Anti-BCMA antibody and application thereof

Abstract

The invention provides an anti-BCMA antibody or an antigen binding fragment thereof and application thereof. The anti-BCMA antibody or the antigen binding fragment thereof comprises a complementary determining region (CDR) sequence selected from SEQ ID NO: 1-40. The anti-BCMA antibody or the antigen binding fragment thereof has high affinity, can effectively recognize and bind to a BCMA antigen, and provides a safer and more effective immunotherapy choice for treatment of related diseases.

Description

Technical Field

[0001] The present application relates to the field of biomedicine, and specifically, to an anti-BCMA antibody and its application. Background Art

[0002] BCMA (B cell maturation antigen, CD269), also known as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), is a protein encoded by the human TNFRSF17 gene. This gene is mainly expressed in mature B lymphocytes and is less expressed in hematopoietic stem cells or non-hematopoietic tissues. BCMA is essential for the survival of long-lived bone marrow plasma cells (PCs), and plays an important role in B cell development and autoimmune responses. Studies have shown that BCMA can specifically bind to tumor necrosis factor superfamily member 13b (TNFSF13B / TALL-1 / BAFF), thereby activating the NF-κB and MAPK8 / JNK signaling pathways. In addition, BCMA also binds to various TRAF family members, which may transmit signals for cell survival and proliferation.

[0003] High expression of BCMA is widely found in a variety of hematological malignancies, especially in tumors derived from precursor B cells, plasma cells and late B cells, such as multiple myeloma (MM), chronic lymphocytic leukemia, acute B lymphocytic leukemia, non-Hodgkin's lymphoma (NHL) and Hodgkin's lymphoma. Serum B cell maturation antigen (sBCMA) is a cleaved form of BCMA, which is low in the serum of normal people, but is usually significantly increased in patients with multiple myeloma and is associated with poor clinical prognosis.

[0004] A variety of therapies have been widely developed for the BCMA target. Clinical studies have shown that antibody-drug conjugates (ADCs), bispecific T cell engagers (TCEs), and chimeric antigen receptor T cell (CAR-T) therapies targeting the BCMA target have shown significant clinical efficacy in the treatment of tumors, especially B-cell-derived malignancies such as multiple myeloma, and autoimmune diseases. These therapies target BCMA through different mechanisms, which can not only directly kill tumor cells through cytotoxic molecules, but also enhance the specific killing effect on BCMA-positive cells by activating other cells in the immune system (such as T cells, NK cells, etc.).

[0005] Although existing anti-BCMA antibodies and immunotherapies have achieved remarkable results, they still face some challenges. High costs, further improvement of efficacy and optimization of safety are key issues that need to be addressed. Therefore, more efficient and safe BCMA therapies still need to be developed to meet the treatment needs of more patients. Summary of the invention

[0006] In view of the problems existing in the prior art, the purpose of the present application is to provide an anti-BCMA antibody and its application.

[0007] Specifically, this application involves the following aspects:

[0008] 1. An anti-BCMA antibody or an antigen-binding fragment thereof, comprising a complementarity determining region (CDR) sequence selected from the following: SEQ ID NO: 1-40.

[0009] 2. The anti-BCMA antibody or antigen-binding fragment thereof according to claim 1, wherein:

[0010] The complementary determining regions include a heavy chain complementary determining region and a light chain complementary determining region;

[0011] The heavy chain complementarity determining region is:

[0012] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 1, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 2, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 3;

[0013] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:9;

[0014] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 15;

[0015] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 21;

[0016] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:25, a CDR2 having an amino acid sequence as shown in SEQ ID NO:14, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:26;

[0017] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:27, a CDR2 having an amino acid sequence as shown in SEQ ID NO:28, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:29;

[0018] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:31, a CDR2 having an amino acid sequence as shown in SEQ ID NO:32, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:33; or

[0019] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:37, a CDR2 having an amino acid sequence as shown in SEQ ID NO:38, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:39; and

[0020] The light chain complementarity determining region is:

[0021] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:4, a CDR2 having an amino acid sequence as shown in SEQ ID NO:5, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:6;

[0022] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 10, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 11, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 12;

[0023] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 18;

[0024] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:22, a CDR2 having an amino acid sequence as shown in SEQ ID NO:23, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:24;

[0025] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:4, a CDR2 having an amino acid sequence as shown in SEQ ID NO:5, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:30;

[0026] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:34, a CDR2 having an amino acid sequence as shown in SEQ ID NO:35, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:36; or

[0027] It comprises a CDR1 with an amino acid sequence as shown in SEQ ID NO:34, a CDR2 with an amino acid sequence as shown in SEQ ID NO:40, and a CDR3 with an amino acid sequence as shown in SEQ ID NO:36.

[0028] 3. The anti-BCMA antibody or antigen-binding fragment thereof according to item 2, wherein the complementarity determining regions comprise the following heavy chain complementarity determining regions and light chain complementarity determining regions:

[0029] (1) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO: 1, a CDR2 comprising the amino acid sequence of SEQ ID NO: 2, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 3, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO: 4, a CDR2 comprising the amino acid sequence of SEQ ID NO: 5, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 6;

[0030] (2) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:7, a CDR2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR3 comprising the amino acid sequence of SEQ ID NO:9, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:10, a CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a CDR3 comprising the amino acid sequence of SEQ ID NO:12;

[0031] (3) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO: 13, a CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 15, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 18;

[0032] (4) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 21, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 24;

[0033] (5) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:25, a CDR2 comprising the amino acid sequence of SEQ ID NO:14, and a CDR3 comprising the amino acid sequence of SEQ ID NO:26, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:16, a CDR2 comprising the amino acid sequence of SEQ ID NO:17, and a CDR3 comprising the amino acid sequence of SEQ ID NO:18;

[0034] (6) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:27, a CDR2 comprising the amino acid sequence of SEQ ID NO:28, and a CDR3 comprising the amino acid sequence of SEQ ID NO:29, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:4, a CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a CDR3 comprising the amino acid sequence of SEQ ID NO:30;

[0035] (7) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:31, a CDR2 comprising the amino acid sequence of SEQ ID NO:32, and a CDR3 comprising the amino acid sequence of SEQ ID NO:33, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:34, a CDR2 comprising the amino acid sequence of SEQ ID NO:35, and a CDR3 comprising the amino acid sequence of SEQ ID NO:36; or

[0036] (8) The heavy chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:37, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:38, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:39, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:34, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:40, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:36.

[0037] 4. An anti-BCMA antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region sequence selected from the following: SEQ ID NO: 41-56, or an amino acid sequence that has at least 80% identity with the heavy chain variable region and the light chain variable region sequence, respectively.

[0038] 5. The anti-BCMA antibody or antigen-binding fragment thereof according to item 4, wherein:

[0039] The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:41, the amino acid sequence shown in SEQ ID NO:43, the amino acid sequence shown in SEQ ID NO:45, the amino acid sequence shown in SEQ ID NO:47, the amino acid sequence shown in SEQ ID NO:49, the amino acid sequence shown in SEQ ID NO:51, the amino acid sequence shown in SEQ ID NO:53, the amino acid sequence shown in SEQ ID NO:55, or an amino acid sequence that is at least 80% identical to each of the amino acid sequences; and

[0040] The light chain variable region comprises the amino acid sequence shown in SEQ ID NO:42, the amino acid sequence shown in SEQ ID NO:44, the amino acid sequence shown in SEQ ID NO:46, the amino acid sequence shown in SEQ ID NO:48, the amino acid sequence shown in SEQ ID NO:50, the amino acid sequence shown in SEQ ID NO:52, the amino acid sequence shown in SEQ ID NO:54, the amino acid sequence shown in SEQ ID NO:56, or an amino acid sequence that is at least 80% identical to each of the amino acid sequences.

[0041] 6. The anti-BCMA antibody or antigen-binding fragment thereof according to item 4, wherein:

[0042] The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:41 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:42;

[0043] The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:43 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:44;

[0044] The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:45 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:46;

[0045] The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:47 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:48;

[0046] The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:49 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:50;

[0047] The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:51 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:52;

[0048] The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 53 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 54; or

[0049] The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:55 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:56.

[0050] 7. The anti-BCMA antibody or antigen-binding fragment thereof according to any one of items 1 to 6, wherein the antibody or antigen-binding fragment thereof is a monoclonal antibody, a recombinant antibody, a fully human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or an antigen-binding fragment thereof.

