Anti-BCMA / anti-4-1BB bispecific antibody and its uses

Abstract

The present invention provides an anti-B cell maturation antigen (BCMA) / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof, and uses thereof. The bispecific antibody or an antigen-binding fragment thereof can have a high binding affinity for both the BCMA protein and the 4-1BB protein, and can be effectively used for preventing or treating diseases (such as cancer) related to BCMA, 4-1BB, or both.

Description

Technical Field

[0001] The present disclosure relates to an anti-BCMA / anti-4-1BB bispecific antibody capable of effectively blocking the interaction between BCMA and its ligand and activating 4-1BB signaling; a method for preparing the same; and uses thereof. The bispecific antibody can have a high binding affinity for both BCMA protein and 4-1BB protein. Background Art

[0002] B-cell maturation antigen (BCMA) is a protein of approximately 20 kDa and belongs to the tumor necrosis factor-receptor (TNFR) superfamily. BCMA is also known to have B-cell Activating Factor (BAFF) and A Proliferation Inducing Ligand (APRIL), which belong to the tumor necrosis factor family. In pathological conditions, BCMA is expressed in neoplastic plasma cells of patients with multiple myeloma (MM), and the survival rate of patients with multiple myeloma decreases as BCMA expression increases (Moreaux et al., Eur J Haematol 2009 83: 119-129). Multiple myeloma is a neoplastic disease caused by monoclonal proliferation of plasma cells. Due to the development of drugs such as thalidomide, bortezomib, and lenalidomide, as well as the development of treatment methods, the initial treatment rate has been improved. However, the survival rate of patients with multiple myeloma has not been significantly improved.

[0003] 4-1BB is a member of the TNF-receptor superfamily (TNFRSF) and is a co-stimulatory molecule expressed after activation of immune cells including both innate and adaptive immune cells. 4-1BB plays an important role in regulating the activities of various immune cells. Agonistic 4-1BB antibodies can enhance immune cell proliferation, survival, cytokine secretion, and the cytolytic activity of CD8 T cells. Many other studies have shown that activation of 4-1BB enhances the immune response to eliminate tumors in mice. Therefore, this indicates that 4-1BB is a promising target molecule in cancer immunology. Although anti-4-1BB antibodies have antitumor efficacy, anti-4-1BB antibodies have caused severe hepatotoxicity in clinical applications.

[0004] Multispecific antibodies targeting two or more antigens have been developed into various classes and forms and are expected to be new drug antibodies with excellent therapeutic effects compared to monoclonal antibodies. Therefore, there is a need to develop multispecific antibodies that can effectively treat cancers such as multiple myeloma. Summary of the Invention

[0005] Technical Problem

[0006] Provided is an anti-B-cell maturation antigen (BCMA) / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof.

[0007] Provided is a pharmaceutical composition for preventing or treating a disease associated with BCMA, 4-1BB, or both.

[0008] Provided is a method for preventing or treating a disease associated with BCMA, 4-1BB, or both in an individual.

[0009] Provided is the use of an anti-BCMA / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof in preventing or treating a disease associated with BCMA, 4-1BB, or both.

[0010] Technical Solution

[0011] Now, reference will be made in detail to the exemplary embodiments shown in the drawings, wherein the same reference numerals always denote the same elements. In this regard, the present exemplary embodiments may have different forms and should not be construed as limited to the descriptions set forth herein. Therefore, the following describes the exemplary embodiments only by referring to the drawings to explain aspects of the present specification. As used herein, the term "and / or" includes any and all combinations of one or more of the related listed items. Expressions such as "at least one", when preceding a list of elements, modify the entire list of elements, rather than individual elements in the list.

[0012] According to one aspect of the present disclosure, an anti-B-cell maturation antigen (BCMA) / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof includes an anti-BCMA antibody or an antigen-binding fragment thereof and an anti-4-1BB antibody or an antigen-binding fragment thereof.

[0013] The term "antibody" can be used interchangeably with "immunoglobulin (Ig)". The structure of the whole antibody includes two full-length light chains and two full-length heavy chains, and the two full-length light chains and two full-length heavy chains are connected by disulfide (SS) bonds. Antibodies can be, for example, IgA, IgD, IgE, IgG or IgM. Antibodies can be monoclonal antibodies or polyclonal antibodies. Antibodies can be antibodies of animal origin, mouse-human chimeric antibodies, humanized antibodies or human antibodies.

[0014] The term "antigen-binding fragment" refers to a fragment of the whole immunoglobulin structure, which can be a part of a polypeptide including an antigen-binding site. For example, the antigen-binding fragment can be scFv, (scFv)2, Fv, Fab, Fab′, Fv F(ab′)2 or a combination thereof.

[0015] There are five types of heavy chains, denoted by γ, δ, α, μ and ε respectively. The type of heavy chain defines the class of the antibody. Each chain of heavy chain types α and γ includes about 450 amino acids, while each chain of μ and ε includes about 550 amino acids. Each heavy chain has two regions, namely the variable region and the constant region.

[0016] There are two types of light chains, denoted by λ and κ respectively. Each light chain includes about 211 to 217 amino acids. Each human antibody includes only one type of light chain. Each light chain includes two consecutive domains, which include a constant region and a variable region.

[0017] The variable region refers to the region in the antibody that binds to the antigen.

[0018] The antibody or its antigen-binding fragment can be modified. For example, the antibody or its antigen-binding fragment can be modified by conjugation or binding, glycosylation, tag attachment or a combination thereof. The antibody can be conjugated with other drugs such as anticancer drugs. For example, the antibody or its antigen-binding fragment can be conjugated to horseradish peroxidase (HRP), alkaline phosphatase, hapten, biotin, streptavidin, fluorescent material, radioactive material, quantum dot, polyethylene glycol (PEG), histidine tag or a combination thereof. The fluorescent material can be ALEXA 532, ALEXA 546, ALEXA 568, ALEXA 680, ALEXA 750, ALEXA 790 or ALEXAFLUOR TM 350.

[0019] Anti-BCMA antibody or its antigen-binding fragment

[0020] An anti-BCMA antibody or an antigen-binding fragment thereof may comprise: a heavy chain variable region comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 10 to 21; a light chain variable region comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 32 and 54 to 64; or the heavy chain variable region and the light chain variable region.

[0021] An anti-4-1BB antibody or an antigen-binding fragment thereof may comprise: a heavy chain variable region comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 81 to 91; a light chain variable region comprising at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 92 to 97; or the heavy chain variable region and the light chain variable region.

[0022] The heavy chain variable region of an anti-BCMA antibody or an antigen-binding fragment thereof may comprise: complementarity-determining region (CDR)-H1 (CDR-H1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 10 to 13; CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 14 to 17; and CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 18 to 21. The term "complementarity-determining region (CDR)" refers to the site in the antibody variable region that confers the binding specificity of the antibody or its antigen-binding fragment to the antigen.

[0023] The light chain variable region of an anti-BCMA antibody or an antigen-binding fragment thereof may comprise: complementarity-determining region-L1 (CDR-L1) comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 22 to 25 and 54 to 62; CDR-L2 comprising an amino acid sequence selected from SEQ ID NOs: 26 to 28; and CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 29 to 32, 63, and 64.

[0024] An anti-BCMA antibody or an antigen-binding fragment thereof may be selected from the group consisting of:

[0025] (1) An antibody or an antigen-binding fragment thereof comprising CDR-H1 having the amino acid sequence of SEQ ID NO: 10, CDR-H2 having the amino acid sequence of SEQ ID NO: 14, and CDR-H3 having the amino acid sequence of SEQ ID NO: 18;

[0026] (2) An antibody or an antigen-binding fragment thereof, comprising a CDR-H1 having the amino acid sequence of SEQ ID NO: 11, a CDR-H2 having the amino acid sequence of SEQ ID NO: 15, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 19;

[0027] (3) An antibody or an antigen-binding fragment thereof, comprising a CDR-H1 having the amino acid sequence of SEQ ID NO: 12, a CDR-H2 having the amino acid sequence of SEQ ID NO: 16, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 20; and

[0028] (4) An antibody or an antigen-binding fragment thereof, comprising a CDR-H1 having the amino acid sequence of SEQ ID NO: 13, a CDR-H2 having the amino acid sequence of SEQ ID NO: 17, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 21.

[0029] The anti-BCMA antibody or an antigen-binding fragment thereof may be selected from the group consisting of:

[0030] (1) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 22, a CDR-L2 having the amino acid sequence of SEQ ID NO: 26, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 29;

[0031] (2) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 23, a CDR-L2 having the amino acid sequence of SEQ ID NO: 27, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 30;

[0032] (3) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 24, a CDR-L2 having the amino acid sequence of SEQ ID NO: 27, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 31;

[0033] (4) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 25, a CDR-L2 having the amino acid sequence of SEQ ID NO: 28, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 32.

[0034] (5) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 54, a CDR-L2 having the amino acid sequence of SEQ ID NO: 27, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 31;

[0035] (6) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 55, a CDR-L2 having the amino acid sequence of SEQ ID NO: 27, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 31;

[0036] (7) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 56, a CDR-L2 having the amino acid sequence of SEQ ID NO: 27, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 31;

[0037] (8) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 57, a CDR-L2 having the amino acid sequence of SEQ ID NO: 27, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 31;

[0038] (9) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 58, a CDR-L2 having the amino acid sequence of SEQ ID NO: 27, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 31;

[0039] (10) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 59, a CDR-L2 having the amino acid sequence of SEQ ID NO: 28, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 32;

[0040] (11) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 60, a CDR-L2 having the amino acid sequence of SEQ ID NO: 28, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 32;

[0041] (12) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 25, a CDR-L2 having the amino acid sequence of SEQ ID NO: 28, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 63;

[0042] (13) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 25, a CDR-L2 having the amino acid sequence of SEQ ID NO: 28, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 64;

[0043] (14) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 61, a CDR-L2 having the amino acid sequence of SEQ ID NO: 28, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 63;

[0044] (15) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 61, a CDR-L2 having the amino acid sequence of SEQ ID NO: 28, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 64;

[0045] (16) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 62, a CDR-L2 having the amino acid sequence of SEQ ID NO: 28, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 63; and

[0046] (17) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 62, a CDR-L2 having the amino acid sequence of SEQ ID NO: 28, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 64.

[0047] The anti-BCMA antibody or an antigen-binding fragment thereof may comprise a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 2 to 5.

[0048] The anti-BCMA antibody or an antigen-binding fragment thereof may comprise a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 6 to 9 and 41 to 53.

[0049] B cell maturation antigen (BCMA) can be a BCMA polypeptide or a fragment thereof. BCMA can also be referred to as tumor necrosis factor receptor superfamily member 17 (TNFRSF17), BCM, CD269, TNFRSF13A, or TNF receptor superfamily member 17. The BCMA polypeptide can include the amino acid sequence of GenBank accession number NP_001183 (human) or GenBank accession number NP_035738 (mouse). The BCMA polypeptide can include the amino acid sequence encoded by the polynucleotide of GenBank accession number NM_001192 (human) or GenBank accession number NM_011608 (mouse). The fragment can be a polypeptide including any part of the amino acid sequence of the BCMA polypeptide.

[0050] An anti-BCMA antibody or an antigen-binding fragment thereof can have an affinity for the BCMA polypeptide or a fragment thereof, thereby specifically binding to BCMA.

[0051] An anti-BCMA antibody or an antigen-binding fragment thereof can inhibit the binding between the BCMA protein and a substance that specifically binds to the BCMA protein. The substance that specifically binds to the BCMA protein can also be referred to as a ligand, such as B cell-activating factor (BAFF), a proliferation-inducing ligand (APRIL), which belong to the tumor necrosis factor family, or a combination thereof.

[0052] Anti-4-1BB antibody or its antigen-binding fragment

[0053] The heavy chain variable region of an anti-4-1BB antibody or an antigen-binding fragment thereof can include: CDR-H1, which includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 81 to 83; CDR-H2, which includes an amino acid sequence selected from SEQ ID NOs: 84 to 86; and CDR-H3, which includes an amino acid sequence selected from SEQ ID NOs: 87 to 91.

[0054] The light chain variable region of an anti-4-1BB antibody or an antigen-binding fragment thereof can include: CDR-L1, which includes an amino acid sequence selected from the group consisting of SEQ ID NOs: 92 and 93; CDR-L2, which includes an amino acid sequence selected from SEQ ID NOs: 94 and 95; and CDR-L3, which includes an amino acid sequence selected from SEQ ID NOs: 96 and 97.

[0055] An anti-4-1BB antibody or an antigen-binding fragment thereof can be selected from the group consisting of:

[0056] (1) An antibody or an antigen-binding fragment thereof, comprising a CDR-H1 having the amino acid sequence of SEQ ID NO: 81, a CDR-H2 having the amino acid sequence of SEQ ID NO: 84, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 87;

[0057] (2) An antibody or an antigen-binding fragment thereof, comprising a CDR-H1 having the amino acid sequence of SEQ ID NO: 81, a CDR-H2 having the amino acid sequence of SEQ ID NO: 84, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 88;

[0058] (3) An antibody or an antigen-binding fragment thereof, comprising a CDR-H1 having the amino acid sequence of SEQ ID NO: 81, a CDR-H2 having the amino acid sequence of SEQ ID NO: 84, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 89;

[0059] (4) An antibody or an antigen-binding fragment thereof, comprising a CDR-H1 having the amino acid sequence of SEQ ID NO: 82, a CDR-H2 having the amino acid sequence of SEQ ID NO: 85, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 90; and

[0060] (5) An antibody or an antigen-binding fragment thereof, comprising a CDR-H1 having the amino acid sequence of SEQ ID NO: 83, a CDR-H2 having the amino acid sequence of SEQ ID NO: 86, and a CDR-H3 having the amino acid sequence of SEQ ID NO: 91.

