Chimeric antigen receptors specific for human CD45RC and uses thereof

Abstract

The present invention relates to the field of immunotherapy. In particular, the present invention relates to chimeric antigen receptors (CARs) specific for human CD45RC, immune cells expressing said CARs and, in particular, CD45RC high The present invention relates to its use as a medicament for preventing or treating related diseases (including autoimmune diseases, unwanted immune responses, monogenic diseases, lymphoma or cancer) or graft versus host disease (GVHD).

Description

[Technical Field]

[0001] The present invention relates to the field of immunotherapy. In particular, the present invention relates to chimeric antigen receptors (CARs) specific for human CD45RC, T cells expressing said CARs and, in particular, CD45RC high The present invention relates to its use as a medicine for preventing or treating related diseases (including autoimmune diseases, unwanted immune responses, monogenic diseases, lymphoma or cancer) or 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 prototypic receptor-like protein tyrosine phosphatase (RPTP). Its expression is restricted to all nucleated hematopoietic cells and is one of the most abundant cell surface glycoproteins, comprising nearly 10 percent of the cell surface and estimated to reside 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 across 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 can be generated by dynamically regulated alternative splicing during both leukocyte differentiation and cell activation, resulting in changes in 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, which contains all three alternatively spliced ​​exons, is approximately 235 kDa, while the smallest isoform, CD45RO, which lacks all three exons, is approximately 180 kDa. In between, isoforms containing only two (e.g., CD45RAB, CD45RBC) or only one (e.g., CD45RB) of the three exons are possible.

[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 + Present on T cells, CD45RO binds to activated and memory CD4 + CD45RABC is expressed on T cells. It is also expressed on B cells and their precursors, on dendritic cells, and on a subgroup of other antigen-presenting cells. It is expressed on effector memory T cells (T EMRA ) also re-express the naive T cell marker CD45RA (Koch et al., 2008. Immun Ageing. 5:6). Importantly, this pattern of isoform expression 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 specific expression patterns of CD45RC isoforms on T cells allow differentiation between functionally distinct alloreactive T cell subsets that exhibit different behaviors with respect to proliferation and cytokine secretion. For example, in rodents, CD4 + and CD8 + Both CD45RC on T cells highHowever, potent T cells have the ability to promote transplant rejection and organ inflammation. h T cells expressing undetectable or low levels of CD45RC are T effector cells (Spickett et al., 1983. J Exp Med. 158(3):795-810; Xystrakis et al., 2004. Eur J Immunol. 34(2):408-17), whereas T cells expressing undetectable or low levels of CD45RC are T h 2 and regulatory T cells, which have been shown to 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 rates of T cells correlate with decreased graft survival in kidney transplant patients (Ordonez et al., 2013. PLoS One. 8(7):e69791).

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

[0009] 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 against recipient cells. Currently, immunosuppression with immunomodulatory drugs such as corticosteroids is the mainstay of GVHD prevention. Although progress has been made with improved long-term survival outcomes, corticosteroids do not prevent GVHD in a high percentage of patients (less than 50% of patients with acute GVHD and 40–50% of patients with chronic GVHD, depending on initial disease severity—Garnett et al., 2013. Ther Adv Hematol. 4(6):366–378). They are associated with significant toxicity, and many of the currently available salvage therapies are associated with increased immunosuppression and infectious complications. Therefore, there remains 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 high We previously described that T cell depletion could be a potential new therapeutic approach to prevent or reduce transplant rejection by increasing tolerogenic regulatory T cells while decreasing aggressive effector T cells. Indeed, transient anti-CD45RC mAb treatment resulted in rapid CD45RC upregulation while preserving memory immunity. high Furthermore, the inventors have shown that short-term anti-CD45RC antibody treatment results in permanent allograft survival without signs of chronic rejection (International Patent No. 2016016442, Picarda et al., 2017. JCI Insight. 2(3):e90088).

[0011] Here, the present inventors have developed a chimeric antigen receptor (CAR) containing an antigen-binding fragment against human CD45RC. This antigen-binding fragment competes with currently commercially available anti-human CD45RC antibodies (such as the MT2 clone) and shows a similar reactivity pattern, but its cytotoxic activity against T cells is significantly superior at the lowest concentration. In fact, the anti-hCD45RC antigen-binding fragment according to the present invention exhibits better affinity than other currently available antigen-binding fragments, thereby providing better therapeutic efficacy.

[0012] Interestingly, CARs according to the present invention can also be useful for the prevention or treatment of certain monogenic diseases in which immune response is involved in the pathology.Monogenic diseases are caused by a single gene defect.More than 4,000 human diseases are caused by these defects related to a specific gene.To date, most treatment options have focused on treating the symptoms of the disorder in an attempt to improve the quality of life of patients.Gene therapy is the main hope for the permanent treatment of this type of disease.However, the development of technology for delivering genes to the appropriate cells affected by the disorder has encountered major obstacles, not least because immune responses to transgene products or vectors limit the effectiveness of treatment.

[0013] Some monogenic disorders are associated with genes involved in the immune system (e.g., primary T-cell and / or B-cell immunodeficiency and polyendocrinopathy-candidiasis-ectodermal dystrophy [APECED]) or with genes unrelated to immune function whose defects are associated with inflammation and / or the immune response (e.g., Duchenne muscular dystrophy [DMD]).

[0014] APECED, also known as autoimmune polyglandular syndrome type 1 (APS1), is a rare, multisystem, autosomal recessive autoimmune disease caused by mutations in the AIRE gene, a transcriptional regulator that enables the expression of tissue-restricted antigens (TRAs) in medullary epithelial thymocytes (mTECs) and autoreactive T cell deletion. In humans, over 100 mutations have been described in the AIRE gene that cause APECED, with a prevalence of 1:19 million (Orphanet, http: / / www.orpha.net). The clinical phenotype of APECED is typically defined by the presence of two of three major symptoms: hypoparathyroidism, adrenal insufficiency (Addison's disease), and chronic mucocutaneous candidiasis (CMC). The disease is also associated with multiple autoimmune and ectodermal 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 single gene disease in which mutations in the DMD gene encoding the protein dystrophin lead to severe X-linked muscular dystrophy, which later affects all voluntary muscles as well as cardiac and respiratory muscles.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 corticoids 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 employed 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 therapies, life expectancy for DMD patients remains significantly reduced.

[0016] Surprisingly, the inventors found that CD45RC high Dmd cells specifically depleted by anti-CD45RC antibody - / - Rat (Dmd mdx demonstrated that treatment with the anti-CD45RC monoclonal antibody Aire increased muscle strength (Ouisse et al., 2019. Front Immunol. 9;10:2131). They also demonstrated that treatment with the anti-CD45RC monoclonal antibody Aire increased muscle strength. - / - Administration of CD45RC to rats high It has been demonstrated to result in potent depletion of T cells, leading to elimination of the symptoms characteristic of APECED (International Patent Application No. 2019115791).

[0017] Thus, CARs according to the present invention represent a promising approach for preventing and / or treating monogenic diseases such as DMD and APECED.

[0018] The present inventors also demonstrated that immune cells can be engineered to express transduced CD45RC-CAR on their cell surface. The present inventors also showed that CD45RC-CAR-transduced cells can induce apoptosis in human T cells and can be activated after contact with human T cells. [Prior art documents] [Patent documents]

[0019] [Patent Document 1] International Patent No. 2016016442 [Patent Document 2] International Patent Application No. 2019115791 [Non-patent literature]

[0020] [Non-Patent Document 1] Trowbridge & Thomas,1994.Annu Rev Immunol.12:85-116 [Non-patent document 2] Hermiston et al.,2003.Annu Rev Immunol.21:107-37 [Non-licensed Document 3] Holmes,2006.Immunology.117(2):145-55 [Non-licensed Document 4] Desai et al.,1994.EMBO J.13(17):4002-10 [Non-licensed Document 5] Palacios & Weiss,2004.Oncogene.23(48):7990-8000 [Non-licensed Document 6] Lowell,2004.Mol Immunol.41(6-7):631-43 [Non-licensed Document 7] Hall et al.,1988.J Immunol.141(8):2781-7 [Non-licensed Document 8] Lynch,2004.Nat Rev Immunol.4(12):931-40 [Non-licensed Document 9] Birkeland et al.,1989.Proc Natl Acad Sci US A.86(17):6734-8 [Non-licensed Document 10] Koch et al.,2008.Immun Ageing.5:6 [Non-licensed Document 11] Spickett et al.,1983.J Exp Med.158(3):795-810 [Non-licensed Document 12] Xystrakis et al., 2004. Eur J Immunol. 34(2):408-17 [Non-licensed Document 13] Xystrakis et al.,2004.Blood.104(10):3294-30 [Non-licensed Document 14] Guillonneau et al.,2007.J Clin Invest.117(4):1096-106 [Non-Patent Document 15] Powrie & Mason,1990.J Exp Med.172(6):1701-8 [Non-Patent Document 16] Ordonez et al.,2013.PLoS One.8(7):e69791 [Non-Patent Document 17] Garnett et al.,2013.Ther Adv Hematol.4(6):366-378 [Non-Patent Document 18] Picarda et al.,2017.JCI Insight.2(3):e90088 [Non-Patent Document 19] Rosenberg et al.,2015.Sci Transl Med.7(299):299rv4 [Non-Patent Document 20] Villalta et al.,2014.Sci Transl Med.6(258):258ra142 [Non-Patent Document 21] Ouisse et al.,2019.Front Immunol.9;10:2131 Summary of the Invention

[0021] The present invention relates to a chimeric antigen receptor (CAR) specific for human CD45RC, said CAR comprising: (a) at least one extracellular binding domain, wherein said binding domain binds to said human CD45RC; (b) optionally, at least one extracellular hinge domain; (c) at least one transmembrane domain, and (d) at least one intracellular signaling domain, wherein the intracellular domain comprises at least one T cell primary signaling domain and optionally at least one T cell costimulatory signaling domain.

[0022] In one embodiment, the extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, wherein the antigen-binding fragment is (a) HCVR containing the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 H -CDR1, (ii) V having a sequence selected from the group consisting of SEQ ID NOs: 4, 5, 6, 8, 100, 116, 117, 118, and 119. H CDR2, and (iii) V of the sequence of SEQ ID NO: 3 H CDR3, 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 has a sequence selected from the group consisting of Asn (N), Ser (S) and Gly (G). L -CDR1, (ii) V having a sequence selected from the group consisting of SEQ ID NOs: 16, 111, and 120. L CDR2, and (iii) V of the sequence of SEQ ID NO: 17 L - CDR3, including

[0023] In one embodiment, the extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, wherein the antigen-binding fragment is (a) HCVR containing the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 H -CDR1, (ii) V having a sequence selected from the group consisting of SEQ ID NOs: 4 and 5 H CDR2, and (iii) V of the sequence of SEQ ID NO: 3 H CDR3, and (b) an LCVR containing the following three CDRs: (i) SEQ ID NO: 15(X 12does not exist) 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

[0024] In one embodiment, the extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, wherein the antigen-binding fragment is (a) HCVR containing 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 containing the following three CDRs: (i) SEQ ID NO: 15(X 12 does not exist) 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

[0025] In one embodiment, the extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, wherein the antigen-binding fragment is (a) HCVR containing the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 H -CDR1, (ii) V having a sequence selected from the group consisting of SEQ ID NOs: 4, 6 and 100 H CDR2, and (iii) V of the sequence of SEQ ID NO: 3 H CDR3, and (b) an LCVR containing the following three CDRs: (i) SEQ ID NOs: 15 and 18 (X 12V having a sequence selected from the group comprising the sequences L -CDR1, (ii) V having a sequence selected from the group consisting of SEQ ID NOs: 16, 111, and 120. L CDR2, and (iii) V of the sequence of SEQ ID NO: 17 L - CDR3, including

[0026] In one embodiment, the extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, wherein the antigen-binding fragment is 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; 14) HCVR of sequence SEQ ID NO: 65 and LCVR of sequence SEQ ID NO: 103; 15) HCVR of sequence SEQ ID NO: 62 and LCVR of sequence SEQ ID NO: 85; 16) HCVR of sequence SEQ ID NO: 101 and LCVR of sequence SEQ ID NO: 82; 17) HCVR of sequence SEQ ID NO: 121 and LCVR of sequence SEQ ID NO: 85; 18) HCVR of sequence SEQ ID NO: 122 and LCVR of sequence SEQ ID NO: 85; 19) HCVR of sequence SEQ ID NO: 123 and LCVR of sequence SEQ ID NO: 85; 20) HCVR of sequence SEQ ID NO: 124 and LCVR of sequence SEQ ID NO: 85; 21) HCVR of sequence SEQ ID NO: 63 and LCVR of sequence SEQ ID NO: 85; 22) HCVR of sequence SEQ ID NO: 67 and LCVR of sequence SEQ ID NO: 85; 23) HCVR of sequence SEQ ID NO: 67 and LCVR of sequence SEQ ID NO: 103; 24) HCVR of sequence SEQ ID NO: 61 and LCVR of sequence SEQ ID NO: 113; 25) the HCVR of sequence SEQ ID NO: 61 and the LCVR of sequence SEQ ID NO: 126, or 26) HCVRs and LCVRs containing non-CDR region sequences that share at least 70% identity with the non-CDR region sequences of the HCVRs and LCVRs described in 1) to 23).

[0027] In one embodiment, the extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, wherein the antigen-binding fragment is (a) HCVR containing the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 H -CDR1, (ii) V having a sequence selected from the group consisting of SEQ ID NOs: 4, 5, 6, 8, 100, 116, 117, 118, and 119. H CDR2, and (iii) V of the sequence of SEQ ID NO: 3 H CDR3, and (b) an LCVR containing the following three CDRs: (i) SEQ ID NOs: 15 and 18 (X in SEQ ID NOs: 15 and 18) 12is selected from the group consisting of Asn (N), Ser (S) and Gly (G) 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, Preferably, the amino acid residue at Kabat position L71 of the LCVR is Phe (F).

[0028] In one embodiment, the extracellular binding domain comprises an scFv fragment against human CD45RC.

[0029] In one embodiment, the hinge domain is the hinge region of human CD8α, preferably having the sequence of SEQ ID NO: 145 or a sequence having at least 70% identity thereto.

[0030] In one embodiment, the transmembrane domain is a transmembrane domain derived from human CD8α, preferably having the sequence of SEQ ID NO: 153 or a sequence having at least 70% identity thereto.

[0031] In one embodiment, the primary intracellular signaling domain comprises the T cell primary intracellular signaling domain of human CD3 zeta, preferably having the sequence of SEQ ID NO: 157 or a sequence with at least 70% identity thereto.

[0032] In one embodiment, the costimulatory signaling domain is selected from the group consisting of a CD28 cytoplasmic signaling domain, a 4-1BB cytoplasmic signaling domain, an OX40 cytoplasmic signaling domain, an ICOS cytoplasmic signaling domain, a CD27 cytoplasmic signaling domain, and a DAP10 cytoplasmic signaling domain.

[0033] In one embodiment, a CAR according to the invention comprises: (i) an anti-human CD45RC scFv comprising an HCVR having preferably the sequence of SEQ ID NO: 61 and an LCVR having the sequence of SEQ ID NO: 81, linked by a linker having preferably the sequence of SEQ ID NO: 134; (ii) a hinge domain derived from CD8α, preferably having the sequence of SEQ ID NO: 145; (iii) a human CD8α transmembrane domain, preferably having the sequence of SEQ ID NO: 153, and (iv) an intracellular signaling domain, preferably comprising a human CD28 signaling domain having the sequence of SEQ ID NO: 167 and a human CD3 zeta signaling domain, preferably having the sequence of SEQ ID NO: 157.

[0034] The present invention also relates to a nucleic acid encoding a CAR according to the present invention.

[0035] The present invention also relates to an expression vector comprising a nucleic acid according to the invention.

[0036] The present invention further relates to immune cell populations engineered to express a CAR according to the present invention on their cell surface.

[0037] In one embodiment, the immune cell population is CD45RC neg It is a cell mass.

[0038] In one embodiment, the immune cell population is a regulatory T cell population, an effector T cell population, a memory T cell population, an NKT cell population, or an MAIT cell population.

[0039] In one embodiment, the immune cell population is a regulatory T cell population, preferably, the regulatory T cell population is CD4 + CD25 + Foxp3 + Tregs, Tr1 cells, TGF-β-secreting Th3 cells, regulatory NKT cells, regulatory γδ T cells, regulatory CD8 + T cells and double-negative regulatory T cells.

[0040] The present invention also relates to a composition comprising at least one immune cell population engineered to express a CAR according to the present invention on its cell surface, said composition preferably being a pharmaceutical composition further comprising at least one pharmaceutically acceptable excipient or carrier.

[0041] The present invention further relates to the population of immune cells according to the invention or the pharmaceutical composition according to the invention for use as a medicament.

[0042] The present invention also relates to the population of immune cells according to the invention or the composition according to the invention for use in inducing immune tolerance, preventing or reducing transplant rejection, or preventing or treating graft-versus-host disease (GVHD) in a subject in need thereof.

[0043] The present invention further relates to a CD45RC1 gene encoding a CD45RC1 gene, the CD45RC1 gene being selected from the group consisting of an autoimmune disease, an unwanted immune response, a monogenic disease, lymphoma, and cancer. high The present invention relates to a population of immune cells according to the invention or a composition according to the invention for use in the prevention, reduction and / or treatment of associated symptoms.

[0044] 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 any associated specific immunoreactivity. "Antibody" refers to such an assembly having significant known specific immunoreactive activity 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.

[0045] Antibodies and immunoglobulins comprise light and heavy chains, with or without interchain covalent bonds. 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 generally focuses on the IgG class of immunoglobulin molecules, all five classes of antibodies are within the scope of the present invention. With regard 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 supporting the heavy chains, starting at the mouth of the "Y" and continuing through the variable region. Antibody light chains are classified as either kappa (κ) or lambda (λ). Each heavy chain class may be associated with either κ or λ light chains. Generally, when immunoglobulins are produced by either hybridomas, B cells, or genetically engineered host cells, the light and heavy chains are covalently linked to each other, and the "tail" regions of the two heavy chains are bound to each other by covalent disulfide bonds or non-covalent bonds. In the heavy chain, the amino acid sequence extends from the N-terminus at the branched 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), and that there are several subclasses within these (e.g., γ1-γ4). It is the nature of this chain that determines the "class" of an antibody as IgG, IgM, IgA1, or IgE, respectively. Immunoglobulin subclasses or "isotypes" (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, etc.) have been well characterized and are known to confer functional specialization. Modified versions of each of these classes and isotypes are readily discernible to one of skill in the art in view of the present disclosure and, therefore, are 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 L domain) and heavy chain variable domain (V HThe quaternary antibody structure, consisting of the V domain and the V domain, combines to form the variable region that defines the three-dimensional antigen-binding site. This quaternary antibody structure forms the antigen-binding site present at the end of each arm of the "Y." More specifically, the antigen-binding site is H Chain and V L Each of the chains is defined by three complementarity determining regions (CDRs).

