Anti-human CD45RC antibodies and uses thereof

Abstract

The present invention relates to isolated anti-human CD45RC antibodies or binding fragments thereof, nucleic acids and expression vectors encoding same, compositions comprising same, and CD45RC antibodies. 高 and its use as a medicine for the prevention and / or treatment of related diseases (including autoimmune diseases, unwanted immune responses, monogenic diseases, lymphoma or cancer), in particular in the prevention and / or treatment of graft-versus-host disease (GVHD). [Selection diagram] None

Description

[Technical Field]

[0001] The present invention relates to isolated anti-human CD45RC antibodies or binding fragments thereof, nucleic acids and expression vectors encoding same, compositions comprising same, and CD45RC antibodies. 高 and its use as a pharmaceutical for the prevention and / or treatment of related diseases (including autoimmune diseases, unwanted immune responses, monogenic diseases, and lymphoma or cancer), in particular in the prevention and / or treatment of graft-versus-host disease (GVHD). [Background technology]

[0002] CD45 (leukocyte common antigen (LCA), EC 3.1.3.48, also known as T200, Ly5, and PTPRC) constitutes the first and prototypic receptor-like protein tyrosine phosphatase (RPTP). Its expression is restricted to all nucleated hematopoietic cells, where it is one of the most abundant cell surface glycoproteins, constituting approximately 10% of the cell surface, and is estimated to be present at approximately 25 μM in the plasma membrane (Trowbridge & Thomas, 1994. Annu Rev Immunol. 12:85-116; Hermiston et al., 2003. Annu Rev Immunol. 21:107-37; Holmes, 2006. Immunology. 117(2):145-55).

[0003] CD45 contains an extracellular domain, a single transmembrane domain, and a large cytoplasmic domain. The transmembrane and cytoplasmic domains are highly conserved among species. In particular, the cytoplasmic domain of CD45 contains two tandemly duplicated phosphatase domains, of which only the membrane-proximal domain possesses enzymatic activity (Desai et al., 1994, EMBO J. 13(17):4002-10). The function of the second, more C-terminal phosphatase domain in CD45 remains uncertain, although it has been suggested that it may indirectly contribute to CD45 activity by stabilizing the first domain. Through this cytoplasmic domain, CD45 functions as a central regulator of phosphotyrosine levels in hematopoietic cells by modulating the activity of the Src family of tyrosine protein kinases (such as Lck in T cells; or Lyn, Fyn, and Lck in B cells) (Palacios & Weiss, 2004. Oncogene. 23(48):7990-8000; Lowell, 2004. Mol Immunol. 41(6-7):631-43).

[0004] In contrast to the transmembrane and cytoplasmic domains, the extracellular domain of CD45 shows higher polymorphism among different leukocyte lineages. Indeed, this extracellular domain is highly glycosylated and contains three alternatively spliced ​​exons (4, 5, and 6—encoding the A, B, and C determinants, respectively) that are both O-linked glycosylated and sialylated (Hermiston et al., 2003. Annu Rev Immunol. 21:107-37; Holmes, 2006. Immunology. 117(2):145-55). Thus, CD45 isoforms differing in size, shape, and charge are generated by dynamically regulated alternative splicing during both leukocyte differentiation and cell activation, which can alter the extracellular domain of the molecule (Hall et al., 1988. J Immunol. 141(8):2781-7; Lynch, 2004. Nat Rev Immunol. 4(12):931-40).

[0005] The largest CD45 isoform, CD45RABC, containing all three alternatively spliced ​​exons, is approximately 235 kDa, while the smallest isoform, CD45RO, lacking all three exons, is approximately 180 kDa. Intermediate isoforms are possible, containing only two (CD45RAB, CD45RAC, CD45RBC) or only one (CD45RA, CD45RB, CD45RC) of the three exons.

[0006] Although the function of different CD45 isoforms is unclear, differential expression of these isoforms correlates with the level of T cell activation, allowing for the separation of naive versus memory T cells (Birkeland et al., 1989. Proc Natl Acad Sci U S A. 86(17):6734-8). For example, CD45RA is expressed on peripheral naive mature CD4 + While present on T cells, CD45RO is expressed on activated memory CD4 + CD45RABC is expressed on T cells. CD45RABC is expressed on B cells and their precursors, on a subgroup of dendritic cells, and on other antigen-presenting cells. Effector memory RA T cells (T EMRA ), terminally differentiated memory T cell subtypes also re-express the naive T cell marker CD45RA (Koch et al., 2008. Immun Ageing. 5:6). Importantly, this isoform expression pattern is highly conserved across species, highlighting its functional role and importance (Hermiston et al., 2003. Annu Rev Immunol. 21:107-37).

[0007] CD4 + and CD8 + The expression pattern of CD45RC isoforms on T cells allows us to distinguish functionally distinct alloreactive T cell subsets that behave differently in terms of proliferation and cytokine secretion. For example, in rodents, CD4 + and CD8 + Both CD45RC on T cells 高 However, potent T cells can promote transplant rejection and organ inflammation.h 1 effector cells (Spickett et al., 1983. J Exp Med. 158(3):795-810; Xystrakis et al., 2004. Eur J Immunol. 34(2):408-17), but undetectable or low levels of CD45RC low / - T cells expressing T h 2 and regulatory T cells, which inhibit allograft rejection, graft-versus-host disease (GVHD), and cell-mediated autoimmune diseases (Xystrakis et al., 2004. Blood. 104(10):3294-30; Guillonneau et al., 2007. J Clin Invest. 117(4):1096-106; Powrie & Mason, 1990. J Exp Med. 172(6):1701-8). In humans, CD45RC expression before transplantation + CD8 + High percentages of T cells correlate with decreased graft survival in kidney transplant patients (Ordonez et al., 2013. PLoS One. 8(7):e69791).

[0008] Therefore, CD45RC 高 Depletion of T cell populations is a promising approach for inducing immune tolerance in humans and thus preventing, reducing and / or treating transplant rejection (particularly GVHD) and autoimmune diseases.

[0009] Graft-versus-host disease (GVHD) is a significant cause of morbidity and mortality in stem cell transplant patients. It is a T cell-mediated immune reactive process in which donor cells react with recipient cells. Currently, immunosuppression with immunomodulatory drugs such as corticosteroids is the mainstay of GVHD prevention. While progress has been made with improved survival outcomes over time, corticosteroids do not prevent GVHD in a high proportion of patients (less than 50% of patients with acute GVHD and 40–50% of patients with chronic GVHD, depending on the severity of the initial disease—Garnett et al., 2013. Ther Adv Hematol. 4(6):366–378), are associated with significant toxicity, and many of the currently available salvage treatments are associated with increased immunosuppression and infectious complications. Therefore, there is an unmet need for the development of new therapeutic strategies for GVHD to improve long-term outcomes after transplantation.

[0010] The present inventors have demonstrated that CD45RC 高 We have previously described that T cell depletion may represent a potentially novel therapy for preventing or reducing transplant rejection by increasing tolerogenic regulatory T cells while decreasing aggressive effector T and B cells. Indeed, transient anti-CD45RC mAb treatment resulted in rapid CD45RC deficiency while preserving memory immunity. 高 Induce T cell apoptosis. Furthermore, the inventors have shown that short-term anti-CD45RC antibody treatment results in durable allograft survival without signs of chronic rejection (International Patent WO2016016442; Picarda et al., 2017. JCI Insight. 2(3):e90088).

[0011] Here, the present inventors have developed a novel monoclonal antibody against human CD45RC. This antibody competes with currently commercially available anti-human CD45RC antibodies (such as the MT2 clone) and shows a comparable reactivity pattern, but exhibits significantly better cytotoxic activity against T cells at the lowest concentration. Indeed, the anti-hCD45RC antibody of the present invention exhibits better affinity than other currently available antibodies, thereby providing superior therapeutic efficacy.

[0012] Interestingly, the antibodies of the present invention may also be useful for the prevention or treatment of certain monogenic diseases in which an immune response is involved in the pathology. Monogenic diseases are caused by defects in a single gene. More than 4,000 human diseases are caused by these defects associated with one specific gene. To date, most treatment options have revolved around treating the symptoms of the disorder in an attempt to improve the patient's quality of life. Gene therapy is the main hope for a durable cure for this type of disease. However, serious obstacles have been encountered during the development of technologies for delivering genes to the appropriate cells affected by the disorder, and in fact, immune responses to the transgene product or vector limit the therapeutic effect.

[0013] Among the monogenic disorders, some are associated with genes involved in the immune system (such as T and / or B cell primary immunodeficiency and polyendocrine disorder candidiasis-ectodermal dystrophy [APECED]) or with genes not associated with immune function, but whose defects are associated with inflammation and / or immune responses (such as Duchenne muscular dystrophy (DMD)).

[0014] APECED, also known as autoimmune polyglandular syndrome type 1 (APS 1), is a rare, multisystem, autosomal recessive autoimmune disease caused by mutations in the AIRE gene, a transcriptional regulator that enables the expression of tissue-specific autoantigens (TRAs) in bone marrow epithelial thymocytes (mTECs) and autoreactive T cell deficiency. In humans, over 100 mutations in the AIRE gene have been described, causing APECED with a prevalence of 1:9:1,000,000 (Orphanet, http: / / www.orpha.net). The clinical phenotype of APECED is typically defined by the presence of two of three major symptoms: hyperparathyroidism, adrenal insufficiency (Addison's disease), and chronic mucocutaneous candidiasis (CMC). The disease is also associated with multiple autoimmune and extrahepatic features such as type 1 diabetes, enamel hypoplasia, vitiligo, premature ovarian failure, keratitis, pernicious anemia, alopecia, exocrine pancreatitis, interstitial lung disease, nephritis, and other disorders.

[0015] DMD is a monogenic disease in which mutations in the DMD gene, which encodes the protein dystrophin, result in a severe X-linked muscular dystrophy that affects all voluntary muscles and, at later stages, cardiac and respiratory muscles. The immune response is involved in the pathophysiology of the disease in both DMD patients and mdx mice (for review, see Rosenberg et al., 2015. Sci Transl Med. 7(299):299rv4). The standard treatment for DMD is corticosteroids such as prednisolone. In mdx mice, treatments that reduce effector immune responses or inflammation, such as intravenous immunoglobulin, tranilast, heme oxygenase-1 inducers, IL-1 receptor antagonists, and IL-2, have also been used to expand regulatory T cells (Tregs) (Villalta et al., 2014. Sci Transl Med. 6(258):258ra142; Rosenberg et al., 2015. Sci Transl Med. 7(299):299rv4). However, despite recent promising new treatments, the life expectancy of DMD patients remains significantly reduced.

[0016] Surprisingly, the inventors found that CD45RC 高 Dmd using anti-CD45RC antibody to specifically deplete cells - / - Rat (Dmd mdx demonstrated that treatment with the anti-CD45RC monoclonal antibody Aire improved muscle strength (Ouisse et al., 2019. Front Immunol, in press). - / - Administration to rats of CD45RC 高 We have also demonstrated that this leads to a strong depletion of T cells, resulting in the elimination of symptoms characteristic of APECED (manuscript in preparation, international patent application WO2019115791).

[0017] Therefore, the antibodies of the present invention are a promising approach for preventing and / or treating monogenic diseases such as DMD and APECED. Summary of the Invention

[0018] The present invention provides an isolated anti-human CD45RC antibody or binding fragment thereof, comprising: (a) HCVR containing the following three CDRs: (i) VH-CDR1 of SEQ ID NO: 1; (ii) a VH-CDR2 having a sequence selected from the group consisting of SEQ ID NOs: 4, 5, 6, 8, 100, 116, 117, 118, and 119; and (iii) a VH-CDR3 of SEQ ID NO: 3; and (b) an LCVR containing the following three CDRs: (i) SEQ ID NO: 15 (SASSSVS-X 12 -YMH) and 18(RASSSVS-X 12 -YMH)(X 12 is absent or is selected from Asn (N), Ser (S) and Gly (G); (ii) VL-CDR2 of SEQ ID NO: 16; and (iii) VL-CDR3 of SEQ ID NO: 17 The present invention relates to an anti-human CD45RC antibody or a binding fragment thereof comprising the compound:

[0019] In one embodiment, the antibody or binding fragment thereof comprises: (a) HCVR containing the following three CDRs: (i) VH-CDR1 of SEQ ID NO: 1; (ii) a VH-CDR2 having a sequence selected from the group consisting of SEQ ID NOs: 4 and 5; and (iii) a VH-CDR3 of SEQ ID NO: 3; and (b) an LCVR containing the following three CDRs: (i) VL-CDR1(X 12 does not exist); (ii) VL-CDR2 of SEQ ID NO: 16; and (iii) VL-CDR3 of SEQ ID NO: 17 Includes:

[0020] In one embodiment, the antibody or binding fragment thereof comprises: (a) HCVR containing the following three CDRs: (i) VH-CDR1 of SEQ ID NO: 1; (ii) VH-CDR2 of SEQ ID NO: 4; and (iii) a VH-CDR3 of SEQ ID NO: 3; and (b) an LCVR containing the following three CDRs: (i) VL-CDR1(X 12 does not exist); (ii) VL-CDR2 of SEQ ID NO: 16; and (iii) VL-CDR3 of SEQ ID NO: 17 Includes:

[0021] In one embodiment, the antibody or binding fragment thereof comprises: (a) HCVR containing the following three CDRs: (i) VH-CDR1 of SEQ ID NO: 1; (ii) a VH-CDR2 having a sequence selected from the group consisting of SEQ ID NOs: 4, 6, and 100; and (iii) a VH-CDR3 of SEQ ID NO: 3; and (b) an LCVR containing the following three CDRs: (i) a VL-CDR1(X) having a sequence selected from the group consisting of SEQ ID NOs: 15 and 18; 12 does not exist); (ii) VL-CDR2 of SEQ ID NO: 16; and (iii) VL-CDR3 of SEQ ID NO: 17 Includes:

[0022] In one embodiment, the antibody or binding fragment thereof comprises: 1) HCVR of SEQ ID NO: 61 and LCVR of SEQ ID NO: 81; 2) HCVR of SEQ ID NO: 62 and LCVR of SEQ ID NO: 82; 3) HCVR of SEQ ID NO: 62 and LCVR of SEQ ID NO: 83; 4) HCVR of SEQ ID NO: 62 and LCVR of SEQ ID NO: 84; 5) HCVR of SEQ ID NO: 63 and LCVR of SEQ ID NO: 82; 6) HCVR of SEQ ID NO: 63 and LCVR of SEQ ID NO: 83; 7) HCVR of SEQ ID NO: 63 and LCVR of SEQ ID NO: 84; 8) HCVR of SEQ ID NO: 64 and LCVR of SEQ ID NO: 82; 9) HCVR of SEQ ID NO: 64 and LCVR of SEQ ID NO: 83; 10) HCVR of SEQ ID NO: 64 and LCVR of SEQ ID NO: 84; 11) HCVR of SEQ ID NO: 101 and LCVR of SEQ ID NO: 85; 12) HCVR of SEQ ID NO: 101 and LCVR of SEQ ID NO: 103; 13) HCVR of SEQ ID NO: 65 and LCVR of SEQ ID NO: 85; 14) HCVR of SEQ ID NO: 65 and LCVR of SEQ ID NO: 103; 15) HCVR of SEQ ID NO: 62 and LCVR of SEQ ID NO: 85; 16) HCVR of SEQ ID NO: 101 and LCVR of SEQ ID NO: 82; 17) HCVR of SEQ ID NO: 121 and LCVR of SEQ ID NO: 85; 18) HCVR of SEQ ID NO: 122 and LCVR of SEQ ID NO: 85; 19) HCVR of SEQ ID NO: 123 and LCVR of SEQ ID NO: 85; 20) HCVR of SEQ ID NO: 124 and LCVR of SEQ ID NO: 85; 21) HCVR of SEQ ID NO: 63 and LCVR of SEQ ID NO: 85; 22) HCVR of SEQ ID NO: 67 and LCVR of SEQ ID NO: 85; 23) HCVR of SEQ ID NO: 67 and LCVR of SEQ ID NO: 103; or 24) HCVR and LCVR containing a non-CDR region sequence that shares at least 70% identity with the non-CDR region sequence of the HCVR and LCVR of 1) to 23). Includes:

[0023] In one embodiment, the antibody or binding fragment thereof comprises: (a) HCVR containing the following three CDRs: (i) VH-CDR1 of SEQ ID NO: 1; (ii) a VH-CDR2 having a sequence selected from the group consisting of SEQ ID NOs: 4, 5, 6, 8, 100, 116, 117, 118, and 119; and (iii) a VH-CDR3 of SEQ ID NO: 3; and (b) an LCVR containing the following three CDRs: (i) SEQ ID NOs: 15 and 18 (X in SEQ ID NOs: 15 and 18) 12 VL-CDR1 having a sequence selected from the group comprising: Asn (N), Ser (S), and Gly (G); (ii) VL-CDR2 of SEQ ID NO: 16; and (iii) VL-CDR3 of SEQ ID NO: 17; (Preferably, the amino acid residue at Kabat position L71 of the LCVR is Phe (F)) Includes:

[0024] The present invention further relates to a nucleic acid encoding the isolated antibody or binding fragment thereof according to the invention.

[0025] The present invention further relates to an expression vector comprising the nucleic acid according to claim 7.

[0026] The present invention further relates to a cell comprising a nucleic acid according to the invention or an expression vector according to the invention.

[0027] The present invention further relates to a pharmaceutical composition comprising an isolated antibody or binding fragment thereof according to the invention, a nucleic acid according to the invention, an expression vector according to the invention or a cell according to the invention, and at least one pharmaceutically acceptable excipient.

[0028] The present invention further relates to an isolated antibody or binding fragment thereof according to the invention, a nucleic acid according to the invention, an expression vector according to the invention, a cell according to the invention or a pharmaceutical composition according to the invention for use as a medicament.

[0029] The present invention further comprises: Inducing immune tolerance in a subject in need thereof; and / or preventing and / or reducing transplant rejection; The present invention relates to an isolated antibody or binding fragment thereof according to the present invention, a nucleic acid according to the present invention, an expression vector according to the present invention, a cell according to the present invention or a pharmaceutical composition according to the present invention for use in

[0030] The present invention further preferably comprises 高 the pathology associated with CD45RC is selected from the group consisting of autoimmune diseases, unwanted immune responses, monogenic diseases, and lymphoma or cancer. 高 The present invention relates to an isolated antibody or binding fragment thereof according to the invention, a nucleic acid according to the invention, an expression vector according to the invention, a cell according to the invention or a pharmaceutical composition according to the invention for use in preventing, reducing and / or treating a pathology associated with

[0031] The present invention further relates to the isolated antibody or binding fragment thereof according to the invention, the nucleic acid according to the invention, the expression vector according to the invention, the cell according to the invention or the pharmaceutical composition according to the invention for use in the prevention and / or treatment of graft-versus-host disease (GVHD).

[0032] The present invention further relates to an in vitro method for detecting or quantifying hCD45RC in a sample, cell, tissue or organ, comprising contacting said sample, cell, tissue or organ with an isolated antibody or binding fragment thereof according to the invention, optionally wherein the isolated antibody or binding fragment thereof is labeled.

[0033] definition "Antibodies" or "Immunoglobulins" As used herein, the term "immunoglobulin" refers to a protein having a combination of two heavy chains and two light chains, regardless of whether it has an associated specific immune reactivity. "Antibody" refers to such an assembly having significant, known specific immune reactivity against an antigen of interest (e.g., human CD45RC). The term "anti-hCD45RC antibody" is used herein to refer to an antibody that exhibits immunological specificity for the human CD45RC protein. As explained elsewhere herein, "specificity" for human CD45RC does not exclude cross-reactivity with species homologs of hCD45RC.

[0034] Antibodies and immunoglobulins comprise light and heavy chains, with or without interchain covalent bonds between them. Basic immunoglobulin structure in vertebrate systems is relatively well understood. The general term "immunoglobulin" encompasses five distinct classes of antibodies that can be biochemically distinguished. While the following discussion will generally be directed to the IgG class of immunoglobulin molecules, all five classes of antibodies are within the scope of the present invention. With respect to IgG, immunoglobulins comprise two identical light polypeptide chains with a molecular weight of approximately 23 kDa and two identical heavy chains with a molecular weight of approximately 53-70 kDa. The four chains are joined by disulfide bonds in a "Y" configuration, with the light chains originating at the mouth of the "Y" and flanking the heavy chains, which continue through the variable region. Antibody light chains are classified as either kappa (κ) or lambda (λ). Each heavy chain class can associate with either κ or λ light chains. Generally, light and heavy chains are covalently linked to each other, and when immunoglobulins are produced by either hybridomas, B cells, or genetically engineered host cells, the "tail" regions of the two heavy chains are linked to each other by covalent disulfide bonds or non-covalent bonds. In heavy chains, the amino acid sequence runs from the N-terminus at the forked end of the Y configuration to the C-terminus at the bottom of each chain. Those skilled in the art will understand that heavy chains are classified as gamma (γ), mu (μ), alpha (α), delta (δ), or epsilon (ε), with several subclasses within them (e.g., γ1-γ4). The nature of the chain determines the "class" of the antibody, as IgG, IgM, IgA, IgD, or IgE, respectively. Immunoglobulin subclasses or "isotypes" (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, etc.) are well characterized and are known to confer functional properties. Modified versions of each of these classes and isotypes are readily discernible to those skilled in the art in view of the present disclosure, and are therefore within the scope of the present invention. As noted above, the variable region of an antibody enables the antibody to selectively recognize and specifically bind to an epitope on an antigen. That is, the light chain variable domain (V) of an antibody Ldomain) and heavy chain variable domain (V H The quaternary antibody structure (V domains) combine to form variable regions that define a three-dimensional antigen-binding site. This quaternary antibody structure forms the antigen-binding sites present at the end of each arm of the "Y." More specifically, the antigen-binding site is H Chain and V L It is defined by three complementarity determining regions (CDRs) on each of the chains.