[0051] 8. The anti-BCMA antibody or antigen-binding fragment thereof according to item 7, wherein the antigen-binding fragment is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment or a scFv fragment.

[0052] 9. The anti-BCMA antibody or antigen-binding fragment thereof according to any one of items 1 to 6, wherein the antibody or antigen-binding fragment thereof comprises the constant domain of human IgG1, IgG2, IgG3 or IgG4.

[0053] 10. A polynucleotide encoding the anti-BCMA antibody or antigen-binding fragment thereof according to any one of items 1 to 9.

[0054] 11. A host cell comprising the polynucleotide according to item 10.

[0055] 12. A method for preparing an anti-BCMA antibody or an antigen-binding fragment thereof, comprising culturing the host cell described in item 11 to thereby prepare the anti-BCMA antibody or antigen-binding fragment thereof as described in any one of items 1 to 9.

[0056] 13. A pharmaceutical composition comprising the anti-BCMA antibody or antigen-binding fragment thereof according to any one of items 1 to 9.

[0057] 14. A pharmaceutical composition according to claim 13, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier.

[0058] 15. A conjugate comprising the anti-BCMA antibody or antigen-binding fragment thereof according to any one of items 1 to 9.

[0059] 16. A fusion protein comprising the anti-BCMA antibody or antigen-binding fragment thereof according to any one of items 1 to 9.

[0060] 17. Use of the anti-BCMA antibody or antigen-binding fragment thereof according to any one of items 1 to 9, the pharmaceutical composition according to item 13 or 14, the conjugate according to item 15, or the fusion protein according to item 16 in the preparation of a medicament for treating and / or preventing BCMA-mediated related diseases.

[0061] Beneficial effects:

[0062] The anti-BCMA antibody or its antigen-binding fragment of the present application has high affinity, can effectively recognize and bind to BCMA antigen, and will not have non-specific cross-reactions with other cell surface molecules; the anti-BCMA antibody or its antigen-binding fragment can efficiently eliminate BCMA-positive cells, providing a safer and more effective immunotherapy option for the treatment of related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 The binding curves of 8 antibodies to recombinant human BCMA-His protein are shown in the figure above. The binding curves of antibodies 1#-4# are shown in the figure above, and the binding curves of antibodies 5#-8# are shown in the figure below.

[0064] Figure 2 The binding curves of 8 antibodies to recombinant monkey BCMA-His protein are shown in the figure above. The binding curves of antibodies 1#-4# are shown in the figure above, and the binding curves of antibodies 5#-8# are shown in the figure below.

[0065] Figure 3 The binding curves of 8 antibodies to H929 cells.

[0066] Figure 4 The results show the detection of NK cell killing effect on H929 cells mediated by 8 antibodies. DETAILED DESCRIPTION

[0067] The present application is further described below in conjunction with examples. It should be understood that the examples are only used to further describe and illustrate the present application and are not used to limit the present application.

[0068] Unless otherwise defined, the technical and scientific terms in this specification have the same meaning as those generally understood by those skilled in the art. Although similar or identical methods and materials as described herein may be used in experiments or practical applications, materials and methods are described herein below. In the event of a conflict, the present specification including the definitions therein shall prevail. In addition, materials, methods and examples are provided for illustration only and are not restrictive. The present application is further described below in conjunction with specific embodiments, but is not intended to limit the scope of the present application.

[0069] definition

[0070] As used herein, the term "BCMA" can be used interchangeably with "CD269" and "TNFRSF17", specifically referring to B cell maturation antigen. In this application, the term "BCMA" can also include a portion of the complete BCMA protein as long as the relevant biological activity is retained.

[0071] As used herein, the term "antibody" is used in the broadest sense and covers various antibody structures, including not only intact (i.e., full-length) antibodies, but also antigen-binding fragments thereof (e.g., Fab, Fab', F(ab')2, Fv), variants thereof, fusion proteins comprising antibody portions, humanized antibodies, chimeric antibodies, diabodies, linear antibodies, single-chain antibodies (scFV), VHH antibodies, multispecific antibodies (e.g., bispecific antibodies), multispecific single-chain antibodies, and any other modified configuration of immunoglobulin molecules comprising an antigen recognition site of desired specificity, including antibody glycosylation variants, antibody amino acid sequence variants, and covalently modified antibodies.

[0072] Typically, a complete or full-length antibody comprises two heavy chains and two light chains. Each heavy chain contains a heavy chain variable region (VH) and the first, second, and third constant regions (CH1, CH2, CH3). Each light chain contains a light chain variable region (VL) and a constant region (CL), and the light chain constant region includes κ (Kappa) or λ (Lambda). A full-length antibody can be any type of antibody, such as IgD, IgE, IgG, IgA, or IgM (or subclasses of the above), but the antibody does not need to belong to any particular class. Based on the antibody amino acid sequence of the constant region of the heavy chain, immunoglobulins can be assigned to different classes. Typically, there are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these classes can be further divided into subclasses (isotypes), such as IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant regions corresponding to different immunoglobulin classes are called α, δ, ε, γ, and μ, respectively. The subunit structures and three-dimensional structures of different classes of immunoglobulins are well known.

[0073] As used herein, the term "antigen binding fragment" refers to a region of a molecule that specifically binds to an antigen. An antigen binding domain can be an antigen binding portion of an antibody or an antigen binding fragment thereof. An antigen binding fragment can include, for example, Fab', F(ab')2, Fab, Fv, rIgG, scFv, hcAb (heavy chain antibody), single domain antibody, VHH, VNAR, sdAb or nanobody.

[0074] As used herein, the term "variable region" refers to the variable region of an antibody light chain or the variable region of an antibody heavy chain, either alone or in combination. As known in the art, the variable regions of the heavy and light chains are each composed of four framework regions (FRs) connected by three complementarity determining regions (CDRs), also referred to as hypervariable regions. The CDRs in each chain are kept close together by the FRs, and together with the CDRs from the other chains, contribute to the formation of the antigen binding site of the antibody.

[0075] As used herein, the term "monoclonal antibody (mAb)" or "mAb" or "Mab" refers to a homogeneous antibody population, i.e., the individual antibodies constituting the population are identical except for possible naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation) that may be present in small amounts. Monoclonal antibodies are highly specific, being directed against a single antigen or epitope. "Monoclonal" indicates the characteristic that the antibody is obtained from a substantially homogeneous antibody population and should not be construed as limiting the structure, source, or preparation method of the antibody. In some embodiments, monoclonal antibodies are prepared by hybridoma methods, phage display methods, yeast display methods, recombinant DNA methods, single cell screening, or single cell sequencing methods.

[0076] As used herein, the term "humanized" antibody refers to a form of a non-human (e.g., murine) antibody that is a chimeric immunoglobulin, an immunoglobulin chain, or a fragment thereof containing minimal sequence derived from a non-human immunoglobulin (e.g., Fv, Fab, Fab', F(ab')2, or other antigen-binding sequence of an antibody). Preferably, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from one or more CDRs of the recipient are replaced with residues from one or more CDRs of a non-human species (such as a mouse, rat, or rabbit) (donor antibody) having the desired specificity, affinity, and capacity.

[0077] As used herein, the term "multispecific antibody" refers to an antibody that binds to two or more different epitopes on at least two or more different targets, including bispecific, trispecific, tetraspecific, pentaspecific, hexaspecific, and the like.

[0078] As used herein, the term "chimeric antibody" refers to an antibody that is a combination of antibody fragments from different species. Specifically, for example, a monoclonal antibody from one species (e.g., mouse) whose Fc constant region is replaced with an Fc constant region from one species (e.g., human) via DNA recombination technology. See, for example, patent application PCT / US86 / 02269; EP / 173,494.

[0079] As used herein, the percentage of "identity", such as 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5% identity, refers to the degree of similarity between amino acid sequences or between nucleotide sequences determined by sequence alignment, which is 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.5%. For example, the proportion of the number of positions with the same base or amino acid residue to the total number of positions determined after two sequences have the same residue at as many positions as possible by introducing spaces, etc. The percentage of "identity" can be determined using software programs known in the art. Preferably, the comparison is performed using default parameters. A preferred comparison program is BLAST. Preferred programs are BLASTN and BLASTP. Details of these programs can be found at the following Internet address: ncbi.nlm.nih.gov / cgi-bin / BLAST.

