Compositions, doses, and methods for treatment of c1s mediated diseases and disorders

Abstract

Provided for herein are compositions, doses, and methods of using an antibody, or an antigen-binding fragment thereof, for the treatment of C1s mediated diseases or disorders.

Description

Attorney Docket No. DIN-005WO PATENTCOMPOSITIONS, DOSES, AND METHODS FOR TREATMENT OF CIS MEDIATED DISEASES AND DISORDERSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 701,870, filed October 1, 2024, which is hereby incorporated by reference in its entirety.FIELD

[0002] Embodiments provided herein related to compositions, doses, and methods for the treatment of Cis mediated diseases and disorders.BACKGROUND

[0003] The complement system is a well-known effector mechanism of the innate immune response, providing not only protection against pathogens and other harmful agents but also recovery from injury. Complement activation due to autoantibodies and alloantibodies can lead to damage to normal cells or rejection of transplanted tissue. The complement pathway comprises a number of proteins that typically exist in the body in inactive form. The classical complement pathway is triggered by activation of the first component of complement, referred to as the Cl complex, which consists of Clq, Clr, and Cis proteins. Upon binding of Cl to an immune complex or other activator, the Cis component, a diisopropyl fluorophosphate (DFP)- sensitive serine protease, cleaves complement components C4 and C2 to initiate activation of the classical complement pathway. The classical complement pathway appears to play a role in many diseases and disorders. For example, sutimlimab (TNT009), marketed as EnJaymo®, is an antibody that inhibits Cis for treatment of hemolysis in adults with cold agglutinin disease. However, sutimlimab binds to both the active form of Cis, and the inactive zymogen proCis, and due to the lack of specificity of sutimlimab for either form of Cis, a very high dose must be administered to overcome circulating levels of proCis, and may limit the clinical use of sutimlimab. Therefore, there is a need in the art for compounds that treat a complement classical pathway-mediated disease or disorder with specificity for active forms of the complement proteins and pharmaceutically acceptable formulations to safely and effectively store and administer these compounds in a therapeutic setting. The embodiments provided for herein satisfy these needs as well as others.SUMMARY1IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0004] In some embodiments, antibodies, or an antigen-binding fragments thereof, are provided comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 1; and the VL comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 2, wherein the VH comprises a mutation at one or more of the following positions: G26, F27, T28, F28, S30, D31, Y32, Y33, M34, S35, Y50, 151, S52, R53, S54, G55, S56, T57, K58, Y59, Y60, A61, D62, S63, V64, K65, G66, A97, R98, D99, E100, N101, Y102, A103, L104, D105, or W106, and wherein the VL comprises a one or more mutations at position selected from the group consisting of: Q24, A25, S26, Q27, D28, 129, S30, N31, Y32, L33 N34, D50, A51, S52, N53, L54, E55, T56, Q89, H90, Y91, E92, D93, Y94, P95, L96, or T97.

[0005] In some embodiments, antibodies, or an antigen-binding fragments thereof, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, I51S, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof, as compared to SEQ ID NO: 1; and the VL comprises one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof, as compared to SEQ ID NO: 2, wherein at least one of the VH and the VL is a variant of the VH comprising the amino acid sequence of SEQ ID NO: 1 and the VL is a variant of the VL comprising the amino acid sequence of SEQ ID NO: 2.

[0006] Also provided herein are compositions and methods of using the same.BRIEF DESCRIPTION OF DRAWINGS

[0007] FIG. 1A-1F represent Cis binding affinities of the variant antibodies provided herein (“+” indicates improved binding,indicates decreased binding, andindicates comparable binding).

[0008] FIG. 2 shows binding sensograms of the variant antibodies provided herein.

[0009] FIG. 3A-3C show binding sensograms of the variant antibodies provided herein at pH 6 or pH 7.4.DETAILED DESCRIPTION

[0010] Provided herein are binding proteins, e.g., antibodies, or antigen-binding fragments thereof, that selectively bind to Cis and have low binding to the zymogen proCis. In some embodiments, the2IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT antibodies inhibit activation of the classical complement pathway and can be used in methods to treat complement mediated disorders, such as, but not limited to those provided for herein. In some embodiments, the selectivity for Cis over proCis can be used to reduce or prevent target mediated clearance of the therapeutic antibody, thus requiring lower doses and frequency of administration of the antibody.

[0011] Also provided herein are pharmaceutical compositions of antibodies that bind and modulate the activity of Cis. The antibodies can be used, for example, to treat Cis mediated disorders.

[0012] It is to be understood that the embodiments described herein are not limited to particular formulations, compositions and experimental conditions disclosed, as such formulations, compositions, and experimental conditions may vary. It is also to be understood that the terminology used herein is only for the purpose of describing particular embodiments, and it is not intended to be limiting.

[0013] The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure.

[0014] Those of ordinary skill in the art will understand that given the amino acid sequence of a variable region of the binding molecules (e.g., antibodies) set forth herein can determine the CDR sequences therein by these or any other conventions used to define CDR, such as, for example, IMGT, Kabat, Chothia, or Contact using web-based tools are available for determining the CDRs in such variable regions based on any known convention. Such tools include those found at www.abysis.org / abysis / sequence_input / key_annotation / key_ nnot tion.cgi and at www.novoprolabs.com / tools / cdr. Accordingly, the disclosure herein of a set of three CDRs in a heavy or light chain variable region based upon one CDR convention is considered the equivalent of that same set of CDRs as determined by any other convention, which can be referred to as “convention equivalents” or “convention equivalent CDRs”.

[0015] Furthermore, the formulations, compositions, and experimental conditions described herein, unless otherwise indicated, use conventional molecular and cellular biological and immunological techniques known within the skill of the art. Such techniques are well known to the skilled worker, and are explained fully in the literature. See, e.g., Ausubel, et al., ed., Current Protocols in Molecular Biology, John Wiley & Sons, Inc., NY, N.Y. (1987-2008), including all supplements, Molecular Cloning: A Laboratory Manual (Fourth Edition), by MR Green and J. Sambrook and Harlow et al., Antibodies: A Laboratory Manual, Chapter 14, Cold Spring Harbor Laboratory, Cold Spring Harbor (2013, 2ndedition).3IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0016] Unless otherwise defined, scientific and technical terms used herein have the meanings that are commonly understood by those of ordinary skill in the art. In the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The use of “or” means “and / or” unless stated otherwise. The use of the term “including,” as well as other forms, such as “includes” and “included,” is not limiting.

[0017] Generally, nomenclature used in connection with cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein is well-known and commonly used in the art. The methods and techniques provided herein are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. Enzymatic reactions are performed according to manufacturer’s specifications, as commonly accomplished in the art or as described herein. The nomenclatures used in connection with and the laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art.

[0018] Unless otherwise required by context, singular’ terms shall include pluralities, and plural terms shall include the singular.

[0019] As used herein, the terms “a” or “and” means that “at least one” or “one or more” unless the context clearly indicates otherwise.

[0020] As used herein, the term “about” means that the numerical value is approximate and small variations would not significantly affect the practice of the disclosed embodiments. Where a numerical limitation is used, unless indicated otherwise by the context, “about” means the numerical value can vary by ±10% and remain within the scope of the disclosed embodiments. Additionally, where a phrase recites “about x to y”, the term “about” modifies both x and y and can be used interchangeably with the phrase “about x to about y” unless context dictates differently.

[0021] As used herein, the terms “comprising” (and any form of comprising, such as “comprise”, “comprises” and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. Any step or composition that uses the transitional phrase4IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT of “comprise” or “comprising” can also be said to describe the same with the transitional phase of “consisting of’ or “consists of.” Further, the singular forms “a” or “an” or “the” include plural references unless the context clearly dictates otherwise. For example, reference to “comprising a therapeutic agent” includes one or a plurality of such therapeutic agents. The term “or” refers to a single element of stated alternative elements, unless the context clearly indicates otherwise. For example, the phrase “A or B” refers to A alone or B alone. The phrase “A, B, or a combination thereof’ refers to A alone, B alone, or a combination of A and B. Similarly, “one or more of A and B” refers to A, B, or a combination of both A and B. The phrase “A and B” refers to a combination of A and B. Furthermore, the various elements, features and steps discussed herein, as well as other known equivalents for each such element, feature or step, can be mixed and matched by one of ordinary skill in this art to perform methods in accordance with principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in particular examples.

[0022] A “disease” in an animal is a state of health wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate. In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Eeft untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0023] ‘ ‘Parenteral” administration of a composition includes, e.g., subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intracisternal injection, intrathecal, or infusion techniques.

[0024] The term “therapeutic” as used herein means a treatment and / or prophylaxis. A therapeutic effect is obtained by suppression, remission, or eradication of a disease state.

[0025] Throughout this disclosure, various aspects of the embodiments can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3, to 6 etc., as well as the individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. Unless otherwise explicitly stated to the contrary, a range that is disclosed also includes the endpoints of the range.5IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0026] The term “composition” as used herein means a product which results from the mixing or combining of more than one element or ingredient.

[0027] As used herein, the term “pharmaceutical composition” refers to a medicinal or pharmaceutical formulation that contains an active ingredient as well as one or more excipients and diluents to enable the active ingredient suitable for the method of administration.

[0028] The term “carrier” as used herein encompasses carriers, excipients, and diluents, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical, cosmetic or other agent across a tissue layer.

[0029] The phrase “pharmaceutically acceptable” is employed herein to refer to those agents of interest / compounds, salts, compositions, pharmaceutical dosage forms, etc., which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and / or other mammals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable bcncfit / risk ratio. In some embodiments, pharmaceutical acceptable means approved by a regulatory agency of the federal or a state government, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for the use in animals (e.g., mammals), and more particularly, in humans.

[0030] As used herein, the term “pharmaceutically acceptable carrier” refers to an excipient or diluent in a pharmaceutical composition. The pharmaceutically acceptable carrier must be compatible with the other ingredients of the formulation and not deleterious to the recipient. The nature of the carrier differs with the mode of administration. For example, for intravenous administration, an aqueous solution carrier is generally used; for oral administration, a solid carrier is generally used.

[0031] As used herein, “stable” a “stable composition” or a “stable pharmaceutical composition” refers to a composition or pharmaceutical composition that maintains one or more of the characteristics of the composition within a defined margin when subject to various stressors such as, but not limited to, heat, agitation, light, temperature, humidity, repeated freeze thaw cycles, and extended storage. Such characteristics include, but are not limited to, pH, presence of aggregates, functional titer, or concentration of protein excipient. In some embodiments, the defined margins for pH, presence of aggregates, functional titer, or concentration of protein excipient are as provided for herein.

[0032] As used herein, the term “antibody” refers to any form of antibody that exhibits the desired biological activity. Thus, it is used in the broadest sense and specifically covers, but is not limited to,6IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT monoclonal antibodies (including full length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), humanized, fully human antibodies, chimeric antibodies and camelized single domain antibodies. An antibody consists of four polypeptide chains; two heavy chains (CHI and CH2) and two light chains (CLI and CL2) connected by disulfide bonds. Each chain is a series of domains: Light chains consist of one variable domain (VL) and one constant domain (CL), while heavy chains contain one variable domain (VH) and three to four constant domains (CHI, CH2, CH3, CH4). “Parental antibodies” are antibodies obtained by exposure of an immune system to an antigen prior to modification of the antibodies for an intended use, such as humanization of an antibody for use as a human therapeutic antibody.

[0033] As used herein, unless otherwise indicated, “antibody fragment” or “antigen-binding fragment” refers to antigen-binding fragments of antibodies, i.e. antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g. fragments that retain one or more CDR regions. Examples of antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodics; linear antibodies; single-chain antibody molecules, e.g., sc-Fv; nanobodics and multispecific antibodies formed from antibody fragments.

[0034] A “Fab fragment” is comprised of one light chain and the CHI and variable regions of one heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0035] An “Fc” region contains two heavy chain fragments comprising the CHI and CH2 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.

[0036] As used herein, the term “fused” or “linked” when used in reference to a protein having different domains or heterologous sequences means that the protein domains are part of the same peptide chain that are connected to one another with either peptide bonds or other covalent bonding. The domains or section can be linked or fused directly to one another or another domain or peptide sequence can be between the two domains or sequences and such sequences would still be considered to be fused or linked to one another. In some embodiments, the various domains or proteins provided for herein are linked or fused directly to one another or a linker sequences, such as a glycine / serine, glycine / alanine linker or other types of peptide linkers generally known to link the two domains together. Two peptide sequences are linked directly if they are directly connected to one another or indirectly if there is a linker7IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT or other structure that links the two regions. A linker can be directly linked to two different peptide sequences or domains.

[0037] A “Fab1fragment” contains one light chain and a portion or fragment of one heavy chain that contains the VH domain and the CHI domain and also the region between the CHI and CH2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form a F(ab') 2 molecule.

[0038] A “F(ab')2 fragment” contains two light chains and two heavy chains containing a portion of the constant region between the Cui and Cn2 domains, such that an interchain disulfide bond is formed between the two heavy chains. A F(ab') 2 fragment thus is composed of two Fab' fragments that are held together by a disulfide bond between the two heavy chains.

[0039] The “Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.

[0040] The term “single-chain Fv” or “scFv” antibody refers to antibody fragments comprising the VH and VL domains of an antibody, wherein these domains arc present in a single polypeptide chain. Generally, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the scFv to form the desired structure for antigen-binding. For a review of scFv, see Pluckthun (1994) THE PHARMACOLOGY OF MONOCLONAL ANTIBODIES, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315. See also, International Patent Application Publication No. WO 88 / 01649 and U.S. Pat. Nos. 4,946, 778 and 5,260,203.

[0041] A “domain antibody” is an immunologically functional immunoglobulin fragment containing only the variable region of a heavy chain or the variable region of a light chain. In some instances, two or more VH regions are covalently joined with a peptide linker to create a bivalent domain antibody. The two VH regions of a bivalent domain antibody may target the same or different antigens.

[0042] A “bivalent antibody” comprises two antigen-binding sites. In some instances, the two binding sites have the same antigen specificities. However, bivalent antibodies may be bispecific (see below).

[0043] A “single-domain antibody” is an immunologically functional immunoglobulin fragment containing only the variable region of a heavy chain or the variable region of a light chain. In some instances, two or more Vnregions are covalently joined with a peptide linker to create a bivalent domain antibody.

[0044] In some embodiments, as provided for herein, antibody molecules can be monospecific (e.g., monovalent or bivalent), bispecific (e.g., bivalent, bivalent, tetravalent, pentavalent, or hexavalent),8IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT trispecific (e.g., trivalent, tetravalent, pentavalent, hexavalent), or with higher orders of specificity (e.g., tetraspecific) and / or higher orders of valency beyond hexavalency. An antibody molecule can comprise a functional fragment of a light chain variable region and a functional fragment of a heavy chain variable region, or heavy and light chains may be fused together into a single polypeptide.

[0045] In certain embodiments, monoclonal antibodies herein also include camelized single domain antibodies. See, e.g., Muyldermans et al. (2001) Trends Biochem. Sci. 26:230; Reichmann et al. (1999) J. Immunol. Methods 231:25; WO 94 / 04678; WO 94 / 25591; U.S. Pat. No. 6,005,079). In one embodiment, the present invention provides single domain antibodies comprising two Vn domains with modifications such that single domain antibodies are formed.

[0046] As used herein, the term “diabodies” refers to small antibody fragments with two antigenbinding sites, which fragments comprise a heavy chain variable domain (VH) connected to a light chain variable domain (VL) in the same polypeptide chain (VH-VL or VL-VH). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies arc described more fully in, e.g., EP 404,097; WO 93 / 11161; and Holliger et al. (1993) Proc. Natl. Acad. Sci. USA 90: 6444-6448. For a review of engineered antibody variants generally see Holliger and Hudson (2005) Nat. Biotechnol. 23:1126-1136.

[0047] Typically, a variant antibody or antigen-binding fragment of the antibodies provided herein retain at least 10% of its Cis binding activity (when compared to a parental antibody that is modified) when that activity is expressed on a molar basis. In some embodiments, a variant antibody (or antigen fragment thereof), or antigen-binding fragment of an antibody provided herein, retains at least 20%, 50%, 70%, 80%, 90%, 95% or 100% or more of the Cis binding affinity as the parental antibody. As described herein, it is also intended that an antibody or antigen-binding fragment of the invention can include conservative or non-conservative amino acid substitutions, which can also be referred to as “conservative variants” or “function conserved variants” of the antibody, that do not substantially alter its biologic activity.

[0048] ‘ ‘Isolated antibody” refers to the purification status of a binding compound and in such context means the molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other material such as cellular debris and growth media. Generally, the term “isolated” is not intended to refer to a complete absence of such material or to an absence of water,9IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT buffers, or salts, unless they are present in amounts that substantially interfere with experimental or therapeutic use of the binding compound as described herein.

[0049] The term “monoclonal antibody”, as used herein, refers to population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations and / or post-translational modifications that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains, particularly their CDRs, that are often specific for different epitopes. The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The “monoclonal antibodies” may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581- 597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0050] As used herein, a “chimeric antibody” is an antibody having the variable domain from a first antibody and constant domain from a second antibody, where the first and second antibodies are from different species. (U.S. Pat. No. 4,816,567; and Morrison et al., (1984) Proc. Natl. Acad. Sci. USA 81: 6851-6855). Typically, the variable domains are obtained from an antibody from an experimental animal (the “parental antibody”), such as a rodent, and the constant domain sequences are obtained from human antibodies, so that the resulting chimeric antibody will be less likely to elicit an adverse immune response in a human subject than the parental (e.g. rodent) antibody.

[0051] As used herein, the term “humanized antibody” refers to forms of antibodies that contain sequences from both human and non-human (e.g., murine, rat) antibodies. In general, the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or substantially all of the framework (FR) regions are those of a human immunoglobulin sequence. The humanized antibody may optionally comprise at least a portion of a human immunoglobulin constant region (Fc).10IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0052] The term “fully human antibody” refers to an antibody that comprises human immunoglobulin protein sequences only. A fully human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, “mouse antibody” refers to an antibody that comprises mouse immunoglobulin sequences only. Alternatively, a fully human antibody may contain rat carbohydrate chains if produced in a rat, in a rat cell, or in a hybridoma derived from a rat cell. Similarly, “rat antibody” refers to an antibody that comprises rat immunoglobulin sequences only.

[0053] In some embodiments, the basic antibody structural unit comprises a tetramer. Each tetramer includes two identical pairs of polypeptide chains, each pair having one “light” (about 25 kDa) and one “heavy” chain (about 50-70 kDa). The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxyterminal portion of the heavy chain may define a constant region primarily responsible for effector function. Typically, human light chains are classified as kappa and lambda light chains. Furthermore, human heavy chains arc typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Within light and heavy chains, the variable and constant regions are joined by a “J” region of about 12 or more amino acids, with the heavy chain also including a “D” region of about 10 more amino acids. See generally, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989).

[0054] The variable regions of each light / heavy chain pair form the antibody binding site. Thus, in general, an intact antibody has two binding sites. However, in bifunctional or bispecific antibodies, the two binding sites are, in general, not the same.

[0055] Typically, the variable domains of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, from N-terminal to C-terminal, both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.', National Institutes of Health, Bethesda, Md.; 5thed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883.11IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0056] As used herein, the term “hypervariable region” refers to the amino acid residues of an antibody that are responsible for antigen-binding. The hypervariable region comprises amino acid residues from a “complementarity determining region” or “CDR” (z.e. residues 24-34 (CDRL1), 50-56 (CDRL2) and 89-97 (CDRL3) in the light chain variable domain and residues 31-35 (CDRH1), 50-65 (CDRH2) and 95-102 (CDRH3) in the heavy chain variable domain; Kabat et al. (1991) Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md.) and / or those residues from a “hypervariable loop” (i.e. residues 26-32 (CDRL1), 50-52 (CDRL2) and 91-96 (CDRL3) in the light chain variable domain and 26-32 (CDRH1), 53-55 (CDRH2) and 96-101 (CDRH3) in the heavy chain variable domain; Chothia and Lesk (1987) J. Mol. Biol. 196: 901-917). The CDRs can also be referenced according to the IMGT system for the identification of CDRs, which is described in Lefranc MP. Unique database numbering system for immunogenetic analysis. Immunol Today (1997) 18:509. As used herein, the term “framework” or “FR” residues refers to those variable domain residues other than the hypervariable region residues defined herein as CDR residues. CDRs provide the majority of contact residues for the binding of the antibody to the antigen or epitope. CDRs of interest can be derived from donor antibody variable heavy and light chain sequences, and include analogs of the naturally occurring CDRs, which analogs also share or retain the same antigen-binding specificity and / or neutralizing ability as the donor antibody from which they were derived.

[0057] As used herein, “specific binding” or “immuno specific binding” or “binds immunospecifically” refer to antibody binding to a predetermined antigen at a much higher affinity than for another antigen(s) (e.g. selectively binds the active form of complement component Cis as compared to inactive Cis, which can also be referred to as proCis zymogen). In some embodiments, the antibody binds the predetermined antigen with a dissociation constant (KD) of 10’7M or less, and such Kois at least twofold less than its KD for binding to a non-specific antigen (e.g., BSA, casein, or another non-specific polypeptide).

[0058] The phrases “an antibody recognizing Cis” and “an antibody specific for Cis” are used interchangeably herein with the term “an antibody which binds immunospecifically to Cis.” In some embodiments, the antibody binds specifically or preferentially to Cis, such as the active form of Cis over other proteins, such as, but not limited to, the inactive form of Cis (proCis). The degree of specificity necessary for an anti-Cls antibody may depend on the intended use of the antibody, and at any rate is defined by its suitability for use for an intended purpose. In some embodiments, the antibody, or binding compound derived from the antigen-binding site of an antibody, of the contemplated method12IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT binds to its antigen (active form of Cis), with an affinity that is at least two-fold greater, at least ten times greater, at least 20-times greater, or at least 100-times greater than the affinity with any other antigen, including, but not limited to inactive Cis.

[0059] Methods for determining mAb specificity and affinity by competitive inhibition can be found in Harlow, et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1988), Colligan et al., eds., Current Protocols in Immunology, Greene Publishing Assoc, and Wiley Interscience, N.Y., (1992, 1993), and Muller, Meth. Enzymol. 92:589 601 (1983), which references are entirely incorporated herein by reference.

[0060] The term “homolog” means protein sequences having between 40% and 100% sequence identity to a reference sequence. Percent identity between two peptide chains can be determined by pair wise alignment using the default settings of the AlignX module of Vector NTI v.9.0.0 (Invitrogen Corp., Carlsbad, Calif.) or other suitable alignment software, such as BLAST. In some embodiments, the antibody, or antigen-binding fragment thereof has, at least 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% homology or identity to a sequence described herein. In some embodiments, the antibody has conservative substitutions as compared to a sequence described herein. Exemplary conservative substitutions are illustrated in Table 1 and are encompassed within the scope of the disclosed subject matter. The conservative substitution may reside in the framework regions, or in antigen-binding sites, as long they do not adversely affect the properties of the antibody. Substitutions may be made to improve antibody properties, for example stability or affinity. Conservative substitutions will produce molecules having functional and chemical characteristics similar to those molecules into which such modifications are made. Exemplary amino acid substitutions are shown in the table below.

[0061] Table 1: Exemplary Conservative Substitutions13IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0062] In some embodiments, valiants of the proteins and peptides provided herein are provided. In some embodiments, a variant comprises a substitution, deletions, or insertion. In some embodiments, the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) substitutions. As described herein, the substitutions can be conservative substitutions. In some embodiments, the substitution is nonconservative. In some embodiments, the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) deletions. In some embodiments, the variant comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 (e.g., 1-10) insertions. In some embodiments, the substitutions, deletions, or insertions are present in the CDRs provided for herein. In some embodiments, the substitutions, deletions, or insertions are not present in the CDRs provided for herein.

[0063] The term “in combination with” as used herein means that the described agents can be administered to an animal or subject together in a mixture, concurrently as single agents or sequentially as single agents in any order.

[0064] The term “epitope” is meant to refer to that portion of any molecule capable of being recognized by and bound by an antibody at one or more of the Ab’s antigen-binding regions. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three-dimensional structural characteristics as well as specific charge characteristics.

[0065] “Expression vector” refers to a vector comprising a recombinant polynucleotide comprising expression control sequences operatively linked to a nucleotide sequence to be expressed. An expression vector comprises sufficient cis-acting elements for expression; other elements for expression can be supplied by the host cell or in an in vitro expression system. Expression vectors include all those known in the art, such as cosmids, plasmids (e.g., naked or contained in liposomes) and viruses (e.g., Sendai viruses, lentiviruses, retroviruses, adenoviruses, and adeno-associated viruses) that incorporate the recombinant polynucleotide.14IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0066] In some embodiments, the antibody is a monoclonal antibody which binds to Cis. The sequence of active Cis is as follows (SEQ ID NO: 1238): residues 1-15 (SEQ ID NO: 1239) constitute the signal peptide which is cleaved during translation, and residues 16-688 (SEQ ID NO: 1240) constitute the mature protein.MWCIVLFSLLAWVYAEPTMYGEILSPNYPQAYPSEVEKSWDIEVPEGYGIHLYFTHLDIELSE NCAYDSVQI ISGDTEEGRLCGQRSSNNPHSP IVEEFQVPYNKLQVIFKSDFSNEERFTGFAAY YVATDINECTDFVDVPCSHFCNNFIGGYFCSCPPEYFLHDDMKNCGVNCSGDVFTALIGEIAS PNYPKPYPENSRCEYQIRLEKGFQVWTLRREDFDVEAADSAGNCLDSLVFVAGDRQFGPYCG HGFPGPLNIETKSNALDI IFQTDLTGQKKGWKLRYHGDPMPCPKEDTPNSVWEPAKAKYVFRD WQITCLDGFEWEGRVGATSFYSTCQSNGKWSNSKLKCQPVDCGIPESIENGKVEDPESTLF GSVIRYTCEEPYYYMENGGGGEYHCAGNGSWVNEVLGPELPKCVPVCGVPREPFEEKQRI IGG SD AD I KNF P WQVF F DNP WAGGAL I NE YWVL T AAHWE GNRE P TMYVG S T S VQT S RL AKS KML T PEHVFIHPGWKLLEVPEGRTNFDNDIALVRLKDPVKMGPTVSP ICLPGTSSDYNLMDGDLGLI SGWGRTEKRDRAVRLKAARLPVAPLRKCKEVKVEKPTADAEAYVFTPNMICAGGEKGMDSCKG DSGGAFAVQDPNDKTKFYAAGLVSWGPQCGTYGLYTRVKNYVDWIMKTMQENSTPRED (SEQ ID NO: 1238);MWCIVLFSLLAWVYA (SEQ ID NO: 1239);EPTMYGEILSPNYPQAYPSEVEKSWDIEVPEGYGIHLYFTHLDIELSENCAYDSVQI ISGDTE EGRLCGQRSSNNPHSP IVEEFQVPYNKLQVIFKSDFSNEERFTGFAAYYVATDINECTDFVDV PCSHFCNNFIGGYFCSCPPEYFLHDDMKNCGVNCSGDVFTALIGEIASPNYPKPYPENSRCEY QIRLEKGFQVWTLRREDFDVEAADSAGNCLDSLVFVAGDRQFGPYCGHGFPGPLNIETKSNA LDI IFQTDLTGQKKGWKLRYHGDPMPCPKEDTPNSVWEPAKAKYVFRDWQITCLDGFEWEG RVGATSFYSTCQSNGKWSNSKLKCQPVDCGIPESIENGKVEDPESTLFGSVIRYTCEEPYYYM ENGGGGEYHCAGNGSWVNEVLGPELPKCVPVCGVPREPFEEKQRI IGGSDADIKNFPWQVFFD NPWAGGALINEYWVLTAAHWEGNREPTMYVGSTSVQTSRLAKSKMLTPEHVFIHPGWKLLEV PEGRTNFDNDIALVRLKDPVKMGPTVSP ICLPGTSSDYNLMDGDLGLISGWGRTEKRDRAVRL KAARLPVAPLRKCKEVKVEKPTADAEAYVFTPNMICAGGEKGMDSCKGDSGGAFAVQDPNDKT KFYAAGLVSWGPQCGTYGLYTRVKNYVDWIMKTMQENSTPRED (SEQ ID NO: 1240).