[0061] The anti-4-1BB antibody or an antigen-binding fragment thereof may be selected from the group consisting of:

[0062] (1) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 92, a CDR-L2 having the amino acid sequence of SEQ ID NO: 94, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 96; and

[0063] (2) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 93, a CDR-L2 having the amino acid sequence of SEQ ID NO: 95, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 97.

[0064] The anti-4-1BB antibody or an antigen-binding fragment thereof may be selected from the group consisting of:

[0065] (1) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 92, a CDR-L2 having the amino acid sequence of SEQ ID NO: 94, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 96; and

[0066] (2) An antibody or an antigen-binding fragment thereof, comprising a CDR-L1 having the amino acid sequence of SEQ ID NO: 93, a CDR-L2 having the amino acid sequence of SEQ ID NO: 95, and a CDR-L3 having the amino acid sequence of SEQ ID NO: 97.

[0067] The anti-4-1BB antibody or an antigen-binding fragment thereof may comprise a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 73 to 80.

[0068] 4-1BB may be a 4-1BB polypeptide or a fragment thereof. 4-1BB may also be referred to as CD137, CDw137, ILA, tumor necrosis factor receptor superfamily member 9 (TNFRSF9), or TNF receptor superfamily member 9. The 4-1BB polypeptide may comprise the amino acid sequence of GenBank accession number NP_001552 (human), or the amino acid sequences of GenBank accession numbers NP_001070976, NP_001070977, or NP_035742 (mouse). The BCMA polypeptide may comprise the amino acid sequence encoded by the polynucleotide of GenBank accession number NM_001561 (human) or GenBank accession numbers NM_001077508, NM_001077509, or NM_011612 (mouse). The fragment may be a polypeptide comprising any portion of the amino acid sequence of the 4-1BB polypeptide.

[0069] The anti-4-1BB antibody or an antigen-binding fragment thereof may have an affinity for the 4-1BB polypeptide or a fragment thereof, thereby specifically binding to 4-1BB. The anti-4-1BB antibody or an antigen-binding fragment thereof is capable of enhancing the immune response and / or treating tumors (cancers) in mammals. Compared with pre-existing anti-4-1BB antibodies, the anti-4-1BB antibody or an antigen-binding fragment thereof is characterized by being localized and / or activated and / or significantly reducing hepatotoxicity only in the tumor microenvironment (TME), and maintaining the efficacy of enhancing the immune response and / or tumor treatment.

[0070] Anti-BCMA / anti-4-1BB bispecific antibody or its antigen-binding fragment

[0071] In the anti-BCMA / anti-4-1BB bispecific antibody or its antigen-binding fragment, the anti-BCMA antibody or its antigen-binding fragment and the anti-4-1BB antibody or its antigen-binding fragment are each independently a chimeric antibody, a humanized antibody, or a human antibody.

[0072] In the bispecific antibody, one of the BCMA targeting portion and the 4-1BB targeting portion can be a full-length antibody, and the other can be an antigen-binding fragment (e.g., scFv) comprising heavy chain CDRs, light chain CDRs, or a combination thereof. The full-length antibody targeting one of the BCMA and 4-1BB proteins and the antigen-binding fragment targeting the other protein can be chemically linked (e.g., covalently linked) directly or through a peptide linker. The antigen-binding fragment (e.g., scFv) can be linked directly or through a peptide linker to the N-terminus (e.g., the N-terminus of the light chain or heavy chain of the full-length antibody), the C-terminus (e.g., the C-terminus of the heavy chain (or Fc or CH3 domain) of the full-length antibody) of the full-length antibody, or both (see Figure 1 ).

[0073] The anti-BCMA / anti-4-1BB bispecific antibody or its antigen-binding fragment can further comprise at least one of the peptide linkers. The term "peptide linker" can be one comprising 1 to 100 amino acids, particularly 2 to 50 amino acids, and can comprise any kind of amino acids without any limitation. The peptide linker can comprise a peptide having an amino acid sequence selected from the group consisting of SEQ ID NO:98 and SEQ ID NO:99.

[0074] In one embodiment, the bispecific antibody can comprise a full-length anti-BCMA antibody, an antigen-binding fragment (e.g., scFv) of the anti-4-1BB antibody, and a peptide linker therebetween. In another embodiment, the bispecific antibody can comprise a full-length anti-4-1BB antibody, an antigen-binding fragment (e.g., scFv) of the anti-BCMA antibody, and a peptide linker therebetween.

[0075] In the anti-BCMA / anti-4-1BB bispecific antibody or its antigen-binding fragment, the antibody can be IgA, IgD, IgE, IgG, or IgM. The antibody can be a monoclonal antibody or a polyclonal antibody. The antigen-binding fragment can be scFv, (scFv)2, Fv, Fab, Fab′, F(ab′)2, or a combination thereof. The antibody or its antigen-binding fragment is modified by conjugation or binding, glycosylation, tag attachment, or a combination thereof.

[0076] In one embodiment, the scFv contained in the bispecific antibody may include a heavy chain variable region and a light chain variable region in any order. For example, the scFv contained in the bispecific antibody may include a heavy chain variable region and a light chain variable region in the direction from the N-terminus to the C-terminus, and optionally include a peptide linker therebetween, or the scFv contained in the bispecific antibody may include a light chain variable region and a heavy chain variable region in the direction from the N-terminus to the C-terminus, and optionally include a peptide linker therebetween.

[0077] The anti-BCMA / anti-4-1BB bispecific antibody or antigen-binding fragment is in the form of IgG-scFv, triomab, a kih IgG with a common light chain, crossmab, vicinal-Fab IgG, dual variable domain immunoglobulin (DVD-Ig), 2-in-1-IgG, scFv2-Fc, bis-nanobody, bispecific T cell engager (BiTE), tandAbs, dual-affinity re-targeting (DART) antibody, DART-Fc, scFv-human serum albumin (HSA)-scFv, docking and locking (DNL) Fab3, minibody, scFv-Fc, scFv-zipper, scFv, Fab, Fab2 (bispecific), Fab3 (trispecific), scFab, Bis-scFv (bispecific), sdAb (VH / VHH), tetrabody, tribody, diabody, camel Ig, IgNAR, IgG, a bispecific construct comprising a kih structure, a bispecific construct comprising a diabody, a tetravalent multispecific antibody, a tetravalent construct, a tetravalent dual variable domain (DVD) construct, a tetravalent IgGScv construct, a tetravalent Mbatryn construct, or a composite antibody, or a combination thereof.

[0078] Depending on BCMA expressed on the cell surface, the anti-BCMA / anti-4-1BB bispecific antibody or its antigen-binding fragment can activate 4-1BB signaling.

[0079] According to another aspect of the present disclosure, a pharmaceutical composition for preventing or treating a disease associated with BCMA, 4-1BB, or both includes an anti-BCMA / anti-4-1BB bispecific antibody or its antigen-binding fragment according to any one of the above embodiments, and a pharmaceutically acceptable carrier.

[0080] BCMA, 4-1BB, the anti-BCMA / anti-4-1BB bispecific antibody, and its antigen-binding fragment are the same as those above.

[0081] Diseases associated with BCMA, 4-1BB, or both can be cancers. The cancer can be a solid cancer or a non-solid cancer. A solid cancer refers to a cancerous tumor that occurs in solid organs such as the liver, lung, breast, or skin, while a non-solid cancer refers to a cancer that affects the blood and is thus called a blood cancer. For example, the cancer can be selected from the group consisting of breast cancer, skin cancer, head and neck cancer, pancreatic cancer, lung cancer, colon cancer, colorectal cancer, gastric cancer, ovarian cancer, prostate cancer, bladder cancer, uterine cancer, liver cancer, kidney cancer, clear cell sarcoma, melanoma, cerebrospinal tumor, brain cancer, thymoma, mesothelioma, esophageal cancer, biliary tract cancer, testicular cancer, germ cell cancer, thyroid cancer, parathyroid cancer, cervical cancer, endometrial cancer, lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, acute leukemia, chronic leukemia, multiple myeloma, Hodgkin's disease, endocrine cancer, and sarcoma.

[0082] The term "prevention" refers to any act of inhibiting or delaying the onset of a disease associated with BCMA, 4-1BB, or both by administering a pharmaceutical composition. The term "treatment" refers to any act of alleviating the symptoms of a disease associated with BCMA, 4-1BB, or both by administering a pharmaceutical composition.

[0083] The pharmaceutical composition can include a pharmaceutically acceptable carrier. The carrier can be interpreted as an excipient, diluent, or adjuvant. For example, the carrier can be selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, normal saline, buffers such as phosphate-buffered saline (PBS), methylparaben, propylparaben, talc, magnesium stearate, glycine, histidine, serine, polysorbate, and mineral oil. The pharmaceutical composition can include fillers, anticoagulants, lubricants, wetting agents, flavoring agents, emulsifying agents, preservatives, or combinations thereof.

[0084] The pharmaceutical composition can be formulated into any form using any common method in the art. For example, the pharmaceutical composition can be formulated into an oral dosage form (e.g., powder, tablet, capsule, syrup, pill, or granule) or a parenteral dosage form (e.g., injection). The pharmaceutical composition can be prepared as a formulation for systemic administration or as a formulation for local administration.

[0085] The pharmaceutical composition may further comprise an anti-cancer drug. The anti-cancer drug may be cetuximab, panitumumab, erlotinib, gefitinib, trastuzumab, T-DM1, pertuzumab, lapatinib, paclitaxel, tamoxifen, cisplatin, anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, 5-fluorouracil (5FU), gemcitabine, or a combination thereof. The pharmaceutical composition may comprise a single composition or separate compositions. For example, the anti-BCMA / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof of the pharmaceutical composition may be a composition in a parenteral dosage form, and the anti-cancer drug may be in an oral dosage form.

[0086] The pharmaceutical composition may comprise an effective amount of an antibody or an antigen-binding fragment thereof, an anti-cancer drug, or a combination thereof. As used herein, the term "effective amount" refers to an amount sufficient to prevent or treat a disease associated with BCMA, 4-1BB, or both when administered to an individual in need of such prevention or treatment. One of ordinary skill in the art can appropriately select the effective amount according to the selected cell or individual. For example, the effective amount may be determined according to factors such as the severity of the disease, the age, weight, health status, gender of the patient, the drug sensitivity of the patient, the administration period, the administration route, the excretion rate, the treatment period, and other factors including drugs combined or used concurrently with the pharmaceutical composition, as well as other factors known in the medical field. The effective amount may be about 0.5 μg to about 2 g of the pharmaceutical composition.

[0087] When administered to an adult, the dosage of the pharmaceutical composition may be, for example, about 0.001 mg / kg to about 100 mg / kg. The number of administrations may be, for example, once a day or multiple times, once a week to once every four weeks, or once a year to twelve times a year.

[0088] According to another aspect of the present disclosure, a method for preventing or treating a disease associated with BCMA, 4-1BB, or both in an individual comprises administering to the individual an anti-BCMA / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof according to any one of the above embodiments.

[0089] BCMA, 4-1BB, the anti-BCMA / anti-4-1BB bispecific antibody, the antigen-binding fragment, prevention, and treatment are the same as above.

[0090] The individual may be a mammal, such as a human, monkey, cow, horse, pig, dog, sheep, goat, or cat. The individual may be an individual suffering from or susceptible to a disease associated with BCMA, 4-1BB, or both, and the disease may be cancer.

[0091] The method may further comprise administering an anti-cancer drug to an individual in need thereof. The anti-cancer drug may be administered simultaneously, separately, or sequentially with the anti-BCMA / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof according to any of the above exemplary embodiments.

[0092] For example, an anti-BCMA / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof, an anti-cancer drug, or a combination thereof can be directly administered to an individual by any method, such as by oral, intravenous, intramuscular, percutaneous, mucosal, intranasal, intratracheal, or subcutaneous administration. The antibody or an antigen-binding fragment thereof, the anti-cancer drug, or the combination thereof can be administered systemically or locally. The antibody or an antigen-binding fragment thereof, the anti-cancer drug, or the combination thereof can be administered alone or together with a pharmaceutically active compound.

[0093] The dosage of the anti-BCMA / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof, the anti-cancer drug, or the combination thereof can vary according to the patient's condition, weight, disease severity, drug formulation, route of administration, and duration of administration, and can be appropriately selected by those of ordinary skill in the art. For example, when administered to an adult, the dosage of the antibody or an antigen-binding fragment thereof, the anti-cancer drug, or the combination thereof can be about 0.001 mg / kg to about 100 mg / kg. The number of administrations can be, for example, once a day or multiple times, once a week to once every four weeks, or once a year to twelve times a year.