[0080] As used herein, the term "conjugate" refers to a molecule conjugated to another molecule. In the present application, the conjugate is a conjugate obtained by conjugating the anti-BCMA antibody or antigen-binding fragment thereof described in the present application to another agent, such as a small molecule drug. In the present application, there is no limitation on small molecule drugs, and those skilled in the art can make routine selections as needed.

[0081] As used herein, the term "fusion protein" refers to a substance obtained by binding an antibody to a substance via a non-peptide linker or a peptide linker, or directly binding. In the present application, the fusion protein refers to a substance obtained by binding the anti-BCMA antibody or its antigen-binding fragment to a substance via a non-peptide linker or a peptide linker, or directly binding. In the present application, there is no limitation on substances and non-peptide linkers, and those skilled in the art can make routine selections as needed.

[0082] As used herein, the term "vector" refers to a nucleic acid molecule capable of amplifying another nucleic acid to which it is linked. The term includes vectors that are self-replicating nucleic acid structures as well as vectors that integrate into the genome of a host cell into which it has been introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operably linked. Such vectors are referred to herein as "expression vectors."

[0083] As used herein, the term "host cell", "host cell line", "host cell culture" or related terms refers to a cell (or a population thereof) into which an exogenous (exogenous or transgenic) nucleic acid has been introduced. The external nucleic acid may include an expression vector operably linked to the transgene, and the host cell may be used to express nucleic acids and / or polypeptides encoded by the external nucleic acid (transgene). The host cell (or its population) may be a cultured cell or may be extracted from an object. Without considering the number of pathways, the host cell (or its population) includes the primary object cell and its progeny. Compared to the parent cell, the progeny cell may or may not carry the same genetic material. The host cell encompasses progeny cells. In one embodiment, the host cell description has been modified, transfected, transduced, transformed and / or manipulated in any way to express any cell (including its progeny) of an antibody as disclosed herein. In one embodiment, the host cell (or its population) may be introduced with an expression vector operably linked to a nucleic acid encoding a desired antibody described herein. The host cell and its population may carry an expression vector stably integrated into the host genome or may carry an extrachromosomal expression vector. In one embodiment, the host cells and populations thereof may carry an extrachromosomal vector that persists after several cell divisions, or persists transiently and disappears after several cell divisions.

[0084] As used herein, the term "human universal framework" is a framework representing the amino acid residues most commonly present in a selection of human immunoglobulin VL or VH framework sequences. In general, human immunoglobulin VL or VH sequences are selected from a subgroup of variable domain sequences. In general, a subgroup of sequences is a subgroup such as Kabat et al., Sequences of Proteins of Immunological Interest, 5th edition, NIH Publication 91-3242, Bethesda MD (1991), Vol. 1-3. In some embodiments, for VL, the subgroup is a subgroup such as Kabat et al. (supra) described. In some embodiments, for VH, the subgroup is a subgroup III such as Kabat et al. (supra) described.

[0085] Anti-BCMA antibody or antigen-binding fragment thereof

[0086] The present application provides an anti-BCMA antibody or an antigen-binding fragment thereof, comprising a complementary determining region (CDR) sequence selected from the following: SEQ ID NO: 1-40. In some embodiments, the anti-BCMA antibody or an antigen-binding fragment thereof comprises a human universal framework region.

[0087] The amino acid sequence of SEQ ID NO: 1 is as follows:

[0088] CDRH1:GYTFTSFV;

[0089] The amino acid sequence of SEQ ID NO:2 is as follows:

[0090] CDRH2: IYPYNDDS;

[0091] The amino acid sequence of SEQ ID NO:3 is as follows:

[0092] CDRH3:ARSGYYGSSEAMDY;

[0093] The amino acid sequence of SEQ ID NO:4 is as follows:

[0094] CDRL1:QDVSTA;

[0095] The amino acid sequence of SEQ ID NO:5 is as follows:

[0096] CDRL2:SAS;

[0097] The amino acid sequence of SEQ ID NO:6 is as follows:

[0098] CDRL3:QQHYSTPWT;

[0099] The amino acid sequence of SEQ ID NO:7 is as follows: CDRH1: GYTFTDYS;

[0100] The amino acid sequence of SEQ ID NO:8 is as follows: CDRH2: INTETGEP;

[0101] The amino acid sequence of SEQ ID NO:9 is as follows: CDRH3: ATSLYYAMDY;

[0102] The amino acid sequence of SEQ ID NO: 10 is as follows: CDRL1: KSVSASGYSF; the amino acid sequence of SEQ ID NO: 11 is as follows: CDRL2: LAS;

[0103] The amino acid sequence of SEQ ID NO: 12 is as follows: CDRL3: QHSRELPRT; the amino acid sequence of SEQ ID NO: 13 is as follows: CDRH1: GYTLTEHI;

[0104] The amino acid sequence of SEQ ID NO: 14 is as follows: CDRH2: FYPGSGSL;

[0105] The amino acid sequence of SEQ ID NO: 15 is as follows: CDRH3: ARHDWDGGFAY;

[0106] The amino acid sequence of SEQ ID NO: 16 is as follows: CDRL1: QSLLHSDGKTY;

[0107] The amino acid sequence of SEQ ID NO: 17 is as follows: CDRL2: LVS;

[0108] The amino acid sequence of SEQ ID NO: 18 is as follows: CDRL3: WQGTHFPWT; the amino acid sequence of SEQ ID NO: 19 is as follows: CDRH1: GFNIKDYY;

[0109] The amino acid sequence of SEQ ID NO:20 is as follows: CDRH2: IDPENGNT;

[0110] The amino acid sequence of SEQ ID NO:21 is as follows: CDRH3: SVGGLYGNYGSWFAY; the amino acid sequence of SEQ ID NO:22 is as follows: CDRL1: QSLVHSNGNTY;

[0111] The amino acid sequence of SEQ ID NO:23 is as follows: CDRL2: KVS;

[0112] The amino acid sequence of SEQ ID NO:24 is as follows: CDRL3: SQNTHVPWT; the amino acid sequence of SEQ ID NO:25 is as follows: CDRH1: GYTLTENI;

[0113] The amino acid sequence of SEQ ID NO:26 is as follows: CDRH3: ATHDWDGGFAY;

[0114] The amino acid sequence of SEQ ID NO:27 is as follows: CDRH1: GYTFTGFV;

[0115] The amino acid sequence of SEQ ID NO:28 is as follows: CDRH2: IYPYNDDT;

[0116] The amino acid sequence of SEQ ID NO:29 is as follows: CDRH3: ARSGYYGTSEALDY; the amino acid sequence of SEQ ID NO:30 is as follows: CDRL3: QQHYIIPWT; the amino acid sequence of SEQ ID NO:31 is as follows: CDRH1: GFPFSNYD;

[0117] The amino acid sequence of SEQ ID NO:32 is as follows: CDRH2: ITSGGSYT;

[0118] The amino acid sequence of SEQ ID NO:33 is as follows: CDRH3: AGQGYYGSCYAMDY; the amino acid sequence of SEQ ID NO:34 is as follows: CDRL1: ENIYGA;

[0119] The amino acid sequence of SEQ ID NO:35 is as follows: CDRL2: GAT;

[0120] The amino acid sequence of SEQ ID NO:36 is as follows: CDRL3: QNVLGIPYT;

[0121] The amino acid sequence of SEQ ID NO:37 is as follows:

[0122] CDRH1:GFAFRNYD;

[0123] The amino acid sequence of SEQ ID NO:38 is as follows:

[0124] CDRH2:IISSGTYT;

[0125] The amino acid sequence of SEQ ID NO:39 is as follows:

[0126] CDRH3: AGQGYYGSNYAMDY;

[0127] The amino acid sequence of SEQ ID NO:40 is as follows:

[0128] CDRL2:GTT.

