Binding molecule against BCMA and its use

Abstract

To provide polypeptides, e.g., antibodies and multispecific binding molecules, which bind BCMA, and which have an improved safety profile (e.g., decreasing cytokine release) while still retaining high efficacy.SOLUTION: Provided is a BCMA binding molecule that comprises specific sequences of CDR-L1, CDR-L2 and CDR-L3, and CDR-H1, CDR-H2 and CDR-H3. Also provided is a bispecific binding molecule such as an anti-CD3 antibody or an antigen-binding domain thereof.SELECTED DRAWING: None

Description

Technical Field

[0001] 1. Cross - reference to related applications This application claims the benefit of priority of the specification of U.S. Provisional Patent Application No. 62 / 679,611, filed on June 1, 2018 and the specification of U.S. Provisional Patent Application No. 62 / 684,046, filed on June 12, 2018 and the entire contents of both of these provisional patent applications are hereby incorporated by reference into this specification.

[0002] 2. Sequence Listing This application includes a sequence listing that was electronically submitted in ASCII format, and this sequence listing is hereby incorporated by reference in its entirety into this specification. This ASCII copy was created on May 10, 2019 and is named NOV - 003WO_SL and is 400,375 bytes in size.

[0003] 3. Incorporation by reference All publications, patents, patent applications, and other documents cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document were individually indicated to be incorporated by reference for all purposes and are hereby incorporated by reference into this specification. If there is a conflict between one or more of the reference documents incorporated by reference herein and the teachings of this disclosure the teachings of this specification shall govern.

Background Art

[0004] BCMA is a member of the tumor necrosis factor receptor (TNFR) family that is expressed in cells of the B - cell lineage. BCMA expression occurs in terminally differentiated B cells that assume the fate of long - lived plasma cells including subpopulations of plasma cells, plasmablasts, activated B cells, and memory - B cells. ​is the highest. BCMA mediates the survival of plasma cells to maintain long-term humoral immunity is involved. The expression of BCMA has been associated with many cancers, autoimmune diseases, and infectious diseases Cancers with increased expression of BCMA include several blood cancers such as multiple myeloma , Hodgkin lymphoma and non-Hodgkin lymphoma, various leukemias, and glioblastoma are mentioned

[0005] BCMA antibody-drug conjugates such as GSK2857916 (GlaxoSmi thkline), as well as bispecific BCMA-binding molecules targeting BMCA and CD3 such as PF06863135 (Pfizer), EM 901 (EngMab), JNJ -64007957 (Janssen) and AMG 420 (Amgen) are in clinical development. Cho et al., 2018, Front Immunol. 9:1821; see International Publication No. 2016 / 0166629 pamphlet for reference

[0006] One of the main safety concerns for any antibody-based drug, including CD3 bispecific molecules, is its potential to induce life-threatening side effects such as cytokine release syndrome ("CRS") Shimabukuro-Vornhagen, A. et al., 2018, J. Immunother Cancer. 6:56 for reference

SUMMARY OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] Therefore, while binding to BCMA and maintaining high efficacy, an improved safety profile ​Polypeptides having a file (e.g., reducing cytokine release), such as antibodies There are unmet medical needs for bispecific binding molecules.

Means for Solving the Problem

[0008] The present disclosure provides BCMA-binding molecules that specifically bind to human BCMA, such as antibodies, antigen-binding fragments thereof and multispecific molecules that specifically bind to human BCMA.

[0009] In one aspect, the present disclosure provides monospecific BCMA-binding molecules (e.g., antibodies and antigen-binding fragments thereof) comprising a BCMA antigen-binding domain ("ABD"). Exemplary BCMA-binding molecules that can be monospecific are described in Section 7.2 and Specific Embodiments 1-142 below. Another aspect of the present disclosure provides a first ABD ("ABD1" or "BCMA ABD") that specifically binds to human BCMA and a second ABD (" ABD2") that specifically binds to a second antigen, such as human CD3 or other components of the TCR complex (sometimes referred to herein as "TCR ABD"), in a multispecific binding molecule ("MBM") (e.g., a bispecific binding molecule ("BBM")). The terms ABD1, ABD2, BCMA ABD, and TCR ABD are used for convenience only and are not intended to indicate any particular form of the BBM. In certain embodiments, the TCR ABD binds to CD3 (sometimes referred to herein as "CD3 ABD", etc.). Accordingly, the disclosure related to ABD2 and TCR ABD is also applicable to CD3 ABD. as described in 142.

