Monoclonal antibody or antigen-binding fragment thereof that specifically binds to BCMA and its use

Abstract

The present invention relates to the fields of biotechnology and medicine, in particular, monoclonal antibodies or antigen-binding fragments thereof that specifically bind to BCMA. The present invention also relates to nucleic acids encoding said antibodies, expression vectors, host cells and methods for producing them, methods for producing antibodies according to the present invention, pharmaceutical compositions comprising antibodies according to the present invention, pharmaceutical compositions comprising antibodies according to the present invention and other therapeutically active compounds, methods for treating BCMA-mediated diseases or disorders, the use of antibodies or pharmaceutical compositions for treating BCMA-mediated diseases or disorders, and the use of antibodies and other therapeutically active compounds for treating BCMA-mediated diseases or disorders.

Description

Technical Field

[0001] The present invention relates to the fields of biotechnology and medicine, in particular, monoclonal antibodies or antigen-binding fragments thereof that specifically bind to BCMA. The present invention also relates to nucleic acids encoding said antibodies, expression vectors, host cells and methods for producing them, methods for producing antibodies according to the invention, pharmaceutical compositions comprising antibodies according to the invention, pharmaceutical compositions comprising antibodies according to the invention and other therapeutically active compounds, methods for treating BCMA-mediated diseases or disorders, the use of antibodies or pharmaceutical compositions for treating BCMA-mediated diseases or disorders, and the use of antibodies and other therapeutically active compounds for treating BCMA-mediated diseases or disorders.

Background Art

[0002] B cell maturation antigen (BCMA, TNFRSF17, and CD269) is a member of the tumor necrosis factor (TNF) receptor superfamily. Its native ligands are B cell activating factor (BAFF; also called BLyS or TALL-1), and a proliferation-inducing ligand (APRIL, TNFSF13, CD256) involved in various aspects of humoral immunity, B cell development, and homeostasis. However, APRIL binds to BCMA with a significantly higher affinity (10 -7 M) than BAFF (10 -9 M) (Yu-Tzu Tai et al., APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment, Blood, 2016, Vol. 127, No. 25, pp. 3225-3236, https: / / doi.org / 10.1182 / blood-2016-01-691162).

[0003] BCMA is expressed in the late stage of B cell differentiation in plasmablasts and plasma cells (plasma cells, PCs). In multiple myeloma (MM), the expression of BCMA is significantly increased in malignant plasma cells compared to normal cells, and the activation of BCMA supports the proliferation and survival of plasma cells through the activation of MEK / ERK, AKT, NFκB, JNK, p38, and Elk-1 (Shih-Feng Cho et al., Targeting B Cell Maturation Antigen (BCMA) in Multiple Myeloma: Potential Uses of BCMA-Based Immunotherapy, Front Immunol, 2018, 9, 1821, https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC6095983).

[0004] BCMA is a promising target for immunotherapy products in various oncological diseases, such as leukemia, lymphoma, or multiple myeloma, because this antigen is characterized by its limited abundance and increased expression in malignant plasma cells compared to normal plasma cells.

[0005] Patent documents WO2012163805, WO2013072406, WO2014089335, WO2017143069 describe various antibodies against BCMA. To date, only one anti-BCMA antibody has been approved for therapeutic use as part of an antibody conjugated to a pharmaceutical in the world (Belantamab mafodotin). In this regard, there is a need for novel antibodies that specifically bind to BCMA.

Summary of the Invention

Means for Solving the Problems

[0006] The group of the inventors of the present invention developed an antibody that specifically binds to BCMA and has high affinity parameters for binding to BCMA. Definitions and General Methods Unless otherwise defined, all technical and scientific terms used in connection with the present invention have the same meaning as commonly understood by one of ordinary skill in the art.

[0007] Furthermore, unless the context dictates otherwise, singular terms shall include plural terms and plural terms shall include singular terms. Typically, cell culture, molecular biology, immunology, microbiology, genetics, analytical chemistry, organic synthetic chemistry, medicinal chemistry and pharmaceutical chemistry, as well as the classifications and methods of the present invention regarding the hybridization and chemistry of proteins and nucleic acids described herein, are well known to those of ordinary skill in the art and are widely used in the art. Enzyme reactions and purification methods are carried out according to the instructions of the manufacturing company, which is common in the art or described herein.

[0008] The term "KD" in this description refers to the affinity constant (or, equilibrium constant), which is calculated by the ratio of Kd to Ka (i.e., Kd / Ka) and is expressed in molar concentration (M). "Binding affinity" refers to the overall strength of the non-covalent interaction between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise indicated, "binding affinity" refers to the intrinsic (characteristic, true) binding affinity that reflects the 1:1 interaction of the members of the binding pair (e.g., an antibody and an antigen). The affinity of molecule X for binding partner Y can generally be represented by the affinity constant (KD). Preferred Kd values are about 200 nM, 150 nM, 100 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 8 nM, 6 nM, 4 nM, 2 nM, 1 nM, or less. Affinity can be measured by methods common in the art, including the methods described in this description. Low-affinity antibodies generally bind to antigens slowly and tend to dissociate easily, while high-affinity antibodies generally bind to antigens quickly and tend to remain bound for a long time. Various methods for measuring binding affinity are known in the art, and any one of these methods can be used for the purposes of the present invention.

[0009] The terms "Kd", "koff", or "kdis" refer to the off rate constant of a specific interaction between a binding molecule and an antigen. The off rate constant koff can be measured using bio-layer interferometry, for example, using an Octet™ system.

[0010] The terms "Ka", "kon", or "on-rate" refer to the association rate constant. The term "R 2 " refers to the coefficient of determination.

[0011] The term "response" refers to the antibody-antigen binding signal. The term "in vitro" refers to biological entities, biological processes, or biological reactions outside the body under artificial conditions. For example, cell growth in vitro should be understood as cell growth in an environment outside the body, such as in a test tube, culture vial, or microplate.

[0012] The term "ED 50 " (EC 50 )(50% effective dose / concentration) refers to the concentration of a formulation that produces a 50% biological effect (which may include cytotoxicity). As used in the following description and claims, unless the context specifically indicates otherwise, the words "include", "comprise", or variations thereof, such as "includes", "including", "comprises", or "comprising", are understood to mean including the stated integer or group of integers but not excluding any other integer or group of integers.

[0013] Antibody The present invention relates to monoclonal antibodies or antigen-binding fragments thereof that specifically bind to BCMA (B-cell maturation antigen, also known as TNFRSF17 and CD269).

[0014] The term "monoclonal antibody" or "mAb" refers to an antibody that is synthesized and isolated as an individual clone population of cells. The antibody of the present invention is a recombinant antibody.

[0015] The term "recombinant antibody" refers to an antibody expressed in a cell or cell line containing a nucleotide sequence encoding the antibody, and the nucleotide sequence is not associated with natural cells. In one aspect, the present invention is an isolated monoclonal antibody or an antigen-binding fragment thereof that specifically binds to BMC, (a)(i) CDR1 having the amino acid sequence SX1X2MS (wherein, X1 = S or G; X2 = A, L, or V); (ii) CDR2 having the amino acid sequence X3YNGGSDRAGX4X5DSVX6G (wherein, X3 = G or C; X4 = F or Y; X5 = A or T; X6 = E or K); and (iii) CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b)(i) CDR1 having the amino acid sequence X7GX8X9SNIGX 10 X 11 X 12 X 13 VX 14 (wherein, X7 = S or T; X8 = S, G, or T; X9 = S, T, I, or R; X 10 = 0 or A; X 11 = S, H, N, G, or T; X 12 = N, R, or Y; X 13 = T, A, I, or D; X 14 = N or H); (ii) The amino acid sequence X 15 X 16 X 17 X 18 having CDR2 with RPS (wherein, X 15 = N, R, K, S, or G; X 16 = D, N, G, T, or H; X 17 = S, N, or T; X 18 = Q or N); and (iii) The amino acid sequence X 19 X 20 WDX 21 X 22 X 23 X 24 X 25 WX 26 having CDR3 (wherein, X 19 = A or S; X 20 = A, S, T, or V; X 21 = G, D, H or S; X 22 = S, D, or R; X 23 = L or V; X 24 = N, T, R, or S; X 25 = V, A, G, or N; X 26 = M, V, or L) comprising a light chain variable domain relating to an isolated monoclonal antibody or an antigen-binding fragment thereof.

[0016] The term "isolated," as used to describe the various antibodies according to this description, refers to an antibody that has been identified, isolated, and / or reproduced in the cells or cell culture in which it is expressed. Impurities (contaminating components) in the natural environment are materials that typically interfere with the diagnostic or therapeutic use of the polypeptide and can include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. An isolated polypeptide is typically prepared by at least one purification step.

[0017] The term "antibody" or "immunoglobulin" (Ig), as used in this description, includes antibodies in general. The term "antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (referred to herein as VH for brevity) and a heavy chain constant region. Each light chain consists of a light chain variable region (referred to herein as VL for brevity) and a light chain constant region. Preferably, the light chain is a kappa (κ) light chain, and the constant domain CL is preferably C kappa (κ).

[0018] An antibody according to the present invention can be of any class (e.g., IgA, IgD, IgE, IgG, and IgM, preferably IgG) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2, preferably IgG1).

[0019] The VL and VH regions can be further differentiated into hypervariable regions called complementarity-determining regions (CDRs) with more conserved regions called framework regions (FRs) interspersed between them. Each VH and VL is composed of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain the binding domains that interact with the antigen.

[0020] The constant region of an antibody can mediate the binding of immunoglobulins to host tissues, or various cells of the immune system (e.g., effector cells) and factors including the first component of the classical complement system (C1q).

[0021] As used herein, the terms “antigen-binding portion” or “antigen-binding fragment” of an antibody refer to one or more antibody fragments that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments included within the term “antigen-binding portion” of an antibody include: (i) the Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) the F(ab’)2 fragment, which is a divalent fragment comprising two Fab fragments linked by disulfide bridges in the hinge region; (iii) the Fd fragment consisting of the VH and CH1 domains; (iv) the Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) the dAb fragment consisting of the VH / VHH domain (Ward et al., (1989) Nature 341:544-546). In addition, the VL and VH of the two regions of the Fv fragment can be encoded by different genes and joined by recombinant methods using a synthetic linker so as to be received as a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain molecules are also contemplated to be included within the term “antigen-binding portion” of an antibody. Such antibody fragments are produced using conventional techniques known to those of skill in the art, and these fragments are screened in the same manner as intact antibodies.

[0022] The "Kabat numbering scheme" or "Kabat numbering" when used in this application refers to a system for numbering amino acid residues that are more variable (i.e., hypervariable) than other amino acid residues in the variable regions of the heavy and light chains of an antibody (Kabat et al., Ann. N.Y. Acad. Sci., Vol. 190: 382-93 (1971); Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed., U.S. Department of Health and Human Services, NIH Publication No. 91-3242 (1991)).

[0023] An antibody of the present invention that "specifically binds" to a target antibody refers to an antibody that binds to an antigen with sufficient affinity and cross-reacts only slightly with other proteins so that the antibody can be used as a diagnostic and / or therapeutic agent targeting a protein or cell or tissue expressing the antigen.

[0024] The term "specifically binds" to a particular polypeptide or an epitope of a particular target polypeptide can be described by examples of molecules having a Kd of at least about 200 nM, or at least about 150 nM, or at least about 100 nM, or at least about 60 nM, or at least about 50 nM, or at least about 40 nM, or at least about 30 nM, or at least about 20 nM, or at least about 10 nM, or at least about 8 nM, or at least about 6 nM, or at least about 4 nM, or at least about 2 nM, or at least about 1 nM, or more to the target.

[0025] In one aspect, the term "specifically binds" refers to a binding in which a molecule binds to an epitope of a particular polypeptide or a particular target polypeptide without substantially binding to any other polypeptide or an epitope of a polypeptide.