[0129] In some embodiments, the complementarity determining regions comprise a heavy chain complementarity determining region and a light chain complementarity determining region;

[0130] The heavy chain complementarity determining region is:

[0131] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 1, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 2, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 3;

[0132] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:9;

[0133] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 15;

[0134] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 21;

[0135] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:25, a CDR2 having an amino acid sequence as shown in SEQ ID NO:14, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:26;

[0136] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:27, a CDR2 having an amino acid sequence as shown in SEQ ID NO:28, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:29;

[0137] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:31, a CDR2 having an amino acid sequence as shown in SEQ ID NO:32, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:33; or

[0138] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:37, a CDR2 having an amino acid sequence as shown in SEQ ID NO:38, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:39; and

[0139] The light chain complementarity determining region is:

[0140] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:4, a CDR2 having an amino acid sequence as shown in SEQ ID NO:5, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:6;

[0141] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 10, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 11, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 12;

[0142] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 18;

[0143] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:22, a CDR2 having an amino acid sequence as shown in SEQ ID NO:23, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:24;

[0144] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:4, a CDR2 having an amino acid sequence as shown in SEQ ID NO:5, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:30;

[0145] comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:34, a CDR2 having an amino acid sequence as shown in SEQ ID NO:35, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:36; or

[0146] It comprises a CDR1 with an amino acid sequence as shown in SEQ ID NO:34, a CDR2 with an amino acid sequence as shown in SEQ ID NO:40, and a CDR3 with an amino acid sequence as shown in SEQ ID NO:36.

[0147] In some embodiments, the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:1, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:2, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:3, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:4, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:6.

[0148] In some embodiments, the heavy chain complementary determining region is CDR1 of the amino acid sequence shown in SEQ ID NO:7, CDR2 of the amino acid sequence shown in SEQ ID NO:8, and CDR3 of the amino acid sequence shown in SEQ ID NO:9, and the light chain complementary determining region is CDR1 of the amino acid sequence shown in SEQ ID NO:10, CDR2 of the amino acid sequence shown in SEQ ID NO:11, and CDR3 of the amino acid sequence shown in SEQ ID NO:12.

[0149] In some embodiments, the heavy chain complementary determining region is CDR1 of the amino acid sequence shown in SEQ ID NO:13, CDR2 of the amino acid sequence shown in SEQ ID NO:14, and CDR3 of the amino acid sequence shown in SEQ ID NO:15, and the light chain complementary determining region is CDR1 of the amino acid sequence shown in SEQ ID NO:16, CDR2 of the amino acid sequence shown in SEQ ID NO:17, and CDR3 of the amino acid sequence shown in SEQ ID NO:18.

[0150] In some embodiments, the heavy chain complementary determining region is CDR1 of the amino acid sequence shown in SEQ ID NO:19, CDR2 of the amino acid sequence shown in SEQ ID NO:20, and CDR3 of the amino acid sequence shown in SEQ ID NO:21, and the light chain complementary determining region is CDR1 of the amino acid sequence shown in SEQ ID NO:22, CDR2 of the amino acid sequence shown in SEQ ID NO:23, and CDR3 of the amino acid sequence shown in SEQ ID NO:24.

[0151] In some embodiments, the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:25, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:14, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:26, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:16, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:17, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:18.

[0152] In some embodiments, the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:27, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:28, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:29, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:4, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:5, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:30.

[0153] In some embodiments, the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:31, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:32, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:33, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:34, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:35, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:36.

[0154] In some embodiments, the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:37, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:38, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:39, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:34, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:40, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:36.

[0155] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region sequence selected from the following: SEQ ID NO:41-56, or an amino acid sequence that has at least 80% identity with the heavy chain variable region and the light chain variable region sequence, respectively.

[0156] The amino acid sequence of SEQ ID NO:41 is as follows:

[0157] EVQLQQSGPELVKPGASVKMSCKASGYTFTSFVMHWVKQKPGQGLEWI GYIYPYNDDSKYNEKFKVKATLTSDKSSSTAYMELSSLTSEDSAVYYCARSGY YGSSEAMDYWGQGTSVTVSS;

[0158] The amino acid sequence of SEQ ID NO:42 is as follows:

[0159] DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWSQQKPGQSPKLLIYS ASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYSTPWTFGGGTK LEIK;

[0160] The amino acid sequence of SEQ ID NO:43 is as follows:

[0161] QIQLVQSGPELKKPGETVKISCKASGYTFTDYSIFWVKQAPGKGLKWMG WINTETGEPIHADDFKGRFVFSLETSASTASLQINNLKNEDAATYFCATSLYYA MDYWGQGTSVSVSS;

[0162] The amino acid sequence of SEQ ID NO:44 is as follows:

[0163] DIVLTQSPASLTVSLGQRATISCRASKSVSASGYSFLHWYQQKPGQPPKLLI YLASNLESGVPARFSASGSGTDFTLNIHPVEEEDAATYYCQHSRELPRTFGGGT KLEIK;

[0164] The amino acid sequence of SEQ ID NO:45 is as follows:

[0165] KVQLQQSGAELVKPGASVKLSCKASGYTLTEHIIHWVKQRSGQGLEWIG WFYPGSGSLKFNEKFKDKATLTADKSSSTVYMELSRLTSEDSAVYFCARHDW DGGFAYWGQGTLVTVSA;

[0166] The amino acid sequence of SEQ ID NO:46 is as follows:

[0167] DVLMTQTPLTLSVTIGQPASISCKSGQSLLHSDGKTYLSWLFQRPGQSPKR LIFLVSKLFSGVPDRFTGSGSGTDFTLRISRVEAEDLGVYYCWQGTHFPWTFGG GTKLEIE;

[0168] The amino acid sequence of SEQ ID NO:47 is as follows:

[0169] EVQLQQSGAELVRSGASLKLSCTASGFNIKDYYMNWVKQRPEQGLEWIG WIDPENGNTEYAPRFQGKATMTADTSSNTVYLHLSSLTSEDTAVYYCSVGGLY GNYGSWFAYWGQGTLVTVSA;

[0170] The amino acid sequence of SEQ ID NO:48 is as follows:

[0171] DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPK LLIFKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQNTHVPWTFG GGTKLEIK;

[0172] The amino acid sequence of SEQ ID NO:49 is as follows:

[0173] KVQLQQSGAELVKPGASVKLSCKASGYTLTENILHWVKQRSGQGLEWIG WFYPGSGSLKYNEKFKDKATMTADKSSSTVYMELRRLTSEDSAVYFCATHDW DGGFAYWGQGTLVTVSA;

[0174] The amino acid sequence of SEQ ID NO:50 is as follows:

[0175] DVLLTQTPLTLSVTIGQPASISCKSGQSLLHSDGKTYLSWLFQRPGQSPKR LIFLVSKLYSGVPDRFTGSGSGTDFTLRISRVEAEDLGVYFCWQGTHFPWTFGG GTRLEIK;

[0176] The amino acid sequence of SEQ ID NO:51 is as follows:

[0177] EVQLQQSGPELVKPGASVKMSCKASGYTFTGFVMHWVKQKPGQGLEWI GYIYPYNDDTDYNEKFKGKATLTSDKSSSTAYLELSSLTSEDSAVYYCARSGYY GTSEALDYWGQGTSVTVSS;

[0178] The amino acid sequence of SEQ ID NO:52 is as follows:

[0179] DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVTWYQQKPGQSPKLLIFS ASYRNTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYIIPWTFGGGTK LEIK;

[0180] The amino acid sequence of SEQ ID NO:53 is as follows:

[0181] EVKLVESGGDLVRPGGSLKLSCVASGFPFSNYDMAWVRQTPEKRLEWVA TITSGGSYTYYSDNVKGRFTLSSRDNARNTLYLQMSSLRSEDTALYYCAGQGY YGSCYAMDYWGQGTSVTVSS;

[0182] The amino acid sequence of SEQ ID NO:54 is as follows:

[0183] DIQMTQSPASSLSASVGETVTITCGPSENIYGALNWYQRKQGKSPQLLIFGA TNLADGMSSRFSGSGSGRQYSLKISRLHPDDVATYYCQNVLGIPYTFGGGTKL EIK;

[0184] The amino acid sequence of SEQ ID NO:55 is as follows:

[0185] EEKLVESGGGLVRPGGSLKLSCAASGFAFRNYDMSWVRQTPEKRLEWVA TIISSGTYTYYPDSLKGRFTISRDNARNTLYLQMSSLRSDDTALYYCAGQGYYG SNYAMDYWGQGTSVTVSS;

[0186] The amino acid sequence of SEQ ID NO:56 is as follows:

[0187] DIQMTQSPASSLSASVGETVTITTCGASENIYGALNWYQRKQGRSPQLLIFGT TNLADGMSSRFSGSGSGRQYSLKISSLHPDDVATYYCQNVLGIPYTFGGGTKL EIK.