[0035] "characterized by having amino acids [...] substituted with different amino acid sequences" As used herein, the phrase "characterized by having amino acids [...] substituted with different amino acids" with reference to a given sequence refers to the presence of "conservative amino acid modifications" in said sequence.

[0036] "Conservative amino acid modifications" "Conservative amino acid modifications" refer to modifications that do not significantly affect or alter the binding characteristics of an antibody or binding fragment thereof containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into an antibody or binding fragment thereof by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.

[0037] Conservative amino acid substitutions typically involve replacing an amino acid residue with an amino acid residue having a side chain with similar physicochemical properties. A particular variable region and CDR sequence may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34 or more amino acid insertions, deletions, and / or substitutions. When substitutions are made, conservative modifications are preferred. Families of amino acid residues with similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), β-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within the CDRs and / or variable regions of an antibody or binding fragment thereof of the invention can be substituted with another amino acid residue from the same side chain family, and the altered antibody can be tested for retained function (i.e., a property described herein, such as binding to hCD45RC) using the assays described herein. In another embodiment, strings of amino acids within the CDRs and / or variable regions of an antibody or binding fragment thereof according to the invention can be replaced with structurally similar strings that differ in the order and / or composition of side chain family members.

[0038] "CD45" As used herein, the term "CD45" (also known as CD45R or PTPRC) refers to a transmembrane glycoprotein that exists in different isoforms. These distinct isoforms of CD45 differ in their extracellular domain structure, resulting from alternative splicing of three variable exons (exons 4, 5, and 6) that encode the A, B, and C determinants of the CD45 extracellular region, respectively. Antibodies that react with restricted epitopes are clustered as "CD45R." Thus, anti-CD45RA, anti-CD45RB, and anti-CD45RC antibodies recognize CD45 isoforms that contain expression of the A, B, and C determinants, respectively. Although the various isoforms of CD45 have different extracellular domains, they share identical extracellular sequences proximal to the membrane, a transmembrane domain, and a large cytoplasmic tail segment containing two aligned, highly conserved, homologous phosphatase domains of approximately 300 residues. CD45 and its isoforms bind non-covalently to lymphocyte phosphatase-associated phosphoprotein (LPAP) on T and B lymphocytes. CD45 has been reported to associate with several other cell surface antigens, including CD1, CD2, CD3, and CD4. CD45 is involved in signaling lymphocyte activation. When preceded by the letter "h" (e.g., hCD45), it means that CD45 is of human origin.

[0039] "CD45RC" The term "CD45RC" as used herein refers to a 200-220 kDa single-chain type I membrane glycoprotein well known to those skilled in the art. CD45RC is an alternatively spliced ​​isoform of CD45 that contains exon 6, encoding the C determinant (hence the term CD45RC, i.e., CD45 restricted to the C determinant), but lacks exons 4 and 5, encoding the A and B determinants, respectively. The amino acid sequence of human CD45RC is shown in SEQ ID NO: 104, corresponding to UniProt accession number P08575-10 (Version 10, modified March 28, 2018 - Checksum: F92C874C9A114890). This CD45RC isoform is expressed on B cells, CD8 + T cells and CD4+ Expressed on a subset of T cells, but not CD8 + or CD4 + Tregs, CD14 + It is not expressed on monocytes or PMNs (Picarda et al., 2017. JCI Insight. 2(3):e90088). Some monoclonal antibodies can recognize epitopes in parts of CD45 that are common to all different isoforms (these are called anti-CD45 antibodies), while other monoclonal antibodies have restricted specificity for a given isoform, depending on the determinant (A, B, or C) they recognize. If preceded by the letter "h" (e.g., hCD45RC), it means that CD45RC is of human origin.

[0040] "CD45RC 高 Cellular antigen" or "CD45RC 高 Cell surface markers As used herein, the term "CD45RC 高 Cellular antigen" or "CD45RC 高 The cell surface marker is CD45RC 高 It refers to the antigen (or epitope) of SEQ ID NO: 23 that is expressed or presented on the surface of cells (including T cells, B cells, and natural killer (NK) cells) and which can be targeted by anti-CD45RC agents (such as antibodies or aptamers) that bind thereto. 高 T cell surface markers include, but are not limited to, the aforementioned CD45RC or other antigens that characterize this population of T cells. Of particular interest is CD45RC 高 T cell surface markers are also expressed in mammals other non-CD45RC 高 Compared with T cells, CD45RC 高 It is preferentially expressed on T cells.

[0041] Then, after generating antibodies to the CD45RC cell surface marker as described above, one skilled in the art can 高 Antibodies that act on cells can be easily selected, and include antibodies that act on cells by antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or CD45RC.高 via induction of CD45RC 高 can be used to deplete cells that express CD45RC (e.g., via apoptosis) after direct antibody binding. 低 / - It cannot be used to induce cell death (Picarda et al., 2017. JCI Insight. 2(3):e90088).

[0042] "CDR" or "Complementarity Determining Region" As used herein, the term "CDR" or "complementarity determining region" refers to the non-contiguous antigen-combining sites found within the variable regions of both heavy and light chain polypeptides. CDRs were identified according to the rules in Table 1, as deduced from Kabat et al., 1991, Sequences of Proteins of Immunological Interest (5th ed.), Bethesda, MD: US Department of Health and Human Services; and Chothia and Lesk, 1987, J Mol Biol. 196(4):901-17.

[0043] Table 1 [Table 1] TIFF0007796531000002.tif82162

[0044] "epitope" As used herein, the term "epitope" refers to a specific sequence of amino acids located on a protein or proteins to which an antibody or binding fragment thereof binds. Epitopes often consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three-dimensional structural characteristics, as well as specific charge characteristics. Epitopes can be linear (or continuous) or conformational, i.e., they include two or more amino acid sequences in different regions of an antigen, which may not necessarily be contiguous.

[0045] "Framework Region" or "FR" or "Non-CDR Region" As used herein, the terms "framework region," "FR," or "non-CDR region" include amino acid residues that are part of a variable region but are not part of a CDR (e.g., using the Kabat / Chocchia definition of a CDR). Thus, a variable region framework is about 100-120 amino acids in length, but includes only amino acids outside the CDRs.

[0046] Specific examples of HCVR and CDR as defined by Kabat / Kotia: -FR1 may correspond to the domain of the variable region encompassing amino acids 1 to 25 according to the Chothia / ABM definition or after 5 residues according to the Kabat definition; -FR2 may correspond to the domain of the variable region encompassing amino acids 36 to 49; -FR3 may correspond to the domain of the variable region encompassing amino acids 67 to 98; -FR4 may correspond to the domain from amino acids 104 to 110 of the variable region to the end of the variable region.

[0047] The framework regions of the light chain are similarly separated by each of the CDRs of the LCVR. In naturally occurring antibodies, the six CDRs present on each monomeric antibody are short, noncontiguous sequences of amino acids specifically arranged to form an antigen-binding site in the assumed three-dimensional configuration of the antibody in an aqueous environment. The remainder of the heavy and light chain variable domains, which exhibit less inter-molecular variability in amino acid sequence, are called framework regions. The framework regions largely adopt a β-sheet structure, with the CDRs forming connecting loops and, in some cases, forming part of the β-sheet structure. Thus, these framework regions act as a scaffold for properly orienting the six CDRs through inter-chain non-covalent interactions. The antigen-binding site formed by the arranged CDRs defines a surface complementary to the epitope on the immunoreactive antigen. This complementary surface promotes non-covalent binding of the antibody to the immunoreactive antigen epitope. The location of the CDRs can be easily identified by those skilled in the art.

[0048] "Heavy Chain Region" As used herein, the term "heavy chain region" includes amino acid sequences derived from the constant domain of an immunoglobulin heavy chain. A protein comprising a heavy chain region is a C H 1 domain, a hinge (e.g., upper, middle, and / or lower hinge region) domain, C H 2 domains, C H In one embodiment, the antibody or binding fragment thereof of the present invention comprises at least one of the Fc region of an immunoglobulin heavy chain (e.g., hinge region, C H 2 domain, and C H In another embodiment, the antibody or binding fragment thereof of the present invention may comprise at least a constant domain (e.g., C H In certain embodiments, at least one, and preferably all, of the constant domains are derived from a human immunoglobulin heavy chain. For example, in one preferred embodiment, the heavy chain region includes a fully human hinge region. In other preferred embodiments, the heavy chain region includes a fully human Fc region (e.g., a hinge, C domain, or both from a human immunoglobulin). H 2 and C H In one embodiment, the constituent constant domains of the heavy chain region are derived from different immunoglobulin molecules. For example, the heavy chain region of the protein comprises a C 3 domain sequence derived from an IgG1 molecule. H In other embodiments, the constant domain is a chimeric domain comprising regions of different immunoglobulin molecules. For example, the hinge may comprise a first region from an IgG1 molecule and a second region from an IgG3 or IgG4 molecule. As noted above, those skilled in the art will appreciate that the constant domains of the heavy chain region may be modified such that they are altered in amino acid sequence from a naturally occurring (wild-type) immunoglobulin molecule. That is, the antibodies or binding fragments thereof of the present invention may comprise a heavy chain constant domain (C H 1. Hinge, C H 2 or C H 3) and / or a light chain constant domain (C L) Exemplary modifications include the addition, deletion, or substitution of one or more amino acids in one or more domains.

[0049] "Hinge region" As used herein, the term "hinge region" refers to a C H 1 domain to C H The hinge region comprises the region of the heavy chain molecule that connects the two N-terminal antigen-binding domains. This hinge region contains approximately 25 residues and is flexible, allowing the two N-terminal antigen-binding domains to move independently. The hinge region can be subdivided into three distinct domains: the upper, middle, and lower hinge domains (Roux et al., 1998. J Immunol. 161(8):4083-90).

[0050] "Super-variable loop" The term "hypervariable loop" is not strictly synonymous with complementarity-determining region (CDR), since hypervariable loops (HVs) are defined based on structure, but CDRs are defined based on sequence variability (Kabat et al., 1991. Sequences of proteins of immunological interest (5th ed.). Bethesda, MD: U.S. Department of Health and Human Services). The limits of HVs and CDRs are defined by several Vs. H and V L They may differ in domain. L Domain and V H The CDRs of a domain can typically be defined according to the Kabat / Chocia definition already discussed above.

[0051] "Identity" or "sameness" As used herein, the terms "identity" or "identical," when used in the context of the relationship between the sequences of two or more amino acid sequences or two or more nucleic acid sequences, refer to the degree of sequence relatedness between the amino acid sequences or nucleic acid sequences, as determined by the number of matches between strings of two or more amino acid residues or nucleic acid residues. "Identity" measures the percentage of identical matches with the smaller of the two or more sequences, with gap alignment (if any), addressed by a particular mathematical model or computer program (i.e., "algorithm").

[0052] The identity of related amino acid or nucleic acid sequences can be readily calculated by known methods. Such methods include Lesk AM (1988). Computational molecular biology: Sources and methods for sequence analysis. New York, NY: Oxford University Press; Smith DW (1993). Biocomputing: Informatics and genome projects. San Diego, CA: Academic Press; Griffin AM & Griffin HG (1994). Computer analysis of sequence data, Part 1. Totowa, NJ: Humana Press; von Heijne G. (1987). Sequence analysis in molecular biology: treasure trove or trivial pursuit. San Diego, CA: Academic press; Gribskov MR & Devereux J. (1991). Sequence analysis primers. New York, NY: Stockton Press; Carillo et al., 1988. SIAM J Appl Math. 48(5):1073-82.

[0053] Preferred methods for determining identity are designed to give the largest match between the sequences tested. Methods for determining identity are described in publicly available computer programs. Preferred computer program methods for determining identity between two sequences include the GCG program package, which includes GAP (Genetics Computer Group, University of Wisconsin, Madison, WI; Devereux et al., 1984. Nucleic Acids Res. 12(1 Pt 1):387-95), BLASTP, BLASTN, and FASTA (Altschul et al., 1990. J Mol Biol. 215(3):403-10). The BLASTX program is publicly available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul et al., NCB / NLM / NIH, Bethesda, Md. 20894). Identity may also be determined using the well-known Smith-Waterman algorithm.

[0054] "Immunospecific," "specific," or "specifically binds" As used herein, an antibody or binding fragment thereof preferably has a binding activity of about 10 6 M -1 More than 10, preferably 7 M -1 , 10 8 M -1 , 5×10 8 M -1 , 10 9 M -1 , 5×10 9 M -1 The affinity constant (K A ), and is said to be "immunospecific for," "specific for," or "specifically binds" to the antigen if it reacts detectably with the antigen (e.g., hCD45RC).

[0055] The affinity of an antibody or its binding fragment for its cognate antigen is also generally expressed as the equilibrium dissociation constant (KD The antibody or binding fragment thereof is preferably about 10 -6 M or less, preferably 10 -7 M, 5 x 10 -8 M, 10 -8 M, 5 x 10 -9 M, 10 -9 K below M D and reacts detectably with the antigen (e.g., hCD45RC), it is said to be "immunospecific for," "specific for," or "specifically binds" to the antigen.

[0056] The affinity of an antibody or binding fragment thereof can be readily determined using conventional techniques, such as those described by Scatchard, 1949. Ann NY Acad Sci. 51:660-672. The binding properties of an antibody or binding fragment thereof to an antigen, cell, or tissue can generally be determined and evaluated using immunodetection methods, including, for example, immunofluorescence-based assays such as ELISA, immunohistochemistry (IHC) and / or fluorescence-activated cell sorting (FACS), or by surface plasmon resonance (SPR, e.g., using BIAcore®).

[0057] "Monoclonal antibodies" As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies within the population are identical except for possible minor naturally occurring mutations. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, monoclonal antibodies are advantageous in that they may be synthesized uncontaminated by other antibodies. The modifier "monoclonal" should not be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies or binding fragments thereof according to the present invention may be prepared by the hybridoma method first described by Kohler et al., 1975. Nature. 256(5517):495-7, or may be produced using recombinant DNA methods in bacterial, eukaryotic, or plant cells (U.S. Patent No. 4,816,567). The "monoclonal antibodies" may also be isolated from phage antibody libraries using, for example, the techniques described in Clackson et al., 1991. Nature. 352(6336):624-8 and Marks et al., 1991. J Mol Biol. 222(3):581-97.

[0058] "Prevent" or "preventing" or "prevention" As used herein, the terms "prevent," "preventing," and "prevention" refer to prophylactic and preventative treatments that reduce the chance that a subject will develop a pathological condition or disorder over a given period of time. Such a reduction may be reflected, for example, in a delay in the onset of at least one symptom of the pathological condition or disorder in the subject.

[0059] "subject" As used herein, the term "subject" refers to a mammal, preferably a human. In one embodiment, the subject may be a "patient," i.e., a warm-blooded animal, more preferably a human, who is scheduled to undergo or is undergoing a medical procedure, or who has been / is / will be the subject of a medical procedure, or is being monitored for the development of a disease. The term "mammal" refers to any mammal, including humans, domestic and farm animals, as well as zoo, sport, or pet animals, such as dogs, cats, cows, horses, sheep, pigs, goats, rabbits, etc. Preferably, the mammal is a primate, more preferably a human.

[0060] "Variable Region" or "Variable Domain" As used herein, the term "variable" refers to a variable domain V H and V L This refers to the fact that certain regions of the V domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its target antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is the V domains that form part of the antigen-binding site. L Domain and V H In each domain, it is concentrated in three segments called "hypervariable loops."

[0061] The first, second, and third hypervariable loops of the Vλ light chain domain are referred to herein as L1(λ), ​​L2(λ), and L3(λ), and V L Domains can be defined as containing 24-33 (L1(λ) consisting of 9, 10 or 11 amino acid residues), 49-53 (L2(λ) consisting of 3 residues), and 90-96 (L3(λ) consisting of 6 residues) (Morea et al., 2000. Methods. 20(3):267-79).

[0062] The first, second, and third hypervariable loops of the Vκ light chain domain are referred to herein as L1(κ), L2(κ), and L3(κ), and V LDomains can be defined as containing 25-33 (L1(κ) consisting of 6, 7, 8, 11, 12, or 13 residues), 49-53 (L2(κ) consisting of 3 residues), and 90-97 (L3(κ) consisting of 6 residues) (Morea et al., 2000. Methods. 20(3):267-79).

[0063] V H The first, second and third hypervariable loops of the domain are referred to herein as H1, H2 and H3, and V H Domains can be defined as including 25-33 (H1, consisting of 7, 8 or 9 residues), 52-56 (H2, consisting of 3 or 4 residues) and 91-105 (H3, highly variable in length) (Morea et al., 2000. Methods. 20(3):267-79).

[0064] Unless otherwise indicated, the terms L1, L2, and L3 refer to V L The terms H1, H2, and H3 refer to the first, second, and third hypervariable loops of the Vκ and Vλ domains and include hypervariable loops from both Vκ and Vλ isotypes. H "Hypervariable loops" refers to the first, second, and third hypervariable loops of a domain and includes hypervariable loops from any of the known heavy chain isotypes, including gamma (γ), mu (μ), alpha (α), delta (δ), or epsilon (ε). Hypervariable loops L1, L2, L3, H1, H2, and H3 may each comprise a portion of a "complementarity determining region" or "CDR," as defined above.

[0065] "Treating" or "Cure" or "Palliation" As used herein, the terms "treating" or "treatment" or "palliative" refer to therapeutic treatments, excluding prophylactic or preventative treatments, where the objective is to slow down (reduce) the target pathological condition or disorder. Those in need of treatment include those who already have the disorder and those suspected of having the disorder. A subject is one who, after administering a therapeutic amount of an isolated antibody or binding fragment thereof, nucleic acid, expression vector, composition, pharmaceutical composition or medicament of the invention, demonstrates that the patient has one of the following: CD45RC 高 Decreased number of CD45RC cells 高 Successful "treatment" of a target pathological condition or disorder is achieved when there is an observable and / or measurable reduction or absence of one or more of the following: a reduction in the proportion of total cells that are resistant to steroids; a reduction to some extent in one or more of the symptoms associated with a particular disease or condition; a reduction in morbidity and mortality; and / or an improvement in quality of life issues. The above parameters for assessing successful disease treatment and amelioration are readily measurable by routine procedures familiar to physicians. DETAILED DESCRIPTION OF THE INVENTION

[0066] Detailed Description The present invention relates to isolated antibodies or binding fragments thereof that bind to human CD45RC (hCD45RC).

[0067] As used herein, an "isolated antibody" is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds hCD45RC is substantially free of antibodies that specifically bind to antigens other than hCD45RC). However, an isolated antibody that specifically binds hCD45RC may have cross-reactivity to other antigens, such as CD45RC molecules from other species. Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals, particularly, but not limited to, enzymes, hormones, and other proteinaceous or non-proteinaceous components, that would interfere with diagnostic or therapeutic uses of the antibody.

[0068] In one embodiment, the isolated antibody or binding fragment thereof is purified.

[0069] In one embodiment, the isolated antibody or binding fragment thereof comprises: (1) 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95% or more by weight of the antibody or binding fragment thereof, as determined by the Lowry method, and most preferably 96%, 97%, 98%, or 99% or more by weight; (2) sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence using a spinning cup sequenator; or (3) Homogeneity as demonstrated by SDS-PAGE under reducing or non-reducing conditions, Coomassie blue, or, preferably, silver staining. It is refined to

[0070] In one embodiment, an antibody or binding fragment thereof according to the invention binds to the extracellular domain of hCD45RC. In one embodiment, an antibody or binding fragment thereof according to the invention binds to at least one epitope present on the extracellular domain of hCD45RC.

[0071] In one embodiment, an antibody or binding fragment thereof according to the invention binds to a C determinant encoded by exon 6 of hCD45. In one embodiment, an antibody or binding fragment thereof according to the invention binds to at least one epitope on a C determinant encoded by exon 6 of hCD45.

[0072] In one embodiment, the amino acid sequence of the C determinant encoded by exon 6 of hCD45 comprises or consists of SEQ ID NO: 23. In one embodiment, the nucleic acid sequence of exon 6 encoding the C determinant of hCD45 comprises or consists of SEQ ID NO: 24. SEQ ID NO: 23 DVPGERSTASTFPTDPVSPLTTTLSLAHHSSAALPARTSNTTITANTS SEQ ID NO: 24 GAtgtcccaggagagaggagtacagccagcacctttcctacagacccagtttccccattgacaaccaccctcagccttgcacaccacagctctgctgccttacctgcacgcacctccaacaccaccatcacagcgaacacctcA

[0073] In one embodiment, the antibody or binding fragment thereof according to the invention binds to at least one epitope comprising or consisting of SEQ ID NO: 23 or a fragment thereof.