[0026] In some embodiments of the present invention, the isolated monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3.

[0027] In some embodiments of the present invention, the isolated monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6.

[0028] In some embodiments of the present invention, the isolated monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15.

[0029] In some embodiments of the present invention, the isolated monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24.

[0030] In some embodiments of the present invention, the isolated monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising a CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, or SEQ ID NO: 35.

[0031] In some embodiments of the present invention, the isolated monoclonal antibody or antigen-binding fragment thereof comprises a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6; and CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain is included.

[0032] In some embodiments of the invention, the isolated monoclonal antibody or antigen-binding fragment thereof (i) CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; (ii) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; (iii) CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; (iv) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; or, (v) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 6, and CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain is included.

[0033] In some embodiments of the invention, the isolated monoclonal antibody or antigen-binding fragment thereof A CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, or SEQ ID NO:15; A CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, or SEQ ID NO:24; and A CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, or SEQ ID NO:35 A light chain variable domain comprising thereof.

[0034] In some embodiments of the invention, the isolated monoclonal antibody or antigen-binding fragment thereof is (i) A CDR1 having the amino acid sequence of SEQ ID NO:8, a CDR2 having the amino acid sequence of SEQ ID NO:16, and a CDR3 having the amino acid sequence of SEQ ID NO:25 A light chain variable domain comprising; (ii) A CDR1 having the amino acid sequence of SEQ ID NO:9, a CDR2 having the amino acid sequence of SEQ ID NO:17, and a CDR3 having the amino acid sequence of SEQ ID NO:26 A light chain variable domain comprising; (iii) A CDR1 having the amino acid sequence of SEQ ID NO:10, a CDR2 having the amino acid sequence of SEQ ID NO:18, and a CDR3 having the amino acid sequence of SEQ ID NO:27 A light chain variable domain comprising; (iv) A CDR1 having the amino acid sequence of SEQ ID NO:11, a CDR2 having the amino acid sequence of SEQ ID NO:19, and a CDR3 having the amino acid sequence of SEQ ID NO:28 A light chain variable domain comprising; (v) A CDR1 having the amino acid sequence of SEQ ID NO: 12, a CDR2 having the amino acid sequence of SEQ ID NO: 20, and a CDR3 having the amino acid sequence of SEQ ID NO: 29 comprising a light chain variable domain; (vi) A CDR1 having the amino acid sequence of SEQ ID NO: 12, a CDR2 having the amino acid sequence of SEQ ID NO: 20, and a CDR3 having the amino acid sequence of SEQ ID NO: 30 comprising a light chain variable domain; (vii) A CDR1 having the amino acid sequence of SEQ ID NO: 10, a CDR2 having the amino acid sequence of SEQ ID NO: 21, and a CDR3 having the amino acid sequence of SEQ ID NO: 31 comprising a light chain variable domain; (viii) A CDR1 having the amino acid sequence of SEQ ID NO: 13, a CDR2 having the amino acid sequence of SEQ ID NO: 22, and a CDR3 having the amino acid sequence of SEQ ID NO: 32 comprising a light chain variable domain; (ix) A CDR1 having the amino acid sequence of SEQ ID NO: 14, a CDR2 having the amino acid sequence of SEQ ID NO: 23, and a CDR3 having the amino acid sequence of SEQ ID NO: 33 comprising a light chain variable domain; (x) A CDR1 having the amino acid sequence of SEQ ID NO: 8, a CDR2 having the amino acid sequence of SEQ ID NO: 24, and a CDR3 having the amino acid sequence of SEQ ID NO: 34 comprising a light chain variable domain; or, (xi) A CDR1 having the amino acid sequence of SEQ ID NO: 15, a CDR2 having the amino acid sequence of SEQ ID NO: 17, and a CDR3 having the amino acid sequence of SEQ ID NO: 35 comprising a light chain variable domain is included.

[0035] In some embodiments of the present invention, the isolated monoclonal antibody or antigen-binding fragment thereof (a) a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6; and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15; a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 24; and a CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, or SEQ ID NO: 35 comprising a light chain variable domain is included.

[0036] In some embodiments of the present invention, the isolated monoclonal antibody or antigen-binding fragment thereof (i) (a) a CDR1 having the amino acid sequence of SEQ ID NO: 1, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) a CDR1 having the amino acid sequence of SEQ ID NO: 8, a CDR2 having the amino acid sequence of SEQ ID NO: 16, and a CDR3 having the amino acid sequence of SEQ ID NO: 25 comprising a light chain variable domain; (ii)(a) A CDR1 having the amino acid sequence of SEQ ID NO: 2, a CDR2 having the amino acid sequence of SEQ ID NO: 5, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) A CDR1 having the amino acid sequence of SEQ ID NO: 9, a CDR2 having the amino acid sequence of SEQ ID NO: 17, and a CDR3 having the amino acid sequence of SEQ ID NO: 26 comprising a light chain variable domain; (iii)(a) A CDR1 having the amino acid sequence of SEQ ID NO: 3, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) A CDR1 having the amino acid sequence of SEQ ID NO: 10, a CDR2 having the amino acid sequence of SEQ ID NO: 18, and a CDR3 having the amino acid sequence of SEQ ID NO: 27 comprising a light chain variable domain; (iv)(a) A CDR1 having the amino acid sequence of SEQ ID NO: 2, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) A CDR1 having the amino acid sequence of SEQ ID NO: 11, a CDR2 having the amino acid sequence of SEQ ID NO: 19, and a CDR3 having the amino acid sequence of SEQ ID NO: 28 comprising a light chain variable domain; (v)(a) A CDR1 having the amino acid sequence of SEQ ID NO: 2, a CDR2 having the amino acid sequence of SEQ ID NO: 5, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) A CDR1 having the amino acid sequence of SEQ ID NO: 12, A CDR2 having the amino acid sequence of SEQ ID NO: 20, and a CDR3 having the amino acid sequence of SEQ ID NO: 29 comprising a light chain variable domain; (vi)(a) A CDR1 having the amino acid sequence of SEQ ID NO: 2, a CDR2 having the amino acid sequence of SEQ ID NO: 6, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) A CDR1 having the amino acid sequence of SEQ ID NO: 12, a CDR2 having the amino acid sequence of SEQ ID NO: 20, and a CDR3 having the amino acid sequence of SEQ ID NO: 30 comprising a light chain variable domain; (vii)(a) A CDR1 having the amino acid sequence of SEQ ID NO: 2, a CDR2 having the amino acid sequence of SEQ ID NO: 5, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) A CDR1 having the amino acid sequence of SEQ ID NO: 10, a CDR2 having the amino acid sequence of SEQ ID NO: 21, and a CDR3 having the amino acid sequence of SEQ ID NO: 31 comprising a light chain variable domain; (viii)(a) A CDR1 having the amino acid sequence of SEQ ID NO: 2, a CDR2 having the amino acid sequence of SEQ ID NO: 5, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) A CDR1 having the amino acid sequence of SEQ ID NO: 13, a CDR2 having the amino acid sequence of SEQ ID NO: 22, and a CDR3 having the amino acid sequence of SEQ ID NO: 32 comprising a light chain variable domain; (ix)(a) A CDR1 having the amino acid sequence of SEQ ID NO: 2, A CDR2 having the amino acid sequence of SEQ ID NO: 5, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) A CDR1 having the amino acid sequence of SEQ ID NO: 12, a CDR2 having the amino acid sequence of SEQ ID NO: 20, and a CDR3 having the amino acid sequence of SEQ ID NO: 30 comprising a light chain variable domain; (x)(a) A CDR1 having the amino acid sequence of SEQ ID NO: 2, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) A CDR1 having the amino acid sequence of SEQ ID NO: 14, a CDR2 having the amino acid sequence of SEQ ID NO: 23, and a CDR3 having the amino acid sequence of SEQ ID NO: 33 comprising a light chain variable domain; (xi)(a) A CDR1 having the amino acid sequence of SEQ ID NO: 2, a CDR2 having the amino acid sequence of SEQ ID NO: 4, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) A CDR1 having the amino acid sequence of SEQ ID NO: 8, a CDR2 having the amino acid sequence of SEQ ID NO: 24, and a CDR3 having the amino acid sequence of SEQ ID NO: 34 comprising a light chain variable domain; or, (xii)(a) A CDR1 having the amino acid sequence of SEQ ID NO: 2, a CDR2 having the amino acid sequence of SEQ ID NO: 5, and a CDR3 having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain; and (b) A CDR1 having the amino acid sequence of SEQ ID NO: 15, A CDR2 having the amino acid sequence of SEQ ID NO: 17, and a CDR3 having the amino acid sequence of SEQ ID NO: 35 a light chain variable domain comprising is included.

[0037] In some embodiments of the invention, the isolated monoclonal antibody or antigen-binding fragment thereof comprises a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, or SEQ ID NO: 43.

[0038] In some embodiments of the invention, the isolated monoclonal antibody or antigen-binding fragment thereof comprises a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54.

[0039] In some embodiments of the invention, the isolated monoclonal antibody or antigen-binding fragment thereof (a) a heavy chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, or SEQ ID NO: 43; and (b) a light chain variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO: 54 is included.

[0040] In some embodiments of the invention, the isolated monoclonal antibody or antigen-binding fragment thereof (i) (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 36, and (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 44; (ii) (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 37, and (b) The variable light domain comprising the amino acid sequence of SEQ ID NO: 45; (iii) (a) The variable heavy domain comprising the amino acid sequence of SEQ ID NO: 38, and (b) The variable light domain comprising the amino acid sequence of SEQ ID NO: 46; (iv) (a) The variable heavy domain comprising the amino acid sequence of SEQ ID NO: 39, and (b) The variable light domain comprising the amino acid sequence of SEQ ID NO: 47; (v) (a) The variable heavy domain comprising the amino acid sequence of SEQ ID NO: 40, and (b) The variable light domain comprising the amino acid sequence of SEQ ID NO: 48; (vi) (a) The variable heavy domain comprising the amino acid sequence of SEQ ID NO: 41, and (b) The variable light domain comprising the amino acid sequence of SEQ ID NO: 49; (vii) (a) The variable heavy domain comprising the amino acid sequence of SEQ ID NO: 40, and (b) The variable light domain comprising the amino acid sequence of SEQ ID NO: 50; (viii) (a) The variable heavy domain comprising the amino acid sequence of SEQ ID NO: 40, and (b) The variable light domain comprising the amino acid sequence of SEQ ID NO: 51; (ix) (a) The variable heavy domain comprising the amino acid sequence of SEQ ID NO: 40, and (b) The variable light domain comprising the amino acid sequence of SEQ ID NO: 49; (x) (a) The variable heavy domain comprising the amino acid sequence of SEQ ID NO: 42, and (b) The variable light domain comprising the amino acid sequence of SEQ ID NO: 52; (xi) (a) The variable heavy domain comprising the amino acid sequence of SEQ ID NO: 43, and (b) The variable light domain comprising the amino acid sequence of SEQ ID NO: 53; Or, (xii) (a) The variable heavy domain comprising the amino acid sequence of SEQ ID NO: 40, and (b) The variable light domain comprising the amino acid sequence of SEQ ID NO: 54 comprising.

[0041] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is a full-length IgG antibody. In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is a full-length IgG antibody of human IgG1, IgG2, IgG3, or IgG4 isotype.

[0042] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is a full-length IgG antibody of human IgG1 isotype. In some embodiments of the present invention, the isolated monoclonal antibody comprises mutations L234A and L235A (or, according to Kabat, L247A and L248A) in CH2 according to the EU numbering of antibody amino acids (Edelman G.M. et al., Proc. Natl. Acad. Sci. USA 63 (1969) 78-85; Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)).

