von Willebrand factor (VWF) inhibitors

Abstract

The present invention relates to inhibitors of von Willebrand factor (VWF), particularly anti-VWF antibodies. The present invention extends to compositions, such as pharmaceutical compositions, and kits that contain the inhibitors. The present invention also extends to methods of making and using the inhibitors in the therapy and diagnosis of conditions caused by platelet-mediated aggregation, including various cardiovascular diseases such as acquired thrombotic thrombocytopenic purpura (aTTP), ischemic stroke, and atherosclerosis.

Description

[Technical field]

[0001] The present invention relates to inhibitors of von Willebrand factor (VWF), particularly but not exclusively to inhibitors targeting the C1-C6 domain of VWF. The invention extends to compositions, such as pharmaceutical compositions, and kits comprising the inhibitors. The invention also extends to methods of using the inhibitors in the therapy and diagnosis of conditions caused by platelet-mediated aggregation, including various cardiovascular diseases such as acquired thrombotic thrombocytopenic purpura (aTTP), ischemic stroke, and atherosclerosis. [Background technology]

[0002] Cardiovascular disease (CVD), including ischemic heart disease, stroke, heart failure, peripheral arterial disease, and multiple other conditions involving the heart and blood vessels, continues to be a leading cause of death worldwide. CVD is characterized by thrombotic events caused by uncontrolled platelet aggregation, which contributes to both cell death and organ failure. Given the central role of platelets in the development of thrombosis, several approved antithrombotic drugs, such as aspirin, clopidogrel, and abciximab, target platelets. Combining these agents inhibits platelet aggregation to a greater extent than either of these agents acting alone, due to their complementary mechanisms of action. However, the use of these antiplatelet agents is hindered by increased bleeding risk, reducing their usefulness in a broader patient population. Thus, there remains a high unmet medical need for therapies that can treat thrombotic disorders without significant bleeding risk.

[0003] Von Willebrand factor (VWF) is a large multimeric glycoprotein present in plasma, endothelial cells, megakaryocytes, and platelets and is a well-established risk factor for thrombotic events. VWF plays a major role in hemostasis, mediating platelet adhesion to sites of vascular injury, and protecting coagulation factor VIII (FVIII) from degradation. After injury, collagen is exposed to blood flow and shear forces in the damaged vessel wall. Plasma VWF binds to the exposed collagen, unwinding its structure and aiding in the adhesion of circulating platelets. Bound VWF then interacts with the platelet receptor GPIb, resulting in platelet tethering. Platelet plug formation is achieved when a critical mass of platelets, VWF, and associated coagulation proteins bind and plug the vessel wall. Other functions have also been reported for VWF, including regulation of inflammation and angiogenesis.

[0004] Accumulation of VWF has been associated with an increased risk of developing CVD. In particular, accumulation of ultra-long VWF (ULvWF) in patients with thrombotic thrombocytopenic purpura (TTP) has been widely studied. Currently, caplacizumab (a monoclonal antibody) is the only approved anti-VWF therapy and has been shown to block VWF binding to platelets and reduce clot formation in TTP patients. However, this antibody works by targeting and inhibiting the A1 domain of VWF (see Figure 1). The A1 domain is essential for collagen binding under low shear conditions and therefore platelet binding, and for normal hemostasis to occur. Thus, treatment with caplacizumab, by targeting this region, poses a significant bleeding risk to patients. For patients suffering from TTP, a rare and fatal clotting disorder, the benefits of taking caplacizumab outweigh the risk of significant bleeding. However, this significant bleeding risk is unacceptable for patients with other CVDs, including ischemic stroke and myocardial infarction. Thus, there is a significant unmet medical need for new antithrombotic therapies that can be used to treat a broader range of thrombotic disorders without the significant bleeding risk. Summary of the Invention

[0005] The inventors have identified a previously untargeted region within the C1-C6 domain of VWF (see FIG. 1) that is essential for VWF to bind collagen and coagulate platelets under high shear rates such as those found in thrombotic conditions. Importantly, the C1-C6 domain is not essential for collagen binding and therefore platelet binding under low shear conditions (i.e. normal bleeding). This therefore identifies the C1-C6 domain of VWF as a potential new therapeutic target for the treatment of multiple conditions caused by platelet-mediated aggregation or thrombosis-related conditions, including aTTP, ischemic stroke, and atherosclerosis.

[0006] Therefore, we hypothesized that by inhibiting the ability of the C1-C6 region of VWF to bind collagen under high shear rates, platelet aggregation in thrombotic conditions may be reduced. Importantly, by targeting this region, VWF retains its ability to bind to platelets (via the A1 domain) under low shear rates as normal for normal hemostasis to occur, and is therefore not subject to the significant problems associated with the use of caplacizumab. This led to further research by the inventors in the development of antibodies capable of targeting the C1-C6 domain of VWF to inhibit its prothrombotic functions. These anti-VWF monoclonal antibodies could be used in the treatment, amelioration, or prevention of multiple thrombosis-related conditions, reducing the risk of significant bleeding and therefore making them much safer than currently available treatments.

[0007] Thus, in a first aspect of the present invention, there is provided an inhibitor that specifically binds to one or more (one or more) of the C1 domain, C2 domain, C3 domain, C4 domain, C5 domain and / or C6 domain of von Willebrand factor (VWF).

[0008] As shown in the Examples, the present inventors have developed antibodies capable of binding to and inhibiting the function of the C1-C6 domain of VWF. For example, as shown in Figures 3A-3H, the present inventors have developed eight antibodies that target within the C1-C6 domain of VWF. Furthermore, as shown in Figures 5 and 6, the present inventors have demonstrated that these antibodies surprisingly significantly reduce platelet aggregation at high shear rates, i.e., pathological conditions, but preserve platelet capture at low shear rates, i.e., normal conditions. This demonstrates that targeting one or more of the C1-C6 domains of VWF inhibits the prothrombotic function of VWF without inhibiting its normal hemostatic function.

[0009] The inventors have demonstrated that the monoclonal antibodies according to the invention bind to the C5 domain of VWF with sub-nM affinity (see FIG. 9). Furthermore, some of the antibody clones showed weak binding to the C3 (Antibody 1-D5) and C4 (Antibody 3-H9) domains of VWF.

[0010] Thus, in one preferred embodiment, the inhibitors of the invention specifically bind to the C3 and C5 domains of VWF (antibody 1-D5), or, in another preferred embodiment, the inhibitors of the invention specifically bind to the C4 and C5 domains of VWF (antibody 3-H9).

[0011] In another preferred embodiment, the inhibitor of the present invention specifically binds to the C5 domain of VWF. In this embodiment, the inhibitor may further bind to one or more of the C1 domain, the C2 domain, the C3 domain, the C4 domain and / or the C6 domain. However, the inhibitor of the present invention may not substantially bind to the C1 domain, the C2 domain, the C3 domain, the C4 domain and / or the C6 domain of VWF. Preferably, the inhibitor of the present invention has substantially no cross-reactivity with the C1 domain, the C2 domain, the C3 domain, the C4 domain and / or the C6 domain of VWF. Preferably, the inhibitor does not substantially bind to the C3 domain and / or the C4 domain of VWF.

[0012] Preferably, the inhibitor of the present invention is capable of inhibiting the function of one or more of the C1, C2, C3, C4, C5, and / or C6 domains of VWF. In a preferred embodiment, the inhibitor of the present invention is capable of inhibiting the function of the C5 domain of VWF. Preferably, the inhibitor is capable of inhibiting the function of one or more of the C1, C2, C3, C4, C5, and / or C6 domains of VWF such that platelet binding is inhibited under conditions of high shear rate, i.e., pathological conditions. Preferably, the inhibitor is capable of inhibiting the function of one or more of the C1, C2, C3, C4, C5, and / or C6 domains of VWF such that platelet binding is not inhibited under conditions of low shear rate, i.e., normal conditions.

[0013] In one embodiment, the amino acid sequence of VWF may be represented by Genbank ID number: NM_000552.5, which is provided herein as SEQ ID NO: 1, as follows: [SEQ ID NO: 1] Thus, the inhibitor may bind to the region between amino acid positions 2255 and 2722 of SEQ ID NO:1, which corresponds to the C1-C6 domains of VWF.

[0014] Thus, preferably, the inhibitor is capable of binding to one or more amino acids between amino acid positions 2255 and 2722 of VWF, corresponding to the C1-C6 domains, provided herein as SEQ ID NO:2 as follows: TQCIGEDGVQHQFLEAWVPDHQPCQICTCLSGRKVNCTTQPCPTAKAPTCGLCEVARLRQNADQCCPEYECVCDPVSCDLPPVPHCERGLQPTLTNPGECRPNFTCACRKEECKRVS PPSCPPHRLPTLRKTQCCDEYECACNCVNSTVSCPLGYLASTATNDCGCTTTTCLPDKVCVHRSTIYPVGQFWEEGCDVCTCTDMEDAVMGLRVAQCSQKPCEDSCRSGFTYVLHEG ECCGRCLPSACEVVTGSPRGDSQSSWKSVGSQWASPENPCLINECVRVKEEVFIQQRNVSCPQLEVPVCPSGFQLSCKTSACCPSCRCERMEACMLNGTVIGPGKTVMIDVCTTCRC MVQVGVISGFKLECRKTTCNPCPLGYKEENNTGECCGRCLPTACTIQLRGGQIMTLKRDETLQDGCDTHFCKVNERGEYFWEKRVTGCPPFDEHKCLAEGGKIMKIPGTCCDTCEEP [SEQ ID NO:2] Thus, preferably the inhibitor binds to one or more amino acids within a sequence comprising or consisting of a sequence substantially as set out in SEQ ID NO: 2 or a variant or fragment thereof.

[0015] In one embodiment, the amino acid sequence of the C1 domain of VWF may be provided herein as SEQ ID NO:3, as follows: TQCIGEDGVQHQFLEAWVPDHQPCQICTCLSGRKVNCTTQPCPTAKAPTCGLCEVARLRQNADQCCPEYECVCDPVSCD [SEQ ID NO:3] Thus, preferably the inhibitor binds to one or more amino acids or epitopes within a sequence comprising or consisting of a sequence substantially as set out in SEQ ID NO: 3 or a variant or fragment thereof.

[0016] In one embodiment, the amino acid sequence of the C2 domain of VWF may be provided herein as SEQ ID NO:4, as follows: LPPVPHCERGLQPTLTNPGECRPNFTCACRKEECKRVSPPSCPPHRLPTLRKTQCCDEYECACNCVNST [SEQ ID NO:4] Thus, preferably the inhibitor binds to one or more amino acids or epitopes within a sequence comprising or consisting of a sequence substantially as set out in SEQ ID NO: 4 or a variant or fragment thereof.

[0017] In one embodiment, the amino acid sequence of the C3 domain of VWF may be provided herein as SEQ ID NO:5, as follows: VCVHRSTIYPVGQFWEEGCDVCTCTDMEDAVMGLRVAQCSQKPCEDSCRSGFTYVLHEGECCGRCLP [SEQ ID NO:5] Thus, preferably the inhibitor binds to one or more amino acids or epitopes within a sequence comprising or consisting of a sequence substantially as set out in SEQ ID NO:5 or a variant or fragment thereof.

[0018] In one embodiment, the amino acid sequence of the C4 domain of VWF may be provided herein as SEQ ID NO:6, as follows: SACEVVTGSPRGDSQSSWKSVGSQWASPENPCLINECVRVKEEVFIQQRNVSCPQLEVPVCPSGFQLSCKTSACCPSCRCE [SEQ ID NO:6] Thus, preferably the inhibitor binds to one or more amino acids or epitopes within a sequence comprising or consisting of a sequence substantially as set out in SEQ ID NO:6 or a variant or fragment thereof.

[0019] In one embodiment, the amino acid sequence of the C5 domain of VWF may be provided herein as SEQ ID NO:7, as follows: RMEACMLNGTVIGPGKTVMIDVCTTCRCMVQVGVISGFKLECRKTTCNPCPLGYKEENNTGECCGRCLP [SEQ ID NO: 7] Thus, preferably the inhibitor binds to one or more amino acids or epitopes within a sequence comprising or consisting of a sequence substantially as set out in SEQ ID NO: 7 or a variant or fragment thereof.

[0020] In one embodiment, the amino acid sequence of the C6 domain of VWF may be provided herein as SEQ ID NO:8, as follows: TACTIQLRGGQIMTLKRDETLQDGCDTHFCKVNERGEYFWEKRVTGCPPFDEHKCLAEGGKIMKIPGTCCDTCEEP [SEQ ID NO:8] Thus, preferably the inhibitor binds to one or more amino acids or epitopes within a sequence comprising or consisting of a sequence substantially as set forth in SEQ ID NO:8 or a variant or fragment thereof.

[0021] Previous therapeutic targeting of VWF has focused on the A1 and A3 domains, such as caplacizumab targeting A1 and 82D6A3 targeting A3. However, the A1 and A3 domains are essential for collagen binding and therefore platelet binding. Therefore, targeting the A1 and A3 domains inhibits platelet binding under low shear rate conditions, i.e., normal conditions, and poses a significant bleeding risk to patients.

[0022] It is therefore important that the inhibitors of the present invention that target one or more of the C1, C2, C3, C4, C5 and / or C6 domains of VWF do so specifically and have no or little cross-reactivity with the A1, A2 and / or A3 domains of VWF, because cross-reactivity could result in significant unwanted off-target effects, such as significant bleeding risks.

[0023] Therefore, preferably, the inhibitor of the present invention does not substantially bind to the A1 domain, the A2 domain, and / or the A3 domain of VWF. Preferably, the inhibitor of the present invention has substantially no cross-reactivity with the A1 domain, the A2 domain, and / or the A3 domain of VWF. Most preferably, the inhibitor of the present invention has substantially no cross-reactivity with the A1 domain of VWF.

[0024] In one embodiment, the amino acid sequence of the A1 domain of VWF may be provided herein as SEQ ID NO: 153, as follows: DLVFLLDGSSRLSEAEFEVLKAFVVDMMERLRISQKWVRVAVVEYHDGSHAYIGLKDRKRPSELRRIASQVKYAGSQVASTSEVLKYTLFQIFSKIDRPEASRITLLLMASQEPQRMSRNFVRYVQKKKKVIVIPVGIGPHANLKQIRLIEKQAPENKAFVLSSVDELEQQRDEI [SEQ ID NO:153] Thus, preferably the inhibitor does not bind to a sequence substantially as defined in SEQ ID NO: 153 or a variant or fragment thereof.

[0025] In one embodiment, the amino acid sequence of the A2 domain of VWF may be provided herein as SEQ ID NO: 154 as follows: DVAFVLEGSDKIGEADFNRSKEFMEEVIQRMDVGQDSIHVTVLQYSYMVTVEYPFSEAQSKGDILQRVREIRYQGGNRTNTGLALRYLSDHSFLVSQGDREQAPNLVYMVTGNPASDEIKRLPGDIQVVPIGVGPNANVQELERIGWPNAPILIQDFETLPREAPDLVQRCC [SEQ ID NO:154] Thus, preferably the inhibitor does not bind to a sequence substantially as defined in SEQ ID NO: 154 or a variant or fragment thereof.

[0026] In one embodiment, the amino acid sequence of the A3 domain of VWF may be provided herein as SEQ ID NO: 155, as follows: DVILLLDGSSSFPASYFDEMKSFAKAFISKANIGPRLTQVSVLQYGSITTIDVPWNVVPEKAHLLSLVDVMQREGGPSQIGDALGFAVRYLTSEMHGARPGASKAVVILVTDVSVDSVDAAADAARSNRVTVFPIGIGDRYDAAQLRILAGPAGDSNVVKLQRIEDLPTMVTLGNSFLHKL [SEQ ID NO:155] Thus, preferably the inhibitor does not bind to a sequence substantially as defined in SEQ ID NO: 155 or a variant or fragment thereof.

[0027] In a preferred embodiment, the inhibitor is an antibody or an antigen-binding fragment thereof. Thus, in a further aspect of the present invention, there is provided an inhibitor which is an antibody or antigen-binding fragment thereof which specifically binds to one or more of the C1, C2, C3, C4, C5 and / or C6 domains of von Willebrand factor (VWF), and preferably does not substantially bind to the A1, A2 and / or A3 domains of VWF.

[0028] The present invention extends to both whole antibodies (i.e., immunoglobulins) having immunospecificity for one or more of the C1, C2, C3, C4, C5 and / or C6 domains of VWF (preferably C5), as well as antigen-binding fragments or regions of the corresponding full-length antibodies.

[0029] Antibodies or antigen-binding fragments thereof can be monovalent, bivalent, or multivalent. A monovalent antibody is a dimer (HL) containing a heavy (H) chain associated with a light chain (L) by a disulfide bridge. A bivalent antibody is a tetramer (H2L2) containing two dimers associated by at least one disulfide bridge. Multivalent antibodies can also be produced, for example by linking multiple dimers. The basic structure of an antibody molecule consists of two identical light chains and two identical heavy chains that are non-covalently associated and optionally linked by disulfide bonds. Each of the heavy and light chains contains an amino-terminal variable region of about 110 amino acids and constant sequences in the remainder of the chain. The variable region includes several hypervariable regions or complementarity determining regions (CDRs), which form the antigen-binding site of the antibody molecule and determine its specificity for the antigen, i.e., one or more of the C1, C2, C3, C4, C5, and / or C6 domains of VWF (preferably C5), or variants or fragments thereof (e.g., epitopes). On either side of the CDRs of the heavy and light chains are framework regions, which are relatively conserved sequences of amino acids that anchor and determine the position of the CDRs. The antibody fragment may include a bispecific antibody (BsAb) or a chimeric antigen receptor (CAR).

[0030] The heavy chain constant region typically comprises H1 , C H2 , and C H3 Each light chain typically contains three domains: a light chain variable region (V L ) and a light chain constant region. The light chain constant region typically comprises L It contains one domain, abbreviated as .

[0031] Each heavy and light chain generally comprises three CDRs and four FRs arranged in the following order (N-terminus to C-terminus): FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. CDRs are involved in antigen binding and confer antigen specificity and binding affinity to the antibody. See Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. (1991), Public Health Service, National Institutes of Health, Bethesda, MD, which is incorporated herein by reference in its entirety.

[0032] The heavy chains of any vertebrate species can be assigned to one of five different classes (or isotypes): IgA, IgD, IgE, IgG, and IgM. These classes are also designated α, δ, ε, γ, and μ, respectively. The IgG and IgA classes are further divided into subclasses based on differences in sequence and function. Humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The IgG antibody class is preferred.

[0033] The light chains of any vertebrate species can be assigned to one of two types, called kappa and lambda, based on the sequence of the constant domain. The constant region consists of one of five heavy chain sequences (μ, γ, ζ, α, or ε) and one of two light chain sequences (κ or λ). The heavy chain constant region sequence determines the antibody isotype and the effector functions of the molecule.

[0034] Preferably, the antibody or antigen-binding fragment thereof is isolated or purified. In a preferred embodiment, the antibody or antigen-binding fragment thereof comprises a polyclonal antibody or antigen-binding fragment thereof. The antibody or antigen-binding fragment thereof may be generated in rabbits, mice, or rats.

[0035] Preferably, the antibody or antigen-binding fragment thereof is obtained by immunizing a host animal with the C1-C6-Fc protein, or a variant or fragment thereof, such as any one or more of the C1, C2, C3, C4, C5, and / or C6 domains, and then harvesting the antibody or antigen-binding fragment thereof. The host animal may be a rabbit.

[0036] In another preferred embodiment, the antibody or antigen-binding fragment thereof comprises a monoclonal antibody or antigen-binding fragment thereof. The antibody or fragment thereof may be mammalian. Preferably, the antibody of the present invention is a human antibody. As used herein, the term "human antibody" may refer to an antibody, such as a monoclonal antibody, that comprises substantially the same heavy and light chain CDR amino acid sequences as found in a particular human antibody that exhibits immunospecificity for one or more of the C1, C2, C3, C4, C5, and / or C6 domains (preferably C5) of VWF, or variants or fragments thereof. Amino acid sequences that are substantially the same as the heavy or light chain CDRs exhibit a significant amount of sequence identity compared to a reference sequence. Such identity is clearly visible or recognizable as representing the amino acid sequence of a particular human antibody. Substantially the same heavy and light chain CDR amino acid sequences may have, for example, minor modifications or conservative substitutions of amino acids. Such a human antibody or fragment thereof retains its function of selectively binding to at least one of the C1, C2, C3, C4, C5, and / or C6 domains of VWF (preferably C5), or a variant or fragment thereof.

[0037] The term "human monoclonal antibodies" can include monoclonal antibodies having substantially or completely human CDR amino acid sequences produced by recombinant methods, e.g., by phage libraries, lymphocytes or hybridoma cells.

