: 331, 332, 375, 212, 139, and 238 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 402, 331, 332, 375, 212, 139, 238.

[0584] In some embodiments, the ISVD is chosen from the group consisting of SEQ ID NO: 402 and SEQ ID NOs: 1-401, 403-488.

[0585] In some embodiments, the ISVD specifically binds to human PD-1 with a dissociation constant (KD) of 10'9moles / litre or less, IO10moles / litre or less, such as 5xl0’9to 10’12moles / litre or less, and preferably IO10to 10’12moles / litre or less and more preferably 5xlO'10to IO’11moles / litre, 5xlO10to 5xl0-11moles / litre, IO10to 1012moles / litre, or IO10to IO’11moles / litre, such as 4.3x IO’11moles / litre, as determined by Surface Plasmon Resonance, e.g., measured at 25°C.

[0586] In some embodiments, the ISVD specifically binds to human PD-1 with a kon-rate of between 105M^s’1to about 107M^s’1, preferably between 5xl05M^s’1and 107M^s’1, more preferably between 105M^s’1and 5xl06M^s’1, such as between 105M^s’1and 1x106M^s’1, such as 3xl05M^s’1, as determined by Surface Plasmon Resonance, e.g., measured at 25°C.

[0587] In some embodiments, the ISVD specifically binds to human PD-1 with a koffrate between IO-3s’1(tl / 2=0.69 s) and 10’8s’1(providing a near irreversible complex with a tl / 2 of multiple days), preferably 10’3s’1and 5xl0’6s’1, more preferably between 5xl0’4s’1and 5xl0’6s’1, such as between 5xl0’4s’1and 10’5s’1, such as 1.3xl0’5s’1, determined by Surface Plasmon Resonance, e.g., measured at 25°C In some embodiments, the ISVD specifically binds to human and cyno PD-1 and does not bind to CD28, CTLA-4, ICOS, and BTLA or other members of the CD28 receptor family.

[0588] In some embodiments, the ISVD antagonizes an activity of PD-L1.

[0589] In some embodiments, the ISVD blocks the interaction of human PD-1 with human PD-L1 with a potency (IC50 value) of 10-8M or lower, more preferably of 5x10-9M or lower, or even of 10-9M or lower, such as between 1011M and IO-8M, between IO10M and IO-9M, between IO10M and IO-8M or between 10'9M and IO-8M, such as 5.11xl0-9M, for example, as measured in a FACS competition assay on CHO cells expressing human PD-1 with hPD-Ll as a competitor.

[0590] In some embodiments, the ISVD blocks the interaction of cyno PD-1 with cyno PD-L1 with a potency (IC50 value) of IO-7M or lower, of 5x10-8M or lower, more preferably of IO-8M or lower, or even of 5xl0-9M or lower, such as between 1011M and IO-7M, between 1011M and IO-8M, between IO10M and IO-7M, between IO10M and 10'9M, between IO10M and IO-8M, between IO-9M and IO-8M or between IO-9M and IO-7M, such as 5.76xl0-8M, for example, as measured in a FACS competition assay on CHO cells expressing cyno PD-1 with hPD-Ll as a competitor.

[0591] In some embodiments, the ISVD blocks the binding of hPD-1 to hPD-Ll by at least 50%, such as at least 60%, 70%, 80%, 90%, 95%, 99% or even more, as determined by ligand competition, AlphaScreen, or competitive binding assays (such as competition ELISA or competition FACS).

[0592] In some embodiments, the ISVD induces T-cell activation with a potency (EC50 value) of 10'8M or lower, more preferably of 5xl0-9M or lower, or even of 10'9M or lower, such as between 1011M and IO-8M, between IO10M and IO-8M, between IO10M and IO-9M or between IO-9M and IO-8M, such as 2.2xl0-9M or 2.8xl0-9M, as determined in a TT assay.