[0043] In some embodiments of the present invention, the isolated monoclonal antibody comprises a heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, or SEQ ID NO: 62.

[0044] In some embodiments of the present invention, the isolated monoclonal antibody comprises a light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO: 73.

[0045] In some embodiments of the present invention, the isolated monoclonal antibody is (i)(a) A heavy chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, or SEQ ID NO: 62; and (b) A light chain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO: 73 comprising.

[0046] In some embodiments of the present invention, the isolated monoclonal antibody is (i)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 55, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 63; (ii)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 64; (iii)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 57, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 65; (iv)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 58, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 66; (v)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 67; (vi)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 60, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 68; (vii)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 69; (viii)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 70; (ix)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 68; (x)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 61, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 71; (xi)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 62, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 72; Or, (xii)(a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 73 is included.

[0047] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01-001. Antibody 01-001 (a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 55, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 63 is included.

[0048] Antibody 01-001 (a) A heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 36; (b) A light chain variable domain comprising the amino acid sequence of SEQ ID NO: 44 is included.

[0049] Antibody 01-001 (a)(i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 1, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 4, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain, and (b)(i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 8, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 16, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 25 comprising a light chain variable domain is included.

[0050] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01-006. Antibody 01-006 is (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 56, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 64 and includes.

[0051] Antibody 01-006 is (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 37; (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 45 and includes.

[0052] Antibody 01-006 is (a) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 5, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 a heavy chain variable domain including, and (b) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 9, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 17, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 26 a light chain variable domain including and includes.

[0053] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01-016. Antibody 01-016 is (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 57, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 65 and includes.

[0054] Antibody 01-016 is (a) Heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 38; (b) Light chain variable domain comprising the amino acid sequence of SEQ ID NO: 46 comprising.

[0055] Antibody 01-016 is (a) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 3, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 4, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 heavy chain variable domain comprising, and (b) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 10, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 18, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 27 light chain variable domain comprising comprising.

[0056] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01-021. Antibody 01-021 is (a) heavy chain comprising the amino acid sequence of SEQ ID NO: 58, and (b) light chain comprising the amino acid sequence of SEQ ID NO: 66 comprising.

[0057] Antibody 01-021 is (a) heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 39; (b) light chain variable domain comprising the amino acid sequence of SEQ ID NO: 47 comprising.

[0058] Antibody 01-021 is (a) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 4, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable domain comprising (b) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 11, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 19, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 28 and a light chain variable domain comprising is included.

[0059] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01-022. Antibody 01-022 (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 67 is included.

[0060] Antibody 01-022 (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 40; (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 48 is included.

[0061] Antibody 01-022 (a) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 5, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 and a heavy chain variable domain comprising (b) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 12, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 20, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 29 and a light chain variable domain comprising is included.

[0062] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01-024. Antibody 01-024 (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 60, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 68 comprises.

[0063] Antibody 01-024 (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 41; (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 49 comprises.

[0064] Antibody 01-024 (a) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 6, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain, and (b) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 12, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 20, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 30 comprising a light chain variable domain comprises.

[0065] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01-025. Antibody 01-025 (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 69 comprises.

[0066] Antibody 01-025 (a) Heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 40; (b) Light chain variable domain comprising the amino acid sequence of SEQ ID NO: 50 comprising.

[0067] Antibody 01-025 is (a) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 5, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain, and (b) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 10, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 21, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 31 comprising a light chain variable domain comprising.

[0068] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01-026. Antibody 01-026 is (a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 70 comprising.

[0069] Antibody 01-026 is (a) Heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 40; (b) Light chain variable domain comprising the amino acid sequence of SEQ ID NO: 51 comprising.

[0070] Antibody 01-026 is (a) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 5, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain, and (b) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 13, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 22, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 32 comprising a light chain variable domain is included.

[0071] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01-027. Antibody 01-027 (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 68 is included.

[0072] Antibody 01-027 (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 40; (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 49 is included.

[0073] Antibody 01-027 (a) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 5, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain, and (b) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 12, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 20, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 30 comprising a light chain variable domain is included.

[0074] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01-030. Antibody 01-030 comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 61, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 71 thereof.

[0075] Antibody 01-030 comprises (a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 42; (b) a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 52 thereof.

[0076] Antibody 01-030 comprises (a) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 4, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 in a heavy chain variable domain, and (b) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 14, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 23, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 33 in a light chain variable domain thereof.

[0077] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01-033. Antibody 01-033 comprises (a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 62, and (b) a light chain comprising the amino acid sequence of SEQ ID NO: 72 thereof.

[0078] Antibody 01-033 comprises (a) Heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 43; (b) Light chain variable domain comprising the amino acid sequence of SEQ ID NO: 53 comprising.

[0079] Antibody 01 - 033 is (a) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 4, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain, and (b) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 8, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 24, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 34 comprising a light chain variable domain comprising.

[0080] In some embodiments of the present invention, the isolated monoclonal antibody that specifically binds to BCMA is antibody 01 - 037. Antibody 01 - 037 is (a) A heavy chain comprising the amino acid sequence of SEQ ID NO: 59, and (b) A light chain comprising the amino acid sequence of SEQ ID NO: 73 comprising.

[0081] Antibody 01 - 037 is (a) Heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 40; (b) Light chain variable domain comprising the amino acid sequence of SEQ ID NO: 54 comprising.

[0082] Antibody 01 - 037 is (a) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 2, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 5, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 7 comprising a heavy chain variable domain, and (b) (i) CDR1 (Kabat) having the amino acid sequence of SEQ ID NO: 15, (ii) CDR2 (Kabat) having the amino acid sequence of SEQ ID NO: 17, (iii) CDR3 (Kabat) having the amino acid sequence of SEQ ID NO: 35 comprising a light chain variable domain is included.

[0083] Nucleic acid molecule In one aspect, the present invention relates to a nucleic acid encoding any one of the above antibodies or antigen-binding fragments thereof that specifically binds to BCMA.

[0084] In any one of the above aspects, the nucleic acid molecule can be isolated. The terms "nucleic acid", "nuclear sequence", "nucleic acid sequence", "polynucleotide", "oligonucleotide", "polynucleotide sequence", and "nucleotide sequence", which are used interchangeably herein, refer to the exact sequence of nucleotides that determines a fragment or region of a nucleic acid, contains or does not contain unnatural nucleotides, and is either double-stranded DNA or RNA, single-stranded DNA or RNA, or a transcript of said DNA, modified or unmodified.

[0085] Unless otherwise indicated, the term nucleotide sequence includes its complement. Thus, a nucleic acid having a particular sequence should be understood to include the complementary strand with the complementary sequence.

[0086] An "isolated" nucleic acid molecule is one that is identified and separated from at least one nucleic acid molecule-impurity. An isolated nucleic acid molecule is different from the form or setting in which it is found in nature. Thus, an isolated nucleic acid molecule is different from a nucleic acid molecule that exists in a cell under natural conditions.

[0087] In one aspect, the present invention relates to a nucleic acid molecule comprising a nucleotide encoding an amino acid sequence analysis selected from SEQ ID NOs: 1 to 73. The nucleic acid molecule can also include any combination of the nucleotide sequences.

[0088] As will be understood by those skilled in the art, due to the redundancy of the genetic code, various different DNA sequences can encode the amino acid sequences of the light or heavy chains (such as VH, VL, CDR, etc.) of the antibodies or fragments thereof according to the present invention. Creating alternative DNA sequences encoding the same amino acid sequence is well within the skill of those skilled in the art. Such variant DNA sequences are within the scope of the present invention.

[0089] In some embodiments of the present invention, the isolated nucleic acid is DNA. The nucleic acid molecule of the present invention can be isolated from any source that produces a monoclonal antibody or an antigen-binding fragment thereof that specifically binds to BCMA. In certain embodiments of the present invention, the nucleic acid molecule of the present invention can be synthesized by chemical synthesis rather than being isolated.

[0090] In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain variable domain of antibody 01-001 and comprising the nucleotide sequence of SEQ ID NO: 74. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain variable domain of antibody 01-001 and comprising the nucleotide sequence of SEQ ID NO: 82.

[0091] In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of antibody 01-001 and comprising the nucleotide sequence of SEQ ID NO: 93. In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of antibody 01-001 and comprising the nucleotide sequence of SEQ ID NO: 101.

[0092] In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain variable domain of antibody 01-006 and comprising the nucleotide sequence of SEQ ID NO: 75. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain variable domain of antibody 01-006 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 83.

[0093] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain of antibody 01-006 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 94. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain of antibody 01-006 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 102.

[0094] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain variable domain of antibody 01-016 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 76. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain variable domain of antibody 01-016 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 84.

[0095] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain of antibody 01-016 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 95. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain of antibody 01-016 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 103.

[0096] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain variable domain of antibody 01-021 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 77. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain variable domain of antibody 01-021 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 85.

[0097] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain of antibody 01-021 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 96. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain of antibody 01-021 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 104.

[0098] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain variable domain of antibody 01-022 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 78. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain variable domain of antibody 01-022 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 86.

[0099] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain of antibody 01-022 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 97. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain of antibody 01-022 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 105.

[0100] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain variable domain of antibody 01-024 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 79. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain variable domain of antibody 01-024 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 87.

[0101] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain of antibody 01-024 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 98. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain of antibody 01-024 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 106.

[0102] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain variable domain of antibody 01-025 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 78. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain variable domain of antibody 01-025 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 88.

[0103] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain of antibody 01-025 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 97. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain of antibody 01-025 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 107.

[0104] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain variable domain of antibody 01-026 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 78. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain variable domain of antibody 01-026 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 89.

[0105] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain of antibody 01-026 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 97. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain of antibody 01-026 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 108.

[0106] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain variable domain of antibody 01-027 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 78. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain variable domain of antibody 01-027 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 87.

[0107] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain of antibody 01-027 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 97. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain of antibody 01-027 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 106.

[0108] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain variable domain of antibody 01-030 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 80. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain variable domain of antibody 01-030 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 90.

[0109] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain of antibody 01-030 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 99. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain of antibody 01-030 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 109.

[0110] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain variable domain of antibody 01-033 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 81. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain variable domain of antibody 01-033 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 91.

[0111] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain of antibody 01-033 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 100. In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the light chain of antibody 01-033 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 110.

[0112] In some embodiments of the present invention, the nucleic acid encodes the amino acid sequence of the heavy chain variable domain of antibody 01-037 and is a nucleic acid comprising the nucleotide sequence of SEQ ID NO: 78. In some aspects of the present invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain variable domain of antibody 01-037 and includes the nucleotide sequence of SEQ ID NO: 92.

[0113] In some aspects of the present invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 01-037 and includes the nucleotide sequence of SEQ ID NO: 97. In some aspects of the present invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 01-037 and includes the nucleotide sequence of SEQ ID NO: 111.

[0114] The nucleic acid molecule can be used to express a monoclonal antibody or an antigen-binding fragment thereof that specifically binds to BCMA. Vector In one aspect, the present invention relates to an expression vector comprising any one of the above nucleic acid molecules that encodes the corresponding amino acid sequence of an antibody that specifically binds to BCMA or a portion thereof (e.g., a heavy chain and / or light chain binding domain sequence). The present invention relates to a vector suitable for the expression of any one of the nucleotide sequences described herein.

[0115] As used herein, the term "vector" means a nucleic acid molecule capable of transporting another nucleic acid molecule to which it is linked. As used in this description, the term "expression" is defined as the transcription and / or translation of a specific nucleotide sequence driven by a promoter.

[0116] In some aspects of the present invention, the vector is a plasmid, i.e., a circular double-stranded piece of DNA into which additional DNA segments can be inserted. In some aspects of the present invention, the vector is a viral (expression) vector into which additional DNA segments can be inserted into the viral genome.