[0038] The term "monoclonal antibody" refers to an antibody from a population of substantially homogeneous antibodies. A population of substantially homogeneous antibodies includes antibodies that are substantially similar and bind to the same epitope, except for variants that may normally arise during the production of monoclonal antibodies. Such variants are generally present in only minor amounts. Monoclonal antibodies are typically obtained by a process that includes the selection of a single antibody from a plurality of antibodies. For example, the selection process can be the selection of a unique clone from a plurality of clones, such as a pool of hybridoma clones, phage clones, yeast clones, bacterial clones, or other recombinant DNA clones. The selected antibody can be further modified, for example, to improve its affinity for the target (by so-called "affinity maturation"), to humanize the antibody, to improve its production in cell culture, and / or to reduce its immunogenicity in a subject.

[0039] The term "humanized antibody" may refer to antibodies from non-human species (e.g., mouse or rabbit) in which the protein sequence has been modified to increase similarity to antibodies naturally produced in humans.

[0040] The antibody may be a recombinant antibody. The term "recombinant human antibody" may include human antibodies produced using recombinant DNA techniques. The term "antigen-binding fragment" may refer to a region of an antibody that has specific binding affinity to a target antigen, for example, one or more of the C1, C2, C3, C4, C5, and / or C6 domains of VWF (preferably C5), or a variant or fragment thereof. Preferably, the fragment is an epitope. The epitope may be linear or conformational. The antigen-binding region may be a hypervariable CDR or a functional portion thereof. The term "functional portion" of a CDR may refer to a sequence within the CDR that exhibits specific affinity to a target antigen. The functional portion of a CDR may include a ligand that specifically binds to one or more of the C1, C2, C3, C4, C5, and / or C6 domains of VWF (preferably C5), or a fragment thereof.

[0041] The term "CDR" may refer to the hypervariable regions in the variable chains of heavy and light chains. There may be one, two, three, or more CDRs in each of the heavy and light chains of an antibody. Usually, there are at least three CDRs in each chain, which, when assembled together, form an antigen-binding site, or three-dimensional binding site, with which an antigen binds or specifically reacts. However, it is hypothesized that there may be four CDRs in the heavy chain of some antibodies.

[0042] The definition of CDR also includes overlapping or subsets of amino acid residues when compared with each other.The exact residue number that encompasses a particular CDR or its functional part varies depending on the sequence and size of CDR.Those skilled in the art can routinely determine which residues constitute a particular CDR by considering the amino acid sequence of the variable region of antibody.

[0043] The amino acid sequence boundaries of the CDRs can be determined using any of several known numbering systems, including those described by Kabat et al., supra (the "Kabat" numbering system), Al-Lazikani et al., 1997, J. Mol. Biol., 273:927-948 (the "Chothia" numbering system), MacCallum et al., 1996, J. Mol. Biol. 262:732-745 (the "Contact" numbering system), Lefranc et al., Dev. Comp. Immunol., 2003, 27:55-77 (the "IMGT" numbering system), and Honegge and Pluckthun, J. Mol. Biol., 2001, 309:657-70 (the "AHo" numbering system).

[0044] The term "functional fragment" of an antibody may refer to a portion of an antibody that retains a functional activity. A functional activity may be, for example, an antigen-binding activity or specificity. A functional activity may also be, for example, an effector function provided by an antibody constant region. The term "functional fragment" is also intended to include fragments produced, for example, by protease digestion or reduction of human monoclonal antibodies and recombinant DNA methods known to those skilled in the art. Human monoclonal antibody functional fragments include, for example, individual heavy or light chains and fragments thereof, such as VL, VH and Fd, monovalent fragments such as Fv, Fab and Fab', bivalent fragments such as F(ab')2, single chain Fv (scFv), and Fc fragments. Alternatively, as described and exemplified herein below, the Fc fragment of an antibody may be disabled by introducing amino acid substitutions in the Fc region that suppress or reduce the effector function of the antibody.

[0045] The term "VL fragment" may refer to a fragment of the light chain of a human monoclonal antibody that contains all or a portion of the light chain variable region, including the CDRs. The VL fragment may further contain light chain constant region sequences.

[0046] The term "VH fragment" may refer to a fragment of the heavy chain of a human monoclonal antibody that contains all or a portion of the heavy chain variable region, including the CDRs. The term "Fd fragment" may refer to the heavy chain variable region, i.e., VH and CH-1, bound to the first heavy chain constant region. The "Fd fragment" does not include the light chain or the second and third constant regions of the heavy chain.

[0047] The term "Fv fragment" may refer to a monovalent antigen-binding fragment of a human monoclonal antibody that contains all or part of the heavy and light chain variable regions, but does not contain the heavy and light chain constant regions. The heavy and light chain variable regions include, for example, the CDRs. For example, an Fv fragment contains all or part of the amino-terminal variable regions of about 110 amino acids of both the heavy and light chains.

[0048] The term "Fab fragment" may refer to a monovalent antigen-binding fragment of a human monoclonal antibody that is larger than an Fv fragment. For example, a Fab fragment contains the variable region and all or part of the first constant domains of the heavy and light chains. Thus, a Fab fragment further contains, for example, about 110 to about 220 amino acid residues of the heavy and light chains.

[0049] The term "Fab' fragment" may refer to a monovalent antigen-binding fragment of a human monoclonal antibody that is larger than a Fab fragment. For example, a Fab' fragment may contain all of the light chain, all of the variable region of the heavy chain, and all or a portion of the first and second constant domains of the heavy chain. For example, a Fab' fragment may further contain some or all of amino acid residues 220-330 of the heavy chain.

[0050] The term "F(ab')2 fragment" may refer to a bivalent antigen-binding fragment of a human monoclonal antibody. The F(ab')2 fragment may, for example, contain all or part of the variable regions of two heavy chains and two light chains, and may further contain all or part of the first constant domains of the two heavy chains and two light chains.

[0051] The term "single-chain Fv (scFv)" may refer to a fusion of a variable domain of the heavy chain (VH) and a variable domain of the light chain (VL) connected by a short linker peptide. The term "bispecific antibody (BsAb)" may refer to a bispecific antibody comprising two scFvs linked together by a shorter connecting peptide.

[0052] Those skilled in the art recognize that the exact boundaries of an antibody fragment are not important, so long as the fragment maintains functional activity. Those skilled in the art can use well-known recombinant methods to engineer polynucleotide sequences to express functional fragments with desired endpoints for a particular application. A functional fragment of an antibody may comprise or consist of a fragment having substantially the same heavy and light chain variable regions as a human antibody.

[0053] Preferably, the antibody or antigen-binding fragment thereof according to the first aspect of the invention is immunospecific for an epitope in one or more of the C1, C2, C3, C4, C5, and / or C6 domains of VWF. In a preferred embodiment, the antibody or antigen-binding fragment thereof is immunospecific for an epitope in the C3 and C5 domains of VWF (Antibody 1-D5). Alternatively, in another preferred embodiment, the antibody or antigen-binding fragment thereof is immunospecific for an epitope in the C4 and C5 domains of VWF (Antibody 3-H9). Even more preferably, the antibody or antigen-binding fragment thereof is immunospecific for an epitope in the C5 domain of VWF. The antigen-binding fragment may comprise or consist of any of the fragments selected from the group consisting of VH, VL, Fd, Fv, Fab, Fab', scFv, F(ab')2, and Fc fragments.

[0054] The antigen-binding fragment may be a single domain antibody (sdAb), also known as a nanobody, which is an antibody fragment consisting of a single monomeric variable antibody domain, as will be appreciated by those skilled in the art.

[0055] The antigen-binding fragment may comprise or consist of any one of the VL antigen-binding region sequences, any one of the VH antigen-binding region sequences, or a combination of the VL and VH antigen-binding regions of a human antibody. The appropriate number and combination of VH and VL antigen-binding region sequences can be determined by one of skill in the art depending on the desired affinity and specificity and use of the antigen-binding fragment. Functional or antigen-binding fragments of antibodies can be easily produced and isolated using methods well known to those of skill in the art. Such methods include, for example, proteolytic methods, recombinant methods, and chemical synthesis. Proteolytic methods for the isolation of functional fragments include using human antibodies as starting materials. Enzymes suitable for proteolytic degradation of human immunoglobulins can include, for example, papain and pepsin. Appropriate enzymes can be readily selected by one of skill in the art depending, for example, on whether a monovalent or bivalent fragment is required. For example, papain cleavage results in two monovalent Fab' fragments that bind to the antigen, and an Fc fragment. Pepsin cleavage results, for example, in a bivalent F(ab') fragment. The F(ab')2 fragment of the present invention can be further reduced using, for example, DTT or 2-mercaptoethanol to produce two monovalent Fab' fragments.

[0056] The functional or antigen-binding fragments of antibodies produced by proteolysis can be purified by affinity and column chromatography procedures. For example, undigested antibody and Fc fragments can be removed by binding to protein A. Furthermore, functional fragments can be purified according to their charge and size, for example, using ion exchange and gel filtration chromatography. Such methods are well known to those skilled in the art.

[0057] Antibody or antigen-binding fragment thereof can be produced by recombinant methodology. It is preferred to first isolate the polynucleotide encoding the desired region of the heavy and light chain of the antibody. Such region can include, for example, all or part of the variable region of the heavy and light chain. Preferably, such region can include the antigen-binding region of the heavy and light chain, preferably the antigen-binding site, most preferably the CDR.

[0058] Polynucleotides encoding the antibodies or antigen-binding fragments thereof of the present invention can be produced using methods known to those of skill in the art. Polynucleotides encoding the antibodies or antigen-binding fragments thereof can be directly synthesized by oligonucleotide synthesis methods known in the art. Alternatively, smaller fragments can be synthesized and joined to form larger functional fragments using recombinant methods known in the art.

[0059] As used herein, the term "immunospecific" may mean that the binding region of an antibody or antigen-binding fragment thereof is capable of specifically binding to and thereby immunoreacting with one or more of the C1, C2, C3, C4, C5, and / or C6 domains of VWF, or variants or fragments thereof (preferably C5). An antibody or antigen-binding fragment thereof may have a specific binding region that is approximately 10 -5 From 10 -13 M -1 , preferably 10 -6 From 10 -9 M -1 , and even more preferably 10 -10 From 10 -12 M -1 Preferably, the antibody can selectively interact with an antigen (one or more of the C1, C2, C3, C4, C5 and / or C6 domains of VWF, preferably C5) with an affinity constant of 0.1 to 0.15.

[0060] The antibody or antigen-binding fragment has an affinity constant of approximately 10-10 M -1 , 10 -9 M -1 , 10 -8 M -1 , 10 -7 M -1 , or 10 -6 M -1 More than 10 -5 M -1 , 10 -4 M -1 or 10 -3 M -1 More preferably still, more than 10 -2 M -1 , 10 -1 M -1 or 10 -2 M -1 More than 10, most preferably +1 M -1 , 10 +2 M -1 or 10 +3 M -1 It is preferred that the antibody does not substantially bind to the A1, A2 and / or A3 domains of VWF, such that the antibody does not substantially bind to the A1, A2 and / or A3 domains of VWF.

[0061] The term "immunoreactive" may mean that the binding region is capable of eliciting an immune response upon binding to one or more of the C1 domain, C2 domain, C3 domain, C4 domain, C5 domain, and / or C6 domain of VWF, or an epitope thereof.

[0062] The term "epitope" may refer to any region of an antigen that has the ability to derive and combine with a binding region of an antibody or antigen-binding fragment thereof. An epitope may be linear. This may mean that an antibody interacts with multiple consecutive amino acids of an antigen, and thus an epitope may consist of these defined amino acids.

[0063] Alternatively, an epitope may be conformational, i.e., non-linear or discontinuous, which may mean that the antibody interacts with several different segments of the primary amino acid sequence of the antigen.

[0064] Thus, the antibody or antigen-binding fragment thereof may comprise a heavy chain. The heavy chain may be selected from the group consisting of IgA, IgD, IgE, IgG and IgM. Preferably, the heavy chain is IgG. Preferably, the heavy chain is IgA.

[0065] The heavy chain may be IgG1. The heavy chain may be IgG2. The heavy chain may be IgG3. The heavy chain may be IgG4. The heavy chain may be IgA1. The heavy chain may be IgA2. As described in the Examples and shown in Figures 3A-3H and 7A-E, the inventors have surprisingly demonstrated that antibodies and antigen-binding fragments designated herein as 1-A2, 4-H3, 1-D5, 3-H9, 1-G5, 4-H9, 4-B12, and 4-C6 can significantly target one or more of the C1-C6 domains of VWF, each of which is defined in detail below. The CDR / FR / VH / VL, HC and LC sequences of these eight antibodies are conveniently summarized in the table shown in Figure 8.

[0066] 1-A2 Thus, in one embodiment, the antibody or antigen-binding fragment thereof is referred to herein as 1-A2. This antibody or antigen-binding fragment thereof may comprise the CDR-H1 domain of SEQ ID NO:9, as provided herein as follows: GIDLTSNA [SEQ ID NO: 9] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 9 or a variant or fragment thereof.

[0067] The antibody or antigen-binding fragment thereof may comprise the CDR-H2 domain of SEQ ID NO: 10, as provided herein: IYGHDTS [SEQ ID NO: 10] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 10, or a variant or fragment thereof.

[0068] The antibody or antigen-binding fragment thereof may comprise the CDR-H3 domain of SEQ ID NO: 11, as provided herein as follows: ARGFIYFDI [SEQ ID NO: 11] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 11 or a variant or fragment thereof.

[0069] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:9, a CDR-H2 domain comprising or consisting of SEQ ID NO:10, and / or a CDR-H3 domain comprising or consisting of SEQ ID NO:11. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:9, a CDR-H2 domain comprising or consisting of SEQ ID NO:10, and a CDR-H3 domain comprising or consisting of SEQ ID NO:11.

[0070] The antibody or antigen-binding fragment thereof may comprise the FR-H1 domain of SEQ ID NO: 12, as provided herein: SQSVEESGGRLVPPGTPLTLTCTVS [SEQ ID NO: 12] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 12 or a variant or fragment thereof.

[0071] The antibody or antigen-binding fragment thereof may comprise the FR-H2 domain of SEQ ID NO: 13, as provided herein: MNWVRQAPGKGLEWIGG [SEQ ID NO: 13] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 13 or a variant or fragment thereof.

[0072] The antibody or antigen-binding fragment thereof may comprise the FR-H3 domain of SEQ ID NO: 14, as provided herein: YYAAWAKGRFTISRTSTTVDLKMTRPTTDDTATYFC [SEQ ID NO: 14] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 14 or a variant or fragment thereof.

[0073] The antibody or antigen-binding fragment thereof may comprise the FR-H4 domain of SEQ ID NO: 15, as provided herein: WGTGTLVTISS [SEQ ID NO: 15] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 15 or a variant or fragment thereof.

[0074] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 12, an FR-H2 domain comprising or consisting of SEQ ID NO: 13, an FR-H3 domain comprising or consisting of SEQ ID NO: 14, and / or an FR-H4 domain comprising or consisting of SEQ ID NO: 15. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 12, an FR-H2 domain comprising or consisting of SEQ ID NO: 13, an FR-H3 domain comprising or consisting of SEQ ID NO: 14, and an FR-H4 domain comprising or consisting of SEQ ID NO: 15.

[0075] The antibody or antigen-binding fragment thereof may comprise a heavy chain variable (VH) sequence as defined in SEQ ID NO: 16, provided herein as follows: QSVEESGGRLVPPGTPLTLTCTVSGIDLTSNAMNWVRQAPGKGLEWIGGIYGHDTSYYAAWAKGRFTISRTSTTVDLKMTRPTTDDTATYFCARGFIYFDIWGTGTLVTISS [SEQ ID NO: 16] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 16, or a variant or fragment thereof.

[0076] One embodiment of a nucleotide sequence encoding a heavy chain variable (VH) region is referred to herein as SEQ ID NO: 17: CAGTCGGTGGAGGAGTCCGGGGGTCGCCTGGTCCCGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCACTAGCAATGCAATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAGGCATTTATGGTCATGATACCTCA TATTACGCGGCCTGGGCGAAAGGCCGATTCACCATCTCCAGAACCTCGACCACAGTGGATCTGAAAATGACCAGGCCGACAACCGACGACACGGCCACCTATTTCTGTGCCAGAGGTTTTATTTATTTTGACATCTGGGGCACAGGCACCCTGGTCACCATCTCTTCA [SEQ ID NO:17] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO: 17, or a variant or fragment thereof.

[0077] The antibody or antigen-binding fragment thereof may comprise the CDR-L1 domain of SEQ ID NO: 18, as provided herein: EDIYSG [SEQ ID NO: 18] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 18 or a variant or fragment thereof.

[0078] The antibody or antigen-binding fragment thereof may comprise the CDR-L2 domain of SEQ ID NO: 19, as provided herein: GAS [SEQ ID NO: 19] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 19 or a variant or fragment thereof.

[0079] The antibody or antigen-binding fragment thereof may comprise the CDR-L3 domain of SEQ ID NO: 20, as provided herein: LGGHSHSTTDLT [SEQ ID NO:20] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 20 or a variant or fragment thereof.

[0080] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 18, a CDR-L2 domain comprising or consisting of SEQ ID NO: 19, and / or a CDR-L3 domain comprising or consisting of SEQ ID NO: 20. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 18, a CDR-L2 domain comprising or consisting of SEQ ID NO: 19, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 20.

[0081] The antibody or antigen-binding fragment thereof may comprise the FR-L1 domain of SEQ ID NO:21, as provided herein: AIEMTQTPPSLSASVGETVRIRCLAS [SEQ ID NO:21] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 21 or a variant or fragment thereof.

[0082] The antibody or antigen-binding fragment thereof may comprise the FR-L2 domain of SEQ ID NO: 22, as provided herein: ISWYQQKPGKPPTLLIY [SEQ ID NO:22] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 22 or a variant or fragment thereof.

[0083] The antibody or antigen-binding fragment thereof may comprise the FR-L3 domain of SEQ ID NO: 23, as provided herein: NLESGVPPRFSGSGSGTDYTLTIGGVQAEDAATYYC [SEQ ID NO:23] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 23 or a variant or fragment thereof.

[0084] The antibody or antigen-binding fragment thereof may comprise the FR-L4 domain of SEQ ID NO: 24, as provided herein: FGAGTKVEIK [SEQ ID NO:24] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 24 or a variant or fragment thereof.

[0085] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO:21, an FR-L2 domain comprising or consisting of SEQ ID NO:22, an FR-L3 domain comprising or consisting of SEQ ID NO:23, and / or an FR-L4 domain comprising or consisting of SEQ ID NO:24. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO:21, an FR-L2 domain comprising or consisting of SEQ ID NO:22, an FR-L3 domain comprising or consisting of SEQ ID NO:23, and an FR-L4 domain comprising or consisting of SEQ ID NO:24.

[0086] The antibody or antigen-binding fragment thereof may comprise a variable light chain (VL) sequence as defined in SEQ ID NO: 25, provided herein as follows: AIEMTQTPPSLSASVGETVRIRCLASEDIYSGISWYQQKPGKPPTLLIYGASNLESGVPPRFSGSGSGTDYTLTIGGVQAEDAATYYCLGGHSHSTTDLTFGAGTKVEIK [SEQ ID NO:25] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:25, or a variant or fragment thereof.

[0087] One embodiment of a nucleotide sequence encoding the light chain variable (VL) region is referred to herein as SEQ ID NO:26: GCAATTGAGATGACCCAGACTCCACCCTCCCTGTCTGCATCTGTGGGAGAAACTGTCAGGATTAGGTGCCTGGCCAGTGAGGACATTTACAGTGGTATATCCTGGTATCAACAGAAGCCAGGGAAACCTCCTACACTCCTGATCTATGGTGCATCCAATTTAGAA TCTGGGGTCCCACCACGGTTCAGTGGCAGTGGATCTGGGACAGATTACACCCTCACCATTGGCGGCGTGCAGGCTGAAGATGCTGCCACCTACTACTGTCTAGGCGGTCATAGCCACAGTACTACCGATTTGACTTTTGGAGCTGGGACCAAGGTGGAAATCAAA [SEQ ID NO:26] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO:26, or a variant or fragment thereof.

[0088] Preferably, the antibody or antigen-binding fragment thereof comprises at least one, at least two, at least three, at least four, at least five, or at least six CDRs. Preferably, the antibody or antigen-binding fragment thereof comprises at least CDR-H3.

[0089] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:9, a CDR-H2 domain comprising or consisting of SEQ ID NO:10, a CDR-H3 domain comprising or consisting of SEQ ID NO:11, a CDR-L1 domain comprising or consisting of SEQ ID NO:18, a CDR-L2 domain comprising or consisting of SEQ ID NO:19, and a CDR-L3 domain comprising or consisting of SEQ ID NO:20.

[0090] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:16, and a light chain variable region comprising or consisting of SEQ ID NO:25.

[0091] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:17, and a light chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:26.

[0092] We next attempted to generate humanized antibodies of 1-A2. The sequences of these humanized antibodies are shown in Figure 10. Unless otherwise noted, the six CDR sequences of these humanized antibodies are identical to the six CDR sequences of the parent antibody 1-A2.