[0188] For example, when the anti-BCMA antibody or antigen-binding fragment thereof comprises an amino acid sequence that is at least 80% identical to the heavy chain variable region and light chain variable region sequences, respectively, it may comprise an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the heavy chain variable region and light chain variable region sequences, respectively.

[0189] In some embodiments, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:41, the amino acid sequence shown in SEQ ID NO:43, the amino acid sequence shown in SEQ ID NO:45, the amino acid sequence shown in SEQ ID NO:47, the amino acid sequence shown in SEQ ID NO:49, the amino acid sequence shown in SEQ ID NO:51, the amino acid sequence shown in SEQ ID NO:53, or the amino acid sequence shown in SEQ ID NO:55; and

[0190] The light chain variable region comprises the amino acid sequence shown in SEQ ID NO:42, the amino acid sequence shown in SEQ ID NO:44, the amino acid sequence shown in SEQ ID NO:46, the amino acid sequence shown in SEQ ID NO:48, the amino acid sequence shown in SEQ ID NO:50, the amino acid sequence shown in SEQ ID NO:52, the amino acid sequence shown in SEQ ID NO:54, or the amino acid sequence shown in SEQ ID NO:56.

[0191] In some embodiments, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:41 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:42.

[0192] In some embodiments, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:43 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:44.

[0193] In some embodiments, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:45 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:46.

[0194] In some embodiments, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:47 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:48.

[0195] In some embodiments, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:49 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:50.

[0196] In some embodiments, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:51 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:52.

[0197] In some embodiments, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:53 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:54.

[0198] In some embodiments, the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:55 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:56.

[0199] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is a monoclonal antibody, a recombinant antibody, a fully human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or an antigen-binding fragment thereof. In some embodiments, the antigen-binding fragment is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment, or a scFv fragment.

[0200] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises the constant domain of human IgG1, IgG2, IgG3, or IgG4.

[0201] Polynucleotides and host cells

[0202] The present application provides a polynucleotide encoding the anti-BCMA antibody or antigen-binding fragment thereof described above.

[0203] The polynucleotides include DNA (gDNA and cDNA) and RNA molecules, as well as nucleotides, which are the basic building blocks of polynucleotides, including nucleotides of natural origin and analogs of modified sugar or base moieties therein. The sequences of the polynucleotides encoding the heavy and light chain variable regions of the present application may be changed. Such changes include additions, deletions, or non-conservative or conservative substitutions of nucleotides.

[0204] DNA encoding the anti-BCMA antibody or antigen-binding fragment thereof can be synthesized using conventional procedures.

[0205] The present application provides a host cell comprising the polynucleotide described above.

[0206] The host cell is a host cell for producing the anti-BCMA antibody or antigen-binding fragment thereof described in the present application, and the host cell for producing the antibody or antigen-binding fragment thereof may be a prokaryotic organism, a yeast or a higher eukaryotic cell, but is not limited thereto. Animal cells that can be used include, but are not limited to, COS-7, BHK, CHO, CHOK1, DXB-11, DG-44, CHO / -DHFR, CV1, COS-7, HEK293, BHK, TM4, VERO, HELA, MDCK, BRL 3A, W138, Hep G2, SK-Hep, MMT, TRI, MRC 5, FS4, 3T3, RIN, A549, PC12, K562, PER.C6, SP2 / 0, NS-0, U20S and HT1080.

[0207] The present application provides a method for preparing an anti-BCMA antibody or an antigen-binding fragment thereof, which comprises culturing the host cell described above to thereby prepare the anti-BCMA antibody or the antigen-binding fragment thereof.

[0208] In the present application, for the cultivation of host cells, host cells can be cultured in various culture media. Any commercially available culture media can be used as culture media. All other necessary supplements well known to those skilled in the art can be added at appropriate concentrations. For culture conditions such as temperature and pH value, all are culture conditions conventional in the art, and those skilled in the art can make conventional selections as needed.

[0209] The anti-BCMA antibody or antigen-binding fragment thereof can be recovered by, for example, centrifugation or ultrafiltration to remove impurities, and the resulting product can be purified using, for example, affinity chromatography. Other purification techniques, such as anion or cation exchange chromatography, hydrophobic interaction chromatography, and hydroxyapatite (HA) chromatography, etc., can also be used.

[0210] Pharmaceutical composition

[0211] The present application provides a pharmaceutical composition comprising the anti-BCMA antibody or antigen-binding fragment thereof described above.

[0212] In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier.

[0213] The pharmaceutically acceptable carrier may include non-toxic buffers such as phosphoric acid, citric acid, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride; benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens (alkyl parabens, such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight polypeptides (e.g., less than about 10 amino acid residues); proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; carbohydrates such as monosaccharides, disaccharides, glucose, mannose, or dextrin; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); and nonionic surfactants such as Tween or polyethylene glycol (PEG), etc.

[0214] Conjugates, fusion proteins

[0215] The present application provides a conjugate comprising the anti-BCMA antibody or antigen-binding fragment thereof as described above.

[0216] In some embodiments, the conjugate further comprises a therapeutic agent and / or a cytotoxin conjugated to the anti-BCMA antibody or antigen-binding fragment thereof.

[0217] The therapeutic agents include, but are not limited to, antitumor antibiotics, mitotic inhibitors, chromatin function inhibitors, anti-angiogenic agents, alkylating agents, antimetabolites, antiestrogens, antiandrogens, and immunomodulators.

[0218] The therapeutic agent includes agents currently known to those skilled in the art that can be used to treat and / or prevent BCMA-related diseases, and is not limited to the agents listed in this application.

[0219] The cytotoxins include but are not limited to MMAE, DM1, PE24, MMAF, PBD, DM2, Amanitin, DM4, PNU-159682, IR700, PE-38, Maytansine, Tubulysin, SG3199, DGN-549PE4E, PE40, PE38, PE25, PE38QQR, PE35, PE38KDEL, PE38DKEL, PE38RDEL, PE38KNEL, and Pseudomonas exotoxin A.

[0220] The present application provides a fusion protein comprising the anti-BCMA antibody or antigen-binding fragment thereof as described above.

[0221] Therapeutic applications

[0222] The present application also provides the use of the above-mentioned anti-BCMA antibody or antigen-binding fragment thereof, the above-mentioned pharmaceutical composition, the above-mentioned conjugate or the above-mentioned fusion protein in the preparation of a drug for treating and / or preventing BCMA-mediated related diseases.

[0223] For example, the BCMA-mediated related diseases are BCMA-positive cancers or autoimmune diseases. The BCMA-positive cancers include multiple myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, Hodgkin's lymphoma, megakaryocytic leukemia, Burkitt's lymphoma and anaplastic large cell lymphoma. The immune diseases include systemic lupus erythematosus.

[0224] Example

[0225] The present application content will be described below in conjunction with specific examples, but the scope of the present application is not limited thereto. Unless otherwise specified, the reagents and instruments used in the following examples are all conventional reagents and instruments in this area and can be obtained commercially. The methods used are all conventional experimental methods, and those skilled in the art can undoubtedly implement the scheme and obtain corresponding results according to the embodiments.

[0226] Example 1 Antibody Screening and Preparation

[0227] Recombinant human BCMA-Fc protein (Bioinron, B528001) and recombinant cynomolgus macaque BCMA-Fc protein (Bioinron, B22777514) were used for immunization, recombinant human BCMA-His protein (Bioinron, B21846208) and recombinant cynomolgus macaque BCMA-His protein (Bioinron, 00FP2K001) were used for B cell sorting and ELISA screening of candidate antibodies, and human BCMA / HEK293T cell line was used for cell binding screening.

[0228] (1) Animal immunization: 10 Balb / c mice were cross-immunized with human BCMA-Fc and cynomolgus monkey BCMA-Fc. The mice were divided into two groups. Each mouse was immunized with 50 μg of human BCMA-Fc mixed with complete Freund's adjuvant for the first immunization. Subsequently, each mouse was immunized with 25 μg of protein mixed with incomplete Freund's adjuvant for the second to fourth immunizations. The second immunogen was human BCMA-Fc, and the third and fourth immunogens were monkey BCMA-Fc. The interval between immunizations was two weeks, and blood was collected after the second, third, and fourth immunizations to determine the serum titer. 25 μg of recombinant human BCMA-Fc protein was used for shock immunization.