[0117] In some embodiments of the present invention, the vector is capable of autonomous replication in the host cell into which it is introduced (e.g., a bacterial vector having a bacterial origin of replication site and an episomal vector). In a further embodiment of the present invention, a vector (non-episomal vector) can be integrated into the genome of the host cell by introduction into the host cell, thereby being replicated together with the host gene. Further, certain vectors can direct the expression of a gene operably linked thereto. Such vectors are referred to herein as "recombinant expression vectors" (or simply "expression vectors").

[0118] In some embodiments of the present invention, expression vectors include plasmids, retroviruses, adenoviruses, adeno-associated viruses (AAVs), plant viruses such as cauliflower mosaic virus, tobacco mosaic virus, cosmids, YACs, and the like. A DNA molecule can be inserted into the vector such that the transcriptional and translational control sequences within the vector perform their intended function of regulating the transcription and translation of the DNA. The expression vector and the expression control sequences can be selected to be compatible with the expression host cell used.

[0119] In one embodiment of the present invention, a DNA molecule encoding in part or in full the sequences of the first and second binding domains (e.g., the heavy and light chain sequences if the binding domain comprises heavy and light chain sequences) can be introduced into separate vectors.

[0120] In one embodiment, any combination of the above DNA molecules is introduced into the same expression vector. In one embodiment of the present invention, the DNA molecule can be introduced into the expression vector by standard methods (e.g., ligation of complementary restriction sites in the antibody and gene fragment of the vector, or blunt-end ligation if no restriction sites are present).

[0121] In some embodiments of the invention, suitable vectors contain restriction sites such that any VH or VL sequence can be readily inserted and expressed, as described above. Polyadenylation and transcription termination can occur at the native chromosomal site downstream of the coding region. The recombinant expression vector can also encode a signal peptide that facilitates secretion of the antibody chain from the host cell. The antibody chain gene can be cloned into the vector such that the signal peptide is in-frame linked to the amino terminus of the immunoglobulin chain. The signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).

[0122] In some aspects of the invention, the vector may include an expression control sequence. As used herein, the term "expression control sequence" refers to a polynucleotide sequence necessary to effect the expression and processing of an inserted coding sequence. It will be understood by those skilled in the art that the design of an expression vector, including the selection of an expression control sequence, can be influenced by factors such as the type of host cell to be transformed and the required expression level of the antibody. Expression control sequences include appropriate transcription initiation, termination, promoter, and enhancer sequences; efficient RNA processing signals, such as splicing and polyadenylation signals; sequences that stabilize cytoplasmic mRNA; sequences that enhance translation efficiency (i.e., Kozak consensus sequences); sequences that enhance protein stability; and, if desired, sequences that enhance protein secretion. The nature of such expression control sequences varies depending on the host organism, and in prokaryotes, such expression control sequences typically include a promoter, a ribosome binding site, and a transcription termination sequence, while in eukaryotes, such expression control sequences typically include a promoter and a transcription termination sequence. Preferred expression control sequences for mammalian expression host cells include virus-like elements that ensure high levels of protein expression in mammalian cells, such as retroviral LTRs, cytomegalovirus (CMV) (e.g., the DMV promoter / enhancer), simian virus 40 (SV40) (e.g., the SV40 promoter / enhancer), adenovirus (e.g., the adenovirus major late promoter (AdMLP)), promoter / enhancers derived from polyomavirus, strong mammalian promoters such as the TTR promoter, the native immunoglobulin promoter, or the actin promoter. Expression control sequences include at least all of the components whose presence is critical for expression and processing.

[0123] In some embodiments of the present invention, in addition to the antibody chain gene and the expression control sequence, the recombinant expression vector of the present invention may carry additional sequences, such as sequences that regulate the replication of the vector in the host cell (e.g., origin of replication) and the replication of the selectable marker gene. The selectable marker gene helps in the selection of the host cell into which the vector is introduced.

[0124] host cell In one aspect, the present invention relates to a method of producing a host cell that produces any of the above antibodies or antigen-binding fragments thereof that specifically bind to BCMA, comprising transforming the cell with the above vector.

[0125] In one aspect, the present invention relates to a host cell that produces any of the above antibodies or antigen-binding fragments thereof that specifically bind to BCMA and contains any one of the above nucleic acids. The term "host cell" as used herein refers to a cell into which a recombinant expression vector is introduced. The present invention relates to, for example, a host cell that may contain a vector according to the present invention as described above. The present invention further relates to, for example, a host cell that contains a nucleotide sequence encoding a heavy chain or an antigen-binding portion thereof, a nucleotide sequence encoding a light chain or an antigen-binding portion thereof, or both. "Host cell" refers not only to a particular subject cell but also to the progeny of such a cell. Such progeny may not actually be identical to the parent cell because the modification may occur in subsequent generations either by mutation or environmental influence, but such cells are still included within the scope of the term "host cell" as used herein.

[0126] The nucleic acid molecules encoding monoclonal antibodies or antigen-binding fragments thereof that specifically bind to BCMA according to the present invention, and vectors containing these nucleic acid molecules, can be used for transfection of mammalian cells, plant cells, bacterial cells, or yeast cells. Transfection can be carried out by any known method for introducing polynucleotides into host cells. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, cationic polymer nucleic acid complex transfection, calcium phosphate precipitation, polybrene-mediated transfection, protoplast fusion, encapsulation of polynucleotides by liposomes, and direct microinjection of DNA into the nucleus. In addition, the nucleic acid molecules can be introduced into mammalian cells by viral (expression) vectors.

[0127] Mammalian cell lines used as host cells for transformation are well-known in the art and include multiple immortalized cell lines available. These include, for example, Chinese hamster ovary (CHO) cells, NS0 cells, SP2 cells, HEK-293T cells, FreeStyle 293 cells (Invitrogen), NIH-3T3 cells, HeLa cells, baby hamster kidney (BHK) cells, African green monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549, SK-HEP1, HUH7, Hep-RG cells, and numerous other cell lines. The cell line is selected by determining which cell line has high expression levels and provides the necessary characteristics of the protein to be produced. Other cell lines that can be used are insect cell lines, such as Sf9 or Sf21 cells. When a recombinant expression vector encoding a monoclonal antibody or an antigen-binding fragment thereof that specifically binds to BCMA is introduced into a mammalian host cell, the antibody or its fragment is produced by culturing the host cell for a sufficient time to allow expression of the antibody or its fragment in the host cell or, more preferably, secretion of the antibody or its fragment into the culture medium in which the host cell is grown. A monoclonal antibody or an antigen-binding fragment thereof that specifically binds to BCMA can be isolated from the culture medium using standard protein purification techniques. Plant host cells include, for example, tobacco (Nicotiana), Arabidopsis, duckweed, corn, wheat, potato, etc. Bacterial host cells include Escherichia coli and Streptomyces species. Yeast hosts include Schizosaccharomyces pombe, Saccharomyces cerevisiae, and Pichia pastoris.

[0128] Furthermore, the production level of monoclonal antibodies or antigen-binding fragments thereof that specifically bind to BCMA from the production cell line can be enhanced using a number of known techniques. For example, the glutamine synthetase gene expression system (GS system) is a common technique for enhancing expression under certain conditions.

[0129] Monoclonal antibodies or antigen-binding fragments thereof that specifically bind to BCMA from various cell lines may have different glycosylation profiles when compared to each other. However, monoclonal antibodies or antigen-binding fragments thereof that specifically bind to BCMA encoded by the nucleic acid molecules described herein, or nucleic acid molecules comprising the amino acid sequences provided herein, are generally part of the present invention regardless of the glycosylation of the binding molecule and regardless of the presence or absence of post-translational modifications.

[0130] The host cells described above are not related to host cells produced using human embryos. The host cells described above are not related to host cells produced by modifying the genetic integrity of human germ cells.

[0131] Method for producing an antibody In one aspect, the present invention is a method for producing an antibody or an antigen-binding fragment thereof that specifically binds to BCMA, the method comprising culturing the host cells in a growth medium under conditions sufficient to produce the antibody or the fragment thereof, and subsequently isolating and purifying the obtained antibody or the fragment thereof if necessary.

[0132] Pharmaceutical composition Another aspect of the present invention is a pharmaceutical composition comprising, as an active ingredient (or as the only active ingredient), a monoclonal antibody according to the present invention or an antigen-binding fragment thereof that specifically binds to BCMA.

[0133] In one aspect, the present invention relates to a pharmaceutical composition for treating a BCMA-mediated disease or disorder, comprising a therapeutically effective amount of any of the above antibodies or antigen-binding fragments thereof in combination with one or more pharmaceutically acceptable excipients.

[0134] "Pharmaceutical composition" means a composition comprising an antibody according to the invention and at least one component selected from the group consisting of pharmaceutically acceptable, pharmacologically compatible fillers, solvents, diluents, carriers, adjuvants, distribution and sensing agents, delivery agents.

[0135] The term "pharmaceutically acceptable" refers to one or more compatible liquid or solid components suitable for administration to a mammal, preferably a human. The term "excipient" is used herein to describe any component other than the antibody according to the invention. These are substances of inorganic or organic nature used in pharmaceutical production / manufacture to impart the physicochemical characteristics required for the drug.

[0136] In some embodiments, the composition is intended to ameliorate, prevent, or treat a disease or disorder that may be mediated by BCMA. The term "BCMA-mediated disease or disorder" refers to any disease or disorder directly or indirectly related to BCMA, including the etiology, occurrence, progression, persistence, or pathology of the disease or disorder.

[0137] "Treat", "treatment", and "therapy" refer to a method of reducing or suppressing at least one of a biological disorder and / or its attendant symptoms. Further, references to "treatment" herein also include references to curative, symptomatic, and prophylactic treatment.

[0138] The term "disorder" means any condition that benefits from the treatment according to the invention. The definition of this term includes chronic and acute disorders or diseases, including pathological conditions that render a mammal susceptible to the disorder.

[0139] "Therapeutically effective amount" refers to the amount of a therapeutic agent administered during treatment that alleviates to some extent one or more symptoms of the disease being treated. The therapeutically effective amount can vary depending on the particular condition being treated, the age, sex and weight of the patient, and factors such as whether the monoclonal antibody or antigen-binding fragment thereof that specifically binds to BCMA is administered as a monotherapy or in combination with one or more additional drugs or treatments.

[0140] In one aspect, the subject or patient to be treated is a mammal, preferably a human subject. The subject can be a male or female of any age. The pharmaceutical compositions of the present invention and methods for their preparation will be apparent to those skilled in the art without doubt. The pharmaceutical compositions should preferably be manufactured in compliance with GMP (Good Manufacturing Practice) requirements.

[0141] In some embodiments of the pharmaceutical composition, the pharmaceutical composition can include a buffer composition, an isotonic agent (osmotic regulator or osmotic agent), a stabilizer, and / or a solubilizing agent. The pharmaceutical composition according to the present invention is a stable composition.

[0142] A pharmaceutical composition is "stable" if the active agent retains physical stability, and / or chemical stability, and / or biological stability over a particular shelf life at a storage temperature, for example, between 2 and 8 °C. Preferably, the active agent retains both physical and chemical stability as well as biological stability. The storage period is adjusted based on the results of stability tests under accelerated or natural degradation conditions.

[0143] The pharmaceutical composition according to the present invention is suitable for parenteral administration as a sterile preparation intended for administration to a subject that bypasses the gastrointestinal tract and penetrates the skin or mucosal barrier by injection, infusion, and implantation. In particular, parenteral administration is contemplated to include, inter alia, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intracerebroventricular, intraurethral, intracranial, intrasynovial, transdermal infusion or injection, and renal dialysis infusion techniques. Intratumoral delivery, such as intratumoral injection, can also be used. Regional perfusion is also contemplated.

[0144] In some embodiments, the pharmaceutical composition is administered intravenously. In some embodiments, intravenous administration is carried out using infusion, prolonged infusion, or continuous long-term infusion.