[0093] <h2 style=";text-align:left;direction:ltr">1-A2_parental(hIgG1) In one embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_parental(hIgG1).

[0094] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 156, or a variant or fragment thereof.

[0095] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:25, or a variant or fragment thereof.

[0096] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:156, and a light chain variable region comprising or consisting of SEQ ID NO:25.

[0097] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0098] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0099] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0100] <h2 style=";text-align:left;direction:ltr"> 1-A2_parental(hIgG1-L234A-L235A-P329G) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_parental (hIgG1-L234A-L235A-P329G).

[0101] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 156, or a variant or fragment thereof.

[0102] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:25, or a variant or fragment thereof.

[0103] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:156, and a light chain variable region comprising or consisting of SEQ ID NO:25.

[0104] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 162, or a variant or fragment thereof.

[0105] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0106] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:162, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0107] <h2 style=";text-align:left;direction:ltr"> 1-A2_parental(hIgG1-Fab) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_parental(hIgG1-Fab).

[0108] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 156, or a variant or fragment thereof.

[0109] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:25, or a variant or fragment thereof.

[0110] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:156, and a light chain variable region comprising or consisting of SEQ ID NO:25.

[0111] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 163, or a variant or fragment thereof.

[0112] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0113] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:163, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0114] <h2 style=";text-align:left;direction:ltr"> 1-A2_H0(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_H0 (hIgG1).

[0115] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 164 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 10 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 11 or a variant or fragment thereof.

[0116] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 18 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 19 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 20 or a variant or fragment thereof.

[0117] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 164, a CDR-H2 domain comprising or consisting of SEQ ID NO: 10, a CDR-H3 domain comprising or consisting of SEQ ID NO: 11, a CDR-L1 domain comprising or consisting of SEQ ID NO: 18, a CDR-L2 domain comprising or consisting of SEQ ID NO: 19, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 20.

[0118] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 165, or a variant or fragment thereof.

[0119] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:25, or a variant or fragment thereof.

[0120] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:165, and a light chain variable region comprising or consisting of SEQ ID NO:25.

[0121] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0122] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0123] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0124] <h2 style=";text-align:left;direction:ltr"> 1-A2_H1(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_H1(hIgG1).

[0125] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 194, or a variant or fragment thereof.

[0126] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:25, or a variant or fragment thereof.

[0127] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:194, and a light chain variable region comprising or consisting of SEQ ID NO:25.

[0128] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0129] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0130] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0131] <h2 style=";text-align:left;direction:ltr"> 1-A2_H2(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_H2(hIgG1).

[0132] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 172, or a variant or fragment thereof.

[0133] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:25, or a variant or fragment thereof.

[0134] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:172, and a light chain variable region comprising or consisting of SEQ ID NO:25.

[0135] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0136] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0137] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0138] <h2 style=";text-align:left;direction:ltr"> 1-A2_L0(hIgG1K) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_L0 (hIgG1K).

[0139] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 156, or a variant or fragment thereof.

[0140] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 190, or a variant or fragment thereof.

[0141] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:156, and a light chain variable region comprising or consisting of SEQ ID NO:190.

[0142] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0143] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0144] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0145] <h2 style=";text-align:left;direction:ltr"> 1-A2_L1(hIgG1K) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_L1(hIgG1K).

[0146] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 156, or a variant or fragment thereof.

[0147] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 191, or a variant or fragment thereof.

[0148] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:156, and a light chain variable region comprising or consisting of SEQ ID NO:191.

[0149] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0150] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0151] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0152] <h2 style=";text-align:left;direction:ltr"> 1-A2_H2_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_H2_L1.

[0153] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 172, or a variant or fragment thereof.

[0154] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 191, or a variant or fragment thereof.

[0155] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:172, and a light chain variable region comprising or consisting of SEQ ID NO:191.

[0156] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0157] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0158] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0159] <h2 style=";text-align:left;direction:ltr"> 1-A2_H2_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_H2_L0.

[0160] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 172, or a variant or fragment thereof.

[0161] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 190, or a variant or fragment thereof.

[0162] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:172, and a light chain variable region comprising or consisting of SEQ ID NO:190.

[0163] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0164] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0165] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0166] <h2 style=";text-align:left;direction:ltr"> 1-A2_H1_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_H1_L1.

[0167] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 194, or a variant or fragment thereof.

[0168] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 191, or a variant or fragment thereof.

[0169] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:194, and a light chain variable region comprising or consisting of SEQ ID NO:191.

[0170] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0171] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0172] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0173] <h2 style=";text-align:left;direction:ltr"> 1-A2_H1_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_H1_L0.

[0174] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 194, or a variant or fragment thereof.

[0175] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 190, or a variant or fragment thereof.

[0176] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:194, and a light chain variable region comprising or consisting of SEQ ID NO:190.

[0177] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0178] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0179] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0180] <h2 style=";text-align:left;direction:ltr"> 1-A2_H0_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is designated herein as 1-A2_H0_L1.

[0181] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 164 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 10 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 11 or a variant or fragment thereof.

[0182] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 18 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 19 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 20 or a variant or fragment thereof.

[0183] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 164, a CDR-H2 domain comprising or consisting of SEQ ID NO: 10, a CDR-H3 domain comprising or consisting of SEQ ID NO: 11, a CDR-L1 domain comprising or consisting of SEQ ID NO: 18, a CDR-L2 domain comprising or consisting of SEQ ID NO: 19, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 20.

[0184] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 165, or a variant or fragment thereof.

[0185] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 191, or a variant or fragment thereof.

[0186] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:165, and a light chain variable region comprising or consisting of SEQ ID NO:191.

[0187] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0188] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0189] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0190] <h2 style=";text-align:left;direction:ltr"> 1-A2_H0_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-A2_H0_L0.

[0191] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 164 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 10 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 11 or a variant or fragment thereof.

[0192] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 18 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 19 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 20 or a variant or fragment thereof.

[0193] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 164, a CDR-H2 domain comprising or consisting of SEQ ID NO: 10, a CDR-H3 domain comprising or consisting of SEQ ID NO: 11, a CDR-L1 domain comprising or consisting of SEQ ID NO: 18, a CDR-L2 domain comprising or consisting of SEQ ID NO: 19, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 20.

[0194] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 165, or a variant or fragment thereof.

[0195] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 190, or a variant or fragment thereof.

[0196] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:165, and a light chain variable region comprising or consisting of SEQ ID NO:190.

[0197] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0198] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0199] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0200] 4-H3 In one embodiment, the antibody or antigen-binding fragment thereof is referred to herein as 4-H3. This antibody or antigen-binding fragment thereof may comprise the CDR-H1 domain of SEQ ID NO: 27, as provided herein as follows: GIDLTSNA [SEQ ID NO:27] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 27 or a variant or fragment thereof.

[0201] The antibody or antigen-binding fragment thereof may comprise the CDR-H2 domain of SEQ ID NO: 28, as provided herein as follows: IYGHDTS [SEQ ID NO:28] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 28 or a variant or fragment thereof.

[0202] The antibody or antigen-binding fragment thereof may comprise the CDR-H3 domain of SEQ ID NO:29, as provided herein: ARGFIYFDI [SEQ ID NO:29] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 29 or a variant or fragment thereof.

[0203] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 27, a CDR-H2 domain comprising or consisting of SEQ ID NO: 28, and / or a CDR-H3 domain comprising or consisting of SEQ ID NO: 29. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 27, a CDR-H2 domain comprising or consisting of SEQ ID NO: 28, and a CDR-H3 domain comprising or consisting of SEQ ID NO: 29.

[0204] The antibody or antigen-binding fragment thereof may comprise the FR-H1 domain of SEQ ID NO: 30, as provided herein: SQSLEESGGRLVPPGTPLTLTCTVS [SEQ ID NO:30] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 30, or a variant or fragment thereof.

[0205] The antibody or antigen-binding fragment thereof may comprise the FR-H2 domain of SEQ ID NO: 31, as provided herein: MNWVRQAPGKGLEWIGG [SEQ ID NO:31] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 31 or a variant or fragment thereof.

[0206] The antibody or antigen-binding fragment thereof may comprise the FR-H3 domain of SEQ ID NO: 32, as provided herein: YYAAWAKGRFTISRTSTTVDLKMTRPTTDDTATYFC [SEQ ID NO:32] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 32 or a variant or fragment thereof.

[0207] The antibody or antigen-binding fragment thereof may comprise the FR-H4 domain of SEQ ID NO: 33, as provided herein: WGTGTLVTISS [SEQ ID NO:33] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 33 or a variant or fragment thereof.

[0208] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 30, an FR-H2 domain comprising or consisting of SEQ ID NO: 31, an FR-H3 domain comprising or consisting of SEQ ID NO: 32, and / or an FR-H4 domain comprising or consisting of SEQ ID NO: 33. Preferably, however, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 30, an FR-H2 domain comprising or consisting of SEQ ID NO: 31, an FR-H3 domain comprising or consisting of SEQ ID NO: 32, and an FR-H4 domain comprising or consisting of SEQ ID NO: 33.

[0209] The antibody or antigen-binding fragment thereof may comprise a heavy chain variable (VH) sequence as defined in SEQ ID NO: 34, provided herein as follows: QSLEESGGRLVPPGTPLTLTCTVSGIDLTSNAMNWVRQAPGKGLEWIGGIYGHDTSYYAAWAKGRFTISRTSTTVDLKMTRPTTDDTATYFCARGFIYFDIWGTGTLVTISS [SEQ ID NO:34] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 34, or a variant or fragment thereof.

[0210] One embodiment of a nucleotide sequence encoding a heavy chain variable (VH) region is referred to herein as SEQ ID NO:35: CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCCCGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGAATCGACCTCACTAGCAATGCAATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAGGCATTTATGGTCATGATACCTCA TATTACGCGGCCTGGGCGAAAGGCCGATTCACCATCTCCAGAACCTCGACCACAGTGGATCTGAAAATGACCAGGCCGACAACCGACGACACGGCCACCTATTTCTGTGCCAGAGGTTTTATTTATTTTGACATCTGGGGCACAGGCACCCTGGTCACCATCTCTTCA [SEQ ID NO:35] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO:35, or a variant or fragment thereof.

[0211] The antibody or antigen-binding fragment thereof may comprise the CDR-L1 domain of SEQ ID NO: 36, as provided herein: EDIASG [SEQ ID NO:36] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 36 or a variant or fragment thereof.

[0212] The antibody or antigen-binding fragment thereof may comprise the CDR-L2 domain of SEQ ID NO: 37, as provided herein: GAS [SEQ ID NO:37] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 37 or a variant or fragment thereof.

[0213] The antibody or antigen-binding fragment thereof may comprise the CDR-L3 domain of SEQ ID NO: 38, as provided herein: LGGYSFSSNGLT [SEQ ID NO:38] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 38 or a variant or fragment thereof.

[0214] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 36, a CDR-L2 domain comprising or consisting of SEQ ID NO: 37, and / or a CDR-L3 domain comprising or consisting of SEQ ID NO: 38. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 36, a CDR-L2 domain comprising or consisting of SEQ ID NO: 37, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 38.

[0215] The antibody or antigen-binding fragment thereof may comprise the FR-L1 domain of SEQ ID NO:39, as provided herein: AYDMTQTPPSLSASVGETVRIRCLAS [SEQ ID NO:39] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 39 or a variant or fragment thereof.

[0216] The antibody or antigen-binding fragment thereof may comprise the FR-L2 domain of SEQ ID NO: 40, as provided herein: ISWYQQKPGKPPTLLIY [SEQ ID NO: 40] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 40 or a variant or fragment thereof.

[0217] The antibody or antigen-binding fragment thereof may comprise the FR-L3 domain of SEQ ID NO: 41, as provided herein: NLESGVPPRFSGSGSGTDYTLTIGGVQAEDAATYYC [SEQ ID NO:41] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 41 or a variant or fragment thereof.

[0218] The antibody or antigen-binding fragment thereof may comprise the FR-L4 domain of SEQ ID NO: 42, as provided herein: FGAGTKVEIK [SEQ ID NO:42] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 42 or a variant or fragment thereof.

[0219] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 39, an FR-L2 domain comprising or consisting of SEQ ID NO: 40, an FR-L3 domain comprising or consisting of SEQ ID NO: 41, and / or an FR-L4 domain comprising or consisting of SEQ ID NO: 42. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 39, an FR-L2 domain comprising or consisting of SEQ ID NO: 40, an FR-L3 domain comprising or consisting of SEQ ID NO: 41, and an FR-L4 domain comprising or consisting of SEQ ID NO: 42.

[0220] The antibody or antigen-binding fragment thereof may comprise a variable light chain (VL) sequence as defined in SEQ ID NO: 43, provided herein as follows: AYDMTQTPPSLSASVGETVRIRCLASEDIASGISWYQQKPGKPPTLLIYGASNLESGVPPRFSGSGSGTDYTLTIGGVQAEDAATYYCLGGYSFSSNGLTFGAGTKVEIK [SEQ ID NO:43] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0221] One embodiment of a nucleotide sequence encoding the light chain variable (VL) region is referred to herein as SEQ ID NO:44: GCTTATGATATGACCCAGACTCCACCCTCCCTGTCTGCATCTGTGGGAGAAACTGTCAGGATTAGGTGCCTGGCCAGTGAGGACATTGCCAGTGGTATATCCTGGTATCAACAGAAGCCAGGGAAACCTCCTACACTCCTGATCTATGGTGCATCCAATTTAGAA TCTGGGGTCCCACCACGGTTCAGTGGCAGTGGATCTGGGACAGATTACACCCTCACCATTGGCGGCGTGCAGGCTGAAGATGCTGCCACCTACTACTGTCTAGGCGGTTATAGTTTCAGTAGTAACGGTTTGACTTTTGGAGCTGGCACCAAGGTGGAGATCAAA [SEQ ID NO:44] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO:44, or a variant or fragment thereof.

[0222] Preferably, the antibody or antigen-binding fragment thereof comprises at least one, at least two, at least three, at least four, at least five, or at least six CDRs. Preferably, the antibody or antigen-binding fragment thereof comprises at least CDR-H3.

[0223] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:27, a CDR-H2 domain comprising or consisting of SEQ ID NO:28, a CDR-H3 domain comprising or consisting of SEQ ID NO:29, a CDR-L1 domain comprising or consisting of SEQ ID NO:36, a CDR-L2 domain comprising or consisting of SEQ ID NO:37, and a CDR-L3 domain comprising or consisting of SEQ ID NO:38.

[0224] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:34, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0225] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:35, and a light chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:44.

[0226] We next attempted to generate humanized antibodies of 4-H3. The sequences of these humanized antibodies are shown in Figure 10. Unless otherwise noted, the six CDR sequences of these humanized antibodies are identical to the six CDR sequences of the parent antibody 4-H3.

[0227] <h2 style=";text-align:left;direction:ltr"> 4-H3_parental (hIgG1) In one embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_parental(hIgG1).

[0228] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 159, or a variant or fragment thereof.

[0229] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0230] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:159, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0231] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0232] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0233] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0234] <h2 style=";text-align:left;direction:ltr"> 4-H3_parental(hIgG1-L234A-L235A-P329G) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_parental(hIgG1-L234A-L235A-P329G).

[0235] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 159, or a variant or fragment thereof.

[0236] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0237] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:159, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0238] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 162, or a variant or fragment thereof.

[0239] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0240] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:162, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0241] <h2 style=";text-align:left;direction:ltr"> 4-H3_parental(hIgG1-Fab) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_parental(hIgG1-Fab).

[0242] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 159, or a variant or fragment thereof.

[0243] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0244] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:159, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0245] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 163, or a variant or fragment thereof.

[0246] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0247] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:163, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0248] <h2 style=";text-align:left;direction:ltr"> 4-H3_H0(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H0(hIgG1).

[0249] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 164 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 28 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 29 or a variant or fragment thereof.

[0250] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 36 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 37 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 38 or a variant or fragment thereof.

[0251] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 164, a CDR-H2 domain comprising or consisting of SEQ ID NO: 28, a CDR-H3 domain comprising or consisting of SEQ ID NO: 29, a CDR-L1 domain comprising or consisting of SEQ ID NO: 36, a CDR-L2 domain comprising or consisting of SEQ ID NO: 37, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 38.

[0252] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 165, or a variant or fragment thereof.

[0253] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0254] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:165, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0255] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0256] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0257] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0258] <h2 style=";text-align:left;direction:ltr"> 4-H3_H1(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H1(hIgG1).

[0259] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 194, or a variant or fragment thereof.

[0260] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0261] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:194, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0262] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0263] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0264] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0265] <h2 style=";text-align:left;direction:ltr"> 4-H3_H2(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H2(hIgG1).

[0266] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 166, or a variant or fragment thereof.

[0267] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0268] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:166, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0269] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0270] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0271] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0272] <h2 style=";text-align:left;direction:ltr"> 4-H3_H3(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H3(hIgG1).

[0273] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 167, or a variant or fragment thereof.

[0274] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0275] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:167, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0276] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0277] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0278] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0279] <h2 style=";text-align:left;direction:ltr"> 4-H3_H4(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H4(hIgG1).

[0280] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 168, or a variant or fragment thereof.

[0281] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0282] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:168, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0283] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0284] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0285] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0286] <h2 style=";text-align:left;direction:ltr"> 4-H3_H5(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H5(hIgG1).

[0287] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 169, or a variant or fragment thereof.

[0288] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0289] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:169, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0290] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0291] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0292] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0293] <h2 style=";text-align:left;direction:ltr"> 4-H3_H6(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H6(hIgG1).

[0294] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 170, or a variant or fragment thereof.

[0295] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0296] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:170, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0297] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0298] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0299] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0300] <h2 style=";text-align:left;direction:ltr"> 4-H3_H7(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H7(hIgG1).

[0301] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 171, or a variant or fragment thereof.

[0302] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0303] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:171, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0304] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0305] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0306] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0307] <h2 style=";text-align:left;direction:ltr"> 4-H3_H8(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H8(hIgG1).

[0308] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 172, or a variant or fragment thereof.

[0309] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:43, or a variant or fragment thereof.

[0310] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:172, and a light chain variable region comprising or consisting of SEQ ID NO:43.

[0311] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0312] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0313] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0314] <h2 style=";text-align:left;direction:ltr"> 4-H3_L0(hIgG1K) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_L0(hIgG1K).

[0315] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 159, or a variant or fragment thereof.

[0316] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 185, or a variant or fragment thereof.

[0317] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:159, and a light chain variable region comprising or consisting of SEQ ID NO:185.

[0318] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0319] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0320] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0321] <h2 style=";text-align:left;direction:ltr"> 4-H3_L1(hIgG1K) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_L1(hIgG1K).

[0322] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 159, or a variant or fragment thereof.

[0323] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 186, or a variant or fragment thereof.

[0324] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:159, and a light chain variable region comprising or consisting of SEQ ID NO:186.

[0325] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0326] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0327] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0328] <h2 style=";text-align:left;direction:ltr"> 4-H3_H8_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H8_L1.

[0329] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 172, or a variant or fragment thereof.

[0330] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 186, or a variant or fragment thereof.

[0331] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:172, and a light chain variable region comprising or consisting of SEQ ID NO:186.

[0332] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0333] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0334] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0335] <h2 style=";text-align:left;direction:ltr"> 4-H3_H8_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H8_L0.

[0336] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 172, or a variant or fragment thereof.

[0337] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 185, or a variant or fragment thereof.

[0338] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:172, and a light chain variable region comprising or consisting of SEQ ID NO:185.

[0339] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0340] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0341] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0342] <h2 style=";text-align:left;direction:ltr"> 4-H3_H7_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H7_L1.

[0343] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 171, or a variant or fragment thereof.

[0344] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 186, or a variant or fragment thereof.

[0345] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:171, and a light chain variable region comprising or consisting of SEQ ID NO:186.

[0346] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0347] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0348] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0349] <h2 style=";text-align:left;direction:ltr"> 4-H3_H7_L0 rep Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H7_L0 rep.

[0350] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 171, or a variant or fragment thereof.

[0351] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 185, or a variant or fragment thereof.

[0352] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:171, and a light chain variable region comprising or consisting of SEQ ID NO:185.

[0353] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0354] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0355] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0356] <h2 style=";text-align:left;direction:ltr"> 4-H3_H6_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H6_L1.

[0357] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 170, or a variant or fragment thereof.

[0358] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 186, or a variant or fragment thereof.

[0359] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:170, and a light chain variable region comprising or consisting of SEQ ID NO:186.

[0360] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0361] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0362] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0363] <h2 style=";text-align:left;direction:ltr"> 4-H3_H6_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H6_L0.

[0364] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 170, or a variant or fragment thereof.

[0365] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 185, or a variant or fragment thereof.

[0366] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:170, and a light chain variable region comprising or consisting of SEQ ID NO:185.