[0046] "Antibody fragments" As used herein, the term "antibody fragment" refers to at least a portion of an intact antibody, preferably the antigen-binding or variable region of the intact antibody, that retains the ability to specifically interact with an epitope of an antigen (e.g., by binding, steric hindrance, stabilization / destabilization, spatial distribution). Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab'), Fv fragments, scFv antibody fragments, disulfide-linked Fvs (sdFvs), Fd fragments consisting of the VH and CHI domains, linear antibodies, single-domain antibodies such as sdAbs (either VL or VH), camelid VHH domains, multispecific antibodies formed from antibody fragments, such as bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region, and isolated CDRs or other epitope-binding fragments of antibodies. Antigen-binding fragments can also be incorporated into single-domain antibodies, maxibodies, minibodies, nanobodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs, and bis-scFvs (see, e.g., Hollinger and Hudson, Nature Biotechnology 23:1126-1136, 2005). Antigen-binding fragments can also be grafted onto polypeptide-based scaffolds, such as fibronectin type III (see U.S. Patent No. 6,703,199, which describes a fibronectin polypeptide minibody). Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, a name reflecting their ability to readily crystallize. The Fab fragment consists of an entire L chain along with the variable region domain (VH) of the H chain and the first constant domain (CH1) of one heavy chain. Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen-binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment which roughly corresponds to two disulfide-linked Fab fragments with divalent antigen-binding activity and is still capable of cross-linking antigen.Fab' fragments differ from Fab fragments by having additional few residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine ​​residues of the constant domains bear a free thiol group. F(ab')2 antibody fragments were originally produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0047] "Binding Fragment" or "Antigen-Binding Fragment" As used herein, the term "binding fragment" refers to a portion or region of an antibody according to the present invention that contains fewer amino acid residues than the whole antibody. A "binding fragment" binds to an antigen and / or competes with the whole antibody from which it is derived for antigen binding (e.g., specific binding to human CD45RC). Antibody-binding fragments include, but are not limited to, any single-chain antibody, Fv, Fab, Fab', Fab'-SH, F(ab)'2, Fd, defucosylated antibodies, diabodies, triabodies, and tetrabodies.

[0048] "[...] characterized by the substitution of an amino acid with a different amino acid" As used herein, the phrase "characterized by the substitution of amino acids with different amino acids" in reference to a given sequence refers to the occurrence of "conservative amino acid modifications" in said sequence.

[0049] "Conservative amino acid modifications" As used herein, the term "conservative amino acid modification" refers to a modification that does not significantly affect or change the binding characteristics of the antibody or its binding fragment containing the amino acid sequence. Such conservative modifications include amino acid substitution, addition, and deletion. Modifications can be introduced into antibodies or their binding fragments by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.

[0050] Conservative amino acid substitution is typically where amino acid residue is replaced with amino acid residue that has side chain with similar physicochemical properties.Particular variable region and CDR sequence can 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 insertion, deletion and / or substitution.When substitution is made, preferred substitution is conservative modification.Family of amino acid residue with similar side chain is 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), beta-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 according to the invention can be replaced 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, for example, binding to hCD45RC) using the assays described herein. In another embodiment, a series 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.

[0051] "CDR" or "Complementarity Determining Region" As used herein, the term "CDR" or "complementarity-determining region" refers to the discontinuous antigen-binding sites found in the variable regions of both heavy and light chain polypeptides. CDRs are identified according to the rules in Table 1, which are inferred from Kabat et al., 1991. Sequences of proteins of immunological interest (5th ed.). Bethesda, MD: U.S. Department of Health and Human Services; and Chothia and Lesk, 1987. J Mol Biol. 196(4):901-17.

[0052] [Table 1] [Table 2]

[0053] "Manipulated" As used herein, the terms "engineered" or "modified" refer to cells that have been transfected, transformed or transduced.

[0054] "epitope" As used herein, the term "epitope" refers to a specific arrangement of amino acids located on one or more 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 and specific charge characteristics. Epitopes can be linear (or contiguous) or conformational, i.e., involve two or more sequences of amino acids from different regions of an antigen, which may not necessarily be contiguous.

[0055] "Fragment" As used herein, the term "fragment" of an antigen refers to any subset of the antigen as a shorter peptide. In some embodiments, a fragment of an antigen is a peptide at least 6 amino acids in length. In some embodiments, a fragment of an antigen is a peptide 6 to 50 amino acids in length, 6 to 30 amino acids in length, or 6 to 20 amino acids in length.

[0056] "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 the variable region but not part of the CDRs (e.g., using the Kabat / Chothia definition of a CDR). Thus, a variable region framework is approximately 100-120 amino acids in length, but includes only amino acids outside the CDRs.

[0057] Specific examples of HCVRs and CDRs defined by Kabat / Chothia: -FR1 may correspond to the domain of the variable region encompassing amino acids 1 to 25 according to the Chothia / AbM definition, or the last 5 residues according to the Kabat definition; -FR2 may correspond to a 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, and FR4 may correspond to the domain of the variable region from amino acids 104-110 to the end of the variable region.

[0058] The framework regions of the light chain are similarly separated by each CDR of the LCVR. In naturally occurring antibodies, the six CDRs present on each monomeric antibody are short, noncontiguous sequences of amino acids that are specifically positioned to form an antigen-binding site when the antibody assumes its three-dimensional configuration in an aqueous environment. The remaining portions of the heavy and light chain variable domains show less inter-molecular variability in amino acid sequence and are referred to as framework regions. The framework regions primarily adopt a β-sheet conformation, and the CDRs form loops that connect, and in some cases form part of, the β-sheet structure. Thus, these framework regions act as a scaffold that orients the six CDRs through inter-chain non-covalent interactions. The antigen-binding site formed by the positioned 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.

[0059] "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 hinge region, middle hinge region, and / or lower hinge region) domain, C H 2 domains, C H In one embodiment, the antibody or binding fragment thereof according to the invention comprises at least one of the three domains of an immunoglobulin heavy chain (e.g., hinge portion, C H 2 domain and C H In another embodiment, the antibody or binding fragment thereof according to the invention may comprise at least a constant domain (e.g., C3 domain). HIn 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 domain. 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 certain embodiments, the constituent constant domains of the heavy chain region are 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 The constant domain may comprise a heavy chain constant domain (C1 domain) and a hinge region derived from an IgG3 or IgG4 molecule. 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, it will be understood by those skilled in the art that the constant domain of the heavy chain region may be modified so that its amino acid sequence differs from that of a naturally occurring (wild-type) immunoglobulin molecule. That is, an antibody or binding fragment thereof according to the present invention may comprise one or more heavy chain constant domains (C2 domains) and a hinge region derived from an IgG3 or IgG4 molecule. H 1. Hinge, C H 2 or C H 3) and / or the light chain constant domain (C L ) Exemplary modifications include addition, deletion, or substitution of one or more amino acids in one or more domains.

[0060] "Hinge region" Within an antibody, the term "hinge region" refers to the 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).

[0061] Within a CAR molecule, the term "hinge region" refers to the region that connects the extracellular binding domain with the transmembrane domain.

[0062] "Super-variable loop" Hypervariable loops (HVs) are defined based on structure, while 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 The term "hypervariable loop" is not strictly synonymous with complementarity determining region (CDR), as these regions may differ in V domains. L Domains and V H The CDRs of a domain can typically be defined according to the Kabat / Chothia definition as previously described herein.

[0063] "Sameness" or "sameness" As used herein, the terms "identity" or "identical," when used in the context of 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 or nucleic acid residues. "Identity" measures the percent of identical matches between the smaller of the two or more sequences with gap alignment (if any) that is accommodated by a particular mathematical model or computer program (i.e., "algorithm").

[0064] The identity of related amino acid or nucleic acid sequences can be readily calculated by known methods. Such methods include, but are not limited to, those described in Lesk A.M. (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 primer. New York, NY: Stockton Press; Carillo et al., 1988. SIAM J Appl Math. 48(5):1073-82.

[0065] Preferred methods for determining identity are designed to maximize the 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, including 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 available from the National Center for Biotechnology Information (NCBI) and other sources (BLAST Manual, Altschul et al., NCB / NLM / NIH Bethesda, Md. 20894). The well-known Smith-Waterman algorithm can also be used to determine identity.

[0066] "immune cells" As used herein, the term "immune cells" generally includes white blood cells (leukocytes) derived from hematopoietic stem cells (HSCs) produced in the bone marrow. Examples of immune cells include, but are not limited to, lymphocytes (T cells, B cells, and natural killer (NK) cells) and bone marrow-derived cells (neutrophils, eosinophils, basophils, monocytes, macrophages, dendritic cells).

[0067] "Immunospecific," "specific," or "specifically binds" As used herein, an antibody or binding fragment thereof is one that detectably binds to an antigen (e.g., hCD45RC), preferably at about 10 6 M -1 or more, preferably about 10 7 M -1 , 10 8 M -1 , 5×10 8 M -1 , 10 9 M-1 , 5×10 9 M -1 Affinity constant (K A ) is said to be "immunospecific," "specific for," or "specifically binds" to that antigen.

[0068] The affinity of an antibody or binding fragment thereof for its cognate antigen is also generally expressed as the equilibrium dissociation constant (K D The antibody or binding fragment thereof detectably binds to the antigen (e.g., hCD45RC), preferably at a concentration of 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 When an antibody reacts with an antigen, it is said to be "immunospecific," "specific for," or "specifically binds" to that antigen.

[0069] 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 assessed using immunodetection methods including, for example, ELISA, immunofluorescence-based assays such as immunohistochemistry (IHC) and / or fluorescence-activated cell sorting (FACS), or by surface plasmon resonance (SPR, e.g., using BIAcore®).

[0070] "Isolated Antibodies" As used herein, the term "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 those that would interfere with the diagnostic or therapeutic use of the antibody, including, but not limited to, enzymes, hormones, and other proteinaceous or non-proteinaceous components.

[0071] "Isolated Nucleic Acids" As used herein, the term "isolated nucleic acid" is intended to refer to a nucleic acid that is substantially separated from other genomic DNA sequences and proteins or complexes, such as ribosomes and polymerases, that naturally accompany the natural sequence. This term encompasses nucleic acid sequences that have been removed from their naturally occurring environment, including recombinant or cloned DNA isolates and chemically synthesized analogs or biologically synthesized analogs in heterologous systems. Substantially pure nucleic acids include nucleic acids in isolated form. Of course, this refers to the nucleic acid that was originally isolated, and does not exclude genes or sequences that are later added to the isolated nucleic acid by the hand of man.

[0072] "Ligand" As used herein, the term "ligand" refers to a member of a ligand / receptor pair that binds to the other member of the pair.

[0073] "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 in the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which contain 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 can be prepared by the hybridoma methodology first described by Kohler et al., 1975. Nature. 256(5517):495-7, or can be produced using recombinant DNA methods in bacterial, eukaryotic, or plant cells (Patent US 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.

[0074] "MAIT cells" As used herein, the term "MAIT cells" refers to mucosal-associated invariant T cells. MAIT cells can be activated through their TCR and TCR-independent signals (e.g., cytokines). MAIT cells can sense bacterial or viral infection and produce effector cytokines and / or degranulate in response to these signals.

[0075] "NK cells" As used herein, "NK cells" or "natural killer cells" refer to cytotoxic lymphocytes that play an important role in innate immunity. NK cells are constantly in contact with other cells. NK cells express activating and inhibitory receptors on their cell surface. This mechanism allows NK cells to recognize whether a cell is "normal" (and therefore not eliminated) or whether a cell is "abnormal," such as a tumor cell or an infected cell (and therefore killed).

[0076] "NKT cells" As used herein, "NKT cells" or "natural killer T cells" refer to cytotoxic lymphocytes that exhibit T lymphocyte markers and NK lymphocyte markers. Natural killer (NK) cells and natural killer T (NKT) cells are two types of cells important in innate immunity. Both NK cells and NKT cells are cytotoxic cells that induce cell death of pathogenic cells as well as tumor cells. The main difference between NK cells and NKT cells is that NK cells are large granular lymphocytes, while NKT cells are a type of T cell.

[0077] "Nucleic Acid" or "Polynucleotide" As used herein, the term "nucleic acid" or "polynucleotide" refers to a polymer of nucleotides covalently linked by phosphodiester bonds, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), in either single-stranded or double-stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogs of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence also implicitly encompasses conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences, as well as the explicitly indicated sequence. Specifically, degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)).

[0078] "Prevent" or "preventing" or "prevention" As used herein, the terms "prevent," "preventing," and "prevention" refer to preventative and prophylactic measures, the purpose of which is to reduce the likelihood 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.

[0079] "promoter" As used herein, the term "promoter" refers to a DNA sequence recognized by the synthetic machinery of a cell or introduced synthetic machinery necessary to initiate the specific transcription of a polynucleotide sequence.

[0080] "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, where the subject is awaiting medical care, receiving medical care, has been the subject of medical treatment, is the subject of medical treatment, or is being monitored for the development of disease. The term "mammal," as used herein, refers to any mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, cats, cows, horses, sheep, pigs, goats, rabbits, etc.; preferably, the mammal is a primate, more preferably a human.

[0081] "Transfected" or "Transformed" or "Transduced" As used herein, the terms "transfected" or "transformed" or "transduced" refer to the process by which exogenous nucleic acid is transferred or introduced into a host cell. A "transfected" or "transformed" or "transduced" cell is one that has been transfected, transformed or transduced with exogenous nucleic acid. The cell includes the primary subject cell and its progeny.

[0082] "Treat" or "Cure" or "Palliation" As used herein, the terms "treat" or "treatment" or "palliative" refer to therapeutic treatment, excluding preventative or prophylactic measures, the purpose of which is to slow (alleviate) the targeted pathological condition or disorder. Those in need of treatment include those already with the disorder and those suspected of having the disorder. A subject is successfully "treated" for a target pathological condition or disorder if, after receiving a therapeutic amount of an isolated antibody or binding fragment thereof, nucleic acid, expression vector, composition, pharmaceutical composition or medicament according to the invention, said subject exhibits an observable and / or measurable decrease in one or more of the following: CD45RC high Decreased number of cells, CD45RC higha reduction in the percent of total cells that are cytotoxic, some alleviation of 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 treatment and improvement of disease are readily measurable by routine procedures familiar to physicians.

[0083] "Treg cells" As used herein, the term "Treg cells" refers to cells that are capable of suppressing, inhibiting, or preventing excessive or unwanted inflammatory responses, such as autoimmune or allergic reactions. In one embodiment, the Treg cell population of the present invention is capable of suppressive activity. In one embodiment, said suppressive activity is contact-independent. In another embodiment, said suppressive activity is contact-dependent. In one embodiment, the Treg cell population of the present invention exhibits a suppressive effect on effector T cells, preferably, said suppressive effect is dependent on TCR expression and / or activation.

[0084] "Teff cells" As used herein, the term "Teff cell" refers to T effector cell. Teff cell includes CD4+ T helper cell and CD8+ cytotoxic T cell. Teff cell plays a central role in cell-mediated immunity after antigen challenge. Treg cell is an important regulator of Teff cell.

[0085] "Memory T cells" As used herein, the term "memory T cells" refers to a subset of T cells that have previously encountered and responded to their cognate antigen. Compared to naive T cells, which have not yet been exposed to an antigen, memory T cells are able to mount a faster and stronger immune response.

[0086] "Variable region" or "variable domain" As used herein, the term "variable" refers to a variable domain V H and V LThis refers to the fact that certain regions of the V domains differ significantly 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 V domains of antibodies. This is due to the fact that the V domains, which form part of the antigen-binding site, are not uniformly distributed throughout the V L Domains and V H Each domain is concentrated in three segments called "hypervariable loops."

[0087] 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 residues 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).

[0088] 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 L Domains can be defined as containing residues 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).

[0089] 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 containing residues 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).

[0090] Unless otherwise indicated, the terms L1, L2 and L3 refer to VL The terms H1, H2, and H3 refer to the first, second, and third hypervariable loops of the Vκ and Vλ domains, respectively, 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 herein above.

[0091] "Mutant" The term "variant" of an antigen, as used herein, refers to an antigen that is substantially identical to the native antigen and shares the same biological activity. The minimal difference between the native antigen and its variant may be, for example, amino acid substitution, deletion, and / or addition. Such variants may contain, for example, conservative amino acid substitutions. In some embodiments, variants of an antigen exhibit at least or about 70, 75, 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% sequence identity with the sequence of the native antigen. DETAILED DESCRIPTION OF THE INVENTION

[0092] A first aspect of the present invention relates to a chimeric antigen receptor (CAR) specific for human CD45RC, the CAR comprising at least one extracellular binding domain that binds to the human CD45RC. In one embodiment, the extracellular binding domain is an antigen-binding domain, such as an antibody or binding fragment thereof, as described below.

[0093] Disclosed herein is an isolated antibody or binding fragment thereof that binds to human CD45RC (hCD45RC). The isolated antibody or binding fragment thereof may be purified.

[0094] Preferably, the isolated antibody or binding fragment thereof comprises: (1) greater than 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95% or more by weight, most preferably greater than 96%, 97%, 98% or 99% by weight, of the antibody or binding fragment thereof as determined by the Lowry method; (2) sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence using a spinning cup sequencer; or (3) Purified to homogeneity as shown by SDS-PAGE under reducing or non-reducing conditions using Coomassie blue or, preferably, silver staining. The antibodies or binding fragments thereof described herein bind to human CD45RC (hCD45RC).

[0095] As used herein, the term "CD45" (also known as CD45R or PTPRC) refers to a transmembrane glycoprotein that exists in different isoforms. These different isoforms of CD45 differ in their extracellular domain structure, resulting from alternative splicing of three variable exons (exons 4, 5, and 6), which 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 the A, B, and C determinants, respectively. The various isoforms of CD45 have different extracellular domains but share the same extracellular sequence proximal to the membrane, as well as a large cytoplasmic tail segment containing a transmembrane domain and two highly conserved phosphatase domains with approximately 300 tandem residues of homology. CD45 and its isoforms noncovalently associate with lymphocyte phosphatase-associated phosphoproteins (LPAPs) 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 implies that CD45 is of human origin.