[0074] In one embodiment, an antibody or binding fragment thereof of the invention binds to at least one epitope comprising or consisting of a sequence sharing at least about 70%, preferably at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 23 or a fragment thereof.

[0075] In one embodiment, the antibody or binding fragment thereof according to the invention binds to at least one epitope comprising or consisting of SEQ ID NO: 24 or a fragment thereof.

[0076] In one embodiment, an antibody or binding fragment thereof of the invention binds to at least one epitope encoded by a nucleic acid sequence comprising or consisting of a sequence sharing at least about 70%, preferably at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 24 or a fragment thereof.

[0077] In one embodiment, an antibody or binding fragment thereof of the invention binds to at least one epitope comprising or consisting of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, or 47 amino acids of SEQ ID NO: 23 or a fragment thereof; or a sequence sharing at least about 70%, preferably at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more with SEQ ID NO: 23 or a fragment thereof.

[0078] In one embodiment, an antibody or binding fragment thereof of the invention binds to at least one epitope comprising or consisting of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 or 47 consecutive amino acids of SEQ ID NO: 23 or a fragment thereof; or a sequence sharing at least about 70%, preferably at least 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more identity to SEQ ID NO: 23 or a fragment thereof.

[0079] In one embodiment, at least one epitopic fragment comprising or consisting of SEQ ID NO: 23 comprises or consists of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 or 47 amino acid residues.

[0080] In one embodiment, the at least one epitopic fragment comprising or consisting of SEQ ID NO: 23 is selected from the group consisting of 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, , 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 73, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100 or more consecutive In some embodiments, the amino acid sequence comprises or consists of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46 or 47 amino acid residues spread across a span of amino acid residues.

[0081] In one embodiment, the sequence comprising SEQ ID NO: 23 is the sequence of hCD45 set forth in SEQ ID NO: 99, which corresponds to UniProt accession number P08575-3 (Version 3 amended on March 28, 2018 - Checksum: 6E942E2BF6B17AC5). SEQ ID NO: 99 (SEQ ID NO: 23 is underlined) MTMYLWLKLLAFGFAFLDTEVFVTGQSPTPSPTGLTTAKMPSVPLSSDPLPTHTTAFSPASTFERENDFSETTTSLSPDNTSTQVSPDSLDNASAFNTTGVSSVQTPHLPTHADSQTPSAGTDTQTFSGSAANAKLNPTPGSNAIS DVPGERSTASTFPTDPVSPLTTTLSLAHHSSAALPARTSNTTITANTS

[0082] In one embodiment, the sequence comprising SEQ ID NO: 23 is the sequence of hCD45 set forth in SEQ ID NO: 104, which corresponds to UniProt accession number P08575-10 (Version 10 amended on March 28, 2018 - Checksum: F92C874C9A114890). SEQ ID NO: 104 (SEQ ID NO: 23 is underlined) MTMYLWLKLLAFGFAFLDTEVFVTGQSPTPSPT DVPGERSTASTFPTDPVSPLTTTLSLAHHSSAALPARTSNTTITANTS

[0083] In one embodiment, an antibody or binding fragment thereof according to the invention does not bind to the A determinant encoded by exon 4 of hCD45. In one embodiment, an antibody or binding fragment thereof according to the invention does not bind to at least one epitope on the A determinant encoded by exon 4 of hCD45.

[0084] In one embodiment, the amino acid sequence of the A determinant encoded by exon 4 of hCD45 comprises or consists of SEQ ID NO:105. SEQ ID NO: 105 GLTTAKMPSVPLSSDPLPTHTTAFSPASTFERENDFSETTTSLSPDNTSTQVSPDSLDNASAFNTT

[0085] In one embodiment, an antibody or binding fragment thereof according to the invention does not bind to a B determinant encoded by exon 5 of hCD45. In one embodiment, an antibody or binding fragment thereof according to the invention does not bind to at least one epitope on a B determinant encoded by exon 5 of hCD45.

[0086] In one embodiment, the amino acid sequence of the B determinant encoded by exon 5 of hCD45 comprises or consists of SEQ ID NO:106. SEQ ID NO: 106 GVSSVQTPHLPTHADSQTPSAGTDTQTFSGSAANAKLNPTPGSNAIS

[0087] In one embodiment, an antibody or binding fragment thereof according to the invention does not bind to hCD45RA. In one embodiment, an antibody or binding fragment thereof according to the invention does not bind to at least one epitope of hCD45RA.

[0088] In one embodiment, the amino acid sequence of hCD45RA comprises or consists of SEQ ID NO: 107 (Version 8 amended on March 28, 2018 - Checksum: F42C1FEC9EDE4BC0), which corresponds to UniProt accession number P08575-8. SEQ ID NO: 107

[0089] In one embodiment, the antibody or binding fragment thereof according to the invention does not bind to hCD45RB. In one embodiment, the antibody or binding fragment thereof according to the invention does not bind to at least one epitope of hCD45RB.

[0090] In one embodiment, the amino acid sequence of hCD45RB comprises or consists of SEQ ID NO: 108, which corresponds to UniProt accession number P08575-9 (Version 9 amended on March 28, 2018 - Checksum: 745870037910C575). SEQ ID NO: 108

[0091] In one embodiment, the antibody or binding fragment thereof according to the invention does not bind to hCD45RAB. In one embodiment, the antibody or binding fragment thereof according to the invention does not bind to at least one epitope of hCD45RAB.

[0092] In one embodiment, the amino acid sequence of hCD45RAB comprises or consists of SEQ ID NO: 109 (Version 5 amended on March 28, 2018 - Checksum: EA40BE995CD98F7C), which corresponds to UniProt accession number P08575-5. SEQ ID NO: 109

[0093] In one embodiment, an antibody or binding fragment thereof according to the invention does not bind to hCD45R0.In one embodiment, an antibody or binding fragment thereof according to the invention does not bind to at least one epitope of hCD45R0.

[0094] In one embodiment, the amino acid sequence of hCD45R0 comprises or consists of SEQ ID NO: 110 (Version 4 amended on March 28, 2018 - Checksum: D3CB364EF4243384), which corresponds to UniProt accession number P08575-4. SEQ ID NO: 110

[0095] In one embodiment, at least one epitope is a conformational epitope. In another embodiment, at least one epitope is a continuous epitope.

[0096] In one embodiment, the antibody or binding fragment thereof of the invention is about 5×10 -7 M or less, preferably about 2.5 × 10 -7 M or less, approximately 1×10 -7 M or less, approximately 7.5 x 10 -8 M or less, about 5 x 10 -8 M or less, approximately 1×10 -8 The equilibrium dissociation constant (K d ) binds to hCD45RC.

[0097] In one embodiment, the antibody or binding fragment thereof of the invention is administered in a concentration of about 1×10 4 M -1 seconds -1 or more, preferably about 5 × 10 4 M -1 seconds -1 More than 1 × 10 5 M -1 seconds -1 That's about 2.5 x 10 5 M -1 seconds -1 That's about 5 x 10 5 M -1 seconds -1 Association rate (K on ) binds to hCD45RC.

[0098] In one embodiment, the antibody or binding fragment thereof of the invention is about 5×10 -2 seconds -1 Less than or equal to about 4 x 10 -2 seconds -1 Below, approximately 3×10 -2 seconds -1 Below, approximately 2×10 -2 seconds -1 Below, approximately 1.5×10 -2 seconds -1 The following dissociation rate (K off ) binds to hCD45RC.

[0099] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: -About 5×10 -7 M or less, preferably about 2.5 × 10 -7 M or less, approximately 1×10 -7 M or less, approximately 7.5 x 10 -8 M or less, about 5 x 10 -8 M or less, approximately 1×10 -8 The equilibrium dissociation constant (K d ); -About 1×10 4 M -1 seconds -1 or more, preferably about 5 × 10 4 M -1 seconds -1 More than 1 × 10 5 M -1 seconds -1 That's about 2.5 x 10 5 M -1 seconds -1 That's about 5 x 10 5 M -1 seconds -1 Association rate (K on ); -About 5×10 -2 seconds -1 Less than or equal to about 4 x 10 -2 seconds -1 Below, approximately 3×10 -2 seconds -1 Below, approximately 2×10 -2 seconds -1 Below, approximately 1.5×10 -2 seconds -1 The following dissociation rate (K off ) At least one, preferably at least two, more preferably three of the above bind to hCD45RC.

[0100] Methods for determining the affinity of an antibody or binding fragment thereof for its ligand (e.g., K d , K. off and K. onMethods for determining the activity of a protein (including determining the activity of a protein) are well known in the art and include, but are not limited to, surface plasmon resonance (SPR), fluorescence activated cell sorting (FACS), enzyme-linked immunosorbent assay (ELISA), AlphaLISA, and KinExA.

[0101] A preferred method is BIAcore®, which relies on SPR using immobilized CD45RC to determine the affinity of an antibody or binding fragment thereof. How to perform this method is further described in the Examples section.

[0102] In one embodiment, the antibody or binding fragment thereof according to the invention is a polyclonal antibody or binding fragment thereof.

[0103] In a preferred embodiment, the antibody or binding fragment thereof according to the invention is a monoclonal antibody or binding fragment thereof.

[0104] In one embodiment, the antibody or binding fragment thereof of the present invention is a molecule selected from the group comprising or consisting of a whole antibody, a single chain antibody, a dimeric single chain antibody, a single domain antibody, an Fv, a Fab, a Fab', a Fab'-SH, a F(ab)'2, a Fd, a defucosylated antibody, a bispecific antibody, a diabody, a triabody, and a tetrabody.

[0105] As used herein, the term "binding fragment" refers to a portion or region of an antibody of the present invention, which contains fewer amino acid residues than the whole antibody. A "binding fragment" binds to an antigen and / or competes with the derived whole antibody for antigen binding (e.g., specific binding to human CD45RC). Antibody-binding fragments include, but are not limited to, single-chain antibodies, Fv, Fab, Fab', Fab'-SH, F(ab)'2, Fd, defucosylated antibodies, diabodies, triabodies, and tetrabodies.

[0106] As used herein, "single-chain antibody" refers to any antibody or binding fragment thereof that is a protein having a primary structure comprising or consisting of a single uninterrupted sequence of contiguous amino acid residues, including, but not limited to, (1) a single-chain Fv molecule (scFv); (2) a single-chain protein comprising only one light-chain variable domain, or a fragment thereof comprising the three CDRs of the light-chain variable domain, without the associated heavy-chain portion; and (3) a single-chain protein comprising only one heavy-chain variable region, or a fragment thereof comprising the three CDRs of the heavy-chain variable region, without the associated light-chain portion.

[0107] "Single-chain Fv," also abbreviated as "sFv" or "scFv," is a Fv consisting of V linked to a single amino acid chain. H and V L scFv refers to an antibody fragment that contains an antibody domain. Preferably, the scFv amino acid sequence contains a V domain that enables the scFv to form the desired structure for antigen binding. H Domains and V L It further contains a peptide linker between the domains (Pluckthun, 1994. Antibodies from Escherichia coli. In Rosenberg & Moore (eds.), The pharmacology of monoclonal antibodies. Handbook of Experimental Pharmacology, 113:269-315. Springer: Berlin, Heidelberg).

[0108] As used herein, "Fv" refers to the minimum antibody fragment containing a complete antigen-recognition and antigen-binding site. This fragment consists of a dimer of one HCVR and one LCVR in tight, non-covalent association. The folding of these two domains results in six hypervariable loops (three loops each from the heavy chain and light chain) that contribute to antigen binding and confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv containing only three antigen-specific CDRs) has the ability to recognize and bind antigen, although with lower affinity than the entire binding site.

[0109] As used herein, "diabody" refers to small antibody fragments prepared by constructing scFv fragments with a short linker (approximately 5-10 residues) between the HCVR and LCVR such that intrachain, rather than interchain, pairing of the variable domains is achieved, resulting in a bivalent fragment, i.e., a fragment with two antigen-binding sites. Bispecific diabodies are heterodimers of two "crossover" scFv fragments in which the HCVRs and LCVRs of the two antibodies are present on different polypeptide chains. Diabodies are more fully described in U.S. Patent EP 0 404 097, patent application WO 1993 011 161, and Holliger et al., 1993. Proc Natl Acad Sci USA. 90(14):6444-8.

[0110] Antibody-binding fragments can be obtained using standard methods. For example, Fab or F(ab')2 fragments can be produced by protease digestion of isolated antibodies in accordance with conventional techniques.

[0111] It will also be understood that the antibodies or binding fragments thereof of the present invention can be modified using known methods. For example, the antibodies or binding fragments thereof may be modified with polyethylene glycol (PEG) to slow in vivo clearance and achieve a more desirable pharmacokinetic profile. Methods for coupling and site-specifically attaching PEG to antibodies or binding fragments thereof are described, for example, in Leong et al., 2001. Cytokine. 16(3):106-19; Delgado et al., 1996. Br J Cancer. 73(2):175-82.

[0112] In one embodiment, the antibody or binding fragment thereof according to the invention is a molecule selected from the group comprising or consisting of unibodies, domain antibodies, and nanobodies.

[0113] "Unibody" is well known in the art and refers to an antibody fragment that lacks the hinge region of an IgG4 antibody. The deletion of the hinge region results in a molecule that is essentially half the size of a traditional IgG4 antibody and has a univalent binding region rather than the bivalent binding region of an IgG4 antibody.

[0114] The term "domain antibody" is well known in the art and refers to the smallest functional binding unit of an antibody, corresponding to the variable region of either the heavy or light chain of the antibody.

[0115] "Single domain antibodies" are well known in the art and refer to antibody-derived proteins that contain the unique structural and functional properties of naturally occurring heavy chain antibodies (Muyldermans, 2013. Annu Rev Biochem. 82:775-97). These heavy chain antibodies contain a single variable domain (V H H)—one such example is a Nanobody®—or one variable domain (V H H) and two constant domains (C H 2 and C H 3) - such as camel antibodies - or one variable domain (V H H) and five constant domains (C H 1. C H 2. C H 3. C H 4 and C H 5)-Shark antibodies etc.

[0116] In one embodiment, the antibody or binding fragment thereof of the present invention comprises or is a mimetic selected from the group consisting of an affibody, an affilin, an affitin, an adnectin, an atrimer, an evasin, a DARPin, an anticalin, an avimer, a fynomer, a versabody, and a duocalin.

[0117] "Affibody" is well known in the art and refers to an affinity protein based on a protein domain of 58 amino acid residues derived from one of the IgG-binding domains of Staphylococcus aureus protein A (Frejd & Kim, 2017. Exp Mol Med. 49(3):e306; U.S. Pat. No. 5,831,012).

[0118] "DARPin" (designed ankyrin repeat protein) is well known in the art and refers to antibody mimetic DRP (designed repeat protein) technology developed to exploit the binding capacity of non-antibody proteins (Binz et al., 2003. J Mol Biol. 332(2):489-503; Pluchthun, 2015. Annu Rev Pharmacol Toxicol. 55:489-511).

[0119] "Anticalins" are well known in the art and refer to another antibody mimetic technology in which the binding specificity is derived from lipocalins (Skerra, 2008. FEBS J. 275(11):2677-83). Anticalins may also be formatted as dual-targeting proteins called "duocalins" (Schlehuber & Skerra, 2001. Biol Chem. 382(9):1335-42).

[0120] "Avimer" is well known in the art and refers to another antibody mimetic technology (Silverman et al., 2005. Nat Biotechnol. 23(12):1556-61).

[0121] "Versabodies" are well known in the art and refer to another antibody mimetic technology (U.S. Patent Application No. 20070191272). They are small 3-5 kDa proteins with more than 15% cysteines forming a high disulfide density scaffold, replacing the hydrophobic core found in typical proteins. Replacing the many hydrophobic amino acids comprising the hydrophobic core with a small number of disulfides results in proteins that are smaller, more hydrophilic (less aggregation and nonspecific binding), more resistant to proteases and heat, and have a lower density of T cell epitopes because the residues most responsible for MHC presentation are hydrophobic. All four of these properties are well known to affect immunogenicity, and they are expected to cause a significant decrease in immunogenicity.

[0122] In one embodiment, antibodies or binding fragments thereof according to the present invention also include multispecific antibodies or binding fragments thereof, i.e., immunospecific for two or more, such as at least two, different antigens, one of which is hCD45RC according to the present invention.

[0123] In one embodiment, the antibody or binding fragment thereof according to the present invention also encompasses polymers of antibodies or binding fragments thereof, i.e., two or more, such as at least two, antibodies or binding fragments thereof, whether identical or different, that are directly or indirectly covalently linked to each other.

[0124] In one embodiment, the antibody or binding fragment thereof of the present invention is an immunoconjugate comprising said antibody or binding fragment thereof, which is further conjugated to a therapeutic agent.

[0125] In one embodiment, the antibody or binding fragment thereof according to the invention is a conjugate comprising said antibody or binding fragment thereof further conjugated to an imaging agent, said conjugate being usable, for example, for imaging applications.

[0126] Hereinafter, unless otherwise explicitly stated, the numbering and definition of the CDRs follows the Kabat / Chocia definition.

[0127] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a heavy chain variable region (herein referred to as HCVR or VCR) comprising at least one, preferably at least two, more preferably the following three complementarity determining regions (CDRs): H (abbreviated as ): V H - CDR1: NYYIG (SEQ ID NO: 1); V H -CDR2:X1-IF-X2-GG-X3-Y-X4-N-X5-X6-X7-X8-X9-X 10 -G (SEQ ID NO: 2); and V H - CDR3: RNFDY (SEQ ID NO: 3), X1 is selected from Asp (D), Ile (I) and Arg (R); X2 is selected from Pro (P) and Ser (S); X3 is selected from Asp (D), Ser (S) and Gly (G); X4 is selected from Ala (A) and Thr (T); X5 is selected from Ser (S) and Tyr (Y); X6 is selected from Asn (N), Ala (A), and Ser (S); X7 is selected from Glu(E), Asp(D), Pro(P) and Gln(Q); X8 is selected from Lys (K) and Ser (S); X9 is selected from Phe (F) and Val (V); and X 10 is selected from Lys (K) and Gln (Q).

[0128] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H -CDR2:X1-IF-X2-GG-X3-Y-X4-N-X5-X6-X7-X8-X9-X 10 -G (SEQ ID NO: 2); and VH - CDR3: RNFDY (SEQ ID NO: 3), Contains DIFPGGDYANSNEKFKG, X1 is selected from Asp (D), Ile (I) and Arg (R); X2 is selected from Pro (P) and Ser (S); X3 is selected from Asp (D), Ser (S) and Gly (G); X4 is selected from Ala (A) and Thr (T); X5 is selected from Ser (S) and Tyr (Y); X6 is selected from Asn (N), Ala (A), and Ser (S); X7 is selected from Glu(E), Asp(D), Pro(P) and Gln(Q); X8 is selected from Lys (K) and Ser (S); X9 is selected from Phe (F) and Val (V); and X 10 is selected from Lys (K) and Gln (Q).

[0129] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGDYANSNEKFKG (SEQ ID NO: 4); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0130] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGDYANSNEKFKG (SEQ ID NO: 4); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0131] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGDYANSNEKVKG (SEQ ID NO: 5); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0132] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGDYANSNEKVKG (SEQ ID NO: 5); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0133] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGGYTNYAEKFQG (SEQ ID NO: 6); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0134] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGGYTNYAEKFQG (SEQ ID NO: 6); and V H- CDR3: RNFDY (SEQ ID NO: 3).

[0135] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGSYTNYSESFQG (SEQ ID NO: 7); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0136] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGSYTNYSESFQG (SEQ ID NO: 7); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0137] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGSYTNYADSVKG (SEQ ID NO: 8); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0138] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGSYTNYADSVKG (SEQ ID NO: 8); and VH - CDR3: RNFDY (SEQ ID NO: 3).

