Isolated bispecific antibodies that specifically bind CD3 and tumor antigens and uses thereof

Abstract

The present invention relates to the fields of biotechnology and medicine, and in particular to bispecific antibodies that specifically bind to CD3 and tumor-associated antigens. Furthermore, the present invention includes pharmaceutical compositions comprising the bispecific antibodies of the present invention, as well as pharmaceutical compositions comprising the bispecific antibodies of the present invention and other therapeutically active compounds. Methods for treating tumor antigen-mediated diseases or disorders are described. The use of bispecific antibodies or pharmaceutical compositions thereof for the treatment of such diseases or disorders is also contemplated. Finally, the present invention encompasses the use of the bispecific antibodies of the present invention and other therapeutically active compounds for the treatment of tumor antigen-mediated diseases or disorders.

Description

[Technical Field]

[0001] The present invention relates to the fields of biotechnology and medicine, and in particular to bispecific antibodies that specifically bind to CD3 and tumor-associated antigens. Furthermore, the present invention includes pharmaceutical compositions comprising the bispecific antibodies of the present invention, as well as pharmaceutical compositions comprising the bispecific antibodies of the present invention and other therapeutically active compounds. Methods for treating tumor antigen-mediated diseases or disorders are described. The use of bispecific antibodies or pharmaceutical compositions thereof for the treatment of such diseases or disorders is also contemplated. Finally, the present invention encompasses the use of the bispecific antibodies of the present invention and other therapeutically active compounds for the treatment of tumor antigen-mediated diseases or disorders. [Background technology]

[0002] Monoclonal antibodies, in the form of chimeric, humanized, or fully human molecules, have proven their value as effective drugs for the treatment of a variety of disorders and diseases. A natural human antibody molecule consists of two heavy chain homodimers, each of which forms a heterodimer with two identical light chain molecules. Conventional monoclonal antibodies consist of a bivalent heavy and light chain heterodimer as a whole molecule.

[0003] Diseases often arise as a result of multiple pathologies and are accompanied by numerous comorbidities. Bispecific antibodies have the ability to bind and neutralize two different antigens per antibody molecule. Bispecific antibodies have become an active area of ​​research due to the potential for significantly improved therapeutic properties (and value) of drugs compared to monoclonal antibodies. Over the past 20 years, numerous solutions for engineered versions of bispecific antibodies have been described in the scientific literature, as described in Brinkmann, U and RE Kontermann, 2017, The Making of Bispecific Antibodies, MAbs; 209 Feb / Mar; 9(2):182-212, doi:10.1080 / 19420862.2016.1268307.

[0004] CD3 (cluster of differentiation 3) is a molecule present on the surface of T lymphocytes. Tumor antigens are present only on cancer cells or are expressed at high levels on tumor cells but at low levels on healthy cells.

[0005] Bispecific antibodies that specifically bind to CD3 and tumor antigens recruit T cells (including tumor-killing cytotoxic CD8 lymphocytes) to cells expressing the tumor antigen. Patent documents WO2016166629, WO2017031104, WO2020018820, WO1999054440, WO2017210485, WO2016020309, and WO2016110576 describe various bispecific antibodies that bind to CD3 and tumor antigens.

[0006] Currently, only two bispecific antibodies that specifically bind to CD3 and tumor antigens have been approved for therapeutic use: blinatumomab, which binds to CD3 and CD19, and catumaxomab, which binds to CD3 and EpCAM. Given the above, there is an urgent need to develop new bispecific antibodies that specifically bind to CD3 and tumor antigens other than CD19 and EpCAM. Summary of the Invention

[0007] The present inventors have developed a bispecific antibody that specifically binds to CD3 and a tumor antigen and has high affinity binding parameters with the CD3 antigen. Definitions and general methods Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by experts in their fields.

[0008] Further, unless the context otherwise requires, singular terms include plural terms and plural terms include the singular. In general, the classifications and methods used in cell culture, molecular biology, immunology, microbiology, genetics, analytical chemistry, synthetic organic chemistry, medical and pharmaceutical chemistry, and hybridization and protein and nucleic acid chemistry described herein are well known to those of skill in the art and are widely used in the art. Enzymatic reactions and purification methods are performed according to manufacturer's instructions as is customary in the art or as described in this document.

[0009] The term "KD" in this description refers to the affinity constant (or equilibrium constant), which is obtained from the ratio of Kd to Ka (i.e., Kd / Ka) and is expressed as a molar concentration (M). "Binding affinity" typically refers to the strength of noncovalent interactions between a single binding site on a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless otherwise specified, "binding affinity" refers to the intrinsic (characteristic, true) binding affinity, which reflects a 1:1 interaction between components of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is typically expressed as an affinity constant (KD). KD values ​​of approximately 200 nM, 150 nM, 100 nM, 60 nM, 50 nM, 40 nM, 30 nM, 20 nM, 10 nM, 8 nM, 6 nM, 4 nM, 2 nM, 1 nM, or less are considered desirable. Affinity can be measured by conventional methods known in the art, including those described herein. Low-affinity antibodies typically bind antigens slowly and tend to dissociate easily, whereas high-affinity antibodies typically bind antigens more quickly and tend to remain bound longer. A variety of methods for measuring binding affinity are known in the art, and any of these methods can be used for the purposes of the present invention.

[0010] The terms "Kd," "koff," or "kdis" specifically refer to the dissociation rate constant of a binding molecule-antigen interaction. The dissociation rate constant, koff, can be measured using biosensor interferometry, for example, using the Octet™ system.

[0011] The terms "Ka," "kon," or "on-rate" refer to the binding rate constant. "R 2 The term " refers to the coefficient of determination.

[0012] The term "Response" refers to the signal produced when an antibody binds to an antigen. The term "in vitro" refers to simulating a biological object, process, or reaction outside the body under artificial conditions. For example, cell growth in vitro should be understood as cell growth in an environment outside the body, such as a test tube, culture flask, or microplate.

[0013] ED 50 (EC 50 The term ) (50% effective dose / concentration) refers to the concentration of a drug at which a measurable biological effect is achieved in 50% of cases (which may include cytotoxicity). In this description and subsequent formulae of the invention, unless otherwise indicated by context, the words "comprise" and "containing" or variations thereof such as "comprises", "contains", etc., are understood to include the entire set of specified wholes but not to exclude other whole sets.

[0014] antibody The present invention relates to bispecific antibodies that specifically bind to CD3 and tumor antigens. The bispecific antibodies according to the present invention are monoclonal antibodies.

[0015] The term "monoclonal antibody" or "mAb" refers to an antibody synthesized and secreted by a single clonal cell population. The bispecific antibodies of the present invention are recombinant antibodies.

[0016] The term "recombinant antibody" means an antibody expressed in a cell or cell line that contains a nucleotide sequence encoding the antibody, wherein said nucleotide sequence is not associated with the cell in nature.

[0017] In one aspect, the present invention provides an isolated bispecific antibody that specifically binds to CD3 and a tumor antigen, comprising: 1) a first antigen-binding fragment that binds to CD3, comprising: (a) a light chain variable domain comprising: (i) CDR1 has the amino acid sequence RASQSX1SSNLA, wherein X1=I or V (ii) CDR2 of the amino acid sequence SEQ ID NO:3, and (iii) a CDR3 having the amino acid sequence QX2YX3NWPLT, wherein: X2=H or Q, X3=N or I; and (b) a heavy chain variable domain comprising: (i) CDR1 of amino acid sequence SEQ ID NO:6 (ii) CDR2 of the amino acid sequence SEQ ID NO:7, and (iii) a CDR3 having the amino acid sequence DNSGYHYYYGX4DI, wherein: X4=M or L and 2) a second antigen-binding fragment that specifically binds to a tumor antigen; The present invention relates to the isolated bispecific antibody, comprising:

[0018] The term "isolated," as used herein to describe various antibodies, refers to an antibody that has been identified, isolated, and / or reproduced from the cell or cell culture in which it is expressed. Impurities (contaminants) from the natural environment are substances that generally interfere with diagnostic or therapeutic uses of the polypeptide and may include enzymes, hormones, other proteins, or non-proteinaceous solutes. Typically, purified polypeptides are obtained by at least one purification step.

[0019] As used herein, the term "antibody" or "immunoglobulin" (Ig) includes whole antibodies. The term "antibody" refers to a glycoprotein consisting of at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain contains a variable heavy chain region (abbreviated herein as VH) and a constant heavy chain region. Each light chain consists of a variable light chain region (abbreviated herein as VL) and a constant light chain region. Preferably, the light chain is a light k chain, and the constant domain CL is a Ck chain.

[0020] The term "bispecific antibody" refers to an antibody that can specifically bind to two different epitopes on a single biological molecule, or that contains antigen-binding fragments that can specifically bind to epitopes on two different biological molecules. As used herein, bispecific antibodies are also referred to as having "dual specificities" or as being "bispecific" antibodies.

[0021] The fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc receptors and with some proteins of the complement system. This property allows antibodies to activate the immune system. The Fc region of IgG, IgA, and IgD isotypes consists of two identical protein fragments, corresponding to the second and third constant domains of the two heavy chains, respectively.

[0022] By "monomeric Fc fragment" is meant the Fc region of the second and third constant domains of either of the two heavy chains (for IgG, IgA, and IgD isotypes). Antibodies according to the present invention may be of any class (e.g., IgA, IgD, IgE, IgG, and IgM, preferably IgG) or subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2, preferably IgG1).

[0023] The VH and VL regions are further subdivided into highly variable regions called complementarity-determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). VH and VL each consist of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain the binding domains that interact with antigens.

[0024] The constant regions of the antibodies can mediate the binding of the immunoglobulin to host tissues or factors, such as various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (C1q).

[0025] As used herein, the term "antigen-binding portion" or "antigen-binding fragment" of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding site" of an antibody include: (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab') fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; 2The fragments include: (i) bivalent fragments containing two Fab fragments linked by a disulfide bond at the hinge region; (ii) fragments consisting of the Fd-VH and CH1 domains; (iii) Fv fragments consisting of the VL and VH domains in a single antibody arm; and (v) dAb fragments consisting of the VH / VHH domains (Ward et al., (1989) Nature 341:544-546). Furthermore, the two regions of an Fv fragment, the VL and VH, are encoded by different genes. These regions can be recombinantly linked using a synthetic linker to obtain a single protein chain (called a single-chain Fv (scFv)) in which the VL and VH domains pair to form a monovalent molecule. See, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain molecules are also envisioned as being included within the "antigen-binding site" of an antibody. Such antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened in the same manner as are intact antibodies.

[0026] As used herein, the term "Kabat numbering" or "Kabat numbering" refers to a system for numbering amino acid residues that are more variable than other amino acid residues (i.e., hypervariable) within the variable regions of antibody heavy and light chains (Kabat et al. Ann. NY Acad. Sci., 190:382-93 (1971); Kabat et al. Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242 (1991)).

[0027] In the present invention, an antibody that "specifically binds" to a target antigen is an antibody that binds to the antigen with such affinity that it can be used as a diagnostic and / or therapeutic agent when targeting a protein, cell, or tissue that expresses the antigen, and whose cross-reactivity with other proteins is negligible.

[0028] The term "specifically binding" to a particular polypeptide or epitope on a particular target polypeptide may be characterized by examples of molecules that have a Kd for the target of at least about 200 nM, or at least about 150 nM, or at least about 100 nM, or at least about 60 nM, or at least about 50 nM, or at least about 40 nM, or at least about 30 nM, or at least about 20 nM, or at least about 10 nM, or at least about 8 nM, or at least about 6 nM, or at least about 4 nM, or at least about 2 nM, or at least about 1 nM or less.

[0029] In one aspect of the invention, the term "specifically binds" refers to binding where a molecule binds to a particular polypeptide or epitope on a particular polypeptide and does not substantially bind to other polypeptides or epitopes on the polypeptide.

[0030] Tumor antigens (TAs) refer to both tumor-specific antigens (TSAs), which are present only in cancer cells and not in healthy cells, and tumor-associated antigens (TAAs), which are expressed at high levels in tumor cells and at low levels in healthy cells. [Brief explanation of the drawings]

[0031] [Figure 1]Figure 1 shows a 7.5% SDS-PAGE electrophoresis gel of a bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 under non-reducing conditions. 1. Protein molecular weight marker; 2.001; 3.002; 4.003; 5.004; 6.005; 7.006; 8.007; 9.008; 10.009; 11.010; 12.011; 13.012; 14.013; 15.014. [Figure 2] Figure 2 shows an electrophoresis gel of a bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 under reducing conditions using 12.5% ​​SDS-PAGE. 1. Protein molecular weight marker; 2. 001; 3. 002; 4. 003; 5. 004; 6. 005; 7. 006; 8. 007; 9. 008; 10. 010. [Figure 3] Figure 3 shows an electrophoresis gel of a bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 under reducing conditions using 12.5% ​​SDS-PAGE. 1. Protein molecular weight marker; 2. 011; 3. 012; 4. 013; 5. 014. [Figure 4] Figure 4 shows an electrophoresis gel of bispecific antibodies that specifically bind to CD3 and the tumor antigen CD20 under non-reducing conditions using 7.5% SDS-PAGE: 1. Protein molecular weight marker; 2. Bispecific antibody 019 (10 μg); 3. Bispecific antibody 019 (40 μg). [Figure 5] Figure 5 shows an electrophoresis gel using 12.5% ​​SDS-PAGE under reducing conditions of a bispecific antibody that specifically binds to CD3 and the tumor antigen CD20. 1. Protein molecular weight markers; 2. Bispecific antibody 019. [Figure 6]Figure 6 shows an electrophoresis gel of purified preparations of bispecific anti-CD3 / anti-AXL antibodies. Electrophoresis was performed on a 12.5% ​​polyacrylamide gel under non-denaturing conditions in the presence of SDS, and the gel was stained with Coomassie G-250. M - molecular mass marker (kDa); 1 - primary antibody against CD3 / AXL; 2 - secondary antibody against CD3 / AXL. [Figure 7] Figure 7 shows an electrophoresis gel of purified bispecific anti-CD3 / anti-AXL antibodies. Electrophoresis was performed on a 7.5% gel under reducing conditions in the presence of DTT, and the gel was stained with Coomassie G-250. M - molecular mass marker (kDa); 1 - primary antibody against CD3 / AXL; 2 - secondary antibody against CD3 / AXL. [Figure 8] Figure 8 is a graph showing the results of evaluating the specific activity of the first and second bispecific antibodies against CD3 / AXL in a reporter cell line, and includes the following results: ● First bispecific antibody against CD3 / AXL + MDA-MB-231, EC50=138ng / mL; ■ Second bispecific antibody against CD3 / AXL + MDA-MB-231, EC50=81ng / mL; ▲ First bispecific antibody against CD3 / AXL; black diamond Second bispecific antibody against CD3 / AXL. [Figure 9] Figure 9 shows a gel of antibodies 01, 06, 016, 021, and 022 electrophoresed in a 7.5% polyacrylamide gel under denaturing, non-reducing conditions after an initial purification step using Protein A resin. M - molecular weight markers: 1 - 01-001; 2 - 01-006; 3 - 01-016; 4 - 01-021; 5 - 01-022. [Figure 10] Figure 10 shows a gel of antibodies 024, 025, 026, 027, 030, 033, and 037 electrophoresed in a 7.5% polyacrylamide gel under denaturing, non-reducing conditions after an initial purification step using Protein A resin. M - molecular weight markers; 1 - 01-024; 2 - 01-025; 3 - 01-026; 4 - 01-027; 5 - 01-030; 6 - 01-033; 7 - 01-037. [Figure 11] Figure 11 shows a gel of bispecific antibodies 02-001, 02-002, 02-003, 02-004, 02-005, 02-006, 02-007, 02-008, 02-009, and 02-010, which specifically bind to CD3 and the tumor antigen BCMA, electrophoresed in a 7.5% polyacrylamide gel under denaturing, non-reducing conditions after an initial purification step on Protein A resin. M - molecular weight marker; 1 - 02-001; 2 - 02-002; 3 - 02-003; 4 - 02-004; 5 - 02-005; 6 - 02-006; 7 - 02-007; 8 - 02-008; 9 - 02-009; 10 - 02-010. [Figure 12] Figure 12 shows a gel of bispecific antibody 02-007, which specifically binds CD3 and the tumor antigen BCMA, electrophoresed in a 7.5% polyacrylamide gel under denaturing, non-reducing conditions after an initial purification step on Protein A resin. M - molecular weight marker; 1- 02-007. [Figure 13] Figure 13 shows a gel of bispecific antibody 02-011, which specifically binds CD3 and the tumor antigen BCMA, electrophoresed in a 7.5% polyacrylamide gel under denaturing, non-reducing conditions after a first purification step on Protein A resin. M - molecular weight marker; 1-02-011. [Figure 14] Figure 14 shows a gel of bispecific antibody 02-012, which specifically binds to CD3 and the tumor antigen BCMA, electrophoresed in a 7.5% polyacrylamide gel under denaturing, non-reducing conditions after a first purification step on Protein A resin. M - molecular weight marker; 1- 02-012. DETAILED DESCRIPTION OF THE INVENTION

[0032] In some embodiments of the present invention, the isolated bispecific antibody comprises a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, which comprises a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO:1 or SEQ ID NO:2.

[0033] In some embodiments of the invention, the isolated bispecific antibody comprises a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, which comprises a CDR3 having an amino acid sequence selected from the following: SEQ ID NO:4 or SEQ ID NO:5.

[0034] In some embodiments of the invention, the isolated bispecific antibody comprises a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, which comprises a CDR3 having an amino acid sequence selected from the following: SEQ ID NO:8 or SEQ ID NO:9.

[0035] In some embodiments of the invention, the isolated bispecific antibody comprises: a CDR1 having an amino acid sequence selected from SEQ ID NO:1 or SEQ ID NO:2; CDR2 of amino acid sequence SEQ ID NO:3; and, a CDR3 having an amino acid sequence selected from SEQ ID NO:4 or SEQ ID NO:5; and a first antigen-binding fragment that specifically binds to CD3, the first antigen-binding fragment comprising the variable domain of the light chain of

[0036] In some embodiments of the invention, the isolated bispecific antibody comprises: CDR1 of amino acid sequence SEQ ID NO:6; CDR2 of amino acid sequence SEQ ID NO:7; and, a CDR3 having an amino acid sequence selected from SEQ ID NO:8 or SEQ ID NO:9; and a first antigen-binding fragment that specifically binds to CD3, the first antigen-binding fragment comprising the heavy chain variable domain of

[0037] In some embodiments of the invention, the isolated bispecific antibody comprises: (a) a CDR1 having an amino acid sequence selected from SEQ ID NO:1 or SEQ ID NO:2; CDR2 of amino acid sequence SEQ ID NO:3; and, a CDR3 having the amino acid sequence QX2YX3NWPLT, X2=H or Q, X3=N or I; a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3; and (b) CDR1 of amino acid sequence SEQ ID NO:6; CDR2 of amino acid sequence SEQ ID NO:7; and, a CDR3 having an amino acid sequence selected from SEQ ID NO:8 or SEQ ID NO:9; a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising: Includes:

[0038] In some embodiments of the invention, the isolated bispecific antibody comprises: (a) a CDR1 having an amino acid sequence selected from SEQ ID NO:1 or SEQ ID NO:2; CDR2 of amino acid sequence SEQ ID NO:3; and, a CDR3 having an amino acid sequence selected from SEQ ID NO:4 or SEQ ID NO:5; a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3; and (b) CDR1 of amino acid sequence SEQ ID NO:6; CDR2 of amino acid sequence SEQ ID NO:7; and, a CDR3 having an amino acid sequence selected from SEQ ID NO:8 or SEQ ID NO:9; a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising: Includes:

[0039] In some embodiments of the invention, the isolated bispecific antibody comprises: (i) Below (a): CDR1 of the amino acid sequence SEQ ID NO:2, CDR2 of the amino acid sequence SEQ ID NO:3, and CDR3 of amino acid sequence SEQ ID NO:4; a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3; and (b) Below: CDR1 of the amino acid sequence SEQ ID NO:6, CDR2 of the amino acid sequence SEQ ID NO:7, and CDR3 of amino acid sequence SEQ ID NO:8; a variable domain of a heavy chain of a first antigen-binding fragment that specifically binds to CD3; or (ii) Below (a): CDR1 of the amino acid sequence SEQ ID NO: 1, CDR2 of the amino acid sequence SEQ ID NO:3, and CDR3 of amino acid sequence SEQ ID NO:4; a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3; and (b) Below: CDR1 of the amino acid sequence SEQ ID NO:6, CDR2 of the amino acid sequence SEQ ID NO:7, and CDR3 of amino acid sequence SEQ ID NO:8; a variable domain of a heavy chain of a first antigen-binding fragment that specifically binds to CD3; or (iii) Below (a): CDR1 of the amino acid sequence SEQ ID NO:2, CDR2 of the amino acid sequence SEQ ID NO:3, and CDR3 of amino acid sequence SEQ ID NO:5; a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3; and (b) Below: CDR1 of the amino acid sequence SEQ ID NO:6, CDR2 of the amino acid sequence SEQ ID NO:7, and CDR3 of amino acid sequence SEQ ID NO:9; a variable domain of a heavy chain of a first antigen-binding fragment that specifically binds to CD3; or (iv) Below (a): CDR1 of the amino acid sequence SEQ ID NO: 1, CDR2 of the amino acid sequence SEQ ID NO:3, and CDR3 of amino acid sequence SEQ ID NO:5; a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3; and (b) Below: CDR1 of the amino acid sequence SEQ ID NO:6, CDR2 of the amino acid sequence SEQ ID NO:7, and CDR3 of amino acid sequence SEQ ID NO:9; a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising: Includes:

[0040] In some embodiments of the invention, the isolated bispecific antibody comprises a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3, wherein the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, or SEQ ID NO:156.