[0096] As used herein, the term "CD45RC" 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, which encodes the C determinant (hence the term CD45RC, i.e., C-determinant-restricted CD45), but lacks exons 4 and 5, which encode the A and B determinants, respectively. The amino acid sequence of human CD45RC is given in SEQ ID NO: 104, corresponding to UniProt Accession P08575-10 (Version 10, revised March 28, 2018 - Checksum: F92C874C9A114890). This CD45RC isoform is expressed on B cells, as well as 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 (A, B, or C), depending on the determinant they recognize. When preceded by the letter "h" (e.g., hCD45RC), it implies that CD45RC is of human origin.

[0097] In one embodiment, the antibody or binding fragment thereof binds to the extracellular domain of hCD45RC.In one embodiment, the antibody or binding fragment thereof binds to at least one epitope present on the extracellular domain of hCD45RC.

[0098] In one embodiment, the antibody or binding fragment thereof binds to a C determinant encoded by exon 6 of hCD45. In one embodiment, the antibody or binding fragment thereof binds to at least one epitope on a C determinant encoded by exon 6 of hCD45.

[0099] 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.

[0100] SEQ ID NO: 23 DVPGERSTASTFPTDPVSPLTTTLSLAHHSSAALPARTSNTTITANTS SEQ ID NO: 24 GATGTCCCAGGAGAGAGGAGTACAGCCAGCACCTTTCCTACAGACCCAGTTTCCCCATTGACAACCACCCTCAGCTTGCACACCACAGCTCTGCTGCCTTACCTGCACGCACCTCCAACACCACCATCACAGCGAACACCTCA

[0101] In one embodiment, the antibody or binding fragment thereof binds to at least one epitope comprising or consisting of SEQ ID NO: 23 or a fragment thereof.

[0102] In one embodiment, the antibody or binding fragment thereof 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.

[0103] In one embodiment, the antibody or binding fragment thereof binds to at least one epitope encoded by a nucleic acid sequence comprising or consisting of SEQ ID NO:24 or a fragment thereof.

[0104] In one embodiment, the antibody or binding fragment thereof 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.

[0105] In one embodiment, the antibody or binding fragment thereof 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 identity to SEQ ID NO: 23 or a fragment thereof.

[0106] In one embodiment, the antibody or binding fragment thereof 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.

[0107] 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.

[0108] In one embodiment, the at least one epitopic fragment comprising or consisting of SEQ ID NO: 23 is 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, 1000, 80, 290, 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, 71 0, 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 The amino acid sequence may comprise or consist 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 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.

[0109] 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 P08575-3 (version 3, modified March 28, 2018 - checksum: 6E942E2BF6B17AC5).

[0110] SEQ ID NO: 99 (SEQ ID NO: 23 is underlined) MTMYLWLKLLAFGFAFLDTEVFVTGQSPTPSPTGLTTAKMPSVPLSSDPLPTHTTAFSPASTFERENDFSETTTSLSPDNTSTQVSPDSLDNASAFNTTGVSSVQTPHLPTHADSQTPSAGTDTQTFSGSAANAKLNPTPGSNAIS DVPGERSTASTFPTDPVSPLTTTLSLAHHSSAALPARTSNTTITANTS

[0111] In one embodiment, the sequence comprising SEQ ID NO: 23 is the sequence of hCD45RC set forth in SEQ ID NO: 104, which corresponds to UniProt accession P08575-10 (version 10, modified March 28, 2018 - checksum: F92C874C9A114890).

[0112] SEQ ID NO: 104 (SEQ ID NO: 23 is underlined) MTMYLWLKLLAFGFAFLDTEVFVTGQSPTPSPT DVPGERSTASTFPTDPVSPLTTTLSLAHHSSAALPARTSNTTITANTS

[0113] In one embodiment, the antibody or binding fragment thereof does not bind to the A determinant encoded by exon 4 of hCD45. In one embodiment, the antibody or binding fragment thereof does not bind to at least one epitope on the A determinant encoded by exon 4 of hCD45.

[0114] 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.

[0115] SEQ ID NO: 105 GLTTAKMPSVPLSSDPLPTHTTAFSPASTFERENDFSETTTSLSPDNTSTQVSPDSLDNASAFNTT

[0116] In one embodiment, the antibody or binding fragment thereof does not bind to a B determinant encoded by exon 5 of hCD45. In one embodiment, the antibody or binding fragment thereof does not bind to at least one epitope on a B determinant encoded by exon 5 of hCD45.

[0117] 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.

[0118] SEQ ID NO: 106 GVSSVQTPHLPTHADSQTPSAGTDTQTFSGSAANAKLNPTPGSNAIS

[0119] In one embodiment, the antibody or binding fragment thereof does not bind to hCD45RA. In one embodiment, the antibody or binding fragment thereof does not bind to at least one epitope of hCD45RA.

[0120] In one embodiment, the amino acid sequence of hCD45RA comprises or consists of SEQ ID NO: 107, which corresponds to UniProt accession P08575-8 (version 8, modified March 28, 2018 - checksum: F42C1FEC9EDE4BC0).

[0121] SEQ ID NO: 107

[0122] In one embodiment, the antibody or binding fragment thereof does not bind to hCD45RB. In one embodiment, the antibody or binding fragment thereof does not bind to at least one epitope of hCD45RB.

[0123] In one embodiment, the amino acid sequence of hCD45RB comprises or consists of SEQ ID NO: 108, which corresponds to UniProt accession P08575-9 (version 9, modified March 28, 2018 - checksum: 745870037910C575).

[0124] SEQ ID NO: 108

[0125] In one embodiment, the antibody or binding fragment thereof does not bind to hCD45RAB. In one embodiment, the antibody or binding fragment thereof does not bind to at least one epitope of hCD45RAB.

[0126] In one embodiment, the amino acid sequence of hCD45RAB comprises or consists of SEQ ID NO: 109, which corresponds to UniProt accession P08575-5 (version 5, modified March 28, 2018 - checksum: EA40BE995CD98F7C).

[0127] SEQ ID NO: 109

[0128] In one embodiment, the antibody or binding fragment thereof does not bind to hCD45R0.In one embodiment, the antibody or binding fragment thereof does not bind to at least one epitope of hCD45R0.

[0129] In one embodiment, the amino acid sequence of hCD45R0 comprises or consists of SEQ ID NO: 110, which corresponds to UniProt accession P08575-4 (version 4, modified March 28, 2018 - checksum: D3CB364EF4243384).

[0130] SEQ ID NO: 110

[0131] In one embodiment, at least one epitope is a conformational epitope. In another embodiment, at least one epitope is a continuous epitope.

[0132] In one embodiment, the antibody or binding fragment thereof 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.

[0133] In one embodiment, the antibody or binding fragment thereof is about 1 x 10 4 M -1 sec -1 or more, preferably about 5 × 10 4 M -1 sec -1 More than 1 × 10 5 M -1 sec -1 That's about 2.5 x 10 5 M -1 sec -1 That's about 5 x 10 5 M -1 sec -1 Association rate (K on ) binds to hCD45RC.

[0134] In one embodiment, the antibody or binding fragment thereof is about 5×10 -2 sec -1 Less than or equal to about 4 x 10 -2 sec -1 Below, approximately 3×10 -2 sec -1 Below, approximately 2×10 -2 sec -1 Below, approximately 1.5×10 -2 sec -1 The following dissociation rate (K off ) binds to hCD45RC.

[0135] In one embodiment, the antibody or binding fragment thereof -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 sec -1 or more, preferably about 5 × 10 4 M -1 sec -1 More than 1 × 10 5 M -1 sec -1 That's about 2.5 x 10 5 M -1 sec -1 That's about 5 x 10 5 M -1 sec -1 Association rate (K on ), and -About 5×10 -2 sec -1 Less than or equal to about 4 x 10 -2 sec -1 Below, approximately 3×10 -2 sec -1 Below, approximately 2×10 -2 sec -1 Below, approximately 1.5×10 -2 sec -1 The following dissociation rate (K off ), at least one, preferably at least two, more preferably three of these bind to hCD45RC.

[0136] The affinity of an antibody or binding fragment thereof for its ligand (e.g., K d , k off , and k onMethods for determining the markers of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-30, IL-31, IL-32, IL-33, IL-34, IL-35, IL-36, IL-37, IL-38, IL-49, IL-41, IL-42, IL-43, IL-44, IL-45, IL-46, IL-47, IL-

[0137] 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.

[0138] In one embodiment, the antibody or binding fragment thereof is a polyclonal antibody or binding fragment thereof.

[0139] In a preferred embodiment, the antibody or binding fragment thereof is a monoclonal antibody or binding fragment thereof.

[0140] In one embodiment, the antibody or binding fragment thereof 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.

[0141] 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 according to conventional techniques. It will also be understood that antibodies or their binding fragments can be modified using known methods. For example, antibodies or their binding fragments can be modified with polyethylene glycol (PEG) to slow in vivo clearance and achieve a more desirable pharmacokinetic profile. Methods for linking and site-specific conjugation of PEG to antibodies or their binding fragments 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.

[0142] In one embodiment, the antibody or binding fragment thereof is a molecule selected from the group comprising or consisting of a unibody, a domain antibody, and a nanobody.

[0143] In one embodiment, the antibody or binding fragment thereof is a mimetic selected from the group comprising or consisting of an affibody, affilin, affitin, addectin, attomers, evasins, DARPins, anticalins, avimers, fynomers, versabodies, and duocalins.

[0144] In one embodiment, antibodies or binding fragments thereof also include multispecific antibodies or binding fragments thereof, i.e., multispecific antibodies or binding fragments thereof that are immunospecific for two or more, e.g., at least two, different antigens, one of which is hCD45RC according to the present invention.

[0145] In one embodiment, an antibody or binding fragment thereof also includes a polymer of an antibody or binding fragment thereof, i.e., two or more, e.g., at least two, antibodies or binding fragments thereof, whether the same or different, that are covalently linked directly or indirectly.

[0146] Hereinafter, unless otherwise stated, the numbering and definitions of the CDRs follow the definitions of Kabat / Chothia.

[0147] In one embodiment, the antibody or binding fragment thereof comprises a heavy chain variable region (referred to herein as HCVR or V) comprising at least one, preferably at least two, and 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); X 10 is selected from Lys (K) and Gln (Q).

[0148] In one embodiment, the antibody or binding fragment thereof comprises 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), 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); X 10 is selected from Lys (K) and Gln (Q).

[0149] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0150] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0151] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0152] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0153] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0154] In one embodiment, the antibody or binding fragment thereof comprises the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1), V HCDR2: DIFPGGGYTNYAEKFQG (SEQ ID NO: 6), and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0155] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0156] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0157] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0158] In one embodiment, the antibody or binding fragment thereof comprises the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1), V HCDR2: DIFPGGSYTNYADSVKG (SEQ ID NO: 8), and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0159] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0160] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0161] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0162] In one embodiment, the antibody or binding fragment thereof comprises the following three CDRs: V H - CDR1: NYYIG (SEQ ID NO: 1), V HCDR2: IIFPGGSYTNYSPSFQG (SEQ ID NO: 10), and V H - CDR3: RNFDY (SEQ ID NO: 3).

[0163] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0164] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0165] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0166] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0167] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0168] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0169] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0170] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0171] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0172] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0173] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0174] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0175] In one embodiment, the antibody or binding fragment thereof comprises a light chain variable region (referred to herein as LCVR or V) comprising at least one, preferably at least two, and 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 absent or 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), X 17 is selected from Gln (Q) and His (H).

[0176] In one embodiment, the antibody or binding fragment thereof comprises 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 absent or 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), X 17 is selected from Gln (Q) and His (H).

[0177] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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), X 17 is Gln(Q).

[0178] In one embodiment, the antibody or binding fragment thereof comprises 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), X 17 is Gln(Q).

[0179] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0180] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0181] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and more preferably the following three CDRs: V L - CDR1: SASSSVSYMH (SEQ ID NO: 15), V LCDR2: NTSN LPS (SEQ ID NO: 16), and V L - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0182] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0183] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0184] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0185] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0186] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0187] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0188] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0189] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0190] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0191] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0192] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0193] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0194] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0195] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0196] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0197] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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 absent or selected from Asn (N), Ser (S) and Gly (G).

[0198] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0199] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0200] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0201] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0202] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0203] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0204] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0205] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0206] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0207] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0208] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0209] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0210] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0211] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0212] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0213] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0214] In one embodiment, the antibody or binding fragment thereof comprises 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 12is selected from Asn (N), Ser (S) and Gly (G).

[0215] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0216] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0217] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0218] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0219] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0220] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0221] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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 absent or selected from Asn (N), Ser (S) and Gly (G).

[0222] In one embodiment, the antibody or binding fragment thereof comprises 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 absent or selected from Asn (N), Ser (S) and Gly (G).

[0223] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0224] In one embodiment, the antibody or binding fragment thereof comprises the following three CDRs: V L -CDR1:SASSSVS-X 12 -YMH (SEQ ID NO: 15), V L CDR2: NTANLPS (SEQ ID NO: 120), and VL - CDR3: QQRSSYPLTF (SEQ ID NO: 17).

[0225] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0226] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0227] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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 12is absent or selected from Asn (N), Ser (S) and Gly (G), X 13 is any amino acid other than Ala (A) or Asn (N).

[0228] In one embodiment, the antibody or binding fragment thereof comprises 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), X 13 is any amino acid other than Ala (A) or Asn (N).

[0229] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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).

[0230] In one embodiment, the antibody or binding fragment thereof comprises 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).

[0231] In one embodiment, the antibody or binding fragment thereof comprises at least one, preferably at least two, and 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), X 13 is any amino acid other than Ala (A) or Asn (N).

[0232] In one embodiment, the antibody or binding fragment thereof comprises 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), X 13 is any amino acid other than Ala (A) or Asn (N).

[0233] In one embodiment, the antibody or binding fragment thereof - 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); X10 is selected from Lys (K) and Gln (Q), X 11 is selected from Ser (S) and Arg (R); X 12 is absent or 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), X 17 is selected from Gln (Q) and His (H).

[0234] In one embodiment, the antibody or binding fragment thereof -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-X 10 -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 VL -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 absent or 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), X 17 is selected from Gln (Q) and His (H).

[0235] In one embodiment, the antibody or binding fragment thereof 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 as defined in Table 2.

[0236] In one embodiment, the antibody or binding fragment thereof 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.

[0237] Table 2. Preferred combinations of CDRs of HCVRs and CDRs of LCVRs. The CDRs are identified by their SEQ ID NOs (where applicable, X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), and X 13 is defined as any amino acid other than Ala (A) or Asn (N). [Table 3] TIFF0007796034000004.tif242160TIFF0007796034000005.tif76160

[0238] In one embodiment, V as defined herein above H -CDR1, V H -CDR2, V H -CDR3, V L -CDR1, V L CDR2 and / or V L - Any of the CDR3 may be characterized by the substitution of 1, 2, 3, 4, 5 or more amino acids by different amino acids.

[0239] In one embodiment, V as defined herein above H -CDR1, V H -CDR2, V H -CDR3, V L -CDR1, V LCDR2 and / or V L - Any of the CDR3s 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 CDR or set of CDRs defined herein above.

[0240] In one embodiment, the antibody or binding fragment thereof 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.

[0241] In one embodiment, the antibody or binding fragment thereof 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.

[0242] In one embodiment, the antibody or binding fragment thereof -HCVR containing the following three CDRs: V of the sequence of 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 of the sequence of SEQ ID NO: 3 H CDR3, and -LCVR containing the following three CDRs: SEQ ID NOs: 15 and 18(X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12V is selected from the group consisting of or including the sequence L -CDR1, V comprising or selected from the group consisting of SEQ ID NOs: 16, 111 and 120 L CDR2, and V of the sequence of SEQ ID NO: 17 L - CDR3, including

[0243] In one embodiment, the antibody or binding fragment thereof -HCVR containing the following three CDRs: V of the sequence of 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 of the sequence of SEQ ID NO: 3 H CDR3, and -LCVR containing the following three CDRs: SEQ ID NO: 15(X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist) L -CDR1, V of sequence SEQ ID NO: 16 L CDR2, and V of the sequence of SEQ ID NO: 17 L - CDR3, including

[0244] In one embodiment, the antibody or binding fragment thereof -HCVR containing the following three CDRs: V of the sequence of SEQ ID NO: 1 H -CDR1, V comprising or selected from the group consisting of SEQ ID NOs: 4, 5, 6 and 100 H CDR2, and V of the sequence of SEQ ID NO: 3 H CDR3, and -LCVR containing the following three CDRs: SEQ ID NOs: 15 and 18(X12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 V is selected from the group consisting of or including the sequence L -CDR1, V of sequence SEQ ID NO: 16 L CDR2, and V of the sequence of SEQ ID NO: 17 L - CDR3, including

[0245] In one embodiment, the antibody or binding fragment thereof -HCVR containing the following three CDRs: V of the sequence of SEQ ID NO: 1 H -CDR1, V comprising or selected from the group consisting of SEQ ID NOs: 4, 6 and 100 H CDR2, and V of the sequence of SEQ ID NO: 3 H CDR3, and -LCVR containing the following three CDRs: SEQ ID NOs: 15 and 18(X 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 V is selected from the group consisting of or including the sequence L -CDR1, V of sequence SEQ ID NO: 16 L CDR2, and V of the sequence of SEQ ID NO: 17 L - CDR3, including

[0246] In one embodiment, the antibody or binding fragment thereof 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.

[0247] In one embodiment, the antibody or binding fragment thereof 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.

[0248] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0249] In one embodiment, the antibody or binding fragment thereof 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.

[0250] In one embodiment, the antibody or binding fragment thereof 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.

[0251] In one embodiment, the antibody or binding fragment thereof 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: 18 12 is absent or selected from Asn (N), Ser (S) and Gly (G), preferably X 12 does not exist.

[0252] In one embodiment, the antibody or binding fragment thereof 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 #7 as defined in Table 2.

[0253] In one embodiment, the antibody or binding fragment thereof 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.

[0254] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0255] In one embodiment, the antibody or binding fragment thereof 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.

[0256] In one embodiment, the antibody or binding fragment thereof 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.

[0257] In one embodiment, the antibody or binding fragment thereof 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, 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.