[0593] Specific examples of such ISVDs that specifically bind to PD-1 have one or more, or all, framework regions as indicated for A0294047E02 and sequence optimized variants thereof in Table A- 2 and A-6 (in addition to the CDRs as defined above). In one embodiment, the ISVD comprises or consists of the full amino acid sequence of A0294047E02 (SEQ ID NO: 402), A029400054 (SEQ ID NO: 1), A029404968 (SEQ ID NO: 2), A029404967 (SEQ ID NO: 3), A029404966 (SEQ ID NO: 4), A029404965 (SEQ ID NO: 5), A029404964 (SEQ ID NO: 6), A029404963 (SEQ ID NO: 7), A029404962 (SEQ ID NO: 8), A029404961 (SEQ ID NO: 9), A029404960 (SEQ ID NO: 10), A029404959 (SEQ ID NO: 11), A029404958 (SEQ ID NO: 12), A029404957 (SEQ ID NO: 13), A029404969 (SEQ ID NO: 14), A029404956 (SEQ ID NO: 15), A029404954 (SEQ ID NO: 16), A029404953 (SEQ ID NO: 17), A029404952 (SEQ ID NO: 18), A029404951 (SEQ ID NO: 19), A029404950 (SEQ ID NO: 20), A029404949 (SEQ ID NO: 21), A029404948 (SEQ ID NO: 22), A029404947 (SEQ ID NO: 23), A029404946 (SEQ ID NO: 24), A029404945 (SEQ ID NO: 25), A029404944 (SEQ ID NO: 26), A029404943 (SEQ ID NO: 27), A029404955 (SEQ ID NO: 28), A029404970 (SEQ ID NO: 29), A029404971 (SEQ ID NO: 30), A029404972 (SEQ ID NO: 31), A029404877 (SEQ ID NO: 32), A029404998 (SEQ ID NO: 33), A029404997 (SEQ ID NO: 34), A029404996 (SEQ ID NO: 35), A029404995 (SEQ ID NO: 36), A029404994 (SEQ ID NO: 37), A029404993 (SEQ ID NO: 38), A029404992 (SEQ ID NO: 39), A029404991 (SEQ ID NO: 40), A029404990 (SEQ ID NO: 41), A029404989 (SEQ ID NO: 42), A029404988 (SEQ ID NO: 43), A029404987 (SEQ ID NO: 44), A029404986 (SEQ ID NO: 45), A029404985 (SEQ ID NO: 46), A029404984 (SEQ ID NO: 47), A029404983 (SEQ ID NO: 48), A029404982 (SEQ ID NO: 49), A029404981 (SEQ ID NO: 50), A029404980 (SEQ ID NO: 51), A029404979 (SEQ ID NO: 52), A029404978 (SEQ ID NO: 53), A029404977 (SEQ ID NO: 54), A029404976 (SEQ ID NO: 55), A029404975 (SEQ ID NO: 56), A029404974 (SEQ ID NO: 57), A029404973 (SEQ ID NO: 58), A029404942 (SEQ ID NO: 59), A029404878 (SEQ ID NO: 60), A029404941 (SEQ ID NO: 61), A029404939 (SEQ ID NO: 62), A029404907 (SEQ ID NO: 63), A029404906 (SEQ ID NO: 64), A029404905 (SEQ ID NO: 65), A029404904 (SEQ ID NO: 66), A029404903 (SEQ ID NO: 67), A029404901 (SEQ ID NO: 68), A029404900 (SEQ ID NO: 69), A029404899 (SEQ ID NO: 70), A029404898 (SEQ ID NO: 71), A029404897 (SEQ ID NO: 72), A029404896 (SEQ ID NO: 73), A029404895 (SEQ ID NO: 74), A029404908 (SEQ ID NO: 75), A029404893 (SEQ ID NO: 76), A029404891 (SEQ ID NO: 77), A029404890 (SEQ ID NO: 78), A029404889 (SEQ ID NO: 79), A029404888 (SEQ ID NO: 80), A029404887 (SEQ ID NO: 81), A029404886 (SEQ ID NO: 82), A029404885 (SEQ ID NO: 83), A029404884 (SEQ ID NO: 84), A029404883 (SEQ ID NO: 85), A029404882 (SEQ ID NO: 86), A029404881 (SEQ ID NO: 87), A029404880 (SEQ ID NO: 88), A029404892 (SEQ ID NO: 89), A029404909 (SEQ ID NO: 90), A029404910 (SEQ ID NO: 91), A029404911 (SEQ ID NO: 92), A029404938 (SEQ ID NO: 93), A029404937 (SEQ ID NO: 94), A029404936 (SEQ ID NO: 95), A029404935 (SEQ ID NO: 96), A029404934 (SEQ ID NO: 97), A029404933 (SEQ ID NO: 98), A029404932 (SEQ ID NO: 99), A029404931 (SEQ ID NO: 100), A029404930 (SEQ ID NO: 101), A029404929 (SEQ ID NO: 102), A029404928 (SEQ ID NO: 103), A029404927 (SEQ ID NO: 104), A029404926 (SEQ ID NO: 105), A029404925 (SEQ ID NO: 106), A029404924 (SEQ ID NO: 107), A029404923 (SEQ ID NO: 108), A029404922 (SEQ ID NO: 109), A029404921 (SEQ ID NO: 110), A029404920 (SEQ ID NO: 111), A029404919 (SEQ ID NO: 112), A029404918 (SEQ ID NO: 113), A029404917 (SEQ ID NO: 114), A029404916 (SEQ ID NO: 115), A029404915 (SEQ ID NO: 116), A029404914 (SEQ ID NO: 117), A029404913 (SEQ ID NO: 118), A029404912 (SEQ ID NO: 119), A029404940 (SEQ ID NO: 120), A029404879 (SEQ ID NO: 121), A029404999 (SEQ ID NO: 122), A029405013 (SEQ ID NO: 123), A029405135 (SEQ ID NO: 124), A029405134 (SEQ ID NO: 125), A029405133 (SEQ ID NO: 126), A029405132 (SEQ ID NO: 127), A029405131 (SEQ ID NO: 128), A029405130 (SEQ ID NO: 129), A029405129 (SEQ ID NO: 130), A029405128 (SEQ ID NO: 131), A029405127 (SEQ ID NO: 132), A029405126 (SEQ ID NO: 133), A029405125 (SEQ ID NO: 134), A029405124 (SEQ ID NO: 135), A029403867 (SEQ ID NO: 136), A029405137 (SEQ ID NO: 137), A029405121 (SEQ ID NO: 138), A029405120 (SEQ ID NO: 139), A029405119 (SEQ ID NO: 140), A029405118 (SEQ ID NO: 141), A029405117 (SEQ ID NO: 142), A029405116 (SEQ ID NO: 143), A029405115 (SEQ ID NO: 144), A029405114 (SEQ ID NO: 145), A029405113 (SEQ ID NO: 146), A029405112 (SEQ ID NO: 147), A029405111 (SEQ ID NO: 148), A029405110 (SEQ ID NO: 149), A029405136 (SEQ ID NO: 150), A029403869 (SEQ ID NO: 151), A029405138 (SEQ ID NO: 152), A029405188 (SEQ ID NO: 153), A029405187 (SEQ ID NO: 154), A029405186 (SEQ ID NO: 155), A029405176 (SEQ ID NO: 156), A029405165 (SEQ ID NO: 157), A029405163 (SEQ ID NO: 158), A029405162 (SEQ ID NO: 159), A029405161 (SEQ ID NO: 160), A029405160 (SEQ ID NO: 161), A029405159 (SEQ ID NO: 162), A029405158 (SEQ ID NO: 163), A029405157 (SEQ ID NO: 164), A029405156 (SEQ ID NO: 165), A029405155 (SEQ ID NO: 166), A029405154 (SEQ ID NO: 167), A029405153 (SEQ ID NO: 168), A029405149 (SEQ ID NO: 169), A029405148 (SEQ ID NO: 170), A029405147 (SEQ ID NO: 171), A029405146 (SEQ ID NO: 172), A029405145 (SEQ ID NO: 173), A029405144 (SEQ ID NO: 174), A029405143 (SEQ ID NO: 175), A029405142 (SEQ ID NO: 176), A029405141 (SEQ ID NO: 177), A029405140 (SEQ ID NO: 178), A029405109 (SEQ ID NO: 179), A029405122 (SEQ ID NO: 180), A029405123 (SEQ ID NO: 181), A029405014 (SEQ ID NO: 182), A029405001 (SEQ ID NO: 183), A029405106 (SEQ ID NO: 184), A029405030 (SEQ ID NO: 185), A029405028 (SEQ ID NO: 186), A029405027 (SEQ ID NO: 187), A029405026 (SEQ ID NO: 188), A029405025 (SEQ ID NO: 189), A029405024 (SEQ ID NO: 190), A029405021 (SEQ ID NO: 191), A029405020 (SEQ ID NO: 192), A029405019 (SEQ ID NO: 193), A029405018 (SEQ ID NO: 194), A029405017 (SEQ ID NO: 195), A029405016 (SEQ ID NO: 196), A029405105 (SEQ ID NO: 197), A029405032 (SEQ ID NO: 198), A029405033 (SEQ ID NO: 199), A029405012 (SEQ ID NO: 200), A029405011 (SEQ ID NO: 201), A029405010 (SEQ ID NO: 202), A029405009 (SEQ ID NO: 203), A029405008 (SEQ ID NO: 204), A029405007 (SEQ ID NO: 205), A029405006 (SEQ ID NO: 206), A029405005 (SEQ ID NO: 207), A029405004 (SEQ ID NO: 208), A029405003 (SEQ ID NO: 209), A029405002 (SEQ ID NO: 210), A029405031 (SEQ ID NO: 211), A029405107 (SEQ ID NO: 212), A029405029 (SEQ ID NO: 213), A029405108 (SEQ ID NO: 214), A029405015 (SEQ ID NO: 215), A029405104 (SEQ ID NO: 216), A029405103 (SEQ ID NO: 217), A029405102 (SEQ ID NO: 218), A029405101 (SEQ ID NO: 219), A029405100 (SEQ ID NO: 220), A029405099 (SEQ ID NO: 221), A029405098 (SEQ ID NO: 222), A029405097 (SEQ ID NO: 223), A029405096 (SEQ ID NO: 224), A029405095 (SEQ ID NO: 225), A029405094 (SEQ ID NO: 226), A029405093 (SEQ ID NO: 227), A029405092 (SEQ ID NO: 228), A029405091 (SEQ ID NO: 229), A029405063 (SEQ ID NO: 230), A029405047 (SEQ ID NO: 231), A029405046 (SEQ ID NO: 232), A029405045 (SEQ ID NO: 233), A029405044 (SEQ ID NO: 234), A029405043 (SEQ ID NO: 235), A029405042 (SEQ ID NO: 236), A029405041 (SEQ ID NO: 237), A029405040 (SEQ ID NO: 238), A029405039 (SEQ ID NO: 239), A029405035 (SEQ ID NO: 240), A029405034 (SEQ ID NO: 241), A029405000 (SEQ ID NO: 242), A029404876 (SEQ ID NO: 243), A029404875 (SEQ ID NO: 244), A029404874 (SEQ ID NO: 245), A029401559 (SEQ ID NO: 246), A029401558 (SEQ ID NO: 247), A029401557 (SEQ ID NO: 248), A029401556 (SEQ ID NO: 249), A029401555 (SEQ ID NO: 250), A029401554 (SEQ ID NO: 251), A029401540 (SEQ ID NO: 252), A029401538 (SEQ ID NO: 253), A029401536 (SEQ ID NO: 254), A029401535 (SEQ ID NO: 255), A029401562 (SEQ ID NO: 256), A029401534 (SEQ ID NO: 257), A029401531 (SEQ ID NO: 258), A029401529 (SEQ ID NO: 259), A029401528 (SEQ ID NO: 260), A029401527 (SEQ ID NO: 261), A029401525 (SEQ ID NO: 262), A029401524 (SEQ ID NO: 263), A029401523 (SEQ ID NO: 264), A029401514 (SEQ ID NO: 265), A029401511 (SEQ ID NO: 266), A029401504 (SEQ ID NO: 267), A029401501 (SEQ ID NO: 268), A029401500 (SEQ ID NO: 269), A029401533 (SEQ ID NO: 270), A029401563 (SEQ ID NO: 271), A029401564 (SEQ ID NO: 272), A029401570 (SEQ ID NO: 273), A029401640 (SEQ ID NO: 274), A029401639 (SEQ ID NO: 275), A029401638 (SEQ ID NO: 276), A029401635 (SEQ ID NO: 277), A029401634 (SEQ ID NO: 278), A029401633 (SEQ ID NO: 279), A029401632 (SEQ ID NO: 280), A029401631 (SEQ ID NO: 281), A029401622 (SEQ ID NO: 282), A029401616 (SEQ ID NO: 283), A029401610 (SEQ ID NO: 284), A029401609 (SEQ ID NO: 285), A029401608 (SEQ ID NO: 286), A029401604 (SEQ ID NO: 287), A029401603 (SEQ ID NO: 288), A029401601 (SEQ ID NO: 289), A029401600 (SEQ ID NO: 290), A029401599 (SEQ ID NO: 291), A029401597 (SEQ ID NO: 292), A029401596 (SEQ ID NO: 293), A029401595 (SEQ ID NO: 294), A029401592 (SEQ ID NO: 295), A029401580 (SEQ ID NO: 296), A029401579 (SEQ ID NO: 297), A029401575 (SEQ ID NO: 298), A029401573 (SEQ ID NO: 299), A029401571 (SEQ ID NO: 300), A029401498 (SEQ ID NO: 301), A029401641 (SEQ ID NO: 302), A029401496 (SEQ ID NO: 303), A029401493 (SEQ ID NO: 304), A029400099 (SEQ ID NO: 305), A029400098 (SEQ ID NO: 306), A029400096 (SEQ ID NO: 307), A029400095 (SEQ ID NO: 308), A029400094 (SEQ ID NO: 309), A029400093 (SEQ ID NO: 310), A029400092 (SEQ ID NO: 311), A029400091 (SEQ ID NO: 312), A029400090 (SEQ ID NO: 313), A029400089 (SEQ ID NO: 314), A029400088 (SEQ ID NO: 315), A029400087 (SEQ ID NO: 316), A029400100 (SEQ ID NO: 317), A029400086 (SEQ ID NO: 318), A029400084 (SEQ ID NO: 319), A029400083 (SEQ ID NO: 320), A029400082 (SEQ ID NO: 321), A029400081 (SEQ ID NO: 322), A029400080 (SEQ ID NO: 323), A029400079 (SEQ ID NO: 324), A029400078 (SEQ ID NO: 325), A029400077 (SEQ ID NO: 326), A029400076 (SEQ ID NO: 327), A029400057 (SEQ ID NO: 328), A029400056 (SEQ ID NO: 329), A029400055 (SEQ ID NO: 330), A029400085 (SEQ ID NO: 331), A029400101 (SEQ ID NO: 332), A029400102 (SEQ ID NO: 333), A029400103 (SEQ ID NO: 334), A029401492 (SEQ ID NO: 335), A029401491 (SEQ ID NO: 336), A029401490 (SEQ ID NO: 337), A029401489 (SEQ ID NO: 338), A029401488 (SEQ ID NO: 339), A029401480 (SEQ ID NO: 340), A029401479 (SEQ ID NO: 341), A029401474 (SEQ ID NO: 342), A029401467 (SEQ ID NO: 343), A029401465 (SEQ ID NO: 344), A029401464 (SEQ ID NO: 345), A029401463 (SEQ ID NO: 346), A029401462 (SEQ ID NO: 347), A029401461 (SEQ ID NO: 348), A029401459 (SEQ ID NO: 349), A029401458 (SEQ ID NO: 350), A029401457 (SEQ ID NO: 351), A029401456 (SEQ ID NO: 352), A029401455 (SEQ ID NO: 353), A029401454 (SEQ ID NO: 354), A029400199 (SEQ ID NO: 355), A029400168 (SEQ ID NO: 356), A029400167 (SEQ ID NO: 357), A029400166 (SEQ ID NO: 358), A029400165 (SEQ ID NO: 359), A029400164 (SEQ ID NO: 360), A029400162 (SEQ ID NO: 361), A029401495 (SEQ ID NO: 362), A029401642 (SEQ ID NO: 363), A029401561 (SEQ ID NO: 364), A029401560 (SEQ ID NO: 365), A029401643 (SEQ ID NO: 366), A029404031 (SEQ ID NO: 367), A029404720 (SEQ ID NO: 368), A029404718 (SEQ ID NO: 369), A029404717 (SEQ ID NO: 370), A029404716 (SEQ ID NO: 371), A029404715 (SEQ ID NO: 372), A029404714 (SEQ ID NO: 373), A029404713 (SEQ ID NO: 374), A029404712 (SEQ ID NO: 375), A029404711 (SEQ ID NO: 376), A029404710 (SEQ ID NO: 377), A029404035 (SEQ ID NO: 378), A029404033 (SEQ ID NO: 379), A029404873 (SEQ ID NO: 380), A029404722 (SEQ ID NO: 381), A029404723 (SEQ ID NO: 382), A029404014 (SEQ ID NO: 383), A029404013 (SEQ ID NO: 384), A029404012 (SEQ ID NO: 385), A029404008 (SEQ ID NO: 386), A029403984 (SEQ ID NO: 387), A029403981 (SEQ ID NO: 388), A029403973 (SEQ ID NO: 389), A029403967 (SEQ ID NO: 390), A029403964 (SEQ ID NO: 391), A029403962 (SEQ ID NO: 392), A029403957 (SEQ ID NO: 393), A029404721 (SEQ ID NO: 394), A029403949 (SEQ ID NO: 395), A029403945 (SEQ ID NO: 396), A029404029 (SEQ ID NO: 397), A029403943 (SEQ ID NO: 398), A029404872 (SEQ ID NO: 399), A029404871 (SEQ ID NO: 400), A029404870 (SEQ ID NO: 401), A029404745 (SEQ ID NO: 403), A029404744 (SEQ ID NO: 404), A029404743 (SEQ ID NO: 405), A029404742 (SEQ ID NO: 406), A029404741 (SEQ ID NO: 407), A029404740 (SEQ ID NO: 408), A029404739 (SEQ ID NO: 409), A029404738 (SEQ ID NO: 410), A029404737 (SEQ ID NO: 411), A029404736 (SEQ ID NO: 412), A029404735 (SEQ ID NO: 413), A029404734 (SEQ ID NO: 414), A029404733 (SEQ ID NO: 415), A029404732 (SEQ ID NO: 416), A029404731 (SEQ ID NO: 417), A029404730 (SEQ ID NO: 418), A029404729 (SEQ ID NO: 419), A029404728 (SEQ ID NO: 420), A029404727 (SEQ ID NO: 421), A029404726 (SEQ ID NO: 422), A029404725 (SEQ ID NO: 423), A029404724 (SEQ ID NO: 424), A029404021 (SEQ ID NO: 425), A029403946 (SEQ ID NO: 426), A029401645 (SEQ ID NO: 427), A029404719 (SEQ ID NO: 428), A029401673 (SEQ ID NO: 429), A029403862 (SEQ ID NO: 430), A029403861 (SEQ ID NO: 431), A029403860 (SEQ ID NO: 432), A029401711 (SEQ ID NO: 433), A029401701 (SEQ ID NO: 434), A029401698 (SEQ ID NO: 435), A029401691 (SEQ ID NO: 436), A029401687 (SEQ ID NO: 437), A029401686 (SEQ ID NO: 438), A029401684 (SEQ ID NO: 439), A029401680 (SEQ ID NO: 440), A029401675 (SEQ ID NO: 441), A029403865 (SEQ ID NO: 442), A029405190 (SEQ ID NO: 443), A029401672 (SEQ ID NO: 444), A029401670 (SEQ ID NO: 445), A029401669 (SEQ ID NO: 446), A029401667 (SEQ ID NO: 447), A029401665 (SEQ ID NO: 448), A029401664 (SEQ ID NO: 449), A029401663 (SEQ ID NO: 450), A029401662 (SEQ ID NO: 451), A029401658 (SEQ ID NO: 452), A029401649 (SEQ ID NO: 453), A029401648 (SEQ ID NO: 454), A029401646 (SEQ ID NO: 455), A029405139 (SEQ ID NO: 456), A029405189 (SEQ ID NO: 457), A029403866 (SEQ ID NO: 458), A029403871 (SEQ ID NO: 459), A029401674 (SEQ ID NO: 460), A029403864 (SEQ ID NO: 461), A029403941 (SEQ ID NO: 462), A029403940 (SEQ ID NO: 463), A029403939 (SEQ ID NO: 464), A029403937 (SEQ ID NO: 465), A029403935 (SEQ ID NO: 466), A029403934 (SEQ ID NO: 467), A029403925 (SEQ ID NO: 468), A029403916 (SEQ ID NO: 469), A029403912 (SEQ ID NO: 470), A029403910 (SEQ ID NO: 471), A029403904 (SEQ ID NO: 472), A029403903 (SEQ ID NO: 473), A029403896 (SEQ ID NO: 474), A029403895 (SEQ ID NO: 475), A029403894 (SEQ ID NO: 476), A029403892 (SEQ ID NO: 477), A029403889 (SEQ ID NO: 478), A029403888 (SEQ ID NO: 479), A029403884 (SEQ ID NO: 480), A029403880 (SEQ ID NO: 481), A029403879 (SEQ ID NO: 482), A029403875 (SEQ ID NO: 483), A029403874 (SEQ ID NO: 484), A029403873 (SEQ ID NO: 485), A029403872 (SEQ ID NO: 486), A029403870 (SEQ ID NO: 487), or A029405191 (SEQ ID NO: 488) (see Table A-2 and A-6).