[0041] In some embodiments of the invention, the isolated bispecific antibody comprises a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3, wherein the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, or SEQ ID NO:157.

[0042] In some embodiments of the invention, the isolated bispecific antibody comprises a light chain and a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, or SEQ ID NO:156; and, (b) the variable domain of the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, or SEQ ID NO:157.

[0043] In some embodiments of the present invention, the isolated bispecific antibody comprises a first antigen-binding fragment that specifically binds to CD3, which is designed in an scFv, Fab, scFab, or CrossMab format.

[0044] In some embodiments of the invention, the isolated bispecific antibody comprises a second antigen-binding fragment that specifically binds to CD3, designed in an scFv, Fab, scFab, or CrossMab format.

[0045] In some embodiments of the invention, the isolated bispecific antibody comprises the light chain and heavy chain variable domains of a first antigen-binding fragment that specifically binds to CD3, (i)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:10; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:16; or (ii)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:16; or (iii)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:10; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:17; or (iv)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:10; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:18; or (v)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:10; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; or (vi)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; or (vii)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:12; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:18; or (viii)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:13, and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:20; or (ix)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:14; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:20; or (x)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:13, and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:21; or (xi)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:13; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:22; or (xii)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:13, and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:23; or (xiii)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:14; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:23; or (xiv)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:15; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:22; or (xv) (a) the variable domain of the light chain of a first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:156; and

[0046] (b) The variable domain of the heavy chain of a first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:157. In some embodiments of the invention, the isolated bispecific antibody is a full-length antibody IgG.

[0047] In some embodiments of the invention, the isolated bispecific antibody is a human full-length antibody IgG of the IgG1, IgG2, IgG3, or IgG4 isotype. In some embodiments of the invention, the isolated bispecific antibody is a full-length antibody IgG of the human IgG1 isotype.

[0048] In some embodiments of the invention, the isolated bispecific antibody comprises the mutations L234A and L235A in the CH2 region according to the EU numbering scheme (Edelman GM et al., Proc. Natl. Acad. Sci. USA 63, 1969, pp. 78-85; Kabat E.A. et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991).

[0049] In some embodiments of the invention, the isolated bispecific antibody comprises the mutations M252Y, S254T, T256E according to the EU numbering scheme in the CH2 region. In some embodiments of the invention, the isolated bispecific antibody comprises the mutations S354C and T366W according to the EU numbering scheme in the CH3 region.

[0050] In some embodiments of the invention, the isolated bispecific antibody comprises the mutations Y349C, T366S, L368A and Y407V according to the EU numbering scheme in the CH3 region.

[0051] In some embodiments of the invention, the bispecific antibody comprises a light chain of a first antigen-binding fragment that specifically binds to CD3, wherein the light chain comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:158, SEQ ID NO:160, or SEQ ID NO:162.

[0052] In some embodiments of the invention, the bispecific antibody comprises a heavy chain of a first antigen-binding fragment that specifically binds to CD3, wherein the heavy chain comprises an amino acid sequence selected from the group consisting of: SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:159, SEQ ID NO:161, or SEQ ID NO:163.

[0053] In some embodiments of the invention, the isolated bispecific antibody comprises a light chain and a heavy chain, (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:158, SEQ ID NO:160, or SEQ ID NO:162; and, (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:159, SEQ ID NO:161, or SEQ ID NO:163.

[0054] In some embodiments of the invention, the isolated bispecific antibody comprises a light chain and a heavy chain of a first antigen-binding fragment that specifically binds to CD3, (i)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:24; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:30; or (ii)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:25; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:30; or (iii)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:24; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:31; or (iv)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:24, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:32; or (v)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:24, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:33; or (vi)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:25, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:33; or (vii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:26, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:32; or (viii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:27, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:34; or (ix) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:28, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:34; or (x)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:27, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:35; or (xi) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:27, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:36; or (xii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:27, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:37; or (xiii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:28, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:37; or (xiv) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:29, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:36; or (xv) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:25, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:38; or (xvi) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:159; or (xvii) (a) the light chain of the first antigen-binding fragment generated in a CrossMab format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 160; and (b) the heavy chain of the first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:161; or (xviii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 162; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:163.

[0055] In some embodiments of the invention, the isolated bispecific antibody is selected from the group consisting of GUCY2C, AXL, GD2, CD19, EpCAM, EGFR, CD20, CEA, HER2 / neu, PSMA, BCMA, MUC17, CD38, FLT3, ENPP3, TPBG, FAP, CD70, Cadherin-19, Mesothelin, CD33, ROR1, IL-3Rα, Cadherin-17, P-cadherin, MUC1, B7-H6, DLL3, B7-H3, CD28, CD155, IRTA2, GPRC5D, RNF43, IL-1RAP, Globo H, Glypican and a second antigen-binding fragment that specifically binds to a tumor antigen selected from the group consisting of: 3, CLDN18, TPBG, LYPD1, PD-L1, GPNMB, NY-ESO-1, MAGE-A4, TACSTD-2, DR5, CD8, TMEFF2, PRLR, CD22, HLA-G, Robo1, EphA2, Prominin-1, HMW-MAA, A33, TAG-72, HER3, IL-23R, CD2, MIF, PD-1, Epha10, GCC, ALP, LFL2, MAGE-A4, STEAP2, CA125, TYRP1, 4-1BB, FRA, CD44v6, Robo4, TIM-3, CLEC12A, B7-H4, FCRL5, SSTR2, c-Kit, MOSPD2, PSA, or CD26.

[0056] In one aspect, the present invention relates to an isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA. In one aspect, the present invention relates to an isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA, the bispecific antibody comprising: 1) a first antigen-binding fragment that binds to CD3, comprising: (a) a light chain variable domain comprising: (i) CDR1 has the amino acid sequence RASQSX1SSNLA, wherein X1=I or V (ii) CDR2 of the amino acid sequence SEQ ID NO:3, and (iii) a CDR3 having the amino acid sequence QX2YX3NWPLT, wherein: X2=H or Q, X3=N or I; and (b) a heavy chain variable domain comprising: (i) CDR1 of amino acid sequence SEQ ID NO:6 (ii) CDR2 of the amino acid sequence SEQ ID NO:7, and (iii) a CDR3 having the amino acid sequence DNSGYHYYYGX4DI, wherein: X4=M or L and 2) a second antigen-binding fragment that specifically binds to a BCMA tumor antigen, comprising: (a) a light chain variable domain comprising: (i) Amino acid sequence X7GX8X9SNIGX 10 X 11 X 12 X 13 VX 14 a CDR1 having X7=S or T; X8=S, G or T; X9=S, T, I or R; X 10 =0 or А; X 11 = S, H, N, G or T; X 12 = N, R or Y; X 13 = T, A, I or D; X 14 = N or H; (ii) amino acid sequence X 15 X 16 X 17 X 18 a CDR2 having an RPS, X 15 = N, R, K, S or G; X 16 = D, N, G, T or H; X 17 = S, N or T; X 18 = Q or N; and (iii) amino acid sequence X19 X 20 WDX 21 X 22 X 23 X 24 X 25 WX 26 a CDR3 having X 19 =A or S; X 20 = A, S, T or V; X 21 = G, D, H or S; X 22 = S, D or R; X 23 = L or V; X 24 = N, T, R or S; X 25 = V, A, G or N; X 26 = M, V or L; and (b) a heavy chain variable domain comprising: (i) a CDR1 having the amino acid sequence SX1X2MS, wherein: X1=S or G; X2=A, L or V; (ii) CDR2 having the amino acid sequence X3YNGGSX0RAGX4X5DSVX6G, wherein X0=D or T; X3=G or C; X4=F or Y; X5=A or T; X6=E or K; and (iii) a CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 83 or SEQ ID NO: 130; Includes:

[0057] Variants of the first antigen-binding fragment that specifically binds to CD3 for the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA are the same as the embodiments of the first antigen-binding fragment that specifically binds to CD3 for the isolated bispecific antibody that specifically binds to CD3 and a tumor antigen described above.

[0058] In some embodiments of the invention, the isolated bispecific antibody comprises: a first antigen-binding fragment that specifically binds to CD3, designed in scFv, Fab, scFab, or CrossMab format; and a second antigen-binding fragment that specifically binds to the BCMA tumor antigen, designed in scFv, Fab, scFab, or CrossMab format; Includes:

[0059] In some embodiments of the invention, an isolated bispecific antibody comprising a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA comprises a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56 or SEQ ID NO:122.

[0060] In some embodiments of the invention, an isolated bispecific antibody comprising a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA comprises a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65 or SEQ ID NO:123.

[0061] In some embodiments of the invention, the isolated bispecific antibody comprising a heavy chain variable domain of a second antigen-binding fragment that specifically binds to BCMA comprises a CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72, SEQ ID NO:73, SEQ ID NO:74, SEQ ID NO:75, SEQ ID NO:76 or SEQ ID NO:124.

[0062] In some embodiments of the invention, the isolated bispecific antibody comprising a heavy chain variable domain of a second antigen-binding fragment that specifically binds to BCMA comprises a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79 or SEQ ID NO:125.

[0063] In some embodiments of the invention, the isolated bispecific antibody comprising a heavy chain variable domain of a second antigen-binding fragment that specifically binds to BCMA comprises a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128 or SEQ ID NO:129.

[0064] In some embodiments of the invention, the isolated bispecific antibody comprises a variable domain of the light chain of a second antigen-binding fragment that specifically binds BCMA, wherein the variable domain is: CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56 or SEQ ID NO:122; a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, or SEQ ID NO:123; and a CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76 or SEQ ID NO: 124; Includes:

[0065] In some embodiments of the invention, the isolated bispecific antibody comprises a heavy chain variable domain of a second antigen-binding fragment that specifically binds BCMA, wherein the variable domain comprises: CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79 or SEQ ID NO:125; a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, or SEQ ID NO:129; and CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO:83 or SEQ ID NO:130 Includes:

[0066] In some embodiments of the invention, the isolated bispecific antibody comprises: (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, the variable domain comprising: CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:53, SEQ ID NO:54, SEQ ID NO:55, SEQ ID NO:56 or SEQ ID NO:122; a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, SEQ ID NO:61, SEQ ID NO:62, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, or SEQ ID NO:123; and a CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76 or SEQ ID NO: 124; Including, and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, wherein the variable domain comprises: CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO:77, SEQ ID NO:78, SEQ ID NO:79 or SEQ ID NO:125; a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO:80, SEQ ID NO:81, SEQ ID NO:82, SEQ ID NO:126, SEQ ID NO:127, SEQ ID NO:128, or SEQ ID NO:129; and CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO:83 or SEQ ID NO:130 Includes:

[0067] In some embodiments of the invention, the isolated bispecific antibody comprises: (i) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 49, CDR2 of the amino acid sequence SEQ ID NO:57 and CDR3 of amino acid sequence SEQ ID NO:66; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 77, CDR2 of the amino acid sequence SEQ ID NO: 80 and CDR3 of amino acid sequence SEQ ID NO:83; or (ii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 50, CDR2 of the amino acid sequence SEQ ID NO:58 and CDR3 of amino acid sequence SEQ ID NO:67; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 78, CDR2 of the amino acid sequence SEQ ID NO:81 and CDR3 of amino acid sequence SEQ ID NO:83; or (iii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 51, CDR2 of the amino acid sequence SEQ ID NO:59 and CDR3 of amino acid sequence SEQ ID NO:68; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 79, CDR2 of the amino acid sequence SEQ ID NO: 80 and CDR3 of amino acid sequence SEQ ID NO:83; or (iv) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 52, CDR2 of the amino acid sequence SEQ ID NO:60 and CDR3 of amino acid sequence SEQ ID NO:69; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 78, CDR2 of the amino acid sequence SEQ ID NO: 80 and CDR3 of amino acid sequence SEQ ID NO:83; or (v) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 53, CDR2 of the amino acid sequence SEQ ID NO:61 and CDR3 of amino acid sequence SEQ ID NO:70; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 78, CDR2 of the amino acid sequence SEQ ID NO:81 and CDR3 of amino acid sequence SEQ ID NO:83; or (vi) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 53, CDR2 of the amino acid sequence SEQ ID NO:61 and CDR3 of amino acid sequence SEQ ID NO:71; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 78, CDR2 of the amino acid sequence SEQ ID NO:82 and CDR3 of amino acid sequence SEQ ID NO:83; or (vii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 54, CDR2 of the amino acid sequence SEQ ID NO:63 and CDR3 of amino acid sequence SEQ ID NO:73; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 78, CDR2 of the amino acid sequence SEQ ID NO:81 and CDR3 of amino acid sequence SEQ ID NO:83; or (viii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 53, CDR2 of the amino acid sequence SEQ ID NO:61 and CDR3 of amino acid sequence SEQ ID NO:71; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 78, CDR2 of the amino acid sequence SEQ ID NO:81 and CDR3 of amino acid sequence SEQ ID NO:83; or (ix) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 55, CDR2 of the amino acid sequence SEQ ID NO:64 and CDR3 of amino acid sequence SEQ ID NO:74; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 78, CDR2 of the amino acid sequence SEQ ID NO: 80 and CDR3 of amino acid sequence SEQ ID NO:83; or (x) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 49, CDR2 of the amino acid sequence SEQ ID NO:65 and CDR3 of amino acid sequence SEQ ID NO:75; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 78, CDR2 of the amino acid sequence SEQ ID NO: 80 and CDR3 of amino acid sequence SEQ ID NO:83; or (xi) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 56, CDR2 of the amino acid sequence SEQ ID NO:58 and CDR3 of amino acid sequence SEQ ID NO:76; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 78, CDR2 of the amino acid sequence SEQ ID NO:81 and CDR3 of amino acid sequence SEQ ID NO:83; or (xii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 51, CDR2 of the amino acid sequence SEQ ID NO:62 and CDR3 of amino acid sequence SEQ ID NO:72; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 78, CDR2 of the amino acid sequence SEQ ID NO:81 and CDR3 of amino acid sequence SEQ ID NO:83; or (xiii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO: 124; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 126 and CDR3 of amino acid sequence SEQ ID NO:130; or (xiv) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO: 124; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 127 and CDR3 of amino acid sequence SEQ ID NO:130; or (xv) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO: 124; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 128 and CDR3 of amino acid sequence SEQ ID NO:130; or (xvi) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO: 124; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 129 and CDR3 of the amino acid sequence SEQ ID NO: 130, Includes:

[0068] In some embodiments of the invention, the isolated bispecific antibody comprises a variable domain of the light chain of a second antigen-binding fragment that specifically binds BCMA, wherein the variable domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, or SEQ ID NO:131.

[0069] In some embodiments of the invention, the isolated bispecific antibody comprises a heavy chain variable domain of a second antigen-binding fragment that specifically binds BCMA, wherein the variable domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141 or SEQ ID NO:142.

[0070] In some embodiments of the invention, the isolated bispecific antibody comprises: (a) a light chain variable domain of a second antigen-binding fragment that specifically binds to BCMA, the variable domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO:84, SEQ ID NO:85, SEQ ID NO:86, SEQ ID NO:87, SEQ ID NO:88, SEQ ID NO:89, SEQ ID NO:90, SEQ ID NO:91, SEQ ID NO:92, SEQ ID NO:93, SEQ ID NO:94, or SEQ ID NO:131; and (b) a heavy chain variable domain of a second antigen-binding fragment that specifically binds to BCMA, wherein the variable domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO:95, SEQ ID NO:96, SEQ ID NO:97, SEQ ID NO:98, SEQ ID NO:99, SEQ ID NO:100, SEQ ID NO:101, SEQ ID NO:102, SEQ ID NO:132, SEQ ID NO:133, SEQ ID NO:134, SEQ ID NO:135, SEQ ID NO:136, SEQ ID NO:137, SEQ ID NO:138, SEQ ID NO:139, SEQ ID NO:140, SEQ ID NO:141, or SEQ ID NO:142; Includes:

[0071] In some embodiments of the invention, the isolated bispecific antibody comprises: (i) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:84; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:95; or (ii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:85; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:96; or (iii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:86; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:97; or (iv) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:87; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:98; or (v) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:88; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:99; or (vi) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:89; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:100; or (vii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:91; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:99; or (viii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:89; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:99; or (ix) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:92; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:101; or (x) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:93; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:102; or (xi) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:94; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:99; or (xii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:90; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:99; or (xiii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:132; or (xiv) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:133; or (xv) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:134; or (xvi) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:135; or (xvii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:136; or (xviii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:137; or (xix) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:138; or (xx) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:139; or (xxi) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:140; or (xxii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:141; or (xxiii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:142; Includes:

[0072] In some embodiments of the invention, the isolated bispecific antibody comprises a light chain of a second antigen-binding fragment that specifically binds BCMA, wherein the light chain is selected from the group consisting of SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:143 or SEQ ID NO:144.

[0073] In some embodiments of the invention, the isolated bispecific antibody comprises a heavy chain of a second antigen-binding fragment that specifically binds BCMA, wherein the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154 or SEQ ID NO:155.

[0074] In some embodiments of the invention, the isolated bispecific antibody comprises: (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises an amino acid sequence selected from the group consisting of SEQ ID NO:103, SEQ ID NO:104, SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:108, SEQ ID NO:109, SEQ ID NO:110, SEQ ID NO:111, SEQ ID NO:112, SEQ ID NO:113, SEQ ID NO:143, or SEQ ID NO:144; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises an amino acid sequence selected from the group consisting of SEQ ID NO:114, SEQ ID NO:115, SEQ ID NO:116, SEQ ID NO:117, SEQ ID NO:118, SEQ ID NO:119, SEQ ID NO:120, SEQ ID NO:121, SEQ ID NO:145, SEQ ID NO:146, SEQ ID NO:147, SEQ ID NO:148, SEQ ID NO:149, SEQ ID NO:150, SEQ ID NO:151, SEQ ID NO:152, SEQ ID NO:153, SEQ ID NO:154, or SEQ ID NO:155; Includes:

[0075] In some embodiments of the invention, the isolated bispecific antibody comprises a light chain and a heavy chain of a second antigen-binding fragment that specifically binds BCMA, wherein: (i)(a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:103; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:114; or (ii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:104; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:115; or (iii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:105; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:116; or (iv) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:106; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:117; or (v) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:107; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:118; or (vi) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:108; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:119; or (vii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:110; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:118; or (viii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:108; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:118; or (ix) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:111; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:120; or or (x) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:112; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:121; or (xi) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:113; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:118; or (xii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:109; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:118; or (xiii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:145; or (xiv) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:146; or (xv) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:147; or (xvi) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:148; or (xvii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:149; or (xviii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:150; or (xix) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:151; or (xx) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:152; or (xxi) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:153; or (xxii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:154; or (xxiii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 144; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:155.

[0076] In some embodiments of the invention, the isolated bispecific antibody comprises: (i) (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO:2, CDR2 of the amino acid sequence SEQ ID NO:3, and CDR3 of amino acid sequence SEQ ID NO:4; (b) a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO:6, CDR2 of the amino acid sequence SEQ ID NO:7, and CDR3 of amino acid sequence SEQ ID NO:8; (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123, and CDR3 of amino acid sequence SEQ ID NO:124; and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 126, and CDR3 of amino acid sequence SEQ ID NO:130; or (ii) (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO:2, CDR2 of the amino acid sequence SEQ ID NO:3, and CDR3 of amino acid sequence SEQ ID NO:4; (b) a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO:6, CDR2 of the amino acid sequence SEQ ID NO:7, and CDR3 of amino acid sequence SEQ ID NO:8; (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123, and CDR3 of amino acid sequence SEQ ID NO:124; and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 127, and CDR3 of amino acid sequence SEQ ID NO:130; or (iii) (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO:2, CDR2 of the amino acid sequence SEQ ID NO:3, and CDR3 of amino acid sequence SEQ ID NO:4; (b) a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO:6, CDR2 of the amino acid sequence SEQ ID NO:7, and CDR3 of amino acid sequence SEQ ID NO:8; (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123, and CDR3 of amino acid sequence SEQ ID NO:124; and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 128, and CDR3 of amino acid sequence SEQ ID NO:130; or (iv) (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO:2, CDR2 of the amino acid sequence SEQ ID NO:3, and CDR3 of amino acid sequence SEQ ID NO:4; (b) a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO:6, CDR2 of the amino acid sequence SEQ ID NO:7, and CDR3 of amino acid sequence SEQ ID NO:8; (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123, and CDR3 of amino acid sequence SEQ ID NO:124; and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 129, and CDR3 of amino acid sequence SEQ ID NO:130; or (v) (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, designed in a CrossMAb format, comprising: CDR1 of the amino acid sequence SEQ ID NO:6, CDR2 of the amino acid sequence SEQ ID NO:7, and CDR3 of amino acid sequence SEQ ID NO:8; (b) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, designed in a CrossMAb format, comprising: CDR1 of the amino acid sequence SEQ ID NO:2, CDR2 of the amino acid sequence SEQ ID NO:3, and CDR3 of amino acid sequence SEQ ID NO:4; (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123, and CDR3 of amino acid sequence SEQ ID NO:124; and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 126, and CDR3 of the amino acid sequence SEQ ID NO: 130, Includes:

[0077] In some embodiments of the invention, the isolated bispecific antibody comprises: (i)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:132; or (ii)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:133; or (iii)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:134; or (iv)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:135; or (v)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:136; or (vi)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:137; or (vii)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:138; or (viii)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:139; or (ix)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:140; or (x)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:141; or (xi) (a) the variable domain of the light chain of a first antigen-binding fragment designed in a CrossMAb format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:156; (b) the variable domain of the heavy chain of a first antigen-binding fragment designed in a CrossMAb format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:157; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:142; or (xii)(a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:142; Includes:

[0078] In some embodiments of the invention, the isolated bispecific antibody comprises a light chain and a heavy chain of a first antigen-binding fragment that specifically binds CD3, and a light chain and a heavy chain of a second antigen-binding fragment that specifically binds BCMA, (i)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:145; or (ii)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:146; or (iii)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:147; or (iv)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:148; or (v)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:149; or (vi)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:150; or (vii)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:151; or (viii)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:152; or (ix)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:153; or (x)(a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:154; or (xi) (a) the light chain of a first antigen-binding fragment designed in a CrossMAb format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 160; (b) the heavy chain of a first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 161; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:144; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:155; or (xii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:162; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:163; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:144; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:155.