[0258] In one embodiment, the antibody or binding fragment thereof 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.

[0259] In one embodiment, the antibody or binding fragment thereof 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.

[0260] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0261] In one embodiment, the antibody or binding fragment thereof 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.

[0262] In one embodiment, the antibody or binding fragment thereof 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.

[0263] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0264] In one embodiment, the antibody or binding fragment thereof 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.

[0265] In one embodiment, the antibody or binding fragment thereof 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.

[0266] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0267] In one embodiment, the antibody or binding fragment thereof 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.

[0268] In one embodiment, the antibody or binding fragment thereof 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.

[0269] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0270] In one embodiment, the antibody or binding fragment thereof 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 #63 as defined in Table 2.

[0271] In one embodiment, the antibody or binding fragment thereof 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.

[0272] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0273] In one embodiment, the antibody or binding fragment thereof 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 #65 as defined in Table 2.

[0274] In one embodiment, the antibody or binding fragment thereof 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.

[0275] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0276] In one embodiment, the antibody or binding fragment thereof 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 #72 as defined in Table 2.

[0277] In one embodiment, the antibody or binding fragment thereof 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.

[0278] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0279] In one embodiment, the antibody or binding fragment thereof 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.

[0280] In one embodiment, the antibody or binding fragment thereof 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.

[0281] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0282] In one embodiment, the antibody or binding fragment thereof 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 #86 as defined in Table 2.

[0283] In one embodiment, the antibody or binding fragment thereof 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.

[0284] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0285] In one embodiment, the antibody or binding fragment thereof 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 #92 as defined in Table 2.

[0286] In one embodiment, the antibody or binding fragment thereof 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.

[0287] In one embodiment, the antibody or binding fragment thereof 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, wherein 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.

[0288] In one embodiment, the antibody or binding fragment thereof 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: QVQLQQSGAELVRPVTSVKMSCKAAGYTFT (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).

[0289] In one embodiment, the antibody or binding fragment thereof comprises an HCVR comprising the four following FRs: V H - FR1: QVQLQQSGAELVRPVTSVKMSCKAAGYTFT (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).

[0290] In one embodiment, the antibody or binding fragment thereof 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).

[0291] In one embodiment, the antibody or binding fragment thereof comprises an HCVR comprising the four 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).

[0292] In one embodiment, the antibody or binding fragment thereof 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).

[0293] In one embodiment, the antibody or binding fragment thereof comprises an HCVR comprising the four 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).

[0294] In one embodiment, the antibody or binding fragment thereof 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).

[0295] In one embodiment, the antibody or binding fragment thereof comprises an HCVR comprising the four 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).

[0296] In one embodiment, the antibody or binding fragment thereof 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).

[0297] In one embodiment, the antibody or binding fragment thereof comprises an HCVR comprising the four 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).

[0298] In one embodiment, the antibody or binding fragment thereof 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).

[0299] In one embodiment, the antibody or binding fragment thereof comprises an HCVR comprising the four 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).

[0300] In one embodiment, the antibody or binding fragment thereof 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).

[0301] In one embodiment, the antibody or binding fragment thereof comprises an HCVR comprising the four 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).

[0302] In one embodiment, the antibody or binding fragment thereof 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).

[0303] In one embodiment, the antibody or binding fragment thereof comprises an HCVR comprising the four 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).

[0304] In one embodiment, the antibody or binding fragment thereof comprises a 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).

[0305] In one embodiment, the antibody or binding fragment thereof comprises an LCVR comprising the four 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).

[0306] In one embodiment, the antibody or binding fragment thereof comprises a 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 Tyr(Y).

[0307] In one embodiment, the antibody or binding fragment thereof 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 Tyr(Y).

[0308] In one embodiment, the antibody or binding fragment thereof comprises a 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 18 is Tyr(Y).

[0309] In one embodiment, the antibody or binding fragment thereof 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).

[0310] In one embodiment, the antibody or binding fragment thereof comprises a 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).

[0311] In one embodiment, the antibody or binding fragment thereof comprises an LCVR comprising the four 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).

[0312] In one embodiment, the antibody or binding fragment thereof comprises a 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).

[0313] In one embodiment, the antibody or binding fragment thereof comprises an LCVR comprising the four following FRs: V L - FR1:DIQLTQSPSFLSASVGDRVTITC (SEQ ID NO: 48), V L - FR2: WYQQKPGKAPKLWIY (SEQ ID NO: 58), VL -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).

[0314] In one embodiment, the antibody or binding fragment thereof comprises a 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).

[0315] In one embodiment, the antibody or binding fragment thereof 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 Phe(F).

[0316] In one embodiment, the antibody or binding fragment thereof comprises a 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).

[0317] In one embodiment, the antibody or binding fragment thereof comprises an LCVR comprising the four 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).

[0318] In one embodiment, the antibody or binding fragment thereof comprises a 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).

[0319] In one embodiment, the antibody or binding fragment thereof 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).

[0320] In one embodiment, the antibody or binding fragment thereof comprises a 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: WFQKPGKAPKLWIY (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).

[0321] In one embodiment, the antibody or binding fragment thereof comprises an LCVR comprising the four following FRs: V L - FR1:DIQLTQSPSFLSASVGDRVTITC (SEQ ID NO: 48), V L - FR2: WFQKPGKAPKLWIY (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).

[0322] In one embodiment, the antibody or binding fragment thereof comprises a combination of (i) the FRs of at least one, preferably at least two, more preferably at least three, and even more preferably four HCVRs and (ii) the FRs of at least one, preferably at least two, more preferably at least three, and even more preferably four LCVRs, wherein said combinations are as defined in Table 3.

[0323] In one embodiment, the antibody or binding fragment thereof 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.

[0324] Table 3. Preferred combinations of FRs of HCVRs and FRs of LCVRs. FRs are listed in their SEQ ID NOs (where applicable, X 18 is selected from Tyr (Y) and Phe (F). [Table 4] TIFF0007796034000007.tif38162

[0325] In one embodiment, V as defined herein 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 -FR4 can be characterized by 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids being substituted with different amino acids.

[0326] In one embodiment, V as defined herein 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 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 herein above.

[0327] In one embodiment, the antibody or binding fragment thereof V as defined herein above H -FR1, V as defined herein above H -CDR1, V as defined herein above H -FR2, V as defined herein above H -CDR2, V as defined herein above H -FR3, V as defined herein above H CDR3, and V as defined herein above H -FR4, or an HCVR comprising or consisting of:

[0328] In one embodiment, the antibody or binding fragment thereof - 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, or an HCVR comprising or consisting of:

[0329] In one embodiment, the antibody or binding fragment thereof - 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, and - V selected from SEQ ID NOs: 28 and 32 H -FR4, or an HCVR comprising or consisting of:

[0330] In a preferred embodiment, the antibody or binding fragment thereof is 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.

[0331] 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 5]

[0332] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence of SEQ ID NO: 61, 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 sequence of the non-CDR region of SEQ ID NO: 61.

[0333] SEQ ID NO: 61 QVQLQQSGAELVRPGTSVKMSCKAAGYTFTNYYIGWVKQRPGHGLEWIGDIFPGGDYANSNEKFKGKATLTADTSSSTAYMQLSSLTSEDSAIYYCVRRNFDYWGQGTTLTVSS

[0334] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence of SEQ ID NO: 62, 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: 62.

[0335] SEQ ID NO: 62 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGDYANSNEKFKGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0336] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence of SEQ ID NO: 63, 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 sequence of the non-CDR region of SEQ ID NO: 63.

[0337] SEQ ID NO: 63 EVQLVQSGAEVKKPGESLKISCKASGYTFTNYYIGWVRQMPGKGLEWIGDIFPGGDYANSNEKFKGQVTLSADKSISTAYLQLSSLKASDTAMYYCVRRNFDYWGQGTLVTVSS

[0338] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence of SEQ ID NO: 64, 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: 64.

[0339] SEQ ID NO: 64 QVQLVESGGGLVKPGGSLRLSCAASGYTFTNYYIGWIRQAPGKGLEWIGDIFPGGDYANSNEKVKGRFTLSADTAKNSAYLQMNSLRAEDTAVYYCVRRNFDYWGQGTLVTVSS

[0340] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence 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.

[0341] SEQ ID NO: 65 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGYTNYAEKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0342] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence of SEQ ID NO: 66, 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: 66.

[0343] SEQ ID NO: 66 EVQLVQSGAEVKKPGESLKISCKGSGYTFTNYYIGWVRQMPGKGLEWIGDIFPGGSYTNYSESFQGQVTLSADKSISTAYLQLSSLKASDTAMYYCVRRNFDYWGQGTLVTVSS

[0344] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence 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.

[0345] SEQ ID NO: 67 QVQLVESGGGLVKPGGSLRLSCAASGFTFSNYYIGWIRQAPGKGLEWIGDIFPGGSYTNYADSVKGRFTLSADTAKNSLYLQMNSLRAEDTAVYYCVRRNFDYWGQGTLVTVSS

[0346] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence of SEQ ID NO: 68, 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: 68.

[0347] SEQ ID NO: 68 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGRIFPGGGYTNYAQKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0348] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence of SEQ ID NO: 69, 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: 69.

[0349] SEQ ID NO: 69 EVQLVQSGAEVKKPGESLKISCKGSGYSFTNYYIGWVRQMPGKGLEWIGIIFPGGSYTNYSPSFQGQVTLSADKSISTAYLQLSSLKASDTAMYYCVRRNFDYWGQGTLVTVSS

[0350] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence 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.

[0351] SEQ ID NO: 70 QVQLVESGGGLVKPGGSLRLSCAASGFTFSNYYIGWIRQAPGKGLEWVGDIFSGGSYTNYADSVKGRFTLSADTAKNSLYLQMNSLRAEDTAVYYCVRRNFDYWGQGTLVTVSS

[0352] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence of SEQ ID NO: 101, 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: 101.

[0353] SEQ ID NO: 101 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGDYTNYAEKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0354] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence 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 sequence of the non-CDR region of SEQ ID NO: 121.

[0355] SEQ ID NO: 121 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGYANYAEKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0356] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence of SEQ ID NO: 122, 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: 122.

[0357] SEQ ID NO: 122 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGYTNYAEKFKGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0358] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence 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 sequence of the non-CDR region of SEQ ID NO: 123.

[0359] SEQ ID NO: 123 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGYTNYNEKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0360] In a preferred embodiment, the antibody or binding fragment thereof comprises an HCVR comprising or consisting of the sequence 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.

[0361] SEQ ID NO: 124 QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYIGWVRQAPGQGLEWIGDIFPGGYTNSAEKFQGRVTLTADTSISTAYMELSRLRSDDTVVYYCVRRNFDYWGQGTLVTVSS

[0362] In one embodiment, the antibody or binding fragment thereof V as defined herein above L -FR1, V as defined herein above L -CDR1, V as defined herein above L -FR2, V as defined herein above L -CDR2, V as defined herein above L -FR3, V as defined herein above L CDR3, and V as defined herein above L -FR4, or an LCVR consisting of them.

[0363] In one embodiment, the antibody or binding fragment thereof - 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, and - V selected from SEQ ID NOs: 47 and 51 L -FR4, or an HCVR comprising or consisting of:

[0364] In one embodiment, the antibody or binding fragment thereof - 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, and - V selected from SEQ ID NOs: 47 and 51 L -FR4, or an HCVR comprising or consisting of:

[0365] In a preferred embodiment, the antibody or binding fragment thereof is L -FR1, V L -CDR1, 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.

[0366] 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 is 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 if is defined). [Table 6]

[0367] In one embodiment, the antibody or binding fragment thereof is V as defined herein above. L -FR1, V L -CDR1, V L -FR2, V L -CDR2, V L-FR3, V L -CDR3 and V L -FR4 combination, or an LCVR consisting of them, 12 does not exist (i.e., X 12 is either Asn (N), Ser (S), or Gly (G), X 18 is Phe(F). In one embodiment, the antibody or binding fragment thereof has V as defined herein above. L -FR1, V L -CDR1, V L -FR2, V L -CDR2, V L -FR3, V L -CDR3 and V L -FR4 combination, or an LCVR consisting of them, 12 If does not exist, X 18 is selected from Tyr (Y) and Phe (F).

[0368] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12 is selected from Asn (N), Ser (S) and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 71 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.

[0369] SEQ ID NO: 71 QIVLTQSPTIMSASPGEKVTITCSASSSVS-X 12 -YMHWFQQKTGTSPRLWIYNTS NLPSGVPARFSGSGSGTSFSLTISRMEAEDAATYYCQQRSSYPLTFGAGTKLELK

[0370] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12is selected from Asn (N), Ser (S) and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 72 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.

[0371] SEQ ID NO:72 DIQLTQSPSFLSASVGDRVTITCSASSSVS-X 12 -YMHWFQQKPGKAPKLWIYNTS NLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0372] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12 is selected from Asn (N), Ser (S) and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 73 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.

[0373] SEQ ID NO: 73 EIVLTQSPDFQSVTPKEKVTITCSASSSVS-X 12 -YMHWFQQKPDQSPKLWIYNTS NLPSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCQQRSSYPLTFGGGTKVEIK

[0374] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12is selected from Asn (N), Ser (S) and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 74 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.

[0375] SEQ ID NO:74 EIVLTQSPATLSLSPGERATLSCSASSSVS-X 12 -YMHWFQQKPGQAPRLWIYNTS NLPSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK

[0376] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12 is selected from Asn (N), Ser (S) and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 75 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.

[0377] SEQ ID NO: 75 DIQLTQSPSFLSASVGDRVTITCRASSSVS-X 12 -YMHWYQQKPGKAPKLWIYNTS NLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0378] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12is selected from Asn (N), Ser (S) and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 76 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.

[0379] SEQ ID NO:76 EIVLTQSPDFQSVTPKEKVTITCRASSSVS-X 12 -YMHWYQQKPDQSPKLWIYNTS NSPSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCQQRSSYPLTFGGGTKVEIK

[0380] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12 is selected from Asn (N), Ser (S) and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 77 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: 77.

[0381] SEQ ID NO:77 EIVLTQSPATLSLSPGERATLSCRASSSV-X 12 -YMHWFQQKPGQAPRLWIYNTS NLPSGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK

[0382] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12is selected from Asn (N), Ser (S) and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 78 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.

[0383] SEQ ID NO:78 DIQLTQSPSFLSASVGDRVTITCRASSSVS-X 12 -YMHWYQQKPGKAPKLWIYATS NLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0384] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12 is selected from Asn (N), Ser (S), and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 79 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.

[0385] SEQ ID NO:79 EIVLTQSPDFQSVTPKEKVTITCRASSSVS-X 12 -YMHWYQQKPDQSPKLWIYNTS NSPSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSSYPLTFGGGTKVEIK

[0386] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12is selected from Asn (N), Ser (S) and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 80 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.

[0387] SEQ ID NO: 80 EIVLTQSPATLSLSPGERATLSCRASSSV-X 12 -YMHWYQQKPGQAPRLWIYNTS NRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK

[0388] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12 is selected from Asn (N), Ser (S), and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 102 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.

[0389] SEQ ID NO: 102 DIQLTQSPSFLSASVGDRVTITCRASSSVS-X 12 -YMHWFQQKPGKAPKLWIYNTS NLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0390] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12is selected from Asn (N), Ser (S) and Gly (G), or an LCVR comprising or consisting of a non-CDR region sequence of SEQ ID NO: 112 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.

[0391] SEQ ID NO: 112 DIQLTQSPSFLSASVGDRVTITCRASSSVS-X 12 -YMHWYQQKPGKAPKLWIYATS NLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0392] In a preferred embodiment, the antibody or binding fragment thereof comprises X 12 is selected from Asn (N), Ser (S), and Gly (G), or an LCVR comprising or consisting of the sequence of SEQ ID NO: 125, or 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: 125.

[0393] SEQ ID NO: 125 QIVLTQSPTIMSASPGEKVTITCSASSSVS-X 12 -YMHWFQQKTGTSPRLWIYNTA NLPSGVPARFSGSGSGTSFSLTISRMEAEDAATYYCQQRSSYPLTFGAGTKLELK

[0394] In a preferred embodiment, the antibody or binding fragment thereof comprises X 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 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.

[0395] SEQ ID NO: 128 DIQLTQSPSFLSASVGDRVTITCRASSSVS-X 12 -YMHWYQQKPGKAPKLWIY-X 13 -TSNLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0396] In one embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of SEQ ID NOs: 71-80, 102, 112, 125 or 128, and X 12 does not exist.

[0397] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0398] SEQ ID NO: 81 QIVLTQSPTIMSASPGEKVTITCSASSSVSYMHWFQQKTGTSPRLWIYNTSNLPSGVPARFSGSGSGTSYSLTISRMEAEDAATYYCQQRSSYPLTFGAGTKLELK

[0399] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0400] SEQ ID NO:82 DIQLTQSPSFLSASVGDRVTITCSASSSVSYMHWFQQKPGKAPKLWIYNTSNLPSGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0401] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0402] SEQ ID NO: 83 EIVLTQSPDFQSVTPKEKVTITCSASSSVSYMHWFQQKPDQSPKLWIYNTSNLPSGVPSRFSGSGSGTDYTLTINSLEAEDAATYYCQQRSSYPLTFGGGTKVEIK

[0403] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0404] SEQ ID NO:84 EIVLTQSPATLSLSPGERATLSCSASSSVSYMHWFQQKPGQAPRLWIYNTSNLPSGIPARFSGSGSGTDYTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK

[0405] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0406] SEQ ID NO: 85 DIQLTQSPSFLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKLWIYNTSNLPSGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0407] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0408] SEQ ID NO:86 EIVLTQSPDFQSVTPKEKVTITCRASSSVSYMHWYQQKPDQSPKLWIYNTSNSPSGVPSRFSGSGSGTFTLTINSLEAEDAATYYCQQRSSYPLTFGGGTKVEIK

[0409] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0410] SEQ ID NO:87 EIVLTQSPATLSLSPGERATLSCRASSSVSYMHWFQQKPGQAPRLWIYNTSNLPSGIPARFSGSGSGTDYTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK

[0411] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0412] SEQ ID NO: 88 DIQLTQSPSFLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKLWIYATSNLQSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0413] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0414] SEQ ID NO:89 EIVLTQSPDFQSVTPKEKVTITCRASSSVSYMHWYQQKPDQSPKLWIYNTSNSPSGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCHQRSSYPLTFGGGTKVEIK

[0415] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0416] SEQ ID NO: 90 EIVLTQSPATLSLSPGERATLSCRASSSVSYMHWYQQKPGQAPRLWIYNTSNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSSYPLTFGGGTKVEIK

[0417] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0418] SEQ ID NO: 103 DIQLTQSPSFLSASVGDRVTITCRASSSVSSYMHWFQQKPGKAPKLWIYNTSNLPSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0419] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0420] SEQ ID NO: 113 DIQLTQSPSFLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKLWIYATSNLPSGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0421] In a preferred embodiment, the antibody or binding fragment thereof comprises an LCVR comprising or consisting of the sequence 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.