[0067] The difference between inactive Cis and active Cis is that inactive proCis is cleaved at the peptide bond between R437 and 1438 and undergoes a conformational change. The two fragments generated by this cleavage remain associated by a disulfide bond. Without wishing to be bound by a particular theory, proCis is a single chain 86,000 Da protein that is the native form of Cis proteins (e.g., serine protease). Cis is a subunit of the Cl complex which is the first complement component in the cascade referred to as the classical pathway of complement. ProCis is an inactive zymogen until Cl is activated. Cl complex binds to and is activated by antigen- antibody complexes (immune complexes) yielding Clr enzyme. Clr enzyme in the Cl complex activates proCis generating Cis enzyme. Cl complex is a non-covalent calcium-dependent complex of one Clq, two Clr and two Cis molecules.15IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTClq binds through two or more of its six arms to the Fc domains of IgG or IgM. The binding of multiple arms to immune complexes causes the two Clr proteins in the complex (protease zymogens) to activate producing two proteases that cleave and activate the two proCis in the complex (Morikis, D. and Lambris, J.D. (2005)). This activation of proCis is caused by cleavage into the two chain Cis enzyme with 58,000 and 28,000 dalton fragments.

[0068] In some embodiments, antibodies (e.g. an anti-Cls antibody) are provided herein. In some embodiments, the antibody is a recombinant antibody that binds to Cis. In some embodiments, the antibody binds to the active form of Cis. In some embodiments, the antibody binds to active form preferentially over the inactive form of Cis. In some embodiments, the antibody binds to the active form with an affinity that is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, or 200% higher as compared to its affinity for the inactive form of Cis. In some embodiments, the Cis protein is a human Cis protein, such as the active form of Cis. In some embodiments, the antibody does not specifically bind to the inactive form of the Cis protein. As used herein, the term “recombinant antibody” refers to an antibody that is not naturally occurring. In some embodiments, the term “recombinant antibody” refers to an antibody that is not isolated from a human subject. In some embodiments, the antibody binds with at least 100X more affinity to the active form of Cis as compared to proCis.

[0069] In some embodiments, an antibody, or an antigen-binding fragment thereof comprises any CDR sequence provided herein. In some embodiments, an antibody, or an antigen-binding fragment thereof comprises any heavy chain variable polypeptide provided herein. In some embodiments, an antibody, or an antigen-binding fragment thereof comprises any light chain variable polypeptide provided herein. In some embodiments, an antibody, or an antigen-binding fragment thereof comprises any heavy chain polypeptide provided herein. In some embodiments, an antibody, or an antigen-binding fragment thereof comprises any light chain polypeptide provided herein. In some embodiments, an antibody, or an antigen-binding fragment thereof comprises any combination of CDR sequences as provided for any one MAB1-MAB61 below. In some embodiments, an antibody, or an antigen-binding fragment thereof comprises any combination of a heavy chain variable polypeptide and a light chain variable polypeptide as provided for any one MAB1-MAB61 below. In some embodiments, an antibody, or an antigenbinding fragment thereof comprises any combination of a heavy chain polypeptide and a light chain polypeptide as provided for any one MAB1-MAB61 below.

[0070] In some embodiments, an antibody, or an antigen-binding fragment thereof comprises a variant of VH of SEQ ID NO: 1 and / or a variant of VL of SEQ ID NO: 2:16IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTEVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIRQAPGKGLEWVS YISRSGSTKYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR DENYALDWWGQGTLVTVSS ( SEQ ID NO : 1 ) ;DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIY DASNLETGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQHYEDYPLTF GGGTKVEIK ( SEQ ID NO : 2 ) .

[0071] In some embodiments, the antibody comprises a variant of the VH of SEQ ID NO: 1 and the parental (non-variant) VL of SEQ ID NO: 2.

[0072] In some embodiments, the antibody comprises a non-variant (parental) of the VH of SEQ ID NO: 1 and a variant VL of SEQ ID NO: 2.

[0073] In some embodiments, the variant VH comprises a mutation at a position that corresponds to G26 of SEQ ID NO: 1. In some embodiments, the mutation at G26 is G26A, G26M, G26R, G26C, G26N, G26D, G26E, G26Q, G26H, G26K, G26I, G26L, G26F, G26Y, G26W, G26P, G26S, G26T, or G26V. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0074] In some embodiments, the variant VH comprises a mutation at a position that corresponds to F27 of SEQ ID NO: 1 . In some embodiments, the mutation at F27 is F27A, F27M, F27R, F27N, F27D, F27E, F27Q, F27H, F27K, F27I, F27L, F27C, F27Y, F27W, F27P, F27S, F27T, or F27V. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0075] In some embodiments, the variant VH comprises a mutation at a position that corresponds to T28 of SEQ ID NO: 1. In some embodiments, the mutation at T28 is T28A, T28R, T28C, T28N, T28D, T28E, T28Q, T28H, T28K, T28I, T28L, T28M, T28F, T28Y, T28W, T28P, T28S, T28G, or T28V.In some embodiments, the mutation can be any naturally occurring amino acid residue other than methionine or cysteine.

[0076] In some embodiments, the variant VH comprises a mutation at a position that corresponds to F29 of SEQ ID NO: 1. In some embodiments, the mutation at F29 is F29A, F29R, F29C, F29N, F29D, F29E, F29Q, F29H, F29K, F29M, F29I, F29L, F29G, F29Y, F29W, F29P, F29S, F29T, or F29V. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0077] In some embodiments, the variant VH comprises a mutation at a position that corresponds to S30 of SEQ ID NO: 1. In some embodiments, the mutation at S30 is S30A, S30R, S30C, S30N, S30D,17IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTS30E, S30Q, S30H, S30M, S30K, S30I, S30L, S30F, S30Y, S30W, S30P, S30G, S30T, or S30V.In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0078] In some embodiments, the variant VH comprises a mutation at a position that corresponds to D31 of SEQ ID NO: 1. In some embodiments, the mutation at D31 is D31M, D31A, D31R, D31C, D31N, D31G, D31E, D31Q, D31H, D31K, D31I, D31L, D31F, D31Y, D31W, D31P, D31S, D31T, or D31V.In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0079] In some embodiments, the variant VH comprises a mutation at a position that corresponds to Y32 of SEQ ID NO: 1. In some embodiments, the mutation at Y32 is Y32M, Y32A, Y32R, Y32C, Y32N, Y32D, Y32E, Y32Q, Y32H, Y32K, Y32I, Y32L, Y32F, Y32G, Y32W, Y32P, Y32S, Y32T, or Y32V.In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0080] In some embodiments, the variant VH comprises a mutation at a position that corresponds to Y33 of SEQ ID NO: 1. In some embodiments, the mutation at Y33 is Y33M, Y33A, Y33R, Y33C, Y33N, Y33D, Y33E, Y33Q, Y33H, Y33K, Y33I, Y33L, Y33F, Y33G, Y33W, Y33P, Y33S, Y33T, or Y33V.In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0081] In some embodiments, the variant VH comprises a mutation at a position that corresponds to M34 of SEQ ID NO: 1. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine. In some embodiments, the mutation at M34 is M34A, M34R, M34C, M34N, M34D, M34G, M34E, M34Q, M34H, M34K, M34I, M34L, M34F, M34Y, M34W, M34P, M34S, M34T, or M34V.

[0082] In some embodiments, the variant VH comprises a mutation at a position that corresponds to S35 of SEQ ID NO: 1. In some embodiments, the mutation at S35 is S35A, S35M, S35R, S35C, S35N, S35D, S35E, S35Q, S35H, S35K, S35I, S35L, S35F, S35Y, S35W, S35P, S35G, S35T, or S35V. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0083] In some embodiments, the variant VH comprises a mutation at a position that corresponds to Y50 of SEQ ID NO: 1. In some embodiments, the mutation at Y50 is Y50M, Y50A, Y50R, Y50C, Y50N, Y50D, Y50E, Y50Q, Y50H, Y50K, Y50I, Y50L, Y50F, Y50G, Y50W, Y50P, Y50S, Y50T, or18IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTY50V.In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0084] In some embodiments, the variant VH comprises a mutation at a position that corresponds to 151 of SEQ ID NO: 1. In some embodiments, the mutation at 151 is 151 A, 15 IM, 151R, 151C, 15 IN, I51D, I51E, I51Q, I51H, I51K, I51G, I51L, I51F, I51Y, I51W, I51P, 15 IS, I51T, or I51V.In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0085] In some embodiments, the variant VH comprises a mutation at a position that corresponds to S52 of SEQ ID NO: 1. S52A, S52M, S52R, S52C, S52N, S52D, S52E, S52Q, S52H, S52K, S52I, S52L, S52F, S52Y, S52W, S52P, S52G, S52T, or S52V.In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine. In some embodiments, the mutation at S52 is

[0086] In some embodiments, the variant VH comprises a mutation at a position that corresponds to R53 of SEQ ID NO: 1. R53 is R53A, R53M, R53G, R53C, R53N, R53D, R53E, R53Q, R53H, R53K, R53I, R53L, R53F, R53Y, R53W, R53P, R53S, R53T, or R53V. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine. In some embodiments, the mutation at

[0087] In some embodiments, the variant VH comprises a mutation at a position that corresponds to S54 of SEQ ID NO: 1. In some embodiments, the mutation at S54 is S54A, S54R, S54C, S54N, S54D, S54E, S54Q, S54H, S54K, S54I, S54L, S54F, S54Y, S54W, S54P, S54G, S54T, S54M, or S54V. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0088] In some embodiments, the variant VH comprises a mutation at a position that corresponds to G55 of SEQ ID NO: 1. In some embodiments, the mutation at G55 is G55M, G55A, G55R, G55C, G55N, G55D, G55E, G55Q, G55H, G55K, G55I, G55L, G55F, G55Y, G55W, G55P, G55S, G55T, or G55V. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0089] In some embodiments, the variant VH comprises a mutation at a position that corresponds to S56 of SEQ ID NO: 1. In some embodiments, the mutation at S56 is S56M, S56A, S56R, S56C, S56N, S56D, S56E, S56Q, S56H, S56K, S56I, S56L, S56F, S56Y, S56W, S56P, S56G, S56T, or S56V.In19IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0090] In some embodiments, the variant VH comprises a mutation at a position that corresponds to T57 of SEQ ID NO: 1. In some embodiments, the mutation at T57 is T57M, T57A, T57R, T57C, T57N, T57D, T57E, T57Q, T57H, T57K, T57I, T57L, T57F, T57Y, T57W, T57P, T57S, T57G, or T57V.In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0091] In some embodiments, the variant VH comprises a mutation at a position that corresponds to K58 of SEQ ID NO: 1. In some embodiments, the mutation at K58 is K58M, K58A, K58R, K58C, K58N, K58D, K58E, K58Q, K58H, K58G, K58I, K58L, K58F, K58Y, K58W, K58P, K58S, K58T, or K58V. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0092] In some embodiments, the variant VH comprises a mutation at a position that corresponds to Y59 of SEQ ID NO: 1. . In some embodiments, the mutation at Y59 is Y59M, Y59A, Y59R, Y59C, Y59N, Y59D, Y59E, Y59Q, Y59H, Y59K, Y59I, Y59L, Y59F, Y59G, Y59W, Y59P, Y59S, Y59T, or Y59V. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine

[0093] In some embodiments, the variant VH comprises a mutation at a position that corresponds to Y60 of SEQ ID NO: 1. In some embodiments, the mutation at Y60 is Y60M, Y60A, Y60R, Y60C, Y60N, Y60D, Y60E, Y60Q, Y60H, Y60K, Y60I, Y60L, Y60F, Y60G, Y60W, Y60P, Y60S, Y60T, or Y60V.In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0094] In some embodiments, the variant VH comprises a mutation at a position that corresponds to A61 of SEQ ID NO: 1. In some embodiments, the mutation at A61 is A61A, A61M, A61R, A61C, A61N, A61D, A61E, A61Q, A61H, A61K, A61I, A61L, A61F, A61Y, A61W, A61P, A61S, A61T, or A61V.In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0095] In some embodiments, the variant VH comprises a mutation at a position that corresponds to D62 of SEQ ID NO: 1. In some embodiments, the mutation at D62 is D62A, D62C, D62E, D62F, D62G, D62H, D62I, D62K, D62L, D62M, D62N, D62P, D62Q, D62R, D62S, D62T, D62V, D62W, or20IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTD62Y.In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0096] In some embodiments, the variant VH comprises a mutation at a position that corresponds to S63 of SEQ ID NO: 1. In some embodiments, the mutation at S63 is S63A, S63C, S63E, S63F, S63G, S63H, S63I, S63K, S63L, S63M, S63N, S63P, S63Q, S63R, S63D, S63T, S63V, S63W, or S63Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0097] In some embodiments, the variant VH comprises a mutation at a position that corresponds to V64 of SEQ ID NO: 1. In some embodiments, the mutation at V64 is V64A, V64C, V64E, V64F, V64G, V64H, V64I, V64K, V64L, V64M, V64N, V64P, V64Q, V64R, V64S, V64T, V64D, V64W, or V64Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0098] In some embodiments, the variant VH comprises a mutation at a position that corresponds to K65 of SEQ ID NO: 1. In some embodiments, the mutation at K65 is K65A, K65C, K65E, K65F, K65G, K65H, K65I, K65D, K65L, K65M, K65N, K65P, K65Q, K65R, K65S, K65T, K65V, K65W, or K65Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0099] In some embodiments, the variant VH comprises a mutation at a position that corresponds to G66 of SEQ ID NO: 1. In some embodiments, the mutation at G66 is G66A, G66C, G66E, G66F, G66D, G66H, G66I, G66K, G66L, G66M, G66N, G66P, G66Q, G66R, G66S, G66T, G66V, G66W, or G66Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0100] In some embodiments, the variant VH comprises a mutation at a position that corresponds to A97 of SEQ ID NO: 1. In some embodiments, the mutation at A97 is A97D, A97C, A97E, A97F, A97G, A97H, A97I, A97K, A97L, A97M, A97N, A97P, A97Q, A97R, A97S, A97T, A97V, A97W, or A97Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0101] In some embodiments, the variant VH comprises a mutation at a position that corresponds to R98 of SEQ ID NO: 1. In some embodiments, the mutation at R98 is R98A, R98C, R98E, R98F, R98G, R98H, R98I, R98K, R98L, R98M, R98N, R98P, R98Q, R98D, R98S, R98T, R98V, R98W, or R98Y. In21IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0102] In some embodiments, the variant VH comprises a mutation at a position that corresponds to D99 of SEQ ID NO: 1. In some embodiments, the mutation at D99 is D99A, D99C, D99E, D99F, D99G, D99H, D99I, D99K, D99L, D99M, D99N, D99P, D99Q, D99R, D99S, D99T, D99V, D99W, or D99Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0103] In some embodiments, the variant VH comprises a mutation at a position that corresponds to E100 of SEQ ID NO: 1. In some embodiments, the mutation at E100 is E100A, E100C, E100D, E100F, E100G, E100H, E100I, E100K, E100L, E100M, E100N, E100P, E100Q, E100R, E100S, E100T, E100V, E100W, or E100Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0104] In some embodiments, the variant VH comprises a mutation at a position that corresponds to N101 of SEQ ID NO: 1. In some embodiments, the mutation at N101 is N101A, N101C, N101E, N101F, N101G, N101H, N101I, N101K, N101L, N101M, N101D, N101P, N101Q, N101R, N101S, N101T, N101V, N101W, or N101Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0105] In some embodiments, the variant VH comprises a mutation at a position that corresponds to Y102 of SEQ ID NO: 1. In some embodiments, the mutation at Y102 is Y 102A, Y 102C, Y 102E, Y102F, Y102G, Y102H, Y102I, Y102K, Y102L, Y102M, Y102N, Y102P, Y102Q, Y102R, Y102S, Y102T, Y102V, Y102W, or Y102D. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0106] In some embodiments, the variant VH comprises a mutation at a position that corresponds to A103 of SEQ ID NO: 1. In some embodiments, the mutation at A103 is A103D, A103C, A103E, A103F, A103G, A103H, A103I, A103K, A103L, A103M, A103N, A103P, A103Q, A103R, A103S, A103T, A103V, A103W, or A103Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0107] In some embodiments, the variant VH comprises a mutation at a position that corresponds to L104 of SEQ ID NO: 1. In some embodiments, the mutation at L104 is L104A, L104C, L104E, L104F, L104G, L104H, L104I, L104K, L104D, L104M, L104N, L104P, L104Q, L104R, L104S, L104T,22IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTL104V, L104W, or L104Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0108] In some embodiments, the variant VH comprises a mutation at a position that corresponds to D105 of SEQ ID NO: 1. In some embodiments, the mutation at D105 is D105A, D105C, D105E, D105F, D105G, D105H, D105I, D105K, D105L, D105M, D105N, D105P, D105Q, D105R, D105S, D105T, D105V, D105W, or D105Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0109] In some embodiments, the variant VH comprises a mutation at a position that corresponds to W106 of SEQ ID NO: 1. In some embodiments, the mutation at W106 is W106A, W106C, W106E, W106F, W106G, W106H, W106I, W106K, W106L, W106M, W106N, W106P, W106Q, W106R, W106S, W106T, W106V, W106D, or W106Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0110] In some embodiments, the VH comprises one or more mutations at the positions provided for herein and above. That is the mutations can be single or combinations of mutations at different positions.

[0111] In some embodiments, the VH comprises a sequence as set forth in the following VH Variant Table 2:23IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT24IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT25IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT26IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT27IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT28IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT29IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT30IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT31IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT32IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT33IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT34IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT35IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT36IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT37IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT38IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT39IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT40IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT41IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT42IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT43IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT44IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT45IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT46IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT47IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT48IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT49IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT50IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT51IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT52IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT53IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT54IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT55IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT56IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT57IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT58IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT59IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT60IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT61IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0112] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,62IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT91. 92. 93. 94. 95. 96. 97. 98. 99. 100. 101. 102. 103. 104. 105. 106. 107. 108. 109. 110. 111. 112. 113114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705.63IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0113] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises: a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 6263, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 9091, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617,64IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638,639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659,660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680,681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701,702, 703, 704, or 705; and a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 2.

[0114] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VH having an amino acid sequence of any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99.100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498,65IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519,520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540,541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561,562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582,583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603,604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624,625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645,646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666,667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687,688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705.

[0115] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises: a VH having an amino acid sequence of any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120,121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141,142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162,163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183,184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204,205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225,226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246,247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267,268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288,289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309,310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330,331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351,352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372,373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393,394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414,415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435,66IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456,457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477,478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498,499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519,520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540,541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561,562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582,583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603,604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624,625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645,646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666,667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687,688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705; and a VL having an amino acid sequence of SEQ ID NO: 2.

[0116] In some embodiments, the VH variants provided for herein are combined with a VL variant as provided for herein or the parental VL, which comprises the amino acid of SEQ ID NO: 2.

[0117] In some embodiments, the variant VL comprises a mutation at a position that corresponds to Q24 of SEQ ID NO: 2. In some embodiments, the mutation at Q24 is Q24A, Q24C, Q24D, Q24E, Q24F, Q24G, Q24H, Q24I, Q24K, Q24L, Q24M, Q24N, Q24P, Q24R, Q24S, Q24T, Q24V, Q24W, or Q24Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0118] In some embodiments, the variant VL comprises a mutation at a position that corresponds to A25 of SEQ ID NO: 2. In some embodiments, the mutation at A25 is A25C, A25D, A25E, A25F, A25G, A25H, A25I, A25K, A25L, A25M, A25N, A25P, A25Q, A25R, A25S, A25T, A25V, A25W, or A25Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0119] In some embodiments, the variant VL comprises a mutation at a position that corresponds to S26 of SEQ ID NO: 2. In some embodiments, the mutation at S26 is S26A, S26C, S26D, S26E, S26F, S26G, S26H, S26I, S26K, S26L, S26M, S26N, S26P, S26Q, S26R, S26T, S26V, S26W, S26Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.67IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0120] In some embodiments, the variant VL comprises a mutation at a position that corresponds to Q27 of SEQ ID NO: 2. In some embodiments, the mutation at Q27 is Q27A, Q27C, Q27D, Q27E, Q27F, Q27G, Q27H, Q27I, Q27K, Q27L, Q27M, Q27N, Q27P, Q27R, Q27S, Q27T, Q27V, Q27W, or Q27Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0121] In some embodiments, the variant VL comprises a mutation at a position that corresponds to D28 of SEQ ID NO: 2. In some embodiments, the mutation at D28 is D28A, D28C, D28E, D28F, D28G, D28H, D28I, D28K, D28L, D28M, D28N, D28P, D28Q, D28R, D28S, D28T, D28V, D28W, or D28Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0122] In some embodiments, the variant VL comprises a mutation at a position that corresponds to 129 of SEQ ID NO: 2. In some embodiments, the mutation at 129 is I29A, I29C, I29D, I29E, I29F, I29G, I29H, I29K, I29L, I29M, I29N, I29P, I29Q, I29R, I29S, I29T, I29V, I29W, or I29Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0123] In some embodiments, the variant VL comprises a mutation at a position that corresponds to S30 of SEQ ID NO: 2. In some embodiments, the mutation at S30 is S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, or S30Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0124] In some embodiments, the variant VL comprises a mutation at a position that corresponds to N31 of SEQ ID NO: 2. In some embodiments, the mutation at N31 is N31A, N31C, N31D, N31E, N31F, N31G, N31H, N31I, N31K, N31L, N31M, N31P, N31Q, N31R, N31S, N31T, N31V, N31W, or N31Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0125] In some embodiments, the variant VL comprises a mutation at a position that corresponds to Y32 of SEQ ID NO: 2. In some embodiments, the mutation at Y32 is Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, or Y32W. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.68IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0126] In some embodiments, the variant VL comprises a mutation at a position that corresponds to L33 of SEQ ID NO: 2. In some embodiments, the mutation at L33 is L33A, L33C, L33D, L33E, L33F, L33G, L33H, L33I, L33K, L33M, L33N, L33P, L33Q, L33R, L33S, L33T, L33V, L33W, or L33Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0127] In some embodiments, the variant VL comprises a mutation at a position that corresponds to N34 of SEQ ID NO: 2. In some embodiments, the mutation at N34 is N34A, N34C, N34D, N34E, N34F, N34G, N34H, N34I, N34K, N34L, N34M, N34P, N34Q, N34R, N34S, N34T, N34V, N34W, or N34Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0128] In some embodiments, the variant VL comprises a mutation at a position that corresponds to D50 of SEQ ID NO: 2. In some embodiments, the mutation at D50 is D50A, D50C, D50E, D50F, D50G, D50H, D50I, D50K, D50L, D50M, D50N, D50P, D50Q, D50R, D50S, D50T, D50V, D50W, or D50Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0129] In some embodiments, the variant VL comprises a mutation at a position that corresponds to A51 of SEQ ID NO: 2. In some embodiments, the mutation at A51 is A51C, A51D, A51E, A51F, A51G, A51H, A51I, A51K, A51L, A51M, A51N, A51P, A51Q, A51R, A51S, A51T, A51V, A51W, or A51Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0130] In some embodiments, the variant VL comprises a mutation at a position that corresponds to S52 of SEQ ID NO: 2. In some embodiments, the mutation at S52 is S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, or S52Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0131] In some embodiments, the variant VL comprises a mutation at a position that corresponds to N53 of SEQ ID NO: 2. In some embodiments, the mutation at N53 is N53A, N53C, N53D, N53E, N53F, N53G, N53H, N53I, N53K, N53L, N53M, N53P, N53Q, N53R, N53S, N53T, N53V, N53W, or N53Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.69IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0132] In some embodiments, the variant VL comprises a mutation at a position that corresponds to L54 of SEQ ID NO: 2. In some embodiments, the mutation at L54 is L54A, L54C, L54D, L54E, L54F, L54G, L54H, L54I, L54K, L54M, L54N, L54P, L54Q, L54R, L54S, L54T, L54V, L54W, or L54Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0133] In some embodiments, the variant VL comprises a mutation at a position that corresponds to E55 of SEQ ID NO: 2. In some embodiments, the mutation at E55 is E55A, E55C, E55D, E55F, E55G, E55H, E55I, E55K, E55L, E55M, E55N, E55P, E55Q, E55R, E55S, E55T, E55V, E55W, or E55Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0134] In some embodiments, the variant VL comprises a mutation at a position that corresponds to T56 of SEQ ID NO: 2. In some embodiments, the mutation at T56 is T56A, T56C, T56D, T56E, T56F, T56G, T56H, T56I, T56K, T56L, T56M, T56N, T56P, T56Q, T56R, T56S, T56V, T56W, or T56Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0135] In some embodiments, the variant VL comprises a mutation at a position that corresponds to Q89 of SEQ ID NO: 2. In some embodiments, the mutation at Q89 is Q89A, Q89C, Q89D, Q89E, Q89F, Q89G, Q89H, Q89I, Q89K, Q89L, Q89M, Q89N, Q89P, Q89R, Q89S, Q89T, Q89V, Q89W, or Q89Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0136] In some embodiments, the variant VL comprises a mutation at a position that corresponds to H90 of SEQ ID NO: 2. In some embodiments, the mutation at H90 is H90A, H90C, H90D, H90E, H90F, H90G, H90I, H90K, H90L, H90M, H90N, H90P, H90Q, H90R, H90S, H90T, H90V, H90W, or H90Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0137] In some embodiments, the variant VL comprises a mutation at a position that corresponds to Y91 of SEQ ID NO: 2. In some embodiments, the mutation at Y91 is Y91A, Y91C, Y91D, Y91E, Y91F, Y91G, Y91H, Y91I, Y91K, Y91L, Y91M, Y91N, Y91P, Y91Q, Y91R, Y91S, Y91T, Y91V, or Y91W. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.70IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0138] In some embodiments, the variant VL comprises a mutation at a position that corresponds to E92 of SEQ ID NO: 2. In some embodiments, the mutation at E92 is E92A, E92C, E92D, E92F, E92G, E92H, E92I, E92K, E92L, E92M, E92N, E92P, E92Q, E92R, E92S, E92T, E92V, E92W, or E92Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0139] In some embodiments, the variant VL comprises a mutation at a position that corresponds to D93 of SEQ ID NO: 2. In some embodiments, the mutation at D93 is D93A, D93C, D93E, D93F, D93G, D93H, D93I, D93K, D93L, D93M, D93N, D93P, D93Q, D93R, D93S, D93T, D93V, D93W, or D93Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0140] In some embodiments, the variant VL comprises a mutation at a position that corresponds to Y94 of SEQ ID NO: 2. In some embodiments, the mutation at Y94 is Y94A, Y94C, Y94D, Y94E, Y94F, Y94G, Y94H, Y94I, Y94K, Y94L, Y94M, Y94N, Y94P, Y94Q, Y94R, Y94S, Y94T, Y94V, or Y94W. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0141] In some embodiments, the variant VL comprises a mutation at a position that corresponds to P95 of SEQ ID NO: 2. In some embodiments, the mutation at P95 is P95A, P95C, P95D, P95E, P95F, P95G, P95H, P95I, P95K, P95L, P95M, P95N, P95Q, P95R, P95S, P95T, P95V, P95W, P95Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0142] In some embodiments, the variant VL comprises a mutation at a position that corresponds to L96 of SEQ ID NO: 2. In some embodiments, the mutation at L96 is L96A, L96C, L96D, L96E, L96F, L96G, L96H, L96I, L96K, L96M, L96N, L96P, L96Q, L96R, L96S, L96T, L96V, L96W, or L96Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.

[0143] In some embodiments, the variant VL comprises a mutation at a position that corresponds to T97 of SEQ ID NO: 2. In some embodiments, the mutation at T97 is T97A, T97C, T97D, T97E, T97F, T97G, T97H, T97I, T97K, T97L, T97M, T97N, T97P, T97Q, T97R, T97S, T97V, T97W, or T97Y. In some embodiments, the mutation is any naturally occurring amino acid residue other than methionine or cysteine.71IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0144] In some embodiments, the VL comprises one or more mutations at the positions provided for herein and above. That is the mutations can be single or combinations of mutations at different positions.