[0094] According to another aspect of the present disclosure, there is provided the use of an anti-BCMA / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof according to any one of the above embodiments in the prevention or treatment of a disease associated with BCMA, 4-1BB, or both.

[0095] BCMA, 4-1BB, the anti-BCMA / anti-4-1BB bispecific antibody, the antigen-binding fragment, prevention, treatment, and the disease associated with BCMA, 4-1BB, or both are the same as above.

[0096] Beneficial effects

[0097] As described above, according to one or more exemplary embodiments, there are provided an anti-BCMA / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof and its use. The anti-BCMA / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof can be effectively used for the prevention or treatment of a disease associated with BCMA, 4-1BB, or both.

[0098] Brief description of the drawings

[0099] These and / or other aspects will become apparent and easier to understand from the following description of exemplary embodiments in conjunction with the accompanying drawings, in which:

[0100] Figure 1 Schematic diagram of a bispecific antibody according to an embodiment of the present disclosure;

[0101] Figures 2A to 2C are graphs showing the results of the target protein binding assay using DACE, and Figures 2D to 2F are graphs showing the cell surface binding assay using the FACS system;

[0102] Figures 3A to 3D are graphs showing the results of the 4-1BB reporter bioassay;

[0103] Figures 4A to 4C are graphs showing the results of the PBMC-based study;

[0104] Figure 5A is a graph showing the results of the target protein binding assay using DACE (5D5 WT and 5D5 mutant), Figure 5B is a graph showing the results of the target protein binding assay using DACE (5A6 WT and 5A6 mutant), Figure 5C is a graph showing the results of the target protein binding assay using DACE (WT and mutant), and Figure 5D is a graph showing the cell surface binding assay using the FACS system (WT and mutant).

[0105] Figures 6A to 6C are graphs showing the results of the in vitro 4-1BB activation assay;

[0106] Figure 7 is a graph showing the results of the monkey cross-reactivity assay by DACE;

[0107] Figures 8A to 8C are graphs showing the inhibition of tumor growth in humanized NOG mice carrying H929 by the BCMAx4-1BB bispecific antibody;

[0108] Figure 9A is a photograph showing tumor-infiltrating lymphocytes (TIL), and Figure 9B is a graph showing the analysis results of tumor-infiltrating lymphocytes; and

[0109] Figures 10A and 10B are graphs showing the individual results (n = 3) and the total results (n = 3) of the pharmacokinetics of the anti-BCMA / anti-4-1BB bispecific antibody in cynomolgus monkeys, respectively.

[0110] Figure 11 is a graph showing the tumor growth curve after administration of the anti-BCMA / anti-4-1BB bispecific antibody ((*P < 0.05; **P < 0.01). Detailed Description of the Embodiments

[0111] One or more embodiments of the present disclosure will now be described in detail with reference to the following examples. However, these examples are for illustrative purposes only and are not intended to limit the scope of one or more embodiments of the present disclosure.

[0112] Example 1. Preparation of Anti-BCMA Monoclonal Antibody

[0113] 1-1. Preparation of Antigen

[0114] Antigens were prepared for the production of anti-BCMA antibodies as follows. Polypeptides comprising amino acid residues 5-54, 1-51, 1-54, and 4-48 from the N-terminus of the amino acid sequence of human BCMA (GenBank accession number NP_001183.2, SEQ ID NO: 1) were used as antigens, respectively.

[0115] Specifically, an antigen comprising amino acid residues 5-54 of human BCMA ( Z02731) (“human BCMA(5-54)”) was prepared; an antigen comprising amino acid residues 1-51 of human BCMA (internally produced, expressed in CHO cells) fused to the Fc region of human IgG1 (“human BCMA-Fc(1-51)”) was prepared; an antigen comprising amino acid residues 1-54 of human BCMA fused to the Fc region and a His tag at its C-terminus (10620-H03H, Sino Biological Inc.) (“human BCMA-Fc / His(1-54)”) was prepared; and an antigen comprising amino acid residues 4-48 of human BCMA fused to the Fc region (internally produced, expressed in HEK293 cells) (“human BCMA-Fc(4-48)”) was prepared.

[0116] Human BCMA-Fc(4-48) was prepared as follows. The polynucleotide encoding amino acid residues 4-48 of human BCMA was cloned into pAB1-Fc, which is an animal cell expression vector containing a CMV promoter. The cloned vector was transfected into HEK293E cells, and human BCMA-Fc(4-48) was purified using protein A affinity chromatography. Human BCMA-Fc(1-51) was prepared in the same manner as described above.

[0117] 1-2. Library Phage Preparation and Phage Display Panning

[0118] Preparation of a human single-chain fragment variable (ScFv) phage library cell capable of binding to various antigens (Mol. Cells OT, 225-235, February 28, 2009). The prepared phage library was infected with helper phage, and then phage packaging was induced. Thereafter, the culture product was centrifuged at 4,500 rpm for 15 minutes at 4°C, and then 4% (w / v) polyethylene glycol 6000 (PEG 6000) (Fluka, 81253) and 3% (w / v) NaCl (Sigma, S7653) were added to the supernatant and dissolved well, and then cultured on ice for 1 hour. The obtained product was centrifuged at 8,000 rpm for 20 minutes at 4°C, and the pellets were resuspended in phosphate buffered saline (PBS), and then centrifuged again at 12,000 rpm for 10 minutes at 4°C to obtain the supernatant containing library phage. The obtained library phage was stored at 4°C before use.

[0119] A total of three rounds of panning were performed in the following manner to screen for antibodies reactive to human BCMA or cross-reactive to human BCMA and monkey BCMA. 5 μg of the antigen prepared according to Example 1-1 was added to an immunotube (maxisorp 444202) and cultured at 4°C for 16 hours to coat the protein on the surface of the tube. The supernatant was removed therefrom, and bovine serum albumin (BSA) was added thereto to block non-specific binding.

[0120] 1 012 CFU of the phage library prepared according to Example 1-2 was mixed with 1.5% (w / v) BSA, and the mixture was added to the immunoassay tube coated with the target protein and reacted at 37°C for 1 hour to allow BCMA-specific phage to bind to the target protein. Subsequently, after washing multiple times with PBS-T (phosphate buffered saline solution containing 0.05% (v / v) Tween 20), the phage bound to BCMA was recovered by using 100 mM triethylamine solution. The recovered phage was neutralized with 1 M Tris buffer (pH 7.4), and then it was used to infect Escherichia coli K12 ER2738, and the phage was recovered again. This cycle includes target binding, elution, neutralization, infection, and recovery, and was repeated four times. As the panning rounds progressed, the number of washing processes with PBS-T was increased to amplify and concentrate antigen-specific phage.

[0121] 1-3. Screening of monoclonal phage antibodies

[0122] A monoclonal phage antibody screening procedure was performed to select monoclonal antibodies specifically binding to BCMA from the phage library.

[0123] Specifically, the phage library obtained according to Examples 1-2 was serially diluted and cultured on a solid medium containing LB-tetracycline / carbenicillin to obtain single colonies. Each colony was cultured in a 96-well deep well plate to an OD600 of 0.5 to 0.7. 20 MOI of helper phage was added to each well and reacted at 37 °C for 1 hour. Thereafter, kanamycin was added to each well and cultured overnight at 30 °C. On the next day, the culture was centrifuged and the supernatant was collected, and then an enzyme linked immunosorbent assay (ELISA) was performed to select BCMA-specific phages. Each well of the ELISA plate was coated with 100 ng of recombinant BCMA and then cultured with PBS-B (PBS containing 3% BSA) to prevent non-specific binding. Thereafter, the plate was washed with PBS. The prepared monoclonal phages were added to each well, cultured at 37 °C for 1 hour, and the plate was washed 3 times with PBS-T. To detect the bound phages, an anti-hemagglutinin (HA) antibody conjugated with horseradish peroxidase (HRP) was added to each well. After the step of washing with PBS-T, tetramethylbenzidine (TMB, Sigma, T0440) was added. Clones having an absorbance of 0.5 or greater at a wavelength of 450 nm and having an absorbance at least 5 times greater than that of the control group using anti-HA HRP alone were selected. Four antibody clones (B58, 5B5, 5D5, and 5A6) that specifically bind to human BCMA were selected.

[0124] From the nucleotide sequences encoding the selected antibodies, the amino acid sequences of the heavy chain variable regions (SEQ ID NOs: 2 to 5) and the amino acid sequences of the light chain variable regions (SEQ ID NOs: 6 to 9) were analyzed, and the complementarity determining regions (CDRs) were determined according to Kabat definitions. The determined CDR amino acid sequences (N->C) of the heavy chain and the light chain are shown in Tables 1 and 2, respectively.

[0125]

Table 1

[0126]

[0127]

Table 2

[0128]

[0129] The nucleotide sequences encoding the heavy chain variable region and the nucleotide sequences encoding the light chain variable region are shown in Table 3 below.

[0130]

Table 3

[0131] Antibody Nucleotide sequence encoding the heavy chain variable region Nucleotide sequence encoding the light chain variable region B58 SEQ ID NO: 33 SEQ ID NO: 37 5B5 SEQ ID NO: 34 SEQ ID NO: 38 5D5 SEQ ID NO: 35 SEQ ID NO: 39 5A6 SEQ ID NO: 36 SEQ ID NO: 40

[0132] 1-4. Production of anti-BCMA IgG antibodies from selected anti-BCMA phages

[0133] Polynucleotides having nucleotide sequences encoding the antibodies selected according to Examples 1-3 were synthesized. The prepared polynucleotides were cloned into animal cell culture vectors (heavy chain expression vector: pAB1-HC, and light chain expression vector: pAB1-LC). A total of 8 vectors containing polynucleotides encoding the heavy and light chains were prepared for each of the four antibody clones (B58, 5A6, 5D5, and 5B5). Each prepared pAB1-HC vector contained an IgG1-type sequence.

[0134] CHO-S cells were cultured in CD-CHO (Gibco, 10743) medium, and the prepared vectors were introduced into CHO-S cells using polyethylenimine (PEI). The transduced CHO-S cells were cultured in CD-CHO medium at 8% CO2 and 37 °C with shaking (110 rpm) for about 7 days.

[0135] After collecting the cultured supernatant, it was passed through a MabSelect SuRe column (GE healthcare, 5 mL) equilibrated with equilibration buffer (50 mM Tris-HCl, pH 7.5, 100 mM NaCl) to bind the expressed antibody to the column. The antibody was eluted with a solution of 50 mM sodium citrate (pH 3.4) and 100 mM NaCl, and then neutralized with 1 M Tris-HCl (pH 9.0) to obtain a final pH of 7.2. Then the buffer was replaced with PBS (pH 7.4), and the anti-BCMA IgG antibodies B58, 5A6, 5D5, and 5B5 were stored at 4 °C until use.

[0136] 1-5. Preparation of 5A6 and 5D5 mutants

[0137] To improve the productivity of the selected 5A6 and 5D5 antibodies, mutant antibodies were prepared by mutating one or two amino acid residues in the light chain CDR of the antibody according to the nucleotide sequences in Table 3.

[0138] The amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 of the 5D5 mutant antibody and the 5A6 mutant antibody are shown in Tables 4 and 5, respectively. In Tables 4 and 5, the underlined and bold amino acid residues are the mutated parts (WT: wild type, LM: light chain mutant). The light chain variable regions of the 5D5 mutant antibody and the 5A6 mutant antibody have the amino acid sequences of SEQ ID NO: 41 to 45 and SEQ ID NO: 46 to 53, respectively.

[0139]

Table 4

[0140]

[0141]

Table 5

[0142]

[0143] Example 2. Preparation of Anti-4-1BB Monoclonal Antibody

[0144] 2-1. Screening of Fully Human Monoclonal Antibodies Against 4-1BB (Phage Library Immunotube Panning)

[0145] For the panning of the library against the target molecule, a total of four rounds of panning were performed using immunotubes coated with 4-1BB.

[0146] The bacterial colonies from the output of the 3rd round of panning were grown to turbidity in SB medium containing carbenicillin in a 96-deep well plate. At this time, 10 11 pfu of VCSM13 helper phage was added to each well. After infecting for 1 hour at 37 °C with gentle shaking (80 rpm), 70 μg / mL of kanamycin was added, and the cells were cultured overnight with shaking at 200 rpm at 30 °C.

[0147] On the next day, the plate was centrifuged and the supernatant containing phage was added to an ELISA plate coated with 4-1BB antigen blocked with 3% (w / v) BSA in PBST. After culturing at room temperature for 1 hour, the plate was washed 3 times with PBST, and anti-M13 antibody was added. The plate was cultured for 1 hour, washed 3 times with PBST, and the binding activity was measured using tetramethylbenzidine (TMB).

[0148] Plasmid DNA was amplified for 4-1BB-specific antibody sequencing. The variable heavy chain and light chain (VH and VL) regions were analyzed to identify unique sequences and determine sequence diversity. Three antibody clones (41B01, 41B02, and AB41) that specifically bind to human 4-1BB were selected. As described in Example 1-5, 41B01 M4, 41B01 M11, 41B01 M12, 41B01 M13, and 41B02 M1 mutants were prepared from the selected antibodies.