[0422] SEQ ID NO: 126 QIVLTQSPTIMSASPGEKVTITCSASSSVSYMHWFQQKTGTSPRLWIYNTANLPSGVPARFSGSGSGTSYSLTISRMEAEDAATYYCQQRSSYPLTFGAGTKLELK

[0423] In a preferred embodiment, the antibody or binding fragment thereof comprises X 13 is any amino acid other than Ala (A) or Asn (N), 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: 129.

[0424] SEQ ID NO: 129 DIQLTQSPSFLSASVGDRVTITCRASSSVSYMHWYQQKPGKAPKLWIY-X 13 -TS NLPSGVPSRFSGSGSGTEYTLTISSLQPEDFATYYCQQRSSYPLTFGGGTKVEIK

[0425] In one embodiment, the antibody or binding fragment thereof - HCVR as defined herein above, and -LCVR, as defined herein above.

[0426] In one embodiment, the antibody or binding fragment thereof - 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 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 -X 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 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: 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 102, 112, 125 or 128.

[0427] In one embodiment, the antibody or binding fragment thereof - 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 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 -X 13 is any amino acid other than Ala (A) or Asn (N), or 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: 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 103, 113, 126 or 129.

[0428] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 71, and X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0429] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0430] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0431] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 61 and the LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0432] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0433] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0434] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0435] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0436] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0437] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0438] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0439] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 112, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0440] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 61 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0441] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 71, and X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0442] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0443] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0444] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 62 and the LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0445] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0446] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0447] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 62 and the LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0448] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 62 and the LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0449] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0450] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0451] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0452] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 112, and X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0453] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 62 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0454] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0455] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 63 and the LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0456] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0457] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 63 and the LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0458] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0459] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0460] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0461] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0462] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0463] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0464] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0465] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 112, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0466] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 63 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0467] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 64 and the LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0468] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 64 and the LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0469] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0470] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0471] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0472] In one embodiment, the antibody or binding fragment thereof comprises a HCVR of SEQ ID NO: 64 and a LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0473] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0474] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0475] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0476] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0477] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0478] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 112, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0479] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 64 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0480] In one embodiment, the antibody or binding fragment thereof comprises a HCVR of SEQ ID NO: 65 and a LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0481] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0482] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0483] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0484] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0485] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0486] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0487] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0488] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0489] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0490] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0491] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 112, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0492] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 65 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0493] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0494] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0495] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0496] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0497] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0498] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0499] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0500] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0501] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0502] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0503] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0504] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 112, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0505] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 66 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0506] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0507] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0508] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0509] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0510] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0511] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0512] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0513] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0514] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0515] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0516] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0517] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 112, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0518] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 67 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0519] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0520] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 68 and the LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0521] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0522] In one embodiment, the antibody or binding fragment thereof comprises a HCVR of SEQ ID NO: 68 and a LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0523] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 68 and the LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0524] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 68 and the LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0525] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0526] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 78, and X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0527] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0528] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0529] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 68 and the LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0530] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 112, and X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0531] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 68 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0532] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0533] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0534] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0535] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0536] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0537] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0538] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0539] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0540] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 79, and X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0541] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0542] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0543] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 112, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0544] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 69 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0545] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0546] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0547] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0548] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0549] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0550] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0551] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0552] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0553] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0554] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0555] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0556] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 112, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0557] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 70 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0558] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0559] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0560] In one embodiment, the antibody or binding fragment thereof comprises a HCVR of SEQ ID NO: 101 and a LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0561] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0562] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0563] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0564] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0565] In one embodiment, the antibody or binding fragment thereof comprises a HCVR of SEQ ID NO: 101 and a LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0566] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0567] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0568] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0569] In one embodiment, the antibody or binding fragment thereof comprises a HCVR of SEQ ID NO: 101 and a LCVR of SEQ ID NO: 112, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0570] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 101 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0571] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0572] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 121 and the LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0573] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 121 and the LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0574] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 121 and the LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0575] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0576] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0577] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0578] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 121 and the LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0579] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0580] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0581] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0582] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 112, and X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0583] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 121 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0584] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 122 and the LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0585] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0586] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 122 and the LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0587] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 122 and the LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0588] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 122 and the LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0589] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 122 and the LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0590] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 122 and the LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0591] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 122 and the LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0592] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 122 and the LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0593] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 122 and the LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0594] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0595] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 112, and X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0596] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 122 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0597] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 123 and the LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0598] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 123 and the LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0599] In one embodiment, the antibody or binding fragment thereof comprises a HCVR of SEQ ID NO: 123 and a LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0600] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 123 and the LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0601] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 123 and the LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0602] In one embodiment, the antibody or binding fragment thereof comprises a HCVR of SEQ ID NO: 123 and a LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0603] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 123 and the LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0604] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 123 and the LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0605] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0606] In one embodiment, the antibody or binding fragment thereof comprises a HCVR of SEQ ID NO: 123 and a LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0607] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0608] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 112, and X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0609] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 123 and an LCVR of SEQ ID NO: 125, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0610] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 124 and the LCVR of SEQ ID NO: 71, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0611] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 124 and the LCVR of SEQ ID NO: 72, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0612] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 124 and the LCVR of SEQ ID NO: 73, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0613] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 74, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0614] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 124 and the LCVR of SEQ ID NO: 75, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0615] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 124 and the LCVR of SEQ ID NO: 76, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0616] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 124 and the LCVR of SEQ ID NO: 77, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0617] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 124 and the LCVR of SEQ ID NO: 78, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0618] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 124 and the LCVR of SEQ ID NO: 79, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0619] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO: 124 and the LCVR of SEQ ID NO: 80, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0620] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 102, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0621] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 112, and 12 is selected from Asn (N), Ser (S) and Gly (G).

[0622] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO: 124 and an LCVR of SEQ ID NO: 125, and X 12 is selected from Asn (N), Ser (S) and Gly (G).

[0623] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:81.

[0624] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:82.

[0625] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:83.

[0626] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:84.

[0627] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:85.

[0628] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:86.

[0629] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:87.

[0630] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:88.

[0631] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:89.

[0632] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:90.

[0633] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:103.

[0634] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:113.

[0635] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:61 and the LCVR of SEQ ID NO:126.

[0636] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:81.

[0637] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:82.

[0638] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:83.

[0639] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:84.

[0640] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:85.

[0641] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:86.

[0642] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:87.

[0643] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:88.

[0644] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:89.

[0645] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:90.

[0646] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:103.

[0647] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:113.

[0648] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:62 and the LCVR of SEQ ID NO:126.

[0649] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:81.

[0650] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:82.

[0651] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:83.

[0652] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:84.

[0653] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:85.

[0654] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:86.

[0655] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:87.

[0656] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:88.

[0657] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:89.

[0658] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:90.

[0659] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:103.

[0660] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:113.

[0661] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:63 and the LCVR of SEQ ID NO:126.

[0662] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:81.

[0663] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:82.

[0664] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:83.

[0665] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:84.

[0666] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:85.

[0667] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:86.

[0668] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:87.

[0669] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:88.

[0670] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:89.

[0671] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:90.

[0672] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:103.

[0673] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:113.

[0674] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:64 and the LCVR of SEQ ID NO:126.

[0675] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:81.

[0676] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:82.

[0677] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:83.

[0678] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:84.

[0679] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO:65 and an LCVR of SEQ ID NO:85.

[0680] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:86.

[0681] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:87.

[0682] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:88.

[0683] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:89.

[0684] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:90.

[0685] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:103.

[0686] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:113.

[0687] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:65 and the LCVR of SEQ ID NO:126.

[0688] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:81.

[0689] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:82.

[0690] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:83.

[0691] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:84.

[0692] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:85.

[0693] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:86.

[0694] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:87.

[0695] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:88.

[0696] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:89.

[0697] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:90.

[0698] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:103.

[0699] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:113.

[0700] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:66 and the LCVR of SEQ ID NO:126.

[0701] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:81.

[0702] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:82.

[0703] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:83.

[0704] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:84.

[0705] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:85.

[0706] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:86.

[0707] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO:67 and an LCVR of SEQ ID NO:87.

[0708] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:88.

[0709] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:89.

[0710] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:90.

[0711] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:103.

[0712] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:113.

[0713] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:67 and the LCVR of SEQ ID NO:126.

[0714] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:81.

[0715] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:82.

[0716] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:83.

[0717] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:84.

[0718] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:85.

[0719] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:86.

[0720] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:87.

[0721] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:88.

[0722] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:89.

[0723] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:90.

[0724] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:103.

[0725] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:113.

[0726] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:68 and the LCVR of SEQ ID NO:126.

[0727] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:81.

[0728] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:82.

[0729] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:83.

[0730] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:84.

[0731] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:85.

[0732] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:86.

[0733] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:87.

[0734] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:88.

[0735] In one embodiment, the antibody or binding fragment thereof comprises an HCVR of SEQ ID NO:69 and an LCVR of SEQ ID NO:89.

[0736] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:90.

[0737] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:103.

[0738] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:113.

[0739] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:69 and the LCVR of SEQ ID NO:126.

[0740] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:81.

[0741] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:82.

[0742] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:83.

[0743] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:84.

[0744] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:85.

[0745] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:86.

[0746] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:87.

[0747] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:88.

[0748] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:89.

[0749] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:90.

[0750] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:103.

[0751] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:113.

[0752] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:70 and the LCVR of SEQ ID NO:126.

[0753] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:81.

[0754] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:82.

[0755] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:83.

[0756] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:84.

[0757] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:85.

[0758] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:86.

[0759] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:87.

[0760] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:88.

[0761] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:89.

[0762] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:90.

[0763] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:103.

[0764] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:113.

[0765] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:101 and the LCVR of SEQ ID NO:126.

[0766] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:81.

[0767] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:82.

[0768] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:83.

[0769] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:84.

[0770] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:85.

[0771] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:86.

[0772] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:87.

[0773] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:88.

[0774] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:89.

[0775] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:90.

[0776] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:103.

[0777] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:113.

[0778] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:121 and the LCVR of SEQ ID NO:126.

[0779] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:81.

[0780] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:82.

[0781] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:83.

[0782] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:84.

[0783] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:85.

[0784] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:86.

[0785] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:87.

[0786] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:88.

[0787] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:89.

[0788] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:90.

[0789] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:103.

[0790] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:113.

[0791] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:122 and the LCVR of SEQ ID NO:126.

[0792] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:81.

[0793] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:82.

[0794] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:83.

[0795] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:84.

[0796] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:85.

[0797] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:86.

[0798] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:87.

[0799] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:88.

[0800] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:89.

[0801] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:90.

[0802] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:103.

[0803] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:113.

[0804] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:123 and the LCVR of SEQ ID NO:126.

[0805] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:81.

[0806] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:82.

[0807] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:83.

[0808] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:84.

[0809] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:85.

[0810] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:86.

[0811] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:87.

[0812] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:88.

[0813] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:89.

[0814] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:90.

[0815] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:103.

[0816] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:113.

[0817] In one embodiment, the antibody or binding fragment thereof comprises the HCVR of SEQ ID NO:124 and the LCVR of SEQ ID NO:126.

[0818] In one embodiment, any of the HCVRs and / or LCVRs defined herein above can be characterized by the substitution 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 or more amino acids with different amino acids.

[0819] In one embodiment, the sequence of a non-CDR region of any of the HCVRs and / or LCVRs defined herein above may be characterized by the substitution 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 or more amino acids by different amino acids.

[0820] In one embodiment, any of the HCVRs and / or LCVRs defined herein above 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 HCVR and / or LCVR defined herein above.

[0821] In one embodiment, the sequence of a non-CDR region of any of the HCVRs and / or LCVRs defined herein above 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 the sequence of a non-CDR region of a particular HCVR and / or LCVR defined herein above.

[0822] Also described herein are isolated nucleic acids encoding antibodies or binding fragments thereof that bind to hCD45RC, as disclosed above in the "Antibodies or Antigen-Binding Fragments" section.

[0823] In one embodiment, the isolated nucleic acid is purified.

[0824] In one embodiment, the isolated nucleic acid is (1) Absorbance or fluorescence method (e.g., absorbance ratio at 260 nm and 280 nm (A 260 / 280 by measuring the nucleic acid); or (2) Purified to homogeneity as demonstrated by agarose gel electrophoresis and the use of intercalating agents such as ethidium bromide, SYBR Green, GelGreen, etc.

[0825] In one embodiment, the nucleic acid encoding the antigen-binding fragment comprises or consists of a sequence encoding the HCVR of an antibody or binding fragment thereof disclosed in the "Antibodies or Antigen-Binding Fragments" section.

[0826] In one embodiment, the nucleic acid encoding the antigen-binding fragment comprises or consists of the sequence of SEQ ID NO: 95 or any sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 95 and encoding the HCVR of SEQ ID NO: 61 and a murine or chimeric antibody or binding fragment thereof.

[0827] SEQ ID NO: 95 CAGGTCCAGCTGCAACAGTCTGGCGCTGAGCTGGTTAGGCCTGGGACTTCAGTGAAGATGTCCTGCAAGGCCGCTGGATACACCTTCACTAACTACTACATAGGTTGGGTAAAGCAGAGGCCTGGACATGGCCTTGAGTGGATCGGAGATATTTTCCCTGGAGGTGACTAT GCCAACAGCAATGAGAAGTTCAAGGGCAAAGCCACACTGACTGCAGACACATCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCCATCTATTACTGTGTGAGAAGGAACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTGTCCTCA

[0828] In one embodiment, the nucleic acid encoding the antigen-binding fragment comprises or consists of a sequence encoding the LCVR of an antibody or binding fragment thereof disclosed in the "Antibodies or Antigen-Binding Fragments" section.

[0829] In one embodiment, the nucleic acid encoding the antigen-binding fragment comprises or consists of the sequence of SEQ ID NO: 96, or any sequence that shares at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 96 and encodes the LCVR of the murine or chimeric antibody of SEQ ID NO: 81, or a binding fragment thereof.

[0830] SEQ ID NO:96 CAAATTGTTCTCACCCAGTCTCCAACAATCATGTCTGCATCTCCAGGGGAGAAGGTGACCATAACCTGCAGTGCCAGCTCAAGTGTAAGTTACATGCACTGGTTCCAGCAGAAGACAGGCACTTCTCCCAGACTCTGGATTTATAACACATCCAACCTG CCTTCTGGAGTCCCCGCTCGCTTCAGTGGCAGTGGATCTGGGACCTCTTACTCTCTCACAATCAGCCGAATGGAGGCTGAAGATGCTGCCACTTATTACTGCCAGCAAAGGAGTAGTTACCCACTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA

[0831] In one embodiment, the nucleic acid encoding the antigen-binding fragment is - a sequence encoding the HCVR of an antibody or antigen-binding fragment thereof disclosed in the "Antibody or antigen-binding fragment" section, and - a sequence encoding the LCVR of an antibody or antigen-binding fragment thereof disclosed in the "Antibody or antigen-binding fragment" section.

[0832] In one embodiment, the nucleic acid encoding the antigen-binding fragment is - the sequence of SEQ ID NO: 95 or any sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 95, and - comprising or consisting of the sequence SEQ ID NO: 96 or any sequence sharing at least 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more identity with SEQ ID NO: 96.

[0833] Those skilled in the art will readily appreciate that they can design nucleic acid sequences that encode all other HCVRs and LCVRs disclosed herein, particularly the humanized antibodies or antigen-binding fragments thereof disclosed in the "Antibodies or Antigen-Binding Fragments" section.

[0834] It will be further understood that those of skill in the art are familiar with molecular biology methods aimed at modifying nucleic acid sequences to improve recombinant production rates, for example, by codon optimization, etc. Finally, the present application encompasses any nucleic acid encoding any of the HCVRs and / or LCVRs disclosed herein.

[0835] The present invention provides a chimeric receptor specific for human CD45RC, the CAR comprising: (a) at least one extracellular binding domain, wherein said binding domain binds to said human CD45RC; (b) optionally, at least one extracellular hinge domain; (c) at least one transmembrane domain, and (d) at least one intracellular signaling domain, wherein the intracellular domain comprises at least one T cell primary signaling domain and optionally at least one T cell costimulatory signaling domain.

[0836] As used herein, the term "chimeric receptor" (CR) or "chimeric antigen receptor" (CAR) refers to a polypeptide or set of polypeptides, typically two polypeptides in the simplest embodiment, that, when present in an immune cell, provides the cell with specificity for a target ligand and intracellular signal generation. In some embodiments, the set of polypeptides are contiguous with each other. In some embodiments, the chimeric receptor is a chimeric fusion protein comprising the set of polypeptides. In some embodiments, the set of polypeptides comprises a dimerization switch that can link the polypeptides to each other in the presence of a dimerization molecule, e.g., linking a ligand-binding domain to an intracellular signaling domain. In one embodiment, the chimeric receptor comprises an optional leader sequence at the amino-terminus (N-ter) of the chimeric receptor fusion protein. In one embodiment, the chimeric receptor further comprises a leader sequence N-terminal to the extracellular ligand-binding domain, where the leader sequence is optionally cleaved from the ligand-binding domain during cellular processing and localization of the chimeric receptor to the cell membrane.

[0837] In some embodiments, the chimeric receptor comprises one or more polypeptides.

[0838] In some embodiments, the extracellular binding domain is an antigen binding domain, and thus the chimeric receptor may also be referred to as a chimeric antigen receptor (or CAR). The chimeric receptor or chimeric antigen receptor of the present invention comprises at least one extracellular binding domain, which binds to human CD45RC.

[0839] In some embodiments, the extracellular domain of a chimeric receptor of the invention comprises at least one ligand-binding domain or antigen-binding domain. In some embodiments, the antigen-binding domain is an antibody or antigen-binding fragment.

[0840] In some embodiments, a chimeric receptor of the invention comprises an antibody or antigen-binding fragment thereof against human CD45RC, such as any of the antibodies or antigen-binding fragments thereof described above in the "Antibodies or Antigen-Binding Fragments" section.