[0367] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0368] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0369] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0370] <h2 style=";text-align:left;direction:ltr"> 4-H3_H5_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H5_L1.

[0371] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 169, or a variant or fragment thereof.

[0372] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 186, or a variant or fragment thereof.

[0373] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:169, and a light chain variable region comprising or consisting of SEQ ID NO:186.

[0374] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0375] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0376] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0377] <h2 style=";text-align:left;direction:ltr"> 4-H3_H5_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H5_L0.

[0378] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 169, or a variant or fragment thereof.

[0379] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 185, or a variant or fragment thereof.

[0380] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:169, and a light chain variable region comprising or consisting of SEQ ID NO:185.

[0381] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0382] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0383] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0384] <h2 style=";text-align:left;direction:ltr"> 4-H3_H4_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H4_L1.

[0385] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 168, or a variant or fragment thereof.

[0386] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 186, or a variant or fragment thereof.

[0387] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:168, and a light chain variable region comprising or consisting of SEQ ID NO:186.

[0388] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0389] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0390] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0391] <h2 style=";text-align:left;direction:ltr"> 4-H3_H4_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H4_L0.

[0392] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 168, or a variant or fragment thereof.

[0393] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 185, or a variant or fragment thereof.

[0394] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:168, and a light chain variable region comprising or consisting of SEQ ID NO:185.

[0395] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0396] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0397] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0398] <h2 style=";text-align:left;direction:ltr"> 4-H3_H3_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H3_L1.

[0399] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 167, or a variant or fragment thereof.

[0400] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 186, or a variant or fragment thereof.

[0401] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:167, and a light chain variable region comprising or consisting of SEQ ID NO:186.

[0402] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0403] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0404] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0405] <h2 style=";text-align:left;direction:ltr"> 4-H3_H3_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H3_L0.

[0406] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 167, or a variant or fragment thereof.

[0407] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 185, or a variant or fragment thereof.

[0408] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:167, and a light chain variable region comprising or consisting of SEQ ID NO:185.

[0409] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0410] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0411] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0412] <h2 style=";text-align:left;direction:ltr"> 4-H3_H2_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H2_L1.

[0413] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 166, or a variant or fragment thereof.

[0414] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 186, or a variant or fragment thereof.

[0415] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:166, and a light chain variable region comprising or consisting of SEQ ID NO:186.

[0416] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0417] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0418] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0419] <h2 style=";text-align:left;direction:ltr"> 4-H3_H2_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H2_L0.

[0420] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 166, or a variant or fragment thereof.

[0421] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 185, or a variant or fragment thereof.

[0422] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:166, and a light chain variable region comprising or consisting of SEQ ID NO:185.

[0423] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0424] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0425] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0426] <h2 style=";text-align:left;direction:ltr"> 4-H3_H1_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H1_L1.

[0427] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 194, or a variant or fragment thereof.

[0428] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 186, or a variant or fragment thereof.

[0429] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:194, and a light chain variable region comprising or consisting of SEQ ID NO:186.

[0430] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0431] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0432] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0433] <h2 style=";text-align:left;direction:ltr"> 4-H3_H1_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H1_L0.

[0434] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 194, or a variant or fragment thereof.

[0435] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 185, or a variant or fragment thereof.

[0436] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:194, and a light chain variable region comprising or consisting of SEQ ID NO:185.

[0437] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0438] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0439] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0440] <h2 style=";text-align:left;direction:ltr"> 4-H3_H0_L1 rep Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H0_L1 rep.

[0441] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 164 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 28 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 29 or a variant or fragment thereof.

[0442] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 36 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 37 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 38 or a variant or fragment thereof.

[0443] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 164, a CDR-H2 domain comprising or consisting of SEQ ID NO: 28, a CDR-H3 domain comprising or consisting of SEQ ID NO: 29, a CDR-L1 domain comprising or consisting of SEQ ID NO: 36, a CDR-L2 domain comprising or consisting of SEQ ID NO: 37, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 38.

[0444] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 165, or a variant or fragment thereof.

[0445] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 186, or a variant or fragment thereof.

[0446] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:165, and a light chain variable region comprising or consisting of SEQ ID NO:186.

[0447] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0448] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0449] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0450] <h2 style=";text-align:left;direction:ltr"> 4-H3_H0_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 4-H3_H0_L0.

[0451] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 164 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 28 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 29 or a variant or fragment thereof.

[0452] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 36 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 37 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 38 or a variant or fragment thereof.

[0453] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 164, a CDR-H2 domain comprising or consisting of SEQ ID NO: 28, a CDR-H3 domain comprising or consisting of SEQ ID NO: 29, a CDR-L1 domain comprising or consisting of SEQ ID NO: 36, a CDR-L2 domain comprising or consisting of SEQ ID NO: 37, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 38.

[0454] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 165, or a variant or fragment thereof.

[0455] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 185, or a variant or fragment thereof.

[0456] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:165, and a light chain variable region comprising or consisting of SEQ ID NO:185.

[0457] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0458] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0459] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0460] 1-D5 In one embodiment, the antibody or antigen-binding fragment thereof is referred to herein as 1-D5. This antibody or antigen-binding fragment thereof may comprise the CDR-H1 domain of SEQ ID NO: 45, as provided herein as follows: GFSLNNYI [SEQ ID NO:45] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 45 or a variant or fragment thereof.

[0461] The antibody or antigen-binding fragment thereof may comprise the CDR-H2 domain of SEQ ID NO: 46, as provided herein: ISTGGST [SEQ ID NO:46] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 46 or a variant or fragment thereof.

[0462] The antibody or antigen-binding fragment thereof may comprise the CDR-H3 domain of SEQ ID NO: 47, as provided herein: ARGGSSAGAGFNI [SEQ ID NO:47] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 47 or a variant or fragment thereof.

[0463] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 45, a CDR-H2 domain comprising or consisting of SEQ ID NO: 46, and / or a CDR-H3 domain comprising or consisting of SEQ ID NO: 47. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 45, a CDR-H2 domain comprising or consisting of SEQ ID NO: 46, and a CDR-H3 domain comprising or consisting of SEQ ID NO: 47.

[0464] The antibody or antigen-binding fragment thereof may comprise the FR-H1 domain of SEQ ID NO: 48, as provided herein: QQQLVESGGRLVTPGTPLTLTCAVS [SEQ ID NO:48] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 48 or a variant or fragment thereof.

[0465] The antibody or antigen-binding fragment thereof may comprise the FR-H2 domain of SEQ ID NO:49, as provided herein: MGWVRQAPGKGLEYIGI [SEQ ID NO:49] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 49 or a variant or fragment thereof.

[0466] The antibody or antigen-binding fragment thereof may comprise the FR-H3 domain of SEQ ID NO:50, as provided herein: YYASWAKGRFTISRTSTTMDLKMTSLTTEDTATYFC [SEQ ID NO:50] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 50, or a variant or fragment thereof.

[0467] The antibody or antigen-binding fragment thereof may comprise the FR-H4 domain of SEQ ID NO:51, as provided herein: WGPGTLVTVSS [SEQ ID NO:51] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO:51 or a variant or fragment thereof.

[0468] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 48, an FR-H2 domain comprising or consisting of SEQ ID NO: 49, an FR-H3 domain comprising or consisting of SEQ ID NO: 50, and / or an FR-H4 domain comprising or consisting of SEQ ID NO: 51. Preferably, however, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 48, an FR-H2 domain comprising or consisting of SEQ ID NO: 49, an FR-H3 domain comprising or consisting of SEQ ID NO: 50, and an FR-H4 domain comprising or consisting of SEQ ID NO: 51.

[0469] The antibody or antigen-binding fragment thereof may comprise a heavy chain variable (VH) sequence as defined in SEQ ID NO:52, provided herein as follows: QQQLVESGGRLVTPGTPLTLTCAVSGFSLNNYIMGWVRQAPGKGLEYIGIISTGGSTYYASWAKGRFTISRTSTTMDLKMTSLTTEDTATYFCARGGSSAGAGFNIWGPGTLVTVSS [SEQ ID NO:52] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:52, or a variant or fragment thereof.

[0470] One embodiment of a nucleotide sequence encoding a heavy chain variable (VH) region is referred to herein as SEQ ID NO:53: CAGCAGCAGCTGGTGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTAACCTGCGCAGTCTCTGGATTTTCCCTCAATAACTACATCATGGGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATACATCGGAATCATTAGTACTGGTGGTAGCACATACT ACGCGAGCTGGGCAAAAGGCCGATTCACCATTCCAGAACCTCGACCACGATGGATCTGAAAATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGGGGTAGTAGTGCTGGTGCGGGATTTAATATCTGGGGCCCGGGCACCCTGGTCACCGTCTCCTCA [SEQ ID NO:53] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO:53, or a variant or fragment thereof.

[0471] The antibody or antigen-binding fragment thereof may comprise the CDR-L1 domain of SEQ ID NO:54, as provided herein: QSINSG [SEQ ID NO:54] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 54 or a variant or fragment thereof.

[0472] The antibody or antigen-binding fragment thereof may comprise the CDR-L2 domain of SEQ ID NO:55, as provided herein: KAS [SEQ ID NO:55] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 55 or a variant or fragment thereof.

[0473] The antibody or antigen-binding fragment thereof may comprise the CDR-L3 domain of SEQ ID NO:56, as provided herein: QSYHYISANGAT [SEQ ID NO:56] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 56 or a variant or fragment thereof.

[0474] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 54, a CDR-L2 domain comprising or consisting of SEQ ID NO: 55, and / or a CDR-L3 domain comprising or consisting of SEQ ID NO: 56. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 54, a CDR-L2 domain comprising or consisting of SEQ ID NO: 55, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 56.

[0475] The antibody or antigen-binding fragment thereof may comprise the FR-L1 domain of SEQ ID NO:57, as provided herein: DIVMTQTPSSVSAAVGDTVTIQCQAS [SEQ ID NO:57] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 57 or a variant or fragment thereof.

[0476] The antibody or antigen-binding fragment thereof may comprise the FR-L2 domain of SEQ ID NO:58, as provided herein: LAWYQQKPGQPPKRLIY [SEQ ID NO:58] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 58 or a variant or fragment thereof.

[0477] The antibody or antigen-binding fragment thereof may comprise the FR-L3 domain of SEQ ID NO:59, as provided herein: TLASGVPSRFRGSGSGTDFTLTISDLECADAATYYC [SEQ ID NO:59] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO:59 or a variant or fragment thereof.

[0478] The antibody or antigen-binding fragment thereof may comprise the FR-L4 domain of SEQ ID NO: 60, as provided herein: FGGGTEVVVE [SEQ ID NO:60] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 60 or a variant or fragment thereof.

[0479] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 57, an FR-L2 domain comprising or consisting of SEQ ID NO: 58, an FR-L3 domain comprising or consisting of SEQ ID NO: 59, and / or an FR-L4 domain comprising or consisting of SEQ ID NO: 60. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 57, an FR-L2 domain comprising or consisting of SEQ ID NO: 58, an FR-L3 domain comprising or consisting of SEQ ID NO: 59, and an FR-L4 domain comprising or consisting of SEQ ID NO: 60.

[0480] The antibody or antigen-binding fragment thereof may comprise a variable light chain (VL) sequence as defined in SEQ ID NO:61, provided herein as follows: DIVMTQTPSSVSAAVGDTVTIQCQASQSINSGLAWYQQKPGQPPKRLIYKASTLASGVPSRFRGSGSGTDFTLTISDLECADAATYYCQSYHYISANGATFGGGTEVVVE [SEQ ID NO:61] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:61, or a variant or fragment thereof.

[0481] One embodiment of a nucleotide sequence encoding the light chain variable (VL) region is referred to herein as SEQ ID NO:62: GATATTGTTATGACCCAGACTCCCTCCTCCGTGTCTGCAGCTGTGGGAGACACAGTCACCATCCAGTGCCAGGCCAGTCAGAGCATTAATAGTGGTTTGGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCGCCTGATCTACAAGGCATCCACTCTGGCA TCTGGGGTCCCATCGCGGTTCAGAGGCAGTGGATCTGGGACAGACTTCACTCTCACCATCAGCGACCTGGAGTGTGCCGATGCTGCCACTTACTACTGTCAAAGCTATCATTATATTAGTGCTAATGGTGCTACTTTCGGCGGAGGGACCGAGGTGGTCGTCGAA [SEQ ID NO:62] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO:62, or a variant or fragment thereof.

[0482] Preferably, the antibody or antigen-binding fragment thereof comprises at least one, at least two, at least three, at least four, at least five, or at least six CDRs. Preferably, the antibody or antigen-binding fragment thereof comprises at least CDR-H3.

[0483] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:45, a CDR-H2 domain comprising or consisting of SEQ ID NO:46, a CDR-H3 domain comprising or consisting of SEQ ID NO:47, a CDR-L1 domain comprising or consisting of SEQ ID NO:54, a CDR-L2 domain comprising or consisting of SEQ ID NO:55, and a CDR-L3 domain comprising or consisting of SEQ ID NO:56.

[0484] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:52, and a light chain variable region comprising or consisting of SEQ ID NO:61.

[0485] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:53, and a light chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:62.

[0486] We next attempted to generate humanized antibodies of 1-D5. The sequences of these humanized antibodies are shown in Figure 10. Unless otherwise noted, the six CDR sequences of these humanized antibodies are identical to the six CDR sequences of the parent antibody 1-D5.

[0487] <h2 style=";text-align:left;direction:ltr"> 1-D5_parental(hIgG1) In one embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_parental(hIgG1).

[0488] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:52, or a variant or fragment thereof.

[0489] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:61, or a variant or fragment thereof.

[0490] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:52, and a light chain variable region comprising or consisting of SEQ ID NO:61.

[0491] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0492] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0493] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0494] <h2 style=";text-align:left;direction:ltr"> 1-D5_parental(hIgG1-L234A-L235A-P329G) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_parental (hIgG1-L234A-L235A-P329G).

[0495] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:52, or a variant or fragment thereof.

[0496] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:61, or a variant or fragment thereof.

[0497] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:52, and a light chain variable region comprising or consisting of SEQ ID NO:61.

[0498] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 162, or a variant or fragment thereof.

[0499] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0500] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:162, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0501] <h2 style=";text-align:left;direction:ltr"> 1-D5_parental(hIgG1-Fab) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_parental(hIgG1-Fab).

[0502] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:52, or a variant or fragment thereof.

[0503] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:61, or a variant or fragment thereof.

[0504] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:52, and a light chain variable region comprising or consisting of SEQ ID NO:61.

[0505] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 163, or a variant or fragment thereof.

[0506] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0507] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:163, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0508] <h2 style=";text-align:left;direction:ltr"> 1-D5_H0(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_H0(hIgG1).

[0509] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 173 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 46 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 47 or a variant or fragment thereof.

[0510] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 54 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 55 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 56 or a variant or fragment thereof.

[0511] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 173, a CDR-H2 domain comprising or consisting of SEQ ID NO: 46, a CDR-H3 domain comprising or consisting of SEQ ID NO: 47, a CDR-L1 domain comprising or consisting of SEQ ID NO: 54, a CDR-L2 domain comprising or consisting of SEQ ID NO: 55, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 56.

[0512] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 174, or a variant or fragment thereof.

[0513] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:61, or a variant or fragment thereof.

[0514] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:174, and a light chain variable region comprising or consisting of SEQ ID NO:61.

[0515] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0516] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0517] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0518] <h2 style=";text-align:left;direction:ltr"> 1-D5_H1(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_H1(hIgG1).

[0519] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 175, or a variant or fragment thereof.

[0520] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:61, or a variant or fragment thereof.

[0521] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:175, and a light chain variable region comprising or consisting of SEQ ID NO:61.

[0522] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0523] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0524] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0525] <h2 style=";text-align:left;direction:ltr"> 1-D5_H2(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_H2(hIgG1).

[0526] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 176, or a variant or fragment thereof.

[0527] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:61, or a variant or fragment thereof.

[0528] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:176, and a light chain variable region comprising or consisting of SEQ ID NO:61.

[0529] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0530] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0531] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0532] <h2 style=";text-align:left;direction:ltr"> 1-D5_L0(hIgG1K) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_L0 (hIgG1K).

[0533] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:52, or a variant or fragment thereof.

[0534] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 187, or a variant or fragment thereof.

[0535] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:52, and a light chain variable region comprising or consisting of SEQ ID NO:187.

[0536] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0537] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0538] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0539] <h2 style=";text-align:left;direction:ltr"> 1-D5_L1(hIgG1K) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_L1(hIgG1K).

[0540] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:52, or a variant or fragment thereof.

[0541] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 188, or a variant or fragment thereof.

[0542] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:52, and a light chain variable region comprising or consisting of SEQ ID NO:188.

[0543] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0544] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0545] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0546] <h2 style=";text-align:left;direction:ltr"> 1-D5_H2_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_H2_L1.

[0547] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 176, or a variant or fragment thereof.

[0548] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 188, or a variant or fragment thereof.

[0549] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:176, and a light chain variable region comprising or consisting of SEQ ID NO:188.

[0550] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0551] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0552] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0553] <h2 style=";text-align:left;direction:ltr"> 1-D5_H2_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_H2_L0.

[0554] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 176, or a variant or fragment thereof.

[0555] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 187, or a variant or fragment thereof.

[0556] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:176, and a light chain variable region comprising or consisting of SEQ ID NO:187.

[0557] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0558] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0559] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0560] <h2 style=";text-align:left;direction:ltr"> 1-D5_H1_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_H1_L1.

[0561] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 175, or a variant or fragment thereof.

[0562] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 188, or a variant or fragment thereof.

[0563] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:175, and a light chain variable region comprising or consisting of SEQ ID NO:188.

[0564] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0565] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0566] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0567] <h2 style=";text-align:left;direction:ltr"> 1-D5_H1_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_H1_L0.

[0568] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 175, or a variant or fragment thereof.

[0569] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 187, or a variant or fragment thereof.

[0570] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:175, and a light chain variable region comprising or consisting of SEQ ID NO:187.

[0571] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0572] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0573] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0574] <h2 style=";text-align:left;direction:ltr"> 1-D5_H0_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_H0_L1.

[0575] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 173 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 46 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 47 or a variant or fragment thereof.

[0576] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 54 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 55 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 56 or a variant or fragment thereof.

[0577] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 173, a CDR-H2 domain comprising or consisting of SEQ ID NO: 46, a CDR-H3 domain comprising or consisting of SEQ ID NO: 47, a CDR-L1 domain comprising or consisting of SEQ ID NO: 54, a CDR-L2 domain comprising or consisting of SEQ ID NO: 55, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 56.

[0578] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 174, or a variant or fragment thereof.

[0579] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 188, or a variant or fragment thereof.

[0580] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:174, and a light chain variable region comprising or consisting of SEQ ID NO:188.

[0581] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0582] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0583] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0584] <h2 style=";text-align:left;direction:ltr"> 1-D5_H0_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-D5_H0_L0.

[0585] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 173 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 46 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 47 or a variant or fragment thereof.

[0586] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 54 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 55 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 56 or a variant or fragment thereof.

[0587] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 173, a CDR-H2 domain comprising or consisting of SEQ ID NO: 46, a CDR-H3 domain comprising or consisting of SEQ ID NO: 47, a CDR-L1 domain comprising or consisting of SEQ ID NO: 54, a CDR-L2 domain comprising or consisting of SEQ ID NO: 55, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 56.

[0588] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 174, or a variant or fragment thereof.

[0589] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 187, or a variant or fragment thereof.

[0590] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:174, and a light chain variable region comprising or consisting of SEQ ID NO:187.

[0591] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0592] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0593] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0594] 3-H9 In one embodiment, the antibody or antigen-binding fragment thereof is referred to herein as 3-H9. This antibody or antigen-binding fragment thereof may comprise the CDR-H1 domain of SEQ ID NO:63, as provided herein as follows: GFSLSNYD [SEQ ID NO:63] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 63 or a variant or fragment thereof.

[0595] The antibody or antigen-binding fragment thereof may comprise the CDR-H2 domain of SEQ ID NO:64, as provided herein as follows: IHAIGIT [SEQ ID NO:64] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 64 or a variant or fragment thereof.

[0596] The antibody or antigen-binding fragment thereof may comprise the CDR-H3 domain of SEQ ID NO:65, as provided herein: ARGLVDLNM [SEQ ID NO:65] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 65 or a variant or fragment thereof.

[0597] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 63, a CDR-H2 domain comprising or consisting of SEQ ID NO: 64, and / or a CDR-H3 domain comprising or consisting of SEQ ID NO: 65. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 63, a CDR-H2 domain comprising or consisting of SEQ ID NO: 64, and a CDR-H3 domain comprising or consisting of SEQ ID NO: 65.

[0598] The antibody or antigen-binding fragment thereof may comprise the FR-H1 domain of SEQ ID NO:66, as provided herein: SQSLEESGGRLVTPGTPLTLTCSVS [SEQ ID NO:66] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 66 or a variant or fragment thereof.