[0139] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: RIFPGGGYTNYAQKFQG (SEQ ID NO: 9); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0140] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: RIFPGGGYTNYAQKFQG (SEQ ID NO: 9); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0141] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: IIFPGGSYTNYSPSFQG (SEQ ID NO: 10); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0142] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: IIFPGGSYTNYSPSFQG (SEQ ID NO: 10); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0143] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFSGGSYTNYADSVKG (SEQ ID NO: 11); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0144] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFSGGSYTNYADSVKG (SEQ ID NO: 11); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0145] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGDYTNYAEKFQG (SEQ ID NO: 100); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0146] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGDYTNYAEKFQG (SEQ ID NO: 100); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0147] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGGYANYAEKFQG (SEQ ID NO: 116); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0148] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGGYANYAEKFQG (SEQ ID NO: 116); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0149] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H - CDR2: DIFPGGGYTNYAEKFKG (SEQ ID NO: 117); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0150] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H- CDR2: DIFPGGGYTNYAEKFKG (SEQ ID NO: 117); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0151] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGGYTNYNEKFQG (SEQ ID NO: 118); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0152] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGGYTNYNEKFQG (SEQ ID NO: 118); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0153] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H CDR2: DIFPGGGYTNSAEKFQG (SEQ ID NO: 119); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0154] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); VH CDR2: DIFPGGGYTNSAEKFQG (SEQ ID NO: 119); and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0155] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a light chain variable region (herein referred to as LCVR or V) comprising at least one, preferably at least two, more preferably the following three complementarity determining regions (CDRs): L (abbreviated as ): V L -CDR1:X 11 -ASSSVS-X 12 -YMH(SEQ ID NO:12); V L -CDR2:X 13 -TSN-X 14 -X 15 -X 16 (SEQ ID NO: 13); and V L -CDR3:X 17 -QRSSYPLTF (SEQ ID NO: 14), X 11 is selected from Ser (S) and Arg (R); X 12 is selected from Asn (N), Ser (S) and Gly (G); X 13 is selected from Asn (N) and Ala (A); or X 13 is any amino acid other than Ala (A) or Asn (N); X 14 is selected from Leu (L), Ser (S) and Arg (R); X 15 is selected from Pro (P), Ala (A) and Gln (Q); X 16 is selected from Ser (S) and Thr (T); and X 17 is selected from Gln (Q) and His (H).

[0156] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:X 11 -ASSSVS-X 12 -YMH(SEQ ID NO:12); V L -CDR2:X 13 -TSN-X 14 -X 15 -X 16 (SEQ ID NO: 13); and V L -CDR3:X 17 -QRSSYPLTF (SEQ ID NO: 14), X 11 is selected from Ser (S) and Arg (R); X 12 is selected from Asn (N), Ser (S) and Gly (G); X 13 is selected from Asn (N) and Ala (A); or X 13 is any amino acid other than Ala (A) or Asn (N); X 14 is selected from Leu (L), Ser (S) and Arg (R); X 15 is selected from Pro (P), Ala (A) and Gln (Q); X 16 is selected from Ser (S) and Thr (T); and X 17 is selected from Gln (Q) and His (H).

[0157] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three complementarity determining regions (CDRs): V L -CDR1:X 11 -ASSSVS-X 12 -YMH(SEQ ID NO:12); V L -CDR2:X 13 -TSN-X 14 -X15 -X 16 (SEQ ID NO: 13); and V L -CDR3:X 17 -QRSSYPLTF (SEQ ID NO: 14), X 11 is Ser(S); X 12 is absent or selected from Asn (N), Ser (S) and Gly (G); X 13 is Asn(N); or X 13 is any amino acid other than Ala (A) or Asn (N); X 14 is Leu(L); X 15 is Pro(P); X 16 is Ser(S); and X 17 is Gln(Q).

[0158] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:X 11 -ASSSVS-X 12 -YMH(SEQ ID NO:12); V L -CDR2:X 13 -TSN-X 14 -X 15 -X 16 (SEQ ID NO: 13); and V L -CDR3:X 17 -QRSSYPLTF (SEQ ID NO: 14), X 11 is Ser(S); X 12 is absent or selected from Asn (N), Ser (S) and Gly (G); X 13 is Asn(N); or X 13 is any amino acid other than Ala (A) or Asn (N); X14 is Leu(L); X 15 is Pro(P); X 16 is Ser(S); and X 17 is Gln(Q).

[0159] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:SASSSVS-X 12 -YMH(SEQ ID NO:15); V L CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0160] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:SASSSVS-X 12 -YMH(SEQ ID NO:15); V L CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0161] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L - CDR1: SASSSVSYMH (SEQ ID NO: 15); VL CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0162] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L - CDR1: SASSSVSYMH (SEQ ID NO: 15); V L CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0163] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:SASSSVS-X 12 -YMH(SEQ ID NO:15); V L CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0164] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:SASSSVS-X 12 -YMH(SEQ ID NO:15); V L CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0165] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0166] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0167] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0168] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0169] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0170] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSN LPS (SEQ ID NO: 16); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0171] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L-CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0172] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0173] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0174] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0175] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0176] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0177] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: ATSNLQS (SEQ ID NO: 20); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0178] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: ATSNLQS (SEQ ID NO: 20); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0179] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: ATSNLQS (SEQ ID NO: 20); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0180] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: ATSNLQS (SEQ ID NO: 20); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0181] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: ATSNLQS (SEQ ID NO: 20); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0182] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: ATSNLQS (SEQ ID NO: 20); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0183] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L - CDR3: HQRSSYPLTF (SEQ ID NO: 21), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0184] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: VL -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L - CDR3: HQRSSYPLTF (SEQ ID NO: 21), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0185] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L - CDR3: HQRSSYPLTF (SEQ ID NO: 21).

[0186] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L - CDR3: HQRSSYPLTF (SEQ ID NO: 21).

[0187] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L- CDR3: HQRSSYPLTF (SEQ ID NO: 21), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0188] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNSPS (SEQ ID NO: 19); and V L - CDR3: HQRSSYPLTF (SEQ ID NO: 21), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0189] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNRAT (SEQ ID NO: 22); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0190] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNRAT (SEQ ID NO: 22); and VL - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0191] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: NTSNRAT (SEQ ID NO: 22); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0192] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: NTSNRAT (SEQ ID NO: 22); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0193] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNRAT (SEQ ID NO: 22); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0194] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: NTSNRAT (SEQ ID NO: 22); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0195] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: ATSNLPS (SEQ ID NO: 111); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0196] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: ATSNLPS (SEQ ID NO: 111); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0197] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: ATSNLPS (SEQ ID NO: 111); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0198] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L CDR2: ATSNLPS (SEQ ID NO: 111); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0199] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L CDR2: ATSNLPS (SEQ ID NO: 111); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0200] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V LCDR2: ATSNLPS (SEQ ID NO: 111); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0201] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:SASSSVS-X 12 -YMH(SEQ ID NO:15); V L CDR2: NTANLPS (SEQ ID NO: 120); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0202] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:SASSSVS-X 12 -YMH(SEQ ID NO:15); V L CDR2: NTANLPS (SEQ ID NO: 120); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X12 is absent or selected from Asn (N), Ser (S) and Gly (G).

[0203] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:SASSSVS-X 12 -YMH(SEQ ID NO:15); V LCDR2: NTANLPS (SEQ ID NO: 120); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0204] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:SASSSVS-X 12 -YMH(SEQ ID NO:15); V L CDR2: NTANLPS (SEQ ID NO: 120); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0205] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:SASSSVS-X 12 -YMH(SEQ ID NO:15); V L CDR2: NTANLPS (SEQ ID NO: 120); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0206] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:SASSSVS-X 12 -YMH(SEQ ID NO:15); V L CDR2: NTANLPS (SEQ ID NO: 120); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X12 is selected from Asn (N), Ser (S) and Gly (G).

[0207] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L -CDR2:X 13 -TSNLPS (SEQ ID NO: 127); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), and X 13 is any amino acid other than Ala (A) or Asn (N).

[0208] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L -CDR2:X 13 -TSNLPS (SEQ ID NO: 127); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), and X 13 is any amino acid other than Ala (A) or Asn (N).

[0209] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L-CDR2:X 13 -TSNLPS (SEQ ID NO: 127); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 13 is any amino acid other than Ala (A) or Asn (N).

[0210] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L - CDR1: RASSSVSYMH (SEQ ID NO: 18); V L -CDR2:X 13 -TSNLPS (SEQ ID NO: 127); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 13 is any amino acid other than Ala (A) or Asn (N).

[0211] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L -CDR2:X 13 -TSNLPS (SEQ ID NO: 127); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), and X 13 is any amino acid other than Ala (A) or Asn (N).

[0212] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following three CDRs: V L-CDR1:RASSSVS-X 12 -YMH(SEQ ID NO:18); V L -CDR2:X 13 -TSNLPS (SEQ ID NO: 127); and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17), X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), and X 13 is any amino acid other than Ala (A) or Asn (N).

[0213] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H -CDR2:X1-IF-X2-GG-X3-Y-X4-N-X5-X6-X7-X8-X9-X 10 -G (SEQ ID NO: 2); and V H CDR3: RNFDY (SEQ ID NO: 3); and - an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V L -CDR1:X 11 -ASSSVS-X 12 -YMH(SEQ ID NO:12); V L -CDR2:X 13 -TSN-X 14 -X 15 -X 16 (SEQ ID NO: 13); and V L -CDR3:X 17 -QRSSYPLTF (SEQ ID NO: 14), (X1 is selected from Asp (D), Ile (I) and Arg (R); X2 is selected from Pro (P) and Ser (S); X3 is selected from Asp (D), Ser (S) and Gly (G); X4 is selected from Ala (A) and Thr (T); X5 is selected from Ser (S) and Tyr (Y); X6 is selected from Asn (N), Ala (A), and Ser (S); X7 is selected from Glu(E), Asp(D), Pro(P) and Gln(Q); X8 is selected from Lys (K) and Ser (S); X9 is selected from Phe (F) and Val (V); X 10 is selected from Lys (K) and Gln (Q); X 11 is selected from Ser (S) and Arg (R); X 12 is selected from Asn (N), Ser (S) and Gly (G); X 13 is selected from Asn (N) and Ala (A); or X 13 is any amino acid other than Ala (A) or Asn (N); X 14 is selected from Leu (L), Ser (S) and Arg (R); X 15 is selected from Pro (P), Ala (A) and Gln (Q); X 16 is selected from Ser (S) and Thr (T); and X 17 is selected from Gln (Q) and His (H) Includes:

[0214] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: -HCVR containing the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1); V H -CDR2:X1-IF-X2-GG-X3-Y-X4-N-X5-X6-X7-X8-X9-X10 -G (SEQ ID NO: 2); and V H CDR3: RNFDY (SEQ ID NO: 3); and -LCVR containing the following three CDRs: V L -CDR1:X 11 -ASSSVS-X 12 -YMH(SEQ ID NO:12); V L -CDR2:X 13 -TSN-X 14 -X 15 -X 16 (SEQ ID NO: 13); and V L -CDR3:X 17 -QRSSYPLTF (SEQ ID NO: 14), (X1 is selected from Asp (D), Ile (I) and Arg (R); X2 is selected from Pro (P) and Ser (S); X3 is selected from Asp (D), Ser (S) and Gly (G); X4 is selected from Ala (A) and Thr (T); X5 is selected from Ser (S) and Tyr (Y); X6 is selected from Asn (N), Ala (A), and Ser (S); X7 is selected from Glu(E), Asp(D), Pro(P) and Gln(Q); X8 is selected from Lys (K) and Ser (S); X9 is selected from Phe (F) and Val (V); X 10 is selected from Lys (K) and Gln (Q); X 11 is selected from Ser (S) and Arg (R); X 12 is selected from Asn (N), Ser (S) and Gly (G); X 13 is selected from Asn (N) and Ala (A); or X 13 is any amino acid other than Ala (A) or Asn (N); X 14 is selected from Leu (L), Ser (S) and Arg (R); X 15 is selected from Pro (P), Ala (A) and Gln (Q); X 16 is selected from Ser (S) and Thr (T); and X 17 is selected from Gln (Q) and His (H) Includes:

[0215] In one embodiment, an antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of at least one, preferably at least two, more preferably three HCVRs, and (ii) the CDRs of at least one, preferably at least two, more preferably three LCVRs, wherein said combinations are as defined in Table 2.

[0216] In one embodiment, an antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combinations being as defined in Table 2.

[0217] Table 2. Preferred combinations of CDRs of HCVRs and CDRs of LCVRs. The CDRs are defined by their SEQ ID NOs (where applicable, X 12 is absent or selected from Asn (N), Ser (S) and Gly (G); 13 is any amino acid other than Ala (A) or Asn (N). [Table 2] TIFF0007796531000004.tif230162TIFF0007796531000005.tif122162

[0218] In one embodiment, V as defined above H -CDR1, V H -CDR2, V H -CDR3, VL -CDR1, V L CDR2 and / or V L - Any of the CDR3 can be characterized as having 1, 2, 3, 4, 5 or more amino acids substituted with different amino acids.

[0219] In one embodiment, V as defined above H -CDR1, V H -CDR2, V H -CDR3, V L -CDR1, V L CDR2 and / or V L - Any of the CDR3s may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a particular CDR or set of CDRs defined above.

[0220] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs, and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, said combinations being selected from combinations #1, #2, #7, #14, #20, #26, #49, #50, #63, #65, #72, #79, #86 and #92 as defined in Table 2.

[0221] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combinations being selected from combinations #1, #2, #7, #14, #20, #26, #49, #50, #63, #65, #72, #79, #86 and #92 as defined in Table 2.

[0222] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: -HCVR containing the following three CDRs: V in SEQ ID NO: 1 H -CDR1; V comprising or selected from the group consisting of SEQ ID NOs: 4, 5, 6, 7, 8, 100, 116, 117, 118 and 119 H -CDR2; and V in SEQ ID NO:3 H -CDR3; and -LCVR containing the following three CDRs: V comprising or selected from the group consisting of SEQ ID NOs: 15 and 18 L -CDR1(in the formula, X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist); V comprising or selected from the group consisting of SEQ ID NOs: 16, 111 and 120 L -CDR2; and V of SEQ ID NO: 17 L -CDR3, Includes:

[0223] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: -HCVR containing the following three CDRs: V in SEQ ID NO: 1 H -CDR1; V comprising or selected from the group consisting of SEQ ID NOs: 4 and 5 H -CDR2; and V in SEQ ID NO:3 H -CDR3; and -LCVR containing the following three CDRs: V of SEQ ID NO: 15 L -CDR1(in the formula, X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist); V of SEQ ID NO: 16 L -CDR2; and V of SEQ ID NO: 17 L -CDR3, Includes:

[0224] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: -HCVR containing the following three CDRs: V in SEQ ID NO: 1 H -CDR1; V selected from the group consisting of or including SEQ ID NOs: 4, 5, 6 and 100 H -CDR2; and VH-CDR3 of SEQ ID NO: 3; and -LCVR containing the following three CDRs: V comprising or selected from the group consisting of SEQ ID NOs: 15 and 18 L -CDR1(in the formula, X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist); V of SEQ ID NO: 16 L -CDR2; and V of SEQ ID NO: 17 L -CDR3, Includes:

[0225] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: -HCVR containing the following three CDRs: V in SEQ ID NO: 1 H -CDR1; V selected from the group consisting of or including SEQ ID NOs: 4, 6 and 100 H -CDR2; and VH-CDR3 of SEQ ID NO: 3; and -LCVR containing the following three CDRs: V comprising or selected from the group consisting of SEQ ID NOs: 15 and 18 L -CDR1(in the formula, X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist); V of SEQ ID NO: 16 L -CDR2; and V of SEQ ID NO: 17 L -CDR3, Includes:

[0226] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs, and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, said combination being combination #1 as defined in Table 2.

[0227] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #1 as defined in Table 2.

[0228] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 4 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 15, 16 and 17, and X of SEQ ID NO: 15 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0229] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, said combination being combination #2 as defined in Table 2.

[0230] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #2 as defined in Table 2.

[0231] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 4 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 18, 16 and 17; wherein X of SEQ ID NO: 1812 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0232] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs, and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, wherein said combination is combination #7 as defined in Table 2.

[0233] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #7 as defined in Table 2.

[0234] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 5 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 15, 16 and 17, and X of SEQ ID NO: 15 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0235] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, said combination being combination #14 as defined in Table 2.

[0236] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #14 as defined in Table 2.

[0237] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 6 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 18, 16 and 17, and X of SEQ ID NO: 18 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0238] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, said combination being combination #20 as defined in Table 2.

[0239] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #20 as defined in Table 2.

[0240] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 7 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 18, 16 and 17, and X of SEQ ID NO: 18 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0241] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, said combination being combination #26 as defined in Table 2.

[0242] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #26 as defined in Table 2.

[0243] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 8 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 18, 16 and 17, and X of SEQ ID NO: 18 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0244] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, said combination being combination #49 as defined in Table 2.

[0245] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #49 as defined in Table 2.

[0246] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 100 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 15, 16 and 17, and X of SEQ ID NO: 15 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0247] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, said combination being combination #50 as defined in Table 2.

[0248] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #50 as defined in Table 2.

[0249] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 100 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 18, 16 and 17, and X of SEQ ID NO: 18 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0250] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, wherein said combination is combination #63 as defined in Table 2.

[0251] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #63 as defined in Table 2.

[0252] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 100 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 18, 111 and 17, and wherein X of SEQ ID NO: 1812 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0253] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, wherein said combination is combination #65 as defined in Table 2.

[0254] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #65 as defined in Table 2.

[0255] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 116 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 18, 16 and 17, and X of SEQ ID NO: 18 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0256] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, wherein said combination is combination #72 as defined in Table 2.

[0257] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #72 as defined in Table 2.

[0258] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 117 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 18, 16 and 17, and X of SEQ ID NO: 18 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0259] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, said combination being combination #79 as defined in Table 2.

[0260] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #79 as defined in Table 2.

[0261] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 118 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 18, 16 and 17, and X of SEQ ID NO: 18 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0262] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, wherein said combination is combination #86 as defined in Table 2.

[0263] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #86 as defined in Table 2.

[0264] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 119 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 18, 16 and 17, and X of SEQ ID NO: 18 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0265] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, wherein said combination is combination #92 as defined in Table 2.

[0266] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of three HCVRs and (ii) the CDRs of three LCVRs, said combination being combination #92 as defined in Table 2.

[0267] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a combination of (i) the CDRs of the three HCVRs set forth as SEQ ID NOs: 1, 4 and 3, and (ii) the CDRs of the three LCVRs set forth as SEQ ID NOs: 15, 120 and 17, and X of SEQ ID NO: 15 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0268] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following framework regions (FRs): V H - FR1: QVQLQQSGAELVRPGTSVKMSCKAAGYTFT (SEQ ID NO: 25); V H -FR2:WVKQRPGHGLEWIG (SEQ ID NO: 26); V H -FR3:KATLTADTSSSTAYMQLSSLTSEDSAIYYCVR (SEQ ID NO: 27); V H - FR4:WGQGTTLTVSS (SEQ ID NO: 28).

[0269] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following four FRs: V H - FR1: QVQLQQSGAELVRPGTSVKMSCKAAGYTFT (SEQ ID NO: 25); V H -FR2:WVKQRPGHGLEWIG (SEQ ID NO: 26); V H -FR3:KATLTADTSSSTAYMQLSSLTSEDSAIYYCVR (SEQ ID NO: 27); V H - FR4:WGQGTTLTVSS (SEQ ID NO: 28).

[0270] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V H - FR1: QVQLVQSGAEVKKPGASVKVSCKASGYTFT (SEQ ID NO: 29); V H - FR2: WVRQAPGQGLEWIG (SEQ ID NO: 30); V H- FR3:RVTLTADTSISTAYMELSRLRSDDTVVYYCVR (SEQ ID NO: 31); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0271] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following four FRs: V H - FR1: QVQLVQSGAEVKKPGASVKVSCKASGYTFT (SEQ ID NO: 29); V H - FR2: WVRQAPGQGLEWIG (SEQ ID NO: 30); V H - FR3:RVTLTADTSISTAYMELSRLRSDDTVVYYCVR (SEQ ID NO: 31); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0272] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V H - FR1:EVQLVQSGAEVKKPGESLKISCKASGYTFT (SEQ ID NO: 33); V H - FR2: WVRQMPGKGLEWIG (SEQ ID NO: 34); V H - FR3: QVTLSADKSISTAYLQLSSLKASDTAMYYCVR (SEQ ID NO: 35); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0273] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following four FRs: V H - FR1:EVQLVQSGAEVKKPGESLKISCKASGYTFT (SEQ ID NO: 33); V H- FR2: WVRQMPGKGLEWIG (SEQ ID NO: 34); V H - FR3: QVTLSADKSISTAYLQLSSLKASDTAMYYCVR (SEQ ID NO: 35); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0274] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V H - FR1: QVQLVESGGGLVKPGGSLRLSCAASGYTFT (SEQ ID NO: 36); V H - FR2: WIRQAPGKGLEWIG (SEQ ID NO: 37); V H -FR3:RFTLSADTAKNSAYLQMNSLRAEDTAVYYCVR (SEQ ID NO: 38); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0275] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following four FRs: V H - FR1: QVQLVESGGGLVKPGGSLRLSCAASGYTFT (SEQ ID NO: 36); V H - FR2: WIRQAPGKGLEWIG (SEQ ID NO: 37); V H -FR3:RFTLSADTAKNSAYLQMNSLRAEDTAVYYCVR (SEQ ID NO: 38); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0276] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V H - FR1:EVQLVQSGAEVKKPGESLKISCKGSGYTFT (SEQ ID NO: 39); V H - FR2: WVRQMPGKGLEWIG (SEQ ID NO: 34); V H - FR3: QVTLSADKSISTAYLQLSSLKASDTAMYYCVR (SEQ ID NO: 35); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0277] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following four FRs: V H - FR1:EVQLVQSGAEVKKPGESLKISCKGSGYTFT (SEQ ID NO: 39); V H - FR2: WVRQMPGKGLEWIG (SEQ ID NO: 34); V H - FR3: QVTLSADKSISTAYLQLSSLKASDTAMYYCVR (SEQ ID NO: 35); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0278] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V H -FR1:QVQLVESGGGLVKPGGSLRLSCAASGFTFS (SEQ ID NO: 40); V H - FR2: WIRQAPGKGLEWIG (SEQ ID NO: 37); V H - FR3: RFTLSADTAKNSLYLQMNSLRAEDTAVYYCVR (SEQ ID NO: 41); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0279] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following four FRs: V H -FR1:QVQLVESGGGLVKPGGSLRLSCAASGFTFS (SEQ ID NO: 40); V H - FR2: WIRQAPGKGLEWIG (SEQ ID NO: 37); V H - FR3: RFTLSADTAKNSLYLQMNSLRAEDTAVYYCVR (SEQ ID NO: 41); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0280] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V H -FR1:EVQLVQSGAEVKKPGESLKISCKGSGYSFT (SEQ ID NO: 42); V H - FR2: WVRQMPGKGLEWIG (SEQ ID NO: 34); V H - FR3: QVTLSADKSISTAYLQLSSLKASDTAMYYCVR (SEQ ID NO: 35); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0281] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following four FRs: V H -FR1:EVQLVQSGAEVKKPGESLKISCKGSGYSFT (SEQ ID NO: 42); V H - FR2: WVRQMPGKGLEWIG (SEQ ID NO: 34); V H - FR3: QVTLSADKSISTAYLQLSSLKASDTAMYYCVR (SEQ ID NO: 35); V H- FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0282] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an HCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V H -FR1:QVQLVESGGGLVKPGGSLRLSCAASGFTFS (SEQ ID NO: 40); V H -FR2:WIRQAPGKGLEWVG (SEQ ID NO: 43); V H - FR3: RFTLSADTAKNSLYLQMNSLRAEDTAVYYCVR (SEQ ID NO: 41); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0283] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR comprising the following four FRs: V H -FR1:QVQLVESGGGLVKPGGSLRLSCAASGFTFS (SEQ ID NO: 40); V H -FR2:WIRQAPGKGLEWVG (SEQ ID NO: 43); V H - FR3: RFTLSADTAKNSLYLQMNSLRAEDTAVYYCVR (SEQ ID NO: 41); V H - FR4:WGQGTLVTVSS (SEQ ID NO: 32).