[0841] In some embodiments, the extracellular binding domain of a CAR of the invention comprises an antibody against human CD45RC as described above in the "Antibody or Antigen-Binding Fragment" section.

[0842] In some embodiments, the extracellular binding domain of a CAR of the invention comprises an antigen-binding fragment against human CD45RC as described above in the "Antibody or Antigen-Binding Fragment" section.

[0843] In one embodiment, the extracellular binding domain comprises: (a) HCVR containing the following three CDRs: (i) V of SEQ ID NO: 1 H -CDR1, (ii) V having a sequence selected from the group consisting of SEQ ID NOs: 4, 5, 6, 8, 100, 116, 117, 118, and 119. H CDR2, and (iii) V of the sequence of SEQ ID NO: 3 H CDR3, 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 has a sequence selected from the group consisting of Asn (N), Ser (S) and Gly (G). 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.

[0844] In one embodiment, the extracellular binding domain comprises: (a) HCVR containing the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 H -CDR1, (ii) V having a sequence selected from the group consisting of SEQ ID NOs: 4 and 5 H CDR2, and (iii) V of the sequence of SEQ ID NO: 3 H CDR3, and (b) an LCVR containing the following three CDRs: (i) SEQ ID NO: 15(X 12 does not exist) 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.

[0845] In one embodiment, the extracellular binding domain comprises: (a) HCVR containing the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 H -CDR1, (ii) V of SEQ ID NO: 4 H CDR2, and (iii) V of the sequence of SEQ ID NO: 3 H CDR3, and (b) an LCVR containing the following three CDRs: (i) SEQ ID NO: 15(X 12 does not exist) 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.

[0846] In one embodiment, the extracellular binding domain comprises: (a) HCVR containing the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 H -CDR1, (ii) V having a sequence selected from the group consisting of SEQ ID NOs: 4, 6 and 100 H CDR2, and (iii) V of the sequence of SEQ ID NO: 3 H CDR3, and (b) an LCVR containing the following three CDRs: (i) SEQ ID NOs: 15 and 18 (X 12 V having a sequence selected from the group comprising the sequences 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.

[0847] In one embodiment, the extracellular binding domain comprises: 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; 14) HCVR of sequence SEQ ID NO: 65 and LCVR of sequence SEQ ID NO: 103; 15) HCVR of sequence SEQ ID NO: 62 and LCVR of sequence SEQ ID NO: 85; 16) HCVR of sequence SEQ ID NO: 101 and LCVR of sequence SEQ ID NO: 82; 17) HCVR of sequence SEQ ID NO: 121 and LCVR of sequence SEQ ID NO: 85; 18) HCVR of sequence SEQ ID NO: 122 and LCVR of sequence SEQ ID NO: 85; 19) HCVR of sequence SEQ ID NO: 123 and LCVR of sequence SEQ ID NO: 85; 20) HCVR of sequence SEQ ID NO: 124 and LCVR of sequence SEQ ID NO: 85; 21) HCVR of sequence SEQ ID NO: 63 and LCVR of sequence SEQ ID NO: 85; 22) HCVR of sequence SEQ ID NO: 67 and LCVR of sequence SEQ ID NO: 85; 23) HCVR of sequence SEQ ID NO: 67 and LCVR of sequence SEQ ID NO: 103, or 24) At least one antigen-binding fragment comprising an HCVR and an LCVR comprising a non-CDR region sequence that shares at least 70% identity with the non-CDR region sequence of the HCVR and LCVR described in 1) to 23).

[0848] In one embodiment, the extracellular binding domain comprises: (a) HCVR containing the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 H -CDR1, (ii) V having a sequence selected from the group consisting of SEQ ID NOs: 4, 5, 6, 8, 100, 116, 117, 118, and 119. H CDR2, and (iii) V of the sequence of SEQ ID NO: 3 H CDR3, 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 is selected from the group consisting of Asn (N), Ser (S) and Gly (G) 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, and at least one antigen-binding fragment comprising Preferably, the amino acid residue at Kabat position L71 of the LCVR is Phe (F).

[0849] The antibody or antigen-binding fragment thereof comprised in the CAR of the present invention can exist in various forms in which the ligand-binding domain is expressed as part of a continuous polypeptide chain, including, for example, a single-domain antibody fragment (sdAb), a single-chain antibody (scFv), a humanized antibody, or a bispecific antibody (Harlow et al., 1999, In: Using Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, NY; Harlow et al., 1989, In: Antibodies: A Laboratory Manual, Cold Spring Harbor, New York; Houston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); Bird et al., Science 242:423-426 (1988)). In some embodiments, the antigen-binding domain of the chimeric receptor of the present invention comprises an antibody fragment or antigen-binding fragment. In some embodiments, the chimeric receptor comprises an antigen-binding fragment comprising an scFv.

[0850] In some embodiments, the antibody or antigen-binding fragment is an antibody molecule selected from the group consisting of a humanized antibody, a single-chain antibody, a dimeric single-chain antibody, an Fv, an scFv, an Fab, an F(ab)'2, a defucosylated antibody, a bispecific antibody, a diabody, a triabody, and a tetrabody.

[0851] "Single-chain antibody" refers to any antibody or fragment thereof that is a protein having a primary structure comprising or consisting of a single uninterrupted sequence of consecutive amino acid residues, including, but not limited to, (1) a single-chain Fv molecule (scFv), (2) a single-chain protein containing only one light-chain variable domain, or a fragment thereof containing the three CDRs of the light-chain variable domain and no associated heavy-chain portion, and (3) a single-chain protein containing only one heavy-chain variable region, or a fragment thereof containing the three CDRs of the heavy-chain variable region without the associated light-chain portion.

[0852] "Single-chain Fv", also abbreviated as "sFv" or "scFv", is a V linked to a single amino acid chain. H and V L scFv refers to an antibody fragment containing an antibody domain. Preferably, the scFv amino acid sequence contains a peptide linker between the V and V domains that enables the scFv to form the desired structure for antigen binding. H Domains and V L Between the domains are further included (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).

[0853] "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 from each heavy 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 to an antigen, albeit with lower affinity than the entire binding site.

[0854] "Diabodies" refer to small antibody fragments prepared by constructing scFv fragments with a short linker (approximately 5-10 residues) between the HCVR and LCVR such that interchain, rather than intrachain, 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 reside on different polypeptide chains. Diabodies are more fully described in patent EP0404097, patent application WO1993011161, and Holliger et al., 1993. Proc Natl Acad Sci USA. 90(14):6444-8.

[0855] In some embodiments, the antibody is an antibody fragment selected from the group consisting of a unibody, a single domain antibody, and a nanobody.

[0856] "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.

[0857] 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.

[0858] "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 a single variable domain (V H H) and two constant domains (C H 2 and C H 3)—e.g., camelid antibodies—or a single 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) - may contain, for example, shark antibodies.

[0859] In some embodiments, the antibody is an antibody mimetic selected from the group consisting of an affibody, an affilin, an affitin, an addectin, an atrimer, an evasin, a DARPin, an anticalin, an avimer, a fynomer, a versabody, and a duocalin.

[0860] "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; Patent US 5,831,012).

[0861] "DARPins" (Designed Ankyrin Repeat Proteins) refers to antibody-mimetic DRP (Designed Repeat Protein) technology, which is well known in the art and has been 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).

[0862] "Anti-cullin" refers to another antibody mimetic technology known in the art, whose binding specificity is derived from lipocalins (Skerra, 2008. FEBS J. 275(11):2677-83). Anti-cullins can also be formatted as dual-targeting proteins called "duocalins" (Schlehuber & Skerra, 2001. Biol Chem. 382(9):1335-42).

[0863] "Avimer" is well known in the art and refers to another antibody mimetic technology (Silverman et al., 2005. Nat Biotechnol. 23(12):1556-61).

[0864] "Versabodies" are well known in the art and refer to another antibody mimetic technology (patent application US20070191272). They are small 3-5 kDa proteins with >15% cysteines, forming a high disulfide density scaffold that replaces the hydrophobic core of 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, since the residues most responsible for MHC presentation are hydrophobic. All four of these properties are known to affect immunogenicity, and together they are expected to cause a significant reduction in immunogenicity.

[0865] In one embodiment, antibodies or binding fragments thereof also include multispecific antibodies or binding fragments thereof, i.e., multispecific antibodies or binding fragments thereof that are immunospecific for two or more, e.g., at least two, different antigens, one of which is hCD45RC according to the present invention.

[0866] In one embodiment, an antibody or binding fragment thereof also includes a polymer of an antibody or binding fragment thereof, i.e., two or more, e.g., at least two, antibodies or binding fragments thereof, whether the same or different, that are covalently linked directly or indirectly.

[0867] Antibody fragments and derivatives (as used in this application, unless otherwise specified or clearly contradicted by the context) can be produced by techniques known in the art. A "fragment" comprises a portion of an intact antibody, generally the antigen-binding site or variable region. Examples of antibody fragments include Fab, Fab', Fab'-SH, F(ab')2, and Fv fragments, diabodies, any antibody fragment that is a polypeptide having a primary structure consisting of a single, uninterrupted sequence of contiguous amino acid residues (referred to herein as a "single-chain antibody fragment" or "single-chain polypeptide"), including, but not limited to, (1) a single-chain Fv molecule, (2) a single-chain polypeptide containing only a light-chain variable domain or a fragment thereof containing the three CDRs of the light-chain variable domain without the associated heavy-chain portion, and (3) a single-chain polypeptide containing only a heavy-chain variable domain or a fragment thereof containing the three CDRs of the heavy-chain variable domain without the associated light-chain portion, as well as multispecific antibodies formed from antibody fragments. Antibody fragments can be obtained using standard methods. The precise amino acid sequence boundaries of a given CDR can be determined using any one of a number of well-known schemes, or a combination thereof, including those described by Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al., JMB 273:927-948 (1997) ("Chothia" numbering scheme).

[0868] In some embodiments, the antigen-binding domain of a CAR of the invention comprises or consists of an antibody fragment, such as, for example, an scFv. In certain embodiments, the antigen-binding domain is an scFv.

[0869] In some embodiments, a CAR of the present invention comprises an extracellular binding domain for a first antigen, hCD45RC, and at least one other extracellular binding domain for another antigen. Such a CAR can bind to at least two different antigens.

[0870] In one embodiment, said at least one other extracellular binding domain is an antibody or antigen-binding fragment thereof directed against a specific antigen.

[0871] In one embodiment, said at least one other extracellular binding domain comprises or consists of an antibody fragment, such as, for example, an scFv.

[0872] In one embodiment, the scFv is H Chain and V L It includes a linker that connects the chains.

[0873] In one embodiment, the linker is a short oligo- or polypeptide, preferably having a length in the range of 2 to 10 amino acids.

[0874] For example, a glycine-serine duplex provides a particularly suitable linker (GS linker). Examples of Gly / Ser linkers include, but are not limited to, the GS linker, G2S linker, G3S linker, and G4S linker.

[0875] A non-limiting example of a G2S linker is GGS.

[0876] The G3S linker is (GGGS) n or (SEQ ID NO: 130) n The amino acid sequence (Gly-Gly-Gly-Ser) is also known as n where n is a positive integer greater than or equal to 1 (e.g., n=1, n=2, n=3, n=4, n=5, n=6, n=7, n=8, n=9, or n=10, etc.). An example of a G3S linker includes, but is not limited to, GGGSGGGGSGGGS (SEQ ID NO: 131).

[0877] Examples of G4S linkers include, but are not limited to, (Gly4Ser) corresponding to GGGGS (SEQ ID NO: 132), (Gly4Ser)2 corresponding to GGGGSGGGGS (SEQ ID NO: 133), (Gly4Ser)3 corresponding to GGGGSGGGGGSGGGGS (SEQ ID NO: 134), and (Gly4Ser)4 corresponding to GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 135).

[0878] In one embodiment, the linker is a (G4S)3 linker (SEQ ID NO: 134) which can be encoded by the sequence of SEQ ID NO: 136.

[0879] SEQ ID NO: 136 GGAGGTGGAGGCTCTGGCGGTGGAGGAAGTGGTGGGGGAGGCTCT

[0880] In one embodiment, the linker is a (G4S)3 linker (SEQ ID NO: 134) which can be encoded by the sequence of SEQ ID NO: 137.

[0881] SEQ ID NO: 137 GGTGGCGGTGGCTCGGGCGGTGGTGGGTCGGGTGGCGGCGGATCT

[0882] In one embodiment, the scFv comprises or consists of the nucleic acid sequence of SEQ ID NO: 173, which encodes the amino acid sequence of SEQ ID NO: 138.

[0883] SEQ ID NO: 138 AAGGTCCAGCTGCAACAGTCTGGCGCTGAGCTGGTTAGGCCTGGGACTTCAGTGAAGATGTCCTGCAAGGCCGCTGGATACACCTTCACTAACTACTACATAGGTTGGGTAAAGCAGAGGCCTGGACATGGCCTTGAGTGGATCGGAGATATTTTCCCTGGAGGTGACTATGCCAA CAGCAATGAGAAGTTCAAGGGACAAAGCCACACTGACTGCAGCACATCCTCCAGCACAGCCTACATGCAGCTCAGCAGCCTGACATCTGAGGACTCTGCCATCTATTACTGTGTGAAGGAACTTTGACTACTGGGGCCAAGGCACCACTCTCACAGTGCCTCAGGTGGCGGTG GCTCGGGCGGTGGTGGGTCGGGTGGCGGCGGATCCAAATTGTTCTCACCCAGTCTCCAACAATCATGTCTGCATCTCCAGGGGAGAAGGTGACCATAACCTGCAGTGCCAGCTCAAGTGTAAGTTACATGCACTGGTTCCAGCAGAAGACAGGCACTTCTCCCAGACTCTGGATT TATAACACATCCAACCTGCCTTCTGGAGTCCCCGCTCGCTTCAGTGGCAGTGGATCTGGGACCTCTTTACTCTCTCACAATCAGCCGAATGGAGGCTGAAGATGCTGCCACTTATTACTGCCAAGCAAAGGAGTAGTTACCCACTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA sequence number 173 KVQLQQSGAELVRPGTSVKMSCKAAGYTFTNYYIGWVKQRPGHGLEWIGDIFPGGDYANSNEKFKGKATLTADTSSSTAYMQLSSLTSEDSAIYYCVRRNFDYWGQGTTLTVSSGGGGGSGGGSGGGGSQIVLTQSPTIMSASPGEKVTITCSASSSVSYMHWFQQKTGTSPRLWIYNTSNLPSGVPARFSGSGSGTSYSLTISRMEAEDAATYYCQQRSSYPLTFGAGTKLELK

[0884] In some embodiments, the antibody comprised in the CAR of the present invention is a multispecific antibody molecule, e.g., comprises multiple immunoglobulin variable domain sequences, wherein a first plurality of immunoglobulin variable domain sequences has binding specificity for a first epitope and a second plurality of immunoglobulin variable domain sequences has binding specificity for a second epitope. In some embodiments, the multispecific antibody molecule is a bispecific antibody molecule. Bispecific antibodies have specificity for two antigens and are characterized by a first immunoglobulin variable domain sequence having binding specificity for a first epitope and a second immunoglobulin variable domain sequence having binding specificity for a second epitope.

[0885] In some embodiments, the extracellular domain comprises an antigen-binding domain (e.g., an antigen-binding fragment) described in the "Antibodies or Antigen-Binding Fragments" section herein.

[0886] In some embodiments, the extracellular binding domain is connected to the transmembrane domain by a hinge domain.

[0887] In one embodiment, the hinge domain is a short oligopeptide or polypeptide linker, as described herein above, preferably having a length in the range of 2 to 10 amino acids.

[0888] In some embodiments, the hinge domain is a Gly / Ser linker as described above.

[0889] Another example of a hinge domain that can be used in the present invention is described in WO2012 / 138475, which is incorporated herein by reference.

[0890] In one embodiment, the hinge domain comprises an amino acid sequence selected from the group comprising the amino acid sequence AGSSSSGGSTTGGSTT (SEQ ID NO: 139), the amino acid sequence GTTAASGSSGGSSSGA (SEQ ID NO: 140), the amino acid sequence SSATATAGTGSSTGST (SEQ ID NO: 141), and the amino acid sequence TSGSTGTAASSTSTST (SEQ ID NO: 142).

[0891] In one embodiment, the hinge domain is encoded by the nucleotide sequence GGTGGCGGAGGTTCTGGAGGTGGAGGTTCC (SEQ ID NO: 143).

[0892] In another embodiment, the hinge domain is the KIR2DS2 hinge corresponding to KIRRDSS (SEQ ID NO: 144).

[0893] In one embodiment, the hinge domain comprises or consists of the amino acid sequence of a CD8 hinge (SEQ ID NO: 145) or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 145. In one embodiment, the hinge domain is a CD8 hinge encoded by a nucleic acid sequence (SEQ ID NO: 146) or a nucleic acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 146.

[0894] SEQ ID NO: 145 TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD SEQ ID NO: 146 ACCACGACGCCAGCGCCGCGACCACCAACACCGGCGCCCACCATCGCGTCGCAGCCCCTGTCCCTGCGCCCAGAGGCGTGCCGGCCAGCGGCGGGGGGCGCAGTGCACACGAGGGGGCTGGACTTCGCCTGTGAT

[0895] In another embodiment, the hinge domain comprises or consists of the amino acid sequence of an IgG4 hinge (SEQ ID NO: 147), or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 147.

[0896] SEQ ID NO: 147 ESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIE KTISKAKGQPREPQVYTLPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKM

[0897] In one embodiment, the hinge domain is an IgG4 hinge encoded by the nucleic acid sequence (SEQ ID NO: 148) or a nucleic acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 148.