[0079] In one aspect of the invention, there is provided an isolated bispecific antibody that specifically binds to CD3 and BCMA tumor antigens, comprising: 1) A first antigen-binding fragment that specifically binds to CD3, designed in a CrossMAb format, comprising: (a) a light chain variable domain comprising: (i) CDR1 of the amino acid sequence SEQ ID NO:6; (ii) CDR2 of the amino acid sequence SEQ ID NO:7, and CDR3 of amino acid sequence SEQ ID NO:8; and (b) a heavy chain variable domain comprising: (i) CDR1 of the amino acid sequence SEQ ID NO:2; (ii) CDR2 of the amino acid sequence SEQ ID NO:3, and (iii) CDR3 of amino acid sequence SEQ ID NO:4; the first antigen-binding fragment comprising: and 2) a second antigen-binding fragment that specifically binds to a BCMA tumor antigen, comprising: (a) a light chain variable domain comprising: (i) CDR1 of the amino acid sequence SEQ ID NO: 122; CDR2 of the amino acid sequence SEQ ID NO: 123, and (iii) CDR3 of amino acid sequence SEQ ID NO:124; and (b) a heavy chain variable domain comprising: (i) CDR1 of the amino acid sequence SEQ ID NO: 125; (i) CDR1 of the amino acid sequence SEQ ID NO:126, and (iii) CDR3 of amino acid sequence SEQ ID NO:130; the second antigen-binding fragment comprising: The present invention relates to the isolated bispecific antibody, comprising:

[0080] In some embodiments of the invention, the isolated bispecific antibody comprises: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:156; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:157; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:142.

[0081] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is a full-length antibody IgG. In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is a full-length antibody IgG of the human IgG1, IgG2, IgG3, or IgG4 isotype.

[0082] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is a full-length antibody IgG of the human IgG1 isotype. In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA comprises the mutations L234A and L235A according to the EU numbering scheme in the CH2 region.

[0083] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA comprises the mutations M252Y, S254T, T256E according to the EU numbering scheme in the CH2 region.

[0084] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA comprises the mutations S354C and T366W according to the EU numbering scheme in the CH3 region.

[0085] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA comprises the mutations Y349C, T366S, L368A and T366W according to the EU numbering scheme in the CH3 region.

[0086] In some embodiments of the invention, the isolated bispecific antibody comprises: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:160; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:161; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:144; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:155.

[0087] In some embodiments of the invention, the isolated bispecific antibody is a bispecific antibody that specifically binds to CD3 and the tumor antigen CD20. In some embodiments of the invention, a bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 may be selected from the group comprising 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, or 019.

[0088] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 001. Antibody 001 includes: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and It contains the CDR3 of amino acid sequence SEQ ID NO:44.

[0089] Antibody 001 includes: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:10; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:16; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0090] Antibody 001 includes: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:24; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:30; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0091] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 002. Antibody 002 comprises: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0092] Antibody 002 comprises: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:16; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0093] Antibody 002 comprises: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:25; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:30; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0094] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 003. Antibody 003 contains: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0095] Antibody 003 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:10; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:17; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0096] Antibody 003 contains: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:24; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:31; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0097] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 004. Antibody 004 comprises: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0098] Antibody 004 comprises: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:10; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:18; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0099] Antibody 004 comprises: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:24; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:32; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0100] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 005. Antibody 005 contains: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0101] Antibody 005 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:10; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0102] Antibody 005 contains: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:24; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:33; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0103] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 006. Antibody 006 comprises: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0104] Antibody 006 comprises: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0105] Antibody 006 comprises: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:25; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:33; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0106] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 007. Antibody 007 includes: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 of amino acid sequence SEQ ID NO:1 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0107] Antibody 007 includes: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:12; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:18; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0108] Antibody 007 includes: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:26; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:32; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0109] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 008. Antibody 008 comprises: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:5 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:9 and (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0110] Antibody 008 comprises: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:13; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:20; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0111] Antibody 008 comprises: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:27; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:34; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0112] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 009. Antibody 009 includes: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:5 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:9 and (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0113] Antibody 009 includes: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:14; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:20; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0114] Antibody 009 includes: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:28; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:34; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0115] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 010. Antibody 010 includes: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:5 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:9 and (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0116] Antibody 010 includes: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:13; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:21; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0117] The antibody 010 contains the following: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:27; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:35; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0118] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 011. Antibody 011 includes: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:5 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:9 and (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0119] Antibody 011 includes: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:13; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:22; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0120] Antibody 011 includes: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:27; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:36; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0121] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 012. Antibody 012 comprises: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:5 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:9 and (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0122] Antibody 012 comprises: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:13; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:23; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0123] Antibody 012 comprises: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:27; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:37; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0124] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 013. Antibody 013 includes: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:5 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:9 and (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0125] Antibody 013 includes: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:14; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:23; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0126] Antibody 013 includes: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:28; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:37; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0127] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 014. Antibody 014 comprises: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 of amino acid sequence SEQ ID NO:1 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:5 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:9 and (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0128] Antibody 014 comprises: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO:15; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:22; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0129] Antibody 014 comprises: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:29; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:36; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0130] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 is antibody 019. Antibody 019 includes: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to CD20: CDR1 of amino acid sequence SEQ ID NO:39 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 40 and CDR3 of amino acid sequence SEQ ID NO:41 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising: CDR1 of amino acid sequence SEQ ID NO:42 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 43 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:44.

[0131] Antibody 019 includes: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to CD20 comprises the amino acid sequence SEQ ID NO:45; and, The variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:46.

[0132] Antibody 019 includes: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:25; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:38; (c) a light chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:47; and, (d) The heavy chain of a second antigen-binding fragment that specifically binds to CD20, comprising the amino acid sequence SEQ ID NO:48.

[0133] The Examples describe antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037, which specifically bind to BCMA and are characterized by the following amino acid sequences:

[0134] Antibodies 01-001 that specifically bind to BCMA include: (a) a light chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:49 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:57 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:66 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 (Kabat) of amino acid sequence SEQ ID NO:77; (ii) CDR2 of amino acid sequence SEQ ID NO:80 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0135] Antibodies 01-001 that specifically bind to BCMA include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:84; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:95.

[0136] Antibodies 01-001 that specifically bind to BCMA include: (a) a light chain comprising the amino acid sequence SEQ ID NO:103; and A heavy chain comprising the amino acid sequence SEQ ID NO:114.

[0137] Antibodies 01-006 that specifically bind to BCMA include: (a) a light chain variable domain, comprising: (i) CDR1 (Kabat) of amino acid sequence SEQ ID NO:50; (ii) CDR2 of amino acid sequence SEQ ID NO:58 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:67 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:78 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:81 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0138] Antibodies 01-006 that specifically bind to BCMA include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:85; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:96.

[0139] Antibodies 01-006 that specifically bind to BCMA include: (a) a light chain comprising the amino acid sequence SEQ ID NO:104; and A heavy chain comprising the amino acid sequence SEQ ID NO:115.

[0140] Antibodies 01-016 that specifically bind to BCMA include: (a) a light chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:51 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:59 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:68 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:79 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:80 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0141] Antibodies 01-016 that specifically bind to BCMA include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:86; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:97.

[0142] Antibodies 01-016 that specifically bind to BCMA include: (a) a light chain comprising the amino acid sequence SEQ ID NO:105; and A heavy chain comprising the amino acid sequence SEQ ID NO:116.

[0143] Antibodies 01-021 that specifically bind to BCMA include: (a) a light chain variable domain, comprising: (i) CDR1 (Kabat) of amino acid sequence SEQ ID NO:52; (ii) CDR2 of amino acid sequence SEQ ID NO:60 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:69 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:78 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:80 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0144] Antibodies 01-021 that specifically bind to BCMA include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:87; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:98.

[0145] Antibodies 01-021 that specifically bind to BCMA include: (a) a light chain comprising the amino acid sequence SEQ ID NO:106; and A heavy chain comprising the amino acid sequence SEQ ID NO:117.

[0146] Antibodies 01-022 that specifically bind to BCMA include: (a) a light chain variable domain, comprising: (i) CDR1 (Kabat) of amino acid sequence SEQ ID NO:53; (ii) CDR2 of amino acid sequence SEQ ID NO:61 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:70 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:78 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:81 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0147] Antibodies 01-022 that specifically bind to BCMA include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:88; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:99.

[0148] Antibodies 01-022 that specifically bind to BCMA include: (a) a light chain comprising the amino acid sequence SEQ ID NO:107; and A heavy chain comprising the amino acid sequence SEQ ID NO:118.

[0149] Antibodies 01-024 that specifically bind to BCMA include: (a) a light chain variable domain, comprising: (i) CDR1 (Kabat) of amino acid sequence SEQ ID NO:53; (ii) CDR2 of amino acid sequence SEQ ID NO:61 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:71 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:78 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:82 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0150] Antibodies 01-024 that specifically bind to BCMA include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:89; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:100.

[0151] Antibodies 01-024 that specifically bind to BCMA include: (a) a light chain comprising the amino acid sequence SEQ ID NO:108; and A heavy chain comprising the amino acid sequence SEQ ID NO:119.

[0152] Antibodies 01-025 that specifically bind to BCMA include: (a) a light chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:51 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:62 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:72 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:78 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:81 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0153] Antibodies 01-025 that specifically bind to BCMA include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:90; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:99.

[0154] Antibodies 01-025 that specifically bind to BCMA include: (a) a light chain comprising the amino acid sequence SEQ ID NO:109; and A heavy chain comprising the amino acid sequence SEQ ID NO:118.

[0155] Antibodies 01-026 that specifically bind to BCMA include: (a) a light chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:54 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:63 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:73 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:78 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:81 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0156] Antibodies 01-026 that specifically bind to BCMA include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:91; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:99.

[0157] Antibodies 01-026 that specifically bind to BCMA include: (a) a light chain comprising the amino acid sequence SEQ ID NO:110; and A heavy chain comprising the amino acid sequence SEQ ID NO:118.

[0158] Antibodies 01-027 that specifically bind to BCMA include: (a) a light chain variable domain, comprising: (i) CDR1 (Kabat) of amino acid sequence SEQ ID NO:53; (ii) CDR2 of amino acid sequence SEQ ID NO:61 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:71 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:78 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:81 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0159] Antibodies 01-027 that specifically bind to BCMA include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:89; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:99.

[0160] Antibodies 01-027 that specifically bind to BCMA include: (a) a light chain comprising the amino acid sequence SEQ ID NO:108; and A heavy chain comprising the amino acid sequence SEQ ID NO:118.

[0161] Antibodies 01-030 that specifically bind to BCMA include: (a) a light chain variable domain, comprising: (i) CDR1 (Kabat) of amino acid sequence SEQ ID NO:55; (ii) CDR2 of amino acid sequence SEQ ID NO:64 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:74 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:78 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:80 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0162] Antibodies 01-030 that specifically bind to BCMA include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:92; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:101.

[0163] Antibodies 01-030 that specifically bind to BCMA include: (a) a light chain comprising the amino acid sequence SEQ ID NO:111; and A heavy chain comprising the amino acid sequence SEQ ID NO:120.

[0164] Antibodies 01-033 that specifically bind to BCMA include: (a) a light chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:49 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:65 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:75 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:78 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:80 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0165] Antibodies 01-033 that specifically bind to BCMA include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:93; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:102.

[0166] Antibodies 01-033 that specifically bind to BCMA include: (a) a light chain comprising the amino acid sequence SEQ ID NO:112; and A heavy chain comprising the amino acid sequence SEQ ID NO:121.

[0167] Antibodies that specifically bind to BCMA, such as 01-037, include: (a) a light chain variable domain, comprising: (i) CDR1 (Kabat) of amino acid sequence SEQ ID NO:56; (ii) CDR2 of amino acid sequence SEQ ID NO:58 (Kabat); (iii) CDR3 of amino acid sequence SEQ ID NO:76 (Kabat); and (b) a heavy chain variable domain, comprising: (i) CDR1 of amino acid sequence SEQ ID NO:78 (Kabat); (ii) CDR2 of amino acid sequence SEQ ID NO:81 (Kabat); (iii) CDR3 (Kabat) of amino acid sequence SEQ ID NO:83.

[0168] Antibodies that specifically bind to BCMA, such as 01-037, include: (a) a light chain variable domain comprising the amino acid sequence SEQ ID NO:94; and (b) The variable domain of the heavy chain comprising the amino acid sequence SEQ ID NO:99.

[0169] Antibodies that specifically bind to BCMA, such as 01-037, include: (a) a light chain comprising the amino acid sequence SEQ ID NO:113; and A heavy chain comprising the amino acid sequence SEQ ID NO:118.

[0170] In some embodiments of the invention, the isolated bispecific antibody that specifically binds CD3 and the tumor antigen BCMA is an antibody selected from the group consisting of 02-001, 02-002, 02-003, 02-004, 02-005, 02-006, 02-007, 02-008, 02-009, 02-010, 02-011, or 02-012.

[0171] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-001. Antibody 02-001 contains: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 127 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0172] Antibody 02-001 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:132.

[0173] Antibody 02-001 contains: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:145.

[0174] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-002. Antibody 02-002 contains: (iii) (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 128 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0175] Antibody 02-002 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:133.

[0176] Antibody 02-002 contains: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:146.

[0177] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-003. Antibody 02-003 contains: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 127 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0178] Antibody 02-003 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:134.

[0179] Antibody 02-003 contains: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:147.

[0180] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-004. Antibody 02-004 contains: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 of amino acid sequence SEQ ID NO:128 (Kabat); and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0181] Antibody 02-004 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:135.

[0182] Antibody 02-004 contains: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:148.

[0183] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-005. Antibody 02-005 contains: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 126 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0184] Antibody 02-005 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:136.

[0185] Antibody 02-005 contains: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:149.

[0186] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-006. Antibody 02-006 contains: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 127 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0187] Antibody 02-006 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:137.

[0188] Antibody 02-006 contains: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:150.

[0189] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-007. Antibody 02-007: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 127 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0190] Antibody 02-007 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:138.

[0191] Antibody 02-007: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:151.

[0192] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-008. Antibody 02-008 contains: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 128 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0193] Antibody 02-008 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:139.

[0194] Antibody 02-008 contains: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:152.

[0195] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-009. Antibody 02-009 contains: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 129 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0196] Antibody 02-009 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:140.

[0197] Antibody 02-009 contains: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:153.

[0198] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-010. Antibody 02-010 contains: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 128 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0199] Antibody 02-010 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:141.

[0200] Antibody 02-010: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:158; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:154.

[0201] In some embodiments of the present invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-011. Antibody 02-011 comprises a first antigen-binding fragment that specifically binds to CD3, engineered in a CrossMAb format.

[0202] The CrossMAb format herein refers to the substitution of light and heavy chain variable domains for each other. Antibody 02-011 contains: (b) a light chain variable domain of a first antigen-binding fragment that specifically binds to CD3, designed in a CrossMAb format, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (b) a light chain variable domain of a first antigen-binding fragment that specifically binds to CD3, designed in a CrossMAb format, comprising: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 126 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0203] Antibody 02-011 contains: (a) the variable domain of the light chain of a first antigen-binding fragment designed in a CrossMAb format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:156; (b) the variable domain of the heavy chain of a first antigen-binding fragment designed in a CrossMAb format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:157; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:142.

[0204] Antibody 02-011 contains: (a) the light chain of a first antigen-binding fragment designed in a CrossMAb format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:160; (b) the heavy chain of a first antigen-binding fragment designed in a CrossMAb format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 161; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:144; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:155.

[0205] In some embodiments of the invention, the isolated bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA is antibody 02-012. Antibody 02-012 contains: (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3: CDR1 (Kabat) of amino acid sequence SEQ ID NO:2; CDR2 (Kabat) of amino acid sequence SEQ ID NO:3 and CDR3 of amino acid sequence SEQ ID NO:4 (Kabat); (b) a heavy chain variable domain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of amino acid sequence SEQ ID NO:6 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO:7 and CDR3 of amino acid sequence SEQ ID NO:8 (Kabat); (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA: CDR1 of amino acid sequence SEQ ID NO:122 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 123 and CDR3 of amino acid sequence SEQ ID NO:124 (Kabat); and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO:125 (Kabat); CDR2 (Kabat) of amino acid sequence SEQ ID NO: 126 and CDR3 (Kabat) of amino acid sequence SEQ ID NO:130.

[0206] Antibody 02-012 contains: (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:142.

[0207] Antibody 02-012 contains: (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO:162; (b) a heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising the amino acid sequence SEQ ID NO:163; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:144; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO:155.

[0208] The hypervariable regions of the light and heavy chain variable domains (LCDR1, 2, 3 and HCDR1, 2, 3) of all the above antibodies are designated according to the Kabat numbering system. It will be apparent to those skilled in the art that the hypervariable regions of the light and heavy chain variable domains (LCDR1, 2, 3 and HCDR1, 2, 3) can also be designated according to other well-known numbering systems, such as IMGT, Chothia, or AbM. Thus, all of the above antibodies characterized by the hypervariable regions of the light and heavy chain variable domains (LCDR1, 2, 3 and HCDR1, 2, 3) according to the IMGT, Chothia, or AbM numbering system are also within the scope of the present invention.

[0209] nucleic acid molecule In one aspect, the invention relates to a nucleic acid encoding any of the aforementioned bispecific antibodies that specifically bind to CD3 and a tumor antigen.

[0210] In one aspect, the invention relates to a nucleic acid encoding any of the aforementioned bispecific antibodies that specifically bind to CD3 and the tumor antigen BCMA. In any of the above embodiments of the invention, the nucleic acid molecule may be isolated.

[0211] The terms "nucleic acid," "nucleic acid sequence," "polynucleotide," "oligonucleotide," "polynucleotide sequence," and "nucleotide sequence," used interchangeably herein, refer to a specific sequence of modified or unmodified nucleotides, defining a fragment or region of a nucleic acid, with or without non-naturally occurring nucleotides, either double-stranded DNA or RNA, or single-stranded DNA or RNA, or a transcription product of said DNA.

[0212] Unless otherwise specified, the term nucleotide sequence also includes its complementary sequence. Thus, a nucleic acid having a particular sequence should be understood to encompass a complementary strand, having its complementary sequence.

[0213] An "isolated" nucleic acid molecule is a nucleic acid molecule that is distinguished and separated from at least one contaminant nucleic acid molecule. An isolated nucleic acid molecule is different from the form or set in which it is found in nature. Thus, an isolated nucleic acid molecule is different from the nucleic acid molecule that exists in cells under natural conditions.

[0214] In one aspect, the present invention relates to a nucleic acid molecule comprising a nucleotide sequence that encodes an amino acid sequence selected from SEQ ID NOs: 1-165. The nucleic acid molecule may also include any combination of the specified nucleotide sequences.

[0215] It will be apparent to those skilled in the art that, in view of the degeneracy of the genetic code, the amino acid sequences of the light or heavy chains of the bispecific antibodies according to the present invention, or fragments thereof (VH, VL, CDRs, etc.), can be encoded by a wide range of different DNA sequences. Those skilled in the art will be familiar with the creation of such alternative DNA sequences that encode the same amino acid sequence. Such variant DNA sequences are within the scope of the present invention.

[0216] In some embodiments of the invention, the isolated nucleic acid is DNA. The nucleic acid molecules of the invention can be isolated from any source that produces the monoclonal bispecific antibody or antigen-binding fragment thereof of the invention. In certain embodiments of the invention, the nucleic acid molecules of the invention are not isolated but rather can be synthesized by chemical synthesis.

[0217] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3 of antibodies 001, 003, 004, and 005, and comprises the nucleotide sequence of SEQ ID NO:166.

[0218] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, antibody 002, 006, 019, 02-001, 02-002, 02-003, 02-004, 02-005, 02-006, 02-007, 02-008, 02-009, 02-010, or 02-012, and comprises the nucleotide sequence of SEQ ID NO:167.

[0219] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of a first antigen-binding fragment of antibody 007 that specifically binds to CD3, and comprises the nucleotide sequence of SEQ ID NO:168.

[0220] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3 of antibodies 008, 010, 011, and 012, and comprises the nucleotide sequence of SEQ ID NO:169.

[0221] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of a first antigen-binding fragment of antibodies 009 and 013 that specifically binds to CD3, and comprises the nucleotide sequence of SEQ ID NO:170.