[0149] From the nucleotide sequences encoding the selected antibodies, the amino acid sequences of the heavy chain variable regions of the antibodies (SEQ ID NOs: 65 to 72) and the amino acid sequences of the light chain variable regions (SEQ ID NOs: 73 to 80) were analyzed, and the CDRs were determined according to the Kabat definition. The determined CDR amino acid sequences (N->C) of the heavy and light chains are shown in Tables 6 and 7, respectively.

[0150] [Table 6]

[0151]

[0152] [Table 7]

[0153]

[0154]

[0155] 2-2. Antigen-binding ability of anti-4-1BB antibody to human 4-1BB

[0156] (1) Antigen binding measured by ELISA

[0157] To evaluate the antigen-binding activity, the candidate antibodies were tested by ELISA. Briefly, 0.1 μg / mL of human 4-1BB-Fc protein in PBS was coated on a microtiter plate, incubated overnight at 4 °C at 100 μl / well, and then blocked with 5% (w / v) BSA at 100 μl / well. Humanized antibodies 41B01 and 41B02 diluted 5-fold starting from 10 μg / mL were added to each well and incubated at room temperature for 1 to 2 hours. The plate was washed with PBS / Tween, and then incubated with goat anti-human IgG antibody conjugated with HRP at room temperature for 1 hour. After washing, the plate was developed with TMB and analyzed by a spectrophotometer at OD 450 to 630 nm.

[0158] (2) Cell binding measured by FACS

[0159] To evaluate the antigen-binding characteristics, the binding of the candidate antibodies to mammalian-expressed 4-1BB was analyzed by FACS. Briefly, 4-1BB-T lymphocyte (Jurkat) cells were cultured with the antibodies (41B01 and 41B02). After washing with FACS buffer (1% (w / v) BSA in PBS), FITC anti-human IgG antibody was added to each well and incubated at 4 °C for 1 hour. The MFI of FITC was evaluated by a flow cytometer (FACS Calibrer).

[0160] (3) Protein kinetics of 4-1BB

[0161] To explore the binding kinetics of humanized antibodies, in this example, Octet Red 96 was used for affinity ranking. 41B01 and 41B02 are shown in Table 8 below.

[0162] [Table 8]

[0163] Antibody KD (M) kon (1 / Ms) kdis (1 / s) Chi <![CDATA[R 2 > 41B01 1.80E-10 6.58E+05 1.19E-04 0.0392 0.9987 41B02 1.01E-09 5.95E+05 6.03E-04 0.0525 0.9973

[0164] As shown in Table 8, the tested anti-4-1BB antibodies showed high 4-1BB binding affinity.

[0165] Example 3. Definition of anti-BCMA / anti-4-1BB bispecific antibody

[0166] 3-1. Preparation of anti-BCMA / anti-4-1BB bispecific antibody

[0167] As shown in Table 9, various anti-BCMA / anti-4-1BB bispecific antibody candidates were prepared in the form of full-length IgG (anti-BCMA antibody)-scFv (anti-4-1BB antibody). The constant region of the anti-BCMA antibody contained in the bispecific antibody could still be modified by introducing more than one mutation or change into human IgG1. In the example, NA mutation (N297A) was introduced.

[0168] [Table 9]

[0169]

[0170]

[0171] Anti-BCMA IgG and anti-4-1BB scFv clones prepared in Example 1 and Example 2 were respectively selected exemplarily to prepare anti-BCMA / anti-4-1BB bispecific antibodies in the form of IgG-scFv fusion, in which the scFv antibody fragment of one antigen was fused to the C-terminus of the IgG of the other antigen. When BCMA was placed in the intact IgG part, IgG1 with a reduced ADCC mutation backbone (N297A mutation; Cancer Cell, Volume 19, Issue 1, pp. 101-113, etc.) was used, and when 4-1BB was placed in the intact IgG part, IgG4 was used. The amino acid sequences of anti-BCMA IgG and 41BB scF scFv are shown in Table 10 and Table 11 respectively.

[0172] [Table 10]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178]

[0179]

Table 11

[0180]

[0181]

[0182] The DNA fragment 1 having the nucleotide sequence of the heavy chain of the IgG antibody encoding the anti-BCMA / anti-4-1BB bispecific antibody was inserted into pcDNA 3.4 (Invitrogen, A14697; plasmid 1), and the DNA fragment 2 having the nucleotide sequence of the light chain of the IgG antibody encoding the anti-BCMA / anti-4-1BB bispecific antibody was inserted into pcDNA3.4 (Invitrogen, A14697; plasmid 2). Subsequently, the DNA fragment 3 encoding scFv was fused to the portion of the DNA fragment 1 corresponding to the C-terminus of the Fc region of the IgG antibody inserted into plasmid 1 by using the DNA fragment 4 encoding a 15-amino acid length linker peptide consisting of (GGGGS)4 (SEQ ID NO: 98) or by using the DNA fragment 5 encoding an 18-amino acid length linker peptide consisting of (GS)9 (SEQ ID NO: 99) to construct a vector for expressing the bispecific antibody. In addition, to stabilize scFv, as described in Example 2, additional modifications were applied to generate disulfide bonds, and VL103-VH44 (VL103: VL has a G->C mutation at position 103; VH 44: VH has a G->C mutation at position 44) was fused to the C-terminus of the light chain and the C-terminus of the heavy chain, respectively.

[0183] The amino acid sequence of the prepared bispecific antibody is shown in Table 12.

[0184]

Table 12

[0185]

[0186]

[0187]

[0188] For the purposes of improving stability and potency, reducing immunogenicity, etc., one or more point mutations in the amino acid sequence can be applied to the antibodies presented below.

[0189] 3-2. Antigen Binding Ability of Anti-BCMA / Anti-4-1BB Antibody (Full-Length IgG Form) to Target Proteins

[0190] (1) Antigen Binding Measured by Dual Antigen Captured ELISA (DACE)

[0191] To evaluate antigen binding activity, ELISA tests were performed on the candidate antibodies. Briefly, 0.5 μg / mL of human BCMA-Fc protein in PBS was coated on microtiter plates and incubated overnight at 4 °C to 100 μl / well, and then blocked with 1% (w / v) BSA at 100 μl / well. Bispecific antibodies diluted 3-fold starting from 20 μg / mL were added to each well and incubated at 37 °C for 1 hour. The plates were washed with PBS / Tween, and then incubated with 0.8 μg / mL of human 4-1BBhis protein containing 1% (w / v) BSA at 37 °C for 1 hour. The plates were washed with PBST (0.05% (v / v) Tween 20 in PBS). Then the plates were developed with TMB substrate and analyzed by spectrophotometer at OD 450 to 630 nm.

[0192] As shown in Figures 2A to 2C, all bispecific antibodies were able to bind to both human BCMA and 4-1BB proteins in a dose-dependent manner. The EC50 (nM) values are summarized in Table 13.

[0193]

Table 13

[0194]

[0195]

[0196] (2) Cell Surface Binding Test by Flow Cytometry

[0197] To evaluate antigen-binding properties, the binding of candidate antibodies to BCMA-expressing cells was analyzed by FACS. Briefly, CHOK1 expressing human BCMA (CHOK1-hBCMA) or H929 expressing endogenous BCMA cells were treated with 100 nM of the designated antibody for 1 hour at 4°C. CHOK1 cells were used as the BCMA-negative control group. After washing with FACS buffer (1% (w / v) BSA in PBS), the cells were incubated with FITC anti-human IgG antibody for 1 hour at 4°C and then subjected to FACS analysis. As shown in Figures 2D to 2F, the anti-BCMAx4-1BB antibody bound to CHOK1-hBCMA and H929 cell lines expressing BCMA, but not to BCMA-negative CHOK1. These results indicate that the anti-BCMA / anti-4-1BB bispecific antibody can specifically bind to the tumor-targeting antigen (BCMA). The results of Figures 2D to 2F were quantified and summarized in Table 14.

[0198] [Table 14]

[0199]

[0200] 3-3. In Vitro 4-1BB Activation Assay (Reporter Bioassay) of Anti-BCMA / anti-4-1BB Bispecific Antibody

[0201] In this assay, the GloResponse NFκB-luc2 / 4-1BB Jurkat cell line, which was genetically modified to stably express human 4-1BB and luciferase downstream of the response element, was used as the effector cell, and cancer cells expressing or not expressing BCMA were used as the target cells. Briefly, CHOK1-hBCMA (BCMA-positive, 2.5×10 TM ) or CHOK1 (BCMA-negative, 2.5×10 4 ) was placed in white 96-well assay plates containing 100 μl of medium each. The plates were incubated overnight in a humidified incubator at 37°C with 5% CO2. After overnight incubation, 100 μl of the medium was removed and 25 μl of the assay medium (RPMI1640 containing 1% (v / v) FBS) was dispensed into the pre-plated target cells. For suspension cells, H929 (BCMA-positive, 2.5×10 4 ) or Jurkat (BCMA-negative, 2.5×10 5 ) was placed in white 96-well assay plates containing 25 μl of the assay medium. 25 μl of each bispecific antibody (diluted 5-fold from 50 nM or 4-fold from 200 nM) was added to the plates. Harvest GLORESPONSE 5 ) was added to the plates. Harvest GLORESPONSE TMThe NFκB-luc2 / 4-1BB Jurkat cell line was resuspended with the assay medium. Dispense 25 μl of GLORESPONSE TM NFκB-luc2 / 4-1BB Jurkat cell line such that each well was seeded with 2.5×10 4 cells. Incubate in a humidified incubator at 37 °C with 5% CO2. During incubation, reconstitute the BIO-GLO TM reagent according to the manufacturer's instructions. After 6 hours of incubation, add 75 parts of BIO-GLO TM reagent per well to the assay plate. Wait for 5 minutes and measure luminescence using a microplate reader. Evaluate the four-parameter logistic curve using GraphPad software. The test results using CHOK1-hBCMA, CHOK1, H929, and Jurkat cells are shown in Figures 3A to 3D, respectively.

[0202] As shown in Figures 3A to 3D, compared with the individual application of anti-4-1BB or crosslinking of 4-1BB, the tested BCMAx4-1BB bispecific antibody showed stronger 4-1BB signal activation in the presence of the tumor antigen (BCMA). Moreover, BMUR, as an agonistic anti-4-1BB monoclonal antibody (reference antibody), had an in vitro 4-1BB activation effect in the absence of BCMA (Figures 3B and 3D).

[0203] This means that the anti-BCMA / anti-4-1BB antibody can only act specifically in the presence of BCMA-expressing cancer cells and not in the presence of an agonistic anti-4-1BB antibody. The results of Figures 3A to 3D were quantified and summarized in Tables 15 and 16 (Table 15: CHOK1-hBCMA (EC50, nM), Table 16: H929 (EC50, nM)).

[0204]

Table 15

[0205] ×AB41 ×41B01 ×41B02 BMUR 5A6(NA) 0.0397 0.0616 0.0413 0.1025 5D5(NA) 0.0426 0.0691 0.0314 5B5(NA) 0.0741 0.0316 0.003

[0206]

Table 16

[0207] ×41B01 ×41B02 BMUR 5A6(NA) 3.164 14.34 0.069 5D5(NA) 5.354 10.92 5B5(NA) 5.756 12.11

[0208] 3-4. In vitro 4-1BB activation test of anti-BCMA / anti-4-1BB bispecific antibody (human PBMC-based test)

[0209] In the presence of anti-human CD3 antibody and the antibody to be tested, human PBMCs were co-cultured with the CHOK1 cell line (not expressing human BCMA) or gene-modified CHOK1-hBCMA (stably expressing human BCMA). Briefly, PBMCs were seeded at 3×10 per well 4Cells were seeded, and CHOK1 or CHOK1-hBCMA was co-seeded at 1×10 4 cells per well. Bispecific antibodies (diluted 4-fold starting from 20 nM) and monoclonal antibodies (diluted 4-fold starting from 26.67 nM) were added to the wells of the plate. After incubation, the concentration of IFN-γ secreted in the supernatant was measured using a Human IFN-γ Quantikine ELISA Kit (R&D Systems, SIF50).

[0210] As shown in FIGS. 4A to 4C, the anti-BCMA / anti-4-1BB antibody induced more cytokine release than the monoclonal antibody or BMUR (agonistic anti-4-1BB monoclonal antibody).

[0211] 3-5. Comparison of target protein binding activity (wild type vs. mutant)

[0212] To stabilize the anti-BCMA / anti-4-1BB bispecific antibody, one or more point mutations were introduced into the amino acid sequences in the CDRs of the heavy or light chains of the antibody as shown in Table 4. To evaluate the antigen-binding activity, the candidate antibodies (wild-type clones and mutant clones) were subjected to a dual antigen capture ELISA (DACE) test as performed in Example 3-2(1). The results obtained are shown in FIGS. 5A and 5B.