[0284] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V L - FR1:QIVLTQSPTIMSASPGEKVTITC (SEQ ID NO: 44); V L - FR2: WFQQKTGTSPRLWIY (SEQ ID NO: 45); V L -FR3:GVPARFSGSGSGTS-X 18 - SLTISRMEAEDAATYYC (SEQ ID NO: 46); V L - FR4:GAGTKLELK (SEQ ID NO: 47), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Tyr(Y).

[0285] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following four FRs: V L - FR1:QIVLTQSPTIMSASPGEKVTITC (SEQ ID NO: 44); V L - FR2: WFQQKTGTSPRLWIY (SEQ ID NO: 45); V L -FR3:GVPARFSGSGSGTS-X 18 - SLTISRMEAEDAATYYC (SEQ ID NO: 46); V L - FR4:GAGTKLELK (SEQ ID NO: 47), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Tyr(Y).

[0286] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V L - FR1:DIQLTQSPSFLSASVGDRVTITC (SEQ ID NO: 48); V L - FR2: WFQQKPGKAPKLWIY (SEQ ID NO: 49); V L -FR3:GVPSRFSGSGSGTE-X 18 -TLTISSLQPEDFATYYC (SEQ ID NO: 50); VL - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Tyr(Y).

[0287] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an LCVR comprising the following four FRs: V L - FR1:DIQLTQSPSFLSASVGDRVTITC (SEQ ID NO: 48); V L - FR2: WFQQKPGKAPKLWIY (SEQ ID NO: 49); V L -FR3:GVPSRFSGSGSGTE-X 18 -TLTISSLQPEDFATYYC (SEQ ID NO: 50); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Tyr(Y).

[0288] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V L -FR1:EIVLTQSPDFQSVTPKEKVTITC (SEQ ID NO: 52); V L - FR2: WFQQKPDQSPKLWIY (SEQ ID NO: 53); V L -FR3:GVPSRFSGSGSGTD-X 18 -TLTINSLEAEDAATYYC (SEQ ID NO: 54); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18is Tyr(Y).

[0289] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising the four following FRs: V L -FR1:EIVLTQSPDFQSVTPKEKVTITC (SEQ ID NO: 52); V L - FR2: WFQQKPDQSPKLWIY (SEQ ID NO: 53); V L -FR3:GVPSRFSGSGSGTD-X 18 -TLTINSLEAEDAATYYC (SEQ ID NO: 54); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Tyr(Y).

[0290] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V L -FR1:EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 55); V L - FR2: WFQQKPGQAPRLWIY (SEQ ID NO: 56); V L -FR3:GIPARFSGSGSGTD-X 18 -TLTISSLEPEDFAVYYC (SEQ ID NO: 57); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Tyr(Y).

[0291] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising the four following FRs: VL -FR1:EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 55); V L - FR2: WFQQKPGQAPRLWIY (SEQ ID NO: 56); V L -FR3:GIPARFSGSGSGTD-X 18 -TLTISSLEPEDFAVYYC (SEQ ID NO: 57); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Tyr(Y).

[0292] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V L - FR1:DIQLTQSPSFLSASVGDRVTITC (SEQ ID NO: 48); V L - FR2: WYQQKPGKAPKLWIY (SEQ ID NO: 58); V L -FR3:GVPSRFSGSGSGTE-X 18 -TLTISSLQPEDFATYYC (SEQ ID NO: 50); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Tyr(Y).

[0293] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising the four following FRs: V L - FR1:DIQLTQSPSFLSASVGDRVTITC (SEQ ID NO: 48); V L - FR2: WYQQKPGKAPKLWIY (SEQ ID NO: 58); V L -FR3:GVPSRFSGSGSGTE-X 18 -TLTISSLQPEDFATYYC (SEQ ID NO: 50); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Tyr(Y).

[0294] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V L - FR1:DIQLTQSPSFLSASVGDRVTITC (SEQ ID NO: 48); V L - FR2: WYQQKPGKAPKLWIY (SEQ ID NO: 58); V L -FR3:GVPSRFSGSGSGTE-X 18 -TLTISSLQPEDFATYYC (SEQ ID NO: 50); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Phe(F).

[0295] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising the four following FRs: V L - FR1:DIQLTQSPSFLSASVGDRVTITC (SEQ ID NO: 48); V L - FR2: WYQQKPGKAPKLWIY (SEQ ID NO: 58); V L -FR3:GVPSRFSGSGSGTE-X 18 -TLTISSLQPEDFATYYC (SEQ ID NO: 50); VL - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Phe(F).

[0296] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V L -FR1:EIVLTQSPDFQSVTPKEKVTITC (SEQ ID NO: 52); V L - FR2: WYQQKPDQSPKLWIY (SEQ ID NO: 59); V L -FR3:GVPSRFSGSGSGTD-X 18 -TLTINSLEAEDAATYYC (SEQ ID NO: 54); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Phe(F).

[0297] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising the four following FRs: V L -EIVLTQSPDFQSVTPKEKVTITC (SEQ ID NO: 52); V L - FR2: WYQQKPDQSPKLWIY (SEQ ID NO: 59); V L -GVPSRFSGSGSGTD-X 18 -TLTINSLEAEDAATYYC (SEQ ID NO: 54); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Phe(F).

[0298] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V L -FR1:EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 55); V L - FR2: WYQQKPGQAPRLWIY (SEQ ID NO: 60); V L -FR3:GIPARFSGSGSGTD-X 18 -TLTISSLEPEDFAVYYC (SEQ ID NO: 57); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Phe(F).

[0299] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising the four following FRs: V L -FR1:EIVLTQSPATLSLSPGERATLSC (SEQ ID NO: 55); V L - FR2: WYQQKPGQAPRLWIY (SEQ ID NO: 60); V L -FR3:GIPARFSGSGSGTD-X 18 -TLTISSLEPEDFAVYYC (SEQ ID NO: 57); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Phe(F).

[0300] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising at least one, preferably at least two, more preferably at least three, and even more preferably four of the following FRs: V L - FR1:DIQLTQSPSFLSASVGDRVTITC (SEQ ID NO: 48); V L - FR2: WFQQKPGKAPKLWIY (SEQ ID NO: 49); V L -FR3:GVPSRFSGSGSGTE-X 18 -TLTISSLQPEDFATYYC (SEQ ID NO: 50); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Phe(F).

[0301] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR comprising the four following FRs: V L - FR1:DIQLTQSPSFLSASVGDRVTITC (SEQ ID NO: 48); V L - FR2: WFQQKPGKAPKLWIY (SEQ ID NO: 49); V L -FR3:GVPSRFSGSGSGTE-X 18 -TLTISSLQPEDFATYYC (SEQ ID NO: 50); V L - FR4:GGGTKVEIK (SEQ ID NO: 51), X 18 is selected from Tyr (Y) and Phe (F), preferably X 18 is Phe(F).

[0302] In one embodiment, an antibody or binding fragment thereof of the present invention comprises a combination of (i) at least one, preferably at least two, more preferably at least three, and even more preferably four FRs of HCVRs and (ii) at least one, preferably at least two, more preferably at least three, and even more preferably four FRs of LCVRs, said combinations being as defined in Table 3.

[0303] In one embodiment, an antibody or binding fragment thereof according to the invention comprises a combination of (i) the FRs of four HCVRs and (ii) the FRs of four LCVRs, said combinations being as defined in Table 3.

[0304] Table 3. Preferred combinations of FRs of HCVRs and FRs of LCVRs. FRs are defined by their SEQ ID NOs (where applicable, X 18 is selected from Tyr (Y) and Phe (F). [Table 3] TIFF0007796531000007.tif71162

[0305] In one embodiment, V as defined above H -FR1, V H -FR2, V H -FR3, V H -FR4, V L -FR1, V L -FR2, V L -FR3 and / or V L Any of the -FR4s can be characterized as having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids substituted with different amino acids.

[0306] In one embodiment, V as defined above H -FR1, V H -FR2, V H -FR3, V H -FR4, V L -FR1, V L -FR2, VL -FR3 and / or V L Any of the -FR4s can be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a particular FR or set of FRs defined above.

[0307] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: The above V H -FR1, The above V H -CDR1, The above V H -FR2, The above V H -CDR2, The above V H -FR3, The above V H CDR3, and The above V H -FR4 It includes HCVRs that comprise or consist of:

[0308] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: V selected from SEQ ID NOs: 25, 29, 33, 36, 39, 40 and 42 H -FR1; V selected from SEQ ID NO: 1 H -CDR1; V selected from SEQ ID NOs: 26, 30, 34, 37 and 43 H -FR2; V selected from SEQ ID NO: 2 H -CDR2; V selected from SEQ ID NOs: 27, 31, 35, 38 and 41 H -FR3; V selected from SEQ ID NO: 3 H -CDR3; and V selected from SEQ ID NOs: 28 and 32 H -FR4 It includes HCVRs that comprise or consist of:

[0309] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: V selected from SEQ ID NOs: 25, 29, 33, 36, 39, 40 and 42 H -FR1; V selected from SEQ ID NO: 1 H -CDR1; V selected from SEQ ID NOs: 26, 30, 34, 37 and 43 H -FR2; V selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 100, 116, 117, 118 and 119 H -CDR2; V selected from SEQ ID NOs: 27, 31, 35, 38 and 41 H -FR3; V selected from SEQ ID NO: 3 H -CDR3; V selected from SEQ ID NOs: 28 and 32 H -FR4 It includes HCVRs that comprise or consist of:

[0310] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises V H -FR1, V H -CDR1, V H -FR2, V H -CDR2, V H -FR3, V H -CDR3 and V H -FR4 combinations, wherein said combinations are as defined in Table 4.

[0311] Table 4. Preferred HCVRs. The CDRs and FRs are defined by their SEQ ID NOs. The penultimate column refers to the SEQ ID NO of the entire HCVR. [Table 4]

[0312] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 61; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 61. SEQ ID NO: 61 QVQLQQSGAELVRPGTSVKMSCKAAGYTFTNYYIGWVKQRPGHGLEWIGDIFPGGDYANSNEKFKGKATLTADTSSSTAYMQLSSLTSEDSAIYYCVRRNFDYWGQGTTLTVSS

[0313] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 62; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 62. SEQ ID NO: 62 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGDYANSNEKFKGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0314] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 63; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 63. SEQ ID NO: 63 EVQLVQSGAEVKKPGESLKISCKASGYTFTNYYIGWVRQMPGKGLEWIGDIFPGGDYANSNEKFKGQVTLSADKSISTAYLQLSSLKASDTAMYYCVRRNFDYWGQGTLVTVSS

[0315] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 64; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 64. SEQ ID NO: 64 QVQLVESGGGLVKPGGSLRLSCAASGYTFTNYYIGWIRQAPGKGLEWIGDIFPGGDYANSNEKVKGRFTLSADTAKNSAYLQMNSLRAEDTAVYYCVRRNFDYWGQGTLVTVSS

[0316] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 65; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 65. SEQ ID NO: 65 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGYTNYAEKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0317] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 66; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 66. SEQ ID NO: 66 EVQLVQSGAEVKKPGESLKISCKGSGYTFTNYYIGWVRQMPGKGLEWIGDIFPGGSYTNYSESFQGQVTLSADKSISTAYLQLSSLKASDTAMYYCVRRNFDYWGQGTLVTVSS

[0318] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an HCVR comprising or consisting of SEQ ID NO: 67; or an HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 67. SEQ ID NO: 67 QVQLVESGGGLVKPGGSLRLSCAASGFTFSNYYIGWIRQAPGKGLEWIGDIFPGGSYTNYADSVKGRFTLSADTAKNSLYLQMNSLRAEDTAVYYCVRRNFDYWGQGTLVTVSS

[0319] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 68; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 68. SEQ ID NO: 68 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGRIFPGGGYTNYAQKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0320] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 69; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 69. SEQ ID NO: 69 EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYYIGWVRQMPGKGLEWIGIIFPGGSYTNYSPSFQGQVTLSADKSISTAYLQLSSLKASDTAMYYCVRRNFDYWGQGTLVTVSS

[0321] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 70; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 70. SEQ ID NO: 70 QVQLVESGGGLVKPGGSLRLSCAASGFTFSNYYIGWIRQAPGKGLEWVGDIFSGGSYTNYADSVKGRFTLSADTAKNSLYLQMNSLRAEDTAVYYCVRRNFDYWGQGTLVTVSS

[0322] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 101; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 101. SEQ ID NO: 101 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGDYTNYAEKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0323] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 121; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 121. SEQ ID NO: 121 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGYANYAEKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0324] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 122; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 122. SEQ ID NO: 122 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGYTNYAEKFKGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0325] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 123; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 123. SEQ ID NO: 123 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGYTNYNEKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0326] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises a HCVR comprising or consisting of SEQ ID NO: 124; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 124. SEQ ID NO: 124 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGYTNSAEKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0327] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: The above V L -FR1, The above V L -CDR1, The above V L -FR2, The above V L -CDR2, The above V L -FR3, The above V L CDR3, and The above V L -FR4, The present invention also includes an LCVR comprising or consisting of:

[0328] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: V selected from SEQ ID NOs: 44, 48, 52 and 55 L -FR1; V selected from SEQ ID NO: 12 L -CDR1; V selected from SEQ ID NOs: 45, 49, 53, 56, 58, 59 and 60 L -FR2; V selected from SEQ ID NO: 13 L -CDR2; V selected from SEQ ID NOs: 46, 50, 54 and 57 L -FR3; V selected from SEQ ID NO: 14 L -CDR3; V selected from SEQ ID NOs: 47 and 51 L -FR4 It includes HCVRs that comprise or consist of:

[0329] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: V selected from SEQ ID NOs: 44, 48, 52 and 55 L -FR1; V selected from SEQ ID NOs: 15 and 18 L -CDR1; V selected from SEQ ID NOs: 45, 49, 53, 56, 58, 59 and 60 L -FR2; V selected from SEQ ID NOs: 16, 19, 20, 22, 111 and 120 L -CDR2; V selected from SEQ ID NOs: 46, 50, 54 and 57 L -FR3; V selected from SEQ ID NOs: 17 and 21 L -CDR3; V selected from SEQ ID NOs: 47 and 51 L -FR4 It includes HCVRs that comprise or consist of:

[0330] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises V L -FR1, V L -CDR, V L -FR2, V L -CDR2, V L -FR3, V L -CDR3 and V L -FR4 combinations, said combinations being as defined in Table 5.

[0331] Table 5. Preferred LCVRs. CDRs and FRs are defined by their SEQ ID NOs. The penultimate column refers to the SEQ ID NO of the entire LCVR (X 12 is absent or selected from Asn (N), Ser (S), and Gly (G); and X 18 is selected from Tyr (Y) and Phe (F); and a preferred X 12 and X 18 has a second sequence number in which [Table 5]

[0332] In one embodiment, the antibody or binding fragment thereof according to the invention has the V L -FR1, V L -CDR, V L -FR2, V L -CDR2, V L -FR3, V L -CDR3 and V L -FR4 combination, 12 If does not exist, X 18 is Phe(F) (i.e., X12 is any of Asn (N), Ser (S) and Gly (G). In one embodiment, the antibody or binding fragment thereof of the present invention has V as defined above. L -FR1, V L -CDR, V L -FR2, V L -CDR2, V L -FR3, V L -CDR3 and V L -FR4 combination, 12 If does not exist, X 18 is selected from Tyr (Y) and Phe (F).

[0333] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 71. 12 is selected from Asn (N), Ser (S) and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 71. SEQ ID NO:71 QIVLTQSPTIMSASPGEKVTITCSASSSVS-X 12 -YMHWFQQKTGTSPRLWIYNTSNLPSGVPARFSGSGSGTSFSLTISRMEAEDAATYYCQQRSSYPLTFGAGTKLELK

[0334] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 72. 12 is selected from Asn (N), Ser (S) and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 72. SEQ ID NO:72 DIQLTQSPSFLSASVGDRVTITCSASSSVS-X 12 -YMHWFQQKPGKAPKLWIYNTSNLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0335] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 73. 12 is selected from Asn (N), Ser (S), and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 73. SEQ ID NO: 73 EIVLTQSPDFQSVTPKEKVTITCSASSSVS-X 12 -YMHWFQQKPDQSPKLWIYNTSNLPSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCQQRSSYPLTFGGGTKVEIK

[0336] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 74. 12 is selected from Asn (N), Ser (S) and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 74. SEQ ID NO:74 EIVLTQSPATLSLSPGERATLSCSASSSVS-X 12 -YMHWFQQKPGQAPRLWIYNTSNLPSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK

[0337] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 75. 12 is selected from Asn (N), Ser (S) and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 75. SEQ ID NO: 75 DIQLTQSPSFLSASVGDRVTITCRASSSVS-X 12 -YMHWYQQKPGKAPKLWIYNTSNLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0338] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 76. 12 is selected from Asn (N), Ser (S) and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 76. SEQ ID NO:76 EIVLTQSPDFQSVTPKEKVTITCRASSSVS-X 12 -YMHWYQQKPDQSPKLWIYNTSNSPSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCQQRSSYPLTFGGGTKVEIK

[0339] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 77. 12is selected from Asn (N), Ser (S) and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with a non-CDR region sequence of SEQ ID NO: 77. SEQ ID NO:77 EIVLTQSPATLSLSPGERATLSCRASSSVS-X 12 -YMHWFQQKPGQAPRLWIYNTSNLPSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK

[0340] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 78. 12 is selected from Asn (N), Ser (S) and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 78. SEQ ID NO:78 DIQLTQSPSFLSASVGDRVTITCRASSSVS-X 12 -YMHWYQQKPGKAPKLWIYATSNLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0341] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 79. 12 is selected from Asn (N), Ser (S), and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 79. SEQ ID NO:79 EIVLTQSPDFQSVTPKEKVTITCRASSSVS-X 12 -YMHWYQQKPDQSPKLWIYNTSNSPSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSSYPLTFGGGTKVEIK

[0342] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 80. 12 is selected from Asn (N), Ser (S) and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 80. SEQ ID NO: 80 EIVLTQSPATLSLSPGERATLSCRASSSVS-X 12 -YMHWYQQKPGQAPRLWIYNTSNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK

[0343] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 102. 12 is selected from Asn (N), Ser (S) and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 102. SEQ ID NO: 102 DIQLTQSPSFLSASVGDRVTITCRASSSVS-X 12 -YMHWFQQKPGKAPKLWIYNTSNLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0344] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 112. 12 is selected from Asn (N), Ser (S) and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 112. SEQ ID NO: 112 DIQLTQSPSFLSASVGDRVTITCRASSSVS-X 12 -YMHWYQQKPGKAPKLWIYATSNLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0345] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 125. 12 is selected from Asn (N), Ser (S) and Gly (G); or comprises an LCVR comprising or consisting of a non-CDR region sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 125. SEQ ID NO: 125 QIVLTQSPTIMSASPGEKVTITCSASSSVS-X 12 -YMHWFQQKTGTSPRLWIYNTANLPSGVPARFSGSGSGTSFSLTISRMEAEDAATYYCQQRSSYPLTFGAGTKLELK

[0346] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 128. 12 is selected from Asn (N), Ser (S), and Gly (G); and X 13is any amino acid other than Ala (A) or Asn (N); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 128. SEQ ID NO: 128 DIQLTQSPSFLSASVGDRVTITCRASSSVS-X 12 -YMHWYQQKPGKAPKLWIY-X 13 -TSNLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0347] In one embodiment, the antibody or binding fragment thereof of the present invention is selected from the group consisting of SEQ ID NOs: 71 to 80, 102, 112, 125 and 128 (wherein X 12 The LCVR includes an LCVR that contains or consists of (where 'is not present').