[0222] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of a first antigen-binding fragment of antibody 014 that specifically binds to CD3, and comprises the nucleotide sequence of SEQ ID NO:171.

[0223] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of a first antigen-binding fragment that specifically binds to CD3, antibodies 001, 003, 004, and 005, and comprises the nucleotide sequence of SEQ ID NO:172.

[0224] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the light chain of a first antigen-binding fragment that specifically binds to CD3, antibody 002, 006, 019, 02-001, 02-002, 02-003, 02-004, 02-005, 02-006, 02-007, 02-008, 02-009, 02-010, or 02-012, and comprises the nucleotide sequence of SEQ ID NO:173.

[0225] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of antibody 007, a first antigen-binding fragment that specifically binds to CD3, and comprises the nucleotide sequence of SEQ ID NO:174.

[0226] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of a first antigen-binding fragment that specifically binds to CD3, antibody 008, 010, 011, and 012, and comprises the nucleotide sequence of SEQ ID NO:175.

[0227] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of a first antigen-binding fragment that specifically binds to CD3, antibodies 009 and 013, and comprises the nucleotide sequence of SEQ ID NO:176.

[0228] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of antibody 014, a first antigen-binding fragment that specifically binds to CD3, and comprises the nucleotide sequence of SEQ ID NO:177.

[0229] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 001, 002, and comprises the nucleotide sequence of SEQ ID NO:178.

[0230] In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of the first antigen-binding fragment of antibody 003 that specifically binds to CD3, and comprises the nucleotide sequence of SEQ ID NO:179.

[0231] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 004, or 007, and comprises the nucleotide sequence of SEQ ID NO:180.

[0232] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 005, 006, 019, 02-001, 02-002, 02-003, 02-004, 02-005, 02-006, 02-007, 02-008, 02-009, 02-010, and 02-012, and comprises the nucleotide sequence of SEQ ID NO:181.

[0233] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 008, 009, and comprises the nucleotide sequence of SEQ ID NO:182.

[0234] In some embodiments of the present invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a first antigen-binding fragment of antibody 010 that specifically binds to CD3, and comprises the nucleotide sequence of SEQ ID NO:183.

[0235] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 011, or 014, and comprises the nucleotide sequence of SEQ ID NO:184.

[0236] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 012, or 013, and comprises the nucleotide sequence of SEQ ID NO:185.

[0237] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 001, 002, and comprises the nucleotide sequence of SEQ ID NO:186.

[0238] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 003, and comprises the nucleotide sequence of SEQ ID NO:187.

[0239] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 004, 007, and comprises the nucleotide sequence of SEQ ID NO:188.

[0240] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 005, 006, 019, 02-001, 02-002, 02-003, 02-004, 02-005, 02-006, 02-007, 02-008, 02-009, 02-010, and 02-012, and comprises the nucleotide sequence of SEQ ID NO:189.

[0241] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 008, 009, and comprises the nucleotide sequence of SEQ ID NO:190.

[0242] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 010, and comprises the nucleotide sequence of SEQ ID NO:191.

[0243] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 011, 014, and comprises the nucleotide sequence of SEQ ID NO:192.

[0244] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 012, 013, and comprises the nucleotide sequence of SEQ ID NO:193.

[0245] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 019, and comprises the nucleotide sequence of SEQ ID NO:194.

[0246] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the light chain of a second antigen-binding fragment that specifically binds to CD20, antibody 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 019, and comprises the nucleotide sequence of SEQ ID NO:195.

[0247] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the heavy chain of a second antigen-binding fragment that specifically binds to CD20, antibody 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, 019, and comprises the nucleotide sequence of SEQ ID NO:196.

[0248] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the light chain of antibody 01-001 and comprising the nucleotide sequence of SEQ ID NO:197.

[0249] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of antibody 01-006 and comprises the nucleotide sequence of SEQ ID NO:198.

[0250] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the light chain of antibody 01-016 and comprising the nucleotide sequence of SEQ ID NO:199.

[0251] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the light chain of antibody 01-021 and comprises the nucleotide sequence of SEQ ID NO:200.

[0252] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the light chain of antibody 01-022 and comprising the nucleotide sequence of SEQ ID NO:201.

[0253] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the light chain of antibodies 01-024 and 01-027 and comprising the nucleotide sequence of SEQ ID NO:202.

[0254] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of antibody 01-025 and comprises the nucleotide sequence of SEQ ID NO:203.

[0255] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of antibody 01-026 and comprises the nucleotide sequence of SEQ ID NO:204.

[0256] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of antibody 01-030 and comprises the nucleotide sequence of SEQ ID NO:205.

[0257] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the light chain of antibody 01-033 and comprises the nucleotide sequence of SEQ ID NO:206.

[0258] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of antibody 01-037 and comprises the nucleotide sequence of SEQ ID NO:207.

[0259] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the heavy chain of antibody 01-001 and comprises the nucleotide sequence of SEQ ID NO:208.

[0260] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the heavy chain of antibody 01-006 and comprises the nucleotide sequence of SEQ ID NO:209.

[0261] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the heavy chain of antibody 01-016 and comprises the nucleotide sequence of SEQ ID NO:210.

[0262] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the heavy chain of antibody 01-021 and comprises the nucleotide sequence of SEQ ID NO:211.

[0263] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of antibodies 01-022, 01-025, 01-026, 01-027, and 01-037 and comprising the nucleotide sequence of SEQ ID NO:212.

[0264] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the heavy chain of antibody 01-024 and comprises the nucleotide sequence of SEQ ID NO:213.

[0265] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the heavy chain of antibody 01-030 and comprises the nucleotide sequence of SEQ ID NO:214.

[0266] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the variable domain of the heavy chain of antibody 01-033 and comprises the nucleotide sequence of SEQ ID NO:215.

[0267] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 01-001 and comprises the nucleotide sequence of SEQ ID NO:216. In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 01-006 and comprises the nucleotide sequence of SEQ ID NO:217.

[0268] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 01-016 and comprises the nucleotide sequence of SEQ ID NO:218. In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 01-021 and comprises the nucleotide sequence of SEQ ID NO:219.

[0269] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 01-022 and comprises the nucleotide sequence of SEQ ID NO:220. In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibodies 01-024 and 01-027 and comprises the nucleotide sequence of SEQ ID NO:221.

[0270] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 01-025 and comprises the nucleotide sequence of SEQ ID NO:222. In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 01-026 and comprises the nucleotide sequence of SEQ ID NO:223.

[0271] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 01-030 and comprises the nucleotide sequence of SEQ ID NO:224. In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 01-033 and comprises the nucleotide sequence of SEQ ID NO:225.

[0272] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the light chain of antibody 01-037 and comprises the nucleotide sequence of SEQ ID NO:226. In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 01-001 and comprises the nucleotide sequence of SEQ ID NO:227.

[0273] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 01-006 and comprises the nucleotide sequence of SEQ ID NO:228. In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 01-016 and comprises the nucleotide sequence of SEQ ID NO:229.

[0274] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 01-021 and comprises the nucleotide sequence of SEQ ID NO:230. In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of antibodies 01-022, 01-025, 01-026, 01-027 and 01-037 and comprises the nucleotide sequence of SEQ ID NO:231.

[0275] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 01-024 and comprises the nucleotide sequence of SEQ ID NO:232. In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 01-030 and comprises the nucleotide sequence of SEQ ID NO:233.

[0276] In some embodiments of the invention, the nucleic acid is a nucleic acid that encodes the amino acid sequence of the heavy chain of antibody 01-033 and comprises the nucleotide sequence of SEQ ID NO:234. In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-001, 02-002, 02-003, 02-004, 02-005, 02-006, 02-007, 02-008, 02-009, 02-010, 02-011, 02-012, and comprises the nucleotide sequence of SEQ ID NO:235.

[0277] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-001, and comprises the nucleotide sequence of SEQ ID NO:236.

[0278] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-002, and comprises the nucleotide sequence of SEQ ID NO:237.

[0279] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-003, and comprises the nucleotide sequence of SEQ ID NO:238.

[0280] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-004, and comprises the nucleotide sequence of SEQ ID NO:239.

[0281] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-005, and comprises the nucleotide sequence of SEQ ID NO:240.

[0282] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-006, and comprises the nucleotide sequence of SEQ ID NO:241.

[0283] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-007, and comprises the nucleotide sequence of SEQ ID NO:242.

[0284] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-008, and comprises the nucleotide sequence of SEQ ID NO:243.

[0285] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-009, and comprises the nucleotide sequence of SEQ ID NO:244.

[0286] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-010, and comprises the nucleotide sequence of SEQ ID NO:245.

[0287] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-011, or 02-012, and comprises the nucleotide sequence of SEQ ID NO:246.

[0288] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the light chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-001, 02-002, 02-003, 02-004, 02-005, 02-006, 02-007, 02-008, 02-009, 02-010, and comprises the nucleotide sequence of SEQ ID NO:247.

[0289] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-011, or 02-012, and comprises the nucleotide sequence of SEQ ID NO:248.

[0290] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the heavy chain of the second antigen-binding fragment that specifically binds to BCMA, antibody 02-001, and comprises the nucleotide sequence of SEQ ID NO:249.

[0291] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the heavy chain of the second antigen-binding fragment that specifically binds to BCMA, antibody 02-002, and comprises the nucleotide sequence of SEQ ID NO:250.

[0292] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the heavy chain of the second antigen-binding fragment that specifically binds to BCMA, antibody 02-003, and comprises the nucleotide sequence of SEQ ID NO:251.

[0293] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of the second antigen-binding fragment that specifically binds BCMA, antibody 02-004, and comprises the nucleotide sequence of SEQ ID NO:252.

[0294] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the heavy chain of the second antigen-binding fragment that specifically binds to BCMA, antibody 02-005, and comprises the nucleotide sequence of SEQ ID NO:253.

[0295] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of the second antigen-binding fragment that specifically binds BCMA, antibody 02-006, and comprises the nucleotide sequence of SEQ ID NO:254.

[0296] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the heavy chain of the second antigen-binding fragment that specifically binds to BCMA, antibody 02-007, and comprises the nucleotide sequence of SEQ ID NO:255.

[0297] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the heavy chain of the second antigen-binding fragment that specifically binds to BCMA, antibody 02-008, and comprises the nucleotide sequence of SEQ ID NO:256.

[0298] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the heavy chain of the second antigen-binding fragment that specifically binds to BCMA, antibody 02-009, and comprises the nucleotide sequence of SEQ ID NO:257.

[0299] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of the second antigen-binding fragment that specifically binds BCMA, antibody 02-010, and comprises the nucleotide sequence of SEQ ID NO:258.

[0300] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, antibody 02-011, or 02-012, and comprises the nucleotide sequence of SEQ ID NO:259.

[0301] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the light chain of a first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3, antibody 02-11, and comprises the nucleotide sequence of SEQ ID NO:260.

[0302] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the variable domain of the heavy chain of a first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3, antibody 02-11, and comprises the nucleotide sequence of SEQ ID NO:261.

[0303] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the light chain of a first antigen-binding fragment that specifically binds to CD3, antibody 02-001, 02-002, 02-003, 02-004, 02-005, 02-006, 02-007, 02-008, 02-009, 02-010, and comprises the nucleotide sequence of SEQ ID NO:262.

[0304] In some embodiments of the invention, the nucleic acid encodes the amino acid sequence of the heavy chain of a first antigen-binding fragment that specifically binds to BCMA, antibody 02-001, 02-002, 02-003, 02-004, 02-005, 02-006, 02-007, 02-008, 02-009, 02-010, and comprises the nucleotide sequence of SEQ ID NO:263.

[0305] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of a first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3, antibody 02-011, and comprises the nucleotide sequence of SEQ ID NO:264.

[0306] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of a first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3, antibody 02-011, and comprises the nucleotide sequence of SEQ ID NO:265.

[0307] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the light chain of a first antigen-binding fragment that specifically binds to CD3, antibody 02-012, and is produced in scFv format, comprising the nucleotide sequence of SEQ ID NO:266.

[0308] In some embodiments of the invention, the nucleic acid is a nucleic acid encoding the amino acid sequence of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, antibody 02-012, and is produced in scFv format, comprising the nucleotide sequence of SEQ ID NO:267.

[0309] The nucleic acid molecules can be used to express a recombinant monoclonal bispecific antibody or antigen-binding fragment thereof of the invention. Vector In one aspect, the present invention relates to an expression vector comprising any of the aforementioned nucleic acid molecules encoding the corresponding amino acid sequence of a bispecific antibody that specifically binds to CD3 and a tumor antigen, or a portion thereof (e.g., the sequence of the heavy and / or light chain binding domains). The present invention relates to a vector suitable for expressing any of the nucleotide sequences described herein.

[0310] In one aspect, the present invention relates to an expression vector comprising any of the aforementioned nucleic acid molecules encoding the corresponding amino acid sequence of a bispecific antibody that specifically binds to BCMA and a tumor antigen, or a portion thereof (e.g., the sequence of the heavy and / or light chain binding domains). The present invention relates to a vector suitable for expressing any of the nucleotide sequences described herein.

[0311] As used herein, the term "vector" means a nucleic acid molecule capable of transporting another nucleic acid to which it has been linked. As used herein, the term "expression" is defined as the initiation of transcription and / or translation of a particular nucleotide sequence by its promoter.

[0312] In some embodiments of the invention, the vector is a plasmid, ie, a circular double-stranded piece of DNA into which additional DNA segments can be inserted. In some embodiments of the invention, the vector is a viral (expression) vector, which allows for the insertion of additional DNA segments into the viral genome.

[0313] In some embodiments of the invention, vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal vectors). In other embodiments of the invention, vectors (e.g., non-episomal vectors) may be integrated into the genome of a host cell upon introduction into the host cell and are replicated along with the host genome. Additionally, some vectors are capable of directing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply "expression vectors").

[0314] In some embodiments of the present invention, expression vectors include plasmids, retroviruses, adenoviruses, adeno-associated viruses (AAV), plant viruses such as cauliflower mosaic virus and tobacco mosaic virus, cosmids, YACs, etc. DNA molecules can be inserted into vectors such that transcriptional and translational control sequences within the vector perform their intended regulatory function with respect to DNA transcription and translation. Expression vectors and expression control sequences can be selected to be compatible with the host expression cell used.

[0315] In one embodiment of the present invention, DNA molecules encoding part or all of the sequences of the first binding domain and the second binding domain (e.g., the heavy chain sequence and the light chain sequence, if the binding domain comprises a heavy chain sequence and a light chain sequence) can be inserted into separate vectors.

[0316] In one embodiment of the present invention, any combination of the above-mentioned DNA molecules is inserted into the same expression vector. In one embodiment of the present invention, the DNA molecule can be introduced into an expression vector by standard methods (e.g., by ligating complementary restriction sites on the antibody gene fragment and vector, or by blunt-end ligation if no restriction sites are present).

[0317] In some embodiments of the invention, a suitable vector is one that contains restriction sites so that any VH or VL sequence can be easily incorporated and expressed as described above. The recombinant expression vector may also encode a signal peptide that facilitates production of the antibody chain by the host cell. The antibody chain gene can be cloned into the vector such that the signal peptide is joined in reading frame to the amino terminus of the immunoglobulin chain. The signal peptide may be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide of a protein without immunoglobulin properties).

[0318] In some embodiments of the present invention, vectors may contain expression control sequences. As used herein, the term "expression control sequence" refers to a polynucleotide sequence necessary to affect the expression and processing of a coding sequence into which it is inserted. Those skilled in the art will understand that the design of an expression vector, including the selection of expression control sequences, may depend on factors such as the choice of host cell type for transformation and the desired level of antibody expression. Expression control sequences include transcription initiation and termination, promoter and enhancer regions, RNA processing signals such as splicing and polyadenylation, sequences that maintain cytoplasmic mRNA stability, sequences that increase translation efficiency (Kozak sequences), sequences that increase protein stability, and, optionally, sequences that increase protein secretion. The nature of such expression control sequences varies depending on the host organism. In prokaryotes, these control sequences typically include a promoter, a ribosome binding site, and a transcription termination sequence. In eukaryotes, such expression control sequences generally include a promoter and a transcription termination sequence. Preferred expression control sequences for mammalian host expression cells include viral elements that provide high levels of protein expression in mammalian cells, such as promoters and / or enhancers from retroviral LTRs, cytomegalovirus (CMV) (CMV promoter / enhancer), simian virus 40 (SV40) (SV40 promoter / enhancer), adenovirus (adenovirus major late promoter (AdMLP)), polyoma virus, and strong mammalian promoters such as the TTR promoter, native immunoglobulin promoters, or actin promoter. Expression control sequences include, at a minimum, all components essential for expression and processing.

[0319] In some embodiments of the invention, in addition to the antibody chain genes and expression control sequences, the recombinant expression vectors of the invention can carry additional sequences, such as sequences that control vector replication in host cells (e.g., origin of replication sites) and selectable marker genes that facilitate selection of host cells into which the vector has been introduced.

[0320] host cell In one aspect, the invention relates to a method for obtaining a host cell for producing any of the aforementioned bispecific antibodies that specifically bind to CD3 and a tumor antigen, the method comprising transforming the cell with the aforementioned vector.

[0321] In one aspect, the invention relates to a host cell comprising any of the aforementioned nucleic acids for producing any of the aforementioned bispecific antibodies that specifically bind to CD3 and a tumor antigen. In one aspect, the invention relates to a method of obtaining a host cell for producing any of the above-mentioned bispecific antibodies that specifically bind to CD3 and the tumor antigen BCMA, the method comprising transforming the cell with an above-mentioned vector.

[0322] In one aspect, the invention relates to a host cell comprising any of the aforementioned nucleic acids for producing any of the aforementioned bispecific antibodies that specifically bind to CD3 and the tumor antigen BCMA.

[0323] As used herein, the term "host cell" refers to a cell into which a recombinant expression vector has been introduced. The present invention relates to host cells, for example, containing the vectors of the present invention described above. The present invention also relates to host cells containing, for example, a nucleotide sequence encoding a heavy chain or antigen-binding portion thereof of a first antigen-binding fragment, a nucleotide sequence encoding a light chain or antigen-binding portion thereof of a first antigen-binding fragment, a nucleotide sequence encoding a heavy chain or antigen-binding portion thereof of a second antigen-binding fragment, a nucleotide sequence encoding a light chain or antigen-binding portion thereof of a second antigen-binding fragment, or all four thereof. It should be understood that "host cell" refers not only to the particular cell designated, but also to the progeny of that cell. While such progeny may not be identical to the parent cell due to possible mutations or environmental influences in subsequent generations, such cells are still within the scope of the term "host cell" as used herein.

[0324] Nucleic acid molecules encoding the monoclonal bispecific antibodies or antigen-binding fragments thereof of the present invention, and vectors containing these nucleic acid molecules, can be used to transfect mammalian, plant, bacterial, or yeast cells. Transfection can be carried out by known methods for introducing polynucleotides into host cells. Methods for introducing heterologous polynucleotides into mammalian cells are well known in the art and include dextran-mediated transfection, transfection via complexes of nucleic acids with positively charged polymers, transfection via calcium phosphate precipitation, polybrene-mediated transfection, protoplast fusion, transfection via liposome-encapsulated polynucleotides, and direct microinjection of DNA into the nucleus. Additionally, viral (expression) vectors can be used to introduce nucleic acid molecules into mammalian cells.

[0325] Mammalian cell lines used as hosts for transformation are well known in the art and include many readily available immortalized cell lines. These include, for example, Chinese hamster ovary (CHO) cells, NS0 cells, SP2 cells, HEK-293T cells, 293 Freestyle cells (Invitrogen), NIH-3T3 cells, HeLa cells, baby hamster kidney (BHK) cells, African green monkey kidney (COS) cells, human hepatocellular carcinoma cells (e.g., Hep G2), A549, SK-HEP1, HUH7, Hep-RG cells, and many others. Cell lines are selected by determining which cell lines have high expression levels and possess the necessary characteristics for the protein being produced. Other cell lines that can be used include insect cell lines such as Sf9 and Sf21. When a recombinant expression vector encoding a bispecific antibody of the invention is introduced into mammalian host cells, the antibody or fragment thereof is produced by culturing the host cells for a period of time sufficient to express the antibody or fragment thereof in the host cells, or preferably, to secrete the antibody or fragment thereof into the culture medium in which the host cells are grown. The bispecific antibody of the invention can be isolated from the culture medium using standard protein purification methods. For example, plant host cells include Nicotiana, Arabidopsis, duckweed, corn, wheat, potato, etc. Bacterial host cells include species of the genera Escherichia and Streptomyces. Yeast host cells include Schizosaccharomyces pombe, Saccharomyces cerevisiae, Pichia pastoris, etc.

[0326] Furthermore, the level of bispecific antibody product from the production cell lines according to the invention can be increased using several well-known methods, for example, the glutamine synthetase (GS) gene expression system is very commonly used to enhance expression under certain conditions.

[0327] Bispecific antibodies according to the invention from different cell lines will most likely differ from each other in their glycosylation profiles. However, bispecific antibodies according to the invention that are encoded by the nucleic acid molecules described herein or that comprise the amino acid sequences described herein are part of the invention, regardless of the glycosylation state of the binding molecule, and more generally, regardless of the presence or absence of post-translational modifications.

[0328] The host cells do not mean host cells obtained using human embryos. The host cells do not refer to host cells obtained by altering the genetic integrity of the human germ line.