[0010] In another aspect, the present disclosure provides a first ABD ("ABD1" or "BCMA ABD") that specifically binds to human BCMA and a second ABD (" ABD2") that specifically binds to a second antigen, such as human CD3 or other components of the TCR complex (sometimes referred to herein as "TCR ABD"), in a multispecific binding molecule ("MBM") (e.g., a bispecific binding molecule ("BBM")). The terms ABD1, ABD2, BCMA ABD, and TCR ABD are used for convenience only and are not intended to indicate any particular form of the BBM. In certain embodiments, the TCR ABD binds to CD3 (sometimes referred to herein as "CD3 ABD", etc.). Accordingly, the disclosure related to ABD2 and TCR ABD is also applicable to CD3 ABD. ABD2") that specifically binds to a second antigen, such as human CD3 or other components of the TCR complex (sometimes referred to herein as "TCR ABD"), in a multispecific binding molecule ("MBM") (e.g., a bispecific binding molecule ("BBM")). The terms ABD1, ABD2, BCMA ABD, and TCR ABD are used for convenience only and are not intended to indicate any particular form of the BBM. In certain embodiments, the TCR ABD binds to CD3 (sometimes referred to herein as "CD3 ABD", etc.). Accordingly, the disclosure related to ABD2 and TCR ABD is also applicable to CD3 ABD. TCR ABD"), in a multispecific binding molecule ("MBM") (e.g., a bispecific binding molecule ("BBM")). The terms ABD1, ABD2, BCMA ABD, and TCR ABD are used for convenience only and are not intended to indicate any particular form of the BBM. In certain embodiments, the TCR ABD binds to CD3 (sometimes referred to herein as "CD3 ABD", etc.). Accordingly, the disclosure related to ABD2 and TCR ABD is also applicable to CD3 ABD. For example, bispecific binding molecules ("BBMs")). The terms ABD1, ABD2, BCMA ABD, and TCR ABD are used for convenience only and are not intended to indicate any particular form of the BBM. In certain embodiments, the TCR ABD binds to CD3 (sometimes referred to herein as "CD3 ABD", etc.). Accordingly, the disclosure related to ABD2 and TCR ABD is also applicable to CD3 ABD. ABD and TCR ABD are for convenience only and are not intended to indicate any particular form of the BBM. In certain embodiments, the TCR ABD binds to CD3 (sometimes referred to herein as "CD3 ABD", etc.). Accordingly, the disclosure related to ABD2 and TCR ABD is also applicable to CD3 ABD. Accordingly, the disclosure related to ABD2 and TCR ABD is also applicable to CD3 ABD. Therefore, the disclosure related to ABD2 and TCR ABD is also applicable to CD3 ABD. Such multispecific molecules can direct CD3+ effector T cells to BCMA+ sites such that CD3+ effector T cells can be used to attack and lyse BCMA+ cells and tumors. Exemplary features of MBMs are described in Sections 7.2-7 .6 and specific embodiments 143-716 below. .

[0011] The ABDs can be immunoglobulin-based or non-immunoglobulin-based, and the MBMs can include any combination of immunoglobulin-based ABDs or immunoglobulin-based ABDs and non-immunoglobulin-based ABDs. Immunoglobulin-based ABDs that can be used in BCMA-binding molecules are described in Sections 7.2 and 7.3.1 and specific embodiments 14 7-329 below. Non-immunoglobulin-based ABDs that can be used in MBMs are described in Section 7.3.2 and specific embodiments 330-331 below. Further features of exemplary ABDs that bind to BCMA are described in Section 7.2 and specific embodiments 14 7-155 below. Further features of exemplary ABDs that bind to components of the TCR complex are described in Section 7.3.3 and specific embodiments 156-331 below.

[0012] The ABDs of the BCMA-binding molecule (or portions thereof) can be linked to each other, for example, by short peptide linkers or Fc domains. Methods and components for linking ABDs and portions thereof to form BCMA-binding molecules are described in Section 7.4 and specific embodiments 332 -620 below.

[0013] In certain embodiments, the MBMs of the disclosure are BBMs. BBMs have at least two​​​​​​​​​ having an ABD of (i.e., the BBM is at least divalent), but may have three or more ABDs For example, the BBM may have three ABDs (i.e., trivalent) or four ABDs (i.e., tetravalent), provided that the BBM has at least one ABD capable of binding to BCMA and at least one ABD capable of binding to a target antigen other than BCMA Exemplary divalent, trivalent, and tetravalent BBM forms are shown in Figure 1 and described in Section 7.5 below and in certain embodiments 621 - 681.