[0348] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 81; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 81. SEQ ID NO: 81 QIVLTQSPTIMSASPGEKVTITCSASSSVSYMHWFQQKTGTSPRLWIYNTSNLPSGVPARFSGSGSGTSYSLTISRMEAEDAATYYCQQRSSYPLTFGAGTKLELK

[0349] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 82; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 82. SEQ ID NO:82 DIQLTQSPSFLSASVGDRVTITCSASSSVSYMHWFQQKPGKAPKLWIYNTSNLPSGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0350] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 83; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 83. SEQ ID NO: 83 EIVLTQSPDFQSVTPKEKVTITCSASSSVSYMHWFQQKPDQSPKLWIYNTSNLPSGVPSRFSGSGSGTDYTLTINSLEAEDAATYYCQQRSSYPLTFGGGTKVEIK

[0351] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 84; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 84. SEQ ID NO:84 EIVLTQSPATLSLSPGERATLSCSASSSVSYMHWFQQKPGQAPRLWIYNTSNLPSGIPARFSGSGSGTDYTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK

[0352] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 85; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 85. SEQ ID NO: 85 DIQLTQSPSFLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKLWIYNTSNLPSGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0353] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 86; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 86. SEQ ID NO:86 EIVLTQSPDFQSVTPKEKVTITCRASSSVSYMHWYQQKPDQSPKLWIYNTSNSPSGVPSRFSGSGSGTFTLTINSLEAEDAATYYCQQRSSYPLTFGGGTKVEIK

[0354] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 87; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 87. SEQ ID NO:87 EIVLTQSPATLSLSPGERATLSCRASSSVSYMHWFQQKPGQAPRLWIYNTSNLPSGIPARFSGSGSGTDYTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEI

[0355] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 88; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 88. SEQ ID NO: 88 DIQLTQSPSFLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKLWIYATSNLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0356] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 89; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 89. SEQ ID NO:89 EIVLTQSPDFQSVTPKEKVTITCRASSSVSYMHWYQQKPDQSPKLWIYNTSNSPSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSSYPLTFGGGTKVEIK

[0357] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 90; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 90. SEQ ID NO: 90 EIVLTQSPATLSLSPGERATLSCRASSSVSYMHWYQQKPGQAPRLWIYNTSNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK

[0358] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 103; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 103. SEQ ID NO: 103 DIQLTQSPSFLSASVGDRVTITCRASSSVSSYMHWFQQKPGKAPKLWIYNTSNLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0359] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 113; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 113. SEQ ID NO: 113 DIQLTQSPSFLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKLWIYATSNLPSGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0360] In a preferred embodiment, the antibody or binding fragment thereof of the present invention comprises an LCVR comprising or consisting of SEQ ID NO: 126; or an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 126. SEQ ID NO: 126 QIVLTQSPTIMSASPGEKVTITCSASSSVSYMHWFQQKTGTSPRLWIYNTANLPSGVPARFSGSGSGTSYSLTISRMEAEDAATYYCQQRSSYPLTFGAGTKLEL

[0361] In a preferred embodiment, the antibody or binding fragment thereof according to the invention comprises an LCVR(X) comprising or consisting of SEQ ID NO: 129. 13 is any amino acid other than Ala (A) or Asn (N); or comprises an LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NO: 129. SEQ ID NO: 129 DIQLTQSPSFLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKLWIY-X 13 -TSNLPSGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0362] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: HCVR as defined above; and LCVR as defined above Includes:

[0363] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: - a HCVR selected from SEQ ID NOs: 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 101, 121, 122, 123, and 124; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NOs: 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 101, 121, 122, 123, or 124; and LCVR(X) selected from SEQ ID NOs: 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 102, 112, 125 and 128 12 is selected from Asn (N), Ser (S) and Gly (G), and X 13 is any amino acid other than Ala (A) or Asn (N); or a LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NOs: 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 102, 112, 125 and 128, Includes.

[0364] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: - a HCVR selected from SEQ ID NOs: 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 101, 121, 122, 123, and 124; or a HCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NOs: 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 101, 121, 122, 123, or 124; and LCVR(X) selected from SEQ ID NOs: 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 103, 113, 126 and 129 13 is any amino acid other than Ala (A) or Asn (N); or a LCVR comprising or consisting of a non-CDR region sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the non-CDR region sequence of SEQ ID NOs: 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 103, 113, 126 and 129, Includes.

[0365] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0366] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0367] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0368] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 74 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0369] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0370] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0371] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0372] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0373] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0374] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0375] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0376] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0377] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0378] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0379] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0380] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0381] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0382] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0383] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0384] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0385] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0386] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0387] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 80 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0388] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0389] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0390] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0391] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0392] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0393] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0394] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 74 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0395] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0396] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0397] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0398] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0399] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0400] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 80 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0401] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0402] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0403] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0404] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0405] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0406] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0407] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 74 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0408] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0409] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0410] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0411] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0412] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0413] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 80 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0414] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0415] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0416] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0417] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0418] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0419] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0420] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR (X) of SEQ ID NO: 74. 12 is selected from Asn (N), Ser (S) and Gly (G).

[0421] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0422] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0423] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0424] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0425] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0426] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 80 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0427] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0428] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0429] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0430] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0431] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0432] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0433] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 74 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0434] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0435] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0436] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0437] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0438] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0439] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 80 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0440] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0441] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0442] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0443] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0444] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0445] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0446] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 74 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0447] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0448] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0449] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0450] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0451] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0452] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0453] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0454] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0455] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0456] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0457] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0458] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0459] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0460] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0461] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0462] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0463] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0464] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0465] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR (X) of SEQ ID NO: 80. 12 is selected from Asn (N), Ser (S) and Gly (G).

[0466] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0467] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0468] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0469] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0470] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0471] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0472] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 74 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0473] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0474] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0475] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0476] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0477] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0478] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 80 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0479] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0480] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0481] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0482] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0483] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0484] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0485] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0486] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0487] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0488] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0489] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0490] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0491] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 80 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0492] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0493] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0494] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0495] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0496] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0497] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0498] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 74 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0499] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0500] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0501] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0502] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0503] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0504] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 80 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0505] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0506] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0507] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0508] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0509] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0510] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0511] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0512] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR (X) of SEQ ID NO: 75. 12 is selected from Asn (N), Ser (S) and Gly (G).

[0513] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0514] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0515] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0516] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0517] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0518] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0519] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0520] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0521] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0522] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0523] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0524] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 74 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0525] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0526] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0527] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0528] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0529] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0530] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 80 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0531] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0532] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0533] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0534] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0535] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0536] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0537] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 74 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0538] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0539] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0540] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0541] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0542] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0543] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR (X) of SEQ ID NO: 80. 12 is selected from Asn (N), Ser (S) and Gly (G).

[0544] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0545] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0546] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0547] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 71 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0548] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 72 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0549] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 73 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0550] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 74 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0551] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 75 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0552] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 76 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0553] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 77 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0554] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 78 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0555] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 79 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0556] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 80 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0557] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 102 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0558] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 112 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0559] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 125 (X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0560] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:81.

[0561] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:82.

[0562] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:83.

[0563] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:84.

[0564] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:85.

[0565] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:86.

[0566] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:87.

[0567] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:88.

[0568] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:89.

[0569] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:90.

[0570] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:103.

[0571] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:113.

[0572] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:61 and an LCVR of SEQ ID NO:126.

[0573] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:81.

[0574] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:82.

[0575] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:83.

[0576] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:84.

[0577] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:85.

[0578] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:86.

[0579] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:87.

[0580] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:88.

[0581] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:89.

[0582] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:90.

[0583] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:103.

[0584] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:113.

[0585] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:62 and an LCVR of SEQ ID NO:126.

[0586] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:81.

[0587] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:82.

[0588] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:83.

[0589] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:84.

[0590] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:85.

[0591] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:86.

[0592] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:87.

[0593] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:88.

[0594] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:89.

[0595] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:90.

[0596] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:103.

[0597] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:113.

[0598] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:63 and an LCVR of SEQ ID NO:126.

[0599] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:81.

[0600] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:82.

[0601] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:83.

[0602] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:84.

[0603] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:85.

[0604] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:86.

[0605] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:87.

[0606] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:88.

[0607] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:89.

[0608] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:90.

[0609] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:103.

[0610] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:113.

[0611] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:64 and an LCVR of SEQ ID NO:126.

[0612] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:81.

[0613] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:82.

[0614] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:83.

[0615] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:84.

[0616] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:85.

[0617] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:86.

[0618] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:87.

[0619] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:88.

[0620] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:89.

[0621] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:90.

[0622] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:103.

[0623] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:113.

[0624] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:126.

[0625] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:81.

[0626] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:82.

[0627] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:83.

[0628] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:84.

[0629] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:85.

[0630] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:86.

[0631] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:87.

[0632] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:88.

[0633] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:89.

[0634] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:90.

[0635] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:103.

[0636] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:113.

[0637] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:66 and an LCVR of SEQ ID NO:126.

[0638] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:81.

[0639] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:82.

[0640] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:83.

[0641] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:84.

[0642] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:85.

[0643] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:86.

[0644] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:87.

[0645] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:88.

[0646] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:89.

[0647] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:90.

[0648] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:103.

[0649] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:113.

[0650] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:126.

[0651] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:81.

[0652] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:82.

[0653] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:83.

[0654] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:84.

[0655] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:85.

[0656] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:86.

[0657] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:87.

[0658] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:88.

[0659] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:89.

[0660] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:90.

[0661] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:103.

[0662] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:113.

[0663] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:68 and an LCVR of SEQ ID NO:126.

[0664] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:81.

[0665] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:82.

[0666] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:83.

[0667] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:84.

[0668] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:85.

[0669] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:86.

[0670] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:87.

[0671] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:88.

[0672] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:89.

[0673] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:90.

[0674] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:103.

[0675] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:113.

[0676] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:126.

[0677] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:81.

[0678] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:82.

[0679] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:83.

[0680] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:84.

[0681] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:85.

[0682] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:86.

[0683] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:87.

[0684] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:88.

[0685] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:90.

[0686] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:103.

[0687] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:113.

[0688] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:70 and an LCVR of SEQ ID NO:126.

[0689] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:81.

[0690] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:82.

[0691] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:83.

[0692] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:84.

[0693] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:85.

[0694] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:86.

[0695] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:87.

[0696] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:88.

[0697] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:89.

[0698] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:90.

[0699] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:103.

[0700] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:113.

[0701] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:101 and an LCVR of SEQ ID NO:126.

[0702] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:121 and an LCVR of SEQ ID NO:81.

[0703] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:121 and an LCVR of SEQ ID NO:82.

[0704] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO:83.

[0705] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:121 and an LCVR of SEQ ID NO:84.

[0706] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO:85.

[0707] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:121 and an LCVR of SEQ ID NO:86.

[0708] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO:87.

[0709] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:121 and an LCVR of SEQ ID NO:88.

[0710] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:121 and an LCVR of SEQ ID NO:89.

[0711] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO:90.

[0712] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 103.

[0713] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:121 and an LCVR of SEQ ID NO:113.

[0714] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:121 and an LCVR of SEQ ID NO:126.

[0715] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO:81.

[0716] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:122 and an LCVR of SEQ ID NO:82.

[0717] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO:83.

[0718] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:122 and an LCVR of SEQ ID NO:84.

[0719] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO:85.

[0720] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:122 and an LCVR of SEQ ID NO:86.

[0721] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO:87.

[0722] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:122 and an LCVR of SEQ ID NO:88.

[0723] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:122 and an LCVR of SEQ ID NO:89.

[0724] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO:90.

[0725] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 103.

[0726] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:122 and an LCVR of SEQ ID NO:113.

[0727] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:122 and an LCVR of SEQ ID NO:126.

[0728] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO:81.

[0729] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO:82.

[0730] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO:83.

[0731] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO:84.

[0732] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO:85.

[0733] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:123 and an LCVR of SEQ ID NO:86.

[0734] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO:87.

[0735] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO:88.

[0736] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO:89.

[0737] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO:90.

[0738] In one embodiment, the antibody or binding fragment thereof of the invention comprises an HCVR of SEQ ID NO:123 and an LCVR of SEQ ID NO:103.

[0739] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:123 and an LCVR of SEQ ID NO:113.

[0740] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:123 and an LCVR of SEQ ID NO:126.

[0741] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO:81.

[0742] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:124 and an LCVR of SEQ ID NO:82.

[0743] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:124 and an LCVR of SEQ ID NO:83.

[0744] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:124 and an LCVR of SEQ ID NO:84.

[0745] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:124 and an LCVR of SEQ ID NO:85.

[0746] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:124 and an LCVR of SEQ ID NO:86.

[0747] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO:87.

[0748] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:124 and an LCVR of SEQ ID NO:88.

[0749] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:124 and an LCVR of SEQ ID NO:89.

[0750] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO:90.

[0751] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 103.

[0752] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:124 and an LCVR of SEQ ID NO:113.

[0753] In one embodiment, an antibody or binding fragment thereof according to the invention comprises an HCVR of SEQ ID NO:124 and an LCVR of SEQ ID NO:126.

[0754] In one embodiment, any of the above HCVRs and / or LCVRs can be characterized as having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or more amino acids substituted with different amino acids.

[0755] In one embodiment, the sequence of a non-CDR region of any of the HCVRs and / or LCVRs defined above may be characterized as having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 or more amino acids substituted with different amino acids.

[0756] In one embodiment, any of the HCVRs and / or LCVRs defined above may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the particular HCVR and / or LCVR defined above.

[0757] In one embodiment, the sequence of a non-CDR region of any of the HCVRs and / or LCVRs defined above may be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with the sequence of a non-CDR region of any of the specific HCVRs and / or LCVRs defined above.

[0758] In one embodiment, the antibody or binding fragment thereof of the invention comprises a complete or substantially complete human heavy chain constant region (referred to herein as HCCR or C H ) and / or a light chain constant region (abbreviated herein as LCCR or C L (abbreviated as "individuals").

[0759] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an HCCR comprising or consisting of SEQ ID NO:91. SEQ ID NO: 91 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0760] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an HCCR comprising or consisting of SEQ ID NO:114. SEQ ID NO: 114 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0761] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an HCCR comprising or consisting of SEQ ID NO:115. SEQ ID NO: 115 ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCVAAAHHHHHH

[0762] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCCR comprising or consisting of SEQ ID NO:92. SEQ ID NO:92 RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0763] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: - a HCCR comprising or consisting of SEQ ID NO: 91, 114 or 115; and LCCR comprising or consisting of SEQ ID NO: 92 Includes:

[0764] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: - a HCCR comprising or consisting of SEQ ID NO: 91; and LCCR comprising or consisting of SEQ ID NO: 92 Includes:

[0765] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: - a HCCR comprising or consisting of SEQ ID NO: 114; and LCCR comprising or consisting of SEQ ID NO: 92 Includes:

[0766] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: - a HCCR comprising or consisting of SEQ ID NO: 115; and LCCR comprising or consisting of SEQ ID NO: 92 Includes:

[0767] In one embodiment, the HCCR having SEQ ID NO: 91, 114 or 115 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48 , 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or more amino acids.

[0768] In one embodiment, the LCCR having SEQ ID NO: 92 can be characterized as having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or more amino acids substituted with different amino acids.

[0769] In one embodiment, the HCCR having SEQ ID NO: 91, 114 or 115 and / or the LCCR having SEQ ID NO: 92 is substituted with a different amino acid, wherein 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, , 92, 93, 94, 95, 96, 97, 98, 99 or more amino acids.

[0770] In one embodiment, the HCCR having SEQ ID NO: 91, 114 or 115 can be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 91, 114 or 115, respectively.

[0771] In one embodiment, the LCCR having SEQ ID NO: 92 can be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 92.

[0772] In one embodiment, the HCCR of SEQ ID NO: 91, 114 or 115 and / or the LCCR having SEQ ID NO: 92 can be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 91, 114 or 115 and / or SEQ ID NO: 92, respectively.

[0773] In one embodiment, the antibody or binding fragment thereof of the present invention comprises an HCCR and an LCCR comprising amino acid sequences homologous to the amino acid sequences of SEQ ID NO: 91, 114 or 115, and SEQ ID NO: 92, respectively, and the antibody or binding fragment thereof retains desired functional properties.

[0774] In one embodiment, the antibody or binding fragment thereof of the present invention comprises a complete or substantially complete mouse HCCR and / or LCCR.

[0775] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an HCCR comprising or consisting of SEQ ID NO:93. SEQ ID NO: 93 AKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVPSSTWPSETVTCNVAHPASSTKVDKKIVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEV HTAQTQPREEQFNSTFRSVSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTISKTKGRPKAPQVYTIPPPKEQMAKDKVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEAGNTFTCSVLHEGLHNHHTEKSLSHSPG

[0776] In one embodiment, the antibody or binding fragment thereof according to the invention comprises an LCCR comprising or consisting of SEQ ID NO: 94. SEQ ID NO:94 RADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVKWKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC

[0777] In one embodiment, the antibody or binding fragment thereof according to the invention comprises: - a HCCR comprising or consisting of SEQ ID NO: 93; and LCCR comprising or consisting of SEQ ID NO: 94 Includes:

[0778] In one embodiment, the HCCR having SEQ ID NO: 93 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 20, 2 , 92, 93, 94, 95, 96, 97 or more amino acids.

[0779] In one embodiment, the LCCR having SEQ ID NO: 94 can be characterized as having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32 or more amino acids substituted with different amino acids.

[0780] In one embodiment, the LCCR having SEQ ID NO: 93 and / or SEQ ID NO: 94 is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, , 91, 92, 93, 94, 95, 96, 97 or more amino acids.

[0781] In one embodiment, the HCCR having SEQ ID NO: 93 can be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 93.

[0782] In one embodiment, the LCCR having SEQ ID NO: 94 can be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 94.

[0783] In one embodiment, the HCCR having SEQ ID NO: 93 and / or the LCCR having SEQ ID NO: 94 can be characterized as having an amino acid sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 93 and / or SEQ ID NO: 94, respectively.

[0784] In one embodiment, the antibody or binding fragment thereof of the present invention comprises an HCCR and an LCCR comprising amino acid sequences homologous to the amino acid sequences of SEQ ID NO: 93 and SEQ ID NO: 94, respectively, and the antibody or binding fragment thereof retains the desired functional properties.

[0785] In one embodiment, the antibody or binding fragment thereof according to the invention is a murine, chimeric or humanized antibody or fragment thereof.

[0786] In one embodiment, the antibody or binding fragment thereof according to the invention is a murine antibody or fragment thereof.

[0787] As used herein, "murine antibodies or binding fragments thereof" includes antibodies and binding fragments thereof in which the variable regions (including CDRs and FRs) and constant regions are derived from a mouse.

[0788] In one embodiment, the murine antibody or binding fragment thereof according to the invention comprises the CDRs of at least one, preferably at least two, more preferably three HCVRs set forth in SEQ ID NOs: 1, 2 and 3; and / or the CDRs of at least one, preferably at least two, more preferably three LCVRs set forth in SEQ ID NOs: 12, 13 and 14 (wherever applicable, X 12 does not exist).

[0789] In a preferred embodiment, the murine antibody or binding fragment thereof according to the invention comprises the CDRs of at least one, preferably at least two, more preferably three HCVRs set forth in SEQ ID NOs: 1, 4 and 3; and / or the CDRs of at least one, preferably at least two, more preferably three LCVRs set forth in SEQ ID NOs: 15, 16 and 17 (where applicable, X ... 12 does not exist).

[0790] In a preferred embodiment, the murine antibody or binding fragment thereof according to the invention comprises at least one, preferably at least two, more preferably at least three, and even more preferably four HCVR FRs set forth in SEQ ID NOs: 25, 26, 27 and 28; and / or at least one, preferably at least two, more preferably at least three, and even more preferably four LCVR FRs set forth in SEQ ID NOs: 44, 45, 46 and 47 (where applicable, X 18 is Tyr (Y).

[0791] In a preferred embodiment, a murine antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 61 and / or the LCVR set forth in SEQ ID NO: 71 or 81.

[0792] In a preferred embodiment, the murine antibody or binding fragment thereof according to the present invention may further comprise the HCCR set forth in SEQ ID NO:93 and / or the LCCR set forth in SEQ ID NO:94.

[0793] In a preferred embodiment, a murine antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the variable region set forth in SEQ ID NO: 61 and / or the constant region set forth in SEQ ID NO: 93.

[0794] In a preferred embodiment, a murine antibody or binding fragment thereof according to the invention may therefore comprise a light chain comprising the variable region set forth in SEQ ID NO: 71 or 81 and / or the constant region set forth in SEQ ID NO: 94.