[0329] How to obtain antibodies In one aspect, the present invention relates to a method for obtaining a bispecific antibody that specifically binds to CD3 and a tumor antigen, the method comprising culturing the above-mentioned host cell in a culture medium under conditions sufficient to produce a specific antibody or a fragment thereof, and isolating and purifying the obtained antibody.

[0330] In one aspect, the present invention relates to a method for obtaining a bispecific antibody that specifically binds to CD3 and the tumor antigen BCMA, comprising culturing said host cell in a culture medium under conditions sufficient to produce the specified antibody or fragment thereof, and subsequently isolating and purifying the obtained antibody.

[0331] Pharmaceutical Composition In one aspect, the present invention relates to a pharmaceutical composition comprising as an active ingredient (or as the only active ingredient) a bispecific antibody according to the present invention, which specifically binds to CD3 and a tumor antigen.

[0332] In one aspect, the present invention relates to a pharmaceutical composition comprising a bispecific antibody of the invention that specifically binds to CD3 and a tumor antigen as an active ingredient (or the only active ingredient), in combination with one or more pharmaceutically acceptable excipients.

[0333] In one aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a bispecific antibody of the invention that specifically binds to CD3 and a tumor antigen as an active ingredient (or as the only active ingredient), in combination with one or more pharmaceutically acceptable excipients.

[0334] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by a tumor antigen comprising a therapeutically effective amount of any bispecific antibody according to the invention that specifically binds to CD3 and a tumor antigen, in combination with one or more pharmaceutically acceptable excipients.

[0335] In another aspect, the present invention relates to a pharmaceutical composition comprising as an active ingredient (or as the only active ingredient) a bispecific antibody according to the invention, which specifically binds to CD3 and the tumor antigen BCMA.

[0336] In one aspect, the present invention relates to a pharmaceutical composition comprising a bispecific antibody of the invention that specifically binds to CD3 and BCMA tumor antigens as an active ingredient (or the only active ingredient), in combination with one or more pharmaceutically acceptable excipients.

[0337] In one aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a bispecific antibody of the invention that specifically binds to CD3 and BCMA tumor antigens as an active ingredient (or as the only active ingredient), in combination with one or more pharmaceutically acceptable excipients.

[0338] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by a tumor antigen comprising a therapeutically effective amount of any bispecific antibody according to the invention which specifically binds to CD3 and BCMA tumor antigens in combination with one or more pharmaceutically acceptable excipients.

[0339] A "pharmaceutical composition" refers to a composition comprising an antibody of the present invention and at least one component selected from the group consisting of pharmaceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, adjuvants, dispersing agents, absorption agents, and delivery agents.

[0340] The term "pharmaceutically acceptable" means one or more compatible liquid or solid components that are suitable for administration to a mammal, preferably a human. The term "excipient" or "auxiliary substance" as used herein refers to any component other than the antibody according to the invention. These are substances of inorganic or organic origin that are used in the process of manufacturing and preparing pharmaceutical formulations and that impart the necessary physicochemical properties to the pharmaceutical formulation.

[0341] In some embodiments, the composition is intended for the amelioration, prevention, or treatment of a disease or disorder that may be mediated by a tumor antigen. The term "tumor antigen-mediated disease or disorder" refers to any disease or disorder that is directly or indirectly associated with a tumor antigen, including the etiology, onset, progression, persistence, or pathology of the disease or disorder.

[0342] "Treating," "treatment," and "therapy" refer to a method of alleviating or eliminating at least one of a biological disorder and / or associated symptoms. Furthermore, as used herein, reference to "treatment" includes reference to curative, palliative, and prophylactic therapy.

[0343] The term "disorder" means any condition that may be ameliorated as a result of treatment according to the present invention. The term includes chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to developing such a disorder.

[0344] A "therapeutically effective amount" is the amount of a therapeutic agent administered during treatment that is considered to relieve to some extent one or more of the symptoms of the disease being treated. The therapeutically effective amount may vary depending on factors such as the particular condition being treated, the age, sex, and weight of the patient, and whether the bispecific antibody according to the invention is administered as the sole treatment or in combination with one or more additional drugs or therapies.

[0345] In one embodiment, the subject or patient is a mammal, preferably a human subject, and may be male or female and of any age. The pharmaceutical compositions of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Preferably, the preparation of pharmaceutical compositions is carried out in accordance with GMP (Good Manufacturing Practice) requirements.

[0346] In certain embodiments, the pharmaceutical composition may include a buffer composition, an isotonicity agent (osmolality adjusting agent or osmotic adjusting agent), a stabilizer, and / or a solubilizing agent. The pharmaceutical compositions of the present invention are stable.

[0347] A pharmaceutical composition is considered "stable" if the active agent maintains physical stability, chemical stability, and / or biological activity throughout the specified shelf life under storage conditions, e.g., 2-8°C. Preferably, the active agent maintains physical stability, chemical stability, and biological activity. The storage period is determined based on the results of stability studies conducted under accelerated and real-time storage conditions.

[0348] The pharmaceutical composition of the present invention is suitable for parenteral administration in the form of a sterile pharmaceutical product intended for administration to subjects with compromised skin or mucosal integrity by injection, infusion, or implantation, bypassing the gastrointestinal tract.In particular, parenteral administration includes, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intravenous, intraarterial, intrathecal, intraventricular, intraurethral, ​​intracranial, intraarticular injection or infusion, and kidney dialysis infusion techniques.Intratumoral delivery, such as intratumoral injection, may also be applicable.Local perfusion is also considered.

[0349] In some embodiments, the pharmaceutical composition is administered intravenously. In certain embodiments, intravenous administration is by infusion, continuous infusion, or continuous drip.

[0350] In some embodiments, the pharmaceutical composition is administered subcutaneously. In some embodiments, the subcutaneous administration is by subcutaneous injection. In some embodiments, the pharmaceutical composition is in an injectable form.

[0351] In certain embodiments, the injectable pharmaceutical form is an infusion solution. In certain embodiments, the injectable dosage form is a solution for subcutaneous injection. Injectable dosage forms can be prepared in standard pharmaceutical forms such as, but not limited to, ampoules, vials, polymeric containers, pre-filled syringes, and auto-injectors.

[0352] In some embodiments, the pharmaceutical composition is provided in a dry form, i.e., as a powder or granules for reconstitution with a suitable solvent (e.g., sterile pyrogen-free water) prior to administration. Such pharmaceuticals can be obtained, for example, by lyophilization (a process known in the art as freeze-drying, which involves freezing the formulation and then removing the frozen solvent).

[0353] In some embodiments, the pharmaceutical composition is a lyophilizate for preparing a solution for injection. In some embodiments, the pharmaceutical composition is a lyophilizate for preparing a solution for subcutaneous administration.

[0354] In some embodiments, the pharmaceutical composition is a concentrate for preparing an infusion solution. In some embodiments, the pharmaceutical composition is a concentrate for preparing a solution for subcutaneous administration.

[0355] In one aspect, the present invention relates to a pharmaceutical composition comprising a bispecific antibody of the present invention that specifically binds to CD3 and a tumor antigen and at least one other therapeutically active compound. In one aspect, the present invention relates to a pharmaceutical composition comprising a bispecific antibody according to the invention which specifically binds to CD3 and the tumor antigen BCMA, and at least one other therapeutically active compound.

[0356] In one aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a bispecific antibody of the invention that specifically binds to CD3 and a tumor antigen, and at least one other therapeutically active compound.

[0357] In one aspect, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a bispecific antibody of the invention that specifically binds to CD3 and the tumor antigen BCMA, and at least one other therapeutically active compound.

[0358] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by a tumor antigen, comprising any of the bispecific antibodies described above and at least one other therapeutically active compound.

[0359] In one aspect, the invention relates to a pharmaceutical composition comprising any of the aforementioned bispecific antibodies and further comprising at least one other therapeutically active compound. In one aspect, the invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by a tumor antigen, comprising any of the bispecific antibodies described above and further comprising at least one other therapeutically active compound.

[0360] In one aspect, the invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by a tumor antigen, comprising any of the bispecific antibodies described above and at least one other therapeutically active compound selected from an antibody, a small molecule compound, a hormone therapy agent, or a combination thereof.

[0361] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by a tumor antigen, comprising a therapeutically effective amount of any of the aforementioned bispecific antibodies and at least one other therapeutically active compound.

[0362] In one aspect, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of any of the aforementioned bispecific antibodies, and further comprising at least one other therapeutically active compound. In one aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by a tumor antigen, comprising a therapeutically effective amount of any of the aforementioned bispecific antibodies and further at least one other therapeutically active compound.

[0363] In one aspect, the present invention relates to a pharmaceutical composition for the treatment of a disease or disorder mediated by a tumor antigen, comprising a therapeutically effective amount of any of the aforementioned bispecific antibodies and at least one other therapeutically active compound selected from an antibody, a small molecule, a hormone therapy agent, or a combination thereof.

[0364] In some embodiments of the pharmaceutical composition, the disease or disorder mediated by a tumor antigen is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, acute B-lymphoblastic leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

[0365] Therapeutic uses of bispecific antibodies according to the invention In one embodiment, a bispecific antibody according to the invention that specifically binds to CD3 and a tumor antigen is used in the treatment of a disease mediated by the activity of the tumor antigen.

[0366] In one embodiment, a bispecific antibody of the invention that specifically binds to CD3 and the tumor antigen BCMA is used to treat a disease mediated by the activity of the BCMA tumor antigen. In some embodiments, the subject or patient to be treated is a mammal, preferably a human, and can be of any sex and age.

[0367] In one aspect, the present invention relates to a method for treating a disease or disorder mediated by a tumor antigen, comprising administering to a subject in need thereof a therapeutically effective amount of any of the bispecific antibodies or pharmaceutical compositions described above.

[0368] In one aspect, the present invention relates to a method of treating a disease or disorder mediated by a tumor antigen, comprising administering to a subject in need thereof a therapeutically effective amount of any of the bispecific antibodies described above and at least one other therapeutically active compound.

[0369] In some embodiments, the disease or disorder mediated by a tumor antigen is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, acute B lymphoblastic leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

[0370] In some embodiments, the other therapeutically active compound is selected from an antibody, a small molecule, a hormone therapy agent, or a combination thereof. In one aspect, the present invention relates to the use of an aforementioned bispecific antibody or an aforementioned pharmaceutical composition for treating a disease or disorder mediated by a tumor antigen in a subject in need of such treatment.

[0371] In one aspect, the present invention relates to the use of the aforementioned bispecific antibody and at least one other therapeutically active compound for the treatment of a disease or disorder mediated by a tumor antigen.

[0372] In some embodiments, the disease or disorder mediated by a tumor antigen is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, acute B lymphoblastic leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

[0373] In some embodiments of the use, the other therapeutically active compound is selected from an antibody, a small molecule, a hormone therapy agent, or a combination thereof. Uses or methods described herein relating to a combination of a bispecific antibody according to the invention with one or more other therapeutic agents are understood to mean, refer to or include the following:

[0374] 1) simultaneous administration of such a combination of a bispecific antibody of the invention and a therapeutic agent to a patient in need of treatment, where these components are formulated together in a single pharmaceutical composition from which each component is released to the patient substantially simultaneously; 2) Simultaneous administration of such a combination of a bispecific antibody of the invention and a therapeutic agent to a patient in need of treatment, where these components are separately formulated in different pharmaceutical compositions and these pharmaceutical compositions are administered to the patient substantially simultaneously, thereby achieving substantially simultaneous release of each component to the patient; 3) Sequential administration of such a combination of a bispecific antibody according to the invention and a therapeutic agent to a patient in need of treatment, wherein the components are formulated separately in individual pharmaceutical compositions and administered sequentially to the patient with a significant time interval between each administration, and wherein the components are then released into the patient at substantially different times.

[0375] 4) Sequential administration of such a combination of a bispecific antibody according to the invention and a therapeutic agent to a patient in need of treatment, wherein the components are formulated together in a single pharmaceutical composition from which they are released in a controlled manner and then released to the patient simultaneously, sequentially, or simultaneously and / or at different times, and each component may be administered by the same or different routes.

[0376] The bispecific antibodies according to the invention can be administered without additional therapeutic treatment, i.e. as monotherapy. In some embodiments of the method of treatment or use, the bispecific antibody according to the invention may be administered in combination with a proteasome inhibitor.

[0377] In some embodiments of the method of treatment or use, the bispecific antibody according to the invention may be administered in combination with an anti-tumor immunomodulator (e.g., lenalidomide, pomalidomide). In some embodiments of the methods of treatment or uses, an anti-tumor immunomodulatory agent (e.g., lenalidomide, pomalidomide).

[0378] In some embodiments of the method of treatment or use, the bispecific antibody of the invention may be administered in combination with cytostatic chemotherapy (e.g., cyclophosphamide, etoposide, etc.).

[0379] In some embodiments of the methods of treatment or uses, the bispecific antibody of the invention may be administered in combination with a tyrosine kinase inhibitor. In some embodiments of the methods of treatment or uses, the bispecific antibody of the invention may be administered in combination with a BCL2 inhibitor.

[0380] In some embodiments of the method of treatment or use, the bispecific antibody of the invention may be administered in combination with an exportin 1 antagonist. In some embodiments of the method of treatment or use, the bispecific antibody according to the invention may be administered in combination with a corticosteroid.

[0381] In some embodiments of the method of treatment or use, the bispecific antibody according to the invention may be administered in combination with an anti-tumor monoclonal antibody (e.g., daratumumab). In some embodiments of the method of treatment or use, the bispecific antibody according to the invention may be administered in combination with a targeted therapy.

[0382] In some embodiments of the method of treatment or use, the bispecific antibody according to the invention may be administered in combination with a cytokine agonist monoclonal antibody (e.g., IL15SA, IL2).

[0383] In some embodiments of the method of treatment or use, the bispecific antibody of the invention may be administered in combination with a cytokine antagonistic monoclonal antibody (e.g., anti-IL-6R, anti-TNF).

[0384] In some embodiments of the method of treatment or use, the bispecific antibody of the invention may be administered in combination with a G-CSF (granulocyte colony stimulating factor) agent. In some embodiments of the method of treatment or use, the bispecific antibody according to the invention may be administered in combination with hematopoietic stem cell transplantation.

[0385] In some embodiments of the method of treatment or use, the bispecific antibody according to the invention may be administered in combination with radiation therapy. In some embodiments of the method of treatment or use, a suitable dosage of the bispecific antibody according to the invention is in the range of 0.1-200 mg / kg. [Example]

[0386] In order that this invention may be better understood, the following examples are set forth, which are for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0387] Although the above invention has been described in detail through illustrations and examples to avoid unclear interpretation, those skilled in the art will understand that certain modifications and variations can be made without departing from the basic principles and scope of the accompanying embodiments of the invention.

[0388] Materials and General Methods General information on the nucleotide sequences of human immunoglobulin light and heavy chains is available in Kabat E.A. et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991. Amino acids in antibody chains are numbered according to the EU numbering scheme (Edelman GM et al., Proc. Natl. Acad. Sci. USA 63, 1969, pp. 78-85; Kabat E.A. et al., Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991). recombinant DNA technology DNA manipulations were performed using standard methods as described by Sambrook J. et al., Molecular cloning: A laboratory manual; Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989. Molecular biology reagents were used according to the manufacturer's instructions.

[0389] Gene synthesis The required gene fragments were derived from chemically synthesized oligonucleotides. Gene fragments of 300–1400 base pairs each flanked by distinct restriction enzyme sites were constructed by oligonucleotide annealing and ligation, PCR amplification, and restriction site-mediated cloning. The DNA sequences of the subcloned gene fragments were verified by DNA sequencing.

[0390] DNA sequencing The DNA sequence was determined by Sanger sequencing. DNA and protein sequence analysis and sequence data processing The software packages Unipro UGENE V.1.29 and SnapGene Viewer were used for sequence generation, mapping, analysis, annotation, and illustration.

[0391] Expression vector The antibodies described in the application were expressed using various expression plasmids designed for antibody expression in prokaryotic cells (E. coli) and transient expression in eukaryotic cells (CHO cells). In addition to the expression cassette, the antibody vectors contained a replication origin to ensure plasmid replication in E. coli and genes conferring resistance to various antibiotics (ampicillin, kanamycin).

[0392] Fusions of genes encoding the antibody chains specified below were performed using PCR and / or gene synthesis, assembly, and recombination methods involving the joining of corresponding nucleic acid segments, such as by using known restriction enzyme sites in the relevant vectors. Subcloned nucleotide sequences were verified by DNA sequencing. For short-term transfections, large quantities of plasmids were produced by extracting them from transformed E. coli cultures.

[0393] Example 1 Design and generation of a genetic construct for a bispecific antibody that specifically binds to CD3 and the tumor antigen CD20 The first chain of a first antigen-binding fragment that specifically binds to CD3 of any bispecific antibody selected from 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, or 019 comprises a heavy chain variable domain comprising a b2M protein sequence and a crystallizable IgG1 fragment comprising L240A, L241A substitutions to reduce the effector properties of the antibody, M258Y, S260T, T262E to extend the clearance time of the antibody, and S360C, T372W for proper heterodimerization of the heavy chains of the bispecific antibody. The second chain of the first antigen-binding fragment that specifically binds to CD3 of any bispecific antibody selected from 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, or 019 comprises a light chain variable domain comprising a CD1b protein sequence.

[0394] The chain of the second antigen-binding fragment that specifically binds to CD20 of any bispecific antibody selected from 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, or 019 comprises heavy and light chain variable domains and heavy and light chain constant domains, respectively. The heavy chain constant domain contains substitutions L238A and L239A to reduce effector function, substitutions M256Y, S258T, and T260E to extend circulating half-life, and substitutions Y353C, T358S, L372A, and Y411V for proper heterodimerization of the bispecific antibody heavy chain.

[0395] Cloning was performed according to standard methods. For the first antigen-binding fragment chain that specifically binds to CD3 of any bispecific antibody selected from 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, or 019, PCR products of the variable domain, b2M and CD1b dimerization domain, and overlapping constant domain were generated, and then the PCR products of the domains were combined by PCR using primers containing restriction sites. The full-length sequence of the first antigen-binding fragment chain that specifically binds to CD3 was cloned into the pEE-HCLALA_IgG1 vector using the SalI / BamHI restriction enzyme sites. For the second antigen-binding fragment chain of any bispecific antibody selected from 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, or 019 that specifically binds to CD20, PCR products containing the heavy and light chain variable domain genes of the antibody were generated using primers containing restriction enzyme sites. The heavy chain variable domain was cloned into the pEE-HCholeLALAYTE_IgG1 vector using the SalI / NheI restriction enzyme sites. The light chain variable domain was cloned into the pEE-CK vector using the SalI / BsiWI restriction enzyme sites. The resulting gene constructs were used for transient protein expression in CHO-T cell lines.

[0396] Example 2 Production of a recombinant bispecific antibody that specifically binds CD3 and the tumor antigen CD20 in mammalian cell suspension culture Full-length bispecific antibodies selected from 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, or 019 were produced using stable cell lines derived from Chinese hamster ovary (CHO) cells. Cells were cultured in a split-flask orbital shaker incubator in serum-free medium at 37°C, 70% humidity, 5% CO2, and 150 rpm. For transient expression, linear polyethyleneimine was used to generate 2-2.2 × 10 6Cells were transfected at a concentration of 1000 c / ml. The DNA to PEI ratio was 1:3 / 1:10. Nine days after transfection, the culture medium was separated from the cells by filtration through a depth filter with a pore size of 0.5 / 0.22 μm.

[0397] The antibody was purified by affinity chromatography. The purified culture medium was passed through a column loaded with 10-20 mg of protein per mL of resin and pre-equilibrated with phosphate-buffered saline (PBS, pH 7.4). The column was then washed with PBS to remove nonspecifically bound components. The bound antibody was eluted with 0.1 M glycine buffer (pH 3.5). Viral inactivation was then performed. The protein was then transferred to 20 mM acetate buffer (pH 5.0) using a dialysis cassette and further purified with a cation exchange resin.

[0398] To assess the purity of bispecific antibodies selected from 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, 014, or 019, SDS-PAGE and size-exclusion HPLC were used. Electrophoresis was performed on 7.5% polyacrylamide gels under denaturing, non-reducing conditions and on 12.5% ​​polyacrylamide gels under denaturing, reducing conditions. Protein purity was determined based on the intensity of stained bands when 10 μg of protein was loaded per lane. Electrophoretic profiles are shown in Figures 1-5.

[0399] Example 3: Affinity determination of the interaction of bispecific antibodies selected from 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013 or 014 with the human CD3 antigen (epsilon and delta subunits) The interaction of bispecific antibodies selected from 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, or 014 with human CD3 antigen (epsilon and delta subunits) was studied using a ForteBio Octet RED384 instrument and an AR2G biosensor (ForteBio). Recombinant human CD3 antigen (epsilon and delta subunits) was used in this study. The experiment consisted of sensor activation, protein loading onto the sensor, blocking of unreacted activation groups, recording the baseline, recording analyte association, and recording dissociation. Measurements were performed at 30°C. Sensor activation was performed for 300 seconds in an aqueous solution containing 20 mM EDC and 10 mM sNHS. Human CD3 antigen (epsilon and delta subunits) was loaded onto the biosensor surface for 900 seconds in 10 mM sodium acetate buffer (pH 5.0). The protein concentration during loading was 10 μg / mL. Blocking of unreacted active sites on the sensor surface was performed for 300 seconds in 1 M ethanolamine solution at pH 8.5 (pH adjusted by adding hydrochloric acid). The baseline and all subsequent experimental steps were performed in kinetic buffer. During the association phase (300 seconds), the antigen-loaded sensor was immersed in a well containing an analyte antibody solution prepared in kinetic buffer. The analyte concentration was 10 μg / mL. During the dissociation phase (600 seconds), the sensor was immersed in a well containing kinetic buffer, and the baseline was recorded.