[0014] The present disclosure further provides a nucleic acid encoding a BCMA binding molecule (in either a single nucleic acid or multiple nucleic acids), as well as a recombinant host cell and cell line engineered to express this nucleic acid and the BCMA binding molecule. Exemplary nucleic acids, host cells, and cell lines are described in Section 7 .7 below and in certain embodiments 1051 - 1057. The present disclosure further provides a BCMA binding molecule having an extended in vivo half - life. Examples of such

[0015] BCMA binding molecules are described in Section 7.8 below and in certain embodiments 836 - 845. The present disclosure further provides a drug conjugate comprising a BCMA binding molecule. Such a conjugate is referred to herein as an "antibody - drug conjugate" or "ADC" for convenience, even though a portion of the ABD may be a non - immunoglobulin domain.

[0016] Examples of ADCs are described in Section 7.9 below and in certain embodiments 851 - 889.

[0017] The present disclosure also provides a BCMA binding molecule and a polypeptide, marker, diagnostic agent, or detectable agent​​​ or further provide a conjugate comprising a solid carrier. Examples of such conjugates are , described in Sections 7.10 and 7.11 and specific embodiments 846 - 850 and 890 - 8 91 below.

[0018] Pharmaceutical compositions comprising BCMA binding molecules and ADCs are also provided. Examples of pharmaceutical compositions are described in Section 7.12 below and specific embodiment 892.

[0019] For example, for treating a proliferative disease (e.g., cancer) in which BCMA is expressed, for treating an autoimmune disease, and for treating other diseases and conditions related to the expression of BCMA , methods of using BCMA binding molecules, ADCs, and pharmaceutical compositions are further provided herein . Exemplary methods are described in Section 7.13 below and specific embodiments 893 - 971 and 1012 - 1050.

[0020] The present disclosure further provides methods of using BCMA binding molecules, ADCs, and pharmaceutical compositions in combination with other agents and therapies . Exemplary agents, therapies, and methods of combination therapy are described in Section 7.14 below and specific embodiments 972 - 1011. BRIEF DESCRIPTION OF THE DRAWINGS

[0021]

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Best Mode for Carrying Out the Invention

[0022] 7.1. Definitions As used herein, the following terms are intended to have the following meanings .

[0023] ADCC: As used herein, "ADCC" or "antibody-dependent cell-mediated cytotoxicity" means a cell-mediated reaction in which non-specific cytotoxic cells expressing FcγRs recognize bound antibody on a target cell and subsequently cause lysis of the target cell. ADCC correlates with binding to FcγRIIIa; increased binding to FcγRIIIa results in increased ADCC activity.

[0024] ADCP: As used herein, "ADCP" or antibody-dependent cell-mediated phagocytosis means a cell-mediated reaction in which non-specific phagocytic cells expressing FcγRs recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.

[0025] Additional agent: For convenience, an agent used in combination with an antigen-binding molecule of the present disclosure is referred to herein as an "additional" agent.

[0026] Antibody: As used herein, the term "antibody" refers to a polypeptide (or set of polypeptides) of the immunoglobulin family that can bind non-covalently, reversibly and specifically to an antigen. For example, a natural "antibody" of the IgG type is a tetramer comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain has a heavy chain variable region (abbreviated herein as VH) and a heavy chain (or set of polypeptides) that can bind non-covalently, reversibly and specifically to an antigen. For example, a natural "antibody" of the IgG type is a tetramer comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain has a heavy chain variable region (abbreviated herein as VH) and a heavy chain and a heavy chain ​​​​​​​​​It is composed of constant regions. The heavy chain constant region consists of three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated as VL herein) and a light chain constant region. The light chain constant region consists of one domain (abbreviated as CL herein). The VH and VL regions can be further subdivided into hypervariable regions called complementary determining regions (CDRs), with more conserved regions called framework regions (FRs) interspersed therebetween. Each VH and VL is composed of three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody can mediate the binding of immunoglobulins to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (Clq). The term "antibody" includes, but is not limited to, monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, chimeric antibodies, bispecific or multispecific antibodies, and anti-idiotype (anti-Id) antibodies (e.g., including anti-Id antibodies against the antibodies of the present disclosure). Antibodies can be of any isotype / class (e.g., IgG, IgE, IgM, IgD, IgA, and IgY) or

[0027] subclass (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2). Both the light and heavy chains are divided into regions of structural and functional It will be appreciated that the variable domains of both the heavy and light chains determine antigen recognition and specificity. . Conversely, the constant domains of the light chain (CL) and heavy chain (CH1, CH2, or CH3) confer important biological properties such as secretion, transplacental mobility, Fc receptor binding, complement binding, etc. By convention, the numbering of the constant region domains increases as they become more distal from the antigen-binding site or amino terminus of the antibody. In a wild-type antibody, the N-terminus is the variable region and the C-terminus is the constant region; the CH3 and CL domains actually contain the carboxy termini of the heavy and light chains, respectively.