[0145] In some embodiments, the VL comprises a sequence as set forth in the following VL VariantTable 3:72IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT73IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT74IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT75IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT76IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT77IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT78IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT79IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT80IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT81IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT82IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT83IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT84IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT85IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT86IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT87IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT88IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT89IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT90IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT91IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT92IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT93IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT94IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT95IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT96IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT97IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT98IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT99IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0146] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 706,707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727,728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748,749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769,100IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790,791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811,812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832,833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853,854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874,875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895,896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916,917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937,938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958,959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979,980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999,1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031,1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047,1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063,1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079,1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111,1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127,1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143,1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159,1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175,1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191,1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207,1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218.[001471 In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises: a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 706,707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727,728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748,749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769,101IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790,791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811,812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832,833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853,854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874,875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895,896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916,917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937,938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958,959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979,980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999,1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031,1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047,1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063,1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079,1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111,1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127,1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143,1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159,1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175,1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191,1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207,1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218; and a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 1.

[0148] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VL having an amino acid sequence of any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756,102IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777,778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798,799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819,820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840,841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861,862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882,883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903,904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924,925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945,946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966,967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987,988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022,1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038,1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054,1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070,1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102,1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118,1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134,1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150,1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166,1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182,1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198,1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214,1215, 1216, 1217, or 1218.

[0149] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises: a VL having an amino acid sequence of any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714,715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735,736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756,757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777,103IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798,799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819,820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840,841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861,862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882,883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903,904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924,925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945,946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966,967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987,988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022,1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038,1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054,1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070,1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086,1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102,1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134,1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150,1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166,1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182,1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198,1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214,1215, 1216, 1217, or 1218; and a VH having an amino acid sequence of SEQ ID NO: 1.[001501 In some embodiments, the antibody comprises one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, I51S, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D,104IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT15 IS, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 1. For example, is the antibody comprises a mutation of D31A, the antibody does not comprise another mutation at residue 31.

[0151] In some embodiments, the antibody comprises a mutations of T28D, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S30G, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S30K, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S30L, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S30Q, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S30R, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S30T, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S30V, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S30W, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S30Y, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of D31A, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of D31E, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of D31F, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of D31G, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of D31I, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of D31K, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of D31Q, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of D31T, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of D31V, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of D31W, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of D31Y, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S35D, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of 15 IS, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S52N, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of S52T, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of G55L, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of A97T, as compared to SEQ ID NO: 1. In105IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT some embodiments, the antibody comprises a mutations of N101S, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a mutations of W106F, as compared to SEQ ID NO: 1.

[0152] In some embodiments, the antibody comprises a VH comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, 15 IS, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a VH comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, I51S, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 1.

[0153] In some embodiments, the antibody comprises a heavy chain comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, 15 IS, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a heavy chain comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, 15 IS, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 1.

[0154] In some embodiments, the antibody comprises a HCDR1 comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, or any combination thereof, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a HCDR1 comprsing one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 1.

[0155] In some embodiments, the antibody comprises a HCDR2 comprising one or more mutations selected from any one of: 15 IS, S52N, S52T, G55L, or any combination thereof, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a HCDR2 comprising one or more mutations106IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT selected from any one of: 15 IS, S52N, S52T, G55L, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 1.

[0156] In some embodiments, the antibody comprises a HCDR3 comprising one or more mutations selected from any one of: A97T, N101S, W106F, or any combination thereof, as compared to SEQ ID NO: 1.

[0157] In some embodiments, the antibody comprises a HCDR1, HCDR2, and HCDR3 comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, 15 IS, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a HCDR1, HCDR2, and HCDR3 comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, 15 IS, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 1.

[0158] In some embodiments, the antibody comprises one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 2.

[0159] In some embodiments, the antibody comprises a mutations of D28T, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a mutations of N31K, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a mutations of N31Q, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a mutations of S52R, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a mutations of Q89A, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a mutations of Q89T, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a mutations of H90E, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a mutations of T97G, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a mutations of T97L, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a mutations of T97N, as compared to SEQ ID NO: 2.107IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0160] In some embodiments, the antibody comprises a VL comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a VL comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 2.

[0161] In some embodiments, the antibody comprises a light chain comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a light chain comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 2.

[0162] In some embodiments, the antibody comprises a LCDR1 comprising one or more mutations selected from any one of: D28T, N31K, N31Q, or any combination thereof, as compared to SEQ ID NO: 1. In some embodiments, the antibody comprises a VL comprising one or more mutations selected from any one of: D28T, N31K, N31Q, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 2.

[0163] In some embodiments, the antibody comprises a LCDR2 comprising a mutation of S52R, as compared to SEQ ID NO: 2.

[0164] In some embodiments, the antibody comprises a LCDR3 comprising one or more mutations selected from any one of: Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a LCDR3 comprising one or more mutations selected from any one of: Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 2.

[0165] In some embodiments, the antibody comprises a LCDR1, LCDR2, and LCDR3 comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a LCDR1, LCDR2, and LCDR3 comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 2.108IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0166] In some embodiments, the antibody comprises one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, I51S, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof, as compared to SEQ ID NO: 1; and one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, I51S, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 1; and one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 2.

[0167] In some embodiments, the antibody comprises a VH comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, 15 IS, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof, as compared to SEQ ID NO: 1; and a VL comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a VH comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, 15 IS, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 1; and a VL comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 2.

[0168] In some embodiments, the antibody comprises a heavy chain comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, I51S, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof, as compared to SEQ ID NO: 1; and a light chain comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof, as compared to SEQ ID NO: 2. In some109IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT embodiments, the antibody comprises a heavy chain comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, 15 IS, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 1; and a light chain comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 2.

[0169] In some embodiments, the antibody comprises a HCDR1, HCDR2, and HCDR3 comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, 15 IS, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof, as compared to SEQ ID NO: 1; and a LCDR1, LCDR2, and LCDR3 comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof, as compared to SEQ ID NO: 2. In some embodiments, the antibody comprises a HCDR1, HCDR2, and HCDR3 comprising one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, I51S, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 1; and a LCDR1, LCDR2, and LCDR3 comprising one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof provided that each residue comprises only one mutation, as compared to SEQ ID NO: 2.

[0170] In some embodiments, the antibody comprises one or more mutations as provided herein and one or more CDRs in the VH and / or VL as set forth below. For example, if the VL comprises a mutation and the VH does not comprise a mutation, the VH can comprise a set of CDRs as set forth below. In some embodiments, one of the CDRs of the VH can have a mutation and the other CDRs are as set forth below. In some embodiments, if the VH comprises a mutation and the VL does not comprise a mutation, the VL can comprise a set of CDRs as set forth below. Different CDR notations / definitions are provided.110IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0171] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises the VH comprising the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, 1225, or 1228, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, 1226, or 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221, 1227, or 1230. In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises the VL comprising the LCDR 1 having an amino acid sequence of SEQ ID NO: 1222, or 1231, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, or 1232, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224.

[0172] In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises the VH comprising the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221; and the VL comprising the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224. In some embodiments, the antibody, or an antigen-binding fragment thereof, comprises the VH comprising the HCDR1 having an amino acid sequence of SEQ ID NO: 1225, the HCDR2 having an amino acid sequence of SEQ ID NO: 1226, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1227; and the VL comprising the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224. In some embodiments, the antibody,111IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT or an antigen-binding fragment thereof, comprises the VH comprising the HCDR1 having an amino acid sequence of SEQ ID NO: 1228, the HCDR2 having an amino acid sequence of SEQ ID NO: 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1230; and the VL comprising the LCDR1 having an amino acid sequence of SEQ ID NO: 1231, the LCDR2 having an amino acid sequence of SEQ ID NO: 1232, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224.

[0173] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134,135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155,156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176,177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197,198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218,219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239,240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260,261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281,282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302,303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323,324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344,345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365,366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386,387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407,408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428,429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449,450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470,471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491,492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512,112IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533,534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554,555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575,576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596,597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617,618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638,639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659,660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680,681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701,702, 703, 704, or 705, provided that the VH comprises the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, 1225, or 1228, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, 1226, or 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221, 1227, or 1230. In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137,138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158,159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179,180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200,201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221,222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242,243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263,264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284,285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305,306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326,327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347,348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368,113IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389,390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410,411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431,432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452,453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473,474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494,495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515,516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536,537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557,558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578,579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599,600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620,621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641,642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662,663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683,684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705, provided that the VH comprises the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221. In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106,107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127,128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148,149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169,170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190,191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211,212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232,114IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253,254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274,275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295,296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316,317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337,338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358,359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379,380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400,401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421,422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442,443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463,464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484,485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505,506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526,527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547,548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568,569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589,590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610,611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631,632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652,653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673,674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694,695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705, provided that the VH comprises the HCDR1 having an amino acid sequence of SEQ ID NO: 1225, the HCDR2 having an amino acid sequence of SEQ ID NO: 1226, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1227. In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,115IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705, provided that the V H comprises the HCDR1 having an amino acid sequence of SEQ ID NO: 1228,116IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT the HCDR2 having an amino acid sequence of SEQ ID NO: 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1230.

[0174] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises: a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134,135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155,156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176,177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197,198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218,219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239,240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260,261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281,282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302,303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323,324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344,345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365,366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386,387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407,408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428,429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449,450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470,471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491,492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512,513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533,534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554,555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575,117IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596,597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617,618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638,639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659,660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680,681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701,702, 703, 704, or 705, provided that the VH comprises the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, 1225, or 1228, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, 1226, or 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221, 1227, or 1230; and a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 2. In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises: a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115,116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136,137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157,158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178,179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199,200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220,221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241,242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262,263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283,284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304,305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325,326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346,347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367,368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388,118IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409,410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430,431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451,452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472,473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493,494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514,515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535,536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556,557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577,578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598,599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619,620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640,641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661,662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682,683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703,704, or 705, provided that the VH comprises the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221; and a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 2. In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises: a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108,109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129,130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150,151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171,172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192,193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213,119IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234,235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255,256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276,277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297,298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318,319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339,340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360,361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381,382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402,403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423,424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444,445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465,466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486,487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507,508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528,529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549,550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570,571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591,592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612,613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633,634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654,655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675,676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696,697, 698, 699, 700, 701, 702, 703, 704, or 705, provided that the VH comprises the HCDR1 having an amino acid sequence of SEQ ID NO: 1225, the HCDR2 having an amino acid sequence of SEQ ID NO: 1226, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1227; and a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 2. In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises: a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,120IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 4344, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 7172. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86. 87. 88. 89. 90. 91. 92. 93. 94. 95. 96. 97. 98. 99100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687,121IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705, provided that the VH comprises the HCDR1 having an amino acid sequence of SEQ ID NO: 1228, the HCDR2 having an amino acid sequence of SEQ ID NO: 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1230; and a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 2.

[0175] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727,728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748,749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769,770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790,791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811,812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832,833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853,854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874,875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895,896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916,917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937,938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958,959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979,980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999,1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015,1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031,1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047,1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063,1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079,1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111,1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127,122IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159,1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175,1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191,1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207,1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, provided that the VL comprises the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, or 1231, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, or 1232, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224. In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726,727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747,748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768,769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789,790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810,811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831,832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852,853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873,874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894,895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915,916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936,937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957,958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978,979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999,1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015,1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031,1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047,1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063,1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079,1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,123IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111,1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127,1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143,H44, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159,1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175,1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191,1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207,1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, provided that the VL comprises the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224. In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729,730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750,751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771,772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792,793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813,814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834,835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855,856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876,877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897,898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918,919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939,940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960,961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981,982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017,1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033,1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049,1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065,124IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097,1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113,1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129,1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145,1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161,1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177,1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209,1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, provided that the VL comprises the LCDR1 having an amino acid sequence of SEQ ID NO: 1231, the LCDR2 having an amino acid sequence of SEQ ID NO: 1232, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224.

[0176] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises: a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727,728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748,749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769,770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790,791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811,812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832,833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853,854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874,875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895,896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916,917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937,938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958,959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979,980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999,1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031,125IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047,1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063,1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079,1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111,1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127,1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143,1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159,1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175,1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191,1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207,1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, provided that the VL comprises the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, or 1231, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, or 1232, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224; and a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 1. In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises: a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727,728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748,749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769,770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790,791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811,812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832,833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853,854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874,875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895,896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916,917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937,938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958,126IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031,1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047,1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063,1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079,1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111,1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127,1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143,H44, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159,1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175,1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191,1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207,1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, provided that the VL comprises the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224; and a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 1. In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises: a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729,730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750,751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771,772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792,793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813,814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834,835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855,856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876,127IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897,898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918,919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939,940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960,961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981,982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017,1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033,1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049,1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065,1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081,1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097,1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113,1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129,1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145,1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177,1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193,1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209,1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, provided that the VL comprises the LCDR1 having an amino acid sequence of SEQ ID NO: 1231, the LCDR2 having an amino acid sequence of SEQ ID NO: 1232, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224; and a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to SEQ ID NO: 1.

[0177] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 1; and the VL comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 2, wherein the VH comprises a mutation at one or more of the following positions: G26, F27, T28, F28, S30, D31, Y32, Y33, M34, S35, Y50, 151, S52, R53, S54, G55, S56, T57, K58, Y59, Y60, A61, D62, S63, V64, K65, G66, A97, R98, D99, E100,128IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTN101, Y 102, A 103, LI 04, DI 05, or W 106, and wherein the VL comprises a one or more mutations at position selected from the group consisting of: Q24, A25, S26, Q27, D28, 129, S30, N31, Y32, L33 N34, D50, A51, S52, N53, L54, E55, T56, Q89, H90, Y91, E92, D93, Y94, P95, L96, or T97.

[0178] In some embodiments, the VH comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116,117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137,138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158,159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179,180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200,201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221,222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242,243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263,264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284,285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305,306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326,327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347,348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368,369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389,390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410,411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431,432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452,453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473,474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494,495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515,516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536,537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557,558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578,129IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599,600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620,621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641,642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662,663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683,684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705, provided that the VH comprises one or more mutations selected from the group consisting of: G26A, G26C, G26D, G26E, G26F, G26H, G26I, G26K, G26L, G26M, G26N, G26P, G26Q, G26R, G26S, G26T, G26V, G26W, G26Y, F27A, F27C, F27D, F27E, F27G, F27H, F27I, F27K, F27L, F27M, F27N, F27P, F27Q, F27R, F27S, F27T, F27V, F27W, F27Y, T28A, T28C, T28D, T28E, T28F, T28G, T28H, T28I, T28K, T28L, T28M, T28N, T28P, T28Q, T28R, T28S, T28V, T28W, T28Y, F29A, F29C, F29D, F29E, F29G, F29H, F29I, F29K, F29L, F29M, F29N, F29P, F29Q, F29R, F29S, F29T, F29V, F29W, F29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31C, D31E, D31F, D31G, D31H, D31I, D31K, D31L, D31M, D31N, D31P, D31Q, D31R, D31S, D31T, D31V, D31W, D31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, Y33A, Y33C, Y33D, Y33E, Y33F, Y33G, Y33H, Y33I, Y33K, Y33L, Y33M, Y33N, Y33P, Y33Q, Y33R, Y33S, Y33T, Y33V, Y33W, M34A, M34C, M34D, M34E, M34F, M34G, M34H, M34I, M34K, M34L, M34N, M34P, M34Q, M34R, M34S, M34T, M34V, M34W, M34Y, S35A, S35C, S35D, S35E, S35F, S35G, S35H, S35I, S35K, S35L, S35M, S35N, S35P, S35Q, S35R, S35T, S35V, S35W, S35Y, Y50A, Y50C, Y50D, Y50E, Y50F, Y50G, Y50H, Y50I, Y50K, Y50L, Y50M, Y50N, Y50P, Y50Q, Y50R, Y50S, Y50T, Y50V, Y50W, 151 A, 151C, 15 ID, 15 IE, 15 IF, 151G, 151H, 15 IK, I51L, I51M, I51N, I51P, I51Q, I51R, I51S, I51T, I51V, I51W, I51Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, R53A, R53C, R53D, R53E, R53F, R53G, R53H, R53I, R53K, R53L, R53M, R53N, R53P, R53Q, R53S, R53T, R53V, R53W, R53Y, S54A, S54C, S54D, S54E, S54F, S54G, S54H, S54I, S54K, S54L, S54M, S54N, S54P, S54Q, S54R, S54T, S54V, S54W, S54Y, G55A, G55C, G55D, G55E, G55F, G55H, G55I, G55K, G55L, G55M, G55N, G55P, G55Q, G55R, G55S, G55T, G55V, G55W, G55Y, S56A, S56C, S56D, S56E, S56F, S56G, S56H, S56I, S56K, S56L, S56M, S56N, S56P, S56Q, S56R, S56T, S56V, S56W, S56Y, T57A, T57C, T57D, T57E, T57F, T57G, T57H, T57I, T57K, T57L, T57M, T57N, T57P, T57Q, T57R, T57S, T57V, T57W, T57Y, K58A, K58C, K58D, K58E, K58F, K58G, K58H, K58I, K58L,130IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTK58M, K58N, K58P, K58Q, K58R, K58S, K58T, K58V, K58W, K58Y, Y59A, Y59C, Y59D, Y59E, Y59F, Y59G, Y59H, Y59I, Y59K, Y59L, Y59M, Y59N, Y59P, Y59Q, Y59R, Y59S, Y59T, Y59V, Y59W, Y60A, Y60C, Y60D, Y60E, Y60F, Y60G, Y60H, Y60I, Y60K, Y60L, Y60M, Y60N, Y60P, Y60Q, Y60R, Y60S, Y60T, Y60V, Y60W, A61C, A61D, A61E, A61F, A61G, A61H, A61I, A61K, A61L, A61M, A61N, A61P, A61Q, A61R, A61S, A61T, A61V, A61W, A61Y, D62A, D62C, D62E, D62F, D62G, D62H, D62I, D62K, D62L, D62M, D62N, D62P, D62Q, D62R, D62S, D62T, D62V, D62W, D62Y, S63A, S63C, S63D, S63E, S63F, S63G, S63H, S63I, S63K, S63L, S63M, S63N, S63P, S63Q, S63R, S63T, S63V, S63W, S63Y, V64A, V64C, V64D, V64E, V64F, V64G, V64H, V64I, V64K, V64L, V64M, V64N, V64P, V64Q, V64R, V64S, V64T, V64W, V64Y, K65A, K65C, K65D, K65E, K65F, K65G, K65H, K65I, K65L, K65M, K65N, K65P, K65Q, K65R, K65S, K65T, K65V, K65W, K65Y, G66A, G66C, G66D, G66E, G66F, G66H, G66I, G66K, G66L, G66M, G66N, G66P, G66Q, G66R, G66S, G66T, G66V, G66W, G66Y, A97C, A97D, A97E, A97F, A97G, A97H, A97I, A97K, A97L, A97M, A97N, A97P, A97Q, A97R, A97S, A97T, A97V, A97W, A97Y, R98A, R98C, R98D, R98E, R98F, R98G, R98H, R98I, R98K, R98L, R98M, R98N, R98P, R98Q, R98S, R98T, R98V, R98W, R98Y, D99A, D99C, D99E, D99F, D99G, D99H, D99I, D99K, D99L, D99M, D99N, D99P, D99Q, D99R, D99S, D99T, D99V, D99W, D99Y, E100A, E100C, E100D, E100F, E100G, E100H, E1OOI, E100K, E100L, E100M, E100N, E1OOP, E1OOQ, E100R, E1OOS, E100T, E100V, E100W, E100Y, NI01A, N101C, N101D, N101E, N101F, N101G, N101H, N1O1I, N101K, N101L, N101M, N1O1P, N101Q, N101R, N1O1S, N101T, N101V, N101W, N101Y, Y102A, Y102C, Y102D, Y102E, Y102F, Y102G, Y102H, Y102I, Y102K, Y102L, Y102M, Y102N, Y102P, Y102Q, Y102R, Y102S, Y102T, Y102V, Y102W, A103C, A103D, A103E, A1O3F, A103G, A103H, A1O3I, A103K, A103L, A103M, A103N, A103P, A1O3Q, A103R, A1O3S, A103T, A103V, A103W, A103Y, L104A, L104C, L104D, L104E, L104F, L104G, L104H, L104I, L104K, L104M, L104N, L104P, L104Q, L104R, L104S, L104T, L104V, L104W, L104Y, D105A, D105C, D105E, D105F, D105G, D105H, D105I, D105K, D105L, D105M, D105N, D105P, D1O5Q, D105R, D1O5S, D105T, D105V, D105W, D105Y, W106A, W106C, W106D, W106E, W106F, W106G, W106H, W1O6I, W106K, W106L, W106M, W106N, W106P, W106Q, W106R, W106S, W106T, W106V, or W106Y.

[0179] In some embodiments, the VL comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751,131IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772,773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793,794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814,815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835,836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856,857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877,878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898,899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919,920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940,941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961,962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982,983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018,1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034,1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050,1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066,1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082,1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098,1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114,1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130,1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146,1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162,1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178,1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, provided that the VL comprises one or more mutations selected from the group consisting of: Q24A, Q24C, Q24D, Q24E, Q24F, Q24G, Q24H, Q24I, Q24K, Q24L, Q24M, Q24N, Q24P, Q24R, Q24S, Q24T, Q24V, Q24W, Q24Y, A25C, A25D, A25E, A25F, A25G, A25H, A25I, A25K, A25L, A25M, A25N, A25P, A25Q, A25R, A25S, A25T, A25V, A25W, A25Y, S26A, S26C, S26D, S26E, S26F, S26G, S26H, S26I, S26K, S26L, S26M, S26N, S26P, S26Q, S26R, S26T, S26V, S26W, S26Y, Q27A, Q27C, Q27D, Q27E, Q27F, Q27G, Q27H, Q27I,132IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTQ27K, Q27L, Q27M, Q27N, Q27P, Q27R, Q27S, Q27T, Q27V, Q27W, Q27Y, D28A, D28C, D28E, D28F, D28G, D28H, D28I, D28K, D28L, D28M, D28N, D28P, D28Q, D28R, D28S, D28T, D28V, D28W, D28Y, I29A, I29C, I29D, I29E, I29F, I29G, I29H, I29K, I29L, I29M, I29N, I29P, I29Q, I29R, I29S, I29T, I29V, I29W, I29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, N31A, N31C, N31D, N31E, N31F, N31G, N31H, N31I, N31K, N31L, N31M, N31P, N31Q, N31R, N31S, N31T, N31V, N31W, N31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, L33A, L33C, L33D, L33E, L33F, L33G, L33H, L33I, L33K, L33M, L33N, L33P, L33Q, L33R, L33S, L33T, L33V, L33W, L33Y, N34A, N34C, N34D, N34E, N34F, N34G, N34H, N34I, N34K, N34L, N34M, N34P, N34Q, N34R, N34S, N34T, N34V, N34W, N34Y, D50A, D50C, D50E, D50F, D50G, D50H, D50I, D50K, D50L, D50M, D50N, D50P, D50Q, D50R, D50S, D50T, D50V, D50W, D50Y, A51C, A51D, A51E, A51F, A51G, A51H, A51I, A51K, A51L, A51M, A51N, A51P, A51Q, A51R, A51S, A51T, A51V, A51W, A51Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, N53A, N53C, N53D, N53E, N53F, N53G, N53H, N53I, N53K, N53L, N53M, N53P, N53Q, N53R, N53S, N53T, N53V, N53W, N53Y, L54A, L54C, L54D, L54E, L54F, L54G, L54H, L54I, L54K, L54M, L54N, L54P, L54Q, L54R, L54S, L54T, L54V, L54W, L54Y, E55A, E55C, E55D, E55F, E55G, E55H, E55I, E55K, E55L, E55M, E55N, E55P, E55Q, E55R, E55S, E55T, E55V, E55W, E55Y, T56A, T56C, T56D, T56E, T56F, T56G, T56H, T56I, T56K, T56L, T56M, T56N, T56P, T56Q, T56R, T56S, T56V, T56W, T56Y, Q89A, Q89C, Q89D, Q89E, Q89F, Q89G, Q89H, Q89I, Q89K, Q89L, Q89M, Q89N, Q89P, Q89R, Q89S, Q89T, Q89V, Q89W, Q89Y, H90A, H90C, H90D, H90E, H90F, H90G, H90I, H90K, H90L, H90M, H90N, H90P, H90Q, H90R, H90S, H90T, H90V, H90W, H90Y, Y91A, Y91C, Y91D, Y91E, Y91F, Y91G, Y91H, Y91I, Y91K, Y91L, Y91M, Y91N, Y91P, Y91Q, Y91R, Y91S, Y91T, Y91V, Y91W, E92A, E92C, E92D, E92F, E92G, E92H, E92I, E92K, E92L, E92M, E92N, E92P, E92Q, E92R, E92S, E92T, E92V, E92W, E92Y, D93A, D93C, D93E, D93F, D93G, D93H, D93I, D93K, D93L, D93M, D93N, D93P, D93Q, D93R, D93S, D93T, D93V, D93W, D93Y, Y94A, Y94C, Y94D, Y94E, Y94F, Y94G, Y94H, Y94I, Y94K, Y94L, Y94M, Y94N, Y94P, Y94Q, Y94R, Y94S, Y94T, Y94V, Y94W, P95A, P95C, P95D, P95E, P95F, P95G, P95H, P95I, P95K, P95L, P95M, P95N, P95Q, P95R, P95S, P95T, P95V, P95W, P95Y, L96A, L96C, L96D, L96E, L96F, L96G, L96H, L96I, L96K, L96M, L96N, L96P, L96Q, L96R, L96S, L96T, L96V, L96W, L96Y, T97A,133IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTT97C, T97D, T97E, T97F, T97G, T97H, T97I, T97K, T97L, T97M, T97N, T97P, T97Q, T97R, T97S, T97V, T97W, and T97Y.