[0229] (2) Serum titer detection: Serum titer was detected by ELISA and flow cytometry. In the ELISA test, when the mouse serum was diluted at 1:1000, the OD450 should be greater than 2, and when it was diluted at 1:16000, the OD450 should be greater than 1, which was considered to meet the sorting standard. The secondary antibody was goat anti-mouse IgG Fc secondary antibody (Invitrogen, 31437). In the flow cytometry test (serum titer cell binding test), when it was diluted at 1:24300, the mean fluorescence intensity (mean) value should be greater than the blank control group (mean value) × 10;

[0230] (3) Antibody screening: The spleen and bone marrow of mice were removed, plasma cells were enriched using CD138 magnetic beads, and recombinant human BCMA-His protein labeled with AF-488 was used to select specific B lymphocytes using the FRET principle. The single-cell cDNA library was constructed and sequenced by NGS. After bioinformatics analysis, the base and amino acid sequences of the paired light and heavy chains were obtained.

[0231] (4) Expression and purification of candidate antibodies:

[0232] The variable region heavy chain obtained by screening was combined with human IgG1Fc, and the light chain was combined with the light chain Kappa constant region to obtain the full-length human-mouse chimeric antibody sequence; DNA was synthesized according to the antibody protein sequence, an expression vector was constructed, and the antibody was transferred into CHO cells for antibody expression. After protein A affinity purification, a recombinant antibody with an Fc region of hIgG1 subtype was finally prepared. The results are shown in Table 1 below. The candidate antibodies (1#-8#) obtained by screening had high purity.

[0233] Table 1 Expression results of candidate antibodies (1#-8#)

[0234] Antibody ID Yield (mg / L) purity 1# 108 97.66％ 2# 152.75 95.55％ 3# 139 100％ 4# 163.75 98.53％ 5# 142.5 100％ 6# 204 92.76％ 7# 224.5 92.54％ 8# 221 97.75％

[0235] The amino acid sequences of candidate antibodies (1#-8#) are as follows:

[0236] The heavy chain variable region of antibody 1# is:

[0237] EVQLQQSGPELVKPGASVKMSCKASGYTFTSFVMHWVKQKPGQGLEWI GYIYPYNDDSKYNEKFKVKATLTSDKSSSTAYMELSSSLTSEDSAVYYCARSGY YGSSEAMDYWGQGTSVTVSS (SEQ ID NO: 41);

[0238] The light chain variable region of antibody 1# is:

[0239] DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWSQQKPGQSPKLLIYS ASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYSTPWTFGGGTK LEIK(SEQ ID NO:42);

[0240] The heavy chain variable region of antibody 2# is:

[0241] QIQLVQSGPELKKPGETVKISCKASGYTFTDYSIFWVKQAPGKGLKWMG WINTETGEPIHADDFKGRFVFSLETSASTASLQINNLKNEDAATYFCATSLYYA MDYWGQGTSVSVSS(SEQ ID NO:43);

[0242] The light chain variable region of antibody 2# is:

[0243] DIVLTQSPASLTVSLGQRATISCRASKSVSASGYSFLHWYQQKPGQPPKLLI YLASNLESGVPARFSASGSGTDFTLNIHPVEEEDAATYYCQHSRELPRTFGGGT KLEIK(SEQ ID NO:44);

[0244] The heavy chain variable region of antibody 3# is:

[0245] KVQLQQSGAELVKPGASVKLSCKASGYTLTEHIIHWVKQRSGQGLEWIG WFYPGSGSLKFNEKFKDKATLTADKSSSTVYMELSRLTSEDSAVYFCARHDW DGGFAYWGQGTLVTVSA (SEQ ID NO: 45);

[0246] The light chain variable region of antibody 3# is:

[0247] DVLMTQTPLTLSVTIGQPASISCKSGQSLLHSDGKTYLSWLFQRPGQSPKR LIFLVSKLFSGVPDRFTGSGSGTDFTLRISRVEAEDLGVYYCWQGTHFPWTFGG GTKLEIE(SEQ ID NO:46);

[0248] The heavy chain variable region of antibody 4# is:

[0249] EVQLQQSGAELVRSGASLKLSCTASGFNIKDYYMNWVKQRPEQGLEWIG WIDPENGNTEYAPRFQGKATMTADTSSNTVYLHLSSLTSEDTAVYYCSVGGLY GNYGSWFAYWGQGTLVTVSA(SEQ ID NO:47);

[0250] The light chain variable region of antibody 4# is:

[0251] DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPK LLIFKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQNTHVPWTFG GGTKLEIK(SEQ ID NO:48);

[0252] The heavy chain variable region of antibody 5# is:

[0253] KVQLQQSGAELVKPGASVKLSCKASGYTLTENILHWVKQRSGQGLEWIG WFYPGSGSLKYNEKFKDKATMTADKSSSTVYMELRRLTSEDSAVYFCATHDW DGGFAYWGQGTLVTVSA(SEQ ID NO:49);

[0254] The light chain variable region of antibody 5# is:

[0255] DVLLTQTPLTLSVTIGQPASISCKSGQSLLHSDGKTYLSWLFQRPGQSPKR LIFLVSKLYSGVPDRFTGSGSGTDFTLRISRVEAEDLGVYFCWQGTHFPWTFGG GTRLEIK(SEQ ID NO:50);

[0256] The heavy chain variable region of antibody 6# is:

[0257] EVQLQQSGPELVKPGASVKMSCKASGYTFTGFVMHWVKQKPGQGLEWI GYIYPYNDDTDYNEKFKGKATLTSDKSSSTAYLELSSLTSEDSAVYYCARSGYY GTSEALDYWGQGTSVTVSS(SEQ ID NO:51);

[0258] The light chain variable region of antibody 6# is:

[0259] DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVTWYQQKPGQSPKLLIFS ASYRNTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYIIPWTFGGGTK LEIK(SEQ ID NO:52);

[0260] The heavy chain variable region of antibody 7# is:

[0261] EVKLVESGGDLVRPGGSLKLSCVASGFPFSNYDMAWVRQTPEKRLEWVA TITSGGSYTYYSDNVKGRFTLSSRDNARNTLYLQMSSLRSEDTALYYCAGQGY YGSCYAMDYWGQGTSVTVSS(SEQ ID NO:53);

[0262] The light chain variable region of antibody 7# is:

[0263] DIQMTQSPASLSSASVGETVTITCGPSENIYGALNWYQRKQGKSPQLLIFGA TNLADGMSSRFSGSGSGRQYSLKISRLHPDDVATYYCQNVLGIPYTFGGGTKL EIK(SEQ ID NO:54);

[0264] The heavy chain variable region of antibody 8# is:

[0265] EEKLVESGGGLVRPGGSLKLSCAASGFAFRNYDMSWVRQTPEKRLEWVA TIISSGTYTYYPDSLKGRFTISRDNARNTLYLQMSSLRSDDTALYYCAGQGYYG SNYAMDYWGQGTSVTVSS(SEQ ID NO:55);

[0266] The light chain variable region of antibody 8# is:

[0267] DIQMTQSPASSLSASVGETVTITTCGASENIYGALNWYQRKQGRSPQLLIFGTTNLADGMSSRFSGSGSGRQYSLKISSLHPDDVATYYCQNVLGIPYTFGGGTKL EIK(SEQ ID NO:56);

[0268] The heavy chain of antibody 1# is:

[0269] EVQLQQSGPELVKPGASVKMSCKASGYTFTSFVMHWVKQKPGQGLEWIGYIYPYNDDSKYNEKFKVKATLTSDKSSSTAYMELSSLTSEDSAVYYCARSGYYGSSEAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:57);

[0270] The light chain of Antibody 1# is:

[0271] DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVAWSQQKPGQSPKLLIYSASYRYTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYSTPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:58);

[0272] The heavy chain of Antibody 2# is:

[0273] QIQLVQSGPELKKPGETVKISCKASGYTFTDYSIFWVKQAPGKGLKWMGWINTETGEPIHADDFKGRFVFSLETSASTASLQINNLKNEDAATYFCATSLYYAMDYWGQGTSVSVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:59);

[0274] The light chain of Antibody 2# is:

[0275] DIVLTQSPASLTVSLGQRATISCRASKSVSASGYSFLHWYQQKPGQPPKLLIYLASNLESGVPARFSASGSGTDFTLNIHPVEEEDAATYYCQHSRELPRTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:60);

[0276] The heavy chain of Antibody 3# is:

[0277] KVQLQQSGAELVKPGASVKLSCKASGYTLTEHIIHWVKQRSGQGLEWIGWFYPGSGSLKFNEKFKDKATLTADKSSSTVYMELSRLTSEDSAVYFCARHDWDGGFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:61);

[0278] The light chain of Antibody 3# is:

[0279] DVLMTQTPLTLSVTIGQPASISCKSGQSLLHSDGKTYLSWLFQRPGQSPKRLIFLVSKLFSGVPDRFTGSGSGTDFTLRISRVEAEDLGVYYCWQGTHFPWTFGGGTKLEIERTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:62);

[0280] The heavy chain of Antibody 4# is:

[0281] EVQLQQSGAELVRSGASLKLSCTASGFNIKDYYMNWVKQRPEQGLEWIGWIDPENGNTEYAPRFQGKATMTADTSSNTVYLHLSSLTSEDTAVYYCSVGGLYGNYGSWFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:63);

[0282] The light chain of antibody 4# is:

[0283] DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIFKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQNTHVPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:64);

[0284] The heavy chain of antibody 5# is:

[0285] KVQLQQSGAELVKPGASVKLSCKASGYTLTENILHWVKQRSGQGLEWIGWFYPGSGSLKYNEKFKDKATMTADKSSSTVYMELRRLTSEDSAVYFCATHDWDGGFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:65);

[0286] The light chain of antibody 5# is:

[0287] DVLLTQTPLTLSVTIGQPASISCKSGQSLLHSDGKTYLSWLFQRPGQSPKRLIFLVSKLYSGVPDRFTGSGSGTDFTLRISRVEAEDLGVYFCWQGTHFPWTFGGGTRLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:66);

[0288] The heavy chain of antibody 6# is:

[0289] EVQLQQSGPELVKPGASVKMSCKASGYTFTGFVMHWVKQKPGQGLEWIGYIYPYNDDTDYNEKFKGKATLTSDKSSSTAYLELSSLTSEDSAVYYCARSGYYGTSEALDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:67);

[0290] The light chain of antibody 6# is:

[0291] DIVMTQSHKFMSTSVGDRVSITCKASQDVSTAVTWYQQKPGQSPKLLIFSASYRNTGVPDRFTGSGSGTDFTFTISSVQAEDLAVYYCQQHYIIPWTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:68);

[0292] The heavy chain of antibody 7# is:

[0293] EVKLVESGGDLVRPGGSLKLSCVASGFPFSNYDMAWVRQTPEKRLEWVATITSGGSYTYYSDNVKGRFTLSRDNARNTLYLQMSSLRSEDTALYYCAGQGYYGSCYAMDYWGQGTSVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:69);

[0294] The light chain of antibody 7# is:

[0295] DIQMTQSPASLSASVGETVTITCGPSENIYGALNWYQRKQGKSPQLLIFGATNLADGMSSRFSGSGSGRQYSLKISRLHPDDVATYYCQNVLGIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:70);

[0296] The heavy chain of antibody 8# is:

[0297] EEKLVESGGGLVRPGGSLKLSCAASGFAFRNYDMSWVRQTPEKRLEWVATIISSGTYTYYPDSLKGRFTISRDNARNTLYLQMSSLRSDDTALYYCAGQGYYGSNYAMDYWGQ GTSVTVSSASTKGPSVFPLAPSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKT HTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPLPEEKTIS KAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:71);

[0298] The light chain of antibody 8# is:

[0299] DIQMTQSPASLSSASVGETVTITTCGASENIYGALNWYQRKQGRSPQLLIFGTTNLADGMSSRFSGSGSGRQYSLKISSLHPDDVATYYCQNVLGIPYTFGGGTKLEIKRT VAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ IDNO:72).

[0300] Example 2 Anti-BCMA Antibodies Bind to Human or Cynomolgus Monkey BCMA

[0301] The candidate antibodies (1#-8#) were verified to bind to human or cynomolgus monkey BCMA protein by ELISA method, the steps are as follows:

[0302] (1) Protein coating: Coat the plate with protein (recombinant human BCMA-His protein or recombinant cynomolgus monkey BCMA-His protein) at a concentration of 2 μg / mL (100 μL / well), incubate at 37°C for 1 h, wash the plate 6 times and pat dry;

[0303] (2) Blocking: Block with 3% BSA-PBS blocking solution (200 μL / well) at 25°C for 1 h, wash the plate 6 times and pat dry;

[0304] (3) Primary antibody incubation: Add the candidate antibody to be tested to the wells, 100 nM in the first well, dilute 5-fold with blocking solution to form 8 gradients, add blocking solution to the last well as a blank (100 μL / well), incubate at 25°C for 1 h, wash the plate 6 times and pat dry;

[0305] (4) Secondary antibody incubation: The secondary antibody (Invitrogen, A18817) was diluted with blocking buffer (100 μL / well), incubated at 25°C for 1 h, and the plate was washed 6 times and patted dry;

[0306] (5) Color development: TMB (Invitrogen, 002023) (100 μL / well) was added and color was developed at room temperature in the dark for 3-5 min;

[0307] (6) Termination: Add ELISA stop solution (BBI, E661066-0500) (50 μL / well) to terminate;

[0308] (7) Reading and data processing: OD450 was read using a microplate reader, and the data were fitted using GraphPad Prism 8 software.

[0309] The results are as follows Figure 1-Figure 2 As shown, the results showed that antibodies 1#-8# could bind to recombinant human BCMA-His protein and recombinant cynomolgus monkey BCMA-His protein, and presented an obvious dose-dependent curve.

[0310] Example 3 Anti-BCMA Antibodies Bind to BCMA-Expressing Cells

[0311] The binding activity of candidate antibodies to H929 cells expressing human BCMA was detected by flow cytometry, as follows:

[0312] (1) H929 cells (3×10 6 cells / mL) were added to a 96-well plate at 50 μl / well;

[0313] (2) Dilute the positive control (GSK2857916) 3-fold with 0.5% BSA-PBS diluent, add the candidate antibody to be tested to the wells, with a final concentration of 100 nM in the first well, dilute 8 times, and use the dilution in the last well as a blank (50 μL / well), and incubate at 4°C for 1 h;

[0314] (3) Centrifuge at 400 g and 4°C for 5 min, discard the supernatant, and wash twice with 0.5% BSA-PBS dilution solution;

[0315] (4) Add 100 μL of diluted fluorescent secondary antibody (Invitrogen, A18818) and incubate at 4°C for 30 min;

[0316] (5) Centrifuge again and discard the supernatant, then wash twice with 0.5% BSA-PBS diluent;

[0317] (6) After resuspending in 100 μL of 0.5% BSA-PBS diluent, the cells were tested using an analyzer (Attune NxT, Invitrogen), and the data were fitted using GraphPad Prism 8 software.

[0318] The results are as follows Figure 3 As shown, the results showed that antibodies 1#-8# all bound to H929 cells and presented an obvious dose-dependent curve.

[0319] Example 4 Anti-BCMA antibody mediated NK cell killing

[0320] The luciferase reporter gene expression method was used to detect the killing effect of NK cells mediated by candidate antibodies on BCMA-positive cells. The steps are as follows:

[0321] (1) H929 cells expressing the luciferase reporter gene in the exponential growth phase (H929-Luc) were collected and plated at 50 μL / well (0.4×10 6 cells / mL) were resuspended in a 96-well plate;

[0322] (2) The candidate antibody to be tested, the positive control (GSK2857916), and the blank control were diluted 3-fold with culture medium, with a final concentration of 10 nM in the first well, and 8 dilution gradients were added to a 96-well plate (50 μL / well) with H929-Luc, and incubated at 37°C for 20 min;

[0323] (3) The sorted peripheral blood natural killer cells (PBNK, Heyousheng, hPB56-50C) were revived and 50 μL / well (4×10 6 cells / mL) were added to a 96-well plate, centrifuged at 100 g for 30 s, and then incubated at 37 °C for 4 h;

[0324] (4) After incubation, the 96-well plate was equilibrated at room temperature for 15 min, 100 μl of luciferase detection substrate (Genomeditech, GM-040513B) was added, and the reaction was allowed to proceed for 10 min;

[0325] (5) Transfer 200 μl of supernatant to a white opaque 96-well plate, detect the fluorescence intensity using a microplate reader, and fit the data using GraphPad Prism 8 software.