[0594] The SEQ ID NOs for the CDR sequences referred to above are based on the CDR definition according to the AbM definition (see Table A-6). It is noted that the CDR sequences defined according to the Kabat definition, Chothia definition or IMGT definition can likewise be used. Accordingly, the ISVDs provided by the present technology, specifically binding to PD-1 as described above using the AbM definition, can be also described using the Kabat definition, Chothia definition or IMGT definition.

[0595] In one embodiment, the ISVD comprises CDRs (Kabat definition) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-488, preferably SEQ ID NOs: 402, 331, 332, 375, 212, 139, 238.

[0596] In one embodiment, the ISVD comprises CDRs (Chothia definition) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-488, preferably SEQ ID NOs: 402, 331, 332, 375, 212, 139, 238.

[0597] In one embodiment, the ISVD comprises CDRs (IMGT definition) with an amino acid sequence that has at least 70% amino acid sequence identity, preferably at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-488, preferably SEQ ID NOs: 402, 331, 332, 375, 212, 139, 238.

[0598] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 402, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 402.

[0599] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 1, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0600] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 2, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 2. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence Identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 3, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 3.

[0601] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 4, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 4.

[0602] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 5, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 5.

[0603] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 6, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 6.

[0604] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 7, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 7.

[0605] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 8, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 8.

[0606] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 9, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 9.

[0607] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 10, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 10.

[0608] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 11, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 11.

[0609] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 12, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 12.

[0610] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 13, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 13.

[0611] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 14, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 14.

[0612] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 15, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 15.

[0613] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 16, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 16.

[0614] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 17, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 17.

[0615] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 18, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 18.

[0616] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 19, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 19. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 20, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 20.

[0617] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 21, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 21.

[0618] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 22, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 22.

[0619] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 23, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 23.

[0620] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 24, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 24.

[0621] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 25, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 25.

[0622] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 26, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 26.

[0623] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 27, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 27.

[0624] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 28, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 28.

[0625] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 29, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 29.

[0626] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 30, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 30.

[0627] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 31, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 31.

[0628] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 32, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 32.

[0629] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 33, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 33.

[0630] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 34, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 34.

[0631] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 35, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 35.

[0632] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 36, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 36. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 37, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 37.

[0633] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 38, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 38.

[0634] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 39, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 39.

[0635] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 40, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 40.

[0636] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 41, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 41.

[0637] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 42, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 42.

[0638] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 43, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 43.

[0639] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 44, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 44.

[0640] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 45, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 45.

[0641] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 46, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 46.

[0642] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 47, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 47.

[0643] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 48, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 48.

[0644] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 49, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 49.

[0645] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 50, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 50.

[0646] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 51, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 51.

[0647] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 52, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 52.

[0648] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 53, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 53. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 54, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 54.

[0649] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 55, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 55.

[0650] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 56, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 56.

[0651] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 57, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 57.

[0652] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 58, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 58.

[0653] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 59, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 59.

[0654] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 60, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 60.

[0655] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 61, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 61.

[0656] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 62, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 62.

[0657] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 63, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 63.

[0658] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 64, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 64.

[0659] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 65, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 65.

[0660] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 66, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 66.

[0661] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 67, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 67.

[0662] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 68, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 68.

[0663] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 69, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 69.

[0664] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 70, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 70. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 71, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 71.

[0665] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 72, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 72.

[0666] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 73, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 73.

[0667] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 74, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 74.

[0668] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 75, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 75.

[0669] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 76, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 76.

[0670] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 77, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 77.

[0671] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 78, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 78.

[0672] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 79, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 79.

[0673] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 80, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 80.

[0674] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 81, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 81.

[0675] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 82, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 82.

[0676] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 83, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 83.

[0677] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 84, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 84.

[0678] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 85, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 85.

[0679] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 86, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 86.

[0680] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 87, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 87. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 88, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 88.

[0681] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 89, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 89.

[0682] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 90, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 90.

[0683] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 91, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 91.

[0684] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 92, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 92.

[0685] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 93, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 93.

[0686] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 94, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 94.

[0687] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 95, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 95.

[0688] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 96, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 96.

[0689] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 97, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 97.

[0690] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 98, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 98.

[0691] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 99, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 99.

[0692] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 100, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 100.

[0693] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 101, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 101.

[0694] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 102, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 102.

[0695] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence Identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 103, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 103.

[0696] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 104, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 104. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 105, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 105.

[0697] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 106, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 106.

[0698] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 107, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 107.

[0699] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 108, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 108.

[0700] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 109, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 109.

[0701] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 110, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 110.

[0702] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 111, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 111.

[0703] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 112, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 112.

[0704] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 113, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 113.

[0705] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 114, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 114.

[0706] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 115, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 115.

[0707] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 116, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 116.

[0708] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 117, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 117.

[0709] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 118, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 118.

[0710] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 119, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 119.

[0711] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 120, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 120.

[0712] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 121, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 121. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 122, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 122.

[0713] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 123, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 123.

[0714] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 124, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 124.

[0715] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 125, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 125.

[0716] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 126, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 126.

[0717] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 127, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 127.

[0718] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 128, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 128.

[0719] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 129, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 129.

[0720] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 130, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 130.

[0721] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 131, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 131.

[0722] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 132, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 132.

[0723] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 133, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 133.

[0724] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 134, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 134.

[0725] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 135, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 135.

[0726] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 136, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 136.

[0727] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 137, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 137.

[0728] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 138, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 138. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 139, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 139.

[0729] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 140, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 140.

[0730] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 141, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 141.

[0731] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 142, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 142.

[0732] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 143, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 143.

[0733] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 144, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 144.

[0734] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 145, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 145.

[0735] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 146, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 146.

[0736] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 147, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 147.

[0737] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 148, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 148.

[0738] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 149, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 149.

[0739] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 150, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 150.

[0740] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 151, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 151.

[0741] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 152, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 152.

[0742] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 153, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 153.

[0743] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 154, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 154.

[0744] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 155, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 155. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 156, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 156.

[0745] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 157, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 157.

[0746] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 158, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 158.

[0747] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 159, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 159.

[0748] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 160, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 160.

[0749] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 161, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 161.

[0750] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 162, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 162.

[0751] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 163, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 163.

[0752] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 164, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 164.

[0753] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 165, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 165.

[0754] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 166, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 166.

[0755] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 167, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 167.

[0756] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 168, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 168.

[0757] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 169, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 169.

[0758] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 170, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 170.

[0759] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 171, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 171.

[0760] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 172, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 172. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 173, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 173.

[0761] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 174, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 174.

[0762] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 175, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 175.

[0763] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 176, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 176.

[0764] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 177, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 177.

[0765] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 178, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 178.

[0766] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 179, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 179.

[0767] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 180, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 180.

[0768] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 181, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 181.

[0769] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 182, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 182.

[0770] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 183, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 183.

[0771] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 184, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 184.

[0772] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 185, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 185.

[0773] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 186, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 186.

[0774] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 187, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 187.

[0775] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 188, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 188.

[0776] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 189, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 189. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 190, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 190.

[0777] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 191, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 191.

[0778] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 192, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 192.

[0779] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 193, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 193.

[0780] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 194, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 194.

[0781] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 195, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 195.

[0782] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 196, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 196.

[0783] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 197, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 197.

[0784] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 198, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 198.

[0785] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 199, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 199.

[0786] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 200, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 200.

[0787] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 201, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 201.

[0788] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 202, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 202.

[0789] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence Identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 203, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 203.

[0790] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 204, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 204.

[0791] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 205, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 205.

[0792] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 206, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 206. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 207, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 207.

[0793] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 208, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 208.

[0794] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 209, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 209.

[0795] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 2110, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 210.

[0796] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 211, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 211.

[0797] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 212, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 212.

[0798] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 213, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 213.

[0799] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 214, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 214.

[0800] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 215, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 215.

[0801] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 216, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 216.

[0802] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 217, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 217.

[0803] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 218, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 218.

[0804] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 219, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 219.

[0805] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 220, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 220.

[0806] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 221, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 221.

[0807] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 222, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 222.

[0808] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 223, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 223. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 224, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 224.

[0809] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 225, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 225.

[0810] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 226, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 226.

[0811] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 227, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 227.

[0812] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 228, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 228.

[0813] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 229, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 229.

[0814] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 230, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 230.

[0815] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 231, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 231.

[0816] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 232, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 232.

[0817] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 233, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 233.

[0818] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 234, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 234.

[0819] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 235, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 235.

[0820] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 236, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 236.

[0821] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 237, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 237.

[0822] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 238, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 238.

[0823] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 239, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 239.

[0824] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 240, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 240. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 241, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 241.

[0825] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 242, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 242.

[0826] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 243, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 243.

[0827] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 244, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 244.

[0828] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 245, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 245.

[0829] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 246, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 246.

[0830] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 247, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 247.

[0831] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 248, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 248.

[0832] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 249, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 249.

[0833] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 250, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 250.

[0834] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 251, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 251.

[0835] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 252, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 252.

[0836] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 253, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 253.

[0837] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 254, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 254.

[0838] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 255, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 255.

[0839] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 256, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 256.

[0840] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 257, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 257. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 258, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 258.

[0841] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 259, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 259.

[0842] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 260, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 260.

[0843] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 261, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 261.

[0844] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 262, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 262.

[0845] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 263, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 263.

[0846] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 264, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 264.

[0847] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 265, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 265.

[0848] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 266, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 266.

[0849] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 267, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 267.

[0850] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 268, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 268.

[0851] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 269, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 269.

[0852] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 270, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 270.

[0853] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 271, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 271.

[0854] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 272, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 272

[0855] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 273, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 273.

[0856] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 274, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 274. In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 275, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 275.

[0857] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 276, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 276.

[0858] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 277, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 277.

[0859] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or even more than 99%, with SEQ ID NO: 278, wherein the CDRs are as defined above. In one embodiment, the ISVD specifically binding to PD-1 comprises or consists of the amino acid sequence of SEQ ID NO: 278.

[0860] In another embodiment, the ISVD specifically binding to human PD-1 may have a sequence identity of more than 90%, such as more than 95% or e...

Claims

9 CLAIMS1. An immunoglobulin single variable domain (ISVD) specifically binding to human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human PD-1 protein, wherein at least one amino acid residue in the ISVD is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following stretches (of the ectodomain) of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: V64-P83, and I126-E136, preferably when the ISVD and human PD-1 protein are mixed in in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

2. The ISVD according to claim 1, wherein at least one amino acid residue located in the ISVD is capable of interacting with at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least ten, at least fifteen, preferably all, of the following amino acid residues of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: V64, N66, Y68, S73, N74, Q75, T76, D77, K78, P83, 1126, L128, A129, P130, K131, A132, 1134, and E136, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C3. The ISVD according to claim 1 or 2, wherein the at least one amino acid residue located in the ISVD that is capable of interacting with amino acid residues of human PD-1 protein is located in CDR3.