[0898] SEQ ID NO: 148 GAGAGCAAGTACGGCCCTCCCTGCCCCCTGCCCTGCCCCCGAGTTCCTGGGCGGACCCAGCGTGTTCCTGTTCCCCCCAAGCCCAAGGACACCCTGATGATCAGCCGGACCCCGTGACCTGTGTGGTGGTGGACGTGTCCCAGGAGGACCCCGAGGTCCAGTTCA ACTGGTACGTGGACGGCGTGGAGGTGCACAACGCCAAGACCAAGCCCCGGGAGGAGCAGTTCAATAGCACCTACCGGGTGGTGTCCGTGCTGACCGTGCTGCACCAGGACTGGCTGAACGGCAAGGAATACAAGTGTAAGGTGTCCAACAAGGGCCTGCCCAGCATCGAG AAAACCATCAGCAAGGCCAAGGGCCAGCCTCGGGAGCCCCAGGTGTACACCCTGCCCCCTAGCCAAGAGGAGATGACCAAGAACCAGGTGTCCCTGACCTGCCTGGTGAAGGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAACGGCCAGCCCGAGAACAACT ACAAGACCACCCCCCCTGTGCTGGACAGCGACGGCAGCTTCTTTCCTGTACAGCCGGCTGACCGTGGACAAGAGCCGGTGGCAGGAGGGCAACGTCTTTAGCTGCTCCGTGATGCACGAGGCCCTGCACAACCACTACACCCAGAAGAGCCTGAGCCTGTCCCTGGGCAAGATG

[0899] In another embodiment, the hinge domain comprises or consists of the amino acid sequence of an IgD hinge (SEQ ID NO: 149), or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 149.

[0900] SEQ ID NO: 149 RWPESPKAQASSVPTAQPQAEGSLAKATTAPATTRNTGRGGEEKKKEKEKEEQEERETKTPECPSHTQPLGVYLLTPAVQDLWLRDKATFTCFVVGSDLKDAHLTWEVAGKVPTGGVEEGLLERHSNGSQSQHSRLTLPRS LWNAGTSVTCTLNHPSLPPQRLMALREPAAQAPVKLSLNLLASSDPPEAASWLLCEVSGFSPPNILLMWLEDQREVNTSGFAPARPPPQPGSTTFWAWSVLRVPAPPSPQPATYTCVVSHEDSRTLLNASRSLEVSYVTDH

[0901] In one embodiment, the hinge domain is an IgD hinge encoded by the nucleic acid sequence of SEQ ID NO: 150, or a nucleic acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 150.

[0902] SEQ ID NO: 150 AGGTGGCCCGAAAGTCCCAAGGCCCAGGCATCTAGTGTTCCTACTGCACAGCCCCAGGCAGAAGGCAGCCTAGCCAAAGCTACTACTGCACCTGCCACTACGCGCAATACTGGCCGTGGCGGGGAGGAGAAGAAAAAGGAGAAAGAGAAAGAAGAACAGGAAGAGAGGGAGACCAAGACCCCTGAATGTCCATCCCATACCCAGCCGCTGGGCGTCTATCTCTTGACTCCCGCAGTACAGGACTTGTGGCTTAGAGATAAGGCCACCTTTACATGTTTCGTCGTGGGCTCTGACCTGAAGGATGCCCATTTGACTTGGGAGGTTGCCGGAAAGGTACCCACAGGGGGGGTTGAGGAAGGGTTGCTGGAGCGCCATTCCAATGGCTCTCAGAGCCAGCACTCAAGACTCACCCTTCCGAGATCCCTGTGGAACGCCGGGACCTCTGTCACATGTACTCTAAATCATCCTAGCCTGCCCCCACAGCGTCTGATGGCCCTTAGAGAGCCAGCCGCCCAGGCACCAGTTAAGCTTAGCCTGAATCTGCTCGCCAGTAGTGATCCCCCAGAGGCCGCCAGCTGGCTCTTATGCGAAGTGTCCGGCTTTAGCCCGCCCAACATCTTGCTCATGTGGCTGGAGGACCAGCGAGAAGTGAACACCAGCGGCTTCGCTCCAGCCCGGCCCCCACCCCAGCCGGGTTCTACCACATTCTGGGCCTGGAGTGTCTTAAGGGTCCCAGCACCACCTAGCCCCCAGCCAGCCACATACACCTGTGTTGTGTCCCATGAAGATAGCAGGACCCTGCTAAATGCTTCTAGGAGTCTGGAGGTTTCCTACGTGACTGACCATT

[0903] In another embodiment, the hinge region comprises or consists of the amino acid sequence of the CD28 hinge (SEQ ID NO: 151), or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 151.

[0904] SEQ ID NO: 151 IEVMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKP

[0905] In one embodiment, the hinge domain is a CD28 hinge encoded by the nucleic acid of SEQ ID NO: 152 or a nucleic acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 152.

[0906] SEQ ID NO: 152 ATTGAAGTTATGTATCCTCCTCCTTACCTAGACAATGAGAAGAGCAATGGAACCATTATCCATGTGAAAGGGAAACACCTTTGTCCAAGTCCCCTATTTCCCGGACCTTCTAAGCCC

[0907] Examples of transmembrane domains that can be used in the chimeric receptors of the invention include the transmembrane domains of the alpha, beta or zeta chains of the T cell receptor, or CD28, CD3 gamma, CD3 delta, CD3 epsilon, CD3 zeta, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, KIRDS2 , OX40, CD2, CD27, LFA-1 (CD1la, CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRFl), CD160, CD19, IL2R beta, IL2R gamma, IL7Ra, ITGA1, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a, LFA-1, ITGAM, CD11b, PD1, ITGAX, CDl1c, ITGB1, CD29, ITGB2 , CD18, LFA-1, ITGB7, TNFR2, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9(C D229), CD160 (BY55), PSGL1, CDIOO (SEMA4D), SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​PAG / Cbp, NKp44, NKp30, NKp46, NKG2D and / or NKG2C transmembrane domains.

[0908] In some embodiments, the transmembrane domain may comprise the entire transmembrane domain of the molecule from which it is derived, or may comprise a functional fragment or variant thereof.

[0909] In one embodiment, the transmembrane domain comprises or consists of the amino acid sequence of the CD8 transmembrane domain (SEQ ID NO: 153), or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 153. In another embodiment, the transmembrane domain comprises or consists of an amino acid sequence having at least one, two, or three alterations but not more than 20, 10, or five alterations of the amino acid sequence of SEQ ID NO: 153, or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 153.

[0910] SEQ ID NO: 153 IYIWAPLAGTCGVLLLSLVITLYC

[0911] In another embodiment, the transmembrane domain is encoded by the nucleotide sequence of the CD8 transmembrane domain (SEQ ID NO: 154), or a nucleotide sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 154.

[0912] SEQ ID NO: 154 ATCTACATCTGGGCGCCCTTGGCCGGGACTTGTGGGGTCCTTCTCCTGTCACTGGTTATCACCCTTTACTGC

[0913] In another embodiment, the transmembrane domain comprises or consists of the amino acid sequence of the CD28 transmembrane domain (SEQ ID NO: 155), or an amino acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 155.

[0914] SEQ ID NO: 155 FWVLVVVGGVLACYSLLVTVAFIIFWV

[0915] In one embodiment, the transmembrane domain is a CD28 transmembrane domain encoded by the nucleic acid sequence of SEQ ID NO: 156, or a nucleic acid sequence having at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 156.

[0916] SEQ ID NO: 156 TTTTGGGTGCTGGTGGTGGTTGGTGGAGTCCTGGCTTGCTATAGCTTGCTAGTAACAGTGGCCTTTATTATTTTCTGGGTG

[0917] In some embodiments, the transmembrane domain can be recombinant, hi certain embodiments, the recombinant transmembrane domain comprises primarily hydrophobic amino acids, such as valine or leucine.

[0918] As used herein, the term "intracellular signaling domain" refers to the intracellular portion of a molecule. The intracellular signaling domain generates a signal that promotes the immune effector function of the chimeric receptor-containing cell. Examples of immune effector functions in chimeric receptor-T cells can include cytolytic activity, suppressive activity, regulatory activity, and helper activity, including cytokine secretion.

[0919] In some embodiments, the intracellular domain of a CAR of the invention comprises at least one T cell primary signaling domain (or a sequence derived therefrom), and optionally one or more intracellular domains of a T cell costimulatory molecule (or a sequence derived therefrom).

[0920] As used herein, the term "costimulatory molecule" or "costimulatory intracellular signaling domain" refers to a cognate binding partner on a T cell that specifically binds to a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, proliferation. Costimulatory molecules are cell surface molecules other than antigen receptors or their ligands that contribute to an efficient immune response. A costimulatory signaling domain can be the intracellular portion of a costimulatory molecule. Costimulatory molecules can be represented by the following protein families: TNF receptor proteins, immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocyte activation molecules (SLAM proteins), and activating NK cell receptors.

[0921] In some embodiments, the intracellular domain may comprise the entire intracellular portion of the molecule from which it is derived, or the entire native intracellular signaling domain, or a functional fragment or variant thereof.

[0922] In some embodiments, the intracellular signaling domain consists of at least one primary signaling domain (e.g., a T cell primary signaling domain) or a fragment or variant thereof.

[0923] In some embodiments, the intracellular signaling domain consists of at least one costimulatory signaling domain (e.g., a T cell costimulatory molecule intracellular domain) or a fragment or variant thereof.

[0924] In some embodiments, the intracellular signaling domain comprises one or more intracellular domains of a T cell costimulatory molecule, or a fragment or variant thereof, hi some embodiments, the intracellular signaling domain consists of one or more intracellular domains of a T cell costimulatory molecule, or a fragment or variant thereof.

[0925] In one embodiment, the intracellular signaling domain of a CAR of the invention comprises at least one costimulatory domain, or a fragment or variant thereof, and at least one primary signaling domain, or a fragment or variant thereof.

[0926] In one embodiment, the intracellular signaling domain of a CAR of the invention consists of one costimulatory domain, or a fragment or variant thereof, and one primary signaling domain, or a fragment or variant thereof.

[0927] In one embodiment, the intracellular signaling domain of the CAR of the present invention comprises at least one costimulatory domain or a fragment or variant thereof and one primary signaling domain or a fragment or variant thereof, and further comprises an expression system that allows expression of a recombinant protein. In one embodiment, the recombinant protein is a pro-inflammatory cytokine such as IL-12. In one embodiment, the pro-inflammatory cytokine is released by the CAR-engineered cells.

[0928] As used herein, "expression system" refers to a linear or circular DNA molecule comprised of a fragment encoding a nucleic acid sequence encoding a recombinant peptide, polypeptide, or protein of interest operably linked to additional fragments for transcription of the system.

[0929] In some embodiments, the expression system comprises a nucleic acid sequence encoding a proinflammatory cytokine, hi one embodiment, the expression system comprises a nucleic acid sequence encoding IL-12.

[0930] The additional fragment may include a promoter and a stop codon sequence. The expression system may further contain sequences encoding one or more origins of replication, one or more selectable markers, and a ribosome binding site.

[0931] "Operably linked" means that the fragments are positioned so that they function normally, e.g., once transcription is initiated at the promoter, it passes through the coding fragment to a stop codon.

[0932] A "promoter" in the sense of the present invention is an expression control element that allows the binding of RNA polymerase and the initiation of transcription.

[0933] In one embodiment of the invention, the nucleic acid sequence is under the control of a "strong" promoter, which is characterized on the one hand by a high binding affinity of the promoter sequence for an RNA polymerase, usually the corresponding naturally occurring RNA polymerase, and on the other hand by a fast rate of mRNA formation by that RNA polymerase.

[0934] In another embodiment, the nucleic acid sequence is under the control of an "inducible promoter." An "inducible promoter" is a promoter that can be regulated by an external factor, such as the presence of an inducer (also called an "inducer") molecule or the absence of a repressor molecule, or a physical factor such as an increase or decrease in temperature, osmolarity, or pH value.

[0935] In one embodiment of the present invention, the promoter may also be constitutive, i.e., a promoter that controls expression without the need for induction on the one hand and without the possibility of repression on the other hand, so that there is continuous, stable expression at a constant level.

[0936] Advantageously, expression of the recombinant peptide, polypeptide or protein of interest is induced under specific conditions, for example under selection.

[0937] In one embodiment, the expression system is a constitutive expression system. In another embodiment, the expression system is an inducible expression system.

[0938] In one embodiment, the expression system is an expression cassette.

[0939] In some embodiments, the intracellular signaling domain of the CAR of the present invention comprises at least one or two costimulatory domains or fragments or variants thereof and at least one primary signaling domain or fragments or variants thereof. In certain embodiments, one or more of the costimulatory domains are the intracellular domains of T cell costimulatory molecules. In certain embodiments, at least one primary signaling domain is a T cell primary signaling domain.

[0940] In some embodiments, the intracellular signaling domain of a CAR of the invention comprises at least one or two costimulatory domains or fragments or variants thereof, and at least one primary signaling domain or fragment or variant thereof, and at least one expression system allowing for expression of a recombinant pro-inflammatory cytokine.

[0941] Thus, in one embodiment, the CAR-engineered cells express a recombinant pro-inflammatory cytokine, such as IL-12.

[0942] In some embodiments of the invention, the primary signaling domain comprises a signaling domain of a protein selected from the group consisting of CD3 zeta, CD3 gamma, CD3 delta, CD3 epsilon, common FcR gamma (FCER1G), FcR beta (Fc epsilon Rib), CD79a, CD79b, Fc gamma RIIa, DAP10 and DAP12, and sequences derived therefrom.

[0943] In some embodiments, the primary signaling domain is a T cell primary signaling domain that comprises or consists of at least one functional signaling domain of CD3 zeta or a fragment or variant thereof.

[0944] In some embodiments, the T cell primary signaling domain comprises or consists of the CD3 zeta amino acid sequence of SEQ ID NO: 157, or an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 157.

[0945] SEQ ID NO: 157 RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

[0946] In some embodiments, the CD3 zeta primary signaling domain comprises or consists of an amino acid sequence having at least one, two, or three modifications but not more than 20, 10, or 5 modifications compared to the amino acid sequence of SEQ ID NO: 157, or an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 157.

[0947] Thus, in some embodiments, the nucleic acid sequence encoding the T cell primary signaling domain comprises or consists of the CD3 zeta domain nucleic acid sequence of SEQ ID NO: 162, or a nucleotide sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 162.

[0948] In some embodiments, the CD3 zeta primary signaling domain comprises at least 2, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, or 112 amino acids from the sequence of SEQ ID NO: 157, or from a sequence having at least about 70% identity to SEQ ID NO: 157, e.g., at least 2, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, or 112 contiguous amino acids from SEQ ID NO: 157.

[0949] In some embodiments, the CD3 zeta primary signaling domain is encoded by a nucleotide sequence of at least 6, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, or 336 nucleotides from the sequence of SEQ ID NO: 162, or from a sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 162, such as at least 6, 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330, or 336 contiguous nucleotides from SEQ ID NO: 162.

[0950] SEQ ID NO: 162 AGAGTGAAGTTCAGCAGGAGCGCAGACGCCCCCGCGTACCAGCAGGGCCAGAACCAGCTCTATAACGAGCTCAATCTAGGACGAAGAGAGGAGTACGATGTTTTGGACAAGAGACGTGGCCGGGACCCTGAGATGGGGGAAAGCCGAGAAGGAAGAACCCTCAGGAA GGCCTGTACAATGAACTGCAGAAAGATAAGATGGCGGAGGCCTACAGTGAGATTGGGATGAAAGGCGAGCGCCGGAGGGGCAAGGGGCACGATGGCCTTTACCAGGGTCTCAGTACAGCCACCAAGGACACCTACGACGCCCTTCACATGCAGGCCCTGCCCCCTCGC

[0951] In some embodiments, the stimulatory T cell primary signaling domain can contain signaling motifs known as immunoreceptor tyrosine-based activation motifs (ITAMS). Examples of ITAM-containing T cell primary intracellular signaling domains that are particularly useful in the present invention include, but are not limited to, those of (or derived from) CD3 zeta, common FcR gamma (FCER1G), Fc gamma RIIa, FcR beta (Fc epsilon R1b), CD3 gamma, CD3 delta, CD3 epsilon, CD5, CD22, CD66b, CD79a, CD79b, DAP10, and DAP12.

[0952] In some embodiments, the T cell primary signaling domain comprises a modified ITAM domain, e.g., a mutated ITAM domain that has altered (e.g., increased or decreased) activity compared to the native ITAM domain. In some embodiments, the primary signaling domain comprises a modified ITAM-containing primary intracellular signaling domain, e.g., an optimized and / or truncated ITAM-containing primary intracellular signaling domain. In certain embodiments, the primary signaling domain may comprise one, two, three, four, or more ITAM motifs.

[0953] In some embodiments, the intracellular signaling domain of a CAR of the invention comprises a T cell primary signaling domain (such as, for example, a CD3 zeta signaling domain or a fragment or variant thereof) combined with one or more costimulatory signaling domains, wherein said costimulatory signaling domain is the entire costimulatory intracellular signaling domain or a fragment or variant thereof.

[0954] In some embodiments, the costimulatory signaling domain is the intracellular or cytoplasmic domain of a T cell costimulatory molecule.

[0955] In some embodiments, the costimulatory signaling domain is the signaling domain of a T cell costimulatory molecule.

[0956] Examples of costimulatory signaling domains include 4-1BB (CD137), ICOS (CD278), CD27, CD28, CTLA-4 (CD152), PD-1, MHC class I molecules, BTLA, Toll ligand receptor, OX40, CD30, CD40, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, a ligand that specifically binds to CD83, CDS, ICAM-1, GITR, ARHR, BAFFR, HVEM (LIGHTR), SLAMF7, N Kp80 (KLRF1), NKp44, NKp30, NKp46, CD160 (BY55), CD19, CD19a, CD4, CD8 alpha, CD8 beta, IL2ra, IL6Ra, IL2R beta, IL2R gamma, IL7R alpha, IL-13RA1 / RA2, IL-33R (IL1RL1), IL-10RA / RB, IL-4R, IL-5R (CSF2RB), IL-21R, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, I TGAD, CD11d, ITGAE, CD103, ITGAL, CD11a / CD18, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, ITGB7, NKG2D, NKG2C, CD95, TGFB R1 / 2 / 3, TRANCE / RANKL, DNAM1(CD226), SLAMF4(CD244, 2B4), CD84, CD96(Tactile), CEACAM1, CRTAM, Ly9(CD229), PSGL1, CD100(SEMA4D) , CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, ​​LAT, GADS, SLP-76, PAG / Cbp, common gamma chain, CD83, NKp44, NKp30, NKp46, a ligand that specifically binds to NKG2D, and any combination thereof.

[0957] In some embodiments, the chimeric receptor comprises at least one intracellular or cytoplasmic signaling domain of a T cell costimulatory molecule selected from the group consisting of CD28, 4-1BB, OX40, ICOS, CD27, and DAP10.

[0958] In some embodiments, the chimeric receptor comprises at least one costimulatory signaling domain, wherein said costimulatory signaling domain is an entire costimulatory signaling domain or a fragment or variant thereof.