[0795] In one embodiment, the antibody or binding fragment thereof according to the invention is a chimeric antibody or binding fragment thereof.

[0796] As used herein, a "chimeric antibody or binding fragment thereof" refers to an antibody or binding fragment thereof that comprises a first amino acid sequence linked to a second amino acid sequence that does not occur in nature. The amino acid sequences may normally be found in separate proteins that are brought together in a fusion protein, or may normally be found in the same protein, but are placed into a new arrangement within the fusion protein. A chimeric protein can be created, for example, by chemical synthesis, or by creating and translating a polynucleotide in which the peptide regions are encoded in the desired relationship. The term "chimeric antibody or binding fragment thereof" is used herein to refer to an antibody or binding fragment thereof that comprises a first amino acid sequence linked to a second amino acid sequence that does not occur in nature. The amino acid sequences may normally be found in separate proteins that are brought together in a fusion protein, or may normally be found in the same protein, but are placed into a new arrangement within the fusion protein. A chimeric protein can be created, for example, by chemical synthesis, or by creating and translating a polynucleotide in which the peptide regions are encoded in the desired relationship. (a) the constant region or a portion thereof is altered, substituted, or exchanged such that the variable region is linked to a constant region of a different or altered class, effector function, and / or species, or to an entirely different molecule, e.g., an enzyme, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody; or (b) the variable region or portion thereof is modified, substituted, or exchanged with a variable region or portion thereof having a different or altered antigen specificity; or with a corresponding sequence from another species or another antibody class or subclass; It includes antibodies and binding fragments thereof.

[0797] In one embodiment, a chimeric antibody or binding fragment thereof according to the invention comprises a heavy and / or light chain comprising a human constant region and a murine variable region (including murine CDRs and murine FRs).

[0798] In one embodiment, a chimeric antibody or binding fragment thereof according to the invention comprises a human heavy chain and a murine light chain, or a murine heavy chain and a human light chain.

[0799] In one embodiment, the chimeric antibody or binding fragment thereof of the present invention comprises the CDRs of at least one, preferably at least two, more preferably three HCVRs set forth in SEQ ID NOs: 1, 2 and 3, and / or the CDRs of at least one, preferably at least two, more preferably three LCVRs set forth in SEQ ID NOs: 12, 13 and 14.

[0800] In a preferred embodiment, the chimeric antibody or binding fragment thereof of the present invention comprises the CDRs of at least one, preferably at least two, more preferably three HCVRs set forth in SEQ ID NOs: 1, 4 and 3, and / or the CDRs of at least one, preferably at least two, more preferably three LCVRs set forth in SEQ ID NOs: 15, 16 and 17.

[0801] In a preferred embodiment, the chimeric antibody or binding fragment thereof of the present invention comprises at least one, preferably at least two, more preferably three CDRs of the HCVRs set forth in SEQ ID NOs: 1, 4 and 3, and / or at least one, preferably at least two, more preferably three CDRs of the LCVRs set forth in SEQ ID NOs: 18, 111 or 120, and 17, respectively.

[0802] In a preferred embodiment, the chimeric antibody or binding fragment thereof of the present invention may comprise at least one, preferably at least two, more preferably at least three, and even more preferably four HCVR FRs set forth in SEQ ID NOs: 25, 26, 27, and 28, and / or at least one, preferably at least two, more preferably at least three, and even more preferably four LCVR FRs set forth in SEQ ID NOs: 44, 45, 46, and 47.

[0803] In a preferred embodiment, the chimeric antibody or binding fragment thereof of the present invention may comprise at least one, preferably at least two, more preferably at least three, and even more preferably four HCVR FRs set forth in SEQ ID NOs: 25, 26, 27, and 28, and / or at least one, preferably at least two, more preferably at least three, and even more preferably four LCVR FRs set forth in SEQ ID NOs: 48, 58, 50, and 51.

[0804] In a preferred embodiment, a chimeric antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 61 and / or the LCVR set forth in SEQ ID NO: 71 or 81.

[0805] In a preferred embodiment, a chimeric antibody or binding fragment thereof according to the invention may therefore comprise an HCVR as set forth in SEQ ID NO: 61 and / or an LCVR as set forth in SEQ ID NO: 112, 113, 125, 126, 128 or 129.

[0806] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the present invention may further comprise a human HCCR set forth in SEQ ID NO: 91, 114 or 115, and / or a human LCCR set forth in SEQ ID NO: 92.

[0807] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the present invention may further comprise a human HCCR set forth in SEQ ID NO:91 and / or a human LCCR set forth in SEQ ID NO:92.

[0808] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the present invention may further comprise a human HCCR set forth in SEQ ID NO: 114 and / or a human LCCR set forth in SEQ ID NO: 92.

[0809] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the present invention may further comprise a human HCCR set forth in SEQ ID NO: 115 and / or a human LCCR set forth in SEQ ID NO: 92.

[0810] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the present invention may further comprise a human HCCR set forth in SEQ ID NO: 91, 114 or 115, and / or a murine LCCR set forth in SEQ ID NO: 94.

[0811] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the present invention may further comprise a human HCCR set forth in SEQ ID NO:91 and / or a murine LCCR set forth in SEQ ID NO:94.

[0812] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the present invention may further comprise a human HCCR set forth in SEQ ID NO: 114 and / or a murine LCCR set forth in SEQ ID NO: 94.

[0813] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the present invention may further comprise a human HCCR set forth in SEQ ID NO: 115 and / or a murine LCCR set forth in SEQ ID NO: 94.

[0814] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the present invention may further comprise a murine HCCR set forth in SEQ ID NO:93 and / or a human LCCR set forth in SEQ ID NO:92.

[0815] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising a variable region as set forth in SEQ ID NO: 61 and / or a constant region as set forth in SEQ ID NO: 91, 114 or 115.

[0816] In a preferred embodiment, a chimeric antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising a variable region as set forth in SEQ ID NO: 61 and / or a constant region as set forth in SEQ ID NO: 91.

[0817] In a preferred embodiment, a chimeric antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising a variable region as set forth in SEQ ID NO: 61 and / or a constant region as set forth in SEQ ID NO: 114.

[0818] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the variable region set forth in SEQ ID NO: 61 and / or the constant region set forth in SEQ ID NO: 115.

[0819] In a preferred embodiment, the chimeric antibody or binding fragment thereof according to the invention may therefore comprise a light chain comprising the variable region set forth in SEQ ID NO: 71 or 81 and / or the constant region set forth in SEQ ID NO: 92.

[0820] In one embodiment, the antibody or binding fragment thereof according to the invention is a humanized antibody or binding fragment thereof.

[0821] As used herein, a "humanized antibody or binding fragment thereof" refers to a chimeric antibody or binding fragment thereof that contains minimal sequence derived from non-human immunoglobulin. It includes antibodies produced by non-human cells having variable and constant regions that have been modified to more closely resemble antibodies produced by human cells, e.g., by altering the non-human antibody amino acid sequence to incorporate amino acids found in human germline immunoglobulin sequences. Humanized antibodies or binding fragments thereof of the present invention can include, for example, amino acid residues in the CDRs that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or somatic mutation in vivo). The term "humanized antibody or binding fragment thereof" also includes antibodies and binding fragments thereof in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. In other words, the term "humanized antibody or binding fragment thereof" refers to an antibody or binding fragment thereof in which the CDRs of a recipient human antibody are replaced by CDRs from a donor non-human antibody, e.g., a murine antibody. Humanized antibodies or binding fragments thereof may also comprise residues of donor origin in framework sequences. Humanized antibodies or binding fragments thereof may also comprise at least a portion of a human immunoglobulin constant region. Humanized antibodies and binding fragments thereof may also comprise residues that are found neither in the recipient antibody nor in the imported CDR or FR sequences.Humanization can be performed using methods known in the art (e.g., Jones et al., 1986. Nature. 321(6069):522-5; Riechmann et al., 1988. Nature. 332(6162):323-7; Verhoeyen et al., 1988. Science. 239(4847):1534-6; Presta, 1992. Curr Opin. 239(4847):1534-6; including techniques such as "superhumanizing" antibodies (e.g., Tan et al., 2002. J Immunol. 169(2):1119-25) and "resurfacing" (e.g., Staelens et al., 2006. Mol Immunol. 43(8):1243-57; Roguska et al., 1994. Proc Natl Acad Sci USA. 91(3):969-73). Biotechnol. 3(4):394-8; U.S. Patent No. 4,816,567).

[0822] Methods for humanizing the antibodies or binding fragments thereof of the present invention are well known in the art and are described in more detail in the Examples section below. The selection of human variable domains, both light and heavy, used to generate humanized antibodies or binding fragments thereof is very important to reduce antigenicity. According to the so-called "best-fit" method, the variable domain sequences of the antibodies or binding fragments thereof of the present invention are screened against the entire library of known human variable domain sequences. The human sequence that is closest to the mouse sequence is then accepted as the human framework (FR) for the humanized antibody (Sims et al., 1993, J. Immunol. 151(4):2296-308; Chothia & Lesk, 1987, J. Mol. Biol. 196(4):901-17).

[0823] Another approach to humanizing the antibodies or binding fragments thereof of the present invention uses specific FRs from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains. The same framework can be used for several different humanized antibodies (Carter et al., 1992, Proc Natl Acad Sci USA 89(10):4285-9; Presta et al., 1993, J Immunol 151(5):2623-32). It is further important that antibodies be humanized while retaining high affinity for hCD45RC and other favorable biological properties. To achieve this goal, according to a preferred method, humanized antibodies and binding fragments thereof are prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available that illustrate and display probable three-dimensional structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind its epitope. In this way, CDR residues can be selected and combined from the consensus and import sequences so that the desired antibody characteristic, such as increased affinity for hCD45RC, is achieved. In general, the CDR residues are directly and most substantially involved in influencing antigen binding.

[0824] Another method for humanizing the antibodies or binding fragments thereof of the present invention is to use transgenic or transchromosomal animals carrying parts of the human immune system for immunization. As hosts, these animals have had their immunoglobulin genes replaced by functional human immunoglobulin genes. Therefore, antibodies produced by these animals, or antibodies generated in hybridomas made from B cells of these animals, are already humanized. Examples of such transgenic or transchromosomal animals include, but are not limited to: Xenomouse (Abgenix, Fremont, CA), as described in U.S. Patent Nos. 5,939,598, 6,075,181, 6,114,598, 6,150,584, and 6,162,963; HuMAb Mouse® (Medarex, Inc.), described in Lonberg et al., 1994. Nature. 368(6474):856-859; Lonberg & Huszar, 1995. Int Rev Immunol. 13(1):65-93; Harding & Lonberg, 1995. Ann NY Acad Sci. 764:536-46; Taylor et al., 1992. Nucleic Acids Res. 20(23):6287-95; Chen et al., 1993. Int Immunol. 5(6):647-56; Tuaillon et al., 1993. Proc Natl Acad Sci USA. 90(8):3720-4; Choi et al., 1993. Nat Genet. 4(2):117-23; Chen et al., 1993. EMBO J. 12(3):821-30; Tuaillon et al., 1994. J Immunol. 152(6):2912-20; Taylor et al., 1994. Int Immunol. 6(4):579-91; Fishwild et al., 1996. Nat Biotechnol. 14(7):845-51; -KM Mouse®, described in U.S. Patent Application No. WO2002043478; -TC mice, as described in Tomizuka et al., 2000. Proc Natl Acad Sci USA. 97(2):722-7; and - OmniRat™ (OMT, Inc.), described in U.S. Patent Application No. WO2008151081; Geurts et al., 2009. Science. 325(5939):433; Menoret et al., 2010. Eur J Immunol. 40(10):2932-41; Osborn et al., 2013. J Immunol. 190(4):1481-90 Includes:

[0825] Humanized antibodies and binding fragments thereof can also be produced according to a variety of other techniques, such as by using for immunization other transgenic animals engineered to express human antibody repertoires (Jakobovitz et al., 1993. Nature. 362(6417):255-8), or by selecting antibody repertoires using phage display methods. Such techniques are known to those skilled in the art and can be carried out starting from monoclonal antibodies or binding fragments thereof as disclosed in the present application.

[0826] In some embodiments, the antibody or binding fragment thereof of the present invention comprising an HCVR and an LCVR (or CDRs thereof) comprises a first constant domain (C H 1 and / or C L ), the amino acid sequence of which is fully or substantially human.

[0827] In some embodiments, particularly when an antibody or binding fragment thereof according to the invention is intended for human therapeutic use, it is typical for the entire constant region, or at least a portion thereof, to have a completely or substantially human amino acid sequence. H 1 domain, hinge region, C H 2 domains, C H 3 domains and C L Domain (and C, if present) H 4 domains), or any combination thereof, may be fully or substantially human with respect to their amino acid sequence. H 1 domain, hinge region, C H 2 domains, C H 3 domains and C L Domain (and C, if present) H All four domains may have completely or substantially human amino acid sequences.

[0828] The term "substantially human," in the context of the constant region of a humanized or chimeric antibody or binding fragment thereof, refers to at least 70%, preferably at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more amino acid sequence identity with a human constant region.

[0829] In this context, the term "human amino acid sequence" refers to an amino acid sequence encoded by a human immunoglobulin gene, including germline, rearranged, and somatically mutated genes. The present invention also contemplates proteins comprising constant domains of "human" sequence that have been modified by one or more amino acid additions, deletions, or substitutions relative to the human sequence, except in embodiments that explicitly require the presence of an "complete human hinge region."

[0830] The presence of a "fully human hinge region" in the antibody or binding fragment thereof of the present invention can be beneficial both in minimizing immunogenicity and optimizing antibody stability. It is contemplated that one or more amino acid substitutions, insertions, or deletions may be made in the heavy and / or light chain constant regions, particularly in the Fc region. Amino acid substitutions may occur by replacing the substituted amino acid with a different naturally occurring amino acid or a non-natural or modified amino acid. Other structural modifications, such as altered glycosylation patterns (e.g., by adding or deleting N-linked or O-linked glycosylation sites), are also permissible. Depending on the intended use of the antibody or binding fragment thereof, it may be desirable to modify the antibody or binding fragment thereof of the present invention with respect to its binding properties to Fc receptors, e.g., to modulate effector function. For example, cysteine ​​residue(s) may be introduced into the Fc region to allow interchain disulfide bond formation in this region. Homodimeric antibodies generated in this manner may have improved effector functions (Caron et al., 1992. J Exp Med. 176(4):1191-5; Shopes, 1992. J Immunol. 148(9):2918-22).

[0831] In one embodiment, the humanized antibody or binding fragment thereof according to the invention comprises the CDRs of at least one, preferably at least two, more preferably three HCVRs set forth in SEQ ID NOs: 1, 2 and 3, and / or the CDRs of at least one, preferably at least two, more preferably three LCVRs set forth in SEQ ID NOs: 12, 13 and 14 (wherever applicable, X ... 12 is absent or is Ser(S).

[0832] In one embodiment, the humanized antibody or binding fragment thereof according to the invention comprises at least one, preferably at least two, more preferably three CDRs of HCVRs and / or at least one, preferably at least two, more preferably three CDRs of LCVRs (where applicable, X ... 12 is absent or is Ser(S).

[0833] In one embodiment, the humanized antibody or binding fragment thereof of the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 1 H -CDR1; V selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11, 100, 116, 117, 118, and 119 H -CDR2; and V having SEQ ID NO: 3 H -CDR3; and - an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V selected from SEQ ID NOs: 15 and 18 L -CDR1(X 12 is absent or is Ser(S); V selected from SEQ ID NOs: 16, 19, 20, 22, 111 and 120 L -CDR2; and V selected from SEQ ID NOs: 17 and 21 L -CDR3 Includes:

[0834] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 1 H -CDR1; V selected from SEQ ID NOs: 4 and 5 H -CDR2; and V having SEQ ID NO: 3 H -CDR3; and - an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 15 L -CDR1(X 12 does not exist); V having SEQ ID NO: 16 L -CDR2; and V having SEQ ID NO: 17 L -CDR3 Includes:

[0835] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 1 H -CDR1; V selected from SEQ ID NOs: 6, 7 and 8 H -CDR2; and V having SEQ ID NO: 3 H -CDR3; and - an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 18 L -CDR1(X 12 does not exist); V selected from SEQ ID NOs: 16 and 19 L -CDR2; and V having SEQ ID NO: 17 L -CDR3 Includes:

[0836] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 1 H -CDR1; V selected from SEQ ID NOs: 9, 10 and 11 H -CDR2; and V having SEQ ID NO: 3 H -CDR3; and - an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 18 L -CDR1(X 12 does not exist); V selected from SEQ ID NOs: 19, 20 and 22 L -CDR2; and V having SEQ ID NOs: 17 and 21 L -CDR3 Includes:

[0837] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 1 H -CDR1; V having SEQ ID NO: 100 H -CDR2; and V having SEQ ID NO: 3 H -CDR3; and - an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 18 L -CDR1(X 12 is Ser(S)); V having SEQ ID NO: 16 L -CDR2; and V having SEQ ID NO: 17 L -CDR3 Includes:

[0838] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 1 H -CDR1; V selected from SEQ ID NOs: 6, 7, 8 and 100 H -CDR2; and V having SEQ ID NO: 3 H -CDR3; and - an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 18 L -CDR1(X 12 is absent or is Ser(S); V selected from SEQ ID NOs: 16 and 19 L -CDR2; and V having SEQ ID NO: 17 L -CDR3 Includes:

[0839] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the present invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, said combinations being selected from combinations #1, #7, #14, #26 and #50 in Table 2 (wherever applicable, X 12 is absent or is Ser(S).

[0840] In one embodiment, the humanized antibody or binding fragment thereof of the present invention may comprise the FRs of at least one, preferably at least two, more preferably at least three, and even more preferably four HCVRs and / or the FRs of at least one, preferably at least two, more preferably at least three, and even more preferably four LCVRs listed in Table 3.

[0841] In one embodiment, the humanized antibody or binding fragment thereof of the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably at least three, even more preferably four of the following FRs: V selected from SEQ ID NOs: 29, 33, 36, 39, 40 and 42 H -FR1; V selected from SEQ ID NOs: 30, 34, 37 and 43 H -FR2; V selected from SEQ ID NOs: 31, 35, 38 and 41 H -FR3; and V having SEQ ID NO: 32 H -FR4; and an LCVR comprising at least one, preferably at least two, more preferably at least three, even more preferably four of the following FRs: V selected from SEQ ID NOs: 48, 52 and 55 L -FR1; V selected from SEQ ID NOs: 49, 53, 56, 58, 59 and 60 L -FR2; V selected from SEQ ID NOs: 50, 54 and 57 L -FR3; and V having SEQ ID NO: 51 L -FR4 may include:

[0842] In one embodiment, the humanized antibody or binding fragment thereof of the present invention may further comprise a combination of (i) at least one, preferably at least two, more preferably at least three, and even more preferably four FRs of HCVRs and (ii) at least one, preferably at least two, more preferably at least three, and even more preferably four FRs of LCVRs, said combination being selected from the group consisting of those listed in Table 3. Selected from combinations #9, #10, #11, #12, #13, #14, #16, #17, #18, #19, #20, #21, #23, #24, #25, #26, #27, #28, #30, #31, #32, #33, #34, #35, #37, #38, #39, #40, #41, #42, #44, #45, #46, #47, #48, #49, #51, #52, #53, #54, #55 and #56.

[0843] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably at least three, even more preferably four of the following FRs: V selected from SEQ ID NOs: 29, 33 and 36 H -FR1; V selected from SEQ ID NOs: 30, 34 and 37 H -FR2; V selected from SEQ ID NOs: 31, 35 and 38 H -FR3; and V having SEQ ID NO: 32 H -FR4; and an LCVR comprising at least one, preferably at least two, more preferably at least three, even more preferably four of the following FRs: V selected from SEQ ID NOs: 48, 52 and 55 L -FR1; V selected from SEQ ID NOs: 49, 53 and 56 L -FR2; V selected from SEQ ID NOs: 50, 54 and 57 L -FR3; and V having SEQ ID NO: 51 L -FR4 may include:

[0844] In a preferred embodiment, the humanized antibody or binding fragment thereof of the present invention may further comprise a combination of i) at least one, preferably at least two, more preferably at least three, and even more preferably four FRs of HCVRs and (ii) at least one, preferably at least two, more preferably at least three, and even more preferably four FRs of LCVRs, said combinations being selected from combinations #9, #10, #11, #16, #17, #18, #23, #24, and #25 listed in Table 3.

[0845] In one embodiment, the humanized antibody or binding fragment thereof of the invention comprises: HCVRs selected from SEQ ID NOs: 62, 63, 64, 65, 66, 67, 68, 69, 70, 101, 121, 122, 123 and 124; and / or LCVRs selected from SEQ ID NOs: 82, 83, 84, 85, 86, 87, 88, 89, 90, 103, 113, 126 and 129 may include:

[0846] In one embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise any combination of LCVRs selected from SEQ ID NOs: 62, 63, 64, 65, 66, 67, 68, 69, 70, 101, 121, 122, 123 and 124, and SEQ ID NOs: 82, 83, 84, 85, 86, 87, 88, 89, 90, 103, 113, 126 and 129, as detailed above.