[0180] In some embodiments, the VH comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 3839, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 6667, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 9495.96.97.98.99.100. 101. 102.103.104. 105. 106.107.108. 109.110.111.112. 113.114.115. 116.117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127. 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148. 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169. 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190. 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207,208, 209,210,211 212,213,214,215,216, 217,218,219, 220, 221, 222, 223, 224, 225, 226, 227,228,229, 230, 231,232. 233, 234, 235, 236, 237, 238,239, 240, 241,242, 243, 244, 245, 246, 247, 248,249, 250, 251,252, 253. 254, 255, 256, 257, 258, 259, 260, 261,262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274 275, 276, 277, 278, 279, 280, 281,282, 283,284, 285, 286, 287, 288, 289, 290, 291,292, 293,294, 295. 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306,307,308,309,310, 311,312,313,314,315,316. 317,318,319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348,349, 350, 351,352, 353, 354, 355, 356, 357, 358. 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369,370, 371,372, 373, 374, 375, 376, 377, 378, 379. 380,381,382,383,384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400. 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411,412,413,414,415, 416,417,418,419, 420, 421. 422, 423, 424, 425, 426, 427,428,429, 430, 431, 432, 433, 434, 435, 436, 437,438,439, 440, 441,442 443, 444, 445, 446, 447, 448,449, 450, 451,452, 453, 454, 455, 456, 457, 458,459, 460, 461,462, 463. 464, 465, 466, 467, 468, 469,470, 471,472, 473, 474, 475, 476, 477, 478, 479, 480, 481,482, 483,484. 485, 486, 487, 488, 489, 490, 491,492, 493,494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505 506, 507,508,509,510, 511,512,513,514,515, 516,517,518,519, 520, 521, 522, 523, 524, 525, 526. 527,528,529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547. 548,549, 550,551,552, 553,554,555,556,557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568. 569, 570, 571,572, 573, 574, 575, 576, 577, 578,134IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620,621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641,642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662,663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683,684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705, provided that the VH comprises one or more mutations selected from the group consisting of: G26A, G26C, G26D, G26E, G26F, G26H, G26I, G26K, G26L, G26M, G26N, G26P, G26Q, G26R, G26S, G26T, G26V, G26W, G26Y, F27A, F27C, F27D, F27E, F27G, F27H, F27I, F27K, F27L, F27M, F27N, F27P, F27Q, F27R, F27S, F27T, F27V, F27W, F27Y, T28A, T28C, T28D, T28E, T28F, T28G, T28H, T28I, T28K, T28L, T28M, T28N, T28P, T28Q, T28R, T28S, T28V, T28W, T28Y, F29A, F29C, F29D, F29E, F29G, F29H, F29I, F29K, F29L, F29M, F29N, F29P, F29Q, F29R, F29S, F29T, F29V, F29W, F29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31C, D31E, D31F, D31G, D31H, D31I, D31K, D31L, D31M, D31N, D31P, D31Q, D31R, D31S, D31T, D31V, D31W, D31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, Y33A, Y33C, Y33D, Y33E, Y33F, Y33G, Y33H, Y33I, Y33K, Y33L, Y33M, Y33N, Y33P, Y33Q, Y33R, Y33S, Y33T, Y33V, Y33W, M34A, M34C, M34D, M34E, M34F, M34G, M34H, M34I, M34K, M34L, M34N, M34P, M34Q, M34R, M34S, M34T, M34V, M34W, M34Y, S35A, S35C, S35D, S35E, S35F, S35G, S35H, S35I, S35K, S35L, S35M, S35N, S35P, S35Q, S35R, S35T, S35V, S35W, S35Y, Y50A, Y50C, Y50D, Y50E, Y50F, Y50G, Y50H, Y50I, Y50K, Y50L, Y50M, Y50N, Y50P, Y50Q, Y50R, Y50S, Y50T, Y50V, Y50W, 151 A, 151C, I51D, 15 IE, 15 IF, 151G, 151H, 15 IK, I51L, I51M, I51N, I51P, I51Q, I51R, 15 IS, I51T, I51V, I51W, I51Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, R53A, R53C, R53D, R53E, R53F, R53G, R53H, R53I, R53K, R53L, R53M, R53N, R53P, R53Q, R53S, R53T, R53V, R53W, R53Y, S54A, S54C, S54D, S54E, S54F, S54G, S54H, S54I, S54K, S54L, S54M, S54N, S54P, S54Q, S54R, S54T, S54V, S54W, S54Y, G55A, G55C, G55D, G55E, G55F, G55H, G55I, G55K, G55L, G55M, G55N, G55P, G55Q, G55R, G55S, G55T, G55V, G55W, G55Y, S56A, S56C, S56D, S56E, S56F, S56G, S56H, S56I, S56K, S56L, S56M, S56N, S56P, S56Q, S56R, S56T, S56V, S56W, S56Y, T57A, T57C, T57D, T57E, T57F, T57G, T57H, T57I, T57K, T57L, T57M, T57N, T57P, T57Q, T57R, T57S, T57V, T57W, T57Y, K58A, K58C, K58D, K58E, K58F, K58G, K58H, K58I, K58L, K58M, K58N, K58P, K58Q, K58R, K58S, K58T, K58V, K58W, K58Y, Y59A, Y59C, Y59D, Y59E,135IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTY59F, Y59G, Y59H, Y59I, Y59K, Y59L, Y59M, Y59N, Y59P, Y59Q, Y59R, Y59S, Y59T, Y59V, Y59W, Y60A, Y60C, Y60D, Y60E, Y60F, Y60G, Y60H, Y60I, Y60K, Y60L, Y60M, Y60N, Y60P, Y60Q, Y60R, Y60S, Y60T, Y60V, Y60W, A61C, A61D, A61E, A61F, A61G, A61H, A61I, A61K, A61L, A61M, A61N, A61P, A61Q, A61R, A61S, A61T, A61V, A61W, A61Y, D62A, D62C, D62E, D62F, D62G, D62H, D62I, D62K, D62L, D62M, D62N, D62P, D62Q, D62R, D62S, D62T, D62V, D62W, D62Y, S63A, S63C, S63D, S63E, S63F, S63G, S63H, S63I, S63K, S63L, S63M, S63N, S63P, S63Q, S63R, S63T, S63V, S63W, S63Y, V64A, V64C, V64D, V64E, V64F, V64G, V64H, V64I, V64K, V64L, V64M, V64N, V64P, V64Q, V64R, V64S, V64T, V64W, V64Y, K65A, K65C, K65D, K65E, K65F, K65G, K65H, K65I, K65L, K65M, K65N, K65P, K65Q, K65R, K65S, K65T, K65V, K65W, K65Y, G66A, G66C, G66D, G66E, G66F, G66H, G66I, G66K, G66L, G66M, G66N, G66P, G66Q, G66R, G66S, G66T, G66V, G66W, G66Y, A97C, A97D, A97E, A97F, A97G, A97H, A97I, A97K, A97L, A97M, A97N, A97P, A97Q, A97R, A97S, A97T, A97V, A97W, A97Y, R98A, R98C, R98D, R98E, R98F, R98G, R98H, R98I, R98K, R98L, R98M, R98N, R98P, R98Q, R98S, R98T, R98V, R98W, R98Y, D99A, D99C, D99E, D99F, D99G, D99H, D99I, D99K, D99L, D99M, D99N, D99P, D99Q, D99R, D99S, D99T, D99V, D99W, D99Y, E100A, E100C, E100D, E100F, E100G, E100H, E1OOI, E100K, E100L, E100M, E100N, E1OOP, E1OOQ, E100R, E1OOS, E100T, E100V, E100W, E100Y, N101A, N101C, N101D, N101E, N101F, N101G, N101H, N1O1I, N101K, N101L, N101M, N1O1P, N101Q, N101R, N1O1S, N101T, N101V, N101W, N101Y, Y102A, Y102C, Y102D, Y102E, Y102F, Y102G, Y102H, Y102I, Y102K, Y102L, Y102M, Y102N, Y102P, Y102Q, Y102R, Y102S, Y102T, Y102V, Y102W, A103C, A103D, A103E, A1O3F, A103G, A103H, A103I, A103K, A103L, A103M, A103N, A103P, A1O3Q, A103R, A1O3S, A103T, A103V, A103W, A103Y, L104A, L104C, L104D, L104E, L104F, L104G, L104H, L104I, L104K, L104M, L104N, L104P, L104Q, L104R, L104S, L104T, L104V, L104W, L104Y, D105A, D105C, D105E, D105F, D105G, D105H, D105I, D105K, D105L, D105M, D105N, D105P, D1O5Q, D105R, D1O5S, D105T, D105V, D105W, D105Y, W106A, W106C, W106D, W106E, W106F, W106G, W106H, W1O6I, W106K, W106L, W106M, W106N, W106P, W106Q, W106R, W106S, W106T, W106V, or W106Y; and the VL comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780,136IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801,802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822,823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843,844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864,865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885,886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906,907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927,928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948,949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969,970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990,991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024,1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040,1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056,1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072,1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088,1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104,1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120,1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136,1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152,1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168,1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184,1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200,1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216,1217, or 1218, provided that the VL comprises one or more mutations selected from the group consisting of: Q24A, Q24C, Q24D, Q24E, Q24F, Q24G, Q24H, Q24I, Q24K, Q24L, Q24M, Q24N, Q24P, Q24R, Q24S, Q24T, Q24V, Q24W, Q24Y, A25C, A25D, A25E, A25F, A25G, A25H, A25I, A25K, A25L, A25M, A25N, A25P, A25Q, A25R, A25S, A25T, A25V, A25W, A25Y, S26A, S26C, S26D, S26E, S26F, S26G, S26H, S26I, S26K, S26L, S26M, S26N, S26P, S26Q, S26R, S26T, S26V, S26W, S26Y, Q27A, Q27C, Q27D, Q27E, Q27F, Q27G, Q27H, Q27I, Q27K, Q27L, Q27M, Q27N, Q27P, Q27R, Q27S, Q27T, Q27V, Q27W, Q27Y, D28A, D28C, D28E, D28F, D28G, D28H, D28I,137IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTD28K, D28L, D28M, D28N, D28P, D28Q, D28R, D28S, D28T, D28V, D28W, D28Y, I29A, I29C, I29D, I29E, I29F, I29G, I29H, I29K, I29L, I29M, I29N, I29P, I29Q, I29R, I29S, I29T, I29V, I29W, I29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, N31A, N31C, N31D, N31E, N31F, N31G, N31H, N31I, N31K, N31L, N31M, N31P, N31Q, N31R, N31S, N31T, N31V, N31W, N31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, L33A, L33C, L33D, L33E, L33F, L33G, L33H, L33I, L33K, L33M, L33N, L33P, L33Q, L33R, L33S, L33T, L33V, L33W, L33Y, N34A, N34C, N34D, N34E, N34F, N34G, N34H, N34I, N34K, N34L, N34M, N34P, N34Q, N34R, N34S, N34T, N34V, N34W, N34Y, D50A, D50C, D50E, D50F, D50G, D50H, D50I, D50K, D50L, D50M, D50N, D50P, D50Q, D50R, D50S, D50T, D50V, D50W, D50Y, A51C, A51D, A51E, A51F, A51G, A51H, A51I, A51K, A51L, A51M, A51N, A51P, A51Q, A51R, A51S, A51T, A51V, A51W, A51Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, N53A, N53C, N53D, N53E, N53F, N53G, N53H, N53I, N53K, N53L, N53M, N53P, N53Q, N53R, N53S, N53T, N53V, N53W, N53Y, L54A, L54C, L54D, L54E, L54F, L54G, L54H, L54I, L54K, L54M, L54N, L54P, L54Q, L54R, L54S, L54T, L54V, L54W, L54Y, E55A, E55C, E55D, E55F, E55G, E55H, E55I, E55K, E55L, E55M, E55N, E55P, E55Q, E55R, E55S, E55T, E55V, E55W, E55Y, T56A, T56C, T56D, T56E, T56F, T56G, T56H, T56I, T56K, T56L, T56M, T56N, T56P, T56Q, T56R, T56S, T56V, T56W, T56Y, Q89A, Q89C, Q89D, Q89E, Q89F, Q89G, Q89H, Q89I, Q89K, Q89L, Q89M, Q89N, Q89P, Q89R, Q89S, Q89T, Q89V, Q89W, Q89Y, H90A, H90C, H90D, H90E, H90F, H90G, H90I, H90K, H90L, H90M, H90N, H90P, H90Q, H90R, H90S, H90T, H90V, H90W, H90Y, Y91A, Y91C, Y91D, Y91E, Y91F, Y91G, Y91H, Y91I, Y91K, Y91L, Y91M, Y91N, Y91P, Y91Q, Y91R, Y91S, Y91T, Y91V, Y91W, E92A, E92C, E92D, E92F, E92G, E92H, E92I, E92K, E92L, E92M, E92N, E92P, E92Q, E92R, E92S, E92T, E92V, E92W, E92Y, D93A, D93C, D93E, D93F, D93G, D93H, D93I, D93K, D93L, D93M, D93N, D93P, D93Q, D93R, D93S, D93T, D93V, D93W, D93Y, Y94A, Y94C, Y94D, Y94E, Y94F, Y94G, Y94H, Y94I, Y94K, Y94L, Y94M, Y94N, Y94P, Y94Q, Y94R, Y94S, Y94T, Y94V, Y94W, P95A, P95C, P95D, P95E, P95F, P95G, P95H, P95I, P95K, P95L, P95M, P95N, P95Q, P95R, P95S, P95T, P95V, P95W, P95Y, L96A, L96C, L96D, L96E, L96F, L96G, L96H, L96E L96K, L96M, L96N, L96P, L96Q, L96R, L96S, L96T, L96V, L96W, L96Y, T97A, T97C, T97D, T97E, T97F, T97G, T97H, T97I, T97K, T97L, T97M, T97N, T97P, T97Q, T97R, T97S, T97V, T97W, or T97Y.138IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0181] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of the VH sequences provided in the VH Variant Table 2, provided that the VH comprises at least one of mutations as set forth in the table.

[0182] In some embodiments, an antibody, or an antigen-binding fragment thereof, comprises a VL chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence to any one of the VL sequences provided in the VL Variant Table 3, provided that the VL comprises at least one of mutations as set forth in the table.

[0183] In some embodiments, an antibody is provided comprising i) a VH having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of the VH sequences provided in the VH Variant Table 2, provided that the VH comprises at least one of mutations as set forth in the table; and ii) a VL of SEQ ID NO: 2 or a variant thereof as provided for herein. In some embodiments, the VL comprises a VL chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence to any one of the VL sequences provided in the VL Variant Table 3, provided that the VL comprises at least one of mutations as set forth in the table.

[0184] In some embodiments, an antibody is provided comprising i) a VL having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence identity to any one of the VL sequences provided in the VL Variant Table 3, provided that the VL comprises at least one of mutations as set forth in the table; and ii) a VH of SEQ ID NO: 1 or a variant thereof as provided for herein. In some embodiments, the VH comprises a VH chain having at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% amino acid sequence to any one of the VH sequences provided in the VH Variant Table 2, provided that the VH comprises at least one of mutations as set forth in the table.

[0185] In some embodiments, the antibody comprises a Fc domain. The Fc domain can be linked to the heavy or light chain of the antibody. In some embodiments, the Fc domain comprises a mutation to extend the half-life of the antibody. In some embodiments, the Fc domain comprises a mutation such as139IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT those described in U.S. Patent No. 7,670,600, which is hereby incorporated by reference in its entirety. In some embodiment, the constant region comprises a mutation at position at amino acid residue 428 relative to a wild-type human IgG constant domain, numbered according to the EU numbering index of Kabat. Without being bound to any particular theory, an antibody comprising a mutation that corresponds to residue 428 can have an increased half-life compared to the half-life of an IgG having the wild-type human IgG constant domain. In some embodiments, the mutation is a substitution of the native residue with a threonine, leucine, phenylalanine or serine. In some embodiments, the antibody further comprises one or more amino acid substitutions relative to the corresponding wild-type human IgG constant domain at one or more of amino acid residues 251-256, 285-290, 308-314, 385-389, and 429-436, numbered according to the Kabat EU numbering index. The specific mutations or substitutions at these positions are described in U.S. Patent No. 7,670,600, which is hereby incorporated by reference in its entirety.

[0186] Other mutations can be used in the Fc domain, such as those provided for in U.S. Patent No. 8,394,925, which is hereby incorporated by reference in its entirety. In some embodiments, the Fc region is a variant Fc region comprising amino acid substitutions at positions 428 and 434, wherein the amino acid substitutions are a leucine that is not the wild-type amino acid at position 428 and a serine that is not the wild-type amino acid at position 434, wherein the polypeptide is an antibody and wherein numbering is according to the EU Index in Kabat et al. In some embodiments, the Fc region comprises a S228P, L235E, M428L, or N434S substitution. In some embodiments, the Fc region comprises a M428L substitution. In some embodiments, the Fc region comprises a N434S substitution. In some embodiments, the Fc region comprises a M428L and a N434S substitution. In some embodiments, the Fc region comprises a M252Y, S254T, and / or T256E substitution.

[0187] In some embodiments, the antibody comprises a constant region as set forth below with or without the mutations provided for in the list below:>IgG4 S228P L235E LSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPE VTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSHYTQKSLSLSLGK (SEQ ID NO: 1233);>IgG4 S228P L235E YTE140IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLYITREPE VTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK (SEQ ID NO: 1234).

[0188] In some embodiments, the antibody comprises a constant region as provided herein, wherein the C-terminal lysine (K) amino acid has been deleted. In some embodiments, the antibody comprises a constant region as set follows:>IgG4 S228P L235E LS-truncASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLMISRTPE VTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVLHEALHSHYTQKSLSLSLG (SEQ ID NO: 1235);>IgG4 S228P L235E YTE-truncASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSW TVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLFPPKPKDTLYITREPE VTCVWDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRWSVLTVLHQDWLNGKEYKCKVSNKG LPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPP VLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (SEQ ID NO: 1236).

[0189] In some embodiments, the antibody, such as the light chain, comprises a kappa constant region, such as the human constant domain, which can comprise a sequence of: RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKD STYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (human kappa constant domain, SEQ ID NO: 1237).

[0190] The term “purified” with referenced to an antibody refers to an antibody that is substantially free of other material that associates with the molecule in its natural environment. For instance, a purified protein is substantially free of the cellular material or other proteins from the cell or tissue from which it is derived. The term refers to preparations where the isolated protein is sufficiently pure to be analyzed, or at least 70% to 80% (w / w) pure, at least 80%-90% (w / w) pure, 90-95% pure; and, at least 95%, 96%, 97%, 98%, 99%, or 100% (w / w) pure. In some embodiments, the antibody is purified.141IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTCOMPOSITIONS, DOSES, AND METHODS OF ADMINISTRATION

[0191] In some embodiments, a pharmaceutical composition is provided. In some embodiments, the pharmaceutical composition comprises an antibody, or an antigen-binding fragment thereof, as provided for herein.

[0192] In some embodiments, to prepare pharmaceutical or sterile compositions of the anti-Cls antibodies or other proteins provided herein, the antibody, or the antigen-binding fragment thereof, or other proteins provided herein are admixed with a pharmaceutically acceptable carrier or excipient. See, e.g., Remington's Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).

[0193] Formulations of therapeutic or the antibodies provided herein may be prepared by mixing with acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions (see, e.g., Hardman, et al. (2001) Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al.(eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY ; Lieberman, et al.(eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY). In some embodiments, the antibodies are diluted to an appropriate concentration in a sodium acetate solution pH 5-6, and NaCl or sucrose is added for tonicity. Additional agents, such as polysorbate 20 or polysorbate 80, may be added to enhance stability.

[0194] Toxicity and therapeutic efficacy of the antibody compositions, administered alone or in combination with another agent, can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index (LD50 / ED50). In particular’ aspects, antibodies exhibiting high therapeutic indices are desirable. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration.142IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0195] In some embodiments, a composition is administered to a subject in accordance with the Physicians' Desk Reference 2003 (Thomson Healthcare; 57th edition (November 1, 2002)).

[0196] The mode of administration can vary. Suitable routes of administration include oral, rectal, transmucosal, intestinal, parenteral; intramuscular, subcutaneous, intradermal, intramedullary, intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, intraocular, inhalation, insufflation, topical, cutaneous, transdermal, or intra-arterial. In some embodiments, the composition is an injectable pharmaceutical composition. In some embodiments, the composition is formulated for intravenous or subcutaneous injection. In some embodiments, the composition is formulated for intravenous injection. In some embodiments, the composition is formulated for subcutaneous injection.

[0197] In some embodiments, the antibody, or the antigen-binding fragment thereof, can be administered by an invasive route such as by injection. In some embodiments, the antibodies or the antigen-binding fragment thereof, or pharmaceutical composition thereof, is administered intravenously, subcutaneously, intramuscularly, intraarterially, intra-articularly (e.g. in arthritis joints), intratumorally, or by inhalation, aerosol delivery. Administration by non-invasivc routes e.g., orally; for example, in a pill, capsule or tablet) is also within the scope of the present embodiments.

[0198] In some embodiments, the anti-Cls antibody, or the antigen-binding fragment thereof, is administered in combination with at least one additional therapeutic agent, such as, but not limited to any therapeutic used to treat the disorders provided for herein. In some embodiments, the antibody is administered in combination with another treatment for the disorders provided for herein.

[0199] Compositions can be administered with medical devices known in the art. For example, a pharmaceutical composition of the invention can be administered by injection with a hypodermic needle, including, e.g., a prefilled syringe or autoinjector.

[0200] The pharmaceutical compositions may also be administered with a needleless hypodermic injection device; such as the devices disclosed in U.S. Patent Nos. 6,620,135; 6,096,002; 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824 or 4,596,556.

[0201] The pharmaceutical compositions may also be administered by infusion. Examples of well- known implants and modules form administering pharmaceutical compositions include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Patent. No. 4,439,196, which143IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT discloses an osmotic drug delivery system having multi-chamber compartments. Many other such implants, delivery systems, and modules are well known to those skilled in the ait.

[0202] Other devices that can also be used, including, but are not limited to those provided for in U.S. Patent No. 11779704, U.S. Patent No. 11654244, U.S. Patent No. 11612690, U.S. Patent No. 11607494, U.S. Patent No. 11602596, U.S. Patent No. 11541189, U.S. Patent No. 11534556, U.S. Patent No.11524118, U.S. Patent No. 11458257, U.S. Patent No. 11458254, U.S. Patent No. 11426529, U.S.Patent No. 11426524, U.S. Patent No. 11406768, U.S. Patent No. 11383044, U.S. Patent No. 11331437, U.S. Patent No. 11311681, U.S. Patent No. 11291771, U.S. Patent No. 11273265, U.S. Patent No. 11253653, U.S. Patent No. 11229748, U.S. Patent No. 11224697, U.S. Patent No. 11154654, U.S.Patent No. 11141536, U.S. Patent No. 11103647, U.S. Patent No. 11103646, U.S. Patent No. 11065393, U.S. Patent No. 11058822, U.S. Patent No. 10983187, U.S. Patent No. 10980947, U.S. Patent No. 10973988, U.S. Patent No. 10960143, U.S. Patent No. 10894127, U.S. Patent No. 10881799, U.S.Patent No. 10850032, U.S. Patent No. 10814066, U.S. Patent No. 10799647, U.S. Patent No. 10709840, U.S. Patent No. 10632260, U.S. Patent No. 10610646, U.S. Patent No. 10603443, U.S. Patent No. 10596327, U.S. Patent No. 10569025, U.S. Patent No. 10569019, U.S. Patent No. 10561799, U.S.Patent No. 10537685, U.S. Patent No. 10518035, U.S. Patent No. 10493213, U.S. Patent No. 10493212, U.S. Patent No. 10485933, U.S. Patent No. 10471215, U.S. Patent No. 10441729, U.S. Patent No. 10413673, U.S. Patent No. 10376641, U.S. Patent No. 10350363, U.S. Patent No. 10350359, U.S.Patent No. 10350358, U.S. Patent No. 10350356, U.S. Patent No. 10335543, U.S. Patent No. 10331996, U.S. Patent No. 10300211, U.S. Patent No. 10201659, U.S. Patent No. 10149948, U.S. Patent No. 10149945, U.S. Patent No. 10143806, U.S. Patent No. 10137253, U.S. Patent No. 10099017, U.S.Patent No. 9962496, U.S. Patent No. 9962495, U.S. Patent No. 9867948, U.S. Patent No. 9855392, U.S.Patent No. 9821121, U.S. Patent No. 9750887, U.S. Patent No. 9744311, U.S. Patent No. 9566389, U.S.Patent No. 9539385, U.S. Patent No. 9457156, U.S. Patent No. 9320853, U.S. Patent No. 9289561, U.S.Patent No. 9278178, U.S. Patent No. 9205195, U.S. Patent No. 9138543, U.S. Patent No. 9057369, U.S.Patent No. 8998876, U.S. Patent No. 8992487, U.S. Patent No. 8956330, U.S. Patent No. 8945053, U.S.Patent No. 8939944, U.S. Patent No. 8834431, U.S. Patent No. 8827963, U.S. Patent No. 8758292, U.S.Patent No. 8734403, U.S. Patent No. 8721615, U.S. Patent No. 8690837, U.S. Patent No. 8679071, U.S.Patent No. 8672901, U.S. Patent No. 8657788, U.S. Patent No. 8647307, U.S. Patent No. 8591465, U.S.Patent No. 8562570, U.S. Patent No. 8556847, U.S. Patent No. 8491538, U.S. Patent No. 8439864, U.S.Patent No. 8409149, U.S. Patent No. 8409148, U.S. Patent No. 8409145, U.S. Patent No. 8398594, U.S.144IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTPatent No. 8398593, U.S. Patent No. 8343103, U.S. Patent No. 8298175, U.S. Patent No. 8246577, U.S.Patent No. 8216180, U.S. Patent No. 8048037, U.S. Patent No. 8043262, U.S. Patent No. 8043249, U.S.Patent No. 8016797, U.S. Patent No. 7976509, U.S. Patent No. 7955303, U.S. Patent No. 7951113, U.S.Patent No. 7815598, U.S. Patent No. 7749186, U.S. Patent No. 7511480, U.S. Patent No. 7357790, PCTPublication No. WO2023094119, PCT Publication No. WO2023072787, PCT Publication No.WO2023072728, PCT Publication No. WO2023062178, PCT Publication No. W02023057301, PCT Publication No. WO2023057272, PCT Publication No. WO2023051963, PCT Publication No.WO2023046741, PCT Publication No. WO2023046348, PCT Publication No. W02023017114, PCT Publication No. W02023012030, PCT Publication No. W02023001988, PCT Publication No.W02023001430, PCT Publication No. W02023001424, PCT Publication No. WO2023275273, PCT Publication No. WO2022268389, PCT Publication No. WO2022248119, PCT Publication No.WO2022248113, PCT Publication No. WO2022184539, PCT Publication No. WO2022184388, PCT Publication No. WO2022135921, PCT Publication No. WO2022128606, PCT Publication No.WO2022128385, PCT Publication No. WO2022106197, PCT Publication No. WO2022096352, PCT Publication No. W02022090047, PCT Publication No. WO2022069617, PCT Publication No.WO2022069175, PCT Publication No. WO2022058221, PCT Publication No. W02022053307, PCT Publication No. WO2022053248, PCT Publication No. WO2015127965, or PCT Publication No. WO2013170392, each of which is hereby incorporated by reference in its entirety.

[0203] Other devices that can be used to deliver injectables to a subject, including those that can handle larger volumes, include devices provided for in U.S. Patent No. 11833326, U.S. Patent No. 11786173, U.S. Patent No. 11744777, U.S. Patent No. 11571361, U.S. Patent No. 11571360, U.S. Patent No.11571164, U.S. Patent No. 11478583, U.S. Patent No. 11413393, U.S. Patent No. 11109800, U.S. Patent No. 11040138, U.S. Patent No. 11033680, U.S. Patent No. 10729842, U.S. Patent No. 10507285, U.S. Patent No. 10449293, U.S. Patent No. 9925333, U.S. Patent Application Publication No.20230293108, U.S. Patent Application Publication No. 20230285243, U.S. Patent Application Publication No. 20230190582, U.S. Patent Application Publication No. 20230132382, U.S. Patent Application Publication No. 20230104373, U.S. Patent Application Publication No. 20220387705, U.S. Patent Application Publication No. 20220280385, U.S. Patent Application Publication No.20220023533, U.S. Patent Application Publication No. 20210386621, U.S. Patent Application Publication No. 20210338928, U.S. Patent Application Publication No. 20200338257, U.S. Patent Application Publication No. 20200061292, U.S. Patent Application Publication No. 20180207369, PCT145IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENTPublication No. WO2022031784, PCT Publication No. W02022006063, PCT Publication No. WO2021016567, PCT Publication No. WO2020142544, PCT Publication No. W02020118165, PCT Publication No. W02020086581, PCT Publication No. WO2019079335, PCT Publication No. WO2019075337, PCT Publication No. WO2018232171, PCT Publication No. WO2018218082, PCT Publication No. WO2018165588, PCT Publication No. WO2017014847, PCT Publication No. WO2016154413, or PCT Publication No. WO2016153747, each of which is hereby incorporated by reference in its entirety.

[0204] Alternately, one may administer the antibody in a local rather than systemic manner, for example, via injection of the antibody directly into an arthritic joint or pathogen-induced lesion characterized by immunopathology, often in a depot or sustained release formulation. Furthermore, one may administer the antibody in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody, targeting, for example, arthritic joint or pathogen-induced lesion characterized by immunopathology. The liposomes will be targeted to and taken up selectively by the afflicted tissue.

[0205] The administration regimen depends on several factors, including the scrum or tissue turnover rate of the therapeutic antibody, the level of symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of the target cells in the biological matrix. Preferably, the administration regimen delivers sufficient therapeutic antibody to effect improvement in the target disease state, while simultaneously minimizing undesired side effects. Accordingly, the amount of biologic delivered depends in part on the particular therapeutic antibody and the severity of the condition being treated. Guidance in selecting appropriate doses of therapeutic antibodies is available (see, e.g., Wawrzynczak (1996) Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY; Bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, NY ; Baert, et al. (2003) New Engl. J. Med. 348:601-608; Milgrom et al. (1999) New Engl. J. Med. 341:1966-1973;Slamon et al. (2001) New Engl. J. Med. 344:783-792; Beniaminovitz et al. (2000) New Engl. J. Med. 342:613-619; Ghosh et al. (2003) New Engl. J. Med. 348:24-32; Lipsky et al. (2000) New Engl. J. Med. 343:1594-1602).

[0206] Determination of the appropriate dose can be made by the clinician, e.g., using parameters or factors known or suspected in the art to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects. Important diagnostic measures146IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT include those of symptoms of, e.g., the inflammation or level of inflammatory cytokines produced. In general, it is desirable that a biologic that will be used is derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the reagent. In the case of human subjects, for example, chimeric, humanized and fully human antibodies may be desirable.