[0145] In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, subcutaneous administration is carried out using subcutaneous injection. In some embodiments, the pharmaceutical composition is in injectable dosage form.

[0146] In some embodiments, the injectable dosage form is an infusion. In some embodiments, the injectable dosage form is a solution for subcutaneous administration. Injectable formulations can be manufactured in unit dosage forms such as, without limitation, ampoules, vials, plastic containers, pre-filled syringes, auto-injection devices, and the like.

[0147] In some embodiments, the pharmaceutical composition is provided in a dry form, i.e., in powder or granule form, which is reconstituted with a suitable solvent (e.g., sterile pyrogen-free water) prior to administration. Such pharmaceutical formulations are known in the art, for example, by lyophilization, i.e., freeze-drying, a process involving freezing the product and subsequently removing the solvent from the frozen material.

[0148] In some embodiments, the pharmaceutical composition is a lyophilized product for preparing a solution for infusion. In some embodiments, the pharmaceutical composition is a lyophilized product for preparing a solution for subcutaneous administration.

[0149] In some embodiments, the pharmaceutical composition is a concentrate for preparing a solution for infusion. In some embodiments, the pharmaceutical composition is a concentrate for preparing a solution for subcutaneous administration.

[0150] In one aspect, the present invention relates to a pharmaceutical composition comprising a monoclonal antibody according to the present invention or an antigen-binding fragment thereof that specifically binds to BCMA, and at least one other therapeutically active compound.

[0151] In one aspect, the present invention relates to a pharmaceutical composition for treating a BCMA-mediated disease or disorder, comprising any of the above antibodies or an antigen-binding fragment thereof, and at least one other therapeutically active compound.

[0152] In one aspect, the present invention relates to a pharmaceutical composition comprising any of the above antibodies or an antigen-binding fragment thereof, and further comprising at least one other therapeutically active compound. In one aspect, the present invention relates to a pharmaceutical composition for treating a BCMA-mediated disease or disorder, comprising any of the above antibodies or an antigen-binding fragment thereof, and further comprising at least one other therapeutically active compound.

[0153] In one aspect, the present invention relates to a pharmaceutical composition for treating a BCMA-mediated disease or disorder, comprising any of the above antibodies or an antigen-binding fragment thereof, and at least one other therapeutically active compound (which is an antibody, small molecule, hormonal therapeutic agent, or a combination thereof).

[0154] In some embodiments of the pharmaceutical composition, the BCMA-mediated disease or disorder is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma.

[0155] Therapeutic use of a monoclonal antibody or antigen-binding fragment thereof that specifically binds to BCMA In one aspect, an antibody or antigen-binding fragment thereof that specifically binds to BCMA is used for treating disorders mediated by BCMA activity.

[0156] In one aspect, the subject or patient to be treated is a mammal, preferably a human subject. The subject can be a male or female of any age. In one aspect, the present invention relates to a method for treating a BCMA-mediated disease or disorder, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of any of the above antibodies or antigen-binding fragments thereof, or said pharmaceutical composition.

[0157] In one aspect, the present invention relates to a method for treating a BCMA-mediated disease or disorder, the method comprising administering to a subject in need of such treatment a therapeutically effective amount of any of the above antibodies or antigen-binding fragments thereof, and at least one other therapeutically active compound.

[0158] In some embodiments of the method for treatment, the BCMA-mediated disease or disorder is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma.

[0159] In some embodiments of the method for treatment, the other therapeutically active compound is a small molecule, a hormonal therapy agent, or a combination of any of these. In one aspect, the present invention relates to the use of any of the above antibodies or antigen-binding fragments thereof, or the above pharmaceutical composition, for treating a BCMA-mediated disease or disorder in a subject in need of such treatment.

[0160] In one aspect, the present invention relates to the use of any of the above antibodies or antigen-binding fragments thereof, and at least one other therapeutically active compound, for treating a BCMA-mediated disease or disorder.

[0161] In some embodiments for use, the BCMA-mediated disease or disorder is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma.

[0162] In some embodiments of the method for use, the other therapeutically active compound is a small molecule, a hormonal therapeutic agent, or a combination of any of these. As used herein, the use or method relating to an antibody or antigen-binding fragment thereof that specifically binds to BCMA, with one or more other therapeutic agents, is intended to mean, refer to, and include: 1) The simultaneous administration of an antibody or antigen-binding fragment thereof that specifically binds to BCMA, and a combination of therapeutic agents, to a patient in need of treatment, when the components are formulated together in a single dosage form that releases the components to the patient at substantially the same time. 2) The simultaneous administration of an antibody or antigen-binding fragment thereof that specifically binds to BCMA, and a combination of therapeutic agents, to a patient in need of treatment, when the components are formulated separately from each other in separate dosage forms that are ingested by the patient at substantially the same time, whereby the components are released to the patient at substantially the same time. 3) The sequential administration of an antibody or antigen-binding fragment thereof that specifically binds to BCMA, and a combination of therapeutic agents, to a patient in need of treatment, when the components are formulated separately from each other in separate dosage forms that are ingested by the patient sequentially with a significant time interval between each administration, whereby the components are released to the patient at substantially different times, and 4) The sequential administration of an antibody or antigen-binding fragment thereof that specifically binds to BCMA, and a combination of therapeutic agents, to a patient in need of treatment, when the components are formulated together in a single dosage form that controllably releases the components, each part of which can be administered by the same or different routes, whereby the components are released to the patient simultaneously, sequentially, or together at the same and / or different times.

[0163] An antibody that specifically binds to BCMA or an antigen-binding fragment thereof can be administered without further therapeutic treatment, i.e., as an independent therapy. In some aspects of the method or use for treatment, an antibody that specifically binds to BCMA or an antigen-binding fragment thereof can be administered in combination with a proteasome inhibitor.

[0164] In some aspects of the method or use for treatment, an antibody that specifically binds to BCMA or an antigen-binding fragment thereof can be administered in combination with an anti-tumor immunomodulatory agent (e.g., lenalidomide, pomalidomide).

[0165] In some aspects of the method or use for treatment, an antibody that specifically binds to BCMA or an antigen-binding fragment thereof can be administered in combination with a cytostatic chemotherapy (such as cyclophosphamide, etoposide).

[0166] In some aspects of the method or use for treatment, an antibody that specifically binds to BCMA or an antigen-binding fragment thereof can be administered in combination with a tyrosine kinase inhibitor. In some aspects of the method or use for treatment, an antibody that specifically binds to BCMA or an antigen-binding fragment thereof can be administered in combination with a BCL2 inhibitor product.

[0167] In some aspects of the method or use for treatment, an antibody that specifically binds to BCMA or an antigen-binding fragment thereof can be administered in combination with an exportin 1 antagonist product.

[0168] In some aspects of the method or use for treatment, an antibody that specifically binds to BCMA or an antigen-binding fragment thereof can be administered in combination with a glucocorticosteroid. In some aspects of the method or use for treatment, an antibody that specifically binds to BCMA or an antigen-binding fragment thereof can be administered in combination with an anti-tumor monoclonal antibody (e.g., daratumumab).

[0169] In some embodiments of the method for treatment or use, an antibody or antigen-binding fragment thereof that specifically binds to BCMA can be administered in combination with a targeted therapy. In some embodiments of the method for treatment or use, an antibody or antigen-binding fragment thereof that specifically binds to BCMA can be administered in combination with monoclonal antibodies that are agonistic to cytokines (e.g., IL15SA, IL2).

[0170] In some embodiments of the method for treatment or use, an antibody or antigen-binding fragment thereof that specifically binds to BCMA can be administered in combination with monoclonal antibodies that are antagonistic to cytokines (e.g., anti-IL6R, anti-TNF).

[0171] In some embodiments of the method for treatment or use, an antibody or antigen-binding fragment thereof that specifically binds to BCMA can be administered in combination with a G-CSF (granulocyte colony-stimulating factor) product.

[0172] In some embodiments of the method for treatment or use, an antibody or antigen-binding fragment thereof that specifically binds to BCMA can be administered in combination with a hematopoietic stem cell transplantation. In some embodiments of the method for treatment or use, an antibody or antigen-binding fragment thereof that specifically binds to BCMA can be administered in combination with radiotherapy.

[0173] In some embodiments of the method for treatment or use, a suitable dose of the monoclonal antibody or antigen-binding fragment thereof that specifically binds to BCMA according to the present invention is in the range of 0.1 to 200 mg / kg.

Brief Description of the Drawings

[0174]

Figure 1

Figure 2

[0175]

Table 1

Figure 3

Figure 4

[0176] Figures 3 and 4

[0177]

Table 2

Figure 5

[0178] M is the molecular weight marker. 1 - Candidate 01. 2 - Candidate 06.

[0179] 3 - Candidate 016. 4 - Candidate 021. 5 - Candidate 022.

Figure 6

[0180] M is the molecular weight marker. 1 - Candidate 024. 2 - Candidate 025.

[0181] 3 - Candidate 026. 4 - Candidate 027. 5 - Candidate 030.

[0182] It is candidate 033 of 6. It is candidate 037 of 7.

Mode for Carrying Out the Invention

[0183]

Examples

[0184] The following examples are provided for a better understanding of the present invention. These examples are for illustrative purposes only and should not be construed as limiting the scope of the present invention in any way.

[0185] All publications, patents and patent applications listed in this specification are incorporated herein by reference. The foregoing invention has been described in some detail for purposes of clarity of understanding, but it will be readily apparent to those skilled in the art, considering the teachings of the present invention, that certain changes and modifications may be made without departing from the spirit or scope of the appended claims.

[0186] Materials and General Methods General information regarding the nucleotide sequences of human immunoglobulin light and heavy chains is presented in Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991). Amino acids of antibody chains are numbered according to the EU numbering (Edelman, G.M. et al., Proc. Natl. Acad. Sci. USA 63 (1969) 78 - 85; Kabat, E.A. et al., Sequences of Proteins of Immunological Interest, 5th Edition, Public Health Service, National Institutes of Health, Bethesda, MD (1991)).

[0187] Recombinant DNA Technology DNA was manipulated using standard methods as described in Sambrook, J. et al., Molecular cloning: A laboratory manual; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989. Molecular biology reagents were used according to the manufacturer's protocols.

[0188] Gene synthesis Desired gene segments were prepared from oligonucleotides synthesized chemically. Gene segments 300 - 1400 bp in length flanked by single restriction sites were assembled by annealing and ligation of oligonucleotides including PCR amplification, followed by cloning via the restriction sites. The DNA sequence of the subcloned gene fragments was verified by DNA sequencing.

[0189] DNA sequencing DNA sequences were determined by Sanger sequencing. Analysis of DNA and protein sequences, and management of sequence data The Unipro UGENE suite version 1.29 and SnapGene Viewer were used for sequence generation, mapping, analysis, annotation, and illustration.

[0190] Expression vector For the expression of the antibodies described in this application, a variant of the expression plasmid intended for antibody expression in prokaryotic cells (E. coli) transiently expressed in eukaryotic cells (e.g., CHO cells) was applied. In addition to the antibody expression cassette, the vector contained an origin of replication enabling the replication of the plasmid in E. coli and genes conferring resistance to various antibiotics (e.g., ampicillin, kanamycin) to E. coli.

[0191] The described antibody chains were used to generate a fusion gene containing them as described below, and assembled by known recombinant methods and techniques, such as by PCR and / or gene synthesis, and ligated according to nucleic acid segments using unique restriction sites in the corresponding vectors. The subcloned nucleic acid sequences were verified by DNA sequencing. For transient transfection, large amounts of plasmid were prepared from plasmid preparations from transformed E. coli cultures.