[0028] Antibody fragments: As used herein, the term "antibody fragment" of an antibody refers to one or more portions of the antibody. In certain embodiments, these portions are part of the contact domains of the antibody. In certain other embodiments, these portions are antigen-binding fragments, "antigen-binding fragments thereof," "antigen-binding portions," etc., as referred to herein, that non-covalently, reversibly, and specifically bind an antigen. Examples of binding fragments include, but are not limited to, single-chain Fv (scFv), Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; F(ab)2 fragments, divalent fragments containing two Fab fragments linked by a disulfide bridge in the hinge region; Fd fragments consisting of VH and CH1 domains; Fv fragments consisting of the VL and VH domains of a single arm of the antibody; dAb fragments consisting of the VH domain (Ward et al., (1989) Nature 341:544-546); and isolated complementarity determining regions (CDRs) or a CDR-containing fragment. determining regions (CDRs) or a CDR-containing fragment. It is an antigen-binding fragment that retains the ability to bind an antigen non-covalently, reversibly, and specifically. Examples of binding fragments include, but are not limited to, single-chain Fv (scFv), Fab fragments, monovalent fragments consisting of VL, VH, CL, and CH1 domains; F(ab)2 fragments, divalent fragments containing two Fab fragments linked by a disulfide bridge in the hinge region; Fd fragments consisting of VH and CH1 domains; Fv fragments consisting of the VL and VH domains of a single arm of the antibody; dAb fragments consisting of the VH domain (Ward et al., (1989) Nature 341:544-546); and isolated complementarity determining regions (CDRs) or a CDR-containing fragment. consisting of VL, VH, CL, and CH1 domains; F(ab)2 fragments, divalent fragments containing two Fab fragments linked by a disulfide bridge in the hinge region; Fd fragments consisting of VH and CH1 domains; Fv fragments consisting of the VL and VH domains of a single arm of the antibody; dAb fragments consisting of the VH domain (Ward et al., (1989) Nature 341:544-546); and isolated complementarity determining regions (CDRs) or a CDR-containing fragment. from the VH domain (Ward et al., (1989) Nature 341:544-546); and isolated complementarity Examples include the complementarity determining region (CDR). Thus, the term "antibody fragment" includes proteolytic fragments of an antibody (e.g., Fab and F(ab)2 fragments) and modified proteins containing one or more portions of an antibody (e.g., scFv).

[0029] Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intracellular antibodies, bispecific antibodies, trispecific antibodies, tetravalent antibodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, 2005, Nat Biotechnology 23:1126-1136). Antibody fragments can be grafted into scaffolds based on polypeptides such as fibronectin type III (Fn3) (see U.S. Patent No. 6,703,199, which describes fibronectin polypeptide monobodies).

[0030] Antibody fragments can be incorporated into single-chain molecules containing pairs of tandem Fv segments (e.g., VH -CH1-VH-CH1) that together with complementary light chain polypeptides (e.g., VL-VC-VL-VC) form pairs of antigen-binding regions (Zapata et al., 1995, Protein Eng. 8:1057-1062; and U.S. Patent No. 5,641,870).

[0031] Antibody numbering system: As used herein, references to numbered amino acid residues in antibody domains are based on the EU numbering system (e.g., in Tables 1C -1N), unless otherwise specified. This system is described in Edelman et al., 1969, Proc. Nat l. Acad. Sci. USA 63:78-85. First devised by ’l Acad.Sci.USA 63:78-85 and described in detail in Kaba t et al.,1991,in Sequences of Proteins o f Immunological Interest,US Department o f Health and Human Services,NIH,USA .

[0032] Antigen-binding domain: The term “antigen-binding domain” or “ABD” refers to the portion of an antigen-binding molecule that has the ability to non-covalently , reversibly and specifically bind to an antigen. Exemplary ABDs include antigen-binding fragments and scaffolds based on both immunoglobulins and non-immunoglobulins that retain the ability to non-covalently , reversibly and specifically bind to an antigen. As used herein, the term “antigen-binding domain” encompasses antibody fragments that retain the ability to non-covalently , reversibly and specifically bind to an antigen .