[0207] Polypeptides, antibodies, or antigen-binding fragments thereof provided for herein may be provided by continuous infusion, or by doses administered, e.g., daily, 1-7 times per week, weekly, biweekly, every three weeks, monthly, bimonthly, or quarterly. In some embodiments, a total weekly dose is generally at least 0.05 pg / kg body weight, more generally at least 0.2 pg / kg, 0.5 pg / kg, 1 pg / kg, 10 pg / kg, 100 pg / kg, 0.25 mg / kg, 1.0 mg / kg, 2.0 mg / kg, 5.0 mg / kg, 10 mg / kg, 25 mg / kg, 50 mg / kg or more (see, e.g., Yang, et al. (2003) New Engl. J. Med. 349:427-434; Herold, et al. (2002) New Engl. J. Med. 346:1692-1698; Liu, et al. (1999) J. Neurol. Neurosurg. Psych. 67:451-456; Portielji, et al. (20003) Cancer Immunol. Immunother. 52:133-144). Doses may also be provided to achieve a pre-determined target concentration of the antibody in the subject’s serum, such as 0.1, 0.3, 1, 3, 10, 30, 100, 300, 400, 500, 600 pg / ml or more.

[0208] In other embodiments, the antibody is administered subcutaneously or intravenously, on a weekly, biweekly, “every 4 weeks,” monthly, bimonthly, or quarterly basis at 10, 20, 50, 80, 100, 200, 300, 400, 500, 600, 1000 or 2500 mg / subject or as otherwise provided for herein.

[0209] Accordingly, in some embodiments, provided are methods of administering a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided herein.

[0210] In some embodiments, the antibody, or the antigen-binding fragment thereof, as provided for herein, is administered at a dose of about 1 mg / kg to about 60 mg / kg. In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg,147IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg. In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg.

[0211] In some embodiments, the antibody, or the antigen -binding fragment thereof, is administered at a dose of about 60 mg to about 7200 mg. In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a dose of about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900148IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT mg, about 2950 mg, about 3000 mg, about 3050 mg, about 3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg, about 3450 mg, about 3500 mg, about 3550 mg, about 3600 mg, or about 7200 mg. In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a dose of 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg,360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg,590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg,820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg,2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg,2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg,3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, or 3600 mg.

[0212] In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose. In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a one or more subsequent dose. In some embodiments, the antibody, or the antigenbinding fragment thereof, is administered at a first dose and / or one or more subsequent dose. In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose and one or more subsequent dose.

[0213] In some embodiments, the first dose is about 1 mg / kg to about 60 mg / kg. In some embodiments, the first dose is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg,149IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg.In some embodiments, the first dose is 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg.

[0214] In some embodiments, the first dose is about 60 mg to about 7200 mg. In some embodiments, the first dose is about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, about 3000150IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT mg, about 3050 mg, about 3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg, about 3450 mg, about 3500 mg, about 3550 mg, about 3600 mg, or about 7200 mg. In some embodiments, the first dose is 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 10 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg,2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg,2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg,3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, or 3600 mg.

[0215] In some embodiments, the one or more subsequent dose is about 1 mg / kg to about 60 mg / kg. In some embodiments, the one or more subsequent dose is about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg. In some embodiments, the one or more subsequent dose is 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg,151IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg.

[0216] In some embodiments, the one or more subsequent dose is about 60 mg to about 7200 mg. In some embodiments, the one or more subsequent dose is about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, about 3000 mg, about 3050 mg, about 3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg, about 3450 mg, about 3500 mg, about 3550 mg, about 3600 mg, or about 7200 mg. In some embodiments, the one or more subsequent dose is 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400152IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, or 3600 mg.

[0217] In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of about 1 mg / kg to about 60 mg / kg and one or more subsequent dose of about 1 mg / kg to about 60 mg / kg. In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg; and one or more subsequent dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40153IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg.

[0218] In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg,20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg,39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg,58 mg / kg, 59 mg / kg, or 60 mg / kg; and one or more subsequent dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg,24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg,43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg.

[0219] In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of about 60 mg to about 7200 mg and one or more subsequent dose of about 1 mg / kg to about 60 mg / kg. In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg,154IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, about 3000 mg, about 3050 mg, about 3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg, about 3450 mg, about 3500 mg, about 3550 mg, about 3600 mg, or about 7200 mg; and one or more subsequent dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg.

[0220] In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850155IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg,1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg,2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg,2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg,3400 mg, 3450 mg, 3500 mg, 3550 mg, or 3600 mg; and one or more subsequent dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg.

[0221] In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of about 1 mg / kg to about 60 mg / kg and one or more subsequent dose of about 60 mg to about 7200 mg. In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg; and one or more subsequent dose of about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300156IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, about 3000 mg, about 3050 mg, about 3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg, about 3450 mg, about 3500 mg, about 3550 mg, about 3600 mg, or about 7200 mg.

[0222] In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, 32 mg / kg, 33 mg / kg, 34 mg / kg, 35 mg / kg, 36 mg / kg, 37 mg / kg, 38 mg / kg, 39 mg / kg, 40 mg / kg, 41 mg / kg, 42 mg / kg, 43 mg / kg, 44 mg / kg, 45 mg / kg, 46 mg / kg, 47 mg / kg, 48 mg / kg, 49 mg / kg, 50 mg / kg, 51 mg / kg, 52 mg / kg, 53 mg / kg, 54 mg / kg, 55 mg / kg, 56 mg / kg, 57 mg / kg, 58 mg / kg, 59 mg / kg, or 60 mg / kg; and one or more subsequent dose of 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg,330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg,157IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg,1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 mg,2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg, 2550 mg,2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg,3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, or3600 mg.

[0223] In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of about 60 mg to about 7200 mg and one or more subsequent dose of about 60 mg to about 7200 mg. In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg,158IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, about 3000 mg, about 3050 mg, about 3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg, about 3450 mg, about 3500 mg, about 3550 mg, about 3600 mg, or about 7200 mg; and one or more subsequent dose of about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, about 3000 mg, about 3050 mg, about 3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg, about 3450 mg, about 3500 mg, about 3550 mg, about 3600 mg, or about 7200 mg.

[0224] In some embodiments, the antibody, or the antigen-binding fragment thereof, is administered at a first dose of 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390159IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg,1900 mg, 1950 mg, 2000 mg, 2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg,2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg,2900 mg, 2950 mg, 3000 mg, 3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg,3400 mg, 3450 mg, 3500 mg, 3550 mg, or 3600 mg; and one or more subsequent dose of 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg, 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg,1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg,2050 mg, 2100 mg, 2150 mg, 2200 mg, 2250 mg, 2300 mg, 2350 mg, 2400 mg, 2450 mg, 2500 mg,2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg,3050 mg, 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg,3550 mg, or 3600 mg.[002251 In some embodiments, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered in a dose of about 3 g to about 5 g. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered in a dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about 4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, or about 5.0 g. In some160IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered in a dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, or 5.0 g.

[0226] In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered in a first dose of about 3 g to about 5 g. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered in a first dose of about 3.0 g, about 3.1 g, about 3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, or about 5.0 g. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered in a first dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, or 5.0 g.

[0227] In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered in a one or more subsequent dose of about 3 g to about 5 g. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered in a one or more subsequent dose of about 3.0 g, about 3.1 g, about3.2 g, about 3.3 g, about 3.4 g, about 3.5 g, about 3.6 g, about 3.7 g, about 3.8 g, about 3.9 g, about 4.0 g, about 4.1 g, about 4.2 g, about 4.3 g, about 4.4 g, about 4.5 g, about 4.6 g, about 4.7 g, about 4.8 g, about 4.9 g, or about 5.0 g. In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered in a one or more subsequent dose of 3.0 g, 3.1 g, 3.2 g, 3.3 g, 3.4 g, 3.5 g, 3.6 g, 3.7 g, 3.8 g, 3.9 g, 4.0 g, 4.1 g, 4.2 g, 4.3 g, 4.4 g, 4.5 g, 4.6 g, 4.7 g, 4.8 g, 4.9 g, or 5.0 g.

[0228] In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered by intravenous infusion. In some embodiments, the intravenous infusion is administered over about 30 minutes to about 90 minutes, over about 45 minutes to about 90 minutes, or over about 60 minutes to about 90 minutes. In some embodiments, the intravenous infusion is administered over about 30 minutes to about 90 minutes. In some embodiments, the intravenous infusion is administered over about 45 minutes to about 90 minutes. In some embodiments, the intravenous infusion is administered over about 60 minutes to about 90 minutes.161IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0229] In some embodiments, a dosage form in a container is provided. In some embodiments, the dosage form comprises a pharmaceutical composition such as those provided herein. In some embodiments, the container is a plastic vial or a glass vial.

[0230] In some embodiments, a polypeptide, an antibody, or an antigen-binding fragment thereof, such as those provided for herein, is administered as part of a pharmaceutical composition comprising the antibody, or the antigen-binding fragment thereof, such as those provided for herein, and at least one pharmaceutically acceptable excipient.

[0231] Polypeptides, antibodies, antigen-binding fragments thereof, and pharmaceutical compositions may be administered with medical devices known in the art. For example, a pharmaceutical composition of the invention can be administered by injection with a hypodermic needle, including, e.g., a prefilled syringe or autoinjector.

[0232] In some embodiments, a kit, comprising a pharmaceutical composition, such as those provided herein, is provided.

[0233] In some embodiments, to prepare pharmaceutical or sterile compositions of the antibodies or other proteins provided herein, the antibody or antigen-binding fragment thereof or other proteins provided herein are admixed with a pharmaceutically acceptable carrier or excipient. See, e.g., Remington’s Pharmaceutical Sciences and U.S. Pharmacopeia: National Formulary, Mack Publishing Company, Easton, PA (1984).

[0234] Polypeptides, antibodies, antigen-binding fragments thereof, and pharmaceutical compositions may be prepared by mixing with acceptable carriers, excipients, or stabilizers in the form of, e.g., lyophilized powders, slurries, aqueous solutions or suspensions (see, e.g., Hardman, et al. (2001) Goodman and Gilman’s The Pharmacological Basis of Therapeutics, McGraw-Hill, New York, NY; Gennaro (2000) Remington: The Science and Practice of Pharmacy, Lippincott, Williams, and Wilkins, New York, NY; Avis, et al. (eds.) (1993) Pharmaceutical Dosage Forms: Parenteral Medications, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Tablets, Marcel Dekker, NY; Lieberman, et al. (eds.) (1990) Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker, NY; Weiner and Kotkoskie (2000) Excipient Toxicity and Safety, Marcel Dekker, Inc., New York, NY).

[0235] In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition can be administered by an invasive route such as by injection. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical162IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT composition is administered intravenously, subcutaneously, intramuscularly, intraarterially, intraarticularly (e.g. in arthritis joints), or by inhalation, aerosol delivery. Administration by non-invasive routes (e.g., orally; for example, in a pill, capsule or tablet) is also within the scope of the present embodiments.

[0236] The polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition may also be administered with a needleless hypodermic injection device; such as the devices disclosed in U.S. Patent Nos. 6,620,135; 6,096,002; 5,399,163; 5,383,851; 5,312,335;5,064,413; 4,941,880; 4,790,824 or 4,596,556.

[0237] The polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition may also be administered by infusion. Examples of well-known implants and modules form administering pharmaceutical compositions include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No. 4,447,233, which discloses a medication infusion pump for delivering medication at a precise infusion rate; U.S. Patent No. 4,447,224, which discloses a variable flow implantable infusion apparatus for continuous drug delivery; U.S. Patent. No. 4,439,196, which discloses an osmotic drug delivery system having multi-chamber compartments. Many other such implants, delivery systems, and modules are well known to those skilled in the ait.

[0238] Alternately, one may administer the pharmaceutical composition in a local rather than systemic manner, for example, via injection of the antibody directly into an arthritic joint or pathogen-induced lesion characterized by immunopathology, often in a depot or sustained release pharmaceutical composition. Furthermore, one may administer the antibody in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody, targeting, for example, arthritic joint or pathogen-induced lesion characterized by immunopathology. The liposomes will be targeted to and taken up selectively by the afflicted tissue.

[0239] The administration regimen depends on several factors, including the serum or tissue turnover rate of the therapeutic antibody, the level of symptoms, the immunogenicity of the therapeutic antibody, and the accessibility of the target cells in the biological matrix. Preferably, the administration regimen delivers sufficient therapeutic antibody to effect improvement in the target disease state, while simultaneously minimizing undesired side effects. Accordingly, the amount of biologic delivered depends in part on the particular therapeutic antibody and the severity of the condition being treated. Guidance in selecting appropriate doses of therapeutic antibodies is available (see, e.g., Wawrzynczak163IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT(1996) Antibody Therapy, Bios Scientific Pub. Ltd, Oxfordshire, UK; Kresina (ed.) (1991) Monoclonal Antibodies, Cytokines and Arthritis, Marcel Dekker, New York, NY; Bach (ed.) (1993) Monoclonal Antibodies and Peptide Therapy in Autoimmune Diseases, Marcel Dekker, New York, NY; Baert, et al. (2003) New Engl. J. Med. 348:601-608; Milgrom et al. (1999) New Engl. J. Med. 341:1966-1973; Slamon et al. (2001) New Engl. J. Med. 344:783-792; Beniaminovitz et al. (2000) New Engl. J. Med. 342:613-619; Ghosh et al. (2003) New Engl. J. Med. 348:24-32; Lipsky et al. (2000) New Engl. J. Med. 343:1594-1602).

[0240] Determination of the appropriate dose is made by the clinician, e.g., using parameters or factors known or suspected in the ail to affect treatment. Generally, the dose begins with an amount somewhat less than the optimum dose and it is increased by small increments thereafter until the desired or optimum effect is achieved relative to any negative side effects. Important diagnostic measures include those of symptoms of, e.g., the inflammation or level of inflammatory cytokines produced. In general, it is desirable that a biologic that will be used is derived from the same species as the animal targeted for treatment, thereby minimizing any immune response to the reagent. In the case of human subjects, for example, chimeric, humanized and fully human antibodies may be desirable.

[0241] The antibody, the antigen-binding fragment thereof, or the pharmaceutical composition provided herein can be provided by continuous infusion, or by doses administered, e.g., daily, 1-7 times per week, weekly, bi-weekly, monthly, bimonthly, quarterly, semiannually, annually etc. Doses may be provided, e.g., intravenously, subcutaneously, topically, orally, nasally, rectally, intramuscular, intracerebrally, intraspinally, or by inhalation. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered for at least 1-52 weeks or longer. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered for at least 1-104 weeks or longer. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered for at least 1-156 weeks or longer. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) once. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) twice. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) three times. In some embodiments, the polypeptide, the antibody, the antigen-binding164IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) four times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) five times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) six times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) seven times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) eight times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) nine times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 10 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 11 times. In some embodiments, the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 12 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 13 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 14 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 15 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 16 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 17 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 18 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 19 times. In some embodiments, the polypeptide, the antibody, the antigen-165IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT binding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 20 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 21 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 22 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 23 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 24 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g. infusion or subcutaneous injection) 25 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 26 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 27 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 28 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 29 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 30 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 31 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 32 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 33 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 34 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or166IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT subcutaneous injection) 35 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 36 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 37 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 38 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 39 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 40 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 41 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 42 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 43 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 44 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 45 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 46 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 47 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 48 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 49 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 50 times. In some embodiments, the polypeptide, the antibody, the antigen-167IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 51 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 52 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 53 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 54 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 55 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 56 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 57 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 58 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 59 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 60 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 61 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 62 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 63 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 64 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 65 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or168IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT subcutaneous injection) 66 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 67 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 68 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 69 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 70 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 71 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 72 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 73 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 74 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 75 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 76 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 77 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 78 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 79 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 80 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 81 times. In some embodiments, the polypeptide, the antibody, the antigen-169IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT binding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 82 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 83 times. In some embodiments, the polypeptide, the antibody, the antigenbinding fragment thereof, or the pharmaceutical composition is administered (e.g., infusion or subcutaneous injection) 84 times. When the polypeptide, the antibody, the antigen-binding fragment thereof, or the pharmaceutical composition is administered more than once it can be administered according to a schedule, such as the schedules provided for herein.

[0242] As used herein, “inhibit” or “treat” or “treatment” includes a postponement of development of the symptoms associated with a disorder and / or a reduction in the severity of the symptoms of such disorder. The terms further include ameliorating existing uncontrolled or unwanted symptoms, preventing additional symptoms, and ameliorating or preventing the underlying causes of such symptoms. Thus, the terms denote that a beneficial result has been conferred on a vertebrate subject with a disorder, disease or symptom, or with the potential to develop such a disorder, disease or symptom.

[0243] As used herein, the terms “therapeutically effective amount”, “therapeutically effective dose” and “effective amount” refer to an amount of the antibody, or the antigen-binding fragment thereof, that, when administered alone or in combination with an additional therapeutic agent to a cell, tissue, or subject, is effective to cause a measurable improvement in one or more symptoms of a disease or condition or the progression of such disease or condition. A therapeutically effective dose further refers to that amount of the binding compound sufficient to result in at least partial amelioration of symptoms, e.g., treatment, healing, prevention or amelioration of the relevant medical condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient administered alone, a therapeutically effective dose refers to that ingredient alone. When applied to a combination, a therapeutically effective dose refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously. An effective amount of a therapeutic will result in an improvement of a diagnostic measure or parameter by at least 10%; usually by at least 20%; preferably at least about 30%; more preferably at least 40%, and most preferably by at least 50%. An effective amount can also result in an improvement in a subjective measure in cases where subjective measures are used to assess disease severity. In some embodiments, an amount is a therapeutically effective amount if it is an amount that can be used to treat or ameliorate a condition as provided for herein.170IPTS / 200137312.1Attorney Docket No. DIN-005WO PATENT

[0244] ‘ ‘Effective amount” or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result or provides a therapeutic or prophylactic benefit. Such results may include, but are not limited to an amount that when administered to a mammal, causes a detectable level of immune cell activation compared to the immune cell activation detected in the absence of the composition. The immune response can be readily assessed by a plethora of art-recognized methods. The skilled artisan would understand that the amount of the composition administered herein varies and can be readily determined based on a number of factors such as the disease or condition being treated, the age and health and physical condition of the mammal being treated, the severity of the disease, the particular compound being administered, and the like.

[0245] As used herein, the term “individual” or “subject” or “patient” used interchangeably, means any organism, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans. In one embodiment, the subject is a human. A subject can also be referred to as a patient. In some embodiments, the subject is a subject in need thereof. A subject that is “in need thereof’ refers to a subject that has been identified as requiring treatment for the condition that is to be treated and is treated with the specific intent of treating such condition. The conditions can be, for example, any of the conditions described herein.

[0246] Accordingly, in some embodiments, methods of treating a subject with a Cis mediated disorder are provided. In some embodiments, the method comprises administering a pharmaceutical composition comprising an antibody, or an antigen-binding fragment thereof...

Claims

Attorney Docket No. DIN-005WO PATENTWHAT IS CLAIMED:

1. An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% identical to SEQ ID NO: 1; and the VL comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to SEQ ID NO: 2, wherein the VH comprises a mutation at one or more of the following positions: G26, F27, T28, F28, S30, D31, Y32, Y33, M34, S35, Y50, 151, S52, R53, S54, G55, S56, T57, K58, Y59, Y60, A61, D62, S63, V64, K65, G66, A97, R98, D99, E100, N101, Y102, A103, L104, D105, or W106, and wherein the VL comprises a one or more mutations at position selected from the group consisting of: Q24, A25, S26, Q27, D28, 129, S30, N31, Y32, L33 N34, D50, A51, S52, N53, L54, E55, T56, Q89, H90, Y91, E92, D93, Y94, P95, L96, or T97.2 The antibody, or the antigen-binding fragment thereof, of claim 1, wherein the VH comprises the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, 1225, or 1228, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, 1226, or 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221, 1227, or 1230.3 The antibody, or the antigen-binding fragment thereof, of any one of claims 1 or 2, wherein the VH comprises: the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221; the HCDR1 having an amino acid sequence of SEQ ID NO: 1225, the HCDR2 having an amino acid sequence of SEQ ID NO: 1226, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1227; or the HCDR1 having an amino acid sequence of SEQ ID NO: 1228, the HCDR2 having an amino acid sequence of SEQ ID NO: 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO:Attorney Docket No. DIN-005WO PATENT4. The antibody, or the antigen-binding fragment thereof, of any one of claims 1-3, wherein the VL comprises the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, or 1231, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, or 1232, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224.5 The antibody, or the antigen-binding fragment thereof, of any one of claims 1-4, wherein the VL comprises: the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224; or the LCDR1 having an amino acid sequence of SEQ ID NO: 1231, the LCDR2 having an amino acid sequence of SEQ ID NO: 1232, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224.6 The antibody, or the antigen-binding fragment thereof, of any one of claims 1-5, wherein the VH comprises a mutation selected from the group consisting of: G26A, G26C, G26D, G26E, G26F, G26H, G26I, G26K, G26L, G26M, G26N, G26P, G26Q, G26R, G26S, G26T, G26V, G26W, G26Y, F27A, F27C, F27D, F27E, F27G, F27H, F27I, F27K, F27L, F27M, F27N, F27P, F27Q, F27R, F27S, F27T, F27V, F27W, F27Y, T28A, T28C, T28D, T28E, T28F, T28G, T28H, T28I, T28K, T28L, T28M, T28N, T28P, T28Q, T28R, T28S, T28V, T28W, T28Y, F29A, F29C, F29D, F29E, F29G, F29H, F29I, F29K, F29L, F29M, F29N, F29P, F29Q, F29R, F29S, F29T, F29V, F29W, F29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31C, D31E, D31F, D31G, D31H, D31I, D31K, D31L, D31M, D31N, D31P, D31Q, D31R, D31S, D31T, D31V, D31W, D31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, Y33A, Y33C, Y33D, Y33E, Y33F, Y33G, Y33H, Y33I, Y33K, Y33L, Y33M, Y33N, Y33P, Y33Q, Y33R, Y33S, Y33T, Y33V, Y33W, M34A, M34C, M34D, M34E, M34F, M34G, M34H, M34I, M34K, M34L, M34N, M34P, M34Q, M34R, M34S, M34T, M34V, M34W, M34Y, S35A, S35C, S35D, S35E, S35F, S35G, S35H, S35I, S35K, S35L, S35M, S35N, S35P, S35Q, S35R, S35T, S35V, S35W, S35Y, Y50A, Y50C, Y50D, Y50E, Y50F, Y50G, Y50H, Y50I, Y50K, Y50L, Y50M, Y50N, Y50P, Y50Q, Y50R, Y50S, Y50T,Attorney Docket No. DIN-005WO PATENTY50V, Y50W, 151 A, 151C, 15 ID, 15 IE, 15 IF, 151G, 151H, 15 IK, 15 IL, 15 IM, 15 IN, 15 IP, 15 IQ, 151R, 15 IS, 15 IT, 15 IV, 151W, 151Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, R53A, R53C, R53D, R53E, R53F, R53G, R53H, R53I, R53K, R53L, R53M, R53N, R53P, R53Q, R53S, R53T, R53V, R53W, R53Y, S54A, S54C, S54D, S54E, S54F, S54G, S54H, S54I, S54K, S54L, S54M, S54N, S54P, S54Q, S54R, S54T, S54V, S54W, S54Y, G55A, G55C, G55D, G55E, G55F, G55H, G55I, G55K, G55L, G55M, G55N, G55P, G55Q, G55R, G55S, G55T, G55V, G55W, G55Y, S56A, S56C, S56D, S56E, S56F, S56G, S56H, S56I, S56K, S56L, S56M, S56N, S56P, S56Q, S56R, S56T, S56V, S56W, S56Y, T57A, T57C, T57D, T57E, T57F, T57G, T57H, T57I, T57K, T57L, T57M, T57N, T57P, T57Q, T57R, T57S, T57V, T57W, T57Y, K58A, K58C, K58D, K58E, K58F, K58G, K58H, K58I, K58L, K58M, K58N, K58P, K58Q, K58R, K58S, K58T, K58V, K58W, K58Y, Y59A, Y59C, Y59D, Y59E, Y59F, Y59G, Y59H, Y59I, Y59K, Y59L, Y59M, Y59N, Y59P, Y59Q, Y59R, Y59S, Y59T, Y59V, Y59W, Y60A, Y60C, Y60D, Y60E, Y60F, Y60G, Y60H, Y60I, Y60K, Y60L, Y60M, Y60N, Y60P, Y60Q, Y60R, Y60S, Y60T, Y60V, Y60W, A61C, A61D, A61E, A61F, A61G, A61H, A61I, A61K, A61L, A61M, A61N, A61P, A61Q, A61R, A61S, A61T, A61V, A61W, A61Y, D62A, D62C, D62E, D62F, D62G, D62H, D62I, D62K, D62L, D62M, D62N, D62P, D62Q, D62R, D62S, D62T, D62V, D62W, D62Y, S63A, S63C, S63D, S63E, S63F, S63G, S63H, S63I, S63K, S63L, S63M, S63N, S63P, S63Q, S63R, S63T, S63V, S63W, S63Y, V64A, V64C, V64D, V64E, V64F, V64G, V64H, V64I, V64K, V64L, V64M, V64N, V64P, V64Q, V64R, V64S, V64T, V64W, V64Y, K65A, K65C, K65D, K65E, K65F, K65G, K65H, K65I, K65L, K65M, K65N, K65P, K65Q, K65R, K65S, K65T, K65V, K65W, K65Y, G66A, G66C, G66D, G66E, G66F, G66H, G66I, G66K, G66L, G66M, G66N, G66P, G66Q, G66R, G66S, G66T, G66V, G66W, G66Y, A97C, A97D, A97E, A97F, A97G, A97H, A97I, A97K, A97L, A97M, A97N, A97P, A97Q, A97R, A97S, A97T, A97V, A97W, A97Y, R98A, R98C, R98D, R98E, R98F, R98G, R98H, R98I, R98K, R98L, R98M, R98N, R98P, R98Q, R98S, R98T, R98V, R98W, R98Y, D99A, D99C, D99E, D99F, D99G, D99H, D99I, D99K, D99L, D99M, D99N, D99P, D99Q, D99R, D99S, D99T, D99V, D99W, D99Y, E100A, E100C, E100D, E100F, E100G, E100H, E1OOI, E100K, E100L, E100M, E100N, E1OOP, E1OOQ, E100R, E1OOS, E100T, E100V, E100W, E100Y, N101A, N101C, N101D, N101E, N101F, N101G, N101H, N1O1I, N101K, N101L, N101M, N101P, N1O1Q, N101R, N1O1S, N101T, N101V, N101W, N101Y, Y102A, Y102C, Y102D, Y102E, Y102F, Y102G, Y102H, Y102I, Y102K, Y102L, Y102M, Y102N, Y102P, Y102Q, Y102R, Y102S, Y102T, Y102V, Y102W, A103C, A103D, A103E, A1O3F, A103G, A103H, A1O3I, A103K, A103L, A103M, A103N,Attorney Docket No. DIN-005WO PATENTA103P, A103Q, A103R, A103S, A103T, A103V, A103W, A103Y, L104A, L104C, L104D, L104E, L104F, L104G, L104H, L104I, L104K, L104M, L104N, L104P, L104Q, L104R, L104S, L104T, L104V, L104W, L104Y, D105A, D105C, D105E, D105F, D105G, D105H, D105I, D105K, D105L, D105M, D105N, D105P, D105Q, D105R, D105S, D105T, D105V, D105W, D105Y, W106A, W106C, 106D, W106E, W106F, W106G, W106H, W106I, W106K, W106L, W106M, W106N, W106P, 106Q, W106R, W106S, W106T, W106V, and W106Y.7 The antibody, or the antigen-binding fragment thereof, of claims 1-6, wherein the VH comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 1112 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 3940 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 6768 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 9596 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495,Attorney Docket No. DIN-005WO PATENT496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516,517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537,538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558,559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579,580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600,601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621,622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642,643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663,664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684,685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or705.8 The antibody, or the antigen-binding fragment thereof, of claims 1-7, wherein the VH comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11,12 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,96 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138,139 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159,160 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180,181 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201,202 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222,223 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243,244 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264,265 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285,286 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306,307 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327,328 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348,349 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369,370 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390,Attorney Docket No. DIN-005WO PATENT391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411,412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432,433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453,454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474,475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495,496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516,517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537,538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558,559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579,580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600,601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621,622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642,643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663,664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684,685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or705, provided that the VH comprises one or more mutations selected from the group consisting of: G26A, G26C, G26D, G26E, G26F, G26H, G26I, G26K, G26L, G26M, G26N, G26P, G26Q, G26R, G26S, G26T, G26V, G26W, G26Y, F27A, F27C, F27D, F27E, F27G, F27H, F27I, F27K, F27L, F27M, F27N, F27P, F27Q, F27R, F27S, F27T, F27V, F27W, F27Y, T28A, T28C, T28D, T28E, T28F, T28G, T28H, T28I, T28K, T28L, T28M, T28N, T28P, T28Q, T28R, T28S, T28V, T28W, T28Y, F29A, F29C, F29D, F29E, F29G, F29H, F29I, F29K, F29L, F29M, F29N, F29P, F29Q, F29R, F29S, F29T, F29V, F29W, F29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31C, D31E, D31F, D31G, D31H, D31I, D31K, D31L, D31M, D31N, D31P, D31Q, D31R, D31S, D31T, D31V, D31W, D31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, Y33A, Y33C, Y33D, Y33E, Y33F, Y33G, Y33H, Y33I, Y33K, Y33L, Y33M, Y33N, Y33P, Y33Q, Y33R, Y33S, Y33T, Y33V, Y33W, M34A, M34C, M34D, M34E, M34F, M34G, M34H, M34I, M34K, M34L, M34N, M34P, M34Q, M34R, M34S, M34T, M34V, M34W, M34Y, S35A, S35C, S35D, S35E, S35F, S35G, S35H, S35I, S35K, S35L, S35M, S35N, S35P, S35Q, S35R, S35T, S35V, S35W, S35Y, Y50A, Y50C, Y50D, Y50E, Y50F, Y50G, Y50H, Y50I, Y50K, Y50L, Y50M, Y50N, Y50P, Y50Q, Y50R, Y50S, Y50T, Y50V, Y50W, 151 A, 151C, 15 ID, 15 IE, 15 IF, 151G, 151H, 15 IK,Attorney Docket No. DIN-005WO PATENTI51L, I51M, I51N, I51P, I51Q, I51R, 15 IS, I51T, I51V, I51W, I51Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, R53A, R53C, R53D, R53E, R53F, R53G, R53H, R53I, R53K, R53L, R53M, R53N, R53P, R53Q, R53S, R53T, R53V, R53W, R53Y, S54A, S54C, S54D, S54E, S54F, S54G, S54H, S54I, S54K, S54L, S54M, S54N, S54P, S54Q, S54R, S54T, S54V, S54W, S54Y, G55A, G55C, G55D, G55E, G55F, G55H, G55I, G55K, G55L, G55M, G55N, G55P, G55Q, G55R, G55S, G55T, G55V, G55W, G55Y, S56A, S56C, S56D, S56E, S56F, S56G, S56H, S56I, S56K, S56L, S56M, S56N, S56P, S56Q, S56R, S56T, S56V, S56W, S56Y, T57A, T57C, T57D, T57E, T57F, T57G, T57H, T57I, T57K, T57L, T57M, T57N, T57P, T57Q, T57R, T57S, T57V, T57W, T57Y, K58A, K58C, K58D, K58E, K58F, K58G, K58H, K58I, K58L, K58M, K58N, K58P, K58Q, K58R, K58S, K58T, K58V, K58W, K58Y, Y59A, Y59C, Y59D, Y59E, Y59F, Y59G, Y59H, Y59I, Y59K, Y59L, Y59M, Y59N, Y59P, Y59Q, Y59R, Y59S, Y59T, Y59V, Y59W, Y60A, Y60C, Y60D, Y60E, Y60F, Y60G, Y60H, Y60I, Y60K, Y60L, Y60M, Y60N, Y60P, Y60Q, Y60R, Y60S, Y60T, Y60V, Y60W, A61C, A61D, A61E, A61F, A61G, A61H, A61I, A61K, A61L, A61M, A61N, A61P, A61Q, A61R, A61S, A61T, A61V, A61W, A61Y, D62A, D62C, D62E, D62F, D62G, D62H, D62I, D62K, D62L, D62M, D62N, D62P, D62Q, D62R, D62S, D62T, D62V, D62W, D62Y, S63A, S63C, S63D, S63E, S63F, S63G, S63H, S63I, S63K, S63L, S63M, S63N, S63P, S63Q, S63R, S63T, S63V, S63W, S63Y, V64A, V64C, V64D, V64E, V64F, V64G, V64H, V64I, V64K, V64L, V64M, V64N, V64P, V64Q, V64R, V64S, V64T, V64W, V64Y, K65A, K65C, K65D, K65E, K65F, K65G, K65H, K65I, K65L, K65M, K65N, K65P, K65Q, K65R, K65S, K65T, K65V, K65W, K65Y, G66A, G66C, G66D, G66E, G66F, G66H, G66I, G66K, G66L, G66M, G66N, G66P, G66Q, G66R, G66S, G66T, G66V, G66W, G66Y, A97C, A97D, A97E, A97F, A97G, A97H, A97I, A97K, A97L, A97M, A97N, A97P, A97Q, A97R, A97S, A97T, A97V, A97W, A97Y, R98A, R98C, R98D, R98E, R98F, R98G, R98H, R98I, R98K, R98L, R98M, R98N, R98P, R98Q, R98S, R98T, R98V, R98W, R98Y, D99A, D99C, D99E, D99F, D99G, D99H, D99I, D99K, D99L, D99M, D99N, D99P, D99Q, D99R, D99S, D99T, D99V, D99W, D99Y, E100A, E100C, E100D, E100F, E100G, E100H, E100I, E100K, E100L, E100M, E100N, E1OOP, E1OOQ, E100R, E1OOS, E100T, E100V, E100W, E100Y, N101A, N101C, N101D, N101E, N101F, N101G, N101H, N1O1I, N101K, N101L, N101M, N1O1P, N101Q, N101R, N1O1S, N101T, N101V, N101W, N101Y, Y102A, Y102C, Y102D, Y102E, Y102F, Y102G, Y102H, Y102I, Y102K, Y102L, Y102M, Y102N, Y102P, Y102Q, Y102R, Y102S, Y102T, Y102V, Y102W, A103C, A103D, A103E, A103F, A103G, A103H, A1O3I, A103K, A103L, A103M, A103N, A103P, A1O3Q, A103R, A1O3S, A103T, A103V, A103W, A103Y, L104A,Attorney Docket No. DIN-005WO PATENTL104C, L104D, L104E, L104F, L104G, L104H, L104I, L104K, L104M, L104N, L104P, L104Q, L104R, L104S, L104T, L104V, L104W, L104Y, D105A, D105C, D105E, D105F, D105G, D105H, D105I, D105K, D105L, D105M, D105N, D105P, D105Q, D105R, D105S, D105T, D105V, D105W, D105Y, W106A, W106C, W106D, W106E, W106F, W106G, W106H, W106I, W106K, W106L, 106M, W106N, W106P, W106Q, W106R, W106S, W106T, W106V, or W106Y.9 The antibody, or the antigen-binding fragment thereof, of any one of claims 1-8, wherein the VL comprises a mutation selected from the group consisting of: Q24A, Q24C, Q24D, Q24E, Q24F, Q24G, Q24H, Q24I, Q24K, Q24L, Q24M, Q24N, Q24P, Q24R, Q24S, Q24T, Q24V, Q24W, Q24Y, A25C, A25D, A25E, A25F, A25G, A25H, A25I, A25K, A25L, A25M, A25N, A25P, A25Q, A25R, A25S, A25T, A25V, A25W, A25Y, S26A, S26C, S26D, S26E, S26F, S26G, S26H, S26I, S26K, S26L, S26M, S26N, S26P, S26Q, S26R, S26T, S26V, S26W, S26Y, Q27A, Q27C, Q27D, Q27E, Q27F, Q27G, Q27H, Q27I, Q27K, Q27L, Q27M, Q27N, Q27P, Q27R, Q27S, Q27T, Q27V, Q27W, Q27Y, D28A, D28C, D28E, D28F, D28G, D28H, D28I, D28K, D28L, D28M, D28N, D28P, D28Q, D28R, D28S, D28T, D28V, D28W, D28Y, I29A, I29C, I29D, I29E, I29F, I29G, I29H, I29K, I29L, I29M, I29N, I29P, I29Q, I29R, I29S, I29T, I29V, I29W, I29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, N31A, N31C, N31D, N31E, N31F, N31G, N31H, N31I, N31K, N31L, N31M, N31P, N31Q, N31R, N31S, N31T, N31V, N31W, N31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, L33A, L33C, L33D, L33E, L33F, L33G, L33H, L33I, L33K, L33M, L33N, L33P, L33Q, L33R, L33S, L33T, L33V, L33W, L33Y, N34A, N34C, N34D, N34E, N34F, N34G, N34H, N34I, N34K, N34L, N34M, N34P, N34Q, N34R, N34S, N34T, N34V, N34W, N34Y, D50A, D50C, D50E, D50F, D50G, D50H, D50I, D50K, D50L, D50M, D50N, D50P, D50Q, D50R, D50S, D50T, D50V, D50W, D50Y, A51C, A51D, A51E, A51F, A51G, A51H, A51I, A51K, A51L, A51M, A51N, A51P, A51Q, A51R, A51S, A51T, A51V, A51W, A51Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, N53A, N53C, N53D, N53E, N53F, N53G, N53H, N53I, N53K, N53L, N53M, N53P, N53Q, N53R, N53S, N53T, N53V, N53W, N53Y, L54A, L54C, L54D, L54E, L54F, L54G, L54H, L54I, L54K, L54M, L54N, L54P, L54Q, L54R, L54S, L54T, L54V, L54W, L54Y, E55A, E55C, E55D, E55F, E55G, E55H, E55I, E55K, E55L, E55M, E55N, E55P, E55Q, E55R, E55S, E55T, E55V, E55W, E55Y, T56A, T56C, T56D, T56E, T56F, T56G, T56H, T56I, T56K, T56L, T56M, T56N, T56P, T56Q, T56R,Attorney Docket No. DIN-005WO PATENTT56S, T56V, T56W, T56Y, Q89A, Q89C, Q89D, Q89E, Q89F, Q89G, Q89H, Q89I, Q89K, Q89L, Q89M, Q89N, Q89P, Q89R, Q89S, Q89T, Q89V, Q89W, Q89Y, H90A, H90C, H90D, H90E, H90F, H90G, H90I, H90K, H90L, H90M, H90N, H90P, H90Q, H90R, H90S, H90T, H90V, H90W, H90Y, Y91A, Y91C, Y91D, Y91E, Y91F, Y91G, Y91H, Y91I, Y91K, Y91L, Y91M, Y91N, Y91P, Y91Q, Y91R, Y91S, Y91T, Y91V, Y91W, E92A, E92C, E92D, E92F, E92G, E92H, E92I, E92K, E92L, E92M, E92N, E92P, E92Q, E92R, E92S, E92T, E92V, E92W, E92Y, D93A, D93C, D93E, D93F, D93G, D93H, D93I, D93K, D93L, D93M, D93N, D93P, D93Q, D93R, D93S, D93T, D93V, D93W, D93Y, Y94A, Y94C, Y94D, Y94E, Y94F, Y94G, Y94H, Y94I, Y94K, Y94L, Y94M, Y94N, Y94P, Y94Q, Y94R, Y94S, Y94T, Y94V, Y94W, P95A, P95C, P95D, P95E, P95F, P95G, P95H, P95I, P95K, P95L, P95M, P95N, P95Q, P95R, P95S, P95T, P95V, P95W, P95Y, L96A, L96C, L96D, L96E, L96F, L96G, L96H, L96I, L96K, L96M, L96N, L96P, L96Q, L96R, L96S, L96T, L96V, L96W, L96Y, T97A, T97C, T97D, T97E, T97F, T97G, T97H, T97I, T97K, T97L, T97M, T97N, T97P, T97Q, T97R, T97S, T97V, T97W, and T97Y.

10. The antibody, or the antigen-binding fragment thereof, of any one of claims 1-9, wherein the VL comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728,729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749,750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770,771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791,792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812,813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833,834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854,855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875,876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896,897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917,918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938,939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959,960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980,981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000,1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016,Attorney Docket No. DIN-005WO PATENT1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032,1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048,1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064,1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080,1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096,1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128,1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144,1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160,1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176,1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218.

11. The antibody, or the antigen-binding fragment thereof, of any one of claims 1-10, wherein the VL comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728,729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749,750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770,771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791,792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812,813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833,834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854,855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875,876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896,897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917,918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938,939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959,960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980,981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000,1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016,Attorney Docket No. DIN-005WO PATENT1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032,1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048,1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064,1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080,1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096,1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128,1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144,1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160,1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176,1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, provided that the VL comprises one or more mutations selected from the group consisting of: Q24A, Q24C, Q24D, Q24E, Q24F, Q24G, Q24H, Q24I, Q24K, Q24L, Q24M, Q24N, Q24P, Q24R, Q24S, Q24T, Q24V, Q24W, Q24Y, A25C, A25D, A25E, A25F, A25G, A25H, A25I, A25K, A25L, A25M, A25N, A25P, A25Q, A25R, A25S, A25T, A25V, A25W, A25Y, S26A, S26C, S26D, S26E, S26F, S26G, S26H, S26I, S26K, S26L, S26M, S26N, S26P, S26Q, S26R, S26T, S26V, S26W, S26Y, Q27A, Q27C, Q27D, Q27E, Q27F, Q27G, Q27H, Q27I, Q27K, Q27L, Q27M, Q27N, Q27P, Q27R, Q27S, Q27T, Q27V, Q27W, Q27Y, D28A, D28C, D28E, D28F, D28G, D28H, D28I, D28K, D28L, D28M, D28N, D28P, D28Q, D28R, D28S, D28T, D28V, D28W, D28Y, I29A, I29C, I29D, I29E, I29F, I29G, I29H, I29K, I29L, I29M, I29N, I29P, I29Q, I29R, I29S, I29T, I29V, I29W, I29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, N31A, N31C, N31D, N31E, N31F, N31G, N31H, N31I, N31K, N31L, N31M, N31P, N31Q, N31R, N31S, N31T, N31V, N31W, N31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, L33A, L33C, L33D, L33E, L33F, L33G, L33H, L33I, L33K, L33M, L33N, L33P, L33Q, L33R, L33S, L33T, L33V, L33W, L33Y, N34A, N34C, N34D, N34E, N34F, N34G, N34H, N34I, N34K, N34L, N34M, N34P, N34Q, N34R, N34S, N34T, N34V, N34W, N34Y, D50A, D50C, D50E, D50F, D50G, D50H, D50I, D50K, D50L, D50M, D50N, D50P, D50Q, D50R, D50S, D50T, D50V, D50W, D50Y, A51C, A51D, A51E, A51F, A51G, A51H, A51I, A51K, A51L, A51M, A51N, A51P, A51Q, A51R, A51S, A51T, A51V, A51W, A51Y, S52A, S52C, S52D,Attorney Docket No. DIN-005WO PATENTS52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, N53A, N53C, N53D, N53E, N53F, N53G, N53H, N53I, N53K, N53L, N53M, N53P, N53Q, N53R, N53S, N53T, N53V, N53W, N53Y, L54A, L54C, L54D, L54E, L54F, L54G, L54H, L54I, L54K, L54M, L54N, L54P, L54Q, L54R, L54S, L54T, L54V, L54W, L54Y, E55A, E55C, E55D, E55F, E55G, E55H, E55I, E55K, E55L, E55M, E55N, E55P, E55Q, E55R, E55S, E55T, E55V, E55W, E55Y, T56A, T56C, T56D, T56E, T56F, T56G, T56H, T56I, T56K, T56L, T56M, T56N, T56P, T56Q, T56R, T56S, T56V, T56W, T56Y, Q89A, Q89C, Q89D, Q89E, Q89F, Q89G, Q89H, Q89I, Q89K, Q89L, Q89M, Q89N, Q89P, Q89R, Q89S, Q89T, Q89V, Q89W, Q89Y, H90A, H90C, H90D, H90E, H90F, H90G, H90I, H90K, H90L, H90M, H90N, H90P, H90Q, H90R, H90S, H90T, H90V, H90W, H90Y, Y91A, Y91C, Y91D, Y91E, Y91F, Y91G, Y91H, Y91I, Y91K, Y91L, Y91M, Y91N, Y91P, Y91Q, Y91R, Y91S, Y91T, Y91V, Y91W, E92A, E92C, E92D, E92F, E92G, E92H, E92I, E92K, E92L, E92M, E92N, E92P, E92Q, E92R, E92S, E92T, E92V, E92W, E92Y, D93A, D93C, D93E, D93F, D93G, D93H, D93I, D93K, D93L, D93M, D93N, D93P, D93Q, D93R, D93S, D93T, D93V, D93W, D93Y, Y94A, Y94C, Y94D, Y94E, Y94F, Y94G, Y94H, Y94I, Y94K, Y94L, Y94M, Y94N, Y94P, Y94Q, Y94R, Y94S, Y94T, Y94V, Y94W, P95A, P95C, P95D, P95E, P95F, P95G, P95H, P95I, P95K, P95L, P95M, P95N, P95Q, P95R, P95S, P95T, P95V, P95W, P95Y, L96A, L96C, L96D, L96E, L96F, L96G, L96H, L96I, L96K, L96M, L96N, L96P, L96Q, L96R, L96S, L96T, L96V, L96W, L96Y, T97A, T97C, T97D, T97E, T97F, T97G, T97H, T97I, T97K, T97L, T97M, T97N, T97P, T97Q, T97R, T97S, T97V, T97W, and T97Y.

12. The antibody, or the antigen-binding fragment thereof, of claim 1, wherein the VH comprises the amino acid sequence of SEQ ID NO: 1, and the VL comprises one or more mutations at position selected from the group consisting of: Q24, A25, S26, Q27, D28, 129, S30, N31, Y32, L33 N34, D50, A51, S52, N53, L54, E55, T56, Q89, H90, Y91, E92, D93, Y94, P95, L96, and T97.

13. The antibody, or the antigen-binding fragment thereof, of claim 12, wherein the VL comprises a mutation selected from the group consisting of: Q24A, Q24C, Q24D, Q24E, Q24F, Q24G, Q24H, Q24I, Q24K, Q24L, Q24M, Q24N, Q24P, Q24R, Q24S, Q24T, Q24V, Q24W, Q24Y, A25C, A25D, A25E, A25F, A25G, A25H, A25I, A25K, A25L, A25M, A25N, A25P, A25Q, A25R, A25S, A25T, A25V, A25W, A25Y, S26A, S26C, S26D, S26E, S26F, S26G, S26H, S26I, S26K, S26L, S26M, S26N, S26P, S26Q, S26R, S26T, S26V, S26W, S26Y, Q27A, Q27C, Q27D, Q27E, Q27F, Q27G, Q27H, Q27I,Attorney Docket No. DIN-005WO PATENTQ27K, Q27L, Q27M, Q27N, Q27P, Q27R, Q27S, Q27T, Q27V, Q27W, Q27Y, D28A, D28C, D28E, D28F, D28G, D28H, D28I, D28K, D28L, D28M, D28N, D28P, D28Q, D28R, D28S, D28T, D28V, D28W, D28Y, I29A, I29C, I29D, I29E, I29F, I29G, I29H, I29K, I29L, I29M, I29N, I29P, I29Q, I29R, I29S, I29T, I29V, I29W, I29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, N31A, N31C, N31D, N31E, N31F, N31G, N31H, N31I, N31K, N31L, N31M, N31P, N31Q, N31R, N31S, N31T, N31V, N31W, N31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, L33A, L33C, L33D, L33E, L33F, L33G, L33H, L33I, L33K, L33M, L33N, L33P, L33Q, L33R, L33S, L33T, L33V, L33W, L33Y, N34A, N34C, N34D, N34E, N34F, N34G, N34H, N34I, N34K, N34L, N34M, N34P, N34Q, N34R, N34S, N34T, N34V, N34W, N34Y, D50A, D50C, D50E, D50F, D50G, D50H, D50I, D50K, D50L, D50M, D50N, D50P, D50Q, D50R, D50S, D50T, D50V, D50W, D50Y, A51C, A51D, A51E, A51F, A51G, A51H, A51I, A51K, A51L, A51M, A51N, A51P, A51Q, A51R, A51S, A51T, A51V, A51W, A51Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, N53A, N53C, N53D, N53E, N53F, N53G, N53H, N53I, N53K, N53L, N53M, N53P, N53Q, N53R, N53S, N53T, N53V, N53W, N53Y, L54A, L54C, L54D, L54E, L54F, L54G, L54H, L54I, L54K, L54M, L54N, L54P, L54Q, L54R, L54S, L54T, L54V, L54W, L54Y, E55A, E55C, E55D, E55F, E55G, E55H, E55I, E55K, E55L, E55M, E55N, E55P, E55Q, E55R, E55S, E55T, E55V, E55W, E55Y, T56A, T56C, T56D, T56E, T56F, T56G, T56H, T56I, T56K, T56L, T56M, T56N, T56P, T56Q, T56R, T56S, T56V, T56W, T56Y, Q89A, Q89C, Q89D, Q89E, Q89F, Q89G, Q89H, Q89I, Q89K, Q89L, Q89M, Q89N, Q89P, Q89R, Q89S, Q89T, Q89V, Q89W, Q89Y, H90A, H90C, H90D, H90E, H90F, H90G, H90I, H90K, H90L, H90M, H90N, H90P, H90Q, H90R, H90S, H90T, H90V, H90W, H90Y, Y91A, Y91C, Y91D, Y91E, Y91F, Y91G, Y91H, Y91I, Y91K, Y91L, Y91M, Y91N, Y91P, Y91Q, Y91R, Y91S, Y91T, Y91V, Y91W, E92A, E92C, E92D, E92F, E92G, E92H, E92I, E92K, E92L, E92M, E92N, E92P, E92Q, E92R, E92S, E92T, E92V, E92W, E92Y, D93A, D93C, D93E, D93F, D93G, D93H, D93I, D93K, D93L, D93M, D93N, D93P, D93Q, D93R, D93S, D93T, D93V, D93W, D93Y, Y94A, Y94C, Y94D, Y94E, Y94F, Y94G, Y94H, Y94I, Y94K, Y94L, Y94M, Y94N, Y94P, Y94Q, Y94R, Y94S, Y94T, Y94V, Y94W, P95A, P95C, P95D, P95E, P95F, P95G, P95H, P95I, P95K, P95L, P95M, P95N, P95Q, P95R, P95S, P95T, P95V, P95W, P95Y, L96A, L96C, L96D, L96E, L96F, L96G, L96H, L96I, L96K, L96M, L96N, L96P, L96Q, L96R, L96S, L96T, L96V, L96W, L96Y, T97A,Attorney Docket No. DIN-005WO PATENTT97C, T97D, T97E, T97F, T97G, T97H, T97I, T97K, T97L, T97M, T97N, T97P, T97Q, T97R, T97S, T97V, T97W, and T97Y.

14. The antibody, or the antigen-binding fragment thereof, of claim 12, wherein the VL comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742,743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763,764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784,785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805,806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826,827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847,848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868,869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889,890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910,911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931,932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952,953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973,974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994,995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027,1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043,1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059,1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075,1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107,1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123,1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139,1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155,1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187,Attorney Docket No. DIN-005WO PATENT1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, provided that the VL comprises one or more mutations selected from the group consisting of: Q24A, Q24C, Q24D, Q24E, Q24F, Q24G, Q24H, Q24I, Q24K, Q24L, Q24M, Q24N, Q24P, Q24R, Q24S, Q24T, Q24V, Q24W, Q24Y, A25C, A25D, A25E, A25F, A25G, A25H, A25I, A25K, A25L, A25M, A25N, A25P, A25Q, A25R, A25S, A25T, A25V, A25W, A25Y, S26A, S26C, S26D, S26E, S26F, S26G, S26H, S26I, S26K, S26L, S26M, S26N, S26P, S26Q, S26R, S26T, S26V, S26W, S26Y, Q27A, Q27C, Q27D, Q27E, Q27F, Q27G, Q27H, Q27I, Q27K, Q27L, Q27M, Q27N, Q27P, Q27R, Q27S, Q27T, Q27V, Q27W, Q27Y, D28A, D28C, D28E, D28F, D28G, D28H, D28I, D28K, D28L, D28M, D28N, D28P, D28Q, D28R, D28S, D28T, D28V, D28W, D28Y, I29A, I29C, I29D, I29E, I29F, I29G, I29H, I29K, I29L, I29M, I29N, I29P, I29Q, I29R, I29S, I29T, I29V, I29W, I29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, N31A, N31C, N31D, N31E, N31F, N31G, N31H, N31I, N31K, N31L, N31M, N31P, N31Q, N31R, N31S, N31T, N31V, N31W, N31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, L33A, L33C, L33D, L33E, L33F, L33G, L33H, L33I, L33K, L33M, L33N, L33P, L33Q, L33R, L33S, L33T, L33V, L33W, L33Y, N34A, N34C, N34D, N34E, N34F, N34G, N34H, N34I, N34K, N34L, N34M, N34P, N34Q, N34R, N34S, N34T, N34V, N34W, N34Y, D50A, D50C, D50E, D50F, D50G, D50H, D50I, D50K, D50L, D50M, D50N, D50P, D50Q, D50R, D50S, D50T, D50V, D50W, D50Y, A51C, A51D, A51E, A51F, A51G, A51H, A51I, A51K, A51L, A51M, A51N, A51P, A51Q, A51R, A51S, A51T, A51V, A51W, A51Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, N53A, N53C, N53D, N53E, N53F, N53G, N53H, N53I, N53K, N53L, N53M, N53P, N53Q, N53R, N53S, N53T, N53V, N53W, N53Y, L54A, L54C, L54D, L54E, L54F, L54G, L54H, L54I, L54K, L54M, L54N, L54P, L54Q, L54R, L54S, L54T, L54V, L54W, L54Y, E55A, E55C, E55D, E55F, E55G, E55H, E55I, E55K, E55L, E55M, E55N, E55P, E55Q, E55R, E55S, E55T, E55V, E55W, E55Y, T56A, T56C, T56D, T56E, T56F, T56G, T56H, T56I, T56K, T56L, T56M, T56N, T56P, T56Q, T56R, T56S, T56V, T56W, T56Y, Q89A, Q89C, Q89D, Q89E, Q89F, Q89G, Q89H, Q89I, Q89K, Q89L, Q89M, Q89N, Q89P, Q89R, Q89S, Q89T, Q89V, Q89W, Q89Y, H90A, H90C, H90D, H90E, H90F, H90G, H90I, H90K, H90L, H90M, H90N, H90P, H90Q, H90R, H90S, H90T, H90V, H90W, H90Y, Y91A, Y91C, Y91D, Y91E, Y91F, Y91G, Y91H, Y91I, Y91K, Y91L, Y91M, Y91N, Y91P, Y91Q, Y91R, Y91S, Y91T, Y91V, Y91W, E92A, E92C, E92D, E92F,Attorney Docket No. DIN-005WO PATENTE92G, E92H, E92I, E92K, E92L, E92M, E92N, E92P, E92Q, E92R, E92S, E92T, E92V, E92W, E92Y, D93A, D93C, D93E, D93F, D93G, D93H, D93I, D93K, D93L, D93M, D93N, D93P, D93Q, D93R, D93S, D93T, D93V, D93W, D93Y, Y94A, Y94C, Y94D, Y94E, Y94F, Y94G, Y94H, Y94I, Y94K, Y94L, Y94M, Y94N, Y94P, Y94Q, Y94R, Y94S, Y94T, Y94V, Y94W, P95A, P95C, P95D, P95E, P95F, P95G, P95H, P95E P95K, P95L, P95M, P95N, P95Q, P95R, P95S, P95T, P95V, P95W, P95Y, L96A, L96C, L96D, L96E, L96F, L96G, L96H, L96I, L96K, L96M, L96N, L96P, L96Q, L96R, L96S, L96T, L96V, L96W, L96Y, T97A, T97C, T97D, T97E, T97F, T97G, T97H, T97I, T97K, T97L, T97M, T97N, T97P, T97Q, T97R, T97S, T97V, T97W, and T97Y.

15. The antibody, or the antigen-binding fragment thereof, of claim 1, wherein the VL comprises the amino acid sequence of SEQ ID NO: 2, and the VH comprises a mutation at one or more of the following positions: G26, F27, T28, F28, S30, D31, Y32, Y33, M34, S35, Y50, 151, S52, R53, S54, G55, S56, T57, K58, Y59, Y60, A61, D62, S63, V64, K65, G66, A97, R98, D99, E100, N101, Y102, A103, L104, D105, or W106.