[0400] The binding curves were processed using Octet Data Analysis software (v. 9.0) using a 1:1 interaction model. The results are shown in Table 1.

[0401] [Table 1]

[0402] The bispecific antibody interacts with the human CD3 antigen with nanomolar affinity. Example 4 Interaction affinity of bispecific antibodies selected from 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013 or 014 with cynomolgus monkey CD3 antigen (epsilon and delta subunits) The interaction of bispecific antibodies selected from 001, 002, 003, 004, 005, 006, 007, 008, 009, 010, 011, 012, 013, or 014 with cynomolgus monkey CD3 antigen (epsilon and delta subunits) was investigated using a ForteBio Octet RED384 instrument and an AR2G biosensor (ForteBio). The purpose of the experiment was to obtain estimates of the antigen-antibody interaction constants, i.e., the equilibrium dissociation constant (KD), the association rate constant (k), and the dissociation rate constant (kdis). Recombinant cynomolgus monkey CD3 antigen (epsilon and delta subunits) was used in this study. The experiment consisted of the following steps: sensor activation, protein loading onto the sensor, blocking of unreacted activation groups, recording the baseline, recording the analyte association, and recording the dissociation. Measurements were performed at 30°C. Sensor activation was performed for 300 seconds in an aqueous solution containing 20 mM EDC (N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride) and 10 mM sNHS (N-hydroxysulfosuccinimide). CD3 cynomolgus monkey antigen (epsilon and delta subunits) was loaded onto the biosensor surface for 900 seconds in 10 mM sodium acetate buffer (pH 5.0). The protein concentration at loading was 10 μg / mL. Unreacted active sites on the sensor surface were blocked for 300 seconds in 1 M ethanolamine solution at pH 8.5 (pH adjusted by adding hydrochloric acid). The baseline and all subsequent experimental steps were performed in kinetic buffer. During the association phase (300 seconds), the antigen-loaded sensor was immersed in a well containing the analyte antibody solution prepared in kinetic buffer. During the dissociation phase (600 s), the sensor was immersed in a well containing kinetic buffer and a baseline was recorded.

[0403] The binding curves were processed using Octet Data Analysis software (v.9.0) using a 1:1 interaction model. Because the sensorgrams showed rapid signal decay, the dissociation phase was analyzed using only the first 30 seconds of signal decay. Because the observed sensorgrams deviated significantly from the model curve (R^2 < 0.95), the obtained kinetic constant values ​​should only be considered as approximate estimates. The processing results are shown in Table 2.

[0404] [Table 2]

[0405] The bispecific antibody interacts with human CD3 with micromolar or submicromolar affinity. Example 5 Bispecific antibodies that specifically bind to CD3 and tumor antigen CD20 The affinity of 019 for human CD3E / D antigen and cynomolgus monkey CD3D and CD3E antigens was measured using a ForteBio Octet RED 384.

[0406] The binding affinity of the bispecific antibody 019 to human CD3E / D antigen and cynomolgus monkey CD3D & CD3E antigen was analyzed using biolayer interferometry with Octet RED384 (ForteBio). Human CD3E / D antigen CD3E / D and cynomolgus monkey CD3D & CD3E antigen were used in this study.

[0407] This study was performed with covalently immobilized proteins (antigens) on the AR2G biosensor as described in the example above, except that four analyte concentrations were selected for the analysis of binding to human CD3E / D antigens: 136.7 nM, 68.4 nM, 34.2 nM, and 17.1 nM, and five analyte concentrations were selected for the analysis of binding to cynomolgus monkey CD3D and CD3E antigens: 3076 nM, 2051 nM, 1367 nM, 911.1 nM, and 607 nM.

[0408] After each measurement, the sensor was regenerated with 10 mM glycine buffer containing HCl (pH 1.8) to remove bound antibody (three cycles: 5 seconds of regeneration, followed by 5 seconds of neutralization with kinetic buffer). The baseline, association, dissociation, and regeneration steps were then repeated. A total of four sensorgram sets (four replicates) were obtained: one before regeneration and three after regeneration. To obtain numerical values ​​for the kinetic constants (k, association rate constant; k, dissociation rate constant; K, equilibrium dissociation constant), the resulting sensorgrams were analyzed using a 1:1 interaction model ([1:1]) with the Global Fit method (fitting a single set of k, k, and K constants to multiple sensorgrams at different concentrations) using ForteBio Octet Data Analysis 9.0. Final values ​​for the k, k, and K constants were obtained by averaging the corresponding values ​​obtained from the three replicates.

[0409] [Table 3]

[0410] The bispecific antibody 019 interacted with the human CD3E / D antigen with a KD value of 11.4 nM (Table 3). The results of the nonspecific interaction test between the analyte and the sensor without adding antigen are shown in Table 4.

[0411] [Table 4]

[0412] [Table 5]

[0413] For bispecific antibody 019, a low level signal corresponding to specific interaction with cynomolgus monkey CD3D & CD3E antigens was observed, with a KD value of 1800 nM. Based on the obtained sensorgrams, it can be concluded that the bispecific antibody 019 interacts with the recombinant cynomolgus monkey CD3D&CD3E protein, but no high affinity binding is detected (Table 5).

[0414] The results of the nonspecific interaction test between the analyte and the sensor are shown in Table 6.

[0415] [Table 6]

[0416] Example 6 Affinity Measurement of Bispecific Antibody 019 for Human CD20 Using ForteBio Octet RED 384 The affinity of bispecific antibody 019 for the CD20 antigen was examined using biolayer interference assay with Octet RED384 (ForteBio). The biotinylated peptide [NH2]CEPANPSEKNSPSTQYCYSIQS[CH2CH2]biotin (hereafter referred to as the CD20 peptide) containing a fragment of the CD20 amino acid sequence was used as the antigen.

[0417] This study was carried out by noncovalently immobilizing a biotinylated peptide (antigen) on a streptavidin biosensor. The experiment consisted of three main steps: loading the antigen onto the sensor, recording the baseline, recording the analyte association, and recording the dissociation. Antigen loading onto the biosensor surface was carried out in kinetic buffer for 300 s. The antigen concentration (CD20 peptide) at the time of loading was 10 μg / mL. To confirm nonspecific interactions between the analyte (bispecific antibody 019) and the sensor, a sensor without CD20 peptide loading was used (the sensor was immersed in kinetic buffer during the loading step; other steps were the same as for the antigen-loaded sensor). The baseline and all subsequent experimental steps were carried out in kinetic buffer. During the association step (300 s), the CD20 peptide-loaded sensor was immersed in a well containing the analyte solution (bispecific antibody 019) prepared in kinetic buffer. Four analyte concentrations were selected for analysis: 2051 nM, 1367 nM, 911.1 nM, and 607.6 nM. During the dissociation phase (600 s), the sensor was transferred to a well containing kinetic buffer, and a baseline was recorded. Measurements were performed at 30 °C, and all phases were performed under tangential shaking at 1000 rpm. The reference sensor underwent the same experimental procedures as the analyte sensor, except that during the binding phase, the reference sensor was immersed in kinetic buffer without analyte (the signal from the reference sensor was recorded simultaneously with the signal from the analyte sensor). The reference signal was subtracted from the signal obtained from the sensor interacting with the analyte during sensorgram data processing. After each measurement, the sensor was regenerated with 10 mM glycine buffer containing HCl (pH 1.8) to remove bound antibody (three cycles: 5 s of regeneration, followed by 5 s of neutralization with kinetic buffer). The baseline, association, dissociation, and regeneration steps were then repeated. A total of four sensorgram sets were obtained: one before regeneration and three after. Because regeneration did not significantly affect the steady-state values, the average value was calculated from the three repeats after regeneration.The association time studied was 300 s, and the dissociation time was 20 s (these association and dissociation times were used for model fitting of the sensorgrams). To obtain numerical values ​​for the kinetic constants (k = association rate constant, k = dissociation rate constant, K = equilibrium dissociation constant), the resulting sensorgrams were analyzed using ForteBio Octet Data Analysis 9.0 with a 1:1 interaction model ([1:1]) with the Global Fit method (fitting a single set of k = , k = , and K = equilibrium dissociation constant to multiple sensorgrams at different concentrations). Final values ​​for the k = , k = , and K = constants were obtained by averaging the corresponding values ​​obtained from three replicates.

[0418] [Table 7]

[0419] Bispecific antibody 019 interacted with the CD20 peptide antigen with a KD value of 769 nM. Based on the information obtained, it can be concluded that bispecific antibody 019 interacts with the CD20 peptide (Table 7).

[0420] Example 7 Analysis of T cell activation by a bispecific antibody that specifically binds to CD3 and tumor antigen CD20 T cell activation was assessed by the ability of a bispecific anti-CD3 / CD20 antibody to stimulate NFAT-dependent luciferase production in a model CD3-positive cell line, Jurkat-NFAT Luc cl.1, which harbors a luciferase gene under the control of NFAT elements, in the presence of CD20-positive Raji cells. Luciferase activity was detected by adding a mixture of luciferase substrate and lysis buffer. The luminescence level was used to assess the level of activation of the NFAT signaling pathway.

[0421] Jurkat-NFAT Luc cl.1 cells were cultured in suspension in culture flasks in complete growth medium containing 2 mM L-glutamine, 10% heat-inactivated FBS, and up to 0.25 mg / mL of the selective antibiotic hygromycin B. Raji cells were cultured in suspension in complete growth medium in culture flasks.

[0422] On the day of antibody testing, the antibody was diluted to a concentration of 0.1 mg / mL in quantitative assay medium. The antibody solution was then titrated in a round-bottom plate over nine points in five-fold dilution steps, with the tenth point used as a no-antibody control. The diluted samples were dispensed in duplicate into the inner wells of a white culture plate, 25 μL per well. The aCD28 antibody solution, which is involved in the activation of Jurkat-NFAT Luc cl.1, was prepared at a concentration of 600 ng / mL using assay medium. The Raji suspension was diluted to 8 × 10 with the aCD28 solution. 5 The Jurkat NFAT-Luc cl.1 suspension was diluted to 8 × 10 5 c / ml, and 25 μL of the suspension was added to the inner well.

[0423] The plates were mixed and incubated at 37°C in a CO2 incubator for 18-24 hours. At the end of the incubation period, 75 μL of Bio-Glo substrate was added to the assay wells. Luminescence levels were measured in relative luminescence units using a 100 ms integration time. Results were then subjected to statistical analysis.

[0424] The results are shown in Table 8.

[0425] [Table 8]

[0426] The data obtained showed that all bispecific antibodies that specifically bind to CD3 and the tumor antigen CD20 can activate the NFAT signaling pathway in the Jurkat-NFAT Luc cl. cell line, thereby stimulating T cell-dependent cytotoxicity against CD20-positive cells.

[0427] Example 8 Analysis of T cell-dependent cytotoxicity (TDCC) using bispecific anti-CD3 / CD20 antibody 019 To assess TDCC, we chose a flow cytometry method that measures the level of depletion of labeled target cells after incubation with effector cells in the presence of a test antibody.

[0428] PBMCs were isolated from whole blood of healthy donors by Ficoll density gradient centrifugation, and T cells were isolated by magnetic separation. Burkitt's lymphoma Raji cells, which highly express CD20, were selected as target cells. A green fluorescent dye with a long aliphatic tail that integrates into the membrane was selected for labeling of target cells. Labeling was performed using a 7 μM stock dye solution.

[0429] Test antibody 019 was diluted to a concentration of 200 μg / mL and then titrated using 5-fold serial dilutions (9 steps total). 25 μL of diluted antibody was added to each well of a 96-well flat-bottom plate. 25 μL of labeled Raji cells at a concentration of 1×10^6 c / mL and 50 μL of T cells at a concentration of 1.5×10^6 c / mL were added to wells containing the antibody titration solution. The plate was mixed at 600 rpm for 40 seconds. The plate was incubated at 37°C and 5% CO2 for 22 hours. Immediately before loading the samples into the flow cytometer, 0.2 μL of a viability dye (25 mg / mL) and 35 μL of counting beads for absolute cell quantification were added to the samples. TDCC levels were assessed by the absolute reduction in viable Raji cell counts in wells containing the test antibody.

[0430] Statistical analysis of the results was then performed. The results are shown in Table 9.

[0431] [Table 9]

[0432] The analysis results showed that the anti-CD3 / CD20 bispecific antibody 019 exhibited a significant 3.7-fold reduction activity against Raji cells. Example 9: Generation of bispecific antibody sequences that specifically bind to CD3 and tumor antigen AXL The first bispecific antibody that specifically binds to CD3 and the tumor antigen AXL comprises a first antigen-binding fragment that specifically binds to CD3, which consists of a light chain having the amino acid sequence SEQ ID NO:25 and a heavy chain having the amino acid sequence SEQ ID NO:38 (hereinafter referred to as the first anti-CD3 / AXL antibody).

[0433] The second bispecific antibody that specifically binds to CD3 and the tumor antigen AXL comprises a first antigen-binding fragment that specifically binds to CD3, which consists of a light chain having the amino acid sequence SEQ ID NO:158 and a heavy chain having the amino acid sequence SEQ ID NO:159 (hereinafter referred to as the second anti-CD3 / AXL antibody).

[0434] The heavy and light chain variable domain genes for antibodies against AXL and CD3 were synthesized de novo. For this purpose, oligonucleotides of 55–60 nucleotides each were synthesized to form completely overlapping gene sequences. Assembly of each gene was performed using two-round PCR. Fusion of the heavy chain variable domain gene with the human IgG1 Fc fragment and the light chain variable domain with the kappa constant domain (CK) was performed by gene synthesis and assembly using PCR and / or known restriction enzyme and ligation techniques.

[0435] The heavy and light chain antibody genes were cloned into pEE plasmids to produce proteins in the IgG1 format in mammalian cells. Heavy chain heterodimerization of the bispecific anti-AXL / anti-CD3 antibody was ensured by introducing knob-into-hole mutations into the Fc region.

[0436] To obtain an antibody with improved properties, point mutations M252Y, S254T, T256E (YTE) and L234A, L235A (AA) were introduced into the heavy chain Fc constant region. The combination of YTE mutations enabled prolonged pharmacokinetics, while the AA mutations reduced the complement-dependent cytotoxicity of the resulting antibody. The cloned nucleotide sequence was confirmed by DNA sequencing. The resulting plasmid was produced in sufficient quantities in E. coli cells and purified using a plasmid DNA purification kit.

[0437] The prepared gene construct was used for transient protein expression in a CHO cell line. Example 10: Generation of a full-length bispecific antibody that specifically binds to CD3 and tumor antigen AXL The full-length primary and secondary anti-CD3 / AXL antibodies described above were produced by transient transfection in duplicate using stable cell lines derived from Chinese hamster ovary cells (CHO-T line). Suspension culture was performed in a bioreactor on an orbital shaker using serum-free medium. For transient expression, 2-2.2 x 10 cells were used. 6 Transfection was performed using linear polyethyleneimine (PEI) at a concentration of 1000 c / mL. The DNA / PEI ratio was 1:7. On day 10 of culture, the cell suspension was centrifuged at 2000 g for 15 minutes and filtered through a 0.22 μm pore size filter.

[0438] The antibody was purified by affinity chromatography. The protein was then eluted and neutralized with 25 μL of 1 M phosphate buffer (pH 8). To assess the purity of the anti-CD3 / AXL antibody, SDS-PAGE and size-exclusion HPLC were performed. SDS-PAGE was performed on a 7.5% acrylamide gel under reducing conditions and a 12.5% ​​acrylamide gel under non-reducing conditions. The purity of the CD3 / AXL antibody was determined by the intensity of band staining with a protein load of 10 μg per lane. Representative electropherograms are shown in Figures 6 and 7. SEC-HPLC was performed using a column equilibrated with a mobile phase consisting of 0.05 M NaH2PO4 and 0.3 M NaCl, pH 7.0.

[0439] Example 11 In vitro cell assay to measure anti-CD3 specific activity of bispecific antibodies that specifically bind CD3 and tumor antigen AXL The assay used the Jurkat-NFAT-Luc cell line, derived from Jurkat cells and containing a luciferase reporter gene under the control of the NFAT promoter, and the MDA-MB-231 cell line, which naturally expresses the AXL receptor.

[0440] The assay was performed using a 96-well plate designed for luminescence measurement. Each well was filled with a suspension containing 20,000 Jurkat-NFAT-Luc cells, 20,000 MDA-MB-231 cells, and the bispecific anti-CD3 / AXL antibody being tested at the concentrations indicated in the graph. The final volume of the cell suspension in each well was 75 μL. All components of the suspension were prepared in RPMI-1640 medium supplemented with 10% fetal bovine serum. After adding all components, the plate was incubated at 37°C and 5% CO2 for 16 hours. Luciferase activity in each well was then measured using a luminescence detection kit.

[0441] The results, shown in Figure 8, demonstrate that the first and second bispecific anti-CD3 / AXL antibodies exhibit anti-CD3-specific activity in the presence of target cells expressing the AXL receptor. The EC50 values ​​for both bispecific antibodies were similar: 138 ng / mL for the first bispecific anti-CD3 / AXL antibody and 81 ng / mL for the second bispecific anti-CD3 / AXL antibody.

[0442] Example 12. Production of recombinant antigens in mammalian cell suspension cultures The extracellular domain sequence of the human BCMA receptor (SEQ https: / / www.uniprot.org / uniprot / Q02223, residues 1-54) was cloned into the pEE plasmid for protein expression in mammalian cells, and fused to TEV-Fc, Avi-His, and Avi-His-TEV-HSA tags using the SalI / NotI restriction enzyme sites. Plasmids were produced in E. coli cells and purified using Qiagen.

[0443] The antigen was produced in a stable cell line derived from Chinese hamster ovary cells (CHO-T strain). The cells were grown in suspension culture in flasks in an orbital shaker incubator. To express the target antigen, linear polyethyleneimine was introduced into the cells. Nine days after transfection, the culture medium was separated from the cells by filtration through a depth filter with 0.5 / 0.22 μm pore size.

[0444] BCMA-TEV-Fc antigen was isolated and purified from the culture medium using a Protein A affinity chromatography column. The purified culture medium was passed through a column equilibrated with phosphate-buffered saline (PBS, pH 7.4). Bound antibodies were eluted with 0.1 M glycine buffer (pH 2.5). The resulting target protein was dialyzed against PBS (pH 7.4), added with DTT, filtered through a 0.22 μm filter, transferred to a tube, and stored at -70°C. BCMA-Avi-His antigen and BCMA-Avi-His-TEV-HSA antigen were isolated and purified from the culture medium using a Ni-NTA affinity chromatography column. The purified culture medium was passed through a column equilibrated with phosphate-buffered saline (PBS, pH 7.4). Bound antigen was eluted with PBS supplemented with 500 mM imidazole (pH 7.4). The protein was then transferred to PBS by dialysis. The protein was then passed through a gel filtration column. The resulting protein was filtered through a 0.22 μm pore size filter, transferred to a test tube, and stored at −70°C.

[0445] Example 13 Cloning of variable domain genes of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 into expression plasmids Cloning of variable domain antibody genes into pLL and pET22 expression plasmids was performed according to standard protocols using the restriction enzyme ligase method.

[0446] The expression vectors containing the antibody fragments were then introduced into E. coli strains BL21-DE3 and BL21-Gold, and the affinities of the variable antibody fragments from the display library and the antigens were compared and analyzed using ELISA on an automated platform.

[0447] Example 14 Generation and initial analysis of Fab and scFv fragments of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 that specifically bind to human BCMA Fab and scFv were produced using standard methods. E. coli BL21-DE3 and BL21-Gold bacterial cells were transformed with expression vectors containing the scFv and Fab genes, respectively, and then lac operon transcription was induced by adding an inducer. The resulting transformants were cultured, resulting in the expression of scFv and Fab, which were then transported into the periplasmic space of the cells. ELISA was then performed to confirm the binding of scFv and Fab to the hBCMA-Avi-His antigen immobilized on a substrate at a concentration of 0.2 μg / ml in 0.1 M NaHCO3 (pH 9.0) (the antigen was immobilized overnight at +4°C). All subsequent steps were performed at room temperature according to standard ELISA protocols using a high-throughput automated platform based on a robotic system. After each step, 300 μl of 1x PBST was injected into each well in triplicate. Nonspecific binding sites on the plate were blocked with 1% skim milk in 1x PBST. After washing, 60 μl of E. coli cell supernatant was added per well as the assay. Immune complexes were detected using peroxidase-conjugated goat anti-Myc-tag antibody (dilution 1:20,000). 50 μl of TMB substrate solution was added to the substrate / color mixture, and the reaction was allowed to proceed for 15 minutes. The reaction was stopped with 25 μl of 1% H2SO4. The color signal was measured at 450 nm. The degree of antibody binding was proportional to the color signal generated. Clones that produced color signals greater than those of the control antibody were tested for nonspecific binding using ELISA.

[0448] Thus, all analyzed Fab and scFv fragments of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 show specific binding to hBCMA-Avi-His.