[0213] As shown in FIGS. 5A and 5B, all bispecific antibodies were able to bind to both human BCMA and 4-1BB proteins in a dose-dependent manner. And several mutants were found to improve the target protein binding. Among these mutants, 5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12 showed excellent antigen-binding activity compared to the wild-type clone (FIG. 5C). To evaluate the native antigen-binding characteristics, as performed in Example 2-2(2), the binding of 5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12 to mammalian-expressed BCMA was analyzed by FACS. As shown in FIG. 5D, 5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12 showed increased native antigen-binding activity compared to the wild type. The results of the protein-binding test and the cell-binding test were quantified and summarized in Tables 17 and 18 (Table 17: Protein Binding (EC50, nM)).

[0214]

Table 17

[0215]

[0216]

[0217]

Table 18

[0218] Antibody MFI MFI of mutant / MFI of wild type × 100 5D5M4(NA)×41B01 M12 64.8 172.8％ 5A6M6(NA)×41B01 M12 102 101.0％

[0219] 3-6. Binding Affinity of Mutant Bispecific Antibodies to Target Proteins BCMA and 4-1BB (SPR)

[0220] In the SPR assay, on a protein A chip immobilized by amine coupling with anti-BCMA / anti-4-1BB (5D5M4(NA)×41B01 M12 or 5A6M6(NA)×41B01 M12), the anti-BCMA / anti-4-1BB bispecific antibodies obtained from Examples 3 to 5 were respectively captured on flow cells 2, 3, and 4, and flow cell 1 was maintained as a reference. Recombinant human BCMA or human 4-1BB protein flowed over the chip at a concentration of 100 nM to 6.25 nM of human BCMA or 250 nM to 15.625 nM of human 4-1BB and 0.78 nM at 30 μl / min for 300 seconds, followed by a dissociation phase of 400 seconds. Regeneration was performed with 10 mM glycine-HCl (pH 2.0). The resulting results are shown in Tables 19 and 20 below. As shown in Tables 19 and 20, 5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12 showed high affinity for BCMA and 4-1BB (Table 19: Affinity measurement results of 5D5M4(NA)×41B01 M12, Table 20: Affinity measurement results of 5A6M6(NA)×41B01 M12).

[0221]

Table 19

[0222] Target <![CDATA[Ka(×10 5 , 1 / Ms)]]> <![CDATA[Kd(×10 -2 , 1 / s)]]> <![CDATA[K D (×10 -8 ,M)]]> <![CDATA[R max (RU, target = 12.5 RU)]]> hBCMA 40.69 6.503 1.602 13.18 h4-1BB 2.361 9.461 4.009 53.78

[0223]

Table 20

[0224] Target <![CDATA[Ka(×10 5 , 1 / Ms)]]> <![CDATA[Kd(×10 -2 , 1 / s)]]> <![CDATA[K D (×10 -8 ,M)]]> <![CDATA[R max (RU, target = 12.5 RU)]]> hBCMA 5.272 1.186 2.257 13.42 h4-1BB 2.379 9.732 4.102 52.61

[0225] 3-7. In Vitro 4-1BB Activation Test of Mutant Bispecific Antibodies

[0226] The in vitro 4-1BB activity of the candidate antibodies was analyzed using the Promega kit system as in Example 2-3.

[0227] As shown in Figures 6A to 6C, compared with the wild form, the mutant form of the anti-BCMA / anti-4-1BB bispecific antibody showed higher potency in BCMA-positive cancer cells, while none of the clones activated 4-1BB signaling in BCMA-negative cancer cells (Jurkat) (Table 21: In vitro 4-1BB activation results (EC50, nM)). Therefore, 5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12 showed improved target-mediated 4-1BB activation.

[0228]

Table 21

[0229] Antibody name H929 MM1S 5D5WT(NA)×41B01 M12 0.629 2.66 5D5M4(NA)×41B01 M12 0.377 2.41 5A6WT(NA)×41B01 M12 0.459 2.26 5A6M6(NA)×41B01 M12 0.165 1.98

[0230] 3-8. Monkey cross-reactivity test of mutant bispecific antibodies

[0231] To evaluate cross-reactivity, ELISA tests were performed on the candidate antibodies (5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12). Briefly, macaque BCMA-Fc protein (50 ng / well) was coated on microtiter plates overnight at 4 °C and then blocked with 200 μl / well of PBSB (1% (w / v) BSA in PBS). 5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12 diluted 3-fold starting from 100M were added to each well and incubated at 37 °C for 1 hour. The plates were washed with PBST (0.05% (v / v) Tween 20 in PBS) and then incubated with macaque 4-1BB-His protein (80 ng / well) at 37 °C for 1 hour. The plates were washed with PBST (0.05% (v / v) Tween 20 in PBS) and then incubated with anti-his antibody conjugated with HRP at 37 °C for 1 hour. After washing, the plates were developed with TMB and analyzed by spectrophotometer at 450 to 630 nm. As Figure 7 shown, 5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12 bound to macaque BCMA and 4-1BB simultaneously in a dose-dependent manner (Table 22: Protein binding (EC50, nM)).

[0232]

Table 22

[0233] Antibody EC50 (nM) 5D5M4(NA)×41B01 M12 0.926 5A6M6(NA)×41B01 M12 1.66

[0234] 3-9. Inhibition of tumor growth by mutant bispecific antibodies in humanized NOG mice carrying H929

[0235] The anti-BCMA / anti-4-1BB antibody's anti-tumor effect was tested in humanized NOG mice injected with H929 cells. Briefly, H929 cells were injected subcutaneously into the right flanks of 74 non-irradiated female animals by subcutaneous injection of NCI-H929 cells (5×10 6 ). On day 11, purified T cells (10×10 6 ) from three donors were intraperitoneally injected into the mice. When the tumors reached an average volume of 154 mm 3 (day 12), the animals were randomly divided into four groups of 14 mice each. The mice were intravenously injected with Q3D five times (injecting the antibody five times every three days) with the following antibodies: human IgG isotype control group (7.5 mg / kg_ no T cell injection: isotype control group_ 7.5 mpk_ no T cell), human IgG isotype control group (7.5 mg / kg: isotype control group_ 7.5 mpk), anti-BCMA / anti-4-1BB bispecific antibody (5D5M4(NA)×41B01 M12, 10 mg / kg), and anti-BCMA / anti-4-1BB bispecific antibody (5A6M6(NA)×41B01 M12, 10 mg / kg). Tumor volumes were monitored twice weekly by caliper measurement during the trial, and the results obtained are shown in Figures 8A to 8C. As shown in Figures 8A and 8B, D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12 showed significant anti-tumor effects. The tumor growth inhibition rate (TGI%) of D5M4(NA)×41B01 M12 was 44.8%, and that of 5A6M6(NA)×41B01 M12 was 49.4%. Therefore, the efficacy of the two bispecific antibodies was similar.

[0236] 3-10. Analysis of tumor-infiltrating lymphocytes (TILs)

[0237] To evaluate TILs, formalin-fixed and paraffin-embedded tumor tissue sections from hPBMC-transplanted mice carrying H929 were immunostained with anti-CD45 antibody (human leukocyte marker) and anti-CD8 antibody (human cytotoxic T lymphocyte marker). Immunohistochemical techniques were performed by applying an avidin-biotin detection kit. The results obtained are shown in Figures 9A and 9B. As shown in Figures 9A and 9B, compared with the tumor periphery, the anti-BCMA / anti-4-1BB bispecific antibody effectively enhanced the infiltration of immune cells, including CD45+ cells and CD8+ T cells, into the tumor tissue. These results indicate that CD45+ and CD8+ cells increased in the anti-BCMA / anti-4-1BB bispecific treatment group, especially in the tumor compartment.

[0238] 3-11. Pharmacokinetics of Anti-BCMA / Anti-4-1BB Bispecific Antibody in Cynomolgus Monkeys

[0239] Inject 10 mg / kg of anti-BCMA / anti-4-1BB bispecific antibody (5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12) into the great saphenous vein of cynomolgus monkeys. Collect blood samples from each animal via the femoral vein at predetermined intervals of 0.05 to 504 hours before and after administration of the drug. Centrifuge the blood samples to obtain serum. Measure the concentrations of 5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12 in cynomolgus monkey serum using enzyme-linked immunosorbent assay (ELISA). Coat a 96-well plate with human BCMA-Fc protein and then block it with blocking buffer. After that, wash the plate, add standards, quality control samples, and study samples to the plate, and then incubate at 37 °C for 2 hours. Then wash the plate again and incubate it with human 4-1BBhis protein. After washing, detect the bound molecules with an anti-His labeled antibody conjugated with horseradish peroxidase. Develop the plate with TMB substrate and analyze it by spectrophotometer at OD 450 to 650 nm. Determine the concentrations from serum samples using a 4-parameter algorithm from a standard curve prepared with known amounts of 5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12 in appropriate cynomolgus monkey serum. The standard curve ranges for 5D5M4(NA)×41B01 M12 and 5A6M6(NA)×41B01 M12 are from 46 ng / mL to 300,000 ng / mL, and the lower limit of quantitation (LLOQ) is defined as 300 ng / mL. Estimate pharmacokinetic parameters using WinNonlin software (Phoenix WinNonlin 8.0) by non-compartmental model. The results obtained are shown in Figure 10A and Figure 10B. The results of Figure 10A and Figure 10B are quantified and summarized in Table 23 and Table 24, respectively (WinNonlin settings, NCA, linear trapezoidal linear interpolation method, intravenous bolus, half-life calculation time: 24 hours to 240 hours). The results indicate that 5D5M4(NA)×41B01 M12 even has better PK characteristics than 5A6M6(NA)×41B01 M12.

[0240]

Table 23

[0241]

[0242]

Table 24

[0243]

[0244] 3-12. Anti-BCMA / 4-1BB Bispecific Antibody Inhibits Tumor Growth in 4-1BB Knock-in Mice Bearing MC38 Overexpressing BCMA

[0245] The in vivo antitumor efficacy of the anti-BCMA / anti-4-1BB bispecific antibody was evaluated using a human 4-1BB knock-in mouse system bearing MC38 overexpressing BCMA (CRO: Biocytogen). Briefly, MC38-hBCMA (5×10 6 ) cells were inoculated subcutaneously into the right flanks of non-irradiated female animals. On day 7, when the average tumor volume reached 110 mm 3 , the mice were randomly divided into three groups (n = 8 / group). Then, a control isotype antibody (hIgG1) at 7.5 mg / kg and the anti-BCMA / anti-4-1BB bispecific antibody (5D5M4(NA)×41B01 M12) at 2 or 0.4 mg / kg were administered intravenously eight times according to a Q3D (once every three days) dosing schedule. To obtain tumor growth results, tumor volume was monitored twice a week by caliper measurement.

[0246] The results obtained are shown in Figure 11 and Table 25. Table 25 is a summary of the results of tumor growth inhibition by 5D5M4(NA)×41B01 M12 in 4-1BB knock-in mice bearing MC38-hBCMA ((*P<0.05; **P<0.01). In Table 25, Q3D refers to the dosing frequency of once every three days.

[0247]

Table 25

[0248]