[0599] The antibody or antigen-binding fragment thereof may comprise the FR-H2 domain of SEQ ID NO:67, as provided herein: MSWVRQAPGKGLEWIGS [SEQ ID NO:67] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 67 or a variant or fragment thereof.

[0600] The antibody or antigen-binding fragment thereof may comprise the FR-H3 domain of SEQ ID NO:68, as provided herein: YYANWAEGRFTISKTSTTVDLKMTSLTTEDTATYFC [SEQ ID NO:68] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 68 or a variant or fragment thereof.

[0601] The antibody or antigen-binding fragment thereof may comprise the FR-H4 domain of SEQ ID NO:69, as provided herein: WGPGTLVTVSS [SEQ ID NO:69] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO:69 or a variant or fragment thereof.

[0602] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 66, an FR-H2 domain comprising or consisting of SEQ ID NO: 67, an FR-H3 domain comprising or consisting of SEQ ID NO: 68, and / or an FR-H4 domain comprising or consisting of SEQ ID NO: 69. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 66, an FR-H2 domain comprising or consisting of SEQ ID NO: 67, an FR-H3 domain comprising or consisting of SEQ ID NO: 68, and an FR-H4 domain comprising or consisting of SEQ ID NO: 69.

[0603] The antibody or antigen-binding fragment thereof may comprise a heavy chain variable (VH) sequence as defined in SEQ ID NO: 70, provided herein as follows: QSLEESGGRLVTPGTPLTLTCSVSGFSLSNYDMSWVRQAPGKGLEWIGSIHAIGITYYANWAEGRFTISKTSTTVDLKMTSLTTEDTATYFCARGLVDLNMWGPGTLVTVSS [SEQ ID NO:70] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 70, or a variant or fragment thereof.

[0604] One embodiment of a nucleotide sequence encoding a heavy chain variable (VH) region is referred to herein as SEQ ID NO:71, as follows: CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCTTGACACTCACCTGTTCAGTCTCTGGATTCTCCTCAGCAACTACGACATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGACTGGAATGGATCGGGTCCATACATGCTATTGGTATCACA TACTACGCGAACTGGGCGGAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGGCTGGTAGATTTGAACATGTGGGGCCCGGGCACCCTCGTCACTGTCTCTTCA [SEQ ID NO:71] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO:71, or a variant or fragment thereof.

[0605] The antibody or antigen-binding fragment thereof may comprise the CDR-L1 domain of SEQ ID NO: 72, as provided herein as follows: QSVYSNNL [SEQ ID NO:72] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 72 or a variant or fragment thereof.

[0606] The antibody or antigen-binding fragment thereof may comprise the CDR-L2 domain of SEQ ID NO: 73, as provided herein: DAS [SEQ ID NO:73] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 73 or a variant or fragment thereof.

[0607] The antibody or antigen-binding fragment thereof may comprise the CDR-L3 domain of SEQ ID NO: 74, as provided herein: QGSYYSSGWYNT [SEQ ID NO:74] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 74 or a variant or fragment thereof.

[0608] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 72, a CDR-L2 domain comprising or consisting of SEQ ID NO: 73, and / or a CDR-L3 domain comprising or consisting of SEQ ID NO: 74. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 72, a CDR-L2 domain comprising or consisting of SEQ ID NO: 73, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 74.

[0609] The antibody or antigen-binding fragment thereof may comprise the FR-L1 domain of SEQ ID NO: 75, as provided herein: AIKMTQTPSSVSVAVGGTVTINCQSS [SEQ ID NO:75] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 75 or a variant or fragment thereof.

[0610] The antibody or antigen-binding fragment thereof may comprise the FR-L2 domain of SEQ ID NO: 76, as provided herein: LSWYQQKPGQPPKLLIY [SEQ ID NO:76] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 76 or a variant or fragment thereof.

[0611] The antibody or antigen-binding fragment thereof may comprise the FR-L3 domain of SEQ ID NO: 77, as provided herein: TLESGVPSRFKGSGSGTQFTLTISGVQCEDAATYYC [SEQ ID NO:77] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 77 or a variant or fragment thereof.

[0612] The antibody or antigen-binding fragment thereof may comprise the FR-L4 domain of SEQ ID NO: 78, as provided herein: FGGGTEVVVE [SEQ ID NO:78] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 78 or a variant or fragment thereof.

[0613] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 75, an FR-L2 domain comprising or consisting of SEQ ID NO: 76, an FR-L3 domain comprising or consisting of SEQ ID NO: 77, and / or an FR-L4 domain comprising or consisting of SEQ ID NO: 78. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 75, an FR-L2 domain comprising or consisting of SEQ ID NO: 76, an FR-L3 domain comprising or consisting of SEQ ID NO: 77, and an FR-L4 domain comprising or consisting of SEQ ID NO: 78.

[0614] The antibody or antigen-binding fragment thereof may comprise a variable light chain (VL) sequence as defined in SEQ ID NO:79, provided herein as follows: AIKMTQTPSSVSVAVGGTVTINCQSSQSVYSNNLLSWYQQKPGQPPKLLIYDASTLESGVPSRFKGSGSGTQFTLTISGVQCEDAATYYCQGSYYSSGWYNTFGGGTEVVVE [SEQ ID NO:79] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 79, or a variant or fragment thereof.

[0615] One embodiment of a nucleotide sequence encoding the light chain variable (VL) region is referred to herein as SEQ ID NO:80: GCTATTAAAATGACCCAGACTCCATCGTCCGTGTCTGTAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGTCCAGTCAGAGTGTTTATAGTAACAACCTCTTATCTTGGTACCAGCAGAAACCAGGGCAGCCTCCCAAGCTCTTGATCTACGATGCATCCACTCTG GAATCTGGGGTCCCATCGCGGTTCAAAGGCAGTGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGTGCAGTGTGAGGATGCTGCCACTTACTACTGTCAAGGCAGTTATTATAGTAGTGGTTGGTACAATACTTTCGGCGGAGGGACCGAGGTGGTCGTCGAA [SEQ ID NO:80] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO:80, or a variant or fragment thereof.

[0616] Preferably, the antibody or antigen-binding fragment thereof comprises at least one, at least two, at least three, at least four, at least five, or at least six CDRs. Preferably, the antibody or antigen-binding fragment thereof comprises at least CDR-H3.

[0617] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:63, a CDR-H2 domain comprising or consisting of SEQ ID NO:64, a CDR-H3 domain comprising or consisting of SEQ ID NO:65, a CDR-L1 domain comprising or consisting of SEQ ID NO:72, a CDR-L2 domain comprising or consisting of SEQ ID NO:73, and a CDR-L3 domain comprising or consisting of SEQ ID NO:74.

[0618] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:70, and a light chain variable region comprising or consisting of SEQ ID NO:79.

[0619] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:71, and a light chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:80.

[0620] We next attempted to generate humanized antibodies of 3-H9. The sequences of these humanized antibodies are shown in Figure 10. Unless otherwise noted, the six CDR sequences of these humanized antibodies are identical to the six CDR sequences of the parent antibody 3-H9.

[0621] <h2 style=";text-align:left;direction:ltr"> 3-H9_parental(hIgG1) In one embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 3-H9_parental(hIgG1).

[0622] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 160, or a variant or fragment thereof.

[0623] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:79, or a variant or fragment thereof.

[0624] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:160, and a light chain variable region comprising or consisting of SEQ ID NO:79.

[0625] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0626] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0627] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0628] <h2 style=";text-align:left;direction:ltr"> 3-H9_parental(hIgG1-L234A-L235A-P329G) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 3-H9_parental (hIgG1-L234A-L235A-P329G).

[0629] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 160, or a variant or fragment thereof.

[0630] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:79, or a variant or fragment thereof.

[0631] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:160, and a light chain variable region comprising or consisting of SEQ ID NO:79.

[0632] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 162, or a variant or fragment thereof.

[0633] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0634] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:162, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0635] <h2 style=";text-align:left;direction:ltr"> 3-H9_parental(hIgG1-Fab) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 3-H9_parental(hIgG1-Fab).

[0636] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 160, or a variant or fragment thereof.

[0637] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:79, or a variant or fragment thereof.

[0638] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:160, and a light chain variable region comprising or consisting of SEQ ID NO:79.

[0639] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 163, or a variant or fragment thereof.

[0640] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0641] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:163, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0642] <h2 style=";text-align:left;direction:ltr"> 3-H9_H0(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 3-H9_H0(hIgG1).

[0643] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 177 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 64 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 65 or a variant or fragment thereof.

[0644] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 72 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 73 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 74 or a variant or fragment thereof.

[0645] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 177, a CDR-H2 domain comprising or consisting of SEQ ID NO: 64, a CDR-H3 domain comprising or consisting of SEQ ID NO: 65, a CDR-L1 domain comprising or consisting of SEQ ID NO: 72, a CDR-L2 domain comprising or consisting of SEQ ID NO: 73, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 74.

[0646] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 178, or a variant or fragment thereof.

[0647] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:79, or a variant or fragment thereof.

[0648] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:178, and a light chain variable region comprising or consisting of SEQ ID NO:79.

[0649] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0650] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0651] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0652] <h2 style=";text-align:left;direction:ltr"> 3-H9_H1(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 3-H9_H1(hIgG1).

[0653] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 179, or a variant or fragment thereof.

[0654] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:79, or a variant or fragment thereof.

[0655] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:179, and a light chain variable region comprising or consisting of SEQ ID NO:79.

[0656] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0657] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0658] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0659] <h2 style=";text-align:left;direction:ltr"> 3-H9_H2(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 3-H9_H2(hIgG1).

[0660] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 180, or a variant or fragment thereof.

[0661] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:79, or a variant or fragment thereof.

[0662] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:180, and a light chain variable region comprising or consisting of SEQ ID NO:79.

[0663] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0664] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0665] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0666] <h2 style=";text-align:left;direction:ltr"> 3-H9_L0(hIgG1K) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 3-H9_L0 (hIgG1K).

[0667] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 160, or a variant or fragment thereof.

[0668] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 189, or a variant or fragment thereof.

[0669] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:160, and a light chain variable region comprising or consisting of SEQ ID NO:189.

[0670] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0671] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0672] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0673] 3-H9_H2_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 3-H9_H2_L0.

[0674] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 180, or a variant or fragment thereof.

[0675] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 189, or a variant or fragment thereof.

[0676] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:180, and a light chain variable region comprising or consisting of SEQ ID NO:189.

[0677] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0678] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0679] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0680] 3-H9_H1_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 3-H9_H1_L0.

[0681] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 179, or a variant or fragment thereof.

[0682] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 189, or a variant or fragment thereof.

[0683] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:179, and a light chain variable region comprising or consisting of SEQ ID NO:189.

[0684] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0685] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0686] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0687] 3-H9_H0_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 3-H9_H0_L0.

[0688] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 177 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 64 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 65 or a variant or fragment thereof.

[0689] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 72 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 73 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 74 or a variant or fragment thereof.

[0690] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 177, a CDR-H2 domain comprising or consisting of SEQ ID NO: 64, a CDR-H3 domain comprising or consisting of SEQ ID NO: 65, a CDR-L1 domain comprising or consisting of SEQ ID NO: 72, a CDR-L2 domain comprising or consisting of SEQ ID NO: 73, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 74.

[0691] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 178, or a variant or fragment thereof.

[0692] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 189, or a variant or fragment thereof.

[0693] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:178 and a light chain variable region comprising or consisting of SEQ ID NO:189.

[0694] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0695] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0696] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0697] 1-G5 In one embodiment, the antibody or antigen-binding fragment thereof is referred to herein as 1-G5. This antibody or antigen-binding fragment thereof may comprise the CDR-H1 domain of SEQ ID NO: 81, as provided herein as follows: GFSLSSYD [SEQ ID NO:81] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 81 or a variant or fragment thereof.

[0698] The antibody or antigen-binding fragment thereof may comprise the CDR-H2 domain of SEQ ID NO: 82, as provided herein: IHATGIT [SEQ ID NO:82] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 82 or a variant or fragment thereof.

[0699] The antibody or antigen-binding fragment thereof may comprise the CDR-H3 domain of SEQ ID NO: 83, as provided herein as follows: ARGLVDLNM [SEQ ID NO:83] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 83 or a variant or fragment thereof.

[0700] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 81, a CDR-H2 domain comprising or consisting of SEQ ID NO: 82, and / or a CDR-H3 domain comprising or consisting of SEQ ID NO: 83. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 81, a CDR-H2 domain comprising or consisting of SEQ ID NO: 82, and a CDR-H3 domain comprising or consisting of SEQ ID NO: 83.

[0701] The antibody or antigen-binding fragment thereof may comprise the FR-H1 domain of SEQ ID NO: 84, as provided herein: SQSLEESGGRLVTPGTPLTLTCSVS [SEQ ID NO:84] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 84 or a variant or fragment thereof.

[0702] The antibody or antigen-binding fragment thereof may comprise the FR-H2 domain of SEQ ID NO: 85, as provided herein: MTWVRQAPGKGLEWIGS [SEQ ID NO:85] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 85 or a variant or fragment thereof.

[0703] The antibody or antigen-binding fragment thereof may comprise the FR-H3 domain of SEQ ID NO: 86, as provided herein: FYANWAKGRFTTSKTSTTVDLKMTSLTTEDTATYFC [SEQ ID NO:86] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 86 or a variant or fragment thereof.

[0704] The antibody or antigen-binding fragment thereof may comprise the FR-H4 domain of SEQ ID NO: 87, as provided herein: WGPGTLVTVSS [SEQ ID NO:87] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 87 or a variant or fragment thereof.

[0705] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 84, an FR-H2 domain comprising or consisting of SEQ ID NO: 85, an FR-H3 domain comprising or consisting of SEQ ID NO: 86, and / or an FR-H4 domain comprising or consisting of SEQ ID NO: 87. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 84, an FR-H2 domain comprising or consisting of SEQ ID NO: 85, an FR-H3 domain comprising or consisting of SEQ ID NO: 86, and an FR-H4 domain comprising or consisting of SEQ ID NO: 87.

[0706] The antibody or antigen-binding fragment thereof may comprise a heavy chain variable (VH) sequence as defined in SEQ ID NO:88, provided herein as follows: QSLEESGGRLVTPGTPLTLTCSVSGFSLSSYDMTWVRQAPGKGLEWIGSIHATGITFYANWAKGRFTTSKTSTTVDLKMTSLTTEDTATYFCARGLVDLNMWGPGTLVTVSS [SEQ ID NO:88] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:88, or a variant or fragment thereof.

[0707] One embodiment of a nucleotide sequence encoding a heavy chain variable (VH) region is referred to herein as SEQ ID NO:89: CAGTCGTTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCTTGACACTCACCTGTTCAGTCTCTGGATTCTCCCTCAGCAGCTACGACATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGGTCCATACATGCTACTGGTATCACA TTCTACGCGAACTGGGCGAAAGGCCGATTCACCACCTCCAAAACCTCGACCACGGTGGATCTGAAAATGACCAGTCTGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGGGCTGGTAGATTTGAACATGTGGGGCCCGGGCACCCTCGTCACCGTCTCTTCA [SEQ ID NO:89] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO:89, or a variant or fragment thereof.

[0708] The antibody or antigen-binding fragment thereof may comprise the CDR-L1 domain of SEQ ID NO:90, as provided herein: QSVYNNNY [SEQ ID NO: 90] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 90 or a variant or fragment thereof.

[0709] The antibody or antigen-binding fragment thereof may comprise the CDR-L2 domain of SEQ ID NO:91, as provided herein: DAS [SEQ ID NO:91] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 91 or a variant or fragment thereof.

[0710] The antibody or antigen-binding fragment thereof may comprise the CDR-L3 domain of SEQ ID NO:92, as provided herein: QGSYYSGGWDTA [SEQ ID NO:92] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 92 or a variant or fragment thereof.

[0711] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 90, a CDR-L2 domain comprising or consisting of SEQ ID NO: 91, and / or a CDR-L3 domain comprising or consisting of SEQ ID NO: 92. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 90, a CDR-L2 domain comprising or consisting of SEQ ID NO: 91, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 92.

[0712] The antibody or antigen-binding fragment thereof may comprise the FR-L1 domain of SEQ ID NO:93, as provided herein: DPVMTQTASSVSAAVGGTVTINCQAS [SEQ ID NO:93] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 93 or a variant or fragment thereof.

[0713] The antibody or antigen-binding fragment thereof may comprise the FR-L2 domain of SEQ ID NO:94, as provided herein: LSWYQQKPGQPPKLLIY [SEQ ID NO:94] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 94 or a variant or fragment thereof.

[0714] The antibody or antigen-binding fragment thereof may comprise the FR-L3 domain of SEQ ID NO: 95, as provided herein: TLASGVPSRFSGNGSGTQFTLTISGVQCDDAATYYC [SEQ ID NO:95] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 95 or a variant or fragment thereof.

[0715] The antibody or antigen-binding fragment thereof may comprise the FR-L4 domain of SEQ ID NO:96, as provided herein: FGGGTKVVVK [SEQ ID NO:96] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 96 or a variant or fragment thereof.

[0716] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 93, an FR-L2 domain comprising or consisting of SEQ ID NO: 94, an FR-L3 domain comprising or consisting of SEQ ID NO: 95, and / or an FR-L4 domain comprising or consisting of SEQ ID NO: 96. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 93, an FR-L2 domain comprising or consisting of SEQ ID NO: 94, an FR-L3 domain comprising or consisting of SEQ ID NO: 95, and an FR-L4 domain comprising or consisting of SEQ ID NO: 96.

[0717] The antibody or antigen-binding fragment thereof may comprise a variable light chain (VL) sequence as defined in SEQ ID NO:97, provided herein as follows: DPVMTQTASSVSAAVGGTVTINCQASQSVYNNNYLSWYQQKPGQPPKLLIYDASTLASGVPSRFSGNGSGTQFTLTISGVQCDDAATYYCQGSYYSGGWDTAFGGGTKVVVK [SEQ ID NO:97] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising or consisting of a sequence substantially as set forth in SEQ ID NO:97, or a variant or fragment thereof.

[0718] One embodiment of a nucleotide sequence encoding the light chain variable (VL) region is referred to herein as SEQ ID NO:98: GATCCCGTGATGACCCAGACTGCGTCCTCCGTGTCTGCAGCTGTGGGAGGCACAGTCACCATCAATTGCCAGGCCAGTCAGAGTGTTTATAATAACAACTACTTATCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCTTGATCTACGATGCATCCACTCTG GCATCTGGGGTCCCATCCCGGTTCAGCGCAATGGATCTGGGACACAGTTCACTCTCACCATCAGCGGCGTACAGTGTGACGATGCTGCCACTTACTACTGTCAAGGCAGTTATTATAGTGGTGGTTGGGACACTGCTTTCGGCGGAGGGACCAAGGTGGTCGTCAAA [SEQ ID NO:98] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO:98, or a variant or fragment thereof.

[0719] Preferably, the antibody or antigen-binding fragment thereof comprises at least one, at least two, at least three, at least four, at least five, or at least six CDRs. Preferably, the antibody or antigen-binding fragment thereof comprises at least CDR-H3.

[0720] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:81, a CDR-H2 domain comprising or consisting of SEQ ID NO:82, a CDR-H3 domain comprising or consisting of SEQ ID NO:83, a CDR-L1 domain comprising or consisting of SEQ ID NO:90, a CDR-L2 domain comprising or consisting of SEQ ID NO:91, and a CDR-L3 domain comprising or consisting of SEQ ID NO:92.

[0721] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:88, and a light chain variable region comprising or consisting of SEQ ID NO:97.

[0722] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:89, and a light chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:98.

[0723] We next attempted to generate humanized antibodies of 1-G5. The sequences of these humanized antibodies are shown in Figure 10. Unless otherwise noted, the six CDR sequences of these humanized antibodies are identical to the six CDR sequences of the parent antibody 1-G5.

[0724] 1-G5_parental(hIgG1) In one embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_parental(hIgG1).

[0725] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 161, or a variant or fragment thereof.

[0726] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 97, or a variant or fragment thereof.

[0727] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:161, and a light chain variable region comprising or consisting of SEQ ID NO:97.

[0728] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0729] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0730] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0731] 1-G5_parental(hIgG1-L234A-L235A-P329G) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_parental (hIgG1-L234A-L235A-P329G).

[0732] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 161, or a variant or fragment thereof.

[0733] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 97, or a variant or fragment thereof.

[0734] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:161, and a light chain variable region comprising or consisting of SEQ ID NO:97.

[0735] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 162, or a variant or fragment thereof.

[0736] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0737] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:162, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0738] 1-G5_parental (hIgG1-Fab) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_parental(hIgG1-Fab).

[0739] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 161, or a variant or fragment thereof.

[0740] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 97, or a variant or fragment thereof.

[0741] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:161, and a light chain variable region comprising or consisting of SEQ ID NO:97.

[0742] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 163, or a variant or fragment thereof.