4. The ISVD according to any one of the preceding claims, wherein:• the amino acid residue at position 100e (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with A132 in PD-1;• the amino acid residue at position 100h (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with N66 in PD-1;• the amino acid residue at position 100j (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with N66 in PD-1;• the amino acid residue at position 100j (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with Y68 in PD-1;• the amino acid residue at position 100j (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with A132 in PD-1;• the amino acid residue at position 101 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with N66 in PD-1; and / or• the amino acid residue at position 101 (Kabat numbering) is capable of interacting, preferably by forming a hydrogen bond, with K78 in PD-1;preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

5. The ISVD according to any one of the preceding claims, wherein the interacting amino acid residue(s) in the ISVD and in human PD-1 protein are identified by X-ray crystallography by:- Mixing human PD-1 protein, and the ISVD in PBS1X buffer;- Concentrating the protein complex to 10.6 mg / mL;- Crystallizing by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C; - Collecting X-ray diffraction data;- Processing the collected data,preferably as described in Example 13.

6. The ISVD according to any one of the preceding claims, wherein the (discontinuous) epitope comprises or consists of the following amino acid residues of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: V64, N66, Y68, S73, N74, Q75, T76, D77, K78, P83, 1126, L128, A129, P130, K131, A132, 1134, E136.

7. An immunoglobulin single variable domain (ISVD) specifically binding human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the CDR3 (AbM definition) consists of the following amino acid sequence X1X2STTVRX3X4CX5IMYX6YDY (SEQ ID NO: 4702), wherein:• X1 is selected from any amino acid, preferably X1 is selected from A or G;• X2 is selected from any amino acid, preferably X2 is selected T, A, E, G, F, I, D, H, K, S, P, R, Q, Y, V, or L;• X3 is selected from any amino acid, preferably X3 is selected from D or G;• X4is selected from any amino acid, preferably X4is selected from L, M, I, E, A, V, D, H, G, F, K, R, P, S, T, or Y;• X5is selected from any amino acid, preferably X5is selected from G or F; and• X6 is selected from any amino acid, preferably X6 is selected from L, V, or F.

8. The ISVD according to any one of the preceding claims, wherein the following amino acid residue of the ISVD at the following position: R45 (Kabat numbering) is capable of forming salt bridges with at least one of the amino acid residues of human PD-1 protein, preferably when the ISVD and humanPD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

9. The ISVD according to any one of the preceding claims, wherein at least one, preferably all of the following amino acid residues of the ISVD at the following positions: I100e, Y100h, Y100j, and D101 (Kabat numbering) are capable of forming hydrogen bonds with at least one of the amino acid residues of human PD-1 protein, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

10. The ISVD according to any one of the preceding claims, wherein at least one, preferably all, of the following amino acid residues of the ISVD at the following positions: R45, I100e, Y100h, Y100j, and D101, and optionally Q105 (Kabat numbering) is capable of interacting with at least one, preferably all of the following amino acid residues of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: N66, Y68, K78, A132, and E136, and optionally N74, preferably wherein:R45 in the ISVD (Kabat numbering) interacts, preferably by forming a salt bridge, with E136 in human PD-1 protein;I100e in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with A132 in human PD-1 protein;Y100h in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with N66 in human PD-1 protein;Y100j in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with N66 in human PD-1 protein;Y100j in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with Y68 in human PD-1 protein;Y100j in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with A132 in human PD-1 protein;D101 in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with N66 in human PD-1 protein; and / orD101 in the ISVD (Kabat numbering) interacts, preferably by forming a hydrogen bond, with K78 in human PD-1 protein;preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

11. The ISVD according to any one of the preceding claims, wherein said ISVD essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which CDR3 (AbM definition) has an amino acid sequence selected from: a) the amino acid sequence of SEQ ID NO: 691;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 691;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 691.

12. The ISVD according to claim 11, wherein the ISVD comprises V2, Q3, L4, R45, W103 and / or Q105 (Kabat numbering).

13. The ISVD according to any one of the preceding claims, in which V2, Q3, L4, R45, I100e, Y100h, Y100j, D101, and Q105 (Kabat numbering) of the ISVD are capable of interacting with the following amino acids of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: N66, Y68, S73, N74, Q75, K78, A132, and E136, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C.

14. The ISVD according to any one of the preceding claims, wherein the interacting amino acid residue(s) in the ISVD and in human PD-1 protein are identified by X-ray crystallography by:Mixing human PD-1 protein, and the ISVD in PBS1X buffer;Concentrating the protein complex to 10.6 mg / mL;Crystallizing by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C; Collecting X-ray diffraction data;Processing the collected data,preferably as described in Example 13.

15. An immunoglobulin single variable domain (ISVD) specifically binding to human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD cross-blocks the binding to human PD-1 protein of a polypeptide having an amino acid sequence selected from SEQ ID NOs: 1- 488, preferably wherein the ISVD cross-blocks the binding to human PD-1 protein of a polypeptide having an amino acid sequence selected from SEQ ID NO: 402, or wherein the binding of the ISVD tohuman PD-1 protein is cross-blocked by a polypeptide having an amino acid sequence selected from SEQ ID NOs: 1-488.

16. The ISVD according to any one of the preceding claims, wherein the ISVD competes with a polypeptide with an amino acid sequence selected from SEQ ID NO: 1-488 for binding human PD-1 protein, as measured in a competition assay, such as a FACS competition assay.

17. An immunoglobulin single variable domain (ISVD) specifically binding human PD-1, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein CDR3 (AbM definition) consists of the amino acid sequence of one of SEQ ID NOs: 644-711, and wherein the amino acid residue of the ISVD at the following position: 45 (Kabat numbering) is capable of forming salt bridges with at least one of the amino acid residues of human PD-1 protein, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C, preferably wherein the ISVD comprises at least the following amino acid residue: R45 (Kabat numbering).

18. The ISVD according to claim 16 or claim 17, wherein the CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691, optionally wherein the CDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493 and the CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526.

19. An immunoglobulin single variable domain (ISVD) specifically binding human PD-1, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR1 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of GFTLDX1YX2X3G (SEQ ID NO: 2394), wherein Xi is selected from A, D, Q, P, S, G, T, V, I, R, K, E, L, H, F, or Y, X2 is selected from V or F, and X3 is selected from I, E, D, A, F, G, H, L, K, T, M, S, P, R, Y, V, or Q;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GFTLDX1YX2X3G (SEQ ID NO: 2394), wherein X1is selected from A, D, Q, P, S, G, T, V, I, R, K, E, L, H, F, or Y, X2is selected from V or F, and X3is selected from I, E, D, A, F, G, H, L, K, T, M, S, P, R, Y, V, or Q; andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of GFTLDX1YX2X3G (SEQ ID NO: 2394), wherein Xi is selected from A, D, Q, P, S,G, T, V, I, R, K, E, L, H, F, or Y, X2 is selected from V or F, and X3 is selected from I, E, D, A, F, G, H, L, K, T, M, S, P, R, Y, V, or Q;andCDR2 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of CX1SX2X3X4DRX5X6(SEQ ID NO: 2395), wherein X1is selected from L, G, H, K, P, R, S, or T, X2is selected from S, E, G, H, P, or Q, and X3is selected from N, E, A, D, F, G, H, I, K, L, P, Q, R, S, T, V, or Y, X4is selected from G, D, F, H, K, L, P, Q, R, S, T, V, A, or Y, X5is selected from I, A, E, G, H, K, P, R, S, or T, and X6 is selected from N, A, D, E, F, G, H, I, K, L, P, Q, R, S, T, V, or Y;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of CX1SX2X3X4DRX5X6(SEQ ID NO: 2395), wherein X1is selected from L, G, H, K, P, R, S, or T, X2is selected from S, E, G, H, P, or Q, and X3is selected from N, E, A, D, F, G, H, I, K, L, P, Q, R, S, T, V, or Y, X4is selected from G, D, F, H, K, L, P, Q, R, S, T, V, A, or Y, X5is selected from I, A, E, G, H, K, P, R, S, or T, and X6is selected from N, A, D, E, F, G, H, I, K, L, P, Q, R, S, T, V, or Y;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of CX1SX2X3X4DRX5X6(SEQ ID NO: 2395), wherein X1is selected from L, G, H, K, P, R, S, or T, X2is selected from S, E, G, H, P, or Q, and X3is selected from N, E, A, D, F, G, H, I, K, L, P, Q, R, S, T, V, or Y, X4is selected from G, D, F, H, K, L, P, Q, R, S, T, V, A, or Y, X5is selected from I, A, E, G, H, K, P, R, S, or T, and X6is selected from N, A, D, E, F, G, H, I, K, L, P, Q, R, S, T, V, or Y;andCDR3 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of X1X2STX3VRX4X5CX6IX7YX8YDX9 (SEQ ID NO: 2396), wherein X1 is selected from A or G, X2 is selected from T, A, E, G, F, I, D, H, K, S, P, R, Q, Y, V, or L, X3 is selected from T or I, X4is selected from D or G, X5is selected from L, M, I, E, A, V, D, H, G, F, L, K, R, P, S, T, or Y, X6 is selected from G or F, X7is selected from I, M, F, Y, L, A, D, E, G, K, H, P, Q, S, T, V, or R, X8 is selected from L, V, or F, and X9 is selected from Y, E, I, L, or V; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1X2STX3VRX4X5CX6IX7YX8YDX9 (SEQ ID NO: 2396), wherein X1 is selected from A or G, X2 is selected from T, A, E, G, F, I, D, H, K, S, P, R, Q, Y, V, or L, X3 is selected from T or I, X4is selected from D or G, X5is selected from L, M, I, E, A, V, D, H, G, F, L, K, R, P, S, T, or Y, X6 is selected from G or F, X7is selected from I, M, F, Y, L, A, D, E, G, K, H, P, Q, S, T, V, or R, X8 is selected from L, V, or F, and X9 is selected from Y, E, I, L, or V;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of X1X2STX3VRX4X5CX6IX7YX8YDX9 (SEQ ID NO: 2396), wherein X1 is selected from A or G, X2 is selected from T, A, E, G, F, I, D, H, K, S, P, R, Q, Y, V, or L, X3 is selected from T or I, X4is selected from D or G, X5is selected from L, M, I, E, A, V, D, H, G, F, L, K, R, P, S, T, or Y, X6 is selected from G or F, X7is selected from I, M, F, Y, L, A, D, E, G, K, H, P, Q, S, T, V, or R, X8 is selected from L, V, or F, and X9 is selected from Y, E, I, L, or V.

20. The ISVD according to claim 19, in which the amino acid sequences of the CDRs (AbM definition) have at least 80% amino acid sequence identity, more preferably at least 90% amino acid sequence identity, such as 95% amino acid sequence identity or 99% amino acid sequence identity or more, or even essentially 100% amino acid sequence identity with the amino acid sequences of the CDRs of the ISVD with the amino acid sequence selected from SEQ ID NOs: 1-488.

21. The ISVD according to any one of claims 19 or 20, wherein said ISVD essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:CDR1 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of SEQ ID NO: 493;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 493; andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 493;andCDR2 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of SEQ ID NO: 526;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 526;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 526;andCDR3 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of SEQ ID NO: 691;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 691;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 691.