[0033] Antigen-binding domain chain or ABD chain: An individual ABD can exist as one polypeptide chain (e.g., in the case of scFv), or can be formed by the association of two or more polypeptide chains (e.g., in the case of Fab). As used herein, the term “ABD chain” refers to all or part of an ABD that exists on a single polypeptide chain. The use of the term “ABD chain” is intended for convenience and for purposes of explanation only and does not imply a particular form or method of manufacture . .

[0034] Antigen-binding fragment: The term “antigen-binding fragment” of an antibody refers to non-covalently ​​​Refers to a portion of an antibody that retains the ability to bind reversibly and specifically to an antigen.

[0035] Antigen-binding molecule: The term "antigen-binding molecule" refers to a molecule that contains one or more antigen-binding domains, such as an antibody. An antigen-binding molecule can comprise one or more polypeptide chains, for example, one, two, three, four, or more than four polypeptide chains. The polypeptide chains in an antigen-binding molecule can be associated with each other directly or indirectly (e.g., a first polypeptide chain can be associated with a second polypeptide chain, which can then be associated with a third polypeptide chain to form an antigen-binding molecule in which the first and second polypeptide chains are directly associated with each other, or the second and third polypeptide chains are directly associated with each other and the first and third polypeptide chains are indirectly associated with each other via the second polypeptide chain). Associated: In reference to domains or regions within an antigen-binding molecule, the term "associated" refers to a functional relationship between two or more polypeptide chains and / or between two or more positions of a single polypeptide chain. In particular, the term "associated" means that two or more polypeptides (or

[0036] multiple portions of a single polypeptide) are non-covalently associated with each other by, for example, molecular interactions and / or covalently associated with each other by one or more disulfide or chemical cross-links so as to generate a functional antigen-binding domain. Examples of associations that can be present in an antigen-binding molecule include, without limitation, the association between Fc regions within the Fc domain, the association between VH and VL regions in Fab or Fv, and the association between CH1 and CL in Fab.

[0037] ​​​​​​​​​B Cells: As used herein, the term "B cells" refers to a lymphocyte subtype. These cells are of the B-cell lineage, a type of white blood cell found in the blood. Examples of B cells are plasmablasts, plasma Plasma cells, lymphoplasmocytoid cells, memory B cells, follicular B cells, marginal zone B cells, B-1 cells These include B cells, B-2 cells and regulatory B cells.

[0038] B cell malignancies: As used herein, B cell malignancies are characterized by the dysregulation of B cells. Examples of B-cell malignancies include non-Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HCL), and For example, B cell malignancies include, but are not limited to, lymphomas, leukemias, and myelomas. However, multiple myeloma, chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL), Follicular lymphoma, mantle cell lymphoma (MCL), diffuse large B-cell lymphoma ( DLBCL), marginal zone lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (Walker lymphoma) Denström's macroglobulinemia), hairy cell leukemia, primary central nervous system (CNS) ) Lymphoma, primary mediastinal large B-cell lymphoma, mediastinal gray zone lymphoma (MGZL), splenic Extranodal marginal zone B-cell lymphoma, MALT-type extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma The tumor may be a primary effusion lymphoma, and a primary effusion lymphoma, and a plasmacytoid dendritic cell neoplasm.

[0039] BCMA: As used herein, the term "BCMA" refers to a B cell maturation antigen. BCMA (also known as TNFRSF17, BCM or CD269) is a member of the tumor necrosis receptor (TNFR) family and is expressed primarily in terminally differentiated B cells. , expressed, for example, in memory B cells and plasma cells. Its ligand is involved in B cell activation. It includes B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). The protein BCMA is encoded by the gene TNFRSF17. An exemplary BCMA sequence is available in the Uniprot database under accession number Q 02223.

[0040] Binding sequence: Referring to Table 1 (including its sub-parts), the term "binding sequence" means an ABD having a set of CDRs, a VH-VL pair, or an scFv described in the corresponding table.

[0041] Bispecific binding molecule: The term "bispecific binding molecule" or "BBM" refers to a molecule that specifically binds to two antigens and contains two or more ABDs. The BBMs of the present disclosure contain at least one antigen-binding domain specific for BCMA and at least one antigen-binding domain specific for a different antigen, for example, a component of the TCR complex. Representative BB Ms are shown in Figures 1B - 1AG. The BBM can contain one, two, three, four, or more polypeptide chains. more than.

[0042] Bivalent: When used herein in connection with an antigen-binding molecule, the term "bivalent" refers to an antigen-binding molecule having two ABDs. The domains can be the same or different . Thus, a bivalent antigen-binding molecule can be monospecific or bispecific. A bivalent BBM contains an ABD that specifically binds to BCMA and another ABD that binds to a different antigen, for example, a component of the TC R complex.