[0192] Example 1. Production of recombinant antigen in suspension culture of mammalian cells The sequence of the extracellular domain of the human BCMA receptor (SEQ https: / / www.uniprot.org / uniprot / Q02223 (1 - 54aa)) was cloned into the pEE plasmid for protein production in mammalian cells with tags of TEV-Fc, Avi-His, Avi-His-TEV-HSA via SalI / NotI restriction sites. The required amount of plasmid was cultured in E. coli cells and purified using a Qiagen kit.

[0193] The antigen was produced by a cell line obtained from Chinese hamster ovary (CHO-T) cells. Suspension culture was performed in flasks on an orbital incubator shaker. To express the target antigen, the cells were transfected by using linear polyethyleneimine. Nine days after transfection, the culture medium was separated from the cells by filtration through a 0.5 / 0.22 μm deep-bed filter.

[0194] The antigen BCMA-TEV-Fc was isolated from the culture medium and purified using a column with a Protein A affinity chromatography adsorbent. The clear culture medium was passed through a column equilibrated with phosphate-buffered saline (PBS, pH 7.4). The bound antigen was eluted using 0.1 M glycine buffer (pH 2.5). Subsequently, the obtained target protein was dialyzed against PBS (pH 7.4), DTT was added, the mixture was filtered through a 0.22 μm Millex GP, transferred to a tube, and stored at -70 °C. The antigens BCMA-Avi-His and BCMA-Avi-His-TEV-HSA were isolated from the culture medium and purified using a Ni-NTA affinity chromatography column. The clear culture medium was passed through a column equilibrated with phosphate-buffered saline (PBS, pH 7.4). The bound antigen was eluted with PBS (pH 7.4) supplemented with 500 mM imidazole. Subsequently, the protein was dialyzed into PBS. Thereafter, the protein was applied to a gel filtration column. The obtained protein was filtered through a 0.22 μm Millex GP, transferred to a tube, and stored at -70 °C.

[0195] Example 2. Cloning of the variable domain genes of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 into expression plasmids The variable domain genes of the antibodies were cloned into the expression plasmids pLL (Figure 1) and pET22 (Figure 2) according to a standard protocol using the restriction ligation method.

[0196] Subsequently, the expression vectors containing the antigen fragments were transformed into Escherichia coli BL21-DE3 and BL21-Gold strains for affinity comparison analysis of various antibody fragments and antigens in the display library by ELISA using an automated platform.

[0197] Example 3. Generation and primary analysis of Fabs and scFvs of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 that specifically bind to human BCMA Fabs and scFvs were generated according to standard techniques. BL21-DE3 and BL21-Gold bacterial cells of E. coli were transformed with expression vectors containing the scFv and Fab genes, respectively, followed by induction of transcription of the lac operon by addition of an inducer, thus causing expression of the scFv and Fab while culturing the resulting transformants and transporting them to the periplasmic space. Next, ELISA was performed to verify scFV and Fab binding to the substrate-immobilized antigen hBCMA-Avi-His (antigen immobilized overnight at 4°C) at a concentration of 0.2 μg / ml in 0.1 M NaHCO3 (pH 9.0). All further steps were carried out at room temperature according to the standard ELISA protocol using a high-throughput automated platform based on a robotic-assisted system. Washing was performed 3 times at 300 μl / well with 1×PSBST after each step. Nonspecific binding sites on the plate were blocked with 1% non-fat milk in 1×PBST, and after washing, the analyte (60 μl / well of E. coli supernatant) was added. Immune complexes were detected using a peroxidase-conjugated goat anti-Myc tag antibody (1:20000). The substrate chromogenic mixture was stained by adding 50 μl of the substrate solution for 15 minutes. The reaction was stopped using 25 μl of 1% H2SO4. The color signal was measured at a wavelength of 450 nm. The antibody binding level was proportional to the signal generated. Clones with a color signal exceeding that of the control antibody were tested by ELISA for nonspecific binding.

[0198] Thus, the Fabs and scFvs of the tested antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 all exhibit specific binding to hBCMA-Avi-His.

[0199] Example 4. Analysis of non-specific binding of Fab and scFv of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 to other antigens ELISA was also used to analyze the non-specific binding of the scFv and Fab to different antigens. The analysis was performed as described above, except that hCD16-Avi-His-FLAG and cynoIL4R-Fc in 0.1 M NaHCO3 (pH 9.0) were used as antigens for immobilization (the antigen was immobilized overnight at 4°C). hBCMA-Avi-His and cynomolgus monkey BCMA were used as controls for specific binding (the antigen was immobilized overnight at 4°C). All subsequent steps were carried out using a high-throughput automated platform according to the standard ELISA protocol.

[0200] All tested Fab and scFv of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 showed specific binding to hBCMA-Avi-His and cynomolgus monkey BCMA, but did not show non-specific interaction with hCD16-Avi-His-FLAG and cynoIL4R-Fc.

[0201] Example 5. Analysis of the dissociation rate of Fab and scFv of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 by ForteBio The Fab was measured using a ForteBio Octet RED384 system with a FAB2G biosensor (ForteBio). The Fab sample was loaded from the supernatant onto the sensor at a temperature condition of (5 ± 3°C) for 16 - 18 hours. Once loaded, the sensor was transferred to a kinetic buffer solution (4.3 mM Na2HPO4; 500 mM NaCl, 1.5 mM KH2PO4; 2.7 mM KCl; the volume fraction of added Tween 20 was 0.1%; the mass fraction of added BSA was 0.1%; pH 7.4) with 500 mM NaCl, and the given buffer was used for all preparations in the subsequent steps of the experiment with the Fab sample. The measurement was carried out at 30°C. The sensor was equilibrated with the kinetic buffer for at least 10 minutes and then the baseline was recorded (60 seconds). After baseline recording, the sensor with immobilized Fab was immersed in a well containing the analyte solution (recombinant human antigen BCMA - Avi - His - TEV - HSA), where the antigen - Fab complex was allowed to associate for 300 seconds. The human BCMA concentration was 391.2 nM (30 μg / ml). Then, the dissociation of the complex in the kinetic buffer was detected for 600 seconds. To examine the non - specific interaction between the analyte and the sensor (negative control), the inventors used a sensor without the candidate Fab. In the loading step, the negative control sensor was immersed in the supernatant without Fab, and all other steps were the same as those used for the sensor loaded with the Fab sample.

[0202] The scFv was measured using a ForteBio Octet RED384 system with a SAX biosensor (ForteBio). In the measurement, human BCMA was biotinylated at a molar ratio of antigen / biotin of 1:1.5. The interaction kinetics analysis was performed at 30 °C. The analysis was performed using a kinetic buffer (4.3 mM Na2HPO4; 136.9 mM NaCl, 1.5 mM KH2PO4; 2.7 mM KCl; the volume fraction of added Tween 20 was 0.1%; the mass fraction of added BSA was 0.1%; pH 7.4). Biotinylated human BCMA was loaded onto the sensor for 600 seconds, and the concentration of the antigen solution in the kinetic buffer was 20 μg / ml. The baseline was recorded for 120 seconds. After the baseline recording, the sensor with the immobilized antigen was immersed in a well containing the analyte solution (candidate scFv), where the antigen-scFv complex was allowed to associate for 150 seconds (in the association step, the scFv sample was diluted to a concentration of 1200 nM with the kinetic buffer). Subsequently, the dissociation of the antigen-scFv complex in the kinetic buffer was detected for 600 seconds. The reference signal was recorded simultaneously with the recording of the candidate sensorgram and subtracted while the sensorgram was being processed. The reference signal was the signal of the sensor immersed in the kinetic buffer without analyte in the association step, and all other steps were the same as those for the sensor that recorded the test signal. A sensor without antigen loading was used to verify the non-specific interaction between the analyte (candidate scFv) and the sensor. In the loading step, the negative control sensor was immersed in the sodium kinetic buffer without antigen, and all other steps were similar to those used for the antigen-loaded sensor.

[0203] The binding curves were analyzed using Octet Data Analysis (version 9.0) software with a 1:1 interaction model. The analysis results of the Fab and scFv of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 are shown in Table 1. These Fab and scFv were further used to generate full-length antibodies.

[0204]

Table 3

[0205] Example 6. Generation of gene constructs for synthesizing full-length antibodies Cloning was performed by standard techniques. The inventors generated PCR products containing the variable domain genes of the heavy and light chains of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 having primers containing restriction sites. The heavy chain variable domain was cloned into the vector pEE-HCLALA IgG1 via the Sal1 / Nhe1 restriction sites (Figure 3). The light chain variable domain was cloned into the vector pEE-CK via the Sal1 / BsiW1 restriction sites (Figure 4). The resulting gene constructs were transferred for transient production in the CHO-T cell line.

[0206] Example 7. Production of full-length antibodies Full-length antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 were produced in the established cell line obtained from Chinese hamster ovary cells (CHO-T) using transient transfection in two replicates. Suspension culture was performed in an orbital shaking bioreactor using serum-free medium. For transient expression, cells at a concentration of 2 - 2.2×10 6 cells / ml were transfected using linear polyethyleneimine. The DNA / PEI ratio was 1:7. On the 10th day of culture, the cell suspension was centrifuged at 2000g for 15 minutes and filtered through a 0.22 μm filter.

[0207] The antibody was purified by affinity chromatography using a robotic-assisted station. The column was equilibrated with a buffer containing 50 mM NaPB (sodium phosphate buffer), 150 mM NaCl (pH 7.5), the filtered culture medium containing the antibody was applied, and then the column was washed with 8 volumes of a buffer containing 50 mM NaPB, 150 mM NaCl and 4 volumes of 50 mM NaPB (pH 7.5). The protein was eluted with 6 column volumes of a solution of 50 mM NaPB, 100 mM NaCl (pH 3). The resulting sample was neutralized with 25 μl of 1 M phosphate buffer (pH 8).

[0208] The purity of the candidates was monitored using polyacrylamide gel electrophoresis and size exclusion HPLC. Electrophoresis was performed on a 7.5% polyacrylamide gel under denaturing non-reducing conditions. Protein purity was determined by the intensity of band staining with a protein load of 10 μg per lane. The electrophorograms are shown in FIGS. 5 and 6. Size exclusion HPLC was performed with a column mobile phase of 0.05 M NaH2PO4, 0.3 M NaCl pH = 7.0.

[0209] Example 8. Determination of the affinity of full-length antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 for human BCMA by Forte Bio Experiments to study the affinity of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 against human BCMA were performed on the ForteBio Octet RED 384 system. Antibodies at a concentration of 20 μg / ml were immobilized on the surface of Protein A biosensors (ForteBio). The analysis was performed using a kinetic buffer (4.3 mM Na2HPO4; 136.9 mM NaCl, 1.5 mM KH2PO4; 2.7 mM KCl; the volume fraction of added Tween 20 was 0.1%; the mass fraction of added BSA was 0.1%; pH 7.4). After setting the baseline with the kinetic buffer, the sensor with the immobilized antibody was immersed in a well containing the analyte (BCMA) solution, where complex association was carried out for 300 seconds. For each test antibody, the sensorgram of the human BCMA solution at a concentration of 10 μg / ml (130.4 nM) and the reference signal (reference sensorgram) of the kinetic buffer without BCMA were recorded. Then, the dissociation of the complex in the buffer was detected for 600 seconds. To verify the non-specific interaction between the analyte and the sensor (negative control), the inventors used sensors without antibody loading. In the loading step, the negative control sensors were immersed in sodium acetate buffer without antigen, and all other steps were the same as those used for the antigen-loaded sensors.

[0210] After subtracting the reference signal, the binding curve was analyzed using Octet Data Analysis (version 9.0) software with a 1:1 interaction model (Table 2).