[0847] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention comprises: - a HCVR selected from SEQ ID NOs: 62, 63 and 64; and / or - a LCVR selected from SEQ ID NOs: 82, 83 and 84 may include:

[0848] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the present invention may therefore comprise any combination of an HCVR selected from SEQ ID NOs: 62, 63 and 64 and an LCVR selected from SEQ ID NOs: 82, 83 and 84 as detailed above.

[0849] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention comprises: - a HCVR selected from SEQ ID NOs: 62, 63, 64, 65, 67 and 101; and / or - a LCVR selected from SEQ ID NOs: 82, 83, 84, 85 and 103 may include:

[0850] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the present invention may therefore comprise any combination of an HCVR selected from SEQ ID NOs: 62, 63, 64, 65, 67 and 101 and an LCVR selected from SEQ ID NOs: 82, 83, 84, 85 and 103 as detailed above.

[0851] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO:62 and the LCVR set forth in SEQ ID NO:82.

[0852] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 62 and the LCVR set forth in SEQ ID NO: 83.

[0853] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO:62 and the LCVR set forth in SEQ ID NO:84.

[0854] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO:63 and the LCVR set forth in SEQ ID NO:82.

[0855] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO:63 and the LCVR set forth in SEQ ID NO:83.

[0856] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO:63 and the LCVR set forth in SEQ ID NO:84.

[0857] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO:64 and the LCVR set forth in SEQ ID NO:82.

[0858] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO:64 and the LCVR set forth in SEQ ID NO:83.

[0859] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO:64 and the LCVR set forth in SEQ ID NO:84.

[0860] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 101 and the LCVR set forth in SEQ ID NO: 85.

[0861] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO:101 and the LCVR set forth in SEQ ID NO:103.

[0862] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO:65 and the LCVR set forth in SEQ ID NO:85.

[0863] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 65 and the LCVR set forth in SEQ ID NO: 103.

[0864] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 62 and the LCVR set forth in SEQ ID NO: 85.

[0865] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 101 and the LCVR set forth in SEQ ID NO: 82.

[0866] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 121 and the LCVR set forth in SEQ ID NO: 85.

[0867] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 122 and the LCVR set forth in SEQ ID NO: 85.

[0868] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 123 and the LCVR set forth in SEQ ID NO: 85.

[0869] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 124 and the LCVR set forth in SEQ ID NO: 85.

[0870] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 63 and the LCVR set forth in SEQ ID NO: 85.

[0871] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 67 and the LCVR set forth in SEQ ID NO: 85.

[0872] In a preferred embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise the HCVR set forth in SEQ ID NO: 67 and the LCVR set forth in SEQ ID NO: 103.

[0873] In one embodiment, the humanized antibody or binding fragment thereof of the present invention may further comprise an HCCR set forth in SEQ ID NO: 91, 114 or 115 and / or an LCCR set forth in SEQ ID NO: 92.

[0874] In one embodiment, the humanized antibody or binding fragment thereof of the present invention may further comprise the HCCR set forth in SEQ ID NO:91 and / or the LCCR set forth in SEQ ID NO:92.

[0875] In one embodiment, the humanized antibody or binding fragment thereof of the present invention may further comprise the HCCR set forth in SEQ ID NO: 114 and / or the LCCR set forth in SEQ ID NO: 92.

[0876] In one embodiment, the humanized antibody or binding fragment thereof of the present invention may further comprise the HCCR set forth in SEQ ID NO: 115 and / or the LCCR set forth in SEQ ID NO: 92.

[0877] In one embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the constant region set forth in SEQ ID NO: 62, 63, 64, 65, 66, 67, 68, 69, 70 or 101, and / or SEQ ID NO: 91, 114 or 115.

[0878] In one embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the constant region set forth in SEQ ID NO: 62, 63, 64, 65, 66, 67, 68, 69, 70 or 101, and / or SEQ ID NO: 91.

[0879] In one embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the constant region set forth in SEQ ID NO: 62, 63, 64, 65, 66, 67, 68, 69, 70 or 101, and / or SEQ ID NO: 114.

[0880] In one embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the constant region set forth in SEQ ID NO: 62, 63, 64, 65, 66, 67, 68, 69, 70 or 101, and / or SEQ ID NO: 115.

[0881] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising a variable region as set forth in SEQ ID NO: 62, 63 or 64 and / or a constant region as set forth in SEQ ID NO: 91, 114 or 115.

[0882] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising a variable region as set forth in SEQ ID NO: 62, 63 or 64 and / or a constant region as set forth in SEQ ID NO: 91.

[0883] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising a variable region as set forth in SEQ ID NO: 62, 63 or 64 and / or a constant region as set forth in SEQ ID NO: 114.

[0884] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising a variable region as set forth in SEQ ID NO: 62, 63 or 64 and / or a constant region as set forth in SEQ ID NO: 115.

[0885] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the variable regions set forth in SEQ ID NOs: 62, 63, 64, 65, 67 and 101 and / or the constant regions set forth in SEQ ID NOs: 91, 114 or 115.

[0886] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the variable regions set forth in SEQ ID NOs: 62, 63, 64, 65, 67 and 101 and / or the constant region set forth in SEQ ID NO: 91.

[0887] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the variable regions set forth in SEQ ID NOs: 62, 63, 64, 65, 67 and 101 and / or the constant region set forth in SEQ ID NO: 114.

[0888] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the variable regions set forth in SEQ ID NOs: 62, 63, 64, 65, 67 and 101 and / or the constant region set forth in SEQ ID NO: 115.

[0889] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the variable region set forth in SEQ ID NO: 101 and / or the constant region set forth in SEQ ID NO: 114.

[0890] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a heavy chain comprising the variable region set forth in SEQ ID NO: 101 and / or the constant region set forth in SEQ ID NO: 115.

[0891] In one embodiment, a humanized antibody or binding fragment thereof according to the invention may therefore comprise a light chain comprising the constant region set forth in SEQ ID NO: 82, 83, 84, 85, 86, 87, 88, 89, 90 or 103, and / or SEQ ID NO: 92.

[0892] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a light chain comprising a variable region as set forth in SEQ ID NO: 82, 83 or 84 and / or a constant region as set forth in SEQ ID NO: 92.

[0893] In a preferred embodiment, the humanized antibody or binding fragment thereof according to the invention may therefore comprise a light chain comprising a variable region as set forth in SEQ ID NO: 82, 83, 84, 85 or 103 and / or a constant region as set forth in SEQ ID NO: 92.

[0894] According to a particular embodiment, the murine, chimeric or humanized antibody or fragment thereof as defined herein above comprises CDR1 of the LCVR set forth in SEQ ID NO: 12 (preferably set forth in SEQ ID NO: 15 or 18, more preferably set forth in SEQ ID NO: 15) (X 12 is selected from Asn (N), Ser (S), and Gly (G). In this embodiment, X 12 is absent, the amino acid residue at Kabat position L71 of the LCVR is preferably Phe (F); in other words, the murine, chimeric or humanized antibody or fragment thereof according to the present invention preferably comprises FR3(X) of the LCVR as set forth in SEQ ID NO: 46, 50, 54 or 57. 18 is Phe(F). When these characteristics are satisfied (i.e., X 12 is not absent, and preferably at Kabat position L71 (i.e., X 18 ) is further Phe(F)), any of the above embodiments relating to the murine, chimeric or humanized antibody or binding fragment thereof according to the invention apply.

[0895] Thus, according to this specific embodiment, the murine, chimeric or humanized antibody or binding fragment thereof according to the invention comprises the CDRs of at least one, preferably at least two, more preferably at least three HCVRs set forth in SEQ ID NOs: 1, 2 and 3, and / or the CDRs of at least one, preferably at least two, more preferably three LCVRs set forth in SEQ ID NOs: 12, 13 and 14 (where applicable, X and X). 12 is selected from Asn (N), Ser (S) and Gly (G).

[0896] According to this specific embodiment, the murine, chimeric or humanized antibody or binding fragment thereof according to the invention comprises at least one, preferably at least two, more preferably three CDRs of HCVRs and / or at least one, preferably at least two, more preferably three CDRs of LCVRs (where applicable, X ... 12is selected from Asn (N), Ser (S) and Gly (G).

[0897] According to this specific embodiment, the murine, chimeric or humanized antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 1 H -CDR1; V selected from SEQ ID NOs: 4, 5, 6, 7, 8, 9, 10, 11 and 100 H -CDR2; and V having SEQ ID NO: 3 H -CDR3; and - an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V selected from SEQ ID NOs: 15 and 18 L -CDR1(X 12 is selected from Asn (N), Ser (S) and Gly (G); V selected from SEQ ID NOs: 16, 19, 20, 22, 111 and 120 L -CDR2; and V selected from SEQ ID NOs: 17 and 21 L -CDR3 Includes:

[0898] According to this specific embodiment, the murine, chimeric or humanized antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 1 H -CDR1; V selected from SEQ ID NOs: 4, 5, 6, 8, 100, 116, 117, 118 and 119 H -CDR2; and V having SEQ ID NO: 3 H -CDR3; and - an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V selected from SEQ ID NOs: 15 and 18 L -CDR1(X 12 is selected from Asn (N), Ser (S) and Gly (G); V selected from SEQ ID NOs: 16, 111 and 120 L -CDR2; and V having SEQ ID NO: 17 L -CDR3 Includes:

[0899] According to this specific embodiment, the murine, chimeric or humanized antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 1 H -CDR1; V selected from SEQ ID NOs: 4 and 5 H -CDR2; and V having SEQ ID NO: 3 H -CDR3; and - an LCVR comprising at least one, preferably at least two, more preferably the following three CDRs: V having SEQ ID NO: 15 L -CDR1(X 12 is selected from Asn (N), Ser (S) and Gly (G); V having SEQ ID NO: 16 L -CDR2; and V having SEQ ID NO: 17 L -CDR3 Includes:

[0900] According to this specific embodiment, the murine, chimeric or humanized antibody or binding fragment thereof according to the invention comprises a combination of (i) at least one, preferably at least two, more preferably three CDRs of HCVRs and (ii) at least one, preferably at least two, more preferably three CDRs of LCVRs, said combinations being selected from combinations #1, #7, #14, #26 and #50 in Table 2, and, whenever applicable, X12 is selected from Asn (N), Ser (S) and Gly (G).

[0901] According to this specific embodiment, the humanized antibody or binding fragment thereof according to the invention comprises at least one, preferably at least two, more preferably at least three, and even more preferably four HCVR FRs and / or at least one, preferably at least two, more preferably at least three, and even more preferably four LCVR FRs (where applicable, X and X) as set forth in Table 3. 18 may further comprise Phe(F).

[0902] According to this specific embodiment, the murine, chimeric or humanized antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably at least three, even more preferably four of the following FRs: V selected from SEQ ID NOs: 25, 29, 33, 36, 39, 40 and 42 H -FR1; V selected from SEQ ID NOs: 26, 30, 34, 37 and 43 H -FR2; V selected from SEQ ID NOs: 27, 31, 35, 38 and 41 H -FR3; and and V selected from SEQ ID NOs: 28 and 32 H -FR4; and an LCVR comprising at least one, preferably at least two, more preferably at least three, even more preferably four of the following FRs: V selected from SEQ ID NOs: 44, 48, 52 and 55 L -FR1; V selected from SEQ ID NOs: 45, 49, 53, 56, 58, 59 and 60 L -FR2; SEQ ID NOs: 46, 50, 54 and 57 to V L -FR3(X 18 is Phe(F)); and V selected from SEQ ID NOs: 47 and 51 L-FR4 It may further include:

[0903] According to this specific embodiment, the murine, chimeric or humanized antibody or binding fragment thereof according to the invention may further comprise a combination of (i) at least one, preferably at least two, more preferably at least three, and even more preferably four HCVR FRs and (ii) at least one, preferably at least two, more preferably at least three, and even more preferably four LCVR FRs, said combination being selected from any of the combinations listed in Table 3, and, whenever applicable, X 18 is Phe(F).

[0904] According to this specific embodiment, the murine, chimeric or humanized antibody or binding fragment thereof according to the invention comprises: - HCVR comprising at least one, preferably at least two, more preferably at least three, even more preferably four of the following FRs: V selected from SEQ ID NOs: 29, 33, 36, 39, 40 and 42 H -FR1; V selected from SEQ ID NOs: 30, 34, 37 and 43 H -FR2; V selected from SEQ ID NOs: 31, 35, 38 and 41 H -FR3; V having SEQ ID NO: 32 H -FR4; and an LCVR comprising at least one, preferably at least two, more preferably at least three, even more preferably four of the following FRs: V selected from SEQ ID NOs: 48, 52 and 55 L -FR1; V selected from SEQ ID NOs: 49, 53, 56, 58, 59 and 60 L -FR2; V selected from SEQ ID NOs: 50, 54 and 57 L -FR3(X 18 is Phe(F); and V having SEQ ID NO: 51L -FR4 It may further include:

[0905] According to this specific embodiment, the murine, chimeric or humanized antibody or binding fragment thereof of the present invention may further comprise a combination of (i) at least one, preferably at least two, more preferably at least three, and ...

Claims

1. 1. An isolated anti-human CD45RC (hCD45RC) antibody or binding fragment thereof, comprising: The antibodies or binding fragments thereof are as shown in the following table: Table 1 wherein the CDRs are defined by their SEQ ID NOs. An isolated anti-human CD45RC (hCD45RC) antibody or binding fragment thereof.

2. the antibody or binding fragment thereof (a) an HCVR comprising the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 Ｈ - CDR1; (ii) V of the sequence of SEQ ID NO: 4 Ｈ - CDR2; and (iii) V of the sequence of SEQ ID NO: 3 Ｈ - CDR3; and (b) an LCVR comprising the following three CDRs: (i) V of the sequence of SEQ ID NO: 15 Ｌ CDR1 is X １２ does not exist, V Ｌ - CDR1; (ii) V of the sequence of SEQ ID NO: 16 Ｌ - CDR2; and (iii) V of the sequence of SEQ ID NO: 17 Ｌ - CDR3; 2. The isolated antibody or binding fragment thereof of claim 1, comprising:

3. the antibody or binding fragment thereof (a) an HCVR comprising the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 Ｈ - CDR1; (ii) V of the sequence of SEQ ID NO: 5 Ｈ - CDR2; and (iii) V of the sequence of SEQ ID NO: 3 Ｈ - CDR3; and (b) an LCVR comprising the following three CDRs: (i) V of the sequence of SEQ ID NO: 15 Ｌ CDR1 is X １２ does not exist, V Ｌ - CDR1; (ii) V of the sequence of SEQ ID NO: 16 Ｌ - CDR2; and (iii) V of the sequence of SEQ ID NO: 17 Ｌ - CDR3; Including, 2. The isolated antibody or binding fragment thereof of claim 1.

4. the antibody or binding fragment thereof (a) an HCVR comprising the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 Ｈ - CDR1; (ii) V of the sequence of SEQ ID NO: 100 Ｈ - CDR2; and (iii) V of the sequence of SEQ ID NO: 3 Ｈ - CDR3; and (b) an LCVR comprising the following three CDRs: (i) V of the sequence of SEQ ID NO: 18 Ｌ CDR1 is X １２ does not exist, V Ｌ - CDR1; (ii) V of the sequence of SEQ ID NO: 16 Ｌ - CDR2; and (iii) V of the sequence of SEQ ID NO: 17 Ｌ -CDR3 Including, 2. The isolated antibody or binding fragment thereof of claim 1.

5. the antibody or binding fragment thereof (a) an HCVR comprising the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 Ｈ - CDR1; (ii) V of the sequence of SEQ ID NO: 4 Ｈ - CDR2; and (iii) V of the sequence of SEQ ID NO: 3 Ｈ - CDR3; and (b) an LCVR comprising the following three CDRs: (i) V of the sequence of SEQ ID NO: 15 Ｌ CDR1 is X １２ does not exist, V Ｌ - CDR1; (ii) V of the sequence of SEQ ID NO: 120 Ｌ - CDR2; and (iii) V of the sequence of SEQ ID NO: 17 Ｌ -CDR3 Including, 2. The isolated antibody or binding fragment thereof of claim 1.

6. 6. The isolated antibody or binding fragment thereof of claim 5, wherein the antibody or binding fragment thereof comprises the HCVR of the sequence set forth in SEQ ID NO:

62.

7. the antibody or binding fragment thereof (a) an HCVR comprising the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 Ｈ - CDR1; (ii) V of the sequence of SEQ ID NO: 118 Ｈ - CDR2; and (iii) V of the sequence of SEQ ID NO: 3 Ｈ - CDR3; and (b) an LCVR comprising the following three CDRs: (i) V of the sequence of SEQ ID NO: 15 Ｌ CDR1 is X １２ does not exist, V Ｌ - CDR1; (ii) V of the sequence of SEQ ID NO: 120 Ｌ - CDR2; and (iii) V of the sequence of SEQ ID NO: 17 Ｌ -CDR3 Including, 2. The isolated antibody or binding fragment thereof of claim 1.

8. 8. The isolated antibody or binding fragment thereof of claim 7, wherein the antibody or binding fragment thereof comprises the HCVR of the sequence of SEQ ID NO:

123.

9. the antibody or binding fragment thereof 1) HCVR of sequence SEQ ID NO: 61 and LCVR of sequence SEQ ID NO: 81; 2) HCVR of sequence SEQ ID NO: 62 and LCVR of sequence SEQ ID NO: 82; 3) HCVR of sequence SEQ ID NO: 62 and LCVR of sequence SEQ ID NO: 83; 4) HCVR of sequence SEQ ID NO: 62 and LCVR of sequence SEQ ID NO: 84; 5) HCVR of sequence SEQ ID NO: 63 and LCVR of sequence SEQ ID NO: 82; 6) HCVR of sequence SEQ ID NO: 63 and LCVR of sequence SEQ ID NO: 83; 7) HCVR of sequence SEQ ID NO: 63 and LCVR of sequence SEQ ID NO: 84; 8) HCVR of sequence SEQ ID NO: 64 and LCVR of sequence SEQ ID NO: 82; 9) HCVR of sequence SEQ ID NO: 64 and LCVR of sequence SEQ ID NO: 83; 10) HCVR of sequence SEQ ID NO: 64 and LCVR of sequence SEQ ID NO: 84; 11) HCVR of sequence SEQ ID NO: 101 and LCVR of sequence SEQ ID NO: 85; 12) HCVR of sequence SEQ ID NO: 101 and LCVR of sequence SEQ ID NO: 103; 13) HCVR of sequence SEQ ID NO: 65 and LCVR of sequence SEQ ID NO: 85; or 14) HCVRs and LCVRs containing non-CDR region sequences that share at least 90% identity with the non-CDR region sequences of the HCVRs and LCVRs of 1) to 13).

2. The isolated antibody or binding fragment thereof of claim 1, comprising:

10. 10. The isolated antibody or binding fragment thereof of any one of claims 1 to 9, wherein the amino acid residue at Kabat position L71 of the LCVR is Phe (F).

11. A nucleic acid encoding the isolated antibody or binding fragment thereof of any one of claims 1 to 10.

12. An expression vector comprising the nucleic acid of claim 11.

13. A cell comprising the nucleic acid of claim 11 or the expression vector of claim 12.

14. 14. A pharmaceutical composition comprising the isolated antibody or binding fragment thereof of any one of claims 1 to 10, the nucleic acid of claim 11, the expression vector of claim 12 or the cell of claim 13, and at least one pharmaceutically acceptable excipient.

15. 15. A pharmaceutical composition according to claim 14 for use as a medicament.

16. Inducing immune tolerance in a subject in need thereof; and / or preventing and / or reducing transplant rejection; 15. The pharmaceutical composition according to claim 14 for use in

17. CD45RC 高 15. The pharmaceutical composition of claim 14 for use in preventing, reducing and / or treating a condition associated with

18. The CD45RC 高 18. The pharmaceutical composition of claim 17, wherein the pathology associated with is selected from the group consisting of an autoimmune disease, an unwanted immune response, a monogenic disease, and lymphoma or cancer.

19. 15. The pharmaceutical composition according to claim 14 for use in the prevention and / or treatment of graft-versus-host disease (GVHD).

20. 11. An in vitro method for detecting or quantifying hCD45RC in a sample, cell, tissue or organ, comprising contacting said sample, cell, tissue or organ with an isolated antibody or binding fragment thereof according to any one of claims 1 to 10.

21. 21. The method of claim 20, wherein the isolated antibody or binding fragment thereof is labeled.

22. An in vitro method for expanding and / or enhancing regulatory T cells, comprising: with the isolated antibody or binding fragment thereof of any one of claims 1 to 10.

23. 15. The pharmaceutical composition of claim 14 for use in expanding and / or enhancing regulatory T cells in a subject in need thereof.

24. CD45RC 高 An in vitro method for depleting cells, comprising: 高 A sample containing cells, or CD45RC 高 A method comprising contacting a sample suspected of containing cells with the isolated antibody or binding fragment thereof of any one of claims 1 to 10.

25. CD45RC in a subject in need thereof 高 15. The pharmaceutical composition of claim 14 for use in depleting cells.

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