[0249] As Figure 11 and Table 25 show, 5D5M4(NA)×41B01 M12 demonstrated antitumor efficacy. The tumor growth inhibition rate (TGI%) of G2 (5D5M4(NA)×41B01 M12, 2 mg / kg) was approximately 62.2%, and that of G3 (5D5M4(NA)×41B01 M12, 0.4 mg / kg) was approximately 47.4%. Overall, the anti-BCMA / anti-4-1BB bispecific antibody showed excellent antitumor efficacy in human BCMA / MC38 tumors. Sequence Listing <110> ABL BIO INC. <120> Anti-BCMA / anti-4-1BB Bispecific Antibody and Its Use <130> GN-63722-PCT <160> 130 <170> KoPatentIn 3.0 <210> 1 <211> 184 <212> PRT <213> Artificial Sequence <220> <223> Human BCMA (NP_001183.2) <400> 1 Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser 1 5 10 15 Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr 20 25 30 Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser 35 40 45 Val Lys Gly Thr Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu 50 55 60 Ile Ile Ser Leu Ala Val Phe Val Leu Met Phe Leu Leu Arg Lys Ile 65 70 75 80 Asn Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu 85 90 95 Leu Gly Met Ala Asn Ile Asp Leu Glu Lys Ser Arg Thr Gly Asp Glu 100 105 110 Ile Ile Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys 115 120 125 Glu Asp Cys Ile Lys Ser Lys Pro Lys Val Asp Ser Asp His Cys Phe 130 135 140 Pro Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys 145 150 155 160 Thr Asn Asp Tyr Cys Lys Ser Leu Pro Ala Ala Leu Ser Ala Thr Glu 165 170 175 Ile Glu Lys Ser Ile Ser Ala Arg 180 <210> 2 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain variable region of anti-BCMA antibody B58 <400> 2 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Tyr Pro Ser Asp Ser Ser Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro Phe Ala Asn Lys Tyr Arg Gln Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 3 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Heavy Chain Variable Region of Anti-BCMA Antibody 5B5 <400> 3 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly His 20 25 30 Tyr Trp Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Val Ser Gly Ser Gly Gly Asp Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly His Ser Val Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 4 <211> 116 <212> PRT <213> Artificial Sequence <220> <223> Heavy Chain Variable Region of Anti - BCMA Antibody 5D5 <400> 4 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Asp Ser Ser Gly Ser Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Glu His Gly Leu Phe Asp Ser Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser 115 <210> 5 <211> 117 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain variable region of anti-BCMA antibody 5A6 <400> 5 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Asp Ser Asp Asp Phe Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 6 <211> 111 <212> PRT <213> Artificial sequence <220> <223> Light chain variable region of anti - BCMA antibody B58 <400> 6 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 7 <211> 108 <212> PRT <213> Artificial sequence <220> <223> Light chain variable region of anti - BCMA antibody 5B5 <400> 7 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly Ile Asp Ser Tyr 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Ser Trp Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 8 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of anti - BCMA antibody 5D5 <400> 8 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Asp Asp 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 9 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of anti - BCMA antibody 5A6 <400> 9 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 <210> 10 <211> 5 <212> PRT <213> Synthetic Sequence <220> <223> Heavy Chain CDR1 of Anti-BCMA Antibody <400> 10 Asn Tyr Asp Met Ser 1 5 <210> 11 <211> 5 <212> PRT <213> Synthetic Sequence <220> <223> Heavy Chain CDR1 of Anti-BCMA Antibody <400> 11 Gly His Tyr Trp Ser 1 5 <210> 12 <211> 5 <212> PRT <213> Synthetic Sequence <220> <223> Heavy Chain CDR1 of Anti-BCMA Antibody <400> 12 Asp Tyr Gly Leu Ser 1 5 <210> 13 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 of anti - BCMA antibody <400> 13 Asn Tyr Gly Val His 1 5 <210> 14 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 of anti - BCMA antibody <400> 14 Trp Ile Tyr Pro Ser Asp Ser Ser Ile Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 15 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 of anti - BCMA antibody <400> 15 Thr Val Ser Gly Ser Gly Gly Asp Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 16 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR4 of anti - BCMA antibody <400> 16 Leu Ile Asp Ser Ser Gly Ser Ser Thr Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 17 <211> 16 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR5 of anti - BCMA antibody <400> 17 Tyr Ile Ser Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser Leu Lys Ser 1 5 10 15 <210> 18 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 of anti - BCMA antibody <400> 18 Arg Gly Pro Phe Ala Asn Lys Tyr Arg Gln Phe Asp Tyr 1 5 10 <210> 19 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 of anti - BCMA antibody <400> 19 Arg Gly His Ser Val Met Asp Val 1 5 <210> 20 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 of anti - BCMA antibody <400> 20 Lys Glu His Gly Leu Phe Asp Ser 1 5 <210> 21 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 of anti - BCMA antibody <400> 21 Arg Asp Ser Asp Asp Phe Gly Phe Asp Tyr 1 5 10 <210> 22 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 of anti - BCMA antibody <400> 22 Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn Ser Val Ser 1 5 10 <210> 23 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 of anti - BCMA antibody <400> 23 Arg Ala Ser Gln Gly Ile Asp Ser Tyr Val Ala 1 5 10 <210> 24 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 of anti - BCMA antibody <400> 24 Lys Ala Ser Gln Asp Ile Asp Asp Asp Ile Asn 1 5 10 <210> 25 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 of anti-BCMA antibody <400> 25 Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Val Asn 1 5 10 <210> 26 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR2 of anti-BCMA antibody <400> 26 Ala Asp Ser Lys Arg Pro Ser 1 5 <210> 27 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR2 of anti-BCMA antibody <400> 27 Asp Ala Ser Leu Arg Ala Thr 1 5 <210> 28 <211> 7 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR2 of anti-BCMA antibody <400> 28 Asp His Ser Lys Arg Pro Thr 1 5 <210> 29 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 of anti-BCMA antibody <400> 29 Gly Ser Trp Asp Tyr Ser Leu Ser Gly Tyr Val 1 5 10 <210> 30 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 of anti-BCMA antibody <400> 30 Gln Gln Tyr Asn Ser Trp Pro Ile 1 5 <210> 31 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 of anti-BCMA antibody <400> 31 Gln Gln Ser Leu Arg Thr Pro Ile 1 5 <210> 32 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 of anti-BCMA antibody <400> 32 Gln Ser Tyr Asp Ser Ser Thr Val 1 5 <210> 33 <211> 363 <212> DNA <213> Artificial sequence <220> <223> Polynucleotide encoding the heavy chain variable region of anti-BCMA antibody B58 <400> 33 gaggtgcagc tgctggagtc cggcggcggc ctggtgcagc ccggcggctc cctgcggctg 60 tcctgcgccg cctccggctt caccttctcc aactacgaca tgtcctgggt gcggcaggcc 120 cccggcaagg gcctggagtg ggtgtcctgg atctacccct ccgactcctc catctactac 180 gccgactccg tgaagggccg gttcaccatc tcccgggaca actccaagaa caccctgtac 240 ctgcagatga actccctgcg ggccgaggac accgccgtgt actactgcgc ccggggcccc 300 ttcgccaaca agtaccggca gttcgactac tggggccagg gcaccctggt gaccgtgtcc 360 tcc 363 <210> 34 <211> 348 <212> DNA <213> Artificial sequence <220> <223> Polynucleotide encoding the heavy chain variable region of anti-BCMA antibody 5B5 <400> 34 gaggtccagt tgttggaaag cggtggtggt ttggttcaac caggcggtag cctcagactc 60 tcctgcgctg cctccgggtt tactttctca gggcactatt ggtcctgggt ccgtcaggca 120 cctggtaagg gacttgaatg ggtatctaca gtttccggct ccggtggaga cactttttat 180 gcagacagcg ttaaggggcg ctttactata agtcgtgata attccaaaaa tactctctat 240 ctccaaatga actccctccg tgctgaagat accgctgtgt actactgcgc tcgaggtcac 300 tcagtcatgg acgtatgggg gcagggcaca ctggtgaccg tatcttcc 348 <210> 35 <211> 348 <212> DNA <213> Artificial sequence <220> <223> Polynucleotide encoding the heavy chain variable region of anti - BCMA antibody 5D5 <400> 35 gaggtccagt tgttggaaag cggtggtggt ttggttcaac caggcggtag cctcagactc 60 tcctgcgctg cctccgggtt tactttcagc gattatggac tgtcatgggt gcgtcaagct 120 cctggaaaag ggttggagtg ggtgagcctt atagacagca gtgggagtag cactttctac 180 gctgatagcg tgaaaggtag atttactatc tctcgtgata actccaagaa tacattgtat 240 cttcaaatga acagtctgag agctgaggac actgccgttt attattgtgc aaaggaacat 300 ggtcttttcg actcatgggg acagggaaca ctggtgaccg tatcttcc 348 <210> 36 <211> 351 <212> DNA <213> Artificial sequence <220> <223> Polynucleotide encoding the heavy chain variable region of anti - BCMA antibody 5A6 <400> 36 gaggtccagt tgttggaaag cggtggtggt ttggttcaac caggcggtag cctcagactc 60 tcctgcgctg cctccgggtt tactttcagt aactatggag tacattgggt cagacaagcc 120 cccggcaaag gtcttgagtg ggtcagctac atttcctata gcggaggaac ttactataac 180 ccctcactta aaagccgctt cactatatca cgcgataata gcaagaacac cctctatctt 240 caaatgaact ctctgcgagc agaagacacc gccgtgtact attgcgctag agatagcgac 300 gacttcgggt tcgattattg gggacagggc acactggtga ccgtatcttc c 351 <210> 37 <211> 333 <212> DNA <213> Artificial sequence <220> <223> Polynucleotide encoding the light chain variable region of anti-BCMA antibody B58 <400> 37 cagtccgtgc tgacccagcc cccctccgcc tccggcaccc ccggccagcg ggtgaccatc 60 tcctgctccg gctcctcctc caacatcggc tccaactccg tgtcctggta ccagcagctg 120 cccggcaccg cccccaagct gctgatctac gccgactcca agcggccctc cggcgtgccc 180 gaccggttct ccggctccaa gtccggcacc tccgcctccc tggccatctc cggcctgcgg 240 tccgaggacg aggccgacta ctactgcggc tcctgggact actccctgtc cggctacgtg 300 ttcggcggcg gcaccaagct gaccgtgctg ggc 333 <210> 38 <211> 324 <212> DNA <213> Artificial sequence <220> <223> Polynucleotide encoding the light chain variable region of anti-BCMA antibody 5B5 <400> 38 gaaatagtac ttacacagtc ccctggaact ctgtcacttt cccctgggga gcgagctaca 60 ctgagctgtc gtgccagcca gggcattgat agttacgtgg catggtatca gcagaagccc 120 ggccaggctc caaggctgtt gatttacgat gcatcattgc gagccaccgg aatacctgac 180 cgtttctccg gcagtggctc cgggacagac tttaccctta ctatctcacg tctcgagcca 240 gaagactttg cagtgtatta ttgccaacaa tacaacagtt ggcctataac cttcggccag 300 gggacaaaac tggagataaa gcgt 324 <210> 39 <211> 324 <212> DNA <213> Artificial sequence <220> <223> Polynucleotide encoding the light chain variable region of anti-BCMA antibody 5D5 <400> 39 gaaatagtac ttacacagtc ccctggaact ctgtcacttt cccctgggga gcgagctaca 60 ctgagctgta aagcctcaca ggacatagac gatgacatca actggtatca gcaaaaacct 120 ggacaagctc cacgtctcct gatttacgat gcatcactta gggccacagg aattcctgat 180 aggttctctg gtagcggcag tggaaccgat tttaccctca caatatctcg acttgaacca 240 gaagatttcg ccgtttatta ctgtcagcag tcccttagga cccccattac attcggccag 300 gggacaaaac tggagataaa gcgt 324 <210> 40 <211> 321 <212> DNA <213> Artificial sequence <220> <223> Polynucleotide encoding the light chain variable region of anti - BCMA antibody 5A6 <400> 40 caatctgtcc ttacacagcc tccaagcgca agcggcaccc ccggacaaag ggtaacaata 60 tcatgccagg gggattctct tcgcagctat tacgtgaatt ggtatcagca gttgcccggc 120 actgccccca aacttttgat atacgatcac tccaagcgcc ccacaggagt gcctgatagg 180 ttcagcggat ctaagtctgg aacatccgct tctttggcaa tctctgggct gcgaagtgag 240 gacgaggcag actactactg ccagtcttat gacagctcta ctgtagtctt cggaggcggt 300 acaaaactga cagtgctcgg t 321 <210> 41 <211> 108 <212> PRT <213> Artificial sequence <220> <223> Light chain variable region of 5D5 M1 <400> 41 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Asn Asp 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 42 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of 5D5 M2 <400> 42 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Glu Asp 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 43 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of 5D5 M3 <400> 43 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Ala Asp 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 44 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of 5D5 M4 <400> 44 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Asp Ala 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 45 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of 5D5 M5 <400> 45 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Asp Glu 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 46 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Light chain variable region of 5A6 M1 <400> 46 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Glu Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 <210> 47 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Light chain variable region of 5A6 M2 <400> 47 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ala Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 <210> 48 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of 5A6 M3 <400> 48 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Glu Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 <210> 49 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of 5A6 M4 <400> 49 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ala Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 <210> 50 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of 5A6 M5 <400> 50 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Glu Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Glu Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 <210> 51 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of 5A6 M6 <400> 51 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Glu Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ala Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 <210> 52 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Light chain variable region of 5A6 M7 <400> 52 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ala Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Glu Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 <210> 53 <211> 107 <212> PRT <213> Artificial sequence <220> <223> Light chain variable region of 5A6 M8 <400> 53 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ala Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ala Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 <210> 54 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR1 of 5D5 M1 <400> 54 Lys Ala Ser Gln Asp Ile Asp Asn Asp Ile Asn 1 5 10 <210> 55 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR1 of 5D5 M2 <400> 55 Lys Ala Ser Gln Asp Ile Asp Glu Asp Ile Asn 1 5 10 <210> 56 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 of 5D5 M3 <400> 56 Lys Ala Ser Gln Asp Ile Asp Ala Asp Ile Asn 1 5 10 <210> 57 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 of 5D5 M4 <400> 57 Lys Ala Ser Gln Asp Ile Asp Asp Ala Ile Asn 1 5 10 <210> 58 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 of 5D5 M5 <400> 58 Lys Ala Ser Gln Asp Ile Asp Asp Glu Ile Asn 1 5 10 <210> 59 <211> 11 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 of 5A6 M1 <400> 59 Gln Gly Glu Ser Leu Arg Ser Tyr Tyr Val Asn 1 5 10 <210> 60 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR1 of 5A6 M2 <400> 60 Gln Gly Asp Ala Leu Arg Ser Tyr Tyr Val Asn 1 5 10 <210> 61 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR1 of 5A6 M5 and 5A6 M6 <400> 61 Gln Gly Glu Ser Leu Arg Ser Tyr Tyr Val Asn 1 5 10 <210> 62 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR1 of 5D5 M7 and 5D5 M8 <400> 62 Gln Gly Asp Ala Leu Arg Ser Tyr Tyr Val Asn 1 5 10 <210> 63 <211> 8 <212> PRT <213> Artificial Sequence <220> <223> Light chain CDR3 of 5A6 M3, 5A6 M5 and 5A6 M7 <400> 63 Gln Ser Tyr Glu Ser Ser Thr Val 1 5 <210> 64 <211> 8 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR3 of 5A6 M4, 5A6 M6 and 5A6 M8 <400> 64 Gln Ser Tyr Asp Ala Ser Thr Val 1 5 <210> 65 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Heavy chain variable region of anti - 4 - 1BB antibody 41B01 <400> 65 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Gly Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 66 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain variable region of anti-4-1BB antibody 41B01 M4 <400> 66 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ala Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 67 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain variable region of anti-4-1BB antibody 41B01 M11 <400> 67 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ala Gln Arg Gln Ser Met Arg Glu Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 68 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Heavy chain variable region of anti-4-1BB antibody 41B01 M12 <400> 68 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ala Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 69 <211> 121 <212> PRT <213> Artificial sequence <220> <223> Heavy chain variable region of anti-4-1BB antibody 41B01 M13 <400> 69 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Asp Ala Gln Arg Gln Ser Met Arg Glu Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 70 <211> 127 <212> PRT <213> Artificial sequence <220> <223> Heavy chain variable region of anti-4-1BB antibody 41B02 <400> 70 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr Pro Asp Asp Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr Tyr Cys 85 90 95 Ala Lys His Gly Gly Gln Lys Pro Thr Thr Lys Ser Ser Ser Ala Tyr 100 105 110 Gly Met Asp Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 71 <211> 127 <212> PRT <213> Artificial sequence <220> <223> Heavy chain variable region of anti-4-1BB antibody 41B02 M1 <400> 71 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr Pro Asp Asp Gly Asn Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys His Gly Gly Gln Lys Pro Thr Thr Lys Ser Ser Ser Ala Tyr 100 105 110 Gly Met Asp Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 115 120 125 <210> 72 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> Heavy chain variable region of anti-4-1BB antibody AB41 <400> 72 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Ile Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Ser Tyr 20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asn Pro Gly Asn Gly His Thr Asn Tyr Asn Glu Lys Phe 50 55 60 Lys Ser Arg Ala Thr Leu Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr 65 70 75 80 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ser Phe Thr Thr Ala Arg Ala Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ser 115 <210> 73 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of anti-4-1BB antibody 41B01 <400> 73 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 74 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of anti - 4 - 1BB antibody 41B01 M4 <400> 74 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 75 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of anti - 4 - 1BB antibody 41B01 M11 <400> 75 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 76 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of anti-4-1BB antibody 41B01 M12 <400> 76 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 77 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of anti-4-1BB antibody 41B01 M13 <400> 77 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 78 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of anti-4-1BB antibody 41B02 <400> 78 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 79 <211> 111 <212> PRT <213> Artificial Sequence <220> <223> Light chain variable region of anti-4-1BB antibody 41B02 M1 <400> 79 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly 100 105 110 <210> 80 <211> 108 <212> PRT <213> Artificial sequence <220> <223> Light chain variable region of anti-4-1BB antibody AB41 <400> 80 Asp Ile Val Met Thr Gln Ser Pro Ala Phe Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Ser Asp Tyr 20 25 30 Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ala Pro Lys Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Asp Gly His Ser Phe Pro Pro 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg 100 105 <210> 81 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 of 41B01, 41B01 M4, 41B01 M11, 41B01 M12 and 41B01 M13 <400> 81 Ser Tyr Asp Met Ser 1 5 <210> 82 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 of 41B02 and 41B02 M1 <400> 82 Gly Tyr Asp Met Ser 1 5 <210> 83 <211> 5 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR1 of AB41 <400> 83 Ser Tyr Trp Met His 1 5 <210> 84 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 of 41B01, 41B01 M4, 41B01 M11, 41B01 M12 and 41B01 M13 <400> 84 Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 85 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 of 41B02 and 41B02 M1 <400> 85 Val Ile Tyr Pro Asp Asp Gly Asn Thr Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> 86 <211> 17 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR2 of AB41 <400> 86 Glu Ile Asn Pro Gly Asn Gly His Thr Asn Tyr Asn Glu Lys Phe Lys 1 5 10 15 Ser <210> 87 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 of 41B01 <400> 87 Asp Gly Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr 1 5 10 <210> 88 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 of 41B01 M4 and 41B01 M12 <400> 88 Asp Ala Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr 1 5 10 <210> 89 <211> 12 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 of 41B01 M11 and 41B01 M13 <400> 89 Asp Ala Gln Arg Gln Ser Met Arg Glu Phe Asp Tyr 1 5 10 <210> 90 