[0211]

Table 4

[0212] Thus, all test anti-BCMA antibodies specifically bind to human BCMA and have high binding affinity parameters for human BCMA (Table 3). Example 13. Verification of the interaction between full-size antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 and cynomolgus BCMA using the ForteBio system This experiment aimed to confirm the interaction between antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 and cynomolgus BCMA. The interaction between the antibody and cynomolgus BCMA was verified using an AR2G biosensor (ForteBio) in the ForteBio Octet RED384 system. The experiment consisted of the following steps: activating the sensor, loading the protein onto the sensor, quenching the unreacted activation groups, recording the baseline, recording the association of the analyte, and recording the dissociation. The measurements were performed at 30 °C. The sensor was activated for 300 seconds with an aqueous solution containing 20 mM EDC and 10 mM sNHS. Cynomolgus BCMA was loaded onto the surface of the biosensor in 10 mM sodium acetate buffer at pH 5.0 for 300 seconds. The concentration of the loaded protein was 10 μg / ml. The unreacted active centers on the sensor surface were quenched with a 1 M aqueous solution of ethanolamine at pH 8.5 for 300 seconds (the pH value was adjusted by adding hydrochloric acid). To verify the non-specific interaction between the analyte and the sensor (negative control), the inventors used a sensor without antigen (in the loading step, the sensor was immersed in 10 mM sodium acetate buffer at pH 5.0, and all other steps were similar to those used for the antigen-loaded sensor). The baseline and all subsequent steps of the experiment were performed with a dynamic buffer (4.3 mM Na2HPO4; 136.9 mM NaCl, 1.5 mM KH2PO4; 2.7 mM KCl; the volume fraction of added Tween 20 was 0.1%; the mass fraction of added BSA was 0.1%; pH 7.4). In the association step (the duration of the step was 300 seconds), the cynomolgus BCMA-loaded sensor was immersed in a well containing the analyte (test antibody) solution prepared with the dynamic buffer. The concentration of the analyte was 2.5 μg / ml. In the dissociation step, the sensor was immersed in a well with the dynamic buffer, where the baseline was recorded.

[0213] The binding curves were processed using the 1:1 interaction model with Octet Data Analysis (version 9.0) software. The results of the processing are shown in Table 4 (values of kdis < 1.0E-07 (1 / s) and corresponding KD < 1.0E-12 (M) mean that, within the framework of the applied measurement and processing techniques, a given sample exceeded the sensitivity limit of the dissociation rate constant of the model curve describing the sensorgram). The obtained kinetic constant values are estimations by using bivalent analyte (antibody) and can only be used to compare samples. All anti-BCMA antibodies presented signals binding to cynomolgus BCMA in the association step and slow signal decay in the dissociation step, thus confirming a high binding affinity while interacting with this antigen. Therefore, all tested anti-BCMA antibodies specifically bind to cynomolgus BCMA (Table 3).

[0214]

Table 5

[0215] Example 14. Verification of inhibition of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 against the interaction between APRIL and human BCMA by the Forte Bio system The study was performed on the ForteBio Octet RED384 system using an AR2G biosensor (ForteBio). The experiment consisted of the following main steps: loading the human APRIL / TNFSF13 antigen onto the sensor, and verifying the binding of the APRIL / TNFSF13 antigen to a mixture of human BCMA and the test antibody (premix). A human BCMA solution without antibody was used as a positive control. Inhibition of the interaction was determined by comparing the premix signal (response) with the positive control signal.

[0216] The sensor was activated with an aqueous solution containing 20 mM of EDC and 10 mM of sNHS for 300 seconds. The APRIL / TNFSF13 antigen was loaded onto the surface of the biosensor in 10 mM sodium acetate buffer at pH 5.0 for 900 seconds. The loaded APRIL / TNFSF13 protein concentration was 10 μg / ml. To verify the non-specific interaction between the analyte and the sensor, the inventors used a sensor without antigen (in the loading step, the sensor was immersed in sodium acetate buffer at pH 5.0, and all other steps were similar to those used for the antigen-loaded sensor). The unreacted active centers on the sensor surface were quenched with a 1 M aqueous solution of ethanolamine at pH 8.5 (the pH was adjusted by adding hydrochloric acid) for 300 seconds. All steps of the experiment after the quenching step were performed in a dynamic buffer (4.3 mM of Na2HPO4; 136.9 mM of NaCl, 1.5 mM of KH2PO4; 2.7 mM of KCl; the volume fraction of added Tween 20 was 0.1%; the mass fraction of added BSA (bovine serum albumin) was 0.1%; pH 7.4). In the association step (the time of the step was 300 seconds), the protein-loaded sensor was immersed in a well with the analyte solution. A solution containing 720 nM of the test antibody and 71 nM of human BCMA in the dynamic buffer was used as the analyte in the association step. A solution (analyte) with 72 nM of human BCMA was used as a positive control. The measurements were performed at 30 °C. A reference sensor was used in all steps in the same manner as the sensor used for recording the analyte sensorgram, except for the association step, in which the sensor was immersed in the dynamic buffer without the analyte (the reference sensor signal was measured in parallel with the recording of the main sensorgram). The reference signal was subtracted from the analyzed signal while processing the sensorgram.

[0217] The sensorgrams were processed using ForteBio Octet Data Analysis 9.0 software. The results of the experiment are shown in Table 4. The tested antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 inhibit the binding of APRIL / TNFSF13 loaded on the sensor to human BCMA.

[0218]

Table 6-1

[0219]

Table 6-2

[0220] Example 15. Analysis of the Binding of Anti-BCMA Antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 to Human BCMA on the Surface of RPMI8226 Cells by Flow Cytometry The ability of anti-BCMA antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 to bind to human BCMA on the cell surface was evaluated by flow cytometry against the RPMI8226 cell line (multiple myeloma) that stably expresses the BCMA receptor on the surface.

[0221] 25,000 cells in the well were incubated for 30 minutes at +4°C with serial dilutions of the test antibody in staining buffer (PBS + NaN3 + 5% BSA). After that time, the cells were washed twice with cold (+4°C) staining buffer, and the bound antibody was detected by staining for 30 minutes at +4°C with an anti-human Fc secondary antibody labeled with phycoerythrin. Wells without the introduction of the antibody and wells with only the secondary antibody were used as controls. After that time, the cells were washed twice with cold (+4°C) staining buffer and resuspended in 150 μl of cold (+4°C) staining buffer. The sample was then analyzed by flow cytometry. The inventors performed forward and side scatter (FSC and SSC) gating to identify the target cell population, and then performed forward scatter height and forward scatter area (FSC-H and FSC-A) gating to confirm single (singlet) cells in the population.

[0222] Half-maximal effective concentration EC 50 was calculated by plotting a four-parameter logistic regression model, and the data are shown in Table 5.

[0223]

Table 7

[0224] Conclusion: The data obtained show that all the antibodies tested bind to the BCMA target on the surface of multiple myeloma cells. Example 16. Analysis of non-specific binding of anti-BCMA antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 to the surface of BCMA-negative K562 cells by flow cytometry The presence of non-specific binding of anti-BCMA antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 was evaluated by flow cytometry against the K562 cell line (chronic myeloid leukemia) characterized by the absence of BCMA expression on the surface.

[0225] 25,000 K562 cells in the well were incubated for 30 minutes at +4°C with the test antibody diluted in staining buffer (PBS + NaN3 + 5% BSA). After that time, the cells were washed twice with cold (+4°C) staining buffer and the bound antibody was detected by staining for 30 minutes at +4°C with an anti-human Fc secondary antibody labeled with phycoerythrin. Wells without antibody introduction and wells with secondary antibody only were used as controls. After that time, the cells were washed twice with cold (+4°C) staining buffer and resuspended in 150 μl of cold (+4°C) staining buffer. The sample was then analyzed by a flow cytometer. The inventors performed forward and side scatter (FSC and SSC) gating to identify the target cell population and then forward scatter height and forward scatter area (FSC-H and FSC-A) gating to confirm single (singlet) cells in the population.

[0226] RPMI8226 was used as a positive control for cell surface binding of the test antibody to BCMA. Sample preparation was carried out in the same manner as described above for K562. Non-specific binding of the antibody was evaluated by comparing the fluorescence signal levels from the same concentration of antibody in variants of the K562 and RPMI8226 cell lines, and the data are shown in Table 6.

[0227]

Table 8

[0228] Conclusion: The results indicate that none of the antibodies tested exhibited non-specific binding to the BCMA-negative cell line.

Claims

1. An isolated monoclonal antibody or its antigen-binding fragment that specifically binds to BCMA, (a)(i) Amino acid sequence SX １ X ２ CDR1 having MS (in the formula, X １ = S or G; X ２ (= A, L, or V); (ii) Amino acid sequence X ３ YNGGSDRAGX ４ X ５ DSVX ６ CDR2 having G (In the formula, X ３ = G or C; X ４ = F or Y; X ５ = A or T; X ６ (= E or K); and (iii) CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains, including; Furthermore (b) (i) Amino acid sequence X ７ GX ８ X ９ SNIGX １０ X １１ X １２ X １３ VX １４ CDR1 having (in the formula, X ７ = S or T; X ８ = S, G, or T; X ９ = S, T, I, or R; X １０ = 0 or A; X １１ = S, H, N, G, or T; X １２ = N, R, or Y; X １３ = T, A, I, or D; X １４ (= N or H); (ii) Amino acid sequence X １５ X １６ X １７ X １８ CDR2 having RPS (in the formula, X １５ = N, R, K, S, or G; X １６ = D, N, G, T, or H; X １７ = S, N, or T; X １８ (= Q or N); and (iii) Amino acid sequence X １９ X ２０ WDX ２１ X ２２ X ２３ X ２４ X ２５ WX ２６ of The CDR3 (in the formula, X １９ = A or S; X ２０ = A, S, T, or V; X ２１ = G, D, H, or S; X ２２ = S, D, or R; X ２３ = L or V; X ２４ = N, T, R, or S; X ２５ = V, A, G, or N; X ２６ (= M, V, or L) Light chain variable domains including An isolated monoclonal antibody or its antigen-binding fragment, including the above.

2. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the heavy chain variable domain comprises a CDR1 having an amino acid sequence selected from the group of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO:

3.

3. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the heavy chain variable domain comprises a CDR2 having an amino acid sequence selected from the group of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO:

6.

4. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the light chain variable domain comprises a CDR1 having an amino acid sequence selected from the group of SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO:

15.

5. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the light chain variable domain comprises a CDR2 having an amino acid sequence selected from the group of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO:

24.

6. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the light chain variable domain comprises a CDR3 having an amino acid sequence selected from the group of SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, or SEQ ID NO:

35.