[0743] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0744] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:163, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0745] 1-G5_H0(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_H0(hIgG1).

[0746] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 181 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 82 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 83 or a variant or fragment thereof.

[0747] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 90 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 91 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 92 or a variant or fragment thereof.

[0748] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:181, a CDR-H2 domain comprising or consisting of SEQ ID NO:82, a CDR-H3 domain comprising or consisting of SEQ ID NO:83, a CDR-L1 domain comprising or consisting of SEQ ID NO:90, a CDR-L2 domain comprising or consisting of SEQ ID NO:91, and a CDR-L3 domain comprising or consisting of SEQ ID NO:92.

[0749] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 182, or a variant or fragment thereof.

[0750] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 97, or a variant or fragment thereof.

[0751] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:182, and a light chain variable region comprising or consisting of SEQ ID NO:97.

[0752] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0753] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0754] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0755] 1-G5_H1(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_H1(hIgG1).

[0756] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 183, or a variant or fragment thereof.

[0757] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 97, or a variant or fragment thereof.

[0758] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:183, and a light chain variable region comprising or consisting of SEQ ID NO:97.

[0759] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0760] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0761] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0762] 1-G5_H2(hIgG1) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_H2(hIgG1).

[0763] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 184, or a variant or fragment thereof.

[0764] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 97, or a variant or fragment thereof.

[0765] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:184, and a light chain variable region comprising or consisting of SEQ ID NO:97.

[0766] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0767] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0768] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0769] 1-G5_L0(hIgG1K) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_L0 (hIgG1K).

[0770] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 161, or a variant or fragment thereof.

[0771] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 192, or a variant or fragment thereof.

[0772] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:161, and a light chain variable region comprising or consisting of SEQ ID NO:192.

[0773] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0774] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0775] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0776] 1-G5_L1(hIgG1K) Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_L1(hIgG1K).

[0777] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 161, or a variant or fragment thereof.

[0778] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 193, or a variant or fragment thereof.

[0779] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:161, and a light chain variable region comprising or consisting of SEQ ID NO:193.

[0780] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0781] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0782] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0783] 1-G5_H2_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_H2_L1.

[0784] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 184, or a variant or fragment thereof.

[0785] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 193, or a variant or fragment thereof.

[0786] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:184, and a light chain variable region comprising or consisting of SEQ ID NO:193.

[0787] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0788] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0789] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0790] 1-G5_H2_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_H2_L0.

[0791] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 184, or a variant or fragment thereof.

[0792] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 192, or a variant or fragment thereof.

[0793] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:184, and a light chain variable region comprising or consisting of SEQ ID NO:192.

[0794] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0795] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0796] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0797] 1-G5_H1_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_H1_L1.

[0798] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 183, or a variant or fragment thereof.

[0799] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 193, or a variant or fragment thereof.

[0800] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:183, and a light chain variable region comprising or consisting of SEQ ID NO:193.

[0801] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0802] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0803] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0804] 1-G5_H1_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_H1_L1.

[0805] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 183, or a variant or fragment thereof.

[0806] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 192, or a variant or fragment thereof.

[0807] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:183, and a light chain variable region comprising or consisting of SEQ ID NO:192.

[0808] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0809] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0810] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0811] 1-G5_H0_L1 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_H0_L1.

[0812] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 181 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 82 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 83 or a variant or fragment thereof.

[0813] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 90 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 91 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 92 or a variant or fragment thereof.

[0814] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:181, a CDR-H2 domain comprising or consisting of SEQ ID NO:82, a CDR-H3 domain comprising or consisting of SEQ ID NO:83, a CDR-L1 domain comprising or consisting of SEQ ID NO:90, a CDR-L2 domain comprising or consisting of SEQ ID NO:91, and a CDR-L3 domain comprising or consisting of SEQ ID NO:92.

[0815] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 182, or a variant or fragment thereof.

[0816] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 193, or a variant or fragment thereof.

[0817] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:182, and a light chain variable region comprising or consisting of SEQ ID NO:193.

[0818] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0819] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0820] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0821] 1-G5_H0_L0 Alternatively, in another embodiment, the humanized antibody or antigen-binding fragment thereof is referred to herein as 1-G5_H0_L0.

[0822] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 181 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 82 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 83 or a variant or fragment thereof.

[0823] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 90 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 91 or a variant or fragment thereof. Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 92 or a variant or fragment thereof.

[0824] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:181, a CDR-H2 domain comprising or consisting of SEQ ID NO:82, a CDR-H3 domain comprising or consisting of SEQ ID NO:83, a CDR-L1 domain comprising or consisting of SEQ ID NO:90, a CDR-L2 domain comprising or consisting of SEQ ID NO:91, and a CDR-L3 domain comprising or consisting of SEQ ID NO:92.

[0825] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 182, or a variant or fragment thereof.

[0826] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 192, or a variant or fragment thereof.

[0827] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:182, and a light chain variable region comprising or consisting of SEQ ID NO:192.

[0828] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant (HC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 157, or a variant or fragment thereof.

[0829] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain constant (LC) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 158, or a variant or fragment thereof.

[0830] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain constant region comprising or consisting of SEQ ID NO:157, and a light chain constant region comprising or consisting of SEQ ID NO:158.

[0831] 4-H9 In one embodiment, the antibody or antigen-binding fragment thereof is referred to herein as 4-H9. This antibody or antigen-binding fragment thereof may comprise the CDR-H1 domain of SEQ ID NO:99, as provided herein as follows: GFSLNSFA [SEQ ID NO:99] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 99 or a variant or fragment thereof.

[0832] The antibody or antigen-binding fragment thereof may comprise the CDR-H2 domain of SEQ ID NO: 100, as provided herein: ITVDGHT [Sequence number 100] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 100, or a variant or fragment thereof.

[0833] The antibody or antigen-binding fragment thereof may comprise the CDR-H3 domain of SEQ ID NO: 101, as provided herein: AREDAGDAGYIYATYNI [SEQ ID NO: 101] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 101 or a variant or fragment thereof.

[0834] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 99, a CDR-H2 domain comprising or consisting of SEQ ID NO: 100, and / or a CDR-H3 domain comprising or consisting of SEQ ID NO: 101. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 99, a CDR-H2 domain comprising or consisting of SEQ ID NO: 100, and a CDR-H3 domain comprising or consisting of SEQ ID NO: 101.

[0835] The antibody or antigen-binding fragment thereof may comprise the FR-H1 domain of SEQ ID NO: 102, as provided herein: SQSVEESGGRLVTPGTPLTLTCTAS [SEQ ID NO: 102] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 102, or a variant or fragment thereof.

[0836] The antibody or antigen-binding fragment thereof may comprise the FR-H2 domain of SEQ ID NO: 103, as provided herein: MSWVRQAPGKGLEWIGI [SEQ ID NO: 103] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 103 or a variant or fragment thereof.

[0837] The antibody or antigen-binding fragment thereof may comprise the FR-H3 domain of SEQ ID NO: 104, as provided herein: YYASWAKGRFTISKASTTVDLKITSPTTEDTATYFC [SEQ ID NO: 104] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 104 or a variant or fragment thereof.

[0838] The antibody or antigen-binding fragment thereof may comprise the FR-H4 domain of SEQ ID NO: 105, as provided herein: WGPGTLVTVSS [SEQ ID NO: 105] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 105 or a variant or fragment thereof.

[0839] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 102, an FR-H2 domain comprising or consisting of SEQ ID NO: 103, an FR-H3 domain comprising or consisting of SEQ ID NO: 104, and / or an FR-H4 domain comprising or consisting of SEQ ID NO: 105. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 102, an FR-H2 domain comprising or consisting of SEQ ID NO: 103, an FR-H3 domain comprising or consisting of SEQ ID NO: 104, and an FR-H4 domain comprising or consisting of SEQ ID NO: 105.

[0840] The antibody or antigen-binding fragment thereof may comprise a heavy chain variable (VH) sequence as defined in SEQ ID NO: 106, provided herein as follows: QSVEESGGRLVTPGTPLTLTCTASGFSLNSFAMSWVRQAPGKGLEWIGIITVDGHTYYASWAKGRFTISKASTTVDLKITSPTTEDTATYFCAREDAGDAGYIYATYNIWGPGTLVTVSS [SEQ ID NO: 106] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 106, or a variant or fragment thereof.

[0841] One embodiment of a nucleotide sequence encoding a heavy chain variable (VH) region is referred to herein as SEQ ID NO: 107: CAATCGGTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAAATAGCTTTGCGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATTACTGTTGATGGTCACACATACTACGCGAGC TGGGCGAAAGGCCGATTCACCATCTCCAAAGCCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGAGGATGCTGGTGATGCTGGTTATATTTATGCTACCTATAACATCTGGGGCCCAGGGACCCTCGTCACCGTCTCTTCA [SEQ ID NO: 107] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO: 107, or a variant or fragment thereof.

[0842] The antibody or antigen-binding fragment thereof may comprise the CDR-L1 domain of SEQ ID NO: 108, as provided herein: EDIGYG [SEQ ID NO: 108] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 108 or a variant or fragment thereof.

[0843] The antibody or antigen-binding fragment thereof may comprise the CDR-L2 domain of SEQ ID NO: 109, as provided herein: GAN [SEQ ID NO: 109] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 109 or a variant or fragment thereof.

[0844] The antibody or antigen-binding fragment thereof may comprise the CDR-L3 domain of SEQ ID NO: 110, as provided herein: QQGYSTPPT [SEQ ID NO: 110] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 110, or a variant or fragment thereof.

[0845] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 108, a CDR-L2 domain comprising or consisting of SEQ ID NO: 109, and / or a CDR-L3 domain comprising or consisting of SEQ ID NO: 110. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 108, a CDR-L2 domain comprising or consisting of SEQ ID NO: 109, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 110.

[0846] The antibody or antigen-binding fragment thereof may comprise the FR-L1 domain of SEQ ID NO: 111, as provided herein: AIEMTQTPSSLAASVGDTVTITCKAS [SEQ ID NO:111] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 111 or a variant or fragment thereof.

[0847] The antibody or antigen-binding fragment thereof may comprise the FR-L2 domain of SEQ ID NO: 112, as provided herein: LAWYQQKLGIAPKLLIY [SEQ ID NO:112] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 112, or a variant or fragment thereof.

[0848] The antibody or antigen-binding fragment thereof may comprise the FR-L3 domain of SEQ ID NO: 113, as provided herein: TLESGVPSRFSGSGSETDYTLTISSVQAEDAGIYYC [SEQ ID NO:113] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 113 or a variant or fragment thereof.

[0849] The antibody or antigen-binding fragment thereof may comprise the FR-L4 domain of SEQ ID NO: 114, as provided herein: FGAGTMVEIQ [SEQ ID NO:114] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 114 or a variant or fragment thereof.

[0850] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 111, an FR-L2 domain comprising or consisting of SEQ ID NO: 112, an FR-L3 domain comprising or consisting of SEQ ID NO: 113, and / or an FR-L4 domain comprising or consisting of SEQ ID NO: 114. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 111, an FR-L2 domain comprising or consisting of SEQ ID NO: 112, an FR-L3 domain comprising or consisting of SEQ ID NO: 113, and an FR-L4 domain comprising or consisting of SEQ ID NO: 114.

[0851] The antibody or antigen-binding fragment thereof may comprise a variable light chain (VL) sequence as defined in SEQ ID NO: 115, provided herein as follows: AIEMTQTPSSLAASVGDTVTITCKASEDIGYGLAWYQQKLGIAPKLLIYGANTLESGVPSRFSGSGSETDYTLTISSVQAEDAGIYYCQQGYSTPPTFGAGTMVEIQ [SEQ ID NO:115] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 115, or a variant or fragment thereof.

[0852] One embodiment of a nucleotide sequence encoding the light chain variable (VL) region is referred to herein as SEQ ID NO:116: GCGATTGAAATGACCCAGACTCCATCCTCCCTGGCTGCATCTGTGGGAGACACAGTCACCATCACTTGTAAGGCCAGTGAGGACATTGGTTATGGGTTAGCCTGGTATCAGCAGAAACTGGGGATAGCTCCTAAGCTCCTGATCTATGGGGCAAACACTT TAGAATCTGGGGTCCCATCGAGGTTCAGTGGCAGCGGATCAGAGACCGATTACACCCTCACCATCAGCAGCGTGCAGGCTGAAGATGCAGGAATTTATTACTGTCAGCAAGGATATAGTACCCCTCCTACTTTCGGTGCGGGGACCATGGTGGAGATCCAA [SEQ ID NO:116] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO:116, or a variant or fragment thereof.

[0853] Preferably, the antibody or antigen-binding fragment thereof comprises at least one, at least two, at least three, at least four, at least five, or at least six CDRs. Preferably, the antibody or antigen-binding fragment thereof comprises at least CDR-H3.

[0854] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:99, a CDR-H2 domain comprising or consisting of SEQ ID NO:100, a CDR-H3 domain comprising or consisting of SEQ ID NO:101, a CDR-L1 domain comprising or consisting of SEQ ID NO:108, a CDR-L2 domain comprising or consisting of SEQ ID NO:109, and a CDR-L3 domain comprising or consisting of SEQ ID NO:110.

[0855] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:106, and a light chain variable region comprising or consisting of SEQ ID NO:115.

[0856] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:107, and a light chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:116.

[0857] 4-B12 In one embodiment, the antibody or antigen-binding fragment thereof is referred to herein as 4-B12. This antibody or antigen-binding fragment thereof may comprise the CDR-H1 domain of SEQ ID NO: 117, as provided herein as follows: GFSLNSFA [SEQ ID NO:117] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 117 or a variant or fragment thereof.

[0858] The antibody or antigen-binding fragment thereof may comprise the CDR-H2 domain of SEQ ID NO: 118, as provided herein: ITVDGHT [SEQ ID NO:118] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 118 or a variant or fragment thereof.

[0859] The antibody or antigen-binding fragment thereof may comprise the CDR-H3 domain of SEQ ID NO: 119, as provided herein: AREDAGDAGYIYATYNI [SEQ ID NO: 119] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 119 or a variant or fragment thereof.

[0860] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 117, a CDR-H2 domain comprising or consisting of SEQ ID NO: 118, and / or a CDR-H3 domain comprising or consisting of SEQ ID NO: 119. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 117, a CDR-H2 domain comprising or consisting of SEQ ID NO: 118, and a CDR-H3 domain comprising or consisting of SEQ ID NO: 119.

[0861] The antibody or antigen-binding fragment thereof may comprise the FR-H1 domain of SEQ ID NO: 120, as provided herein: SQSVKESEGRLVTPGTPLTLTCTVS [SEQ ID NO: 120] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 120 or a variant or fragment thereof.

[0862] The antibody or antigen-binding fragment thereof may comprise the FR-H2 domain of SEQ ID NO: 121, as provided herein: MSWVRQAPGKGLEWIGI [SEQ ID NO: 121] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 121 or a variant or fragment thereof.

[0863] The antibody or antigen-binding fragment thereof may comprise the FR-H3 domain of SEQ ID NO: 122, as provided herein: YYANWAKDRFTISKASTTVDLKITSPTTEDTATYFC [SEQ ID NO: 122] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 122 or a variant or fragment thereof.

[0864] The antibody or antigen-binding fragment thereof may comprise the FR-H4 domain of SEQ ID NO: 123, as provided herein: WGPGTLVTVSS [SEQ ID NO: 123] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 123 or a variant or fragment thereof.

[0865] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 120, an FR-H2 domain comprising or consisting of SEQ ID NO: 121, an FR-H3 domain comprising or consisting of SEQ ID NO: 122, and / or an FR-H4 domain comprising or consisting of SEQ ID NO: 123. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 120, an FR-H2 domain comprising or consisting of SEQ ID NO: 121, an FR-H3 domain comprising or consisting of SEQ ID NO: 122, and an FR-H4 domain comprising or consisting of SEQ ID NO: 123.

[0866] The antibody or antigen-binding fragment thereof may comprise a heavy chain variable (VH) sequence as defined in SEQ ID NO: 124, provided herein as follows: QSVKESEGRLVTPGTPLTLTCTVSGFSLNSFAMSWVRQAPGKGLEWIGIITVDGHTYYANWAKDRFTISKASTTVDLKITSPTTEDTATYFCAREDAGDAGYIYATYNIWGPGTLVTVSS [SEQ ID NO:124] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 124, or a variant or fragment thereof.

[0867] One embodiment of a nucleotide sequence encoding a heavy chain variable (VH) region is referred to herein as SEQ ID NO: 125: CAGTCGGTGAAGGAGTCCGAGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGTCTCTGGATTCTCCCTCAAATAGCTTTGCGATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGAATCATAACTGTTGATGGTCACACATACTACGCGAAC TGGGCGAAAGACCGATTCACCATCTCCAAAGCCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGAGGATGCTGGTGATGCTGGTTATATTTATGCTACCTATAACATCTGGGGCCCGGGCACCCTGGTCACCGTCTCCTCA [SEQ ID NO: 125] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO: 125, or a variant or fragment thereof.

[0868] The antibody or antigen-binding fragment thereof may comprise the CDR-L1 domain of SEQ ID NO: 126, as provided herein: EDIGYG [SEQ ID NO:126] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 126 or a variant or fragment thereof.

[0869] The antibody or antigen-binding fragment thereof may comprise the CDR-L2 domain of SEQ ID NO: 127, as provided herein: GAN [SEQ ID NO: 127] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 127 or a variant or fragment thereof.

[0870] The antibody or antigen-binding fragment thereof may comprise the CDR-L3 domain of SEQ ID NO: 128, as provided herein: QQGYSTPPT [SEQ ID NO: 128] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 128 or a variant or fragment thereof.

[0871] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 126, a CDR-L2 domain comprising or consisting of SEQ ID NO: 127, and / or a CDR-L3 domain comprising or consisting of SEQ ID NO: 128. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 126, a CDR-L2 domain comprising or consisting of SEQ ID NO: 127, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 128.

[0872] The antibody or antigen-binding fragment thereof may comprise the FR-L1 domain of SEQ ID NO: 129, as provided herein: DPVLTQTASSLAASVGDTVTITCKAS [SEQ ID NO: 129] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 129 or a variant or fragment thereof.

[0873] The antibody or antigen-binding fragment thereof may comprise the FR-L2 domain of SEQ ID NO: 130, as provided herein: LAWYQQKPGQPPKLLIY [SEQ ID NO: 130] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 130, or a variant or fragment thereof.

[0874] The antibody or antigen-binding fragment thereof may comprise the FR-L3 domain of SEQ ID NO: 131, as provided herein: TLESGVPSRFTGSGSETDYTLTISSVQAEDAGIYYC [SEQ ID NO:131] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 131 or a variant or fragment thereof.

[0875] The antibody or antigen-binding fragment thereof may comprise the FR-L4 domain of SEQ ID NO: 132, as provided herein: FGAGTKVEIK [SEQ ID NO: 132] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 132 or a variant or fragment thereof.

[0876] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 129, an FR-L2 domain comprising or consisting of SEQ ID NO: 130, an FR-L3 domain comprising or consisting of SEQ ID NO: 131, and / or an FR-L4 domain comprising or consisting of SEQ ID NO: 132. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 129, an FR-L2 domain comprising or consisting of SEQ ID NO: 130, an FR-L3 domain comprising or consisting of SEQ ID NO: 131, and an FR-L4 domain comprising or consisting of SEQ ID NO: 132.

[0877] The antibody or antigen-binding fragment thereof may comprise a variable light chain (VL) sequence as defined in SEQ ID NO: 133, as provided herein as follows: DPVLTQTASSLAASVGDTVTITCKASEDIGYGLAWYQQKPGQPPKLLIYGANTLESGVPSRFTGSGSETDYTLTISSVQAEDAGIYYCQQGYSTPPTFGAGTKVEIK [SEQ ID NO:133] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 133, or a variant or fragment thereof.

[0878] One embodiment of a nucleotide sequence encoding the light chain variable (VL) region is referred to herein as SEQ ID NO: 134: GATCCTGTGCTGACCCAGACTGCGTCCTCCCTGGCTGCATCTGTGGGAGACACAGTCACCATCACTTGTAAGGCCAGTGAGGACATTGGTTATGGGTTAGCCTGGTATCAGCAGAAACCAGGGCAGCCTCCCAAGCTCCTGATCTATGGGGCAAACACTT TAGAATCTGGGGTCCCATCGAGGTTCACTGGCAGCGGATCAGAGACCGATTACACCCTCACCATCAGCAGCGTGCAGGCTGAAGATGCAGGAATTTATTACTGTCAGCAAGGATATAGTACCCCTCCTACTTTCGGTGCGGGCACCAAGGTAGAAATCAAA [SEQ ID NO:134] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO: 134, or a variant or fragment thereof.

[0879] Preferably, the antibody or antigen-binding fragment thereof comprises at least one, at least two, at least three, at least four, at least five, or at least six CDRs. Preferably, the antibody or antigen-binding fragment thereof comprises at least CDR-H3.