22. An ISVD that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), whereinCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 546, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 547, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 547, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 547, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 547, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 541, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 541, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 541, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 541, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 549, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 549, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 549, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 548, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 549, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 547, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 540, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 542, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 544, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 530, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 604, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 604, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 604, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 603, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 603, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 603, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 603, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 604, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 547, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 535, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 547, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 541, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 531, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 531, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 534, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 534, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 534, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 531, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 531, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 531, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 531, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 531, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 529, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 602, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 527, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 528, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 601, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 532, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 534, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 531, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 534, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 534, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 541, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 541, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 541, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 549, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 549, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 549, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 547, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 549, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 534, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 534, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 578, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 707; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 578, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 703; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 578, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 672; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 578, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 665; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 592, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 701; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 592, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 703; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 592, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 672; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 592, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 665; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 592, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 707; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 593, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 701; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 593, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 703; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 593, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 672; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 593, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 665; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 593, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 707; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 594, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 701; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 594, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 703; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 537, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 593, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 559, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 645; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 553, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 598, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 645; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 593, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 644; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 557, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 645; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 550, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 595, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 555, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 559, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 550, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 645; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 553, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 645; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 591, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 578, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 701; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 701; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 703; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 672; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 665; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 707; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 594, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 672; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 603, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 539, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 678; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 604, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 604, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 604, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 604, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 603, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 603, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 603, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 674; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 594, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 707; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 594, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 665; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 595, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 701; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 595, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 703; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 595, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 672; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 595, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 665; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 595, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 707; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 542, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 676; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 677; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 575, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 570, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 566, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 564, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 567, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 572, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 580, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 587, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 588, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 583, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 568, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 584, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 560, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 586, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2393, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 585, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 561, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 582, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 581, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 592, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 552, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 558, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 590, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 597, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 579, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 577, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 571, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 567, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 690; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 702; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 667; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 673; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 663; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 666; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 661; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 576, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 573, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 562, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 574, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 563, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 556, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 589, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 599, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 681; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 662; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 538, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 594, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 554, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 497, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 499, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 500, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 501, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 502, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 503, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 504, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 505, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 506, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 507, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 508, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 509, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 510, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 511, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 536, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 700; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 569, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 565, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 675; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 687; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 706; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 689; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 669; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 664; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 704; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 684; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 665; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 707; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 704; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 664; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 675; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 649; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 650; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 660; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 648; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 710; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 711; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 657; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 705; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 653; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 647; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 651; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 679; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 705; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 706; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 665; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 707; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 689; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 687; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 551, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 684; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 655; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 699; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 543, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 671; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 683; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2392, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 512, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 513, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 692; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 694; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 689; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 688; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 695; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 682; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 687; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 600, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 696; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 685; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 686; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 697; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 698; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 684; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 708; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 709; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 668; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 557, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 514, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 693; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 646; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 652; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 659; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 658; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 656; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 654; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 515, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 516, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 517, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 518, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 519, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 520, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 521, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 522, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 523, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 596, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 670.

23. The ISVD according to any one of claims 19 to 22, in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 526, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 691; orCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 549, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 680.

24. The ISVD according to any one of claims 19 to 23, wherein the ISVD comprises V2, Q3, L4, R45, W103 and / or Q105 (Kabat numbering).

25. The ISVD according to any one of claims 19 to 24, wherein the amino acid residue of the ISVD at the following position: 45 (Kabat numbering) is capable of forming salt bridges with at least one of the amino acid residues of human PD-1 protein, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 30% PEG3350, 50 mM TRIS, pH 8 at 19°C, preferably wherein the ISVD comprises at least the following amino acid residue: R45 (Kabat numbering).

26. The ISVD according to claim 25, wherein R45 (Kabat numbering) of the ISVD is capable of forming salt bridges with the amino acid residue E136 of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703.

27. The ISVD according to any one of claims 1 to 26, that essentially consists of a heavy chain variable domain sequence that is derived from a conventional four-chain antibody or that essentially consists of a heavy chain variable domain sequence that is derived from a heavy chain antibody.

28. The ISVD according to any one of claims 1 to 27, that essentially consists of a VHH, a humanized VHH, a camelized VH, a domain antibody, a single domain antibody, or a dAb.

29. The ISVD according to any one of claims 1 to 28, which is a humanized ISVD that is chosen from SEQ ID NO: 1-401, 403-488 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 1-488.

30. The ISVD according to any one of claims 1 to 29, which is a humanized ISVD that is chosen from SEQ ID NO: 332, 375, 212, 139, and 238 or from the group consisting of amino acid sequences that have more than 80%, preferably more than 90%, more preferably more than 95%, such as 99% or more amino acid sequence identity with at least one of the amino acid sequences of SEQ ID NOs: 402, 332, 375, 212, 139, 238.

31. The ISVD according to any one of claims 1 to 30, in which the ISVD consists of the amino acid sequence of SEQ ID NO: 402 or 238.

32. The ISVD according to any one of claims 1 to 31, wherein the ISVD specifically binds to human PD-1 with a dissociation constant (KD) of 5xl0’9to 10’12moles / litre or less, and preferably IO10to 10’12moles / litre or less and more preferably 5x10-10to 5xl0-11moles / litre, such as 4.3x 10’11moles / litre, as determined by Surface Plasmon Resonance.

33. The ISVD according to any one of claims 1 to 32, wherein the ISVD specifically binds to human PD-1 with a kon-rate of between 105M^s’1to about 107M^s’1, preferably between 5xl05M^s’1and 107M’1s’1, more preferably between 5xl05M^s’1and 5xl06M^s’1, such as between 5xl05M^s’1and 1x106M^s’1, such as 3xl05M^s’1, as determined by Surface Plasmon Resonance.

34. The ISVD according to any one of claims 1 to 33, wherein the ISVD specifically binds to human PD-1 with a koffrate between IO-3s’1and IO-8s’1, preferably 10’3s’1and 5xl0’6s’1, more preferably between 5xl0’4s’1and 5xl0’6s’1, such as between 5xl0’4s’1and 5xl0’5s’1, such as 1.3xl0’5s’1, as determined by Surface Plasmon Resonance.

35. The ISVD according to any one of claims 1 to 34, wherein the ISVD specifically binds to human and cyno PD-1 and does not bind to CD28, CTLA-4, ICOS, and BTLA or other members of the CD28 receptor family.

36. The ISVD according to any one of claims 1 to 35, wherein the ISVD antagonizes an activity of PD-L1.

37. The ISVD according to any one of claims 1 to 36, wherein the ISVD blocks the interaction of human PD-1 with human PD-L1 with a potency (IC50 value) of 10-8M or lower, more preferably of 5x10-9M or lower, or even of 10-9M or lower, such as between 1011M and IO-8M, between IO10M and IO-9M, between IO10M and IO-8M or between IO-9M and IO-8M, such as 5.11xl0-9M, for example, as measured in a FACS competition assay on CHO cells expressing human PD-1 with hPD-Ll as a competitor.

38. The ISVD according to any one of claims 1 to 37, wherein the ISVD blocks the interaction of cyno PD- 1 with cyno PD-L1 with a potency (IC50 value) of IO-7M or lower, of 5x10-8M or lower, more preferably of IO-8M or lower, or even of 5xl0-9M or lower, such as between 1011M and IO-7M, between 1011M and 10'8M, between IO10M and IO-7M, between IO10M and IO-9M, between 10"10M and IO-8M, between IO-9M and IO-8M or between IO-9M and IO-7M, such as 5.76xl0-8M, for example, as measured in a FACS competition assay on CHO cells expressing cyno PD-1 with hPD-Ll as a competitor.

39. The ISVD according to any one of claims 1 to 38, wherein the ISVD blocks the binding of hPD-1 to hPD-Ll by at least 50%, such as at least 60%, 70%, 80%, 90%, 95%, 99% or even more, as determined by ligand competition, AlphaScreen, or competitive binding assays (such as competition ELISA or competition FACS).

40. The ISVD according to any one of claims 1 to 39, wherein the ISVD induces T-cell activation with a potency (EC50 value) of 10-8M or lower, more preferably of 5x10-9M or lower, or even of 10-9M or lower, such as between 10-11M and 10-8M, between 10-10M and 10-8M, between 10-10M and 10-9M or between 10-9M and 10-8M, such as 2.2x10-9M or 2.8x10-9M, as determined in a TT assay.

41. A polypeptide or construct that comprises or essentially consists of one or more ISVDs according to any one of claims 1 to 40, and optionally further comprises one or more other groups, residues, moieties or binding units, optionally linked via one or more linkers.

42. The polypeptide or construct according to claim 41, in which said one or more other groups, residues, moieties or binding units are amino acid sequences.

43. The polypeptide or construct according to any one of claims 41 to 42, in which said one or more linkers are one or more amino acid sequences.

44. The polypeptide or construct according to any one of claims 41 to 43, in which said one or more other groups, residues, moieties or binding units are immunoglobulin sequences.

45. The polypeptide or construct according to any one of claims 41 to 44, in which said one or more other groups, residues, moieties or binding units are ISVDs.

46. The polypeptide or construct according to any one of claims 41 to 45, in which said one or more other groups, residues, moieties or binding units are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies and dAbs.

47. The polypeptide or construct according to any one of claims 41 to 46, which is a multivalent construct.

48. The polypeptide or construct according to any one of claims 41 to 47, which is a multispecific construct.

49. The polypeptide or construct according to any one of claims 41 to 48, in which said one or more other groups, residues, moieties or binding units provide the polypeptide or construct with increased halflife, compared to the ISVD without the one or more other groups, residues, moieties or binding units.

50. The polypeptide or construct according to claim 49, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of a polyethylene glycol molecule (PEG), serum proteins or fragments thereof, binding units that specifically bind to serum proteins, an Fc portion, and small proteins or peptides that specifically bind to serum proteins.

51. The polypeptide or construct according to claim 50, in which said one or more other groups, residues, moieties or binding units that provide the polypeptide or construct with increased half-life is chosen from the group consisting of human serum albumin or fragments thereof.

52. The polypeptide or construct according to claim 50, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of binding units that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

53. The polypeptide or construct according to claim 52, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life are chosen from the group consisting of VHHs, humanized VHHs, camelized VHs, domain antibodies, single domain antibodies, or dAbs that specifically bind to serum albumin (such as human serum albumin) or a serum immunoglobulin (such as IgG).

54. The polypeptide or construct according to claim 52 or claim 53, in which said one or more other groups, residues, moieties or binding units that provides the polypeptide or construct with increased half-life is an ISVD that specifically binds human serum albumin.

55. The polypeptide or construct according to claim 54, wherein said ISVD that specifically binds human serum albumin essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:CDR1 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of SEQ ID NO: 2436;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 2436; andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 2436;andCDR2 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of SEQ ID NO: 2438;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 2438;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 2438;andCDR3 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of SEQ ID NO: 2440;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 2440;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 2440.

56. The polypeptide or construct according to claim 55, wherein CDR1 consists of the amino acid sequence of SEQ ID NO: 2436, CDR2 consists of the amino acid sequence of SEQ ID NO: 2438, and CDR3 consists of the amino acid sequence of SEQ ID NO: 2440.

57. The polypeptide or construct according to any one of claims 54 to 56, wherein said ISVD that specifically binds human serum albumin is selected from the group consisting of ALB8 (SEQ ID NO: 2401), ALB23 (SEQ ID NO: 2402), ALBX00001 (SEQ ID NO: 2415) and ALB23002 (SEQ ID NO: 2416), preferably the ISVD binding to human serum albumin is ALB23002 (SEQ ID NO: 2416).

58. The polypeptide or construct according to any one of claims 41 to 57, wherein said linker is chosen from the group consisting of SEQ ID NOs: 2418 to 2434.

59. The polypeptide or construct according to any one of claims 41 to 58, further comprising a C-terminal extension.

60. The polypeptide or construct according to claim 59, wherein said C-terminal extension is a C-terminal extension (X)n, in which n is 1 to 10, preferably 1 to 5, such as 1, 2, 3, 4 or 5 (and preferably 1 or 2, such as 1); and each X is an (preferably naturally occurring) amino acid residue that is independently chosen, and preferably independently chosen from the group consisting of alanine (A), glycine (G), valine (V), leucine (L) or isoleucine (I).

61. A nucleic acid that encodes an ISVD according to any one of claims 1 to 40, or a polypeptide according to any one of claims 41 to 60.

62. The nucleic acid according to claim 61, that is in the form of a genetic construct.

63. A (non-human) host or host cell that expresses, or that under suitable circumstances is capable of expressing, an ISVD according to any one of claims 1 to 40, or a polypeptide according to any one of claims 41 to 60; and / or that comprises the nucleic acid according to any one of claims 61 or 62.

64. A method for producing an ISVD according to any one of claims 1 to 40, or a polypeptide according to any one of claims 41 to 60, at least comprising the steps of:a) expressing, in a suitable (non-human) host cell or host organism or in another suitable expression system, a nucleic acid according to any one of claims 61 or 62;optionally followed by:b) isolating and / or purifying the ISVD according to any one of claims 1 to 40, or the polypeptide according to any one of claims 41 to 60.