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 of 41B02 and 41B02 M1 <400> 90 His Gly Gly Gln Lys Pro Thr Thr Lys Ser Ser Ser Ala Tyr Gly Met 1 5 10 15 Asp Gly <210> 91 <211> 10 <212> PRT <213> Artificial sequence <220> <223> Heavy chain CDR3 of AB41 <400> 91 Ser Phe Thr Thr Ala Arg Ala Phe Ala Tyr 1 5 10 <210> 92 <211> 13 <212> PRT <213> Artificial sequence <220> <223> Light chain CDR1 of 41B01, 41B01 M4, 41B01 M11, 41B01 M12, 41B01 M13, 41B02 and 41B02 M1 <400> 92 Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn Tyr Val Thr 1 5 10 <210> 93 <211> 11 <212> PRT <213> Artificial sequence <220> <223> CDR1 of the light chain of AB41 <400> 93 Arg Ala Ser Gln Thr Ile Ser Asp Tyr Leu His 1 5 10 <210> 94 <211> 7 <212> PRT <213> Artificial sequence <220> <223> CDR2 of the light chain of 41B01, 41B01 M4, 41B01 M11, 41B01 M12, 41B01 M13, 41B02 and 41B02 M1 <400> 94 Ala Asp Ser His Arg Pro Ser 1 5 <210> 95 <211> 7 <212> PRT <213> Artificial sequence <220> <223> CDR2 of the light chain of AB41 <400> 95 Tyr Ala Ser Gln Ser Ile Ser 1 5 <210> 96 <211> 11 <212> PRT <213> Artificial sequence <220> <223> CDR3 of the light chain of 41B01, 41B01 M4, 41B01 M11, 41B01 M12, 41B01 M13, 41B02 and 41B02 M1 <400> 96 Ala Thr Trp Asp Tyr Ser Leu Ser Gly Tyr Val 1 5 10 <210> 97 <211> 9 <212> PRT <213> Artificial sequence <220> <223> CDR3 of the light chain of AB41 <400> 97 Gln Asp Gly His Ser Phe Pro Pro Thr 1 5 <210> 98 <211> 20 <212> PRT <213> Artificial sequence <220> <223> Linker (GGGGS)4 <400> 98 Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly 1 5 10 15 Gly Gly Gly Ser 20 <210> 99 <211> 18 <212> PRT <213> Artificial sequence <220> <223> Linker (GS)9 <400> 99 Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 1 5 10 15 Gly Ser <210> 100 <211> 451 <212> PRT <213> Artificial sequence <220> <223> BCMA - heavy chain of B58 antibody <400> 100 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Trp Ile Tyr Pro Ser Asp Ser Ser Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly Pro Phe Ala Asn Lys Tyr Arg Gln Phe Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 115 120 125 Val Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala 130 135 140 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val 145 150 155 160 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala 165 170 175 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val 180 185 190 Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His 195 200 205 Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys 210 215 220 Asp Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly 225 230 235 240 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 245 250 255 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His 260 265 270 Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val 275 280 285 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr 290 295 300 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly 305 310 315 320 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile 325 330 335 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 340 345 350 Tyr Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser 355 360 365 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 370 375 380 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 385 390 395 400 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val 405 410 415 Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met 420 425 430 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser 435 440 445 Pro Gly Lys 450 <210> 101 <211> 216 <212> PRT <213> Artificial sequence <220> <223> BCMA-light chain of B58 antibody <400> 101 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Ser Val Ser Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser Lys Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln 100 105 110 Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu 115 120 125 Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr 130 135 140 Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys 145 150 155 160 Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr 165 170 175 Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His 180 185 190 Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys 195 200 205 Thr Val Ala Pro Ala Glu Cys Ser 210 215 <210> 102 <211> 446 <212> PRT <213> Artificial sequence <220> <223> BCMA - heavy chain of 5B5 antibody <400> 102 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Gly His 20 25 30 Tyr Trp Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Thr Val Ser Gly Ser Gly Gly Asp Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Gly His Ser Val Met Asp Val Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 103 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> BCMA - light chain of 5B5 antibody <400> 103 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Gly Ile Asp Ser Tyr 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Ser Trp Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 104 <211> 446 <212> PRT <213> Artificial Sequence <220> <223> BCMA - Heavy Chain of 5D5, 5D5 M1, 5D5 M2, 5D5 M3 and 5D5 M4 <400> 104 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Asp Ser Ser Gly Ser Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Glu His Gly Leu Phe Asp Ser Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 105 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> BCMA - light chain of 5D5 antibody <400> 105 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Asp Asp 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 106 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> BCMA - light chain of 5D5 M1 antibody <400> 106 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Asn Asp 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 107 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> BCMA - light chain of 5D5 M2 antibody <400> 107 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Glu Asp 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 108 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> BCMA - light chain of 5D5 M3 antibody <400> 108 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Ala Asp 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 109 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> BCMA-Light Chain of 5D5 M4 Antibody <400> 109 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Asp Ala 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 110 <211> 214 <212> PRT <213> Artificial sequence <220> <223> BCMA-light chain of 5D5 M5 antibody <400> 110 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Lys Ala Ser Gln Asp Ile Asp Asp Glu 20 25 30 Ile Asn Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Asp Ala Ser Leu Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser Leu Arg Thr Pro Ile 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 111 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> BCMA - Heavy Chain of 5A6, 5A6 M1, 5A6 M2, 5A6 M3, 5A6 M4, 5A6 M5, 5A6 M6, 5A6 M7 and 5A6 M8 <400> 111 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Asp Ser Asp Asp Phe Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 435 440 445 <210> 112 <211> 212 <212> PRT <213> Artificial sequence <220> <223> BCMA-light chain of 5A6 antibody <400> 112 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Ala Glu Cys Ser 210 <210> 113 <211> 212 <212> PRT <213> Artificial Sequence <220> <223> BCMA - light chain of 5A6 M1 antibody <400> 113 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Glu Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Ala Glu Cys Ser 210 <210> 114 <211> 212 <212> PRT <213> Artificial Sequence <220> <223> BCMA - light chain of 5A6 M2 antibody <400> 114 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ala Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Ala Glu Cys Ser 210 <210> 115 <211> 212 <212> PRT <213> Artificial Sequence <220> <223> BCMA - light chain of 5A6 M3 antibody <400> 115 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Glu Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Ala Glu Cys Ser 210 <210> 116 <211> 212 <212> PRT <213> Artificial sequence <220> <223> BCMA - light chain of 5A6 M4 antibody <400> 116 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ala Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Ala Glu Cys Ser 210 <210> 117 <211> 212 <212> PRT <213> Artificial Sequence <220> <223> BCMA - light chain of 5A6 M5 antibody <400> 117 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Glu Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Glu Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Ala Glu Cys Ser 210 <210> 118 <211> 212 <212> PRT <213> Artificial Sequence <220> <223> BCMA - light chain of 5A6 M6 antibody <400> 118 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Glu Ser Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ala Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Ala Glu Cys Ser 210 <210> 119 <211> 212 <212> PRT <213> Artificial Sequence <220> <223> BCMA - light chain of 5A6 M7 antibody <400> 119 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ala Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Glu Ser Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Ala Glu Cys Ser 210 <210> 120 <211> 212 <212> PRT <213> Artificial sequence <220> <223> BCMA-light chain of 5A6 M8 antibody <400> 120 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Gln Gly Asp Ala Leu Arg Ser Tyr Tyr Val 20 25 30 Asn Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile Tyr 35 40 45 Asp His Ser Lys Arg Pro Thr Gly Val Pro Asp Arg Phe Ser Gly Ser 50 55 60 Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg Ser Glu 65 70 75 80 Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ala Ser Thr Val Val 85 90 95 Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln Pro Lys Ala Ala 100 105 110 Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu Glu Leu Gln Ala Asn 115 120 125 Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe Tyr Pro Gly Ala Val 130 135 140 Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val Lys Ala Gly Val Glu 145 150 155 160 Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys Tyr Ala Ala Ser Ser 165 170 175 Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser His Arg Ser Tyr Ser 180 185 190 Cys Gln Val Thr His Glu Gly Ser Thr Val Glu Lys Thr Val Ala Pro 195 200 205 Ala Glu Cys Ser 210 <210> 121 <211> 251 <212> PRT <213> Artificial Sequence <220> <223> 41B01 scFV <400> 121 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly 100 105 110 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 145 150 155 160 Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu 165 170 175 Trp Val Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 195 200 205 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 210 215 220 Tyr Cys Ala Arg Asp Gly Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr 225 230 235 240 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 122 <211> 251 <212> PRT <213> Artificial sequence <220> <223> 41B01 M4 scFV <400> 122 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly 100 105 110 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 145 150 155 160 Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu 165 170 175 Trp Val Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 195 200 205 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 210 215 220 Tyr Cys Ala Arg Asp Ala Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr 225 230 235 240 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 123 <211> 251 <212> PRT <213> Artificial Sequence <220> <223> 41B01 M11 scFV <400> 123 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly 100 105 110 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 145 150 155 160 Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu 165 170 175 Trp Val Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 195 200 205 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 210 215 220 Tyr Cys Ala Arg Asp Ala Gln Arg Gln Ser Met Arg Glu Phe Asp Tyr 225 230 235 240 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 124 <211> 251 <212> PRT <213> Artificial Sequence <220> <223> 41B01 M12 scFV <400> 124 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly 100 105 110 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 145 150 155 160 Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu 165 170 175 Trp Val Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 195 200 205 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 210 215 220 Tyr Cys Ala Arg Asp Ala Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr 225 230 235 240 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 125 <211> 251 <212> PRT <213> Artificial Sequence <220> <223> 41B01 M13 scFV <400> 125 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly 100 105 110 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 145 150 155 160 Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu 165 170 175 Trp Val Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 195 200 205 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 210 215 220 Tyr Cys Ala Arg Asp Ala Gln Arg Gln Ser Met Arg Glu Phe Asp Tyr 225 230 235 240 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 245 250 <210> 126 <211> 257 <212> PRT <213> Artificial Sequence <220> <223> 41B02 scFV <400> 126 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Arg 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly 100 105 110 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 145 150 155 160 Gly Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu 165 170 175 Trp Val Ser Val Ile Tyr Pro Asp Asp Gly Asn Thr Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 195 200 205 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Ala Ala Val Tyr 210 215 220 Tyr Cys Ala Lys His Gly Gly Gln Lys Pro Thr Thr Lys Ser Ser Ser 225 230 235 240 Ala Tyr Gly Met Asp Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser 245 250 255 Ser <210> 127 <211> 257 <212> PRT <213> Artificial sequence <220> <223> 41B02 M1 scFV <400> 127 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 85 90 95 Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly 100 105 110 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 115 120 125 Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 130 135 140 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 145 150 155 160 Gly Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu 165 170 175 Trp Val Ser Val Ile Tyr Pro Asp Asp Gly Asn Thr Tyr Tyr Ala Asp 180 185 190 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 195 200 205 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 210 215 220 Tyr Cys Ala Lys His Gly Gly Gln Lys Pro Thr Thr Lys Ser Ser Ser 225 230 235 240 Ala Tyr Gly Met Asp Gly Trp Gly Gln Gly Thr Leu Val Thr Val Ser 245 250 255 Ser <210> 128 <211> 247 <212> PRT <213> Artificial Sequence <220> <223> AB41 scFV <400> 128 Asp Ile Val Met Thr Gln Ser Pro Ala Phe Leu Ser Val Thr Pro Gly 1 5 10 15 Glu Lys Val Thr Ile Thr Cys Arg Ala Ser Gln Thr Ile Ser Asp Tyr 20 25 30 Leu His Trp Tyr Gln Gln Lys Pro Asp Gln Ala Pro Lys Leu Leu Ile 35 40 45 Lys Tyr Ala Ser Gln Ser Ile Ser Gly Ile Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Phe Thr Ile Ser Ser Leu Glu Ala 65 70 75 80 Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Asp Gly His Ser Phe Pro Pro 85 90 95 Thr Phe Gly Cys Gly Thr Lys Leu Glu Ile Lys Arg Gly Gly Gly Gly 100 105 110 Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser 115 120 125 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Val Ile Lys Pro Gly Ala 130 135 140 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Ser Tyr 145 150 155 160 Trp Met His Trp Val Arg Gln Ala Pro Gly Gln Cys Leu Glu Trp Ile 165 170 175 Gly Glu Ile Asn Pro Gly Asn Gly His Thr Asn Tyr Asn Glu Lys Phe 180 185 190 Lys Ser Arg Ala Thr Leu Thr Gly Asp Thr Ser Thr Ser Thr Val Tyr 195 200 205 Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys 210 215 220 Ala Arg Ser Phe Thr Thr Ala Arg Ala Phe Ala Tyr Trp Gly Gln Gly 225 230 235 240 Thr Leu Val Thr Val Ser Ser 245 <210> 129 <211> 715 <212> PRT <213> Artificial Sequence <220> <223> Recombinant moiety of 5D5M4(NA)x41B01 M12 bispecific antibody <400> 129 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Gly Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Asp Ser Ser Gly Ser Ser Thr Phe Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Glu His Gly Leu Phe Asp Ser Trp Gly Gln Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala 115 120 125 Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys Leu 130 135 140 Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly 145 150 155 160 Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser Ser 165 170 175 Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser Leu 180 185 190 Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn Thr 195 200 205 Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His Thr 210 215 220 Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe 225 230 235 240 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 245 250 255 Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val 260 265 270 Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 275 280 285 Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser Val 290 295 300 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 305 310 315 320 Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser 325 330 335 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 340 345 350 Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 355 360 365 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 370 375 380 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 385 390 395 400 Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp 405 410 415 Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 420 425 430 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly Ser 435 440 445 Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser 450 455 460 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly Gln 465 470 475 480 Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn Asn 485 490 495 Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 500 505 510 Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 515 520 525 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 530 535 540 Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser Leu 545 550 555 560 Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly Gly 565 570 575 Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly 580 585 590 Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro 595 600 605 Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser 610 615 620 Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu Glu 625 630 635 640 Trp Val Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala Asp 645 650 655 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr 660 665 670 Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr 675 680 685 Tyr Cys Ala Arg Asp Ala Gln Arg Asn Ser Met Arg Glu Phe Asp Tyr 690 695 700 Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 705 710 715 <210> 130 <211> 716 <212> PRT <213> Artificial Sequence <220> <223> Recombinant moiety of 5A6M6(NA)x41B01 M12 bispecific antibody <400> 130 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Gly Val His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser Tyr Ser Gly Gly Thr Tyr Tyr Asn Pro Ser Leu Lys 50 55 60 Ser Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85 90 95 Arg Asp Ser Asp Asp Phe Gly Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu 115 120 125 Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly Cys 130 135 140 Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser 145 150 155 160 Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser 165 170 175 Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Ser 180 185 190 Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser Asn 195 200 205 Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr His 210 215 220 Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 260 265 270 Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Tyr Ala Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys Gly 435 440 445 Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly 450 455 460 Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Ala Ser Gly Thr Pro Gly 465 470 475 480 Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Ser Ser Asn Ile Gly Asn 485 490 495 Asn Tyr Val Thr Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 500 505 510 Leu Ile Tyr Ala Asp Ser His Arg Pro Ser Gly Val Pro Asp Arg Phe 515 520 525 Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu 530 535 540 Arg Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Thr Trp Asp Tyr Ser 545 550 555 560 Leu Ser Gly Tyr Val Phe Gly Cys Gly Thr Lys Leu Thr Val Leu Gly 565 570 575 Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly 580 585 590 Gly Gly Ser Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln 595 600 605 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 610 615 620 Ser Ser Tyr Asp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Cys Leu 625 630 635 640 Glu Trp Val Ser Trp Ile Ser Tyr Ser Gly Gly Ser Ile Tyr Tyr Ala 645 650 655 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn 660 665 670 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 675 680 685 Tyr Tyr Cys Ala Arg Asp Ala Gln Arg Asn Ser Met Arg Glu Phe Asp 690 695 700 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 705 710 715