[0880] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO:117, a CDR-H2 domain comprising or consisting of SEQ ID NO:118, a CDR-H3 domain comprising or consisting of SEQ ID NO:119, a CDR-L1 domain comprising or consisting of SEQ ID NO:126, a CDR-L2 domain comprising or consisting of SEQ ID NO:127, and a CDR-L3 domain comprising or consisting of SEQ ID NO:128.

[0881] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:124, and a light chain variable region comprising or consisting of SEQ ID NO:133.

[0882] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:125, and a light chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:134.

[0883] 4-C6 In one embodiment, the antibody or antigen-binding fragment thereof is referred to herein as 4-C6. This antibody or antigen-binding fragment thereof may comprise the CDR-H1 domain of SEQ ID NO: 135, as provided herein as follows: GFSLNTYV [SEQ ID NO:135] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 135 or a variant or fragment thereof.

[0884] The antibody or antigen-binding fragment thereof may comprise the CDR-H2 domain of SEQ ID NO: 136, as provided herein: INGDSNT [SEQ ID NO:136] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 136 or a variant or fragment thereof.

[0885] The antibody or antigen-binding fragment thereof may comprise the CDR-H3 domain of SEQ ID NO: 137, as provided herein: AREDAADAGYVYATYNI [SEQ ID NO:137] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 137 or a variant or fragment thereof.

[0886] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 135, a CDR-H2 domain comprising or consisting of SEQ ID NO: 136, and / or a CDR-H3 domain comprising or consisting of SEQ ID NO: 137. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 135, a CDR-H2 domain comprising or consisting of SEQ ID NO: 136, and a CDR-H3 domain comprising or consisting of SEQ ID NO: 137.

[0887] The antibody or antigen-binding fragment thereof may comprise the FR-H1 domain of SEQ ID NO: 138, as provided herein: SQSLEESGGRLVTPGTPLTLTCTAS [SEQ ID NO:138] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H1 domain comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 138 or a variant or fragment thereof.

[0888] The antibody or antigen-binding fragment thereof may comprise the FR-H2 domain of SEQ ID NO: 139, as provided herein: MTWVRQAPGKGLEWIGF [SEQ ID NO: 139] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 139 or a variant or fragment thereof.

[0889] The antibody or antigen-binding fragment thereof may comprise the FR-H3 domain of SEQ ID NO: 140, as provided herein: YYANWAKGRFTISKTSTTVDLKITSPTTEDTATYFC [SEQ ID NO:140] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 140 or a variant or fragment thereof.

[0890] The antibody or antigen-binding fragment thereof may comprise the FR-H4 domain of SEQ ID NO: 141, as provided herein: WGTGTLVTISS [SEQ ID NO:141] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-H4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 141 or a variant or fragment thereof.

[0891] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 138, an FR-H2 domain comprising or consisting of SEQ ID NO: 139, an FR-H3 domain comprising or consisting of SEQ ID NO: 140, and / or an FR-H4 domain comprising or consisting of SEQ ID NO: 141. Preferably, however, the antibody or antigen-binding fragment thereof comprises an FR-H1 domain comprising or consisting of SEQ ID NO: 138, an FR-H2 domain comprising or consisting of SEQ ID NO: 139, an FR-H3 domain comprising or consisting of SEQ ID NO: 140, and an FR-H4 domain comprising or consisting of SEQ ID NO: 141.

[0892] The antibody or antigen-binding fragment thereof may comprise a heavy chain variable (VH) sequence as defined in SEQ ID NO: 142, provided herein as follows: QSLEESGGRLVTPGTPLTLTCTASGFSLNTYVMTWVRQAPGKGLEWIGFINGDSNTYYANWAKGRFTISKTSTTVDLKITSPTTEDTATYFCAREDAADAGYVYATYNIWGTGTLVTISS [SEQ ID NO:142] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 142, or a variant or fragment thereof.

[0893] One embodiment of a nucleotide sequence encoding a heavy chain variable (VH) region is referred to herein as SEQ ID NO: 143: CAGTCGCTGGAGGAGTCCGGGGGTCGCCTGGTCACGCCTGGGACACCCCTGACACTCACCTGCACAGCCTCTGGATTCTCCCTCAATACCTATGTAATGACCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAATGGATCGGATTCATTAATGGTGATAGTAACACATACTACGCGAAC TGGGCGAAAGGCCGATTCACCATCTCCAAAACCTCGACCACGGTGGATCTGAAAATCACCAGTCCGACAACCGAGGACACGGCCACCTATTTCTGTGCCAGAGAGGATGCTGCTGATGCTGGTTATGTTTATGCTACCTATAACATCTGGGGCACAGGCACCCTGGTCACCATCTCTTCA [SEQ ID NO:143] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable (VH) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO: 143, or a variant or fragment thereof.

[0894] The antibody or antigen-binding fragment thereof may comprise the CDR-L1 domain of SEQ ID NO: 144, as provided herein: EDIGYG [SEQ ID NO:144] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 144 or a variant or fragment thereof.

[0895] The antibody or antigen-binding fragment thereof may comprise the CDR-L2 domain of SEQ ID NO: 145, as provided herein: GAN [SEQ ID NO:145] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 145 or a variant or fragment thereof.

[0896] The antibody or antigen-binding fragment thereof may comprise the CDR-L3 domain of SEQ ID NO: 146, as provided herein: QQGYSTPPT [SEQ ID NO:146] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 146 or a variant or fragment thereof.

[0897] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 144, a CDR-L2 domain comprising or consisting of SEQ ID NO: 145, and / or a CDR-L3 domain comprising or consisting of SEQ ID NO: 146. However, preferably, the antibody or antigen-binding fragment thereof comprises a CDR-L1 domain comprising or consisting of SEQ ID NO: 144, a CDR-L2 domain comprising or consisting of SEQ ID NO: 145, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 146.

[0898] The antibody or antigen-binding fragment thereof may comprise the FR-L1 domain of SEQ ID NO: 147, as provided herein: AYDMTQTPSSLAASVGDTVTITCKAS [SEQ ID NO:147] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L1 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 147 or a variant or fragment thereof.

[0899] The antibody or antigen-binding fragment thereof may comprise the FR-L2 domain of SEQ ID NO: 148, as provided herein: LNWYQQKLGIAPKLLIY [SEQ ID NO:148] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L2 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 148 or a variant or fragment thereof.

[0900] The antibody or antigen-binding fragment thereof may comprise the FR-L3 domain of SEQ ID NO: 149, as provided herein: TLESGVPSRFSGSGSETDYTLTISSVQAEDAGIYYC [SEQ ID NO: 149] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L3 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 149 or a variant or fragment thereof.

[0901] The antibody or antigen-binding fragment thereof may comprise the FR-L4 domain of SEQ ID NO: 150, as provided herein: FGAGTMVEIK [SEQ ID NO:150] Thus, preferably, the antibody or antigen-binding fragment thereof comprises a FR-L4 domain comprising or consisting of a sequence substantially as set out in SEQ ID NO: 150 or a variant or fragment thereof.

[0902] Preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 147, an FR-L2 domain comprising or consisting of SEQ ID NO: 148, an FR-L3 domain comprising or consisting of SEQ ID NO: 149, and / or an FR-L4 domain comprising or consisting of SEQ ID NO: 150. However, preferably, the antibody or antigen-binding fragment thereof comprises an FR-L1 domain comprising or consisting of SEQ ID NO: 147, an FR-L2 domain comprising or consisting of SEQ ID NO: 148, an FR-L3 domain comprising or consisting of SEQ ID NO: 149, and an FR-L4 domain comprising or consisting of SEQ ID NO: 150.

[0903] The antibody or antigen-binding fragment thereof may comprise a variable light chain (VL) sequence as defined in SEQ ID NO: 151, provided herein as follows: AYDMTQTPSSLAASVGDTVTITCKASEDIGYGLNWYQQKLGIAPKLLIYGANTLESGVPSRFSGSGSETDYTLTISSVQAEDAGIYYCQQGYSTPPTFGAGTMVEIK [SEQ ID NO:151] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising or consisting of a sequence substantially as set forth in SEQ ID NO: 151, or a variant or fragment thereof.

[0904] One embodiment of a nucleotide sequence encoding the light chain variable (VL) region is referred to herein as SEQ ID NO: 152: GCATATGATATGACCCAGACTCCATCCTCCCTGGCTGCATCTGTGGGAGACACAGTCACCATCACTTGTAAGGCCAGTGAGGACATTGGTTATGGGTTGAACTGGTATCAGCAGAAACTAGGGATAGCTCCTAAGCTCCTCATCTATGGGGCAAACACTT TAGAATCCGGGGTCCCATCGAGGTTCAGTGGCAGCGGATCAGAGACCGATTACACCCTCACCATCAGCAGCGTGCAGGCTGAAGATGCAGGAATTTATTACTGTCAGCAAGGATATAGTACCCCTCCTACTTTCGGTGCGGGGACCATGGTGGAGATCAAA [SEQ ID NO:152] Preferably, the antibody or antigen-binding fragment thereof comprises a light chain variable (VL) region encoded by a nucleic acid sequence substantially as set forth in SEQ ID NO: 152, or a variant or fragment thereof.

[0905] Preferably, the antibody or antigen-binding fragment thereof comprises at least one, at least two, at least three, at least four, at least five, or at least six CDRs. Preferably, the antibody or antigen-binding fragment thereof comprises at least CDR-H3.

[0906] Preferably, the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising or consisting of SEQ ID NO: 135, a CDR-H2 domain comprising or consisting of SEQ ID NO: 136, a CDR-H3 domain comprising or consisting of SEQ ID NO: 137, a CDR-L1 domain comprising or consisting of SEQ ID NO: 144, a CDR-L2 domain comprising or consisting of SEQ ID NO: 145, and a CDR-L3 domain comprising or consisting of SEQ ID NO: 146.

[0907] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising or consisting of SEQ ID NO:142, and a light chain variable region comprising or consisting of SEQ ID NO:151.

[0908] Preferably, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:143, and a light chain variable region encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:152.

[0909] As shown in Figures 7A-7E, the inventors have surprisingly demonstrated that antibodies and their antigen-binding fragments, referred to herein as 1-A2, 4-H3, 1-D5, 3-H9 and 1-G5, containing a disabled Fc fragment, can bind to the C1-C6 domains of VWF. The Fc fragment is involved in platelet aggregation and is therefore associated with an increased risk of clotting and thrombosis. Therefore, it is particularly advantageous to disable the Fc fragment of the antibody and reduce the risk of clotting when treating patients with conditions caused by platelet-mediated aggregation.

[0910] Thus, in one embodiment, the antibody or antigen-binding fragment thereof of the present invention comprises a disabled Fc fragment. Preferably, the disabled Fc fragment comprises one or more amino acid substitutions that suppress or reduce the effector function of the antibody or antigen-binding fragment thereof. Preferably, the disabled Fc fragment comprises one or more amino acid substitutions selected from the group consisting of L234A, L235A, and P329G. Preferably, the disabled Fc fragment comprises the amino acid substitutions L234A, L235A, and P329G.

[0911] Thus, most preferably, the antibody or antigen-binding fragment thereof designated herein as 1-A2, 4-H3, 1-D5, 3-H9 or 1-G5 comprises a disabled Fc fragment comprising the amino acid substitutions L234A, L235A, and P329G.

[0912] Furthermore, and as shown in Figures 7A-7E, the inventors have demonstrated that Fab fragments of antibody clones 1-A2, 4-H3, 1-D5, 3-H9 and 1-G5 can surprisingly bind to the C1-C6 domains of VWF. Thus, in another embodiment, the antigen-binding fragments comprise or consist of Fab fragments. Preferably, the antigen-binding fragments referred to herein as 1-A2, 4-H3, 1-D5, 3-H9 and 1-G5 comprise or consist of Fab fragments.

[0913] In another embodiment, the inhibitor can be an interference nucleic acid molecule, comprising antisense oligonucleotide, siRNA or dsRNA, that specifically targets the part of the mRNA that codes for one or more of the C1 domain, C2 domain, C3 domain, C4 domain, C5 domain and / or C6 domain of VWF.The functional interference nucleic acid molecule, comprising antisense oligonucleotide, siRNA molecule or dsRNA molecule, can specifically downregulate the target gene, preferably one or more exons thereof.

[0914] In another embodiment, the inhibitor may be a biological agent, a small molecule drug, a protein, a nucleic acid, or a pharmaceutical agent. Advantageously, therefore, the anti-C1-C6-VWF activity of the inhibitor according to the first aspect of the invention means that it has significant utility as a therapeutic agent alone and can be used in the treatment, amelioration or prevention of conditions caused by platelet-mediated aggregation, such as thrombosis-related conditions.

[0915] Thus, in a second aspect of the invention there is provided an inhibitor according to the first aspect for use in therapy. In a third aspect of the invention there is provided an inhibitor according to the first aspect for use in treating, preventing or ameliorating a condition caused by platelet mediated aggregation.

[0916] According to a fourth aspect of the invention there is provided a method of treating, preventing or ameliorating a condition caused by platelet mediated aggregation in a subject, the method comprising administering, or having administered to a patient in need of such treatment, a therapeutically effective amount of an inhibitor according to the first aspect.

[0917] The condition caused by platelet-mediated aggregation may be selected from the group consisting of thrombus-related conditions, thrombotic thrombocytopenic purpura (TTP) (also referred to as acquired thrombotic thrombocytopenic purpura (aTTP)), acute coronary syndrome (ACS), atherosclerosis, ischemic stroke, atrial fibrillation (AF), acute myocardial infarction (AMI), cardiovascular disease (CVD), thrombosis, unstable angina, stable angina, angina, embolism, deep vein thrombosis, hemolytic uremic syndrome, hemolytic anemia, acute renal failure, thrombolytic complications, disseminated intravascular coagulation, coronary heart disease, thromboembolic complications, restenosis, chronic unstable angina, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis, sepsis, vascular inflammation, glomerulonephritis, and thrombotic conditions resulting from coronavirus infection.

[0918] Preferably, the use or method in treating, preventing or ameliorating a condition caused by platelet mediated aggregation involves inhibiting platelet binding under conditions of high shear rate, i.e. pathological conditions.

[0919] The gradient of blood flow velocity in the laminar layer (the slope of the velocity profile) is highest at the vessel wall. This shear rate is called the wall shear rate. Under normal physiological flow conditions, the wall shear rate is approximately 10 s -1 From about 15,000s in the smallest arteries -1 in severely atherosclerotic arteries, it increases to 40,000s -1Maximum wall shear velocities up to 1000 nm have been reported. One possible method for measuring shear velocity in vivo is further described in Brands et al., 1999, "An integrated system for the non-invasive assessment of vessel wall and hemodynamic properties of large arteries by means of ultrasound". Specifically, a system called the arterial laboratory (ART-lab) measures radio frequency ultrasound signals to determine the hemodynamic properties of arteries. Radio frequency signals received from an echo scanner are acquired using a data acquisition system and then stored on a hard disk. The assessment of blood flow velocity is based on the estimation of the temporal and spatial mean frequency within a given estimation window, which includes radio frequency samples filtered by a clutter filter to distinguish between reflections and scattering. The temporal and spatial mean frequency is directly related to the velocity using the Doppler equation. From this velocity profile, the wall shear velocity is calculated based on the maximum of the derivative of the observed spatial velocity distribution with respect to the radius.

[0920] Preferably, the inhibitor is an antibody or an antigen-binding fragment thereof. Most preferably, the inhibitor is one of the antibodies of Figure 8, or an antigen-binding fragment thereof. It will be understood that the inhibitors (herein referred to as "agents") of the present invention may be used in monotherapy (e.g., the inhibitor alone, more preferably, the use of one of the antibodies described herein) to treat, ameliorate, or prevent conditions caused by platelet-mediated aggregation. Alternatively, the agents of the present invention may be used as an adjunct to, or in combination with, known therapies for treating, ameliorating, or preventing conditions caused by platelet-mediated aggregation, such as aspirin, clopidogrel, abciximab, heparin, warfarin, and direct oral anticoagulants (DOACs), such as dabigatran (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Savaysa), and betrixaban (Bevyxxa).

[0921] The agent of the present invention can be combined in a composition having a number of different forms, depending on the manner in which the composition is used.Thus, for example, the composition can be a powder, a tablet, a capsule, a liquid, an ointment, a cream, a gel, a hydrogel, an aerosol, a spray, a micelle solution, a transdermal patch, a liposomal suspension, or any other suitable form that can be administered to a person or an animal that needs treatment.It will be understood that the vehicle of the pharmaceutical of the present invention must be well tolerated by the subject to which it is given.

[0922] The medicament containing the agent of the present invention can be used in several ways.For example, oral administration may be required, in which case the agent may be contained in a composition that can be taken orally, for example, in the form of a tablet, capsule, or liquid.The composition containing the agent and medicament of the present invention may be administered by inhalation (e.g., intranasally).The composition may be formulated for topical use.For example, cream or ointment may be applied to the skin.

[0923] The drugs and medicaments of the present invention may be incorporated into a sustained or delayed release device. Such a device may be inserted, for example, on or under the skin, and the medicament may be released over a period of weeks or even months. The device may be positioned at least adjacent to the treatment site. Such a device may be particularly advantageous when long-term treatment with the drug used according to the present invention is required and frequent administration (e.g., at least daily injections) is usually required.

[0924] In certain preferred embodiments, the agents and medicaments of the present invention may be administered by injection into the subject's bloodstream or directly to the site requiring treatment. Injection may be intravenous (bolus or infusion) or subcutaneous (bolus or infusion) or intradermal (bolus or infusion).

[0925] It will be understood that the amount of inhibitor (i.e. drug) required is determined by its biological activity and bioavailability, which depends on the mode of administration, the physiochemical properties of the drug, and whether it is used as a monotherapy or in a combination therapy. The frequency of administration is also influenced by the half-life of the drug in the subject being treated. The optimal dosage to be administered can be determined by those skilled in the art and varies depending on the specific drug used, the strength of the pharmaceutical composition, the mode of administration, and the progress of the thrombus-related condition. Additional factors that depend on the specific subject being treated, including the subject's age, weight, sex, diet, and administration time, will require the dosage to be adjusted.

[0926] Generally, depending on the agent, a daily dose of between 0.01 μg / kg body weight and 100 mg / kg body weight of the agent of the present invention can be used to treat, ameliorate or prevent a thrombus-related condition. More preferably, the daily dose of the agent is between 1 μg / kg body weight and 100 mg / kg body weight, more preferably between 10 μg / kg and 10 mg / kg body weight, and most preferably between about 100 μg / kg and 10 mg / kg body weight.

[0927] The agent may be administered before, during, or after the onset of the thrombus-related condition. The daily dose may be given as a single dose (e.g., a single daily injection). Alternatively, the agent may require more than one administration during the day. As an example, the agent may be administered as two (or more depending on the severity of the thrombus-related condition to be treated) daily doses of between 0.07 μg and 700 mg (i.e., assuming a body weight of 70 kg). The patient to be treated may take a first dose upon waking and then a second dose in the evening (for a two-dose regimen), or at inter...

Claims

1. An inhibitor that specifically binds to one or more of the C1 domain, C2 domain, C3 domain, C4 domain, C5 domain, and / or C6 domain of von Willebrand factor (VWF).

2. The inhibitor of claim 1 , which specifically binds to the C5 domain of VWF.

3. The inhibitor of claim 1, which does not substantially bind to the A1 domain, the A2 domain and / or the A3 domain of VWF.

4. The inhibitor of claim 1, which binds to the region between amino acid positions 2255 and 2722 of VWF, substantially as defined in SEQ ID NO:

1.

5. The inhibitor of claim 1 , which binds to one or more amino acids in SEQ ID NO:2, or a variant or fragment thereof.

6. The inhibitor of claim 1 , which binds to one or more amino acids in SEQ ID NO: 3, 4, 5, 6, 7, and / or 8, or variants or fragments thereof.

7. The inhibitor of claim 1 which is a biological agent, a small molecule drug, a protein, a nucleic acid, or a pharmaceutical agent.

8. The inhibitor of claim 7, which is an antisense oligonucleotide, siRNA, or dsRNA that specifically targets a portion of the mRNA encoding one or more of the C1, C2, C3, C4, C5, and / or C6 domains of VWF.

9. The inhibitor of claim 1 which is an antibody or an antigen-binding fragment thereof.

10. 10. The antibody or antigen-binding fragment thereof of claim 9, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof, and optionally the antibody or antigen-binding fragment thereof comprises a disabled Fc fragment, and optionally the disabled Fc fragment comprises one or more amino acid substitutions selected from the group consisting of L234A, L235A, and P329G.