65. A method for producing an ISVD according to any one of claims 1 to 40, or a polypeptide according to any one of claims 41 to 60, said method at least comprising the steps of:a) cultivating and / or maintaining a (non-human) host or host cell according to claim 63 under conditions that are such that said (non-human) host or host cell expresses and / or produces at least one ISVD according to any one of claims 1 to 40, or at least one polypeptide according to any one of claims 41 to 60;optionally followed by:b) isolating and / or purifying the ISVD according to any one of claims 1 to 40, or polypeptide according to any one of claims 41 to 60.

66. A composition comprising at least one ISVD according to any one of claims 1 to 40, at least one polypeptide or construct according to any one of claims 41 to 60, or at least one nucleic acid according to any one of claims 61 or 62.

67. The composition according to claim 66, which is a pharmaceutical composition.

68. The composition according to any one of claims 66 or 67, which is a pharmaceutical composition, that further comprises at least one pharmaceutically acceptable carrier, diluent or excipient and / or adjuvant, and that optionally comprises one or more further pharmaceutically active polypeptides and / or compounds.

69. The ISVD according to any one of claims 1 to 40, the polypeptide or construct according to any one of claims 41 to 60, or the composition according to any one of claims 66 to 68, for use as a medicament.

70. The ISVD according to any one of claims 1 to 40, the polypeptide or construct according to any one of claims 41 to 60, or the composition according to any one of claims 66 to 68, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder.

71. The ISVD according to any one of claims 1 to 40, the polypeptide or construct according to any one of claims 41 to 60, or the composition according to any one of claims 66 to 68, for use in the diagnosis, prevention and / or treatment of at least one disease and / or disorder that is associated with PD-1,with its biological or pharmacological activity, and / or with the biological pathways or signalling in which PD-1 is involved.

72. The ISVD according to any one of claims 1 to 40, the polypeptide or construct according to any one of claims 41 to 60, or the composition according to any one of claims 66 to 68, for use in the diagnosis, prevention and / or treatment of cancer.

73. A method for the diagnosis, prevention and / or treatment of at least one disease and / or disorder, comprising the administration, to a subject in need thereof, of a pharmaceutically active amount of an ISVD according to any one of claims 1 to 40, a polypeptide or construct according to any one of claims 41 to 60, or a composition according to any one of claims 66 to 68.

74. The method according to claim 73, for the diagnosis, prevention and / or treatment of at least one disease or disorder that is associated with PD-1, with its biological or pharmacological activity, and / or with the biological pathways or signalling in which PD-1 is involved, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of claims 1 to 40, a polypeptide or construct according to any one of claims 41 to 60, or composition according to any one of claims 66 to 68.

75. The method according to any one of claims 73 or 74, for the diagnosis, prevention and / or treatment of cancer, said method comprising administering, to a subject in need thereof, a pharmaceutically active amount of at least one ISVD according to any one of claims 1 to 40, a polypeptide or construct according to any one of claims 41 to 60, or a composition according to any one of claims 66 to 68.

76. An immunoglobulin single variable domain (ISVD) specifically binding to human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human PD-1 protein, wherein at least one amino acid residue located in at least one of the CDRs is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following stretches (of the ectodomain) of human PD-1 protein, when numbered in accordance with SEQ. ID NO: 4703: N66-E84, and I126-E136, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 100 mM Na Cacodylate, 300 mM Na Acetate, 10% PEG1000, pH 6.5 at 19°C.

77. An immunoglobulin single variable domain (ISVD) specifically binding human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD comprises an amino acid residue capable of forming salt bridges at at least position 101 (Kabat numbering), and optionally further at position 99 (Kabat numbering), preferably wherein the ISVD comprises at least the following amino acid residue at the following positions: D101, and optionally K99 (Kabat numbering).

78. An immunoglobulin single variable domain (ISVD) specifically binding to human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human PD-1, wherein the ISVD cross-blocks the binding to human PD-1 protein of a polypeptide with the amino acid sequence of SEQ ID Nos: 714-1871 or wherein the ISVD is crossblocked from binding to human PD-1 protein by a polypeptide with the amino acid sequence of SEQ ID Nos: 714-1871.

79. An immunoglobulin single variable domain (ISVD) specifically binding human PD-1, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR1 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of X1X2X3X4X5X6X7X8X9X10 (SEQ ID NO: 4691); wherein X1is selected from G, K, F, A, Y, T, V, H, R, S, P, I, E, L, or D, X2is selected from D, Y, R, E, T, L, K, H, V, S, P, Q, I, G, A, or F, X3is selected from T, I, A, E, H, G, P, F, L, K, Q, V, R, Y, or S, X4is selected from F, K, D, L, T, I, A, E, V, G, H, Y, Q, S, or R, X5is selected from S, I, E, A, F, R, V, Y, L, T, Q, K, D, G, or H, X6is selected from E, Q, V, T, S, F, K, P, I, G, R, L, H, or A, X7is selected from N, R, Q, V, E, Y, H, A, K, L, P, G, F, I, S, or D, X8is selected from D, P, A, T, I, R, V, G, Y, L, F, K, S, I, H, or E, X9is selected from I, R, H, M, G, Y, Q, E, K, F, T, S, A, D, or P, and X10is selected from G, A, L, S, R, H, V, P, Q, E, I, D, Y, T or K;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1X2X3X4X5X6X7X8X9X10 (SEQ ID NO: 4691); wherein Xi is selected from G, K, F, A, Y, T, V, H, R, S, P, I, E, L, or D, X2is selected from D, Y, R, E, T, L, K, H, V, S, P, Q, I, G, A, or F, X3is selected from T, I, A, E, H, G, P, F, L, K, Q, V, R, Y, or S, X4is selected from F, K, D, L, T, I, A, E, V, G, H, Y, Q, S, or R, X5is selected from S, I, E, A, F, R, V, Y, L, T, Q, K, D, G, or H, X6is selected from E, Q, V, T, S, F, K, P, I, G, R, L, H, or A, X7is selected from N, R, Q, V, E, Y, H, A, K, L, P, G, F, I, S, or D, X8is selected from D, P, A, T, I, R, V, G, Y, L, S, I, H, or E, X9 is selected from I, R, H,M, G, Y, Q, E, K, F, T, S, A, D, or P, and Xio is selected from G, A, L, S, R, H, V, P, Q, E, I, D, Y, T, or K;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of X1X2X3X4X5X6X7X8X9X10 (SEQ ID NO: 4691); wherein Xi is selected from G, K, F, A, Y, T, V, H, R, S, P, I, E, L, or D, X2is selected from D, Y, R, E, T, L, K, H, V, S, P, Q, I, G, A, or F, X3is selected from T, I, A, E, H, G, P, F, L, K, Q, V, R, Y, or S, X4is selected from F, K, D, L, T, I, A, E, V, G, H, Y, Q, S, or R, X5is selected from S, I, E, A, F, R, V, Y, L, T, Q, K, D, G, or H, X6is selected from E, Q, V, T, S, F, K, P, I, G, R, L, H, or A, X7is selected from N, R, Q, V, E, Y, H, A, K, L, P, G, F, I, S, or D, Xg is selected from D, P, A, T, I, R, V, G, Y, L, S, I, H, or E, Xg is selected from I, R, H, M, G, Y, Q, E, K, F, T, S, A, D, or P, and Xio is selected from G, A, L, S, R, H, V, P, Q, E, I, D, Y, T, or K;andCDR2 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of X1X2X3X4X5X6X7X8X9X10 (SEQ ID NO: 4692); wherein Xi is selected from A, G, P, F, V, I, R, Q, H, T, S, Y, K, or L, X2is selected from I, H, K, G, L, P, F, A, V, T, E, Y, S, Q, D, or R, X3 is selected from V, K, Y, F, G, Q, A, T, S, P, I, R, D, or L, X4is selected from W, P, Y, Q, G, T, D, H, R, K, S, L, I, V, F, or A, X5is selected from P, K, Y, F, G, I, L, T, Q, H, E, D, A, S, or V, Xg is selected from G, Q, E, P, L, F, K, I, S, A, D, R, H, or V, X7is selected from G, A, H, F, L, Y, T, P, Q, K, I, R, D, V, or S, X8is selected from E, T, I, R, H, Q, D, K, S, P, A, F, Y, V, G, or L, Xg is selected from T, E, L, Y, F, P, Q, I, R, S, D, K, A, V, or H, and Xio is selected from Y, G, I, L, E, D, H, K, A, F, S, R, P, T, Q;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1X2X3X4X5X6X7X8X9X10 (SEQ ID NO: 4692); wherein Xi is selected from A, G, P, F, V, I, R, Q, H, A, T, S, Y, K, or L, X2is selected from I, H, K, G, L, P, F, A, V, T, E, Y, S, Q, D, or R, X3is selected from V, K, Y, F, G, Q, A, T, S, P, I, R, D, or L, X4is selected from W, P, Y, Q, G, T, D, H, R, K, S, L, I, V, F, or A, X5is selected from P, K, Y, F, G, I, L, T, Q, H, E, D, A, S, or V, X6is selected from G, Q, E, P, L, F, K, I, S, A, D, R, H, or V, X7is selected from G, A, H, F, L, Y, T, P, Q, K, I, R, D, V, or S, X8is selected from E, T, I, R, H, Q, D, K, S, P, A, F, Y, V, G, L, or E, X9is selected from T, E, L, Y, F, P, Q, I, S, D, K, A, V, or H, and Xio is selected from Y, G, I, L, E, D, H, K, A, F, S, R, P, T, Q;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of XiX2X3X4X5X6X7X8X9Xio (SEQ ID NO: 4692); wherein Xi is selected from A, G, P, F, V, I, R, Q, H, A, T, S, Y, K, or L, X2is selected from I, H, K, G, L, P, F, A, V, T, E, Y, S, Q, D, or R, X3is selected from V, K, Y, F, G, Q, A, T, S, P, I, R, D, or L, X4is selected from W, P, Y, Q., G, T, D, H, R, K, S, L, I, V, F, or A, X5is selected from P, K, Y, F, G, I, L, T, Q, H, E, D, A, S, or V, Xg is selected from G,Q, E, P, L, F, K, I, S, A, D, R, H, or V, X7is selected from G, A, H, F, L, Y, T, P, Q, K, I, R, D, V, or S, Xg is selected from E, T, I, R, H, Q, D, K, S, P, A, F, Y, V, G, L, or E, Xg is selected from T, E, L, Y, F, P, Q, I, S, D, K, A, V, or H, and Xio is selected from Y, G, I, L, E, D, H, K, A, F, S, R, P, T, Q; andCDR3 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17 (SEQ ID NO: 4693);wherein Xi is selected from K, R, L, Y, T, I, Q, A, F, P, D, H, V, S, or E, X2 is selected from I, H, T, E, Q, S, L, K, D, G, Y, V, F, R, A, or P, X3is selected from F, E, K, A, R, Q, H, T, D, V, L, G, I, Y, or S, X4is selected from S, D, G, F, L, K, I, P, Y, V, A, or T, X5is selected from K, T, R, P, Y, S, E, I, L, H, D, F, V, A, or G, Xg is selected from T, K, A, F, S, G, D, P, H, I, Q, Y, L, or V, X7is selected from G, F, H, Y, I, L, T, E, P, R, S, Q, D, K, or A, X8is selected from T, E, G, V, S, Q, L, H, R, P, A, F, K, I, or Y, Xg is selected from Y, I, A, Q, G, E, F, D, K, L, S, T, R or V, Xio is selected from S, T, G, L, Q, A, I, K, E, H, D, V, R, P, F, or Y, Xn is selected from A, H, Y, V, R, F, G, L, D, E, T, I, K, P, or S, X12 is selected from S, T, I, D, H, V, R, P, L, K, G, Y, V, E, F, or A, X13 is selected from W, Q, F, H, D, S, K, I, T, E, G, R, L, Y, or A, XMis selected from E, R, P, I, T, A, F, D, S, H, V, K, L, G, Y, or Q, X15 is selected from Y, Q, L, G, V, P, K, E, I, R, H, D, or F, Xis is selected from D, L, E, F, P, R, T, I, S, Y, G, A, V, K, or H, and X17 is selected from F, S, T, Y, K, R, A, H, G, I, V, D, Q, P, E, or L; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17 (SEQ ID NO: 4693); wherein Xi is selected from K, R, L, Y, T, I, Q, A, F, P, D, H, V, S, or E, X2is selected from I, H, T, E, Q, S, L, K, D, G, Y, V, F, R, A, or P, X3is selected from F, E, K, A, R, Q, H, T, D, V, L, G, I, Y, or S, X4is selected from S, D, G, F, L, K, I, P, Y, V, A, orT, X5is selected from K, T, R, P, Y, S, E, I, L, H, D, F, V, A, or G, Xg is selected from T, K, A, F, S, G, D, P, H, I, Q, Y, L, or V, X7is selected from G, F, H, Y, I, L, T, E, P, R, S, Q, D, K, or A, Xg is selected from T, E, G, V, S, Q, L, H, R, P, A, F, K, I, or Y, X9is selected from Y, I, A, Q, G, E, F, D, K, L, S, T, R, or V, Xio is selected from S, T, G, L, Q, A, I, K, E, H, D, V, R, P, F, or Y, Xn is selected from A, H, Y, V, R, F, G, L, D, E, T, I, K, P, or S, X12 is selected from S, T, I, D, H, V, R, P, L, K, G, Y, V, E, F, or A, X13 is selected from W, Q., F, H, D, S, K, I, T, E, G, R, L, Y, or A, XMis selected from E, R, P, I, T, A, F, D, S, H, V, K, L, G, Y, or Q, X15 is selected from Y, Q, L, G, V, P, K, E, I, R, H, D, or F, Xig is selected from D, L, E, F, P, R, T, I, S, Y, G, A, V, K, or H, and X17 is selected from F, S, T, Y, K, R, A, H, G, I, V, D, Q, P, E, or L;c) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of XiX2X3X4X5XgX7XgX9XioXiiXi2Xi3Xi4Xi5XigXi7 (SEQ ID NO: 4693); wherein Xi is selected from K, R, L, Y, T, I, Q, A, F, P, D, H, V, S, or E, X2is selected from I, H, T, E, Q, S, L, K, D, G, Y, \J, F, R, A, or P, X3is selected from F, E, K, A, R, Q, H, T, D, V, L, G, I, Y, or S, X4is selected from S, D, G, F, L, K, I, P, Y, V, A, or T, X5is selected from K, T, R, P, Y, S, E, I, L, H, D, F, V, A, or G, Xg isselected from T, K, A, F, S, G, D, P, H, I, Q, Y, L, or V, X7is selected from G, F, H, Y, I, L, T, E, P, R, S, Q, D, K, or A, X8is selected from T, E, G, V, S, Q, L, H, R, P, A, F, K, I, or Y, X9is selected from Y, I, A, Q, G, E, F, D, K, L, S, T, R, or V, Xio is selected from S, T, G, L, Q, A, I, K, E, H, D, V, R, P, F, or Y, Xn is selected from A, H, Y, V, R, F, G, L, D, E, T, I, K, P, or S, Xu is selected from S, T, I, D, H, V, R, P, L, K, G, Y, V, E, F, or A, X is selected from W, Q, F, H, D, S, K, I, T, E, G, R, L, Y, or A, X14 is selected from E, R, P, I, T, A, F, D, S, H, V, K, L, G, Y, or Q, Xi5is selected from Y, Q, L, G, V, P, K, E, I, R, H, D, or F, Xi6is selected from D, L, E, F, P, R, T, I, S, Y, G, A, V, K, or H, and Xu is selected from F, S, T, Y, K, R, A, H, G, I, V, D, Q, P, E, or L.