Claims

1. An anti-B cell maturation antigen (B-cell maturation antigen; Anti-BCMA / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof, comprising: An anti-BCMA antibody or an antigen-binding fragment thereof; And An anti-4-1BB antibody or an antigen-binding fragment thereof, Wherein the anti-BCMA / anti-4-1BB bispecific antibody or an antigen-binding fragment thereof is selected from: (a) A bispecific antibody comprising: An anti-BCMA antibody or an antigen-binding fragment thereof, comprising: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 12, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 16, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 20, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 24, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 27, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 31, and An anti-4-1BB antibody or an antigen-binding fragment thereof, comprising: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (b) A bispecific antibody comprising: An anti-BCMA antibody or an antigen-binding fragment thereof, comprising: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 12, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 16, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 20, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 54, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 27, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 31, and An anti-4-1BB antibody or an antigen-binding fragment thereof, comprising: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (c) A bispecific antibody comprising: An anti-BCMA antibody or an antigen-binding fragment thereof, comprising: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 12, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 16, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 20, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 55, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 27, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 31, and An anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (d) A bispecific antibody, which comprises: An anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 12, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 16, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 20, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 56, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 27, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 31, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (e) A bispecific antibody, which comprises: An anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 12, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 16, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 20, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 57, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 27, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 31, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (f) a bispecific antibody, which comprises: an anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 12, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 16, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 20, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 58, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 27, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 31, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (g) a bispecific antibody, which comprises: an anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 13, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 17, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 21, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 25, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 28, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 32, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (h) A bispecific antibody, which comprises: An anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 13, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 17, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 21, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 59, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 28, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 32, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (i) A bispecific antibody, which comprises: An anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 13, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 17, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 21, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 60, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 28, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 32, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (j) A bispecific antibody, which comprises: An anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 13, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 17, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 21, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 25, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 28, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 63, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (k) a bispecific antibody, which comprises: an anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 13, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 17, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 21, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 25, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 28, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 64, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (l) a bispecific antibody, which comprises: an anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 13, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 17, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 21, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 61, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 28, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 63, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (m) A bispecific antibody, which comprises: An anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 13, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 17, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 21, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 61, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 28, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 64, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; (n) A bispecific antibody, which comprises: An anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 13, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 17, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 21, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 62, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 28, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 63, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 96; and (o) a bispecific antibody, which comprises: an anti-BCMA antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 13, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 17, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 21, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 62, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 28, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO: 64, and an anti-4-1BB antibody or an antigen-binding fragment thereof, which comprises: CDR-H1, which consists of the amino acid sequence of SEQ ID NO: 81, CDR-H2, which consists of the amino acid sequence of SEQ ID NO: 84, CDR-H3, which consists of the amino acid sequence of SEQ ID NO: 88, CDR-L1, which consists of the amino acid sequence of SEQ ID NO: 92, CDR-L2, which consists of the amino acid sequence of SEQ ID NO: 94, and CDR-L3, which consists of the amino acid sequence of SEQ ID NO:

96.

2. The bispecific antibody or antigen-binding fragment thereof according to claim 1, wherein, The anti-BCMA antibody or an antigen-binding fragment thereof comprises: a heavy chain variable region, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 4 and 5, and a light chain variable region, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 8, 9, and 41-53.

3. The bispecific antibody or antigen-binding fragment thereof according to claim 1, wherein, The anti-4-1BB antibody or an antigen-binding fragment thereof comprises: a heavy chain variable region, which comprises the amino acid sequence of SEQ ID NO: 68, and a light chain variable region, which comprises the amino acid sequence of SEQ ID NO:

76.

4. The bispecific antibody or an antigen-binding fragment thereof according to claim 1, which further comprises at least one peptide linker.

5. The bispecific antibody or an antigen-binding fragment thereof according to claim 4, wherein the peptide linker comprises a peptide, which comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 98 and SEQ ID NO:

99.

6. The bispecific antibody or an antigen-binding fragment thereof according to claim 1, wherein the antibody is IgA, IgD, IgE, IgG or IgM; the antibody is a monoclonal antibody or a polyclonal antibody; the antigen-binding fragment is scFv, (scFv)2, Fv, Fab, Fab', F(ab')2 or a combination thereof; or the antibody or an antigen-binding fragment thereof is modified by conjugation or binding, glycosylation, tag attachment or a combination thereof.

7. The bispecific antibody or antigen-binding fragment thereof according to claim 1, wherein the anti-BCMA antibody or antigen-binding fragment thereof and the anti-4-1BB antibody or antigen-binding fragment thereof are each independently a chimeric antibody, a humanized antibody or a human antibody.

8. The bispecific antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, wherein the form of the bispecific antibody or antigen-binding fragment thereof is IgG-scFv, triomab, a kihIgG with a common light chain, crossmab, an adjacent-Fab IgG, a dual variable domain immunoglobulin (DVD-Ig), 2-in-1-IgG, scFv2-Fc, a bispecific T cell engager (BiTE), tandAbs, a dual-affinity re-targeting (DART) antibody, DART-Fc, scFv-human serum albumin (HSA)-scFv, docking and locking (DNL) Fab3, a minibody, scFv-Fc, scFv-zipper, scFv, Fab, bispecific Fab2, trispecific Fab3, scFab, bispecific Bis-scFv, tetrabody, tribody, diabody, IgG, a bispecific construct comprising a kih structure, a bispecific construct comprising a diabody, a tetravalent multispecific antibody, a tetravalent construct, a tetravalent dual variable domain (DVD) construct, a tetravalent IgGScv construct or a composite antibody, or a combination thereof.

9. A pharmaceutical composition for treating a disease associated with BCMA, 4-1BB or both, wherein the composition comprises: the anti-BCMA / anti-4-1BB bispecific antibody or antigen-binding fragment thereof according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier, wherein the disease is a cancer expressing BCMA.

10. The pharmaceutical composition according to claim 9, wherein the cancer is multiple myeloma.

11. Use of the anti-B cell maturation antigen (BCMA) / anti-4-1BB bispecific antibody or antigen-binding fragment thereof according to any one of claims 1 to 8 in the manufacture of a pharmaceutical composition for treating a disease associated with BCMA, 4-1BB or both, wherein the disease is a cancer expressing BCMA, and wherein the cancer is multiple myeloma.

Images