[0959] In some embodiments, the T cell costimulatory signaling domain comprises or consists of an amino acid sequence of a 4-1BB costimulatory intracellular signaling domain (e.g., comprising or consisting of the amino acid sequence of SEQ ID NO: 163), or an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 163. In some embodiments, the T cell costimulatory signaling domain comprises or consists of an amino acid sequence having at least one, two, or three modifications but not more than 20, 10, or 5 modifications compared to the amino acid sequence of SEQ ID NO: 163.

[0960] SEQ ID NO: 163 KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL

[0961] In some embodiments, the T cell costimulatory signaling domain is encoded by a 4-1BB costimulatory intracellular signaling domain nucleotide sequence (e.g., comprising or consisting of the sequence of SEQ ID NO: 164), or a nucleotide sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 164.

[0962] SEQ ID NO: 164 AAACGGGGCAGAAAGAAACTCCTGTATATATTCAAACAACCATTTATGAGACCAGTACAAACTACTCAAGAGGAAGATGGCTGTAGCTGCCGATTTCCAGAAGAAGAAGAAGGAGGATGTGAACTG

[0963] In some embodiments, the 4-1BB costimulatory intracellular signaling domain comprises at least 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, or 42 amino acids from the sequence of SEQ ID NO: 163 or from a sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 163, such as at least 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, or 42 contiguous amino acids from SEQ ID NO: 163.

[0964] In some embodiments, the 4-1BB costimulatory intracellular signaling domain is encoded by at least a 6, 18, 27, 36, 45, 54, 63, 72, 81, 96, 99, 108, 117, or 126 nucleotide sequence from SEQ ID NO: 164 or a sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 164, e.g., at least 6, 18, 27, 36, 45, 54, 63, 72, 81, 96, 99, 108, 117, or 126 contiguous nucleotides from SEQ ID NO: 164.

[0965] In some embodiments, the T cell costimulatory signaling domain comprises or consists of an amino acid sequence of a CD28 costimulatory intracellular signaling domain (e.g., comprising or consisting of the amino acid sequence of SEQ ID NO: 167), or an amino acid sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 167. In some embodiments, the T cell costimulatory signaling domain comprises or consists of an amino acid sequence having at least one, two, or three modifications but not more than 20, 10, or 5 modifications compared to the amino acid sequence of SEQ ID NO: 167.

[0966] SEQ ID NO: 167 RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

[0967] In some embodiments, the T cell costimulatory signaling domain is encoded by a CD28 costimulatory intracellular signaling domain nucleotide sequence (e.g., comprising or consisting of the sequence of SEQ ID NO: 168), or a nucleotide sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 168.

[0968] SEQ ID NO: 168 AGGAGTAAGAGGAGCAGGCTCCTGCACAGTGACTACATGAACATGACTCCCCGCCGCCCCGGGCCCACCCGCAAGCATTACCAGCCCTATGCCCCACCACGCGACTTCGCAGCCTATCGCTCC

[0969] In some embodiments, the CD28 costimulatory intracellular signaling domain comprises at least 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, or 41 amino acids from the sequence of SEQ ID NO: 167, or from a sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 167, such as at least 2, 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, or 41 contiguous amino acids from SEQ ID NO: 167.

[0970] In some embodiments, the CD28 costimulatory intracellular signaling domain is encoded by a nucleotide sequence of at least 6, 18, 27, 36, 45, 54, 63, 72, 81, 96, 99, 108, 117, or 123 nucleotides from the sequence of SEQ ID NO: 168, or from a sequence having at least about 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 168, such as at least 6, 18, 27, 36, 45, 54, 63, 72, 81, 96, 99, 108, 117, or 123 contiguous nucleotides from SEQ ID NO: 168.

[0971] In some embodiments of the present invention, the chimeric receptor comprises at least one intracellular domain of a T cell costimulatory molecule. In certain embodiments, the at least one intracellular domain may be selected from the intracellular domain of 4-1BB and the intracellular domain of CD28. In certain embodiments, the costimulatory intracellular signaling domain is the entire costimulatory intracellular signaling domain or a fragment or variant thereof.

[0972] In some embodiments of the invention, the chimeric receptor comprises a combination of at least two intracellular domains of a T cell costimulatory molecule, in certain embodiments, the costimulatory intracellular signaling domain is the entire costimulatory intracellular signaling domain or a fragment or variant thereof.

[0973] In some embodiments, the chimeric receptor comprises the amino acid sequence of a 4-1BB costimulatory intracellular signaling domain (e.g., comprising or consisting of the amino acid sequence of SEQ ID NO: 163) or a fragment or variant thereof, and the amino acid sequence of a CD28 costimulatory intracellular signaling domain (e.g., comprising or consisting of the amino acid sequence of SEQ ID NO: 167) or a fragment or variant thereof.

[0974] In some embodiments of the invention, a chimeric receptor may comprise at least three costimulatory intracellular signaling domains, said domains being entire costimulatory intracellular signaling domains or fragments or variants thereof.

[0975] In some embodiments, the intracellular signaling domain of a CAR of the invention comprises: a 4-1BB costimulatory intracellular signaling domain having the amino acid sequence of SEQ ID NO: 163 or a fragment or variant thereof, and / or a CD28 costimulatory intracellular signaling domain having the amino acid sequence of SEQ ID NO: 167, and / or - comprising a CD3 zeta primary intracellular signaling domain having the amino acid sequence of SEQ ID NO: 157 or a fragment or variant thereof, The sequences contained in the intracellular domain are expressed in the same frame as a single polypeptide chain.

[0976] Thus, in some embodiments, the nucleic acid sequence encoding the intracellular signaling domain of a CAR of the invention is - the 4-1BB costimulatory intracellular signaling domain nucleic acid sequence of SEQ ID NO: 164 or a fragment or variant thereof, and / or the CD28 costimulatory intracellular signaling domain nucleic acid sequence of SEQ ID NO: 168 or a fragment or variant thereof, and / or - comprising the CD3 zeta primary intracellular signaling domain of SEQ ID NO: 162 or a fragment or variant thereof, The sequences contained in the intracellular domain are expressed in the same frame as a single polypeptide chain.

[0977] In some embodiments, the intracellular signaling domain of a CAR of the invention comprises at least two different domains (e.g., a primary signaling domain, or a fragment or variant thereof, and at least one intracellular domain of a T cell costimulatory molecule, or a fragment or variant thereof) that can be linked to each other randomly or in a specified order.

[0978] Optionally, a short oligopeptide or polypeptide linker, e.g., 2-10 amino acids in length (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids), can form the link between different signaling domains. In some embodiments, a glycine-serine duplex (GS) is used as a suitable linker. In some embodiments, a single amino acid, e.g., alanine (A), glycine (G), is used as a suitable linker. Other examples of linkers are described herein.

[0979] In some embodiments, the intracellular signaling domain of a CAR of the invention comprises two or more (e.g., 2, 3, 4, 5 or more) costimulatory intracellular signaling domains. In some embodiments, any or all of the two or more (e.g., 2, 3, 4, 5 or more) costimulatory signaling domains are separated by a linker molecule, e.g., a linker molecule described herein.

[0980] In some embodiments, the intracellular signaling domain of a chimeric receptor of the invention comprises the primary intracellular signaling domain of CD3 zeta (e.g., SEQ ID NO: 157) and the costimulatory intracellular signaling domain of 4-1BB (e.g., SEQ ID NO: 163).

[0981] In some embodiments, the intracellular signaling domain of a chimeric receptor of the invention comprises the primary intracellular signaling domain of CD3 zeta (e.g., SEQ ID NO: 157) and the costimulatory intracellular signaling domain of CD28 (e.g., SEQ ID NO: 167).

[0982] In some embodiments, a CAR of the invention comprises any combination of an extracellular binding domain described herein, a transmembrane domain described herein, an intracellular signaling domain described herein, and optionally a spacer or hinge domain described herein.

[0983] In some embodiments, the CAR of the present invention further comprises a tag, such as a tag for quality control, enrichment, in vivo tracking, etc. The tag can be located at the N-terminus, C-terminus, and / or internally. Examples of tags that can be used in the CAR of the present invention are well known to those skilled in the art.

[0984] According to a first embodiment, a CAR of the invention comprises at least one extracellular CD45RC-binding domain, optionally an extracellular hinge domain, at least one transmembrane domain and at least one intracellular signaling domain.

[0985] In one embodiment, a CAR of the invention comprises a CD45RC binding domain, a transmembrane domain of CD8 (preferably, SEQ ID NO: 153), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0986] In one embodiment, a CAR of the invention comprises a CD45RC binding domain, a transmembrane domain of CD28 (preferably, SEQ ID NO: 155), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0987] In another embodiment, a CAR of the invention comprises a CD45RC binding domain, a hinge domain of CD8 (preferably, SEQ ID NO: 145), a transmembrane domain of CD8 (preferably, SEQ ID NO: 153), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0988] In one embodiment, a CAR of the invention comprises a CD45RC binding domain, a hinge domain of CD8 (preferably, SEQ ID NO: 145), a transmembrane domain of CD28 (preferably, SEQ ID NO: 155), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0989] In another embodiment, a CAR of the invention comprises a CD45RC binding domain, an IgG4 hinge domain (preferably, SEQ ID NO: 147), a CD8 transmembrane domain (preferably, SEQ ID NO: 153), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0990] In one embodiment, a CAR of the invention comprises a CD45RC binding domain, an IgG4 hinge domain (preferably, SEQ ID NO: 147), a CD28 transmembrane domain (preferably, SEQ ID NO: 155), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0991] In another embodiment, a CAR of the invention comprises a CD45RC binding domain, an IgD hinge domain (preferably, SEQ ID NO: 149), a CD8 transmembrane domain (preferably, SEQ ID NO: 153), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0992] In one embodiment, a CAR of the present invention comprises a CD45RC binding domain, a hinge domain of IgD (preferably, SEQ ID NO: 149), a transmembrane domain of CD28 (preferably, SEQ ID NO: 155), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0993] In another embodiment, a CAR of the invention comprises a CD45RC binding domain, a hinge domain of CD28 (preferably, SEQ ID NO: 151), a transmembrane domain of CD8 (preferably, SEQ ID NO: 153), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0994] In one embodiment, a CAR of the invention comprises a CD45RC binding domain, a hinge domain of CD28 (preferably, SEQ ID NO: 151), a transmembrane domain of CD28 (preferably, SEQ ID NO: 155), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0995] According to a second embodiment, the CAR of the present invention comprises a CD45RC binding domain, optionally an extracellular hinge domain, a transmembrane domain, a single intracellular domain of a T cell costimulatory molecule, and a T cell primary signaling domain.

[0996] In one embodiment, a CAR of the present invention comprises a CD45RC binding domain, a transmembrane domain of CD8 (preferably, SEQ ID NO: 153), an intracellular domain of 4-1BB (preferably, SEQ ID NO: 163), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0997] In one embodiment, a CAR of the invention comprises a CD45RC binding domain, a transmembrane domain of CD8 (preferably, SEQ ID NO: 153), an intracellular domain of CD28 (preferably, SEQ ID NO: 167), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0998] In one embodiment, a CAR of the present invention comprises a CD45RC binding domain, a transmembrane domain of CD28 (preferably, SEQ ID NO: 155), an intracellular domain of 4-1BB (preferably, SEQ ID NO: 163), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[0999] In one embodiment, a CAR of the invention comprises a CD45RC binding domain, a transmembrane domain of CD28 (preferably, SEQ ID NO: 155), an intracellular domain of CD28 (preferably, SEQ ID NO: 167), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[1000] In another embodiment, a CAR of the invention comprises a CD45RC binding domain, a hinge domain of CD8 (preferably, SEQ ID NO: 145), a transmembrane domain of CD8 (preferably, SEQ ID NO: 153), an intracellular domain of 4-1BB (preferably, SEQ ID NO: 163), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[1001] In one embodiment, a CAR of the invention comprises a CD45RC binding domain, a hinge domain of CD8 (preferably, SEQ ID NO: 145), a transmembrane domain of CD8 (preferably, SEQ ID NO: 153), an intracellular domain of CD28 (preferably, SEQ ID NO: 155), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[1002] In one embodiment, a CAR of the present invention comprises a CD45RC binding domain, a hinge domain of CD8 (preferably, SEQ ID NO: 145), a transmembrane domain of CD28 (preferably, SEQ ID NO: 155), an intracellular domain of 4-1BB (preferably, SEQ ID NO: 163), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[1003] In one embodiment, a CAR of the invention comprises a CD45RC binding domain, a hinge domain of CD8 (preferably, SEQ ID NO: 145), a transmembrane domain of CD28 (preferably, SEQ ID NO: 155), an intracellular domain of CD28 (preferably, SEQ ID NO: 167), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[1004] In another embodiment, a CAR of the invention comprises a CD45RC binding domain, an IgG4 hinge domain (preferably, SEQ ID NO: 147), a CD8 transmembrane domain (preferably, SEQ ID NO: 153), a 4-1BB intracellular domain (preferably, SEQ ID NO: 163), and a CD3-zeta primary signaling domain (preferably, SEQ ID NO: 157).

[1005] In one embodiment, a CAR of the invention comprises a CD45RC binding domain, an IgG4 hinge domain (preferably, SEQ ID NO: 147), a CD8 transmembrane domain (preferably, SEQ ID NO: 153), a CD28 intracellular domain (preferably, SEQ ID...

Claims

1. A chimeric antigen receptor (CAR) specific for human CD45RC, comprising: (a) at least one extracellular binding domain, wherein the binding domain comprises at least one antigen-binding fragment that binds to human CD45RC comprising a combination of three HCVR CDRs and three LCVR CDRs as set forth in any row of the following table, wherein the CDRs are defined by their SEQ ID NOs: at least one extracellular binding domain, wherein X 12 is not present in L-CDR1; (b) at least one transmembrane domain, and (c) a chimeric antigen receptor (CAR) comprising at least one intracellular signaling domain, wherein the intracellular domain comprises at least one T cell primary signaling domain.

2. the extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, the antigen-binding fragment comprising: (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) SEQ ID NO: 15(X １２ does not exist) 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. The CAR of claim 1.

3. the extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, the antigen-binding fragment comprising: (a) an HCVR comprising the following three CDRs: (i) V of the sequence of SEQ ID NO: 1 Ｈ - CDR1, (ii) V 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) SEQ ID NO: 15(X １２ does not exist) 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. The CAR of claim 1.

4. the extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, the antigen-binding fragment comprising: (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) SEQ ID NO: 18(X １２ does not exist) Ｌ - CDR1, (ii) the VL-CDR2 of the sequence SEQ ID NO: 16, and (iii) V of the sequence of SEQ ID NO: 17 Ｌ -CDR3. The CAR of claim 1.

5. the extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, the antigen-binding fragment comprising: (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) SEQ ID NO: 15(X １２ does not exist) Ｌ - CDR1, (ii) the VL-CDR2 of the sequence set forth in SEQ ID NO: 120, and (iii) V of the sequence of SEQ ID NO: 17 Ｌ -CDR3. The CAR of claim 1.

6. The CAR described in claim 5, wherein at least one antigen-binding fragment comprises an HCVR of the sequence of SEQ ID NO:

62.

7. The extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, wherein the antigen-binding fragment is: (c) an HCVR comprising the following three CDRs: (i) V H -CDR1 of the sequence SEQ ID NO: 1; (ii) the V H -CDR2 of SEQ ID NO: 118, and (iii) the V H -CDR3 of the sequence SEQ ID NO: 3, and (d) an LCVR comprising the following three CDRs: (i) V L -CDR1 of the sequence SEQ ID NO: 15 (X 12 is absent), (ii) the V L -CDR2 of the sequence SEQ ID NO: 120, and The CAR according to claim 1, comprising (iii) a V L -CDR3 of the sequence of SEQ ID NO:

17.

8. The CAR described in claim 7, wherein at least one antigen-binding fragment comprises an HCVR of the sequence of SEQ ID NO:

123.

9. the extracellular binding domain comprises at least one antigen-binding fragment that binds to human CD45RC, the antigen-binding fragment comprising: 1) the HCVR of sequence SEQ ID NO: 61 and the 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) The CAR according to claim 1, comprising an HCVR and an LCVR comprising a non-CDR region sequence that shares at least 90% identity with the non-CDR region sequence of the HCVR and LCVR according to 1) to 13).

10. (i) anti-human CD45RC scFv, (ii) a hinge domain derived from CD8α; (iii) the human CD8α transmembrane domain, and (iv) an intracellular signaling domain comprising a human CD28 signaling domain and a human CD3 zeta signaling domain.

11. (i) an anti-human CD45RC scFv comprising an HCVR having the sequence of SEQ ID NO: 61 and an LCVR having the sequence of SEQ ID NO: 81 connected by a linker having the sequence of SEQ ID NO: 134; (ii) a hinge domain derived from CD8α having the sequence of SEQ ID NO: 145; (iii) a human CD8α transmembrane domain having the sequence of SEQ ID NO: 153, and (iv) an intracellular signaling domain comprising a human CD28 signaling domain having the sequence of SEQ ID NO: 167 and a human CD3 zeta signaling domain having the sequence of SEQ ID NO:

157.

12. A nucleic acid encoding the CAR according to any one of claims 1 to 11.

13. An expression vector comprising the nucleic acid of claim 12.

14. An immune cell population, which is engineered to express the CAR according to any one of claims 1 to 11 on the cell surface.

15. 15. The immune cell population of claim 14, wherein the immune cell population is a regulatory T cell population.

16. The regulatory T cell population is CD4 ＋ CD25 ＋ Foxp3 ＋ Tregs, Tr1 cells, TGF-β-secreting Th3 cells, regulatory NKT cells, regulatory γδ T cells, regulatory CD8 ＋ 16. The immune cell population of claim 15, wherein the immune cell population is selected from the group consisting of T cells and double-negative regulatory T cells.

17. 17. A pharmaceutical composition comprising at least one immune cell population according to any one of claims 14 to 16, further comprising at least one pharmaceutically acceptable excipient or carrier.

18. 18. A pharmaceutical composition according to claim 17 for use as a medicament.

19. Use in inducing immune tolerance, preventing or reducing transplant rejection, or preventing or treating graft-versus-host disease (GVHD), or in treating a CD45RC gene selected from the group consisting of an autoimmune disease, an unwanted immune response, a monogenic disease, lymphoma, and cancer in a subject in need thereof. ｈｉｇｈ 18. A pharmaceutical composition according to claim 17 for use in the prevention, reduction and / or treatment of associated diseases.

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