80. The ISVD according to claim 79, in which:CDR1 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of SEQ ID NO: 1957;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 1957; andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of SEQ ID NO: 1957;andCDR2 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of SEQ ID NO: 2127;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 2127;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 2127;andCDR3 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of SEQ ID NO: 2337;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of SEQ ID NO: 2337;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of SEQ ID NO: 2337.

81. An ISVD that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), whereinCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2096, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2063, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2117, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2117, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2062, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2062, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2097, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2064, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2064, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2061, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2061, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2097, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2096, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2063, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2064, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2061, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2061, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2096, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2096, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2063, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2117, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2117, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2062, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2062, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2097, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2063, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2097, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2064, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2338; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2339; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2340; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2341; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2342; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2343; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2344; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2364; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2365; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2366; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2367; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2368; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2369; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2370; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2371; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2372; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2373; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2374; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2375; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2376; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2377; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2378; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2379; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2380; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2381; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2382; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2383; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2384; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2385; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2386; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2387; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2388; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1890; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2390; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4044; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3917; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4042; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4002; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3999; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3982; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3833; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4009; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4007; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4005; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3929; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4003; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3813; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3835; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3834; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3847; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3920; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3919; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4000; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4035; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4017; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4021; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4013; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4041; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4032; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4027; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4024; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4036; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3935; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4015; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4019; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4038; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4030; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4039; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4011; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4022; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3900; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3921; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4025; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4031; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3819; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3824; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4045; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3817; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3905; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3818; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4028; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4046; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3918; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3822; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3821; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4047; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3820; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2352; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2096, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2061, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2061, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2096, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2063, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2063, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2171, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3940; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2058, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2359; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2062, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2184, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3940; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2171, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2359; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2184, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2359; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2062, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2117, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2058, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3940; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2064, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2097, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2117, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2064, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2097, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3812; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2171, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2058, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2184, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2003, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2183, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3841; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4001; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3998; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3842; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3844; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2189, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1954, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1961, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1965, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1964, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1958, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2172, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1967, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1962, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1963, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1956, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1959, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1955, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1968, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1960, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2182, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2194, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2186, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2054, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2173, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2174, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2191, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2190, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2185, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2055, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2193, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2192, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2195, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2187, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2091, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2053, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2050, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1984, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1947, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1987, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1981, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1985, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1988, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1979, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1989, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1973, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1983, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1992, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1991, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1994, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1940, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1953, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2180, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1978, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1970, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1982, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1952, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1976, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1972, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1950, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1969, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1951, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1975, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1974, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1948, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1949, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1971, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1986, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1932, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2169, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2059, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2144, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2086, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2087, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2089, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2092, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2167, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2165, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2088, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2077, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2170, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2085, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2090, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2084, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2161, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2083, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1995, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2094, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1943, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2160, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2159, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2095, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2158, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2157, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2166, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2078, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2163, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2093, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2162, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2156, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2164, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2168, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2072, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2081, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2065, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2056, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2068, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2067, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2179, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2070, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2052, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2181, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2177, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2178, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2036, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2175, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2051, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1938, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2073, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1980, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2176, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2079, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2075, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2080, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2076, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2074, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2082, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2071, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2069, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2060, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2066, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2057, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1977, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1945, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2039, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2032, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1908, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2023, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2034, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2029, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2028, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2026, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1905, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2046, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2044, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2045, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2037, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2042, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2043, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2041, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2038, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2035, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1907, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2033, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2040, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1906, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2030, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1927, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2007, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2006, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1925, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1928, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1936, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1931, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2013, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3883, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2009, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1934, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2008, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1935, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1933, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1926, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1929, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1930, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2005, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1996, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2000, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1946, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1990, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1942, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1941, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1944, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1993, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1939, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2002, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1999, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1997, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2004, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2001, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1998, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2031, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1937, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1915, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1910, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1911, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1914, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1913, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1918, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2027, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2025, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1909, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2036, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2024, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1912, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1917, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1916, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1919, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2021, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1923, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2014, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2018, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2012, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1922, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1924, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2019, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2010, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1920, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2011, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2020, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2015, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2017, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2016, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2022, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1921, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2148, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2155, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4034; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3868; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3964; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3869; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4006; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4014; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3865; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3867; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4012; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4004; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2361; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2363; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2362; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3932; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2389; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4008; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3963; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4016; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4020; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3934; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4023; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3816; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4018; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1893; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4010; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4037; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4026; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4029; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4048; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4040; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3968; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4043; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2357; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3975; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2354; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3871; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3879; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3878; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3876; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3875; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2353; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2356; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3977; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3976; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2355; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3866; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3930; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3969; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3967; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3971; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3965; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2360; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3933; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2358; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3873; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3882; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3880; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2359; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3966; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3881; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3874; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3970; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3855; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3864; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3856; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 4033; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3850; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1891; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3990; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3994; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3996; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3892; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3992; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3993; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3988; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3991; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3987; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3851; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3958; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3997; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3950; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3995; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2153, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2149, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3840; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3849; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3848; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3989; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3845; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3838; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3839; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3846; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3843; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3836; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3852; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3837; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3948; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3949; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3953; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3941; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3858; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3863; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3938; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3859; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3861; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3853; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3946; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3862; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3860; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3937; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3857; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3936; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3940; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3956; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3973; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3944; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3960; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3943; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3942; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3961; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3962; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3959; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3945; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3954; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3939; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3951; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3952; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1892; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3854; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3974; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2351; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1966, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2119, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2121, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2115, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2114, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2118, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2120, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2103, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2108, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3813; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2129, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2104, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2109, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2110, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2113, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2106, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2116, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2125, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2124, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2111, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2125, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3937; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2122, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2126, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2123, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2141, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2112, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2133, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2139, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2132, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2138, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2099, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2134, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2150, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2145, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2147, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2146, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2151, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2154, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2152, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2102, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2140, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2136, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2098, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2107, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2108, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2101, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2128, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2137, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2105, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2130, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2143, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2142, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2131, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2100, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2135, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3981; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3978; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2188, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2337; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3986; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3984; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2350; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3980; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2345; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2348; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3979; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2346; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2349; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3985; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3983; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2347; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 1957, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2127, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3877.

82. An immunoglobulin single variable domain (ISVD) specifically binding to human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human PD-1 protein, wherein at least one amino acid residue located in at least one ofthe CDRs is capable of interacting with at least one amino acid residue in at least one, preferably in each, of the following stretches (of the ectodomain) of human PD-1 protein, when numbered in accordance with SEQ ID NO: 4703: W32, Y68-M70, K78, and I126-R139, preferably when the ISVD and human PD-1 protein are mixed in PBS1X buffer and crystallized by hanging drop vapor diffusion using 1 M Na Acetate, 1M (NH4)2HPO4, pH 4.5 at 19°C.

83. An immunoglobulin single variable domain (ISVD) specifically binding human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD comprises an amino acid residue capable of forming hydrogen bonds at at least one, preferably at all, of the following positions: 100, 100b (Kabat numbering) and optionally further at position 32, 52, 54, 57, 99 (Kabat numbering, preferably wherein the ISVD comprises at least one, preferably all of the following amino acid residues at the following positions: S100, Y100b (Kabat numbering) and optionally N32, S52, N54, T57, S99 (Kabat numbering).

84. An immunoglobulin single variable domain (ISVD) specifically binding to human PD-1 protein, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), wherein the ISVD binds to an (discontinuous) epitope on human PD-1, wherein the ISVD cross-blocks the binding to human PD-1 protein of a polypeptide with the amino acid sequence of SEQ ID Nos: 2857-3662 or wherein the ISVD is crossblocked from binding to human PD-1 protein by a polypeptide with the amino acid sequence of SEQ ID Nos: 2857-3662.