[0043] Cancer: The term "cancer" refers to a disease characterized by the uncontrolled (often rapid) growth of abnormal cells. Cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body and It can spread to other sites. Examples of various cancers are described herein and include, but are not limited to, leukemia , multiple myeloma, asymptomatic myeloma, Hodgkin lymphoma and non-Hodgkin lymphoma, such as any BCMA-positive cancer of any of the types described above . The term "cancerous B cell" refers to B cells that are undergoing or have undergone uncontrolled proliferation .

[0044] CD3: The term "CD3" or "cluster of differentiation 3" refers to a group of three differentiated co-receptors of the T cell receptor. CD3 promotes the activation of both cytotoxic T cells (e.g., CD8+ naive T cells) and T helper cells (e.g., CD4+ naive T cells), and consists of four different chains: one CD3γ chain (e.g., Genbank accession numbers NM_000073 and MP_000064 (human)), one CD3δ chain (e.g., Genbank accession numbers NM_000732, NM_001040651, NP_00732 and NP_001035741 (human)) and two CD3ε chains (e.g., Genbank accession numbers NM_000733 and NP_00724 (human)). The chains of CD3 are very closely related cell surface proteins of the immunoglobulin superfamily that contain a single extracellular immunoglobulin domain. The CD3 molecule associates with the T cell receptor (TCR) and the ζ-chain to form the T cell receptor (TCR) complex that functions in generating activation signals in T lymphocytes . . . . . . . . . . .

[0045] Unless explicitly indicated otherwise, references to CD3 in this application may refer to the CD3 co-receptor, the CD3 co-receptor complex or any polypeptide chain of the CD3 co-receptor complex .

[0046] Chimeric antibody: The term "chimeric antibody" (or its antigen-binding fragment) refers to an antibody molecule (or its antigen-binding fragment) in which (a) the constant region or a portion thereof, and the antigen-binding site (variable region), are from different or modified classes, effector functions, and / or species, or are modified, substituted, or exchanged so as to be linked to a completely different molecule, such as an enzyme, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody; or (b) the variable region or a portion thereof is modified, substituted, or exchanged with a variable region having a different or modified antigen specificity. For example, a mouse antibody can be modified by substituting its constant region with a constant region from human immunoglobulin. By substitution with a human constant region, the chimeric antibody can retain its specificity in recognizing an antigen while having reduced antigenicity in humans compared to the original mouse antibody. The constant region or a portion thereof, and the antigen-binding site (variable region), are from different or modified classes, effector functions, and / or species, or are modified, substituted, or exchanged so as to be linked to a completely different molecule, such as an enzyme, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody; or (b) the variable region or a portion thereof is modified, substituted, or exchanged with a variable region having a different or modified antigen specificity. For example, a mouse antibody can be modified by substituting its constant region with a constant region from human immunoglobulin. By substitution with a human constant region, the chimeric antibody can retain its specificity in recognizing an antigen while having reduced antigenicity in humans compared to the original mouse antibody. The constant region or a portion thereof, and the antigen-binding site (variable region), are from different or modified classes, effector functions, and / or species, or are modified, substituted, or exchanged so as to be linked to a completely different molecule, such as an enzyme, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody; or (b) the variable region or a portion thereof is modified, substituted, or exchanged with a variable region having a different or modified antigen specificity. For example, a mouse antibody can be modified by substituting its constant region with a constant region from human immunoglobulin. By substitution with a human constant region, the chimeric antibody can retain its specificity in recognizing an antigen while having reduced antigenicity in humans compared to the original mouse antibody. effector functions, and / or species, or are modified, substituted, or exchanged so as to be linked to a completely different molecule, such as an enzyme, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody; or (b) the variable region or a portion thereof is modified, substituted, or exchanged with a variable region having a different or modified antigen specificity. For example, a mouse antibody can be modified by substituting its constant region with a constant region from human immunoglobulin. By substitution with a human constant region, the chimeric antibody can retain its specificity in recognizing an antigen while having reduced antigenicity in humans compared to the original mouse antibody. The constant region or a portion thereof, and the antigen-binding site (variable region), are from different or modified classes, effector functions, and / or species, or are modified, substituted, or exchanged so as to be linked to a completely different molecule, such as an enzyme, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody; or (b) the variable region or a portion thereof is modified, substituted, or exchanged with a variable region having a different or modified antigen specificity. For example, a mouse antibody can be modified by substituting its constant region with a constant region from human immunoglobulin. By substitution with a human constant region, the chimeric antibody can retain its specificity in recognizing an antigen while having reduced antigenicity in humans compared to the original mouse antibody. effector functions, and / or species, or are modified, substituted, or exchanged so as to be linked to a completely different molecule, such as an enzyme, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody; or (b) the variable region or a portion thereof is modified, substituted, or exchanged with a variable region having a different or modified antigen specificity. For example, a mouse antibody can be modified by substituting its constant region with a constant region from human immunoglobulin. By substitution with a human constant region, the chimeric antibody can retain its specificity in recognizing an antigen while having reduced antigenicity in humans compared to the original mouse antibody. effector functions, and / or species, or are modified, substituted, or exchanged so as to be linked to a completely different molecule, such as an enzyme, toxin, hormone, growth factor, drug, etc., that confers new properties to the chimeric antibody; or (b) the variable region or a portion thereof is modified, substituted, or exchanged with a variable region having a different or modified antigen specificity. For example, a mouse antibody can be modified by substituting its constant region with a constant region from human immunoglobulin. By substitution with a human constant region, the chimeric antibody can retain its specificity in recognizing an antigen while having reduced antigenicity in humans compared to the original mouse antibody.