16. The antibody, or the antigen-binding fragment thereof, of claim 15, wherein the VH comprises a mutation selected from the group consisting of: G26A, G26C, G26D, G26E, G26F, G26H, G26I, G26K, G26L, G26M, G26N, G26P, G26Q, G26R, G26S, G26T, G26V, G26W, G26Y, F27A, F27C, F27D, F27E, F27G, F27H, F27I, F27K, F27L, F27M, F27N, F27P, F27Q, F27R, F27S, F27T, F27V, F27W, F27Y, T28A, T28C, T28D, T28E, T28F, T28G, T28H, T28I, T28K, T28L, T28M, T28N, T28P, T28Q, T28R, T28S, T28V, T28W, T28Y, F29A, F29C, F29D, F29E, F29G, F29H, F29I, F29K, F29L, F29M, F29N, F29P, F29Q, F29R, F29S, F29T, F29V, F29W, F29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31C, D31E, D31F, D31G, D31H, D31I, D31K, D31L, D31M, D31N, D31P, D31Q, D31R, D31S, D31T, D31V, D31W, D31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, Y33A, Y33C, Y33D, Y33E, Y33F, Y33G, Y33H, Y33I, Y33K, Y33L, Y33M, Y33N, Y33P, Y33Q, Y33R, Y33S, Y33T, Y33V, Y33W, M34A, M34C, M34D, M34E, M34F, M34G, M34H, M34I, M34K, M34L, M34N, M34P, M34Q, M34R, M34S, M34T, M34V, M34W, M34Y, S35A, S35C, S35D, S35E, S35F, S35G, S35H, S35I, S35K, S35L, S35M, S35N, S35P, S35Q, S35R, S35T, S35V, S35W, S35Y, Y50A, Y50C, Y50D, Y50E, Y50F, Y50G, Y50H, Y50I, Y50K, Y50L, Y50M, Y50N, Y50P, Y50Q, Y50R, Y50S, Y50T, Y50V, Y50W,Attorney Docket No. DIN-005WO PATENTI51A, I51C, I51D, I51E, I51F, I51G, I51H, I51K, I51L, I51M, I51N, I51P, I51Q, I51R, I51S, I51T, 15 IV, 151W, 151Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, R53A, R53C, R53D, R53E, R53F, R53G, R53H, R53I, R53K, R53L, R53M, R53N, R53P, R53Q, R53S, R53T, R53V, R53W, R53Y, S54A, S54C, S54D, S54E, S54F, S54G, S54H, S54I, S54K, S54L, S54M, S54N, S54P, S54Q, S54R, S54T, S54V, S54W, S54Y, G55A, G55C, G55D, G55E, G55F, G55H, G55I, G55K, G55L, G55M, G55N, G55P, G55Q, G55R, G55S, G55T, G55V, G55W, G55Y, S56A, S56C, S56D, S56E, S56F, S56G, S56H, S56I, S56K, S56L, S56M, S56N, S56P, S56Q, S56R, S56T, S56V, S56W, S56Y, T57A, T57C, T57D, T57E, T57F, T57G, T57H, T57I, T57K, T57L, T57M, T57N, T57P, T57Q, T57R, T57S, T57V, T57W, T57Y, K58A, K58C, K58D, K58E, K58F, K58G, K58H, K58I, K58L, K58M, K58N, K58P, K58Q, K58R, K58S, K58T, K58V, K58W, K58Y, Y59A, Y59C, Y59D, Y59E, Y59F, Y59G, Y59H, Y59I, Y59K, Y59L, Y59M, Y59N, Y59P, Y59Q, Y59R, Y59S, Y59T, Y59V, Y59W, Y60A, Y60C, Y60D, Y60E, Y60F, Y60G, Y60H, Y60I, Y60K, Y60L, Y60M, Y60N, Y60P, Y60Q, Y60R, Y60S, Y60T, Y60V, Y60W, A61C, A61D, A61E, A61F, A61G, A61H, A61I, A61K, A61L, A61M, A61N, A61P, A61Q, A61R, A61S, A61T, A61V, A61W, A61Y, D62A, D62C, D62E, D62F, D62G, D62H, D62I, D62K, D62L, D62M, D62N, D62P, D62Q, D62R, D62S, D62T, D62V, D62W, D62Y, S63A, S63C, S63D, S63E, S63F, S63G, S63H, S63I, S63K, S63L, S63M, S63N, S63P, S63Q, S63R, S63T, S63V, S63W, S63Y, V64A, V64C, V64D, V64E, V64F, V64G, V64H, V64I, V64K, V64L, V64M, V64N, V64P, V64Q, V64R, V64S, V64T, V64W, V64Y, K65A, K65C, K65D, K65E, K65F, K65G, K65H, K65I, K65L, K65M, K65N, K65P, K65Q, K65R, K65S, K65T, K65V, K65W, K65Y, G66A, G66C, G66D, G66E, G66F, G66H, G66I, G66K, G66L, G66M, G66N, G66P, G66Q, G66R, G66S, G66T, G66V, G66W, G66Y, A97C, A97D, A97E, A97F, A97G, A97H, A97I, A97K, A97L, A97M, A97N, A97P, A97Q, A97R, A97S, A97T, A97V, A97W, A97Y, R98A, R98C, R98D, R98E, R98F, R98G, R98H, R98I, R98K, R98L, R98M, R98N, R98P, R98Q, R98S, R98T, R98V, R98W, R98Y, D99A, D99C, D99E, D99F, D99G, D99H, D99I, D99K, D99L, D99M, D99N, D99P, D99Q, D99R, D99S, D99T, D99V, D99W, D99Y, E100A, E100C, E100D, E100F, E100G, E100H, E100I, E100K, E100L, E100M, E100N, E1OOP, E1OOQ, E100R, E1OOS, E100T, E100V, E100W, E100Y, N101A, N101C, N101D, N101E, N101F, N101G, N101H, N1O1I, N101K, N101L, N101M, N101P, N1O1Q, N101R, N1O1S, N101T, N101V, N101W, N101Y, Y102A, Y102C, Y102D, Y102E, Y102F, Y102G, Y102H, Y102I, Y102K, Y102L, Y102M, Y102N, Y102P, Y102Q, Y102R, Y102S, Y102T, Y102V, Y102W, A103C, A103D, A103E, A103F, A103G, A103H, A1O3I, A103K, A103L, A103M, A103N, A1O3P, A103Q, A103R,Attorney Docket No. DIN-005WO PATENTA103S, A103T, A103V, A103W, A103Y, L104A, L104C, L104D, L104E, L104F, L104G, L104H, L104I, L104K, L104M, L104N, L104P, L104Q, L104R, L104S, L104T, L104V, L104W, L104Y, D105A, D105C, D105E, D105F, D105G, D105H, D105I, D105K, D105L, D105M, D105N, D105P, D105Q, D105R, D105S, D105T, D105V, D105W, D105Y, W106A, W106C, W106D, W106E, W106F. 106G, W106H, W106I, W106K, W106L, W106M, W106N, W106P, W106Q, W106R, W106S, 106T, W106V, and W106Y.

17. The antibody, or the antigen-binding fragment thereof, of claim 15, wherein the VH comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 1112, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 3940, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 6768, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 9596, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495,Attorney Docket No. DIN-005WO PATENT496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516,517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537,538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558,559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579,580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600,601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621,622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642,643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663,664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684,685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or705, provided that the VH comprises one or more mutations selected from the group consisting of: G26A, G26C, G26D, G26E, G26F, G26H, G26I, G26K, G26L, G26M, G26N, G26P, G26Q, G26R, G26S, G26T, G26V, G26W, G26Y, F27A, F27C, F27D, F27E, F27G, F27H, F27I, F27K, F27L, F27M, F27N, F27P, F27Q, F27R, F27S, F27T, F27V, F27W, F27Y, T28A, T28C, T28D, T28E, T28F, T28G, T28H, T28I, T28K, T28L, T28M, T28N, T28P, T28Q, T28R, T28S, T28V, T28W, T28Y, F29A, F29C, F29D, F29E, F29G, F29H, F29I, F29K, F29L, F29M, F29N, F29P, F29Q, F29R, F29S, F29T, F29V, F29W, F29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31C, D31E, D31F, D31G, D31H, D31I, D31K, D31L, D31M, D31N, D31P, D31Q, D31R, D31S, D31T, D31V, D31W, D31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, Y33A, Y33C, Y33D, Y33E, Y33F, Y33G, Y33H, Y33I, Y33K, Y33L, Y33M, Y33N, Y33P, Y33Q, Y33R, Y33S, Y33T, Y33V, Y33W, M34A, M34C, M34D, M34E, M34F, M34G, M34H, M34I, M34K, M34L, M34N, M34P, M34Q, M34R, M34S, M34T, M34V, M34W, M34Y, S35A, S35C, S35D, S35E, S35F, S35G, S35H, S35I, S35K, S35L, S35M, S35N, S35P, S35Q, S35R, S35T, S35V, S35W, S35Y, Y50A, Y50C, Y50D, Y50E, Y50F, Y50G, Y50H, Y50I, Y50K, Y50L, Y50M, Y50N, Y50P, Y50Q, Y50R, Y50S, Y50T, Y50V, Y50W, 151 A, 151C, 15 ID, 15 IE, 15 IF, 151G, 151H, 15 IK, I51L, I51M, I51N, 15 IP, I51Q, I51R, I51S, I51T, I51V, I51W, I51Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, R53A, R53C, R53D, R53E, R53F, R53G, R53H, R53I, R53K, R53L, R53M, R53N, R53P, R53Q, R53S, R53T, R53V, R53W, R53Y, S54A, S54C, S54D, S54E, S54F, S54G, S54H, S54I, S54K, S54L, S54M, S54N, S54P, S54Q, S54R, S54T, S54V, S54W, S54Y, G55A, G55C, G55D, G55E, G55F, G55H, G55I, G55K,Attorney Docket No. DIN-005WO PATENTG55L, G55M, G55N, G55P, G55Q, G55R, G55S, G55T, G55V, G55W, G55Y, S56A, S56C, S56D, S56E, S56F, S56G, S56H, S56I, S56K, S56L, S56M, S56N, S56P, S56Q, S56R, S56T, S56V, S56W, S56Y, T57A, T57C, T57D, T57E, T57F, T57G, T57H, T57I, T57K, T57L, T57M, T57N, T57P, T57Q, T57R, T57S, T57V, T57W, T57Y, K58A, K58C, K58D, K58E, K58F, K58G, K58H, K58I, K58L, K58M, K58N, K58P, K58Q, K58R, K58S, K58T, K58V, K58W, K58Y, Y59A, Y59C, Y59D, Y59E, Y59F, Y59G, Y59H, Y59I, Y59K, Y59L, Y59M, Y59N, Y59P, Y59Q, Y59R, Y59S, Y59T, Y59V, Y59W, Y60A, Y60C, Y60D, Y60E, Y60F, Y60G, Y60H, Y60I, Y60K, Y60L, Y60M, Y60N, Y60P, Y60Q, Y60R, Y60S, Y60T, Y60V, Y60W, A61C, A61D, A61E, A61F, A61G, A61H, A61I, A61K, A61L, A61M, A61N, A61P, A61Q, A61R, A61S, A61T, A61V, A61W, A61Y, D62A, D62C, D62E, D62F, D62G, D62H, D62E D62K, D62L, D62M, D62N, D62P, D62Q, D62R, D62S, D62T, D62V, D62W, D62Y, S63A, S63C, S63D, S63E, S63F, S63G, S63H, S63I, S63K, S63L, S63M, S63N, S63P, S63Q, S63R, S63T, S63V, S63W, S63Y, V64A, V64C, V64D, V64E, V64F, V64G, V64H, V64I, V64K, V64L, V64M, V64N, V64P, V64Q, V64R, V64S, V64T, V64W, V64Y, K65A, K65C, K65D, K65E, K65F, K65G, K65H, K65I, K65L, K65M, K65N, K65P, K65Q, K65R, K65S, K65T, K65V, K65W, K65Y, G66A, G66C, G66D, G66E, G66F, G66H, G66I, G66K, G66L, G66M, G66N, G66P, G66Q, G66R, G66S, G66T, G66V, G66W, G66Y, A97C, A97D, A97E, A97F, A97G, A97H, A97I, A97K, A97L, A97M, A97N, A97P, A97Q, A97R, A97S, A97T, A97V, A97W, A97Y, R98A, R98C, R98D, R98E, R98F, R98G, R98H, R98I, R98K, R98L, R98M, R98N, R98P, R98Q, R98S, R98T, R98V, R98W, R98Y, D99A, D99C, D99E, D99F, D99G, D99H, D99I, D99K, D99L, D99M, D99N, D99P, D99Q, D99R, D99S, D99T, D99V, D99W, D99Y, E100A, E100C, E100D, E100F, E100G, E100H, E100I, E100K, E100L, E100M, E100N, E100P, E100Q, E100R, E100S, E100T, E100V, E100W, E100Y, N101A, N101C, N101D, N101E, N101F, N101G, N101H, N101I, N101K, N101L, N101M, N101P, N101Q, N101R, N101S, N101T, N101V, N101W, N101Y, Y102A, Y102C, Y102D, Y102E, Y102F, Y102G, Y102H, Y102I, Y102K, Y102L, Y102M, Y102N, Y102P, Y102Q, Y102R, Y102S, Y102T, Y102V, Y102W, A103C, A103D, A103E, A103F, A103G, A103H, A103I, A103K, A103L, A103M, A103N, A103P, A103Q, A103R, A103S, A103T, A103V, A103W, A103Y, L104A, L104C, L104D, L104E, L104F, L104G, L104H, L104I, L104K, L104M, L104N, L104P, L104Q, L104R, L104S, L104T, L104V, L104W, L104Y, D105A, D105C, D105E, D105F, D105G, D105H, D105I, D105K, D105L, D105M, D105N, D105P, D105Q, D105R, D105S, D105T, D105V, D105W, D105Y, W106A, W106C, W106D, W106E, W106F, W106G, W106H, W106I, W106K, W106L, 106M, W106N, W106P, W106Q, W106R, W106S, W106T, W106V, and W106Y.Attorney Docket No. DIN-005WO PATENT18. The antibody, or the antigen-binding fragment thereof, of claim 1, wherein: the VH comprises a mutation at one or more of the following positions: G26, F27, T28, F28, S30, D31, Y32, Y33, M34, S35, Y50, 151, S52, R53, S54, G55, S56, T57, K58, Y59, Y60, A61, D62, S63, V64, K65, G66, A97, R98, D99, E100, N101, Y102, A103, E104, D105, or W106; and the VE comprises a mutation at one or more of the following positions: Q24, A25, S26, Q27, D28, 129, S30, N31, Y32, E33 N34, D50, A51, S52, N53, E54, E55, T56, Q89, H90, Y91, E92, D93, Y94, P95, E96, or T97.

19. The antibody, or the antigen-binding fragment thereof, of claim 18, wherein: the VH comprises a mutation selected from the group consisting of: G26A, G26C, G26D, G26E, G26F, G26H, G26I, G26K, G26E, G26M, G26N, G26P, G26Q, G26R, G26S, G26T, G26V, G26W, G26Y, F27A, F27C, F27D, F27E, F27G, F27H, F27I, F27K, F27E, F27M, F27N, F27P, F27Q, F27R, F27S, F27T, F27V, F27W, F27Y, T28A, T28C, T28D, T28E, T28F, T28G, T28H, T28I, T28K, T28L, T28M, T28N, T28P, T28Q, T28R, T28S, T28V, T28W, T28Y, F29A, F29C, F29D, F29E, F29G, F29H, F29I, F29K, F29E, F29M, F29N, F29P, F29Q, F29R, F29S, F29T, F29V, F29W, F29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30E, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31C, D31E, D31F, D31G, D31H, D31I, D31K, D31E, D31M, D31N, D31P, D31Q, D31R, D31S, D31T, D31V, D31W, D31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32E, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, Y33A, Y33C, Y33D, Y33E, Y33F, Y33G, Y33H, Y33I, Y33K, Y33E, Y33M, Y33N, Y33P, Y33Q, Y33R, Y33S, Y33T, Y33V, Y33W, M34A, M34C, M34D, M34E, M34F, M34G, M34H, M34I, M34K, M34E, M34N, M34P, M34Q, M34R, M34S, M34T, M34V, M34W, M34Y, S35A, S35C, S35D, S35E, S35F, S35G, S35H, S35I, S35K, S35E, S35M, S35N, S35P, S35Q, S35R, S35T, S35V, S35W, S35Y, Y50A, Y50C, Y50D, Y50E, Y50F, Y50G, Y50H, Y50I, Y50K, Y50E, Y50M, Y50N, Y50P, Y50Q, Y50R, Y50S, Y50T, Y50V, Y50W, 151A, I51C, 15 ID, I51E, I51F, 151G, I51H, 15 IK, I51E, 15 IM, I51N, 15 IP, 15 IQ, 151R, 15 IS, 15 IT, 15 IV, 151W, 151Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52E, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, R53A, R53C, R53D, R53E, R53F, R53G, R53H, R53I, R53K, R53E, R53M, R53N, R53P, R53Q, R53S, R53T, R53V, R53W, R53Y, S54A, S54C, S54D, S54E, S54F, S54G, S54H, S54I, S54K, S54E, S54M, S54N, S54P, S54Q, S54R, S54T, S54V, S54W, S54Y, G55A, G55C, G55D, G55E, G55F, G55H, G55I, G55K, G55L, G55M,Attorney Docket No. DIN-005WO PATENTG55N, G55P, G55Q, G55R, G55S, G55T, G55V, G55W, G55Y, S56A, S56C, S56D, S56E, S56F, S56G, S56H, S56I, S56K, S56L, S56M, S56N, S56P, S56Q, S56R, S56T, S56V, S56W, S56Y, T57A, T57C, T57D, T57E, T57F, T57G, T57H, T57I, T57K, T57L, T57M, T57N, T57P, T57Q, T57R, T57S, T57V, T57W, T57Y, K58A, K58C, K58D, K58E, K58F, K58G, K58H, K58I, K58L, K58M, K58N, K58P, K58Q, K58R, K58S, K58T, K58V, K58W, K58Y, Y59A, Y59C, Y59D, Y59E, Y59F, Y59G, Y59H, Y59I, Y59K, Y59L, Y59M, Y59N, Y59P, Y59Q, Y59R, Y59S, Y59T, Y59V, Y59W, Y60A, Y60C, Y60D, Y60E, Y60F, Y60G, Y60H, Y60I, Y60K, Y60L, Y60M, Y60N, Y60P, Y60Q, Y60R, Y60S, Y60T, Y60V, Y60W, A61C, A61D, A61E, A61F, A61G, A61H, A61I, A61K, A61L, A61M, A61N, A61P, A61Q, A61R, A61S, A61T, A61V, A61W, A61Y, D62A, D62C, D62E, D62F, D62G, D62H, D62E D62K, D62L, D62M, D62N, D62P, D62Q, D62R, D62S, D62T, D62V, D62W, D62Y, S63A, S63C, S63D, S63E, S63F, S63G, S63H, S63I, S63K, S63L, S63M, S63N, S63P, S63Q, S63R, S63T, S63V, S63W, S63Y, V64A, V64C, V64D, V64E, V64F, V64G, V64H, V64I, V64K, V64L, V64M, V64N, V64P, V64Q, V64R, V64S, V64T, V64W, V64Y, K65A, K65C, K65D, K65E, K65F, K65G, K65H, K65I, K65L, K65M, K65N, K65P, K65Q, K65R, K65S, K65T, K65V, K65W, K65Y, G66A, G66C, G66D, G66E, G66F, G66H, G66I, G66K, G66L, G66M, G66N, G66P, G66Q, G66R, G66S, G66T, G66V, G66W, G66Y, A97C, A97D, A97E, A97F, A97G, A97H, A97I, A97K, A97L, A97M, A97N, A97P, A97Q, A97R, A97S, A97T, A97V, A97W, A97Y, R98A, R98C, R98D, R98E, R98F, R98G, R98H, R98I, R98K, R98L, R98M, R98N, R98P, R98Q, R98S, R98T, R98V, R98W, R98Y, D99A, D99C, D99E, D99F, D99G, D99H, D99I, D99K, D99L, D99M, D99N, D99P, D99Q, D99R, D99S, D99T, D99V, D99W, D99Y, E100A, E100C, E100D, E100F, E100G, E100H, E1OOI, E100K, E100L, E100M, E100N, E1OOP, E1OOQ, E100R, E1OOS, E1OOT, E100V, E100W, E100Y, N101A, N101C, N101D, N101E, N101F, N101G, N101H, N1O1I, N101K, N101L, N101M, N101P, N101Q, N101R, N1O1S, N101T, N101V, N101W, N101Y, Y102A, Y102C, Y102D, Y102E, Y102F, Y102G, Y102H, Y102I, Y102K, Y102L, Y102M, Y102N, Y102P, Y102Q, Y102R, Y102S, Y102T, Y102V, Y102W, A103C, A103D, A103E, A1O3F, A103G, A103H, A1O3I, A103K, A103L, A103M, A103N, A1O3P, A103Q, A103R, A1O3S, A103T, A103V, A103W, A103Y, L104A, L104C, L104D, L104E, L104F, L104G, L104H, L104I, L104K, L104M, L104N, L104P, L104Q, L104R, L104S, L104T, L104V, L104W, L104Y, D105A, D105C, D105E, D105F, D105G, D105H, D1O5I, D105K, D105L, D105M, D105N, D105P, D1O5Q, D105R, D1O5S, D1O5T, D105V, D105W, D105Y, W106A, 106C, W106D, W106E, W106F, W106G, W106H, W106I, W106K, W106L, W106M, W106N, 106P, W106Q, W106R, W106S, W106T, W106V, or W106Y; andAttorney Docket No. DIN-005WO PATENT the VL comprises a mutation selected from the group consisting of: Q24A, Q24C, Q24D, Q24E, Q24F, Q24G, Q24H, Q24I, Q24K, Q24L, Q24M, Q24N, Q24P, Q24R, Q24S, Q24T, Q24V, Q24W, Q24Y, A25C, A25D, A25E, A25F, A25G, A25H, A25I, A25K, A25L, A25M, A25N, A25P, A25Q, A25R, A25S, A25T, A25V, A25W, A25Y, S26A, S26C, S26D, S26E, S26F, S26G, S26H, S26I, S26K, S26L, S26M, S26N, S26P, S26Q, S26R, S26T, S26V, S26W, S26Y, Q27A, Q27C, Q27D, Q27E, Q27F, Q27G, Q27H, Q27I, Q27K, Q27L, Q27M, Q27N, Q27P, Q27R, Q27S, Q27T, Q27V, Q27W, Q27Y, D28A, D28C, D28E, D28F, D28G, D28H, D28I, D28K, D28L, D28M, D28N, D28P, D28Q, D28R, D28S, D28T, D28V, D28W, D28Y, I29A, I29C, I29D, I29E, I29F, I29G, I29H, I29K, I29L, I29M, I29N, I29P, I29Q, I29R, I29S, I29T, I29V, I29W, I29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, N31A, N31C, N31D, N31E, N31F, N31G, N31H, N31I, N31K, N31L, N31M, N31P, N31Q, N31R, N31S, N31T, N31V, N31W, N31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, L33A, L33C, L33D, L33E, L33F, L33G, L33H, L33I, L33K, L33M, L33N, L33P, L33Q, L33R, L33S, L33T, L33V, L33W, L33Y, N34A, N34C, N34D, N34E, N34F, N34G, N34H, N34I, N34K, N34L, N34M, N34P, N34Q, N34R, N34S, N34T, N34V, N34W, N34Y, D50A, D50C, D50E, D50F, D50G, D50H, D50I, D50K, D50L, D50M, D50N, D50P, D50Q, D50R, D50S, D50T, D50V, D50W, D50Y, A51C, A51D, A51E, A51F, A51G, A51H, A51I, A51K, A51L, A51M, A51N, A51P, A51Q, A51R, A51S, A51T, A51V, A51W, A51Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, N53A, N53C, N53D, N53E, N53F, N53G, N53H, N53I, N53K, N53L, N53M, N53P, N53Q, N53R, N53S, N53T, N53V, N53W, N53Y, L54A, L54C, L54D, L54E, L54F, L54G, L54H, L54I, L54K, L54M, L54N, L54P, L54Q, L54R, L54S, L54T, L54V, L54W, L54Y, E55A, E55C, E55D, E55F, E55G, E55H, E55I, E55K, E55L, E55M, E55N, E55P, E55Q, E55R, E55S, E55T, E55V, E55W, E55Y, T56A, T56C, T56D, T56E, T56F, T56G, T56H, T56I, T56K, T56L, T56M, T56N, T56P, T56Q, T56R, T56S, T56V, T56W, T56Y, Q89A, Q89C, Q89D, Q89E, Q89F, Q89G, Q89H, Q89I, Q89K, Q89L, Q89M, Q89N, Q89P, Q89R, Q89S, Q89T, Q89V, Q89W, Q89Y, H90A, H90C, H90D, H90E, H90F, H90G, H90I, H90K, H90L, H90M, H90N, H90P, H90Q, H90R, H90S, H90T, H90V, H90W, H90Y, Y91A, Y91C, Y91D, Y91E, Y91F, Y91G, Y91H, Y91I, Y91K, Y91L, Y91M, Y91N, Y91P, Y91Q, Y91R, Y91S, Y91T, Y91V, Y91W, E92A, E92C, E92D, E92F, E92G, E92H, E92I, E92K, E92L, E92M, E92N, E92P, E92Q, E92R, E92S, E92T, E92V, E92W, E92Y, D93A, D93C, D93E, D93F, D93G, D93H, D93I, D93K, D93L, D93M, D93N, D93P, D93Q, D93R, D93S, D93T,Attorney Docket No. DIN-005WO PATENTD93V, D93W, D93Y, Y94A, Y94C, Y94D, Y94E, Y94F, Y94G, Y94H, Y94I, Y94K, Y94L, Y94M, Y94N, Y94P, Y94Q, Y94R, Y94S, Y94T, Y94V, Y94W, P95A, P95C, P95D, P95E, P95F, P95G, P95H, P95I, P95K, P95L, P95M, P95N, P95Q, P95R, P95S, P95T, P95V, P95W, P95Y, L96A, L96C, L96D, L96E, L96F, L96G, L96H, L96I, L96K, L96M, L96N, L96P, L96Q, L96R, L96S, L96T, L96V, L96W, L96Y, T97A, T97C, T97D, T97E, T97F, T97G, T97H, T97I, T97K, T97L, T97M, T97N, T97P T97Q, T97R, T97S, T97V, T97W, or T97Y.

20. The antibody, or the antigen-binding fragment thereof, of claim 18, wherein: the VH comprises an aninr 3 acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to any one of SEQ ID NO: 3, 4, 5, 6, ' , 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, i 16, 27, 28, 29, 30, 31, 32, 33, 34, 35 , 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, i >4, 55, 56, 57, 58, 59, 60, 61, 62, 63 , 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 1 >2, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477,Attorney Docket No. DIN-005WO PATENT478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498,499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519,520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540,541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561,562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582,583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603,604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624,625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645,646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666,667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687,688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705; and the VL comprises an amino acid sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736,737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757,758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778,779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799,800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820,821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841,842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862,863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883,884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904,905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925,926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946,947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967,968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988,989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023,1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039,1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055,1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071,Attorney Docket No. DIN-005WO PATENT1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087,1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103,1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119,1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135,1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151,1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167,1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183,1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199,1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218.