11. the antibody or antigen-binding fragment thereof comprising: (i) a CDR-H1 domain comprising SEQ ID NO:9, a CDR-H2 domain comprising SEQ ID NO:10, a CDR-H3 domain comprising SEQ ID NO:11, a CDR-L1 domain comprising SEQ ID NO:18, a CDR-L2 domain comprising SEQ ID NO:19, and / or a CDR-L3 domain comprising SEQ ID NO:20, or (ii) a CDR-H1 domain comprising SEQ ID NO: 164, a CDR-H2 domain comprising SEQ ID NO: 10, a CDR-H3 domain comprising SEQ ID NO: 11, a CDR-L1 domain comprising SEQ ID NO: 18, a CDR-L2 domain comprising SEQ ID NO: 19, and / or a CDR-L3 domain comprising SEQ ID NO:

20.

10. The antibody or antigen-binding fragment thereof of claim 9, comprising:

12. the antibody or antigen-binding fragment thereof comprising: (i) a heavy chain variable region comprising or consisting of SEQ ID NO: 16, and a light chain variable region comprising or consisting of SEQ ID NO: 25; (ii) a heavy chain variable region comprising or consisting of SEQ ID NO: 156, and a light chain variable region comprising or consisting of SEQ ID NO: 25; (iii) a heavy chain variable region comprising or consisting of SEQ ID NO: 165, and a light chain variable region comprising or consisting of SEQ ID NO: 25; (iv) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 172, and a light chain variable region comprising, or consisting of, SEQ ID NO: 25; (v) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 156, and a light chain variable region comprising, or consisting of, SEQ ID NO: 190; (vi) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 156, and a light chain variable region comprising, or consisting of, SEQ ID NO: 191; (vii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 194, and a light chain variable region comprising, or consisting of, SEQ ID NO: 25; (viii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 172, and a light chain variable region comprising, or consisting of, SEQ ID NO: 191; (ix) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 172, and a light chain variable region comprising, or consisting of, SEQ ID NO: 190; (x) a heavy chain variable region comprising or consisting of SEQ ID NO: 194, and a light chain variable region comprising or consisting of SEQ ID NO: 191; (xi) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 194, and a light chain variable region comprising, or consisting of, SEQ ID NO: 190; (xii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 165, and a light chain variable region comprising, or consisting of, SEQ ID NO: 191; or (xiii) a heavy chain variable region comprising or consisting of SEQ ID NO: 165, and a light chain variable region comprising or consisting of SEQ ID NO:

190. The antibody or antigen-binding fragment thereof of claim 9, comprising:

13. the antibody or antigen-binding fragment thereof comprising: (i) a CDR-H1 domain comprising SEQ ID NO:27, a CDR-H2 domain comprising SEQ ID NO:28, a CDR-H3 domain comprising SEQ ID NO:29, a CDR-L1 domain comprising SEQ ID NO:36, a CDR-L2 domain comprising SEQ ID NO:37, and / or a CDR-L3 domain comprising SEQ ID NO:38, or (ii) a CDR-H1 domain comprising SEQ ID NO: 164, a CDR-H2 domain comprising SEQ ID NO: 28, a CDR-H3 domain comprising SEQ ID NO: 29, a CDR-L1 domain comprising SEQ ID NO: 36, a CDR-L2 domain comprising SEQ ID NO: 37, and / or a CDR-L3 domain comprising SEQ ID NO:

38.

10. The antibody or antigen-binding fragment thereof of claim 9, comprising:

14. the antibody or antigen-binding fragment thereof comprising: (i) a heavy chain variable region comprising or consisting of SEQ ID NO: 34, and a light chain variable region comprising or consisting of SEQ ID NO: 43; (ii) a heavy chain variable region comprising or consisting of SEQ ID NO: 159, and a light chain variable region comprising or consisting of SEQ ID NO: 43; (iii) a heavy chain variable region comprising or consisting of SEQ ID NO: 165, and a light chain variable region comprising or consisting of SEQ ID NO: 43; (iv) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 166, and a light chain variable region comprising, or consisting of, SEQ ID NO: 43; (v) a heavy chain variable region comprising or consisting of SEQ ID NO: 167, and a light chain variable region comprising or consisting of SEQ ID NO: 43; (vi) a heavy chain variable region comprising or consisting of SEQ ID NO: 168, and a light chain variable region comprising or consisting of SEQ ID NO: 43; (vii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 169, and a light chain variable region comprising, or consisting of, SEQ ID NO: 43; (viii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 170, and a light chain variable region comprising, or consisting of, SEQ ID NO: 43; (ix) a heavy chain variable region comprising or consisting of SEQ ID NO: 171, and a light chain variable region comprising or consisting of SEQ ID NO: 43; (x) a heavy chain variable region comprising or consisting of SEQ ID NO: 172, and a light chain variable region comprising or consisting of SEQ ID NO: 43; (xi) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 159, and a light chain variable region comprising, or consisting of, SEQ ID NO: 185; (xii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 159, and a light chain variable region comprising, or consisting of, SEQ ID NO: 186; (xiii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 194, and a light chain variable region comprising, or consisting of, SEQ ID NO: 43; (xiv) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 172, and a light chain variable region comprising, or consisting of, SEQ ID NO: 186; (xv) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 172, and a light chain variable region comprising, or consisting of, SEQ ID NO: 185; (xvi) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 171, and a light chain variable region comprising, or consisting of, SEQ ID NO: 186; (xvii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 171, and a light chain variable region comprising, or consisting of, SEQ ID NO: 185; (xviii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 170, and a light chain variable region comprising, or consisting of, SEQ ID NO: 186; (xix) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 170, and a light chain variable region comprising, or consisting of, SEQ ID NO: 185; (xx) a heavy chain variable region comprising or consisting of SEQ ID NO: 169, and a light chain variable region comprising or consisting of SEQ ID NO: 186; (xxi) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 169, and a light chain variable region comprising, or consisting of, SEQ ID NO: 185; (xxii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 168, and a light chain variable region comprising, or consisting of, SEQ ID NO: 186; (xxiii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 168, and a light chain variable region comprising, or consisting of, SEQ ID NO: 185; (xxiv) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 167, and a light chain variable region comprising, or consisting of, SEQ ID NO: 186; (xxv) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 167, and a light chain variable region comprising, or consisting of, SEQ ID NO: 185; (xxvi) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 166, and a light chain variable region comprising, or consisting of, SEQ ID NO: 186; (xxvii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 166, and a light chain variable region comprising, or consisting of, SEQ ID NO: 185; (xxviii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 194, and a light chain variable region comprising, or consisting of, SEQ ID NO: 186; (xxix) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 194, and a light chain variable region comprising, or consisting of, SEQ ID NO: 185; (xxx) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 165, and a light chain variable region comprising, or consisting of, SEQ ID NO: 186; or (xxxi) a heavy chain variable region comprising or consisting of SEQ ID NO: 168, and a light chain variable region comprising or consisting of SEQ ID NO:

185. The antibody or antigen-binding fragment thereof of claim 9, comprising:

15. the antibody or antigen-binding fragment thereof comprising: (i) a CDR-H1 domain comprising SEQ ID NO: 45, a CDR-H2 domain comprising SEQ ID NO: 46, a CDR-H3 domain comprising SEQ ID NO: 47, a CDR-L1 domain comprising SEQ ID NO: 54, a CDR-L2 domain comprising SEQ ID NO: 55, and / or a CDR-L3 domain comprising SEQ ID NO: 56, or (ii) a CDR-H1 domain comprising SEQ ID NO: 173, a CDR-H2 domain comprising SEQ ID NO: 46, a CDR-H3 domain comprising SEQ ID NO: 47, a CDR-L1 domain comprising SEQ ID NO: 54, a CDR-L2 domain comprising SEQ ID NO: 55, and / or a CDR-L3 domain comprising SEQ ID NO:

56.

10. The antibody or antigen-binding fragment thereof of claim 9, comprising at least one, at least two, at least three, at least four, at least five, or at least six of said CDRs, as appropriate.

16. the antibody or antigen-binding fragment thereof comprising: (i) a heavy chain variable region comprising or consisting of SEQ ID NO: 52, and a light chain variable region comprising or consisting of SEQ ID NO: 61; (ii) a heavy chain variable region comprising or consisting of SEQ ID NO: 174, and a light chain variable region comprising or consisting of SEQ ID NO: 61; (iii) a heavy chain variable region comprising or consisting of SEQ ID NO: 175, and a light chain variable region comprising or consisting of SEQ ID NO: 61; (iv) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 176, and a light chain variable region comprising, or consisting of, SEQ ID NO: 61; (v) a heavy chain variable region comprising or consisting of SEQ ID NO: 52, and a light chain variable region comprising or consisting of SEQ ID NO: 187; (vi) a heavy chain variable region comprising or consisting of SEQ ID NO: 52, and a light chain variable region comprising or consisting of SEQ ID NO: 188; (vii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 176, and a light chain variable region comprising, or consisting of, SEQ ID NO: 188; (viii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 176, and a light chain variable region comprising, or consisting of, SEQ ID NO: 187; (ix) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 175, and a light chain variable region comprising, or consisting of, SEQ ID NO: 188; (x) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 175, and a light chain variable region comprising, or consisting of, SEQ ID NO: 187; (xi) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 174, and a light chain variable region comprising, or consisting of, SEQ ID NO: 188; or (xii) a heavy chain variable region comprising or consisting of SEQ ID NO: 174, and a light chain variable region comprising or consisting of SEQ ID NO:

187. The antibody or antigen-binding fragment thereof of claim 9, comprising:

17. the antibody or antigen-binding fragment thereof comprising: (i) a CDR-H1 domain comprising SEQ ID NO:63, a CDR-H2 domain comprising SEQ ID NO:64, a CDR-H3 domain comprising SEQ ID NO:65, a CDR-L1 domain comprising SEQ ID NO:72, a CDR-L2 domain comprising SEQ ID NO:73, and / or a CDR-L3 domain comprising SEQ ID NO:74, or (ii) a CDR-H1 domain comprising SEQ ID NO: 177, a CDR-H2 domain comprising SEQ ID NO: 64, a CDR-H3 domain comprising SEQ ID NO: 65, a CDR-L1 domain comprising SEQ ID NO: 72, a CDR-L2 domain comprising SEQ ID NO: 73, and / or a CDR-L3 domain comprising SEQ ID NO:

74.

10. The antibody or antigen-binding fragment thereof of claim 9, comprising:

18. the antibody or antigen-binding fragment thereof comprising: (i) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 70, and a light chain variable region comprising, or consisting of, SEQ ID NO: 79; (ii) a heavy chain variable region comprising or consisting of SEQ ID NO: 160, and a light chain variable region comprising or consisting of SEQ ID NO: 79; (iii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 178, and a light chain variable region comprising, or consisting of, SEQ ID NO: 79; (iv) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 179, and a light chain variable region comprising, or consisting of, SEQ ID NO: 79; (v) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 180, and a light chain variable region comprising, or consisting of, SEQ ID NO: 79; (vi) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 160, and a light chain variable region comprising, or consisting of, SEQ ID NO: 189; (vii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 180, and a light chain variable region comprising, or consisting of, SEQ ID NO: 189; (viii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 179, and a light chain variable region comprising, or consisting of, SEQ ID NO: 189; or (ix) a heavy chain variable region comprising or consisting of SEQ ID NO: 178, and a light chain variable region comprising or consisting of SEQ ID NO:

189. The antibody or antigen-binding fragment thereof of claim 9, comprising:

19. the antibody or antigen-binding fragment thereof comprising: (i) a CDR-H1 domain comprising SEQ ID NO: 81, a CDR-H2 domain comprising SEQ ID NO: 82, a CDR-H3 domain comprising SEQ ID NO: 83, a CDR-L1 domain comprising SEQ ID NO: 90, a CDR-L2 domain comprising SEQ ID NO: 91, and / or a CDR-L3 domain comprising SEQ ID NO: 92, or (ii) a CDR-H1 domain comprising SEQ ID NO: 181, a CDR-H2 domain comprising SEQ ID NO: 82, a CDR-H3 domain comprising SEQ ID NO: 83, a CDR-L1 domain comprising SEQ ID NO: 90, a CDR-L2 domain comprising SEQ ID NO: 91, and / or a CDR-L3 domain comprising SEQ ID NO:

92.

10. The antibody or antigen-binding fragment thereof of claim 9, comprising:

20. the antibody or antigen-binding fragment thereof comprising: (i) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 88, and a light chain variable region comprising, or consisting of, SEQ ID NO: 97; (ii) a heavy chain variable region comprising or consisting of SEQ ID NO: 161, and a light chain variable region comprising or consisting of SEQ ID NO: 97; (iii) a heavy chain variable region comprising or consisting of SEQ ID NO: 182, and a light chain variable region comprising or consisting of SEQ ID NO: 97; (iv) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 183, and a light chain variable region comprising, or consisting of, SEQ ID NO: 97; (v) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 184, and a light chain variable region comprising, or consisting of, SEQ ID NO: 97; (vi) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 161, and a light chain variable region comprising, or consisting of, SEQ ID NO: 192; (vii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 161, and a light chain variable region comprising, or consisting of, SEQ ID NO: 193; (viii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 184, and a light chain variable region comprising, or consisting of, SEQ ID NO: 193; (ix) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 184, and a light chain variable region comprising, or consisting of, SEQ ID NO: 192; (x) a heavy chain variable region comprising or consisting of SEQ ID NO: 183, and a light chain variable region comprising or consisting of SEQ ID NO: 193; (xi) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 183, and a light chain variable region comprising, or consisting of, SEQ ID NO: 192; (xii) a heavy chain variable region comprising, or consisting of, SEQ ID NO: 182, and a light chain variable region comprising, or consisting of, SEQ ID NO: 193; or (xiii) a heavy chain variable region comprising or consisting of SEQ ID NO: 182, and a light chain variable region comprising or consisting of SEQ ID NO:

192. The antibody or antigen-binding fragment thereof of claim 9, comprising:

21. 10. The antibody or antigen-binding fragment thereof of claim 9, wherein the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising SEQ ID NO:99, a CDR-H2 domain comprising SEQ ID NO:100, a CDR-H3 domain comprising SEQ ID NO:101, a CDR-L1 domain comprising SEQ ID NO:108, a CDR-L2 domain comprising SEQ ID NO:109, and / or a CDR-L3 domain comprising SEQ ID NO:110, and optionally the antibody or antigen-binding fragment thereof comprises at least one, at least two, at least three, at least four, at least five, or at least six of said CDRs.

22. 10. The antibody or antigen-binding fragment thereof of claim 9, comprising a heavy chain variable region comprising or consisting of SEQ ID NO: 106, and a light chain variable region comprising or consisting of SEQ ID NO:

115.

23. 10. The antibody or antigen-binding fragment thereof of claim 9, wherein the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising SEQ ID NO: 117, a CDR-H2 domain comprising SEQ ID NO: 118, a CDR-H3 domain comprising SEQ ID NO: 119, a CDR-L1 domain comprising SEQ ID NO: 126, a CDR-L2 domain comprising SEQ ID NO: 127, and / or a CDR-L3 domain comprising SEQ ID NO: 128, and optionally the antibody or antigen-binding fragment thereof comprises at least one, at least two, at least three, at least four, at least five, or at least six of said CDRs.

24. 10. The antibody or antigen-binding fragment thereof of claim 9, comprising a heavy chain variable region comprising or consisting of SEQ ID NO: 124, and a light chain variable region comprising or consisting of SEQ ID NO:

133.

25. 10. The antibody or antigen-binding fragment thereof of claim 9, wherein the antibody or antigen-binding fragment thereof comprises a CDR-H1 domain comprising SEQ ID NO: 135, a CDR-H2 domain comprising SEQ ID NO: 136, a CDR-H3 domain comprising SEQ ID NO: 137, a CDR-L1 domain comprising SEQ ID NO: 144, a CDR-L2 domain comprising SEQ ID NO: 145, and / or a CDR-L3 domain comprising SEQ ID NO: 146, and optionally the antibody or antigen-binding fragment thereof comprises at least one, at least two, at least three, at least four, at least five, or at least six of said CDRs.

26. 10. The antibody or antigen-binding fragment thereof of claim 9, comprising a heavy chain variable region comprising or consisting of SEQ ID NO: 142, and a light chain variable region comprising or consisting of SEQ ID NO:

151.

27. An inhibitor according to any one of claims 1 to 8, or an antibody or antigen-binding fragment thereof according to any one of claims 9 to 26, for use in therapy.

28. An inhibitor described in any one of claims 1 to 8, or an antibody or antigen-binding fragment thereof described in any one of claims 9 to 26, for use in treating, preventing or ameliorating a condition caused by platelet-mediated aggregation.

29. 29. The inhibitor, or antibody or antigen-binding fragment thereof, for use according to claim 28, wherein the condition caused by platelet-mediated aggregation can be selected from the group consisting of thrombus-related conditions, thrombotic thrombocytopenic purpura (TTP), acquired thrombotic thrombocytopenic purpura (aTTP), acute coronary syndrome (ACS), atherosclerosis, ischemic stroke, atrial fibrillation (AF), acute myocardial infarction (AMI), cardiovascular disease (CVD), thrombosis, unstable angina, stable angina, angina, embolism, deep vein thrombosis, hemolytic uremic syndrome, hemolytic anemia, acute renal failure, thrombolytic complications, disseminated intravascular coagulation, coronary heart disease, thromboembolic complications, restenosis, chronic unstable angina, peripheral vascular disease, arterial thrombosis, pre-eclampsia, embolism, restenosis, sepsis, vascular inflammation, glomerulonephritis, and thrombotic conditions resulting from coronavirus infection.

30. A pharmaceutical composition comprising an inhibitor according to any one of claims 1 to 8, or an antibody or antigen-binding fragment thereof according to any one of claims 9 to 26, and optionally a pharma- ceutically acceptable vehicle.

31. An antibody or antigen-binding fragment thereof, (i) immunizing a host organism with one or more of the C1, C2, C3, C4, C5, and / or C6 domains of von Willebrand factor (VWF); (ii) harvesting the antibody or antigen-binding fragment thereof from the host; An antibody or antigen-binding fragment thereof obtained by a method comprising:

32. 27. A polynucleotide sequence encoding the antibody or antigen-binding fragment thereof according to any one of claims 9 to 26.

33. 33. An expression cassette comprising the polynucleotide sequence of claim 32.

34. A recombinant vector comprising the expression cassette of claim 33.

35. A host cell comprising any of the following: (a) the polynucleotide sequence of claim 32; (b) the expression cassette of claim 33; or (c) the vector of claim 34.

36. 27. A method for preparing an antibody or antigen-binding fragment thereof according to any one of claims 9 to 26, comprising the steps of: a) introducing the vector of claim 34 into a host cell; b) culturing said host cells under conditions resulting in the production of the antibody or antigen-binding fragment according to any one of claims 9 to 26; The method includes:

37. 27. An antibody or an antigen-binding fragment thereof according to any one of claims 9 to 26 for use in diagnosis or prognosis.

38. 27. An antibody or an antigen-binding fragment thereof according to any one of claims 9 to 26 for use in the diagnosis or prognosis of a condition caused by platelet-mediated aggregation.

39. A kit for diagnosing a subject suffering from a condition caused by platelet-mediated aggregation or for providing a prognosis of the subject's condition, comprising an antibody or antigen-binding fragment thereof described in any one of claims 9 to 26 for detecting VWF in a sample from a test subject.

40. 39. The use according to claim 38, wherein the condition caused by platelet-mediated aggregation can be selected from the group consisting of thrombus-related conditions, thrombotic thrombocytopenic purpura (TTP), acquired thrombotic thrombocytopenic purpura (aTTP), acute coronary syndrome (ACS), atherosclerosis, ischemic stroke, atrial fibrillation (AF), acute myocardial infarction (AMI), cardiovascular disease (CVD), thrombosis, unstable angina, stable angina, angina, embolism, deep vein thrombosis, hemolytic uremic syndrome, hemolytic anemia, acute renal failure, thrombolytic complications, disseminated intravascular coagulation, coronary heart disease, thromboembolic complications, restenosis, chronic unstable angina, peripheral vascular disease, arterial thrombosis, pre-eclampsia, embolism, restenosis, sepsis, vascular inflammation, glomerulonephritis, and thrombotic conditions resulting from coronavirus infection.

41. The kit of claim 39, wherein the condition caused by platelet-mediated aggregation can be selected from the group consisting of thrombus-related conditions, thrombotic thrombocytopenic purpura (TTP), acquired thrombotic thrombocytopenic purpura (aTTP), acute coronary syndrome (ACS), atherosclerosis, ischemic stroke, atrial fibrillation (AF), acute myocardial infarction (AMI), cardiovascular disease (CVD), thrombosis, unstable angina, stable angina, angina, embolism, deep vein thrombosis, hemolytic uremic syndrome, hemolytic anemia, acute renal failure, thrombolytic complications, disseminated intravascular coagulation, coronary heart disease, thromboembolic complications, restenosis, chronic unstable angina, peripheral vascular disease, arterial thrombosis, pre-eclampsia, embolism, restenosis, sepsis, vascular inflammation, glomerulonephritis, and thrombotic conditions resulting from coronavirus infection.

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