[0047] Complementary determining region: As used herein, the term "complementary determining region" or "CDR" refers to the amino acid sequences within the antibody variable region that confer antigen specificity and binding affinity. For example, generally, there are three CDRs in each heavy chain variable region (e.g., CDR-H1, CDR-H2, and CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, and CDR-L3). The exact amino acid sequence boundaries of a given CDR are defined by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest”, 5th Ed. Published by the U.S. Department of Health and Human Services, National Institutes of Health. As used herein, the term "complementary determining region" or "CDR" refers to the amino acid sequences within the antibody variable region that confer antigen specificity and binding affinity. For example, generally, there are three CDRs in each heavy chain variable region (e.g., CDR-H1, CDR-H2, and CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, and CDR-L3). The exact amino acid sequence boundaries of a given CDR are defined by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest”, 5th Ed. Published by the U.S. Department of Health and Human Services, National Institutes of Health. As used herein, the term "complementary determining region" or "CDR" refers to the amino acid sequences within the antibody variable region that confer antigen specificity and binding affinity. For example, generally, there are three CDRs in each heavy chain variable region (e.g., CDR-H1, CDR-H2, and CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, and CDR-L3). The exact amino acid sequence boundaries of a given CDR are defined by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest”, 5th Ed. Published by the U.S. Department of Health and Human Services, National Institutes of Health. As used herein, the term "complementary determining region" or "CDR" refers to the amino acid sequences within the antibody variable region that confer antigen specificity and binding affinity. For example, generally, there are three CDRs in each heavy chain variable region (e.g., CDR-H1, CDR-H2, and CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, and CDR-L3). The exact amino acid sequence boundaries of a given CDR are defined by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest”, 5th Ed. Published by the U.S. Department of Health and Human Services, National Institutes of Health. As used herein, the term "complementary determining region" or "CDR" refers to the amino acid sequences within the antibody variable region that confer antigen specificity and binding affinity. For example, generally, there are three CDRs in each heavy chain variable region (e.g., CDR-H1, CDR-H2, and CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, and CDR-L3). The exact amino acid sequence boundaries of a given CDR are defined by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest”, 5th Ed. Published by the U.S. Department of Health and Human Services, National Institutes of Health. As used herein, the term "complementary determining region" or "CDR" refers to the amino acid sequences within the antibody variable region that confer antigen specificity and binding affinity. For example, generally, there are three CDRs in each heavy chain variable region (e.g., CDR-H1, CDR-H2, and CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, and CDR-L3). The exact amino acid sequence boundaries of a given CDR are defined by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest”, 5th Ed. Published by the U.S. Department of Health and Human Services, National Institutes of Health. As used herein, the term "complementary determining region" or "CDR" refers to the amino acid sequences within the antibody variable region that confer antigen specificity and binding affinity. For example, generally, there are three CDRs in each heavy chain variable region (e.g., CDR-H1, CDR-H2, and CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, and CDR-L3). The exact amino acid sequence boundaries of a given CDR are defined by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest”, 5th Ed. Published by the U.S. Department of Health and Human Services, National Institutes of Health. As used herein, the term "complementary determining region" or "CDR" refers to the amino acid sequences within the antibody variable region that confer antigen specificity and binding affinity. For example, generally, there are three CDRs in each heavy chain variable region (e.g., CDR-H1, CDR-H2, and CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, and CDR-L3). The exact amino acid sequence boundaries of a given CDR are defined by Kabat et al. (1991), “Sequences of Proteins of Immunological Interest”, 5th Ed. Published by the U.S. Department of Health and Human Services, National Institutes of Health. Health, Bethesda, MD (「Kabat」 numbering scheme), Al-L azikani et al., (1997) JMB 273, 927-948 (「Ch othia」 numbering scheme) or combinations thereof and ImMunoGenTics( IMGT) numbering (Lefranc, M.-P., the Immunologist , 7, 132-136 (1999); Lefranc, M.-P. et al., Dev . Comp. Immunol., 27, 55-77 (2003) (「IMGT」 numbering scheme) can be determined using any one of several well-known schemes, including those described by For a given CDR region (e.g., HC CDR1, HC CDR2, H C CDR3, LC CDR1, LC CDR2 or LC CDR3), in certain embodiments, the combined Kabat and Chothia numbering schemes define the CDR as corresponding to the amino acid residues defined as part of the Chothia CDR together with the amino acid residues defined as part of the Kab at CDR. As used herein, CDRs defined according to the 「Chothia」 numbering scheme may also be referred to as 「hypervariable loops」. For example, according to Kabat, the CDR amino acid residues in the heavy chain variable domain (VH) are numbered 3 1-35 (CDR-H1) (e.g., insertions after position 35), 50-65 (CDR-H2) and 95-102 (CDR-H3); the CD