[0449] Example 15 Analysis of nonspecific binding of Fab fragments and scFv fragments of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 to other antigens ELISA was also used to analyze nonspecific binding of the scFv and Fab fragments of interest to other antigens. This study was performed similarly to the above, except that hCD16-Avi-His-FLAG and cynoIL4R-Fc in 0.1 M NaHCO3 (pH 9.0) were used as immobilized antigens (antigens immobilized overnight at 4°C). Specific binding controls included hBCMA-Avi-His and rhesusBCMA (antigens immobilized overnight at 4°C). All subsequent steps were performed according to standard ELISA protocols using a high-throughput automated platform.

[0450] All Fab and scFv fragments of antibodies analyzed, 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037, show specific binding to hBCMA-Avi-His, rhesusBCMA, and do not show nonspecific interactions with hCD16-Avi-His-FLAG and cynoIL4R-Fc.

[0451] Example 16 Analysis of dissociation rates of Fab and scFv fragments of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 in ForteBio Fab fragment measurements were performed on a ForteBio Octet RED 384 instrument using a FAB2G biosensor (ForteBio). Fab samples were loaded onto the sensor from the supernatant at a temperature of (5±3) °C for 16–18 h. After loading, the sensor was transferred to a kinetic buffer containing 500 mM NaCl, which was used for all subsequent steps of the experiments with Fab samples. Measurements were performed at 30 °C. The sensor was equilibrated in the kinetic buffer for at least 10 min, after which a baseline was recorded (60 s). After recording the baseline, the Fab-immobilized sensor was immersed in a well containing the analyte solution (recombinant human BCMA-Avi-His-TEV-HSA antigen), where the antigen-Fab complex was allowed to associate for 300 s. The concentration of human BCMA antigen was 391.2 nM (30 μg / ml). Dissociation of the complex in the kinetic buffer was detected for 600 s. To confirm nonspecific interactions between the analyte and the sensor (negative control), a sensor without Fab antibody fragment loading was used. During the loading step, the negative control sensor was immersed in supernatant containing no Fab. Other steps were the same as for the Fab-loaded sensor.

[0452] Measurement of scFv fragments was performed using a ForteBio Octert RED 384 instrument with a SAX biosensor (ForteBio). Human BCMA antigen was biotinylated at a molar ratio of 1:1.5. The interaction kinetics was analyzed at 30°C. The analysis was performed using kinetic buffer. Biotinylated human BCMA antigen was loaded onto the sensor for 600 seconds, with the antigen solution concentration in kinetic buffer at 20 μg / mL. The baseline after loading was recorded for 120 seconds. After recording the baseline, the antigen-immobilized sensor was immersed in a well containing the analyte solution (scFv antibody fragment), and the antigen-scFv complex was allowed to associate for 150 seconds (the scFv antibody fragment for the association step was diluted to a concentration of 1200 nM in kinetic buffer). Dissociation of the antigen-scFv complex in kinetic buffer was then detected for 600 seconds. A reference signal was recorded in parallel with the antibody sensorgram and subtracted during sensorgram processing. The reference signal was the signal from a sensor immersed in kinetic buffer without analyte during the association phase; the other phases were the same as the sensor recording the signal under investigation. To check for nonspecific interactions between the analyte (scFv antibody fragment) and the sensor, a sensor without antigen loading was used. During the loading phase, a negative control sensor was immersed in kinetic buffer without antigen; the other phases were the same as the sensor loaded with antigen.

[0453] Binding curves were analyzed using a 1:1 interaction model with Octet Data Analysis software (v. 9.0). The results of the analysis of Fab and scFv fragments of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 are shown in Table 10. These Fab and scFv fragments were subsequently used to generate full-length antibodies.

[0454] [Table 10]

[0455] All analyzed Fab and scFv fragments of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 show specific binding to human BCMA-Avi-His-TEV-HSA.

[0456] Example 17: Production of gene constructs for the synthesis of full-length antibodies that specifically bind to BCMA Cloning was performed according to standard methods. Primers containing restriction enzyme sites were used to generate PCR products containing the heavy and light chain variable domain genes of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037. The heavy chain variable domain was cloned into the Sal1 / Nhe1 restriction enzyme sites of the pEE-HCLALA IgG1 vector. The light chain variable domain was cloned into the Sal1 / BsiW1 restriction enzyme sites of the pEE-CK vector. The resulting gene constructs were used for transient protein expression in CHO-T cell lines.

[0457] Example 18: Production of full-length antibodies that specifically bind to BCMA Full-length antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 were produced in duplicate by transient transfection in a permanent Chinese hamster ovary cell line (CHO-T line). Suspension cultures were performed in a bioreactor on an orbital shaker using serum-free medium. For transient expression, 2-2.2 × 10 cells were used. 6 Transfection was performed using linear polyethyleneimine (PEI) at a concentration of 1000 c / mL. The DNA / PEI ratio was 1:7. On day 10 of culture, the cell suspension was centrifuged at 2000 g for 15 minutes and filtered through a 0.22 μm pore size filter.

[0458] The antibody was purified by column affinity chromatography using a robotic station. The column was equilibrated with 50 mM NaPB (sodium phosphate buffer) and 150 mM NaCl (pH 7.5). After the antibody-containing filtered culture medium was added, the column was washed with eight volumes of 50 mM NaPB, 150 mM NaCl buffer, and four volumes of 50 mM NaPB (pH 7.5). The protein was eluted with six column volumes of 50 mM NaPB, 100 mM NaCl (pH 3). The eluate was neutralized by adding 25 μL of 1 M phosphate buffer (pH 8).

[0459] To confirm the purity of the antibody, SDS-PAGE and size-exclusion HPLC were used. Electrophoresis was performed using a 7.5% polyacrylamide gel under denaturing and non-reducing conditions. Protein purity was determined based on the intensity of the stained bands when 10 μg of protein was loaded per lane. Electropherograms are shown in Figures 9 and 10. SEC-HPLC was performed using a column equilibrated with a mobile phase consisting of 0.05 M NaH2PO4 and 0.3 M NaCl, pH 7.0.

[0460] Example 19: Measurement of affinity of full-length antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 for human BCMA at Forte Bio Experiments to examine the binding affinity of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 to human BCMA antigen were performed using a ForteBio Octet RED 384 instrument. Antibodies at a concentration of 20 μg / ml were immobilized on the surface of a Protein A biosensor (ForteBio). Analysis was performed at 30°C using kinetic buffer. After establishing a baseline in kinetic buffer, the antibody-immobilized sensor was immersed in a well containing the analyte solution (BCMA), and the complex was allowed to bind for 300 seconds. For each antibody tested, a sensorgram was recorded for a 10 μg / ml (130.4 nM) human BCMA solution, along with a reference signal (reference sensorgram) in kinetic buffer without BCMA. The dissociation of the complex in the buffer solution was then detected for 600 seconds. To confirm nonspecific interactions between the analyte and the sensor (negative control), a sensor without antibody loading was used. During the loading step, the negative control sensor was immersed in kinetic buffer without antibody. The other steps were the same as those for the antibody-loaded sensor.

[0461] Reference signal-subtracted binding curves were analyzed using Octet Data Analysis software (V. 9.0) with a 1:1 interaction model (Table 11).

[0462] [Table 11]

[0463] Thus, all anti-BCMA antibodies analyzed bind specifically to the human BCMA antigen (Table 11). Example 20: Examination of the interaction of full-length antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 with Rh BCMA on a Forte Bio device The purpose of this experiment was to confirm the interaction of antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 with the Rh BCMA antigen. The interaction of the antibodies with the Rh BCMA antigen was tested using a ForteBio Octet RED384 and AR2G biosensor (ForteBio). The experiment consisted of sensor activation, protein loading onto the sensor, blocking of unreacted activation groups, recording a baseline, recording analyte association, and recording dissociation. Measurements were performed at 30°C. The sensor was activated for 300 seconds in an aqueous solution containing 20 mM EDC and 10 mM sNHS. Rh BCMA antigen was loaded onto the biosensor surface in 10 mM sodium acetate buffer at pH 5.0 for 300 seconds. The protein concentration during loading was 10 μg / mL. Blocking of unreacted active sites on the sensor surface was performed in 1 M ethanolamine solution at pH 8.5 (pH adjusted by adding hydrochloric acid) for 300 seconds. To confirm nonspecific interactions between the analyte and the sensor (negative control), a sensor without antigen loading was used. (During the loading phase, the sensor was immersed in 10 mM sodium acetate buffer at pH 5.0; all other steps were the same as for the antigen-loaded sensor.) The baseline and all subsequent experimental steps were performed in kinetic buffer. During the association phase (300 seconds), the Rh BCMA antigen-loaded sensor was immersed in a well containing an analyte antibody solution prepared in kinetic buffer. The analyte concentration was 2.5 μg / mL. During the dissociation phase, the sensor was immersed in a well containing kinetic buffer, and a baseline was recorded.

[0464] Binding curves were processed using Octet Data Analysis software (V.9.0) using a 1:1 interaction model. All anti-BCMA antibodies showed a signal binding to the Rh BCMA antigen during the association phase, followed by a gradual decrease in the signal during the dissociation phase, confirming their high binding activity upon interaction with this antigen.

[0465] [Table 12]

[0466] Thus, all anti-Rh BCMA antibodies analyzed bind specifically to the BCMA antigen (Table 12). Example 21: Verification of APRIL interaction inhibition using human BCMA antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 at Forte Bio This study was performed using an AR2G biosensor (ForteBio) on a ForteBio Octet RED 384. The experiment consisted of the following steps: Loading the human APRIL / TNFSF13 antigen onto the sensor; Confirming the binding of the APRIL / TNFSF13 antigen to a mixture (premix) of human BCMA and the antibody being tested; As a positive control, a human BCMA solution without added antibody was used. Conclusions regarding the inhibition of the interaction were made based on a comparison of the premix signal (response) with the positive control signal.

[0467] The sensor was activated for 300 seconds in an aqueous solution containing 20 mM EDC and 10 mM sNHS. The APRIL / TNFSF13 antigen was loaded onto the biosensor surface in 10 mM sodium acetate buffer at pH 5.0 for 900 seconds. The APRIL / TNFSF13 protein concentration at the time of loading was 10 μg / ml. To confirm nonspecific interactions between the analyte and the sensor, a sensor without antigen loading was used (in the loading step, the sensor was immersed in sodium acetate buffer at pH 5.0; all other steps were the same as for the antigen-loaded sensor). Unbound active centers on the sensor surface were quenched for 300 seconds in a 1 M aqueous ethanolamine solution at pH 8.5 (pH adjusted by adding hydrochloric acid). All steps of the experiment after the quenching step were performed in the kinetic buffer. In the association step (step duration 300 seconds), the protein-loaded sensor was immersed in a well containing the analyte solution. The analyte used in the association step was a solution containing 710 nM of the test antibody and 71 nM of human BCMA dissolved in kinetic buffer. A solution containing 71 nM of human BCMA (analyte) was also used as a positive control. Measurements were performed at 30°C. The reference sensor underwent all the same experimental procedures as the analyte sensor. However, during the binding step, the reference sensor was immersed in kinetic buffer without analyte (the signal from the reference sensor was recorded simultaneously with the signal from the analyte sensor). During sensorgram processing, the reference signal was subtracted from the analytical signal.

[0468] Sensorgram processing was performed using ForteBio Octet Data Analysis 9.0. The experimental results are shown in Table 13.

[0469] [Table 13-1]

[0470] [Table 13-2]

[0471] Thus, all anti-BCMA antibodies analyzed inhibit the binding of APRIL / TNFSF13 to the human BCMA antigen (Table 13). Example 22 Analysis of Binding of Anti-BCMA Antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, 01-037 to Human BCMA on the Surface of RPMI8226 Cells by Flow Cytometry The ability of anti-BCMA antibodies 01-001, 01-006, 01-016, 01-021, 01-022, 01-024, 01-025, 01-026, 01-027, 01-030, 01-033, and 01-037 to bind to human BCMA antigen on the cell surface was assessed by flow cytometry in the RPMI8226 cell line (multiple myeloma) stably expressing the BCMA receptor on its surface.

[0472] 25,000 cells in a well were incubated with serially diluted antibodies in staining buffer at +4°C for 30 minutes. After the specified time, cells were washed twice with cold (+4°C) staining buffer, and bound antibodies were detected by staining with a secondary antibody against phycoerythrin-conjugated human Fc fragments for 30 minutes ...

Claims

1. 1. An isolated bispecific antibody that specifically binds to CD3 and a tumor antigen, comprising: 1) A first antigen-binding fragment that binds to CD3, comprising: (a) a light chain variable domain comprising: (i) CDR1 has the amino acid sequence RASQSX １ SSNLA, hereby X １ = I or V (ii) CDR2 of the amino acid sequence SEQ ID NO:3, and (iii) amino acid sequence QX ２ YX ３ CDR3 having NWPLT, X ２ = H or Q, X ３ = N or I; and (b) a heavy chain variable domain comprising: (i) CDR1 of amino acid sequence SEQ ID NO:6 (ii) CDR2 of the amino acid sequence SEQ ID NO:7, and (iii) the amino acid sequence DNSGYHYYYGX ４ a CDR3 having a DI, wherein X ４ = M or L and 2) a second antigen-binding fragment that specifically binds to a tumor antigen; 2. The isolated bispecific antibody comprising:

2. 2. The isolated bispecific antibody of claim 1 , wherein the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises a CDR1 having an amino acid sequence selected from SEQ ID NO: 1 or SEQ ID NO:

2.

3. The variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises a CDR3 having an amino acid sequence selected from SEQ ID NO:4 or SEQ ID NO:

5.

2. The isolated bispecific antibody of claim 1.

4. 2. The isolated bispecific antibody of claim 1 , wherein the variable domain of the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises a CDR3 having an amino acid sequence selected from SEQ ID NO: 8 or SEQ ID NO:

9.

5. a CDR1 having an amino acid sequence selected from SEQ ID NO: 1 or SEQ ID NO: 2; CDR2 of amino acid sequence SEQ ID NO:3; and, a CDR3 having an amino acid sequence selected from SEQ ID NO: 4 or SEQ ID NO: 5; 2. The isolated bispecific antibody of claim 1 , comprising a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, comprising:

6. CDR1 of amino acid sequence SEQ ID NO:6; CDR2 of amino acid sequence SEQ ID NO:7; and, a CDR3 having an amino acid sequence selected from SEQ ID NO: 8 or SEQ ID NO: 9; 2. The isolated bispecific antibody of claim 1 , comprising a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising:

7. (a) a CDR1 having an amino acid sequence selected from SEQ ID NO: 1 or SEQ ID NO: 2; CDR2 of amino acid sequence SEQ ID NO:3; and, a CDR3 having an amino acid sequence selected from SEQ ID NO: 4 or SEQ ID NO: 5; a variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3, comprising: and (b) CDR1 of amino acid sequence SEQ ID NO:6; CDR2 of amino acid sequence SEQ ID NO:7; and, a CDR3 having an amino acid sequence selected from SEQ ID NO: 8 or SEQ ID NO: 9; a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising:

2. The isolated bispecific antibody of claim 1 , comprising:

8. (i) (a) below: CDR1 of the amino acid sequence SEQ ID NO: 2, CDR2 of the amino acid sequence SEQ ID NO: 3, and CDR3 of amino acid sequence SEQ ID NO: 4; a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3; and (b) Below: CDR1 of the amino acid sequence SEQ ID NO: 6, CDR2 of the amino acid sequence SEQ ID NO: 7, and CDR3 of amino acid sequence SEQ ID NO:8; a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3; or (ii) (a) below: CDR1 of the amino acid sequence SEQ ID NO: 1, CDR2 of the amino acid sequence SEQ ID NO: 3, and CDR3 of amino acid sequence SEQ ID NO: 4; a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3; and (b) Below: CDR1 of the amino acid sequence SEQ ID NO: 6, CDR2 of the amino acid sequence SEQ ID NO: 7, and CDR3 of amino acid sequence SEQ ID NO:8; a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3; or (iii) (a) Below: CDR1 of the amino acid sequence SEQ ID NO: 2, CDR2 of the amino acid sequence SEQ ID NO: 3, and CDR3 of amino acid sequence SEQ ID NO: 5; a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3; and (b) Below: CDR1 of the amino acid sequence SEQ ID NO: 6, CDR2 of the amino acid sequence SEQ ID NO: 7, and CDR3 of amino acid sequence SEQ ID NO:9; a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3; or (iv) (a) below: CDR1 of the amino acid sequence SEQ ID NO: 1, CDR2 of the amino acid sequence SEQ ID NO: 3, and CDR3 of amino acid sequence SEQ ID NO: 5; a variable domain of a light chain of a first antigen-binding fragment that specifically binds to CD3; and (b) Below: CDR1 of the amino acid sequence SEQ ID NO: 6, CDR2 of the amino acid sequence SEQ ID NO: 7, and CDR3 of amino acid sequence SEQ ID NO:9; a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising:

8. The isolated bispecific antibody of claim 7, comprising:

9. 2. The isolated bispecific antibody of claim 1, wherein the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO:

156.

10. 2. The isolated bispecific antibody of claim 1, wherein the variable domain of the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO:

157.

11. (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, or SEQ ID NO: 156; and, (b) the variable domain of the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, or SEQ ID NO: 157; 2. The isolated bispecific antibody of claim 1.

12. The isolated bispecific antibody according to any one of claims 1 to 11, wherein the first antigen-binding fragment that specifically binds to CD3 is designed in the format of scFv, Fab, scFab, or CrossMab.

13. The isolated bispecific antibody according to any one of claims 1 to 11, wherein the second antigen-binding fragment that specifically binds to a tumor antigen is designed in the format of scFv, Fab, scFab, or CrossMab.

14. 12. The isolated bispecific antibody of claim 11, comprising: (i) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 10; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 16; or (ii) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 11; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 16; or (iii) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 10; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 17; or (iv) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 10; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 18; or (v) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 10; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; or (vi) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 11; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; or (vii) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 12; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 18; or (viii) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 13; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 20; or (ix) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 14; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 20; or (x) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 13; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 21; or (xi) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 13; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 22; or (xii) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 13; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 23; or (xiii) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 14, and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 23; or (xiv) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 15; and (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 22; or (xv) (a) the variable domain of the light chain of a first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 156; and (b) the heavy chain variable domain of the first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 157; The isolated bispecific antibody.

15. 15. The isolated bispecific antibody of any one of claims 1 to 12 and 14, wherein the antibody that specifically binds to CD3 and a tumor antigen is a full-length IgG antibody.

16. 16. The isolated bispecific antibody of claim 15, wherein the full-length IgG antibody is of the human IgG1, IgG2, IgG3, or IgG4 isotype.

17. 17. The isolated bispecific antibody of claim 16, wherein the full-length IgG antibody is of the human IgG1 isotype.

18. 18. The isolated bispecific antibody of claim 17, comprising the mutations L234A and L235A in the CH2 region according to the EU numbering scheme.

19. 18. The isolated bispecific antibody of claim 17, comprising the mutations M252Y, S254T and T256E according to the EU numbering scheme in the CH2 region.

20. 18. The isolated bispecific antibody of claim 17, comprising the mutations S354C and T366W according to the EU numbering scheme in the CH3 region.

21. 18. The isolated bispecific antibody of claim 17, comprising the mutations Y349C, T366S, L368A and Y407V according to the EU numbering scheme in the CH3 region.

22. 2. The isolated bispecific antibody of claim 1, wherein the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 158, SEQ ID NO: 160, or SEQ ID NO:

162.

23. 2. The isolated bispecific antibody of claim 1, wherein the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 159, SEQ ID NO: 161, or SEQ ID NO:

163.

24. (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 158, SEQ ID NO: 160, or SEQ ID NO: 162; and, (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 159, SEQ ID NO: 161, or SEQ ID NO: 163; 2. The isolated bispecific antibody of claim 1.

25. (i) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 24; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 30; or (ii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 25; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 30; or (iii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 24; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 31; or (iv) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 24, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 32; or (v) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 24; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 33; or (vi) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 25; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 33; or (vii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 26; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 32; or (viii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 27; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 34; or (ix) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 28; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 34; or (x) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 27; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 35; or (xi) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 27; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 36; or (xii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 27; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 37; or (xiii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 28, and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 37; or (xiv) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 29; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 36; or (xv) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 25; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 38; or (xvi) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 159; or (xvii) (a) the light chain of the first antigen-binding fragment generated in a CrossMab format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 160; and (b) the heavy chain of the first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 161; or (xviii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 162; and (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 163; 25. The isolated bispecific antibody of claim 24.

26. the second antigen-binding fragment that specifically binds to a tumor antigen is selected from the group consisting of GUCY2C, AXL, GD2, CD19, EpCAM, EGFR, CD20, CEA, HER2 / neu, PSMA, BCMA, MUC17, CD38, FLT3, ENPP3, TPBG, FAP, CD70, Cadherin-19, Mesothelin, CD33, ROR1, IL-3Rα, Cadherin-17, P-cadherin, MUC1, B7-H6, DLL3, B7-H3, CD28, CD155, IRTA2, GPRC5D, RNF43, IL-1RAP, Globo H, and Glypican. 3, CLDN18, TPBG, LYPD1, PD-L1, GPNMB, NY-ESO-1, MAGE-A4, TACSTD-2, DR5, CD8, TMEFF2, PRLR, CD22, HLA-G, Robo1, EphA2, Prominin-1, HMW-MAA, A33, TAG-72, HER3, IL-23R, CD2, MIF, PD-1, E 2. The isolated bispecific antibody of claim 1, wherein the antibody is selected from the group consisting of pha10, GCC, ALP, LFL2, MAGE-A4, STEAP2, CA125, TYRP1, 4-1BB, FRA, CD44v6, Robo4, TIM-3, CLEC12A, B7-H4, FCRL5, SSTR2, c-Kit, MOSPD2, PSA, or CD26.