21. The antibody, or the antigen-binding fragment thereof, of claim 18, wherein: the VH comprises an amino acid sequence that is at least 90% identical to any one of SEQ IDNO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 3132, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 5960, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 7 '3, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405,Attorney Docket No. DIN-005WO PATENT406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705, provided that the VH comprises one or more mutations selected from the group consisting of: G26A, G26C, G26D, G26E, G26F, G26H, G26I, G26K, G26L, G26M, G26N, G26P, G26Q, G26R, G26S, G26T, G26V, G26W, G26Y, F27A, F27C, F27D, F27E, F27G, F27H, F27I, F27K, F27L, F27M, F27N, F27P, F27Q, F27R, F27S, F27T, F27V, F27W, F27Y, T28A, T28C, T28D, T28E, T28F, T28G, T28H, T28I, T28K, T28L, T28M, T28N, T28P, T28Q, T28R, T28S, T28V, T28W, T28Y, F29A, F29C, F29D, F29E, F29G, F29H, F29I, F29K, F29L, F29M, F29N, F29P, F29Q, F29R, F29S, F29T, F29V, F29W, F29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31C, D31E, D31F, D31G, D31H, D31I, D31K, D31L, D31M, D31N, D31P, D31Q, D31R, D31S, D31T, D31V, D31W, D31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, Y33A, Y33C, Y33D, Y33E, Y33F, Y33G, Y33H, Y33I, Y33K, Y33L, Y33M, Y33N, Y33P, Y33Q, Y33R, Y33S, Y33T, Y33V, Y33W, M34A, M34C, M34D, M34E, M34F, M34G, M34H, M34I, M34K, M34L, M34N, M34P, M34Q, M34R, M34S, M34T, M34V, M34W, M34Y, S35A, S35C, S35D, S35E, S35F, S35G, S35H, S35I, S35K, S35L, S35M, S35N, S35P, S35Q, S35R, S35T, S35V, S35W, S35Y, Y50A, Y50C, Y50D, Y50E, Y50F, Y50G, Y50H, Y50I, Y50K, Y50L, Y50M, Y50N, Y50P, Y50Q, Y50R, Y50S, Y50T, Y50V, Y50W, 151 A, 151C, I51D, 15 IE, I51F, I51G, I51H, I51K, I51L, I51M, I51N, I51P, I51Q, I51R, 15 IS, I51T, I51V, I51W, I51Y, S52A,Attorney Docket No. DIN-005WO PATENTS52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, R53A, R53C, R53D, R53E, R53F, R53G, R53H, R53I, R53K, R53L, R53M, R53N, R53P, R53Q, R53S, R53T, R53V, R53W, R53Y, S54A, S54C, S54D, S54E, S54F, S54G, S54H, S54I, S54K, S54L, S54M, S54N, S54P, S54Q, S54R, S54T, S54V, S54W, S54Y, G55A, G55C, G55D, G55E, G55F, G55H, G55I, G55K, G55L, G55M, G55N, G55P, G55Q, G55R, G55S, G55T, G55V, G55W, G55Y, S56A, S56C, S56D, S56E, S56F, S56G, S56H, S56I, S56K, S56L, S56M, S56N, S56P, S56Q, S56R, S56T, S56V, S56W, S56Y, T57A, T57C, T57D, T57E, T57F, T57G, T57H, T57I, T57K, T57L, T57M, T57N, T57P, T57Q, T57R, T57S, T57V, T57W, T57Y, K58A, K58C, K58D, K58E, K58F, K58G, K58H, K58I, K58L, K58M, K58N, K58P, K58Q, K58R, K58S, K58T, K58V, K58W, K58Y, Y59A, Y59C, Y59D, Y59E, Y59F, Y59G, Y59H, Y59I, Y59K, Y59L, Y59M, Y59N, Y59P, Y59Q, Y59R, Y59S, Y59T, Y59V, Y59W, Y60A, Y60C, Y60D, Y60E, Y60F, Y60G, Y60H, Y60I, Y60K, Y60L, Y60M, Y60N, Y60P, Y60Q, Y60R, Y60S, Y60T, Y60V, Y60W, A61C, A61D, A61E, A61F, A61G, A61H, A61I, A61K, A61L, A61M, A61N, A61P, A61Q, A61R, A61S, A61T, A61V, A61W, A61Y, D62A, D62C, D62E, D62F, D62G, D62H, D62I, D62K, D62L, D62M, D62N, D62P, D62Q, D62R, D62S, D62T, D62V, D62W, D62Y, S63A, S63C, S63D, S63E, S63F, S63G, S63H, S63I, S63K, S63L, S63M, S63N, S63P, S63Q, S63R, S63T, S63V, S63W, S63Y, V64A, V64C, V64D, V64E, V64F, V64G, V64H, V64I, V64K, V64L, V64M, V64N, V64P, V64Q, V64R, V64S, V64T, V64W, V64Y, K65A, K65C, K65D, K65E, K65F, K65G, K65H, K65I, K65L, K65M, K65N, K65P, K65Q, K65R, K65S, K65T, K65V, K65W, K65Y, G66A, G66C, G66D, G66E, G66F, G66H, G66I, G66K, G66L, G66M, G66N, G66P, G66Q, G66R, G66S, G66T, G66V, G66W, G66Y, A97C, A97D, A97E, A97F, A97G, A97H, A97I, A97K, A97L, A97M, A97N, A97P, A97Q, A97R, A97S, A97T, A97V, A97W, A97Y, R98A, R98C, R98D, R98E, R98F, R98G, R98H, R98I, R98K, R98L, R98M, R98N, R98P, R98Q, R98S, R98T, R98V, R98W, R98Y, D99A, D99C, D99E, D99F, D99G, D99H, D99I, D99K, D99L, D99M, D99N, D99P, D99Q, D99R, D99S, D99T, D99V, D99W, D99Y, E100A, E100C, E100D, E100F, E100G, E100H, E1OOI, E100K, E100L, E100M, E100N, E100P, E1OOQ, E100R, E1OOS, E100T, E100V, E100W, E100Y, N101A, N101C, N101D, N101E, N101F, N101G, N101H, N1O1I, N101K, N101L, N101M, N101P, N1O1Q, N101R, N1O1S, N101T, N101V, N101W, N101Y, Y102A, Y102C, Y102D, Y102E, Y102F, Y102G, Y102H, Y102I, Y102K, Y102L, Y102M, Y102N, Y102P, Y102Q, Y102R, Y102S, Y102T, Y102V, Y102W, A103C, A103D, A103E, A1O3F, A103G, A103H, A1O3I, A103K, A103L, A103M, A103N, A103P, A103Q, A103R, A1O3S, A103T, A103V, A103W, A103Y, L104A, L104C, L104D, L104E, L104F, L104G, L104H, L104I, L104K, L104M,Attorney Docket No. DIN-005WO PATENTL104N, L104P, L104Q, L104R, L104S, L104T, L104V, L104W, L104Y, D105A, D105C, D105E, D105F, D105G, D105H, D105I, D105K, D105L, D105M, D105N, D105P, D105Q, D105R, D105S, D105T, D105V, D105W, D105Y, W106A, W106C, W106D, W106E, W106F, W106G, W106H, W106I, W106K, W106L, W106M, W106N, W106P, W106Q, W106R, W106S, W106T, W106V, or 106Y; and the VL comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725,726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746,747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767,768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788,789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809,810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830,831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851,852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872,873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893,894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914,915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935,936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956,957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977,978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998,999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031,1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047,1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063,1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079,1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111,1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127,1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143,1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159,1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175,Attorney Docket No. DIN-005WO PATENT1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191,1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207,1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, provided that the VL comprises one or more mutations selected from the group consisting of: Q24A, Q24C, Q24D, Q24E, Q24F, Q24G,Q24H, Q24I, Q24K, Q24L, Q24M, Q24N, Q24P, Q24R, Q24S, Q24T, Q24V, Q24W, Q24Y, A25C, A25D, A25E, A25F, A25G, A25H, A25I, A25K, A25L, A25M, A25N, A25P, A25Q, A25R, A25S, A25T, A25V, A25W, A25Y, S26A, S26C, S26D, S26E, S26F, S26G, S26H, S26I, S26K, S26L, S26M, S26N, S26P, S26Q, S26R, S26T, S26V, S26W, S26Y, Q27A, Q27C, Q27D, Q27E, Q27F, Q27G, Q27H, Q27I, Q27K, Q27L, Q27M, Q27N, Q27P, Q27R, Q27S, Q27T, Q27V, Q27W, Q27Y, D28A, D28C, D28E, D28F, D28G, D28H, D28I, D28K, D28L, D28M, D28N, D28P, D28Q, D28R, D28S, D28T, D28V, D28W, D28Y, I29A, I29C, I29D, I29E, I29F, I29G, I29H, I29K, I29L, I29M, I29N, I29P, I29Q, I29R, I29S, I29T, I29V, I29W, I29Y, S30A, S30C, S30D, S30E, S30F, S30G, S30H, S30I, S30K, S30L, S30M, S30N, S30P, S30Q, S30R, S30T, S30V, S30W, S30Y, N31A, N31C, N31D, N31E, N31F, N31G, N31H, N31I, N31K, N31L, N31M, N31P, N31Q, N31R, N31S, N31T, N31V, N31W, N31Y, Y32A, Y32C, Y32D, Y32E, Y32F, Y32G, Y32H, Y32I, Y32K, Y32L, Y32M, Y32N, Y32P, Y32Q, Y32R, Y32S, Y32T, Y32V, Y32W, L33A, L33C, L33D, L33E, L33F, L33G, L33H, L33I, L33K, L33M, L33N, L33P, L33Q, L33R, L33S, L33T, L33V, L33W, L33Y, N34A, N34C, N34D, N34E, N34F, N34G, N34H, N34I, N34K, N34L, N34M, N34P, N34Q, N34R, N34S, N34T, N34V, N34W, N34Y, D50A, D50C, D50E, D50F, D50G, D50H, D50I, D50K, D50L, D50M, D50N, D50P, D50Q, D50R, D50S, D50T, D50V, D50W, D50Y, A51C, A51D, A51E, A51F, A51G, A51H, A51I, A51K, A51L, A51M, A51N, A51P, A51Q, A51R, A51S, A51T, A51V, A51W, A51Y, S52A, S52C, S52D, S52E, S52F, S52G, S52H, S52I, S52K, S52L, S52M, S52N, S52P, S52Q, S52R, S52T, S52V, S52W, S52Y, N53A, N53C, N53D, N53E, N53F, N53G, N53H, N53I, N53K, N53L, N53M, N53P, N53Q, N53R, N53S, N53T, N53V, N53W, N53Y, L54A, L54C, L54D, L54E, L54F, L54G, L54H, L54I, L54K, L54M, L54N, L54P, L54Q, L54R, L54S, L54T, L54V, L54W, L54Y, E55A, E55C, E55D, E55F, E55G, E55H, E55I, E55K, E55L, E55M, E55N, E55P, E55Q, E55R, E55S, E55T, E55V, E55W, E55Y, T56A, T56C, T56D, T56E, T56F, T56G, T56H, T56I, T56K, T56L, T56M, T56N, T56P, T56Q, T56R, T56S, T56V, T56W, T56Y, Q89A, Q89C, Q89D, Q89E, Q89F, Q89G, Q89H, Q89I, Q89K, Q89L, Q89M, Q89N, Q89P, Q89R, Q89S, Q89T, Q89V, Q89W, Q89Y, H90A, H90C, H90D, H90E, H90F, H90G, H90I, H90K, H90L, H90M, H90N, H90P, H90Q, H90R, H90S, H90T, H90V, H90W, H90Y, Y91A, Y91C, Y91D, Y91E, Y91F, Y91G, Y91H, Y91I, Y91K, Y91L, Y91M, Y91N, Y91P, Y91Q,Attorney Docket No. DIN-005WO PATENTY91R, Y91S, Y91T, Y91V, Y91W, E92A, E92C, E92D, E92F, E92G, E92H, E92I, E92K, E92L, E92M, E92N, E92P, E92Q, E92R, E92S, E92T, E92V, E92W, E92Y, D93A, D93C, D93E, D93F, D93G, D93H, D93I, D93K, D93L, D93M, D93N, D93P, D93Q, D93R, D93S, D93T, D93V, D93W, D93Y, Y94A, Y94C, Y94D, Y94E, Y94F, Y94G, Y94H, Y94I, Y94K, Y94L, Y94M, Y94N, Y94P, Y94Q, Y94R, Y94S, Y94T, Y94V, Y94W, P95A, P95C, P95D, P95E, P95F, P95G, P95H, P95I, P95K, P95L, P95M, P95N, P95Q, P95R, P95S, P95T, P95V, P95W, P95Y, L96A, L96C, L96D, L96E, L96F, L96G, L96H, L96I, L96K, L96M, L96N, L96P, L96Q, L96R, L96S, L96T, L96V, L96W, L96Y, T97A, T97C, T97D, T97E, T97F, T97G, T97H, T97I, T97K, T97L, T97M, T97N, T97P, T97Q, T97R, T97S, T97V, T97W, or T97Y.

22. An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises one or more mutations selected from any one of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, 15 IS, S52N, S52T, G55L, A97T, N101S, W106F, or any combination thereof, as compared to SEQ ID NO: 1; and the VL comprises one or more mutations selected from any one of: D28T, N31K, N31Q, S52R, Q89A, Q89T, H90E, T97G, T97L, T97N, or any combination thereof, as compared to SEQ ID NO: 2, wherein at least one of the VH and the VL is a variant of the VH comprising the amino acid sequence of SEQ ID NO: 1 and the VL is a variant of the VL comprising the amino acid sequence of SEQ ID NO: 2.

23. The antibody, or the antigen-binding fragment thereof, of claim 22, wherein the VH comprises the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, 1225, or 1228, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, 1226, or 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221, 1227, or 1230.

24. The antibody, or the antigen-binding fragment thereof, of any one of claims 22 or 23, wherein the VH comprises:Attorney Docket No. DIN-005WO PATENT the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221; the HCDR1 having an amino acid sequence of SEQ ID NO: 1225, the HCDR2 having an amino acid sequence of SEQ ID NO: 1226, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1227; or the HCDR1 having an amino acid sequence of SEQ ID NO: 1228, the HCDR2 having an amino acid sequence of SEQ ID NO: 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1230.

25. The antibody, or the antigen-binding fragment thereof, of any one of claims 22-24, wherein the VL comprises the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, or 1231, the LCDR2 aving an amino acid sequence of SEQ ID NO: 1223, or 1232, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224.

26. The antibody, or the antigen-binding fragment thereof, of any one of claims 22-25, wherein the VL comprises: the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224; or the LCDR1 having an amino acid sequence of SEQ ID NO: 1231, the LCDR2 having an amino acid sequence of SEQ ID NO: 1232, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224.

27. The antibody, or the antigen-binding fragment thereof, of any one of claims 22-26, wherein: the VH comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87,88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,Attorney Docket No. DIN-005WO PATENT133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153,154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174,175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or 705; and the VL comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746,Attorney Docket No. DIN-005WO PATENT747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767,768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788,789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809,810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830,831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851,852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872,873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893,894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914,915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935,936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956,957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977,978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998,999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063,1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079,1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111,1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127,1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143,1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159,1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175,1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191,1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207,1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218.

28. The antibody, or the antigen-binding fragment thereof, of any one of claims 22-27, wherein: the VH comprises an amino acid sequence that is at least 90% identical to any one of SEQ IDNO: 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,Attorney Docket No. DIN-005WO PATENT60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 8788, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132,133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153,154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174,175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195,196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216,217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237,238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258,259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279,280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300,301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321,322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342,343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363,364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384,385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405,406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426,427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447,448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468,469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489,490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510,511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531,532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552,553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573,574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594,595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615,616, 617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636,637, 638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657,658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678,679, 680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699,700, 701, 702, 703, 704, or 705, provided that the VH comprises one or more n utations selected fromAttorney Docket No. DIN-005WO PATENT the group consisting of: T28D, S30G, S30K, S30L, S30Q, S30R, S30T, S30V, S30W, S30Y, D31A, D31E, D31F, D31G, D31I, D31K, D31Q, D31T, D31V, D31W, D31Y, S35D, 15 IS, S52N, S52T, G55L, A97T, N101S, W106F; and the VL comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725,726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746,747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767,768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788,789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809,810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830,831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851,852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872,873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893,894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914,915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935,936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956,957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977,978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998,999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047,1048, 1049, 1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063,1064, 1065, 1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079,1080, 1081, 1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095,1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111,1112, 1113, 1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127,1128, 1129, 1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143,1144, 1145, 1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159,1160, 1161, 1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175,1176, 1177, 1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207,Attorney Docket No. DIN-005WO PATENT1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, provided that the VL comprises one or more mutations selected from the group consisting of: D28T, N31K, N31Q, S52R, Q89A, Q89T. H90E, T97G, T97L, T97N.

29. An antibody, or an antigen-binding fragment thereof, comprising: a VH having at least at least 95% amino acid sequence identity to any one of SEQ ID NO: 3, 4, 5 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 62 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89 90 91.

92.

93.

94.

95.

96.

97.

98.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

109.

110.

111. 112.113 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553,Attorney Docket No. DIN-005WO PATENT554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574,575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595,596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616,617, 618, 619, 620, 621, 622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637,638, 639, 640, 641, 642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658,659, 660, 661, 662, 663, 664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679,680, 681, 682, 683, 684, 685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700,701, 702, 703, 704, or 705; and a VL having at least 95% amino acid sequence identity to any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729,730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750,751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771,772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792,793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813,814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834,835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855,856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876,877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897,898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918,919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939,940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960,961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981,982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017,1018, 1019, 1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033,1034, 1035, 1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049,1050, 1051, 1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065,1066, 1067, 1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081,1082, 1083, 1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113,1114, 1115, 1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129,Attorney Docket No. DIN-005WO PATENT1130, 1131, 1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145,1146, 1147, 1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161,1162, 1163, 1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177,1178, 1179, 1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193,1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209,1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218, wherein the VH comprises the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, 1225, or 1228, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, 1226, or 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221, 1227, or 1230, and wherein the VL comprises the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, or 1231, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, or 1232, and the LCDR3 aving an amino acid sequence of SEQ ID NO: 1224.

30. The antibody, or the antigen-binding fragment thereof, of claim 29, wherein the VH comprises: the HCDR1 having an amino acid sequence of SEQ ID NO: 1219, the HCDR2 having an amino acid sequence of SEQ ID NO: 1220, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1221; the HCDR1 having an amino acid sequence of SEQ ID NO: 1225, the HCDR2 having an amino acid sequence of SEQ ID NO: 1226, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1227; or the HCDR1 having an amino acid sequence of SEQ ID NO: 1228, the HCDR2 having an amino acid sequence of SEQ ID NO: 1229, and the HCDR3 having an amino acid sequence of SEQ ID NO: 1230.

31. The antibody, or the antigen-binding fragment thereof, of claim 29, wherein the VL comprises: the LCDR1 having an amino acid sequence of SEQ ID NO: 1222, the LCDR2 having an amino acid sequence of SEQ ID NO: 1223, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224; or the LCDR1 having an amino acid sequence of SEQ ID NO: 1231, the LCDR2 having an amino acid sequence of SEQ ID NO: 1232, and the LCDR3 having an amino acid sequence of SEQ ID NO: 1224.Attorney Docket No. DIN-005WO PATENT32. The antibody, or the antigen-binding fragment thereof, of any one of claims 29-31, wherein: the VH comprises an amino acid sequence of any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 3940, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 6768.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94. 9596, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579, 580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621,Attorney Docket No. DIN-005WO PATENT622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642,643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663,664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684,685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or705; and the VL comprises an amino acid sequence of any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773, 774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815, 816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836, 837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857, 858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878, 879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899, 900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920, 921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941, 942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962, 963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983, 984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019,1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035,1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051,1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067,1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083,1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099, 1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115,1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131,1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147,1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163,1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179,Attorney Docket No. DIN-005WO PATENT1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195,1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218.

33. An antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein: the VH comprises an amino acid sequence of any one of SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 3940, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 6768.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

90.

91.

92.

93.

94. 9596, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334, 335, 336, 337, 338, 339, 340, 341, 342, 343, 344, 345, 346, 347, 348, 349, 350, 351, 352, 353, 354, 355, 356, 357, 358, 359, 360, 361, 362, 363, 364, 365, 366, 367, 368, 369, 370, 371, 372, 373, 374, 375, 376, 377, 378, 379, 380, 381, 382, 383, 384, 385, 386, 387, 388, 389, 390, 391, 392, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444, 445, 446, 447, 448, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 459, 460, 461, 462, 463, 464, 465, 466, 467, 468, 469, 470, 471, 472, 473, 474, 475, 476, 477, 478, 479, 480, 481, 482, 483, 484, 485, 486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498, 499, 500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515, 516, 517, 518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533, 534, 535, 536, 537,Attorney Docket No. DIN-005WO PATENT538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552, 553, 554, 555, 556, 557, 558,559, 560, 561, 562, 563, 564, 565, 566, 567, 568, 569, 570, 571, 572, 573, 574, 575, 576, 577, 578, 579,580, 581, 582, 583, 584, 585, 586, 587, 588, 589, 590, 591, 592, 593, 594, 595, 596, 597, 598, 599, 600,601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612, 613, 614, 615, 616, 617, 618, 619, 620, 621,622, 623, 624, 625, 626, 627, 628, 629, 630, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641, 642,643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654, 655, 656, 657, 658, 659, 660, 661, 662, 663,664, 665, 666, 667, 668, 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683, 684,685, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697, 698, 699, 700, 701, 702, 703, 704, or705; and the VL comprises an amino acid sequence of any one of SEQ ID NO: 706, 707, 708, 709, 710, 711, 712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724, 725, 726, 727, 728, 729, 730, 731,732, 733, 734, 735, 736, 737, 738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750, 751, 752,753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763, 764, 765, 766, 767, 768, 769, 770, 771, 772, 773,774, 775, 776, 777, 778, 779, 780, 781, 782, 783, 784, 785, 786, 787, 788, 789, 790, 791, 792, 793, 794,795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805, 806, 807, 808, 809, 810, 811, 812, 813, 814, 815,816, 817, 818, 819, 820, 821, 822, 823, 824, 825, 826, 827, 828, 829, 830, 831, 832, 833, 834, 835, 836,837, 838, 839, 840, 841, 842, 843, 844, 845, 846, 847, 848, 849, 850, 851, 852, 853, 854, 855, 856, 857,858, 859, 860, 861, 862, 863, 864, 865, 866, 867, 868, 869, 870, 871, 872, 873, 874, 875, 876, 877, 878,879, 880, 881, 882, 883, 884, 885, 886, 887, 888, 889, 890, 891, 892, 893, 894, 895, 896, 897, 898, 899,900, 901, 902, 903, 904, 905, 906, 907, 908, 909, 910, 911, 912, 913, 914, 915, 916, 917, 918, 919, 920,921, 922, 923, 924, 925, 926, 927, 928, 929, 930, 931, 932, 933, 934, 935, 936, 937, 938, 939, 940, 941,942, 943, 944, 945, 946, 947, 948, 949, 950, 951, 952, 953, 954, 955, 956, 957, 958, 959, 960, 961, 962,963, 964, 965, 966, 967, 968, 969, 970, 971, 972, 973, 974, 975, 976, 977, 978, 979, 980, 981, 982, 983,984, 985, 986, 987, 988, 989, 990, 991, 992, 993, 994, 995, 996, 997, 998, 999, 1000, 1001, 1002, 1003, 1004, 1005, 1006, 1007, 1008, 1009, 1010, 1011, 1012, 1013, 1014, 1015, 1016, 1017, 1018, 1019,1020, 1021, 1022, 1023, 1024, 1025, 1026, 1027, 1028, 1029, 1030, 1031, 1032, 1033, 1034, 1035,1036, 1037, 1038, 1039, 1040, 1041, 1042, 1043, 1044, 1045, 1046, 1047, 1048, 1049, 1050, 1051,1052, 1053, 1054, 1055, 1056, 1057, 1058, 1059, 1060, 1061, 1062, 1063, 1064, 1065, 1066, 1067,1068, 1069, 1070, 1071, 1072, 1073, 1074, 1075, 1076, 1077, 1078, 1079, 1080, 1081, 1082, 1083,1084, 1085, 1086, 1087, 1088, 1089, 1090, 1091, 1092, 1093, 1094, 1095, 1096, 1097, 1098, 1099,1100, 1101, 1102, 1103, 1104, 1105, 1106, 1107, 1108, 1109, 1110, 1111, 1112, 1113, 1114, 1115,Attorney Docket No. DIN-005WO PATENT1116, 1117, 1118, 1119, 1120, 1121, 1122, 1123, 1124, 1125, 1126, 1127, 1128, 1129, 1130, 1131,1132, 1133, 1134, 1135, 1136, 1137, 1138, 1139, 1140, 1141, 1142, 1143, 1144, 1145, 1146, 1147,1148, 1149, 1150, 1151, 1152, 1153, 1154, 1155, 1156, 1157, 1158, 1159, 1160, 1161, 1162, 1163,1164, 1165, 1166, 1167, 1168, 1169, 1170, 1171, 1172, 1173, 1174, 1175, 1176, 1177, 1178, 1179,1180, 1181, 1182, 1183, 1184, 1185, 1186, 1187, 1188, 1189, 1190, 1191, 1192, 1193, 1194, 1195, 1196, 1197, 1198, 1199, 1200, 1201, 1202, 1203, 1204, 1205, 1206, 1207, 1208, 1209, 1210, 1211, 1212, 1213, 1214, 1215, 1216, 1217, or 1218.

34. A pharmaceutical composition comprising the antibody, or antigen-binding fragment thereof, of any one of claims 1-33 and a pharmaceutically acceptable excipient.

35. A method of treating a Cls-mediated disease or disorder in a subject, such as a subject in need thereof, comprising administering the pharmaceutical composition of claim 34 to the subject.

36. The method of claim 35, wherein the antibody binds to complement component Cis.

37. The method of claim 36, wherein the antibody binds to active complement component Cis.

38. The method of claim 36, wherein the antibody inhibits complement component Cis.

39. The method of claim 38, wherein the antibody inhibits classical component pathway cascade.

40. The method of any one of claims 35-39, wherein the antibody, or the antigen-binding fragment thereof, achieves a serum concentration of about 50 pg / mL to about 300 ug / mL in the subject.

41. The method of claim 40, wherein the antibody, or the antigen-binding fragment thereof, achieves a serum concentration of about 75 ug / mL to about 250 ug / mL.

42. The method of any one of claims 35-41, wherein the antibody, or the antigen-binding fragment thereof, achieves a serum concentration of at least 87 ug / mL, at least 125 ug / mL, or at least 250 ug / mL.Attorney Docket No. DIN-005WO PATENT43. The method of any one of claims 35-42, wherein the antibody, or the antigen-binding fragment thereof, achieves at least 90%, or at least 95% inhibition of the complement pathway.

44. The method of any one of claims 35-43, wherein the antibody, or the antigen-binding fragment thereof, is administered by an intravenous, a subcutaneous, an intramuscular, an intraarterial, an intraarticular, an intratumoral, and / or an inhalation administration.

45. The method of any one of claims 35-44, wherein the Cls-mediated disease or disorder is selected from Myasthenia Gravis, hemolysis, Cold Agglutinin Disease, Immune Thrombocytopenia (ITP), Glomerulopathies, Atypical Hemolytic uremic syndrome, antiphospholipid antibody syndrome, transplant rejection, chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy (MMN), dermatomyositis, anti-MAG neuropathy, due to stroke, or due to spinal cord injury.

46. The method of any one of claims 35-45, wherein the antibody is administered in multiple doses, such as a first dose and then subsequent doses, wherein the first dose can be a loading dose.

47. The method of claim 46, wherein first dose is selected from: about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, or about 60 mg / kg.

48. The method of claims 46 or 47, wherein the one or more subsequent dose is selected from: about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200Attorney Docket No. DIN-005WO PATENT mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1050 mg, about 1100 mg, about 1150 mg, about 1200 mg, about 1250 mg, about 1300 mg, about 1350 mg, about 1400 mg, about 1450 mg, about 1500 mg, about 1550 mg, about 1600 mg, about 1650 mg, about 1700 mg, about 1750 mg, about 1800 mg, about 1850 mg, about 1900 mg, about 1950 mg, about 2000 mg, about 2050 mg, about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, about 2700 mg, about 2750 mg, about 2800 mg, about 2850 mg, about 2900 mg, about 2950 mg, about 3000 mg, about 3050 mg, about 3100 mg, about 3150 mg, about 3200 mg, about 3250 mg, about 3300 mg, about 3350 mg, about 3400 mg, about 3450 mg, about 3500 mg, about 3550 mg, about 3600 mg, about 7200 mg, or about 8300 mg.

49. The method of any one of claims 46-48, wherein the antibody, or the antigen-binding fragment thereof, is administered every 10, 12, 14, or 16 weeks after the first dose.

50. The method of any one of claims 1-49, wherein the antibody is administered intravenously or subcutaneously.

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