[0048] R amino acid residues in the light chain variable domain (VL) are numbered 24-34 (CDR-L1) (e.g., insertions after position 27), 50- 56 (CDR-L2) and 89-97 (CDR-L3). As another example and 95-102 (CDR-H3); the CDR amino acid residues in the light chain variable domain (VL) are numbered 24 - 34 (CDR-L1) (e.g., insertions after position 27), 50 - 56 (CDR-L2) and 89 - 97 (CDR-L3). As another example ​ , according to Chothia, the CDR amino acids in VH are numbered 26 - 32 (CDR-H1) (for example, an insertion after position 31), 52 - 56 (CDR-H2), and 95 - 102 (CDR-H 3); the amino acid residues in VL are numbered 26 - 32 (CDR-L1) (for example, an insertion after position 30), 50 - 52 (CDR-L2), and 91 - 96 (CDR-L 3). By combining the definitions of CDRs from both Kabat and Chothia, the CDRs include, for example, amino acid residues 26 - 35 (CDR-H1), 5 0 - 65 (CDR-H2), and 95 - 102 (CDR-H3) in human VH and amino acid residues 24 - 34 (CDR-L1), 50 - 56 (CDR-L2), and 89 - 97 (CD R-L3) in human VL, or consist of them. According to IMGT, the CDR amino acid residues in VH are numbered approximately 26 - 35 (CDR1), 51 - 57 (CDR2), and 93 - 102 (CDR3) , and the CDR amino acid residues in VL are numbered approximately 27 - 32 (CDR1), 50 - 5 2 (CDR2), and 89 - 97 (CDR3) (numbering according to "Kabat"). According to IMGT, the CDR regions of an antibody can be determined using the program IMGT / Domain Gap Align. Generally, unless otherwise indicated, an antibody molecule can contain any combination of one or more Kabat CDRs and / or Chothia CDRs.

[0049] ​​​​​​​​​Means to be administered to the subject within a time interval.

[0050] Conservative array modification: The term "conservative array modification" refers to an amino acid modification that does not substantially affect or change the binding properties of a BCMA-binding molecule or its components (e.g., ABD or Fc region). Such conservative modifications include amino acid substitutions, additions, and deletions. The modifications can be introduced into the BBM by standard techniques such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are those in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains are defined in the art. These families include amino acids having basic side chains (e.g., lysine, arginine, histidine), amino acids having acidic side chains (e.g., aspartic acid, glutamic acid), amino acids having uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), amino acids having nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), amino acids having β-branched side chains (e.g., threonine, valine, isoleucine), and amino acids having aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, one or more amino acid residues within the BBM can be replaced with other amino acid residues from the same side chain family, and the modified BBM can be tested, for example, for binding to a target molecule and / or for efficient heterodimerization and / or effector function. Or altered amino acid modifications. Include. Modifications can be introduced into the BBM by standard techniques such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions are those in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains Are defined in the art. These families include amino acids having basic side chains (e.g., lysine, arginine, histidine), amino