27. The tumor antigen is BCMA, The second antigen-binding fragment that specifically binds to the BCMA tumor antigen comprises: (a) a light chain variable domain comprising: (i) amino acid sequence X ７ GX ８ X ９ SNIGX １０ X １１ X １２ X １３ VX １４ CDR1 having X ７ = S or T; X ８ = S, G or T; X ９ = S, T, I or R; X １０ = 0 or A; X １１ = S, H, N, G or T; X １２ = N, R or Y; X １３ = T, A, I or D; X １４ = N or H; (ii) amino acid sequence X １５ X １６ X １７ X １８ CDR2 having an RPS, wherein X １５ = N, R, K, S or G; X １６ = D, N, G, T or H; X １７ = S, N or T; X １８ = Q or N; and (iii) amino acid sequence X １９ X ２０ WDX ２１ X ２２ X ２３ X ２４ X ２５ WX ２６ a CDR3 having X １９ = A or S; X ２０ = A, S, T or V; X ２１ = G, D, H or S; X ２２ = S, D or R; X ２３ = L or V; X ２４ = N, T, R or S; X ２５ = V, A, G or N; X ２６ = M, V or L; and (b) a heavy chain variable domain comprising: (i) amino acid sequence SX １ X ２ CDR1 having MS, wherein X １ = S or G; X ２ = A, L or V; (ii) amino acid sequence X ３ YNGGSX ０ RAGX ４ X ５ DSVX ６ CDR2 having G, wherein X ０ = D or T; X ３ = G or C; X ４ = F or Y; X ５ = A or T; X ６ = E or K; and (iii) a CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 83 or SEQ ID NO: 130; 2. The isolated bispecific antibody of claim 1.

28. 28. The isolated bispecific antibody of claim 27, wherein the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO:

122.

29. 28. The isolated bispecific antibody of claim 27, wherein the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, or SEQ ID NO:

123.

30. 28. The isolated bispecific antibody of claim 27, wherein the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises a CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, or SEQ ID NO:

124.

31. 28. The isolated bispecific antibody of claim 27, wherein the variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, or SEQ ID NO:

125.

32. 28. The isolated bispecific antibody of claim 27, wherein the variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, or SEQ ID NO:

129.

33. a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, the variable domain comprising: CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56 or SEQ ID NO: 122; CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65 or SEQ ID NO: 123; and a CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76 or SEQ ID NO: 124; Including, 28. The isolated bispecific antibody of claim 27.

34. a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, the variable domain comprising: a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, or SEQ ID NO: 125; a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, or SEQ ID NO: 129; and CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 83 or SEQ ID NO: 130 Including, 28. The isolated bispecific antibody of claim 27.

35. below: (a) a light chain variable domain of a second antigen-binding fragment that specifically binds to BCMA, the variable domain comprising: a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, or SEQ ID NO: 122; a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, or SEQ ID NO: 123; and a CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76 or SEQ ID NO: 124; Including, and (b) a heavy chain variable domain of a second antigen-binding fragment that specifically binds to BCMA, wherein the variable domain comprises: a CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, or SEQ ID NO: 125; a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 128, or SEQ ID NO: 129; and CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 83 or SEQ ID NO: 130 Including, 28. The isolated bispecific antibody of claim 27, comprising:

36. below: (i) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 49, CDR2 of the amino acid sequence SEQ ID NO: 57 and a CDR3 of amino acid sequence SEQ ID NO: 66; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 77 CDR2 of the amino acid sequence SEQ ID NO: 80 and CDR3 of amino acid sequence SEQ ID NO: 83; or (ii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 50, CDR2 of the amino acid sequence SEQ ID NO: 58 and a CDR3 of amino acid sequence SEQ ID NO: 67; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 78 CDR2 of the amino acid sequence SEQ ID NO: 81 and CDR3 of amino acid sequence SEQ ID NO: 83; or (iii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 51, CDR2 of the amino acid sequence SEQ ID NO: 59 and a CDR3 of amino acid sequence SEQ ID NO: 68; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 79, CDR2 of the amino acid sequence SEQ ID NO: 80 and CDR3 of amino acid sequence SEQ ID NO: 83; or (iv) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 52, CDR2 of the amino acid sequence SEQ ID NO: 60 and a CDR3 of amino acid sequence SEQ ID NO: 69; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 78 CDR2 of the amino acid sequence SEQ ID NO: 80 and CDR3 of amino acid sequence SEQ ID NO: 83; or (v) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 53, CDR2 of the amino acid sequence SEQ ID NO: 61 and a CDR3 of amino acid sequence SEQ ID NO: 70; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 78 CDR2 of the amino acid sequence SEQ ID NO: 81 and CDR3 of amino acid sequence SEQ ID NO: 83; or (vi) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 53, CDR2 of the amino acid sequence SEQ ID NO: 61 and CDR3 of amino acid sequence SEQ ID NO: 71; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 78 CDR2 of amino acid sequence SEQ ID NO: 82 and CDR3 of amino acid sequence SEQ ID NO: 83; or (vii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 54, CDR2 of the amino acid sequence SEQ ID NO: 63 and a CDR3 of amino acid sequence SEQ ID NO: 73; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 78 CDR2 of the amino acid sequence SEQ ID NO: 81 and CDR3 of amino acid sequence SEQ ID NO: 83; or (viii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 53, CDR2 of the amino acid sequence SEQ ID NO: 61 and CDR3 of amino acid sequence SEQ ID NO: 71; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 78 CDR2 of the amino acid sequence SEQ ID NO: 81 and CDR3 of amino acid sequence SEQ ID NO: 83; or (ix) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 55 CDR2 of the amino acid sequence SEQ ID NO: 64 and a CDR3 of amino acid sequence SEQ ID NO: 74; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 78 CDR2 of the amino acid sequence SEQ ID NO: 80 and CDR3 of amino acid sequence SEQ ID NO: 83; or (x) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 49, CDR2 of the amino acid sequence SEQ ID NO: 65 and a CDR3 of amino acid sequence SEQ ID NO: 75; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 78 CDR2 of the amino acid sequence SEQ ID NO: 80 and CDR3 of amino acid sequence SEQ ID NO: 83; or (xi) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 56, CDR2 of the amino acid sequence SEQ ID NO: 58 and a CDR3 of amino acid sequence SEQ ID NO: 76; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 78 CDR2 of the amino acid sequence SEQ ID NO: 81 and CDR3 of amino acid sequence SEQ ID NO: 83; or (xii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 51, CDR2 of the amino acid sequence SEQ ID NO: 62 and a CDR3 of amino acid sequence SEQ ID NO: 72; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 78 CDR2 of the amino acid sequence SEQ ID NO: 81 and CDR3 of amino acid sequence SEQ ID NO: 83; or (xiii) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123 and a CDR3 of amino acid sequence SEQ ID NO: 124; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 126 and CDR3 of amino acid sequence SEQ ID NO: 130; or (xiv) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123 and a CDR3 of amino acid sequence SEQ ID NO: 124; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 127 and CDR3 of amino acid sequence SEQ ID NO: 130; or (xv) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123 and a CDR3 of amino acid sequence SEQ ID NO: 124; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 128 and CDR3 of amino acid sequence SEQ ID NO: 130; or (xvi) (a) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123 and a CDR3 of amino acid sequence SEQ ID NO: 124; and (b) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 129 and CDR3 of the amino acid sequence SEQ ID NO: 130, 36. The isolated bispecific antibody of claim 35, comprising:

37. 28. The isolated bispecific antibody of claim 27, wherein the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, or SEQ ID NO:

131.

38. the variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to BCMA is selected from the group consisting of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 135, SEQ ID NO: 136, SEQ ID NO: 137, SEQ ID NO: 138, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, or SEQ ID NO:

142.

28. The isolated bispecific antibody of claim 27, comprising an amino acid sequence selected from the group consisting of NO:

142.

39. (a) the light chain variable domain of the second antigen-binding fragment that specifically binds to BCMA comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, or SEQ ID NO: 131; and, (b) the variable domain of the heavy chain of the second antigen-binding fragment that specifically binds to BCMA is selected from the group consisting of SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 132, SEQ ID NO: 133, SEQ ID NO: 134, SEQ ID NO: 135, SEQ ID NO: 136, SEQ ID NO: 137, SEQ ID NO: 138, SEQ ID NO: 139, SEQ ID NO: 140, SEQ ID NO: 141, or SEQ ID NO:

142. SEQ ID NO: 142, 28. The isolated bispecific antibody of claim 27.

40. (i) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 84; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 95; or (ii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 85; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 96; or (iii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 86; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 97; or (iv) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 87; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 98; or (v) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 88; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 99; or (vi) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 89; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 100; or (vii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 91; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 99; or (viii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 89; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 99; or (ix) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 92; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 101; or (x) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 93; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 102; or (xi) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 94; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 99; or (xii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 90; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 99; or (xiii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 132; or (xiv) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 133; or (xv) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 134; or (xvi) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 135; or (xvii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 136; or (xviii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 137; or (xix) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 138; or (xx) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 139; or (xxi) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 140; or (xxii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 141; or (xxiii) (a) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (b) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 142; 40. The isolated bispecific antibody of claim 39.

41. 28. The isolated bispecific antibody of claim 27, wherein the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises an amino acid sequence selected from the group consisting of: SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 143, or SEQ ID NO:

144.

42. the heavy chain of the second antigen-binding fragment that specifically binds to BCMA is selected from the group consisting of SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154, or SEQ ID NO:

155.

28. The isolated bispecific antibody of claim 27, comprising an amino acid sequence selected from the group consisting of NO:

155.

43. (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 103, SEQ ID NO: 104, SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 143, or SEQ ID NO: 144; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA is selected from the group consisting of SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 118, SEQ ID NO: 119, SEQ ID NO: 120, SEQ ID NO: 121, SEQ ID NO: 145, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 148, SEQ ID NO: 149, SEQ ID NO: 150, SEQ ID NO: 151, SEQ ID NO: 152, SEQ ID NO: 153, SEQ ID NO: 154, or SEQ ID NO:

155. SEQ ID NO: 155, 28. The isolated bispecific antibody of claim 27.

44. (i)(a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 103; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 114; or (ii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 104; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 115; or (iii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 105; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 116; or (iv) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 106; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 117; or (v) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 107; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 118; or (vi) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 108; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 119; or (vii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 110; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 118; or (viii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 108; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 118; or (ix) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 111; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 120; or or (x) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 112; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 121; or (xi) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 113; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 118; or (xii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 109; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 118; or (xiii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 145; or (xiv) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 146; or (xv) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 147; or (xvi) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 148; or (xvii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 149; or (xviii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 150; or (xix) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 151; or (xx) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 152; or (xxi) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 153; or (xxii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 154; or (xxiii) (a) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 144; and, (b) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 155; 44. The isolated bispecific antibody of claim 43.

45. Including: (i) (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO: 2, CDR2 of the amino acid sequence SEQ ID NO: 3, and CDR3 of amino acid sequence SEQ ID NO: 4; (b) a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO: 6, CDR2 of the amino acid sequence SEQ ID NO: 7, and CDR3 of amino acid sequence SEQ ID NO:8; (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123, and CDR3 of amino acid sequence SEQ ID NO: 124; and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 126, and CDR3 of amino acid sequence SEQ ID NO: 130; or (ii) (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO: 2, CDR2 of the amino acid sequence SEQ ID NO: 3, and CDR3 of amino acid sequence SEQ ID NO: 4; (b) a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO: 6, CDR2 of the amino acid sequence SEQ ID NO: 7, and CDR3 of amino acid sequence SEQ ID NO:8; (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123, and CDR3 of amino acid sequence SEQ ID NO: 124; and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 127, and CDR3 of amino acid sequence SEQ ID NO: 130; or (iii) (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO: 2, CDR2 of the amino acid sequence SEQ ID NO: 3, and CDR3 of amino acid sequence SEQ ID NO: 4; (b) a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO: 6, CDR2 of the amino acid sequence SEQ ID NO: 7, and CDR3 of amino acid sequence SEQ ID NO:8; (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123, and CDR3 of amino acid sequence SEQ ID NO: 124; and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 128, and CDR3 of amino acid sequence SEQ ID NO: 130; or (iv) (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO: 2, CDR2 of the amino acid sequence SEQ ID NO: 3, and CDR3 of amino acid sequence SEQ ID NO: 4; (b) a variable domain of the heavy chain of a first antigen-binding fragment that specifically binds to CD3, comprising: CDR1 of the amino acid sequence SEQ ID NO: 6, CDR2 of the amino acid sequence SEQ ID NO: 7, and CDR3 of amino acid sequence SEQ ID NO:8; (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123, and CDR3 of amino acid sequence SEQ ID NO: 124; and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 129, and CDR3 of amino acid sequence SEQ ID NO: 130; or (v) (a) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, designed in a CrossMAb format, comprising: CDR1 of the amino acid sequence SEQ ID NO: 6, CDR2 of the amino acid sequence SEQ ID NO: 7, and CDR3 of amino acid sequence SEQ ID NO:8; (b) a variable domain of the light chain of a first antigen-binding fragment that specifically binds to CD3, designed in a CrossMAb format, comprising: CDR1 of the amino acid sequence SEQ ID NO: 2, CDR2 of the amino acid sequence SEQ ID NO: 3, and CDR3 of amino acid sequence SEQ ID NO: 4; (c) a variable domain of the light chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 122, CDR2 of the amino acid sequence SEQ ID NO: 123, and CDR3 of amino acid sequence SEQ ID NO: 124; and (d) a variable domain of the heavy chain of a second antigen-binding fragment that specifically binds to BCMA, comprising: CDR1 of the amino acid sequence SEQ ID NO: 125, CDR2 of the amino acid sequence SEQ ID NO: 126, and CDR3 of the amino acid sequence SEQ ID NO: 130, 28. The isolated bispecific antibody of claim 27.

46. below: (i) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 132; or (ii) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 133; or (iii) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 134; or (iv) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 135; or (v) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 136; or (vi) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 137; or (vii) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 138; or (viii) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 139; or (ix) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 140; or (x) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 141; or (xi) (a) the variable domain of the light chain of a first antigen-binding fragment designed in a CrossMAb format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 156; (b) the variable domain of the heavy chain of a first antigen-binding fragment designed in a CrossMAb format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 157; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 142; or (xii) (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence of SEQ ID NO: 11; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 19; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 142; 28. The isolated bispecific antibody of claim 27, comprising:

47. below: (i) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 145; or (ii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 146; or (iii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 147; or (iv) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 148; or (v) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 149; or (vi) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 150; or (vii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 151; or (viii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 152; or (ix) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 153; or (x) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 158; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 159; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 143; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 154; or (xi) (a) the light chain of the first antigen-binding fragment designed in a CrossMAb format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 160; (b) the heavy chain of the first antigen-binding fragment designed in a CrossMab format that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 161; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 144; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 155; or (xii) (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 162; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 163; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 144; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 155; 28. The isolated bispecific antibody of claim 27, comprising:

48. 1. An isolated bispecific antibody that specifically binds to CD3 and BCMA tumor antigens, comprising: 1) A first antigen-binding fragment that specifically binds to CD3, designed in a CrossMAb format, comprising: (a) a light chain variable domain comprising: (i) CDR1 of the amino acid sequence SEQ ID NO:6; (ii) CDR2 of the amino acid sequence SEQ ID NO:7, and CDR3 of amino acid sequence SEQ ID NO:8; and (b) a heavy chain variable domain comprising: (i) CDR1 of the amino acid sequence SEQ ID NO:2; (ii) CDR2 of the amino acid sequence SEQ ID NO:3, and (iii) CDR3 of the amino acid sequence SEQ ID NO:4; the first antigen-binding fragment comprising: and 2) A second antigen-binding fragment that specifically binds to a BCMA tumor antigen, comprising: (a) a light chain variable domain comprising: (i) CDR1 of the amino acid sequence SEQ ID NO: 122; CDR2 of the amino acid sequence SEQ ID NO: 123, and (iii) CDR3 of amino acid sequence SEQ ID NO: 124; and (b) a heavy chain variable domain comprising: (i) CDR1 of the amino acid sequence SEQ ID NO: 125; (i) CDR1 of the amino acid sequence SEQ ID NO: 126, and (iii) a CDR3 having the amino acid sequence SEQ ID NO: 130; the second antigen-binding fragment comprising:

2. The isolated bispecific antibody comprising:

49. (a) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 156; (b) the variable domain of the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 157; (c) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 131; and, (d) the variable domain of the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 142; 49. The isolated bispecific antibody of claim 48, comprising:

50. 50. The isolated bispecific antibody of any one of claims 48-49, wherein the antibody that specifically binds to CD3 and the tumor antigen BCMA is a full-length IgG antibody.

51. 51. The isolated bispecific antibody of claim 50, wherein the full-length IgG antibody is of the human IgG1, IgG2, IgG3, or IgG4 isotype.

52. A full-length IgG antibody is an antibody of the human IgG1 isotype.

52. The isolated bispecific antibody of claim 51.

53. 53. The isolated bispecific antibody of claim 52, comprising the mutations L234A and L235A according to the EU numbering scheme in the CH2 region.

54. 53. The isolated bispecific antibody of claim 52, comprising the mutations M252Y, S254T and T256E according to the EU numbering scheme in the CH2 region.

55. 53. The isolated bispecific antibody of claim 52, comprising the mutations S354C and T366W according to the EU numbering scheme in the CH3 region.

56. 53. The isolated bispecific antibody of claim 52, comprising the mutations Y349C, T366S, L368A and Y407V according to the EU numbering scheme in the CH3 region.

57. (a) the light chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 160; (b) the heavy chain of the first antigen-binding fragment that specifically binds to CD3 comprises the amino acid sequence SEQ ID NO: 161; (c) the light chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 144; and, (d) the heavy chain of the second antigen-binding fragment that specifically binds to BCMA comprises the amino acid sequence SEQ ID NO: 155; 49. The isolated bispecific antibody of claim 48.

58. 58. An isolated nucleic acid encoding the bispecific antibody of any one of claims 1-57.

59. 59. The isolated nucleic acid of claim 58, wherein the nucleic acid is DNA.

60. An expression vector comprising the nucleic acid of any one of claims 58-59.

61. 61. A method for producing a host cell for producing the bispecific antibody of any one of claims 1 to 57, the method comprising transforming the cell with the vector of claim 60.

62. A host cell for producing the antibody or antigen-binding fragment thereof of any one of claims 1-57, comprising a nucleic acid of any one of claims 58-59.

63. 68. A method for producing the bispecific antibody of any one of claims 1-57, comprising culturing a host cell of claim 62 in a culture medium under conditions sufficient to produce the bispecific antibody, and subsequently isolating and purifying the resulting antibody.

64. 100. A pharmaceutical composition for treating a disease or disorder mediated by a tumor antigen, comprising a therapeutically effective amount of a bispecific antibody according to any one of claims 1 to 57 in combination with one or more pharmaceutically acceptable tumor antigens and an excipient.

65. 65. The pharmaceutical composition of claim 64, wherein the disease or disorder mediated by a tumor antigen is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, acute B-lymphoblastic leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

66. 58. A pharmaceutical composition for treating a disease or disorder mediated by a tumor antigen, comprising a bispecific antibody according to any one of claims 1 to 57 and at least one other therapeutically active compound.

67. 67. The pharmaceutical composition of claim 66, wherein the disease or disorder mediated by a tumor antigen is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, acute B-lymphoblastic leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

68. 68. The pharmaceutical composition of any one of claims 66-67, wherein the other therapeutically active compound is an antibody, a small molecule, a hormone therapy agent, or a combination thereof.

69. 69. A method for treating a disease or disorder mediated by a tumor antigen, comprising administering to a subject in need thereof a therapeutically effective amount of the bispecific antibody of any one of claims 1-57 or the pharmaceutical composition of any one of claims 64-68.

70. 70. The method of claim 69, wherein the disease or disorder mediated by a tumor antigen is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, acute B-lymphoblastic leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

71. 100. A method for treating a disease or disorder mediated by a tumor antigen, comprising administering to a subject in need thereof a therapeutically effective amount of the bispecific antibody of any one of claims 1-57 and at least one other therapeutically active compound.

72. 72. The method of treating a disease or disorder according to claim 71, wherein the disease or disorder mediated by a tumor antigen is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, acute B-lymphoblastic leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

73. 73. The method for treating a disease or disorder according to any one of claims 71-72, wherein the other therapeutically active compound is an antibody, a small molecule, a hormone therapy agent, or a combination thereof.

74. 69. Use of a bispecific antibody according to any one of claims 1 to 57 or a pharmaceutical composition according to any one of claims 64 to 68 for the treatment of a disease or disorder mediated by a tumor antigen in a subject in need of such treatment.

75. 75. The use of claim 74, wherein the disease or disorder mediated by a tumor antigen is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, acute B-lymphoblastic leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

76. Use of a bispecific antibody according to any one of claims 1 to 57 and at least one other therapeutically active compound for the treatment of a disease or disorder mediated by a tumor antigen.

77. 77. The use of claim 76, wherein the disease or disorder mediated by a tumor antigen is selected from the group consisting of multiple myeloma, chronic lymphocytic leukemia, acute B-lymphoblastic leukemia, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

78. 77. The use of claim 76, wherein the other therapeutically active compound is an antibody, a small molecule, a hormone therapy agent, or a combination thereof.

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