7. CDR1 having an amino acid sequence selected from the group of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; CDR2 having an amino acid sequence selected from the group of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6; and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, comprising:

8. (i) CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains, including; (ii) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains, including; (iii) CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains, including; (iv) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains, including; or (v) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 6, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains The isolated monoclonal antibody or its antigen-binding fragment according to claim 7, comprising:

9. CDR1 having an amino acid sequence selected from the group of SEQ ID NOs: 8, 9, 10, 11, 12, 13, 14, or 15; CDR2 having an amino acid sequence selected from the group of SEQ ID NOs: 16, 17, 18, 19, 20, 21, 22, 23, or 24; and CDR3 having an amino acid sequence selected from the group of SEQ ID NOs: 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35. Light chain variable domains including The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, comprising:

10. (i) CDR1 having the amino acid sequence of SEQ ID NO: 8, CDR2 having the amino acid sequence of SEQ ID NO: 16, and CDR3 having the amino acid sequence of SEQ ID NO: 25 Light chain variable domains, including; (ii) CDR1 having the amino acid sequence of SEQ ID NO: 9, CDR2 having the amino acid sequence of SEQ ID NO: 17, and CDR3 having the amino acid sequence of SEQ ID NO: 26 Light chain variable domains, including; (iii) CDR1 having the amino acid sequence of SEQ ID NO: 10, CDR2 having the amino acid sequence of SEQ ID NO: 18, and CDR3 having the amino acid sequence of SEQ ID NO: 27 Light chain variable domains, including; (iv) CDR1 having the amino acid sequence of SEQ ID NO: 11, CDR2 having the amino acid sequence of SEQ ID NO: 19, and CDR3 having the amino acid sequence of SEQ ID NO: 28 Light chain variable domains, including; (v) CDR1 having the amino acid sequence of SEQ ID NO: 12, CDR2 having the amino acid sequence of SEQ ID NO: 20, and CDR3 having the amino acid sequence of SEQ ID NO: 29 Light chain variable domains, including; (vi) CDR1 having the amino acid sequence of SEQ ID NO: 12, CDR2 having the amino acid sequence of SEQ ID NO: 20, and CDR3 having the amino acid sequence of SEQ ID NO: 30 Light chain variable domains, including; (vii) CDR1 having the amino acid sequence of SEQ ID NO: 10, CDR2 having the amino acid sequence of SEQ ID NO: 21, and CDR3 having the amino acid sequence of SEQ ID NO: 31 Light chain variable domains, including; (viiii) CDR1 having the amino acid sequence of SEQ ID NO: 13, CDR2 having the amino acid sequence of SEQ ID NO: 22, and CDR3 having the amino acid sequence of SEQ ID NO: 32 Light chain variable domains, including; (ix) CDR1 having the amino acid sequence of SEQ ID NO: 14, CDR2 having the amino acid sequence of SEQ ID NO: 23, and CDR3 having the amino acid sequence of SEQ ID NO: 33 Light chain variable domains, including; (x) CDR1 having the amino acid sequence of SEQ ID NO: 8, CDR2 having the amino acid sequence of SEQ ID NO: 24, and CDR3 having the amino acid sequence of SEQ ID NO: 34 Light chain variable domains, including; or (xi) CDR1 having the amino acid sequence of SEQ ID NO: 15, CDR2 having the amino acid sequence of SEQ ID NO: 17, and CDR3 having the amino acid sequence of SEQ ID NO: 35 Light chain variable domains The isolated monoclonal antibody or its antigen-binding fragment according to claim 9, comprising:

11. (a) CDR1 having an amino acid sequence selected from the group of SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3; CDR2 having an amino acid sequence selected from the group of SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6; and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having an amino acid sequence selected from the group of SEQ ID NOs: 8, 9, 10, 11, 12, 13, 14, or 15; CDR2 having an amino acid sequence selected from the group of SEQ ID NOs: 16, 17, 18, 19, 20, 21, 22, 23, or 24; and CDR3 having an amino acid sequence selected from the group of SEQ ID NOs: 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35. Light chain variable domains including The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, comprising:

12. (i) (a) CDR1 having the amino acid sequence of SEQ ID NO: 1, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 8, CDR2 having the amino acid sequence of SEQ ID NO: 16, and CDR3 having the amino acid sequence of SEQ ID NO: 25 Light chain variable domains, including; (ii) (a) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 9, CDR2 having the amino acid sequence of SEQ ID NO: 17, and CDR3 having the amino acid sequence of SEQ ID NO: 26 Light chain variable domains, including; (iii) (a) CDR1 having the amino acid sequence of SEQ ID NO: 3, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 10, CDR2 having the amino acid sequence of SEQ ID NO: 18, and CDR3 having the amino acid sequence of SEQ ID NO: 27 Light chain variable domains, including; (iv)(a) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 11, CDR2 having the amino acid sequence of SEQ ID NO: 19, and CDR3 having the amino acid sequence of SEQ ID NO: 28 Light chain variable domains, including; (v)(a) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 12, CDR2 having the amino acid sequence of SEQ ID NO: 20, and CDR3 having the amino acid sequence of SEQ ID NO: 29 Light chain variable domains, including; (vi) (a) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 6, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 12, CDR2 having the amino acid sequence of SEQ ID NO: 20, and CDR3 having the amino acid sequence of SEQ ID NO: 30 Light chain variable domains, including; (vii) (a) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 10, CDR2 having the amino acid sequence of SEQ ID NO: 21, and CDR3 having the amino acid sequence of SEQ ID NO: 31 Light chain variable domains, including; (viiii) (a) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 13, CDR2 having the amino acid sequence of SEQ ID NO: 22, and CDR3 having the amino acid sequence of SEQ ID NO: 32 Light chain variable domains, including; (ix)(a) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 12, CDR2 having the amino acid sequence of SEQ ID NO: 20, and CDR3 having the amino acid sequence of SEQ ID NO: 30 Light chain variable domains, including; (x)(a) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 14, CDR2 having the amino acid sequence of SEQ ID NO: 23, and CDR3 having the amino acid sequence of SEQ ID NO: 33 Light chain variable domains, including; (xi)(a) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 4, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 8, CDR2 having the amino acid sequence of SEQ ID NO: 24, and CDR3 having the amino acid sequence of SEQ ID NO: 34 Light chain variable domains, including; or (xi)(a) CDR1 having the amino acid sequence of SEQ ID NO: 2, CDR2 having the amino acid sequence of SEQ ID NO: 5, and CDR3 having the amino acid sequence of SEQ ID NO: 7 Heavy chain variable domains including; and (b) CDR1 having the amino acid sequence of SEQ ID NO: 15, CDR2 having the amino acid sequence of SEQ ID NO: 17, and CDR3 having the amino acid sequence of SEQ ID NO: 35 Light chain variable domains The isolated monoclonal antibody or its antigen-binding fragment according to claim 11, comprising:

13. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the heavy chain variable domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, or SEQ ID NO:

43.

14. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1, wherein the light chain variable domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, or SEQ ID NO:

54.

15. (a) The heavy chain variable domain comprises an amino acid sequence selected from the group of SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, or SEQ ID NO: 43, (b) The light chain variable domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, or 54. The isolated monoclonal antibody or its antigen-binding fragment according to claim 1.

16. (i) (a) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 36, (b) The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 44; (ii) (a) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 37, (b) The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 45; (iii) (a) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 38, (b) The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 46; (iv)(a) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 39, (b) The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 47; (v)(a) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 40, (b) The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 48; (vi) (a) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 41, (b) The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 49; (vii) (a) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 40, (b) The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 50; (viiii) (a) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 40, (b) The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 51; (ix)(a) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 40, (b) The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 49; (x)(a) The heavy chain variable domain comprises the amino acid sequence of Sequence ID No. 42, (b) The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 52; (xi)(a) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 43, (b) The light chain variable domain comprises the amino acid sequence of Sequence ID No. 53; or (xi)(a) The heavy chain variable domain comprises the amino acid sequence of SEQ ID NO: 40, (b) The light chain variable domain comprises the amino acid sequence of SEQ ID NO: 54, The isolated monoclonal antibody or its antigen-binding fragment according to claim 15.

17. The isolated monoclonal antibody according to any one of claims 1 to 16, wherein the isolated monoclonal antibody that specifically binds to BCMA is a full-length IgG antibody.

18. The isolated monoclonal antibody according to claim 17, wherein the full-length IgG antibody is a human IgG1, IgG2, IgG3, or IgG4 isotype.

19. The isolated monoclonal antibody according to claim 18, wherein the full-length IgG antibody is a human IgG1 isotype.

20. The isolated monoclonal antibody according to claim 19, wherein the antibody contains mutations L234A and L235A in the CH2 region according to the EU numbering of amino acids.

21. The isolated monoclonal antibody according to claim 1, comprising a heavy chain containing an amino acid sequence selected from the group consisting of SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, or SEQ ID NO:

62.

22. The isolated monoclonal antibody according to claim 1, comprising a light chain containing an amino acid sequence selected from the group consisting of SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO:

73.

23. (i) (a) a heavy chain comprising an amino acid sequence selected from the group of SEQ ID NOs: 55, 56, 57, 58, 59, 60, 61, or 62; and (b) Light chain containing an amino acid sequence selected from the group of SEQ ID NOs: 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, or 73. The isolated monoclonal antibody according to claim 1, comprising:

24. (i) (a) A heavy chain containing the amino acid sequence of SEQ ID NO: 55, and (b) Light chain containing the amino acid sequence of Sequence ID No. 63; (ii) (a) A heavy chain containing the amino acid sequence of SEQ ID NO: 56, and (b) Light chain containing the amino acid sequence of Sequence ID No. 64; (iii) (a) A heavy chain containing the amino acid sequence of Sequence ID No. 57, and (b) Light chain containing the amino acid sequence of Sequence ID No. 65; (iv)(a) Heavy chain containing the amino acid sequence of SEQ ID NO: 58, and (b) Light chain containing the amino acid sequence of SEQ ID NO: 66; (v)(a) Heavy chain containing the amino acid sequence of SEQ ID NO: 59, and (b) Light chain containing the amino acid sequence of Sequence ID No. 67; (vi) (a) A heavy chain containing the amino acid sequence of SEQ ID NO: 60, and (b) Light chain containing the amino acid sequence of Sequence ID No. 68; (vii) (a) A heavy chain containing the amino acid sequence of Sequence ID No. 59, and (b) Light chain containing the amino acid sequence of Sequence ID No. 69; (viiii) (a) A heavy chain containing the amino acid sequence of Sequence ID No. 59, and (b) Light chain containing the amino acid sequence of SEQ ID NO: 70; (ix)(a) Heavy chain containing the amino acid sequence of SEQ ID NO: 59, and (b) Light chain containing the amino acid sequence of Sequence ID No. 68; (x)(a) Heavy chain containing the amino acid sequence of SEQ ID NO: 61, and (b) Light chain containing the amino acid sequence of SEQ ID NO: 71; (xi)(a) A heavy chain containing the amino acid sequence of SEQ ID NO: 62, and (b) Light chain containing the amino acid sequence of SEQ ID NO: 72; or (xi)(a) Heavy chain containing the amino acid sequence of SEQ ID NO: 59, and (b) Light chain containing the amino acid sequence of SEQ ID NO: 73 The isolated monoclonal antibody according to claim 23, comprising:

25. Encoding an antibody or antigen-binding fragment according to any one of claims 1 to 16 and 21 to 24, Isolated nucleic acids.

26. The isolated nucleic acid according to claim 25, wherein the nucleic acid is DNA.

27. An expression vector comprising the nucleic acid described in claim 25.

28. A method for producing host cells that produce an antibody or antigen-binding fragment according to any one of claims 1 to 16 and 21 to 24, comprising the step of cell transformation with the vector according to claim 27.

29. A host cell for producing an antibody or antigen-binding fragment thereof according to any one of claims 1 to 16 and 21 to 24, comprising the nucleic acid according to claim 25.

30. A method for producing an antibody or antigen-binding fragment thereof according to any one of claims 1 to 16 and 21 to 24, comprising the step of culturing a host cell according to claim 29 in a growth medium under conditions sufficient to produce the antibody.

31. The method according to claim 30, further comprising the step of isolating and purifying the obtained antibody.

32. A pharmaceutical composition for treating BCMA-mediated diseases or disorders, comprising a therapeutically effective amount of an antibody or antigen-binding fragment according to any one of claims 1 to 16 and 21 to 24, in combination with one or more pharmaceutically acceptable excipients.

33. The pharmaceutical composition according to claim 32, wherein the BCMA-mediated disease or disorder is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma.

34. A pharmaceutical composition for treating BCMA-mediated diseases or disorders, comprising an antibody or antigen-binding fragment thereof according to any one of claims 1 to 16 and 21 to 24, and at least one other therapeutically active compound.

35. The pharmaceutical composition according to claim 34, wherein the BCMA-mediated disease or disorder is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia, non-Hodgkin lymphoma, and Hodgkin lymphoma.

36. The pharmaceutical composition according to claim 34, wherein the other therapeutically active compound is an antibody, a small molecule, a hormone therapy agent, or a combination thereof.

Images