[0326] The results are as follows Figure 4 As shown, the results showed that antibodies 1#-8# could mediate NK cell killing of BCMA-positive cells, and the effect was stronger than that of the positive control antibody (GSK2857916).

[0327] The above is only the preferred embodiment of the present application, and does not limit the present application in other forms. Any technician familiar with the profession may use the above disclosed technical content to change or modify it into an equivalent embodiment with equivalent changes. However, any simple modification, equivalent change and modification made to the above embodiment based on the technical essence of the present application without departing from the technical solution of the present application still falls within the protection scope of the technical solution of the present application.

Claims

1. An anti-BCMA antibody or antigen-binding fragment thereof, comprising a complementarity determining region (CDR), wherein the complementarity determining region comprises a heavy chain complementarity determining region and a light chain complementarity determining region; The heavy chain complementarity determining region is: comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 1, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 2, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 3; comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:7, a CDR2 having an amino acid sequence as shown in SEQ ID NO:8, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:9; comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 13, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 14, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 15; comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 19, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 20, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 21; comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:25, a CDR2 having an amino acid sequence as shown in SEQ ID NO:14, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:26; comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:27, a CDR2 having an amino acid sequence as shown in SEQ ID NO:28, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:29; comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:31, a CDR2 having an amino acid sequence as shown in SEQ ID NO:32, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:33; or comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:37, a CDR2 having an amino acid sequence as shown in SEQ ID NO:38, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:39; and The light chain complementarity determining region is: comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:4, a CDR2 having an amino acid sequence as shown in SEQ ID NO:5, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:6; comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 10, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 11, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 12; comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO: 16, a CDR2 having an amino acid sequence as shown in SEQ ID NO: 17, and a CDR3 having an amino acid sequence as shown in SEQ ID NO: 18; comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:22, a CDR2 having an amino acid sequence as shown in SEQ ID NO:23, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:24; comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:4, a CDR2 having an amino acid sequence as shown in SEQ ID NO:5, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:30; comprising a CDR1 having an amino acid sequence as shown in SEQ ID NO:34, a CDR2 having an amino acid sequence as shown in SEQ ID NO:35, and a CDR3 having an amino acid sequence as shown in SEQ ID NO:36; or It comprises a CDR1 with an amino acid sequence as shown in SEQ ID NO:34, a CDR2 with an amino acid sequence as shown in SEQ ID NO:40, and a CDR3 with an amino acid sequence as shown in SEQ ID NO:

36.

2. The anti-BCMA antibody or antigen-binding fragment thereof according to claim 1, wherein the complementarity determining regions comprise the following heavy chain complementarity determining regions and light chain complementarity determining regions: (1) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:1, a CDR2 comprising the amino acid sequence of SEQ ID NO:2, and a CDR3 comprising the amino acid sequence of SEQ ID NO:3, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:4, a CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a CDR3 comprising the amino acid sequence of SEQ ID NO:6; (2) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:7, a CDR2 comprising the amino acid sequence of SEQ ID NO:8, and a CDR3 comprising the amino acid sequence of SEQ ID NO:9, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:10, a CDR2 comprising the amino acid sequence of SEQ ID NO:11, and a CDR3 comprising the amino acid sequence of SEQ ID NO:12; (3) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO: 13, a CDR2 comprising the amino acid sequence of SEQ ID NO: 14, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 15, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO: 16, a CDR2 comprising the amino acid sequence of SEQ ID NO: 17, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 18; (4) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO: 19, a CDR2 comprising the amino acid sequence of SEQ ID NO: 20, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 21, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO: 22, a CDR2 comprising the amino acid sequence of SEQ ID NO: 23, and a CDR3 comprising the amino acid sequence of SEQ ID NO: 24; (5) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:25, a CDR2 comprising the amino acid sequence of SEQ ID NO:14, and a CDR3 comprising the amino acid sequence of SEQ ID NO:26, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:16, a CDR2 comprising the amino acid sequence of SEQ ID NO:17, and a CDR3 comprising the amino acid sequence of SEQ ID NO:18; (6) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:27, a CDR2 comprising the amino acid sequence of SEQ ID NO:28, and a CDR3 comprising the amino acid sequence of SEQ ID NO:29, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:4, a CDR2 comprising the amino acid sequence of SEQ ID NO:5, and a CDR3 comprising the amino acid sequence of SEQ ID NO:30; (7) the heavy chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:31, a CDR2 comprising the amino acid sequence of SEQ ID NO:32, and a CDR3 comprising the amino acid sequence of SEQ ID NO:33, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence of SEQ ID NO:34, a CDR2 comprising the amino acid sequence of SEQ ID NO:35, and a CDR3 comprising the amino acid sequence of SEQ ID NO:36; or (8) The heavy chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:37, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:38, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:39, and the light chain complementary determining region is a CDR1 comprising the amino acid sequence shown in SEQ ID NO:34, a CDR2 comprising the amino acid sequence shown in SEQ ID NO:40, and a CDR3 comprising the amino acid sequence shown in SEQ ID NO:

36.

3. The anti-BCMA antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody comprises a heavy chain variable region and a light chain variable region; wherein the heavy chain variable region comprises an amino acid sequence as shown in SEQ ID NO:41, an amino acid sequence as shown in SEQ ID NO:43, an amino acid sequence as shown in SEQ ID NO:45, an amino acid sequence as shown in SEQ ID NO:47, an amino acid sequence as shown in SEQ ID NO:49, an amino acid sequence as shown in SEQ ID NO:51, an amino acid sequence as shown in SEQ ID NO:53, an amino acid sequence as shown in SEQ ID NO:55, or an amino acid sequence that is at least 90% identical to said amino acid sequence, respectively; and The light chain variable region comprises the amino acid sequence shown in SEQ ID NO:42, the amino acid sequence shown in SEQ ID NO:44, the amino acid sequence shown in SEQ ID NO:46, the amino acid sequence shown in SEQ ID NO:48, the amino acid sequence shown in SEQ ID NO:50, the amino acid sequence shown in SEQ ID NO:52, the amino acid sequence shown in SEQ ID NO:54, the amino acid sequence shown in SEQ ID NO:56, or an amino acid sequence that is at least 90% identical to each of the amino acid sequences.

4. The anti-BCMA antibody or antigen-binding fragment thereof according to claim 3, wherein: The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:41 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:42; The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:43 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:44; The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:45 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:46; The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:47 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:48; The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:49 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:50; The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:51 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:52; The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 53 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 54; or The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:55 and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:

56.

5. The anti-BCMA antibody or antigen-binding fragment thereof according to any one of claims 1 to 4, wherein: The antibody or antigen-binding fragment thereof is a monoclonal antibody, a recombinant antibody, a fully human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody or an antigen-binding fragment of these antibodies, preferably, the antigen-binding fragment is a Fab fragment, a Fab' fragment, a F(ab')2 fragment, a Fv fragment or a scFv fragment; or The antibody or antigen-binding fragment thereof comprises the constant domain of human IgG1, IgG2, IgG3 or IgG4.

6. A polynucleotide encoding the anti-BCMA antibody or antigen-binding fragment thereof according to any one of claims 1 to 5. A host cell comprising the polynucleotide of claim 6.

8. A method for preparing an anti-BCMA antibody or an antigen-binding fragment thereof, comprising culturing the host cell of claim 7 to prepare the anti-BCMA antibody or the antigen-binding fragment thereof according to any one of claims 1 to 5.

9. A pharmaceutical composition comprising the anti-BCMA antibody or antigen-binding fragment thereof according to any one of claims 1 to 5; Preferably, the pharmaceutical composition comprises a pharmaceutically acceptable carrier.

10. A conjugate comprising the anti-BCMA antibody or antigen-binding fragment thereof according to any one of claims 1 to 5.

11. A fusion protein comprising the anti-BCMA antibody or antigen-binding fragment thereof according to any one of claims 1 to 5.

12. Use of the anti-BCMA antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, the pharmaceutical composition according to claim 9, the conjugate according to claim 10 or the fusion protein according to claim 11 in the preparation of a medicament for treating and / or preventing BCMA-mediated related diseases.

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