85. An immunoglobulin single variable domain (ISVD) specifically binding human PD-1, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR1 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of XiX^X^sXgXyXgMA (SEQ ID NO: 4608), wherein Xi is selected from G, T, D, F, S, R, E, H, I, A, V, or K, X2is selected from R, M, D, H, Y, F, V, L, Q, K, P, A, I, or G, wherein X3is selected from M, F, R, S, I, D, V, K, T, Y, A, E, or G, X4is selected from H, R, S, E, P, G, Q, K, A, D, T, V, I, F, Y, or L, X5is selected from S, T, K, G, I, Y, H, F, D, E, V, P, and L, X6is selected from I, V, S, K, E, D, Q, R, P, G, T, L, or F, X7is selected from N, G, V, E, L, I, Y, Q, T, F, P, or H, and Xg is selected from A, D, E, I, H, S, V, L, K, G, T, or Y;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of XiX2X3X4X5X6X7XglVIA (SEQ ID NO: 4608), wherein Xi is selected from G, T, D, F, S, R, E, H, I, A, V, orK, X2 is selected from R, M, D, H, Y, F, V, L, Q, K, P, A, I, or G, wherein X3 is selected from M, F, R, S, I, D, V, K, T, Y, A, E, or G, X4is selected from H, R, S, E, P, G, Q, K, A, D, T, V, I, F, Y, or L, X5is selected from S, T, K, G, I, Y, H, F, D, E, V, P, and L, X6is selected from I, V, S, K, E, D, Q, R, P, G, T, L, or F, X7is selected from N, G, V, E, L, I, Y, Q, T, F, P, or H, and Xg is selected from A, D, E, E, I, H, S, V, L, K, G, T, or Y; andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of X1X2X3X4X5X6X7X8MA (SEQ ID NO: 4608), wherein Xi is selected from G, T, D, F, S, R, E, H, I, A, V, or K, X2 is selected from R, M, D, H, Y, F, V, L, Q, K, P, A, I, or G, wherein X3 is selected from M, F, R, S, I, D, V, K, T, Y, A, E, or G, X4is selected from H, R, S, E, P, G, Q, K, A, D, T, V, I, F, Y, or L, X5is selected from S, T, K, G, I, Y, H, F, D, E, V, P, and L, X6is selected from I, V, S, K, E, D, Q, R, P, G, T, L, or F, X7is selected from N, G, V, E, L, I, Y, Q, T, F, P, or H, and Xg is selected from A, D, E, E, I, H, S, V, L, K, G, T, or Y;andCDR2 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of X^XsX^sXgXyXgXgXio (SEQ ID NO: 4609), wherein Xi is selected from L, V, I, T, F, E, Q, D, R, G, S, A, P, H, or K, X2is selected from I, G, Y, A, Q, H, T, L, S, D, R, K, or P, and X3is selected from S, G, L, V, K, F, I, T, E, A, D, H, P, Q, or R, X4is selected from W, L, K, S, Q, V, D, L, H, T, E, I, A, R, P, Y, G, or F, X5is selected from G, L, T, Y, R, V, P, Q, F, A, and S, Xg is selected from N, D, H, T, A, F, E, S, V, Q, I, L, R, Y, G, X7is selected from G, Q, F, S, I, H, R, E, V, P, L, D, T, or A, X8is selected from I, Q, T, L, P, V, Y, H, D, R, E, A, G, F, S, or K, X9is selected from T, L, D, Q, I, S, G, F, E, A, Y, P, V, or K, and X10 is selected from Y, P, R, T, G, A, S, Q, D, E, L, K, I, F, V, or H;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of XiX2X3X4X5X6X7X8X9Xio (SEQ ID NO: 4609), wherein Xi is selected from L, V, I, T, F, E, Q, D, R, G, S, A, P, H, or K, X2 is selected from I, G, Y, A, Q, H, T, L, S, D, R, K, or P, and X3 is selected from S, G, L, V, K, F, I, T, E, A, D, H, P, Q, or R, X4is selected from W, L, K, S, Q, V, D, L, H, T, E, I, A, R, P, Y, G, or F, X5is selected from G, L, T, Y, R, V, P, Q, F, A, and S, X6is selected from N, D, H, T, A, F, E, S, V, Q, I, L, R, Y, G, X7is selected from G, Q, F, S, I, H, R, E, V, P, L, D, T, or A, X8is selected from I, Q, T, L, P, V, Y, H, D, R, E, A, G, F, S, or K, X9is selected from T, L, D, Q, I, S, G, F, E, A, Y, P, V, or K, and X10 is selected from Y, P, R, T, G, A, S, Q, D, E, L, K, I, F, V, or Hc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of XiX2X3X4X5X6X7X8X9Xio (SEQ ID NO: 4609), wherein Xi is selected from L, V, I, T, F, E, Q, D, R, G, S, A, P, H, or K, X2 is selected from I, G, Y, A, Q, H, T, L, S, D, R, K, or P, and X3 is selected from S, G, L, V, K, F, I, T, E, A, D, H, P, Q, or R, X4is selected from W, L, K, S, Q, V, D, L, H, T, E, I, A, R, P, Y, G, or F, X5is selected from G, L, T, Y, R, V, P, Q, F, A, and S, X6is selected from N, D, H, T, A, F, E, S, V, Q, I, L, R, Y, G, X7is selected from G, Q, F, S, I, H, R, E, V, P, L, D, T, or A, X8is selected from I, Q, T, L, P, V, Y, H,D, R, E, A, G, F, S, or K, Xg is selected from T, L, D, Q, I, S, G, F, E, A, Y, P, V, or K, and Xio is selected from Y, P, R, T, G, A, S, Q, D, E, L, K, I, F, V, or H;andCDR3 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of X1X2X3X4X5X6X7X8X9X10 (SEQ ID NO: 4610), wherein Xi is selected from E, P, D, A, K, I, Y, H, R, F, S, T, V, G, or Q, X2is selected S, F, A, Y, E, I, D, K, G, R, P, Q, T, H, or L, and X3is selected Y, D, F, E, R, K, I, T, A, Q, S, V, H, G, or P, X4is selected from G, L, I, H, S, V, R, P, E, A, K, Y, T, F, A, D, H, or R, X5is selected from S, D, K, Y, A, L, I, P, V, Q, E, R, T, G, or F, Xg is selected from S, T, K, P, H, I, G, V, Q, R, D, L, or E, X7is selected from W, C, P, K, Y, V, F, A, I, T, L, H, G, Q, R, D, or E, X8is selected from Y, F, Q, P, K, T, R, D, I, E, L, H, V, A, G, or S, and Xg is selected from D, N, A, S, L, K, T, F, I, G, Y, R, V, E, or H, and X10 is selected from S, D, V, H, A, L, E, T, Y, K, F, I, Q, R, G, or P;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of XiX2X3X4X5X6X7X8X9Xio (SEQ ID NO: 4610), wherein Xi is selected from E, P, D, A, K, I, Y, H, R, F, S, T, V, G, or Q, X2is selected S, F, A, Y, E, I, D, K, G, R, P, Q, T, H, or L, and X3is selected Y, D, F, E, R, K, I, T, A, Q, S, V, H, G, or P, X4is selected from G, L, I, H, S, V, R, P, E, A, K, Y, T, F, A, D, H, or R, X5is selected from S, D, K, Y, A, L, I, P, V, Q, E, R, T, G, or F, X6is selected from S, T, K, P, H, I, G, V, Q, R, D, L, or E, X7is selected from W, C, P, K, Y, V, F, A, I, T, L, H, G, Q, R, D, or E, X8is selected from Y, F, Q, P, K, T, R, D, I, E, L, H, V, A, G, or S, and Xg is selected from D, N, A, S, L, K, T, F, I, G, Y, R, V, E, or H, and X10 is selected from S, D, V, H, A, L, E, T, Y, K, F, I, Q, R, G, or P;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of XiX2X3X4X5X6X7X8X9Xio (SEQ ID NO: 4610), wherein Xi is selected from E, P, D, A, K, I, Y, H, R, F, S, T, V, G, or Q, X2is selected S, F, A, Y, E, I, D, K, G, R, P, Q, T, H, or L, and X3is selected Y, D, F, E, R, K, I, T, A, Q, S, V, H, G, or P, X4is selected from G, L, I, H, S, V, R, P, E, A, K, Y, T, F, A, D, H, or R, X5is selected from S, D, K, Y, A, L, I, P, V, Q, E, R, T, G, or F, X6is selected from S, T, K, P, H, I, G, V, Q, R, D, L, or E, X7is selected from W, C, P, K, Y, V, F, A, I, T, L, H, G, Q, R, D, or E, X8is selected from Y, F, Q, P, K, T, R, D, I, E, L, H, V, A, G, or S, and Xg is selected from D, N, A, S, L, K, T, F, I, G, Y, R, V, E, or H, and X10 is selected from S, D, V, H, A, L, E, T, Y, K, F, I, Q, R, G, or P.

86. An immunoglobulin single variable domain (ISVD) specifically binding human PD-1, that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), in which:CDR1 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of GRXHSINAMA (SEQ ID NO: 4704), wherein X is selected from M, V and T;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRXHSINAMA (SEQ ID NO: 4704), wherein X is selected from M, V and T;c) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequences of GRXHSINAMA (SEQ ID NO: 4704), wherein X is selected from M, V and T;and- CDR2 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of LISWGXGITY (SEQ ID NO: 4705), wherein X is selected from N and F; b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of LISWGXGITY (SEQ ID NO: 4705), wherein X is selected from N and F; c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of LISWGXGITY (SEQ ID NO: 4705), wherein X is selected from N and F;and- CDR3 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of ESYGXSWYDS (SEQ ID NO: 4706); wherein X is selected from S and A;b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of ESYGXSWYDS (SEQ ID NO: 4706); wherein X is selected from S and A;c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of ESYGXSWYDS (SEQ ID NO: 4706); wherein X is selected from S and A.

87. The ISVD according to claim 86, in which:CDR1 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of GRMHSINAMA (SEQ ID NO: 2498);b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRMHSINAMA (SEQ ID NO: 2498); andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of GRMHSINAMA (SEQ ID NO: 2498);andCDR2 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of LISWGNGITY (SEQ ID NO: 2451); b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of LISWGNGITY (SEQ ID NO: 2451); c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of LISWGNGITY (SEQ ID NO: 2451);andCDR3 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of ESYGSSWYDS (SEQ ID NOs: 2804);b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of ESYGSSWYDS (SEQ ID NOs: 2804);c) amino acid sequences that have 3, 1, or 1 amino acid difference with the amino acid sequence of ESYGSSWYDS (SEQ ID NOs: 2804).

88. The ISVD according to claim 86, in which:CDR1 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of GRVHSINAMA (SEQ ID NO: 2552);b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of GRVHSINAMA (SEQ ID NO: 2552); andc) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequences of GRVHSINAMA (SEQ ID NO: 2552);andCDR2 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of LISWGFGITY (SEQ ID NO: 2652);b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of LISWGFGITY (SEQ ID NO: 2652);c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of LISWGFGITY (SEQ ID NO: 2652);andCDR3 (AbM definition) has an amino acid sequence selected from:a) the amino acid sequence of ESYGASWYDS (SEQ ID NOs: 2741);b) amino acid sequences that have at least 80% amino acid identity with the amino acid sequence of ESYGASWYDS (SEQ ID NOs: 2741);c) amino acid sequences that have 3, 2, or 1 amino acid difference with the amino acid sequence of ESYGASWYDS (SEQ ID NOs: 2741).

89. An ISVD that essentially consists of 4 framework regions (FR1 to FR4, respectively) and 3 complementarity determining regions (CDR1 to CDR3, respectively), whereinCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2453, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2456, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2559, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 3810, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2455, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2556, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2560, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2557, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2450, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2561, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2454, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2558, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2458, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2460, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2553, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2459, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2554, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2464, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2466, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2462, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2465, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2457, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2463, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2461, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2470, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2549, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2550, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2471, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2468, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2552, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2472, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2551, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2555, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2467, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2469, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2473, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2542, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2547, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2476, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2543, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2480, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2544, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2540, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2477, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2475, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2548, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2545, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2538, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2474, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2546, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2541, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2535, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2486, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2482, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2484, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2537, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2483, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2481, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2815; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2536, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2478, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2479, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2539, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2481, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2487, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2485, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2534, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2528, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2490, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2489, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2529, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2530, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2531, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2492, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2533, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2532, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2488, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2494, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2525, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2491, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2495, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2526, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2524, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2527, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2493, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2521, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2496, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2497, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2512, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2511, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2516, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2515, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2520, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2605, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2522, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2517, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2518, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2514, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2519, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2523, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2499, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2502, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2503, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2504, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2500, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2505, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2509, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2508, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2510, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2501, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2513, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2507, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2506, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2451, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2698, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2569, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2699, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2564, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2562, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2705, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2695, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2697, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2566, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2700, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2563, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2706, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2565, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2570, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2572, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2701, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2571, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2619, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2575, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2704, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2694, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2702, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2568, CDR3 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2804; or in whichCDR1 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2498, CDR2 (AbM definition) consists of the amino acid sequence of SEQ ID NO: 2703, CDR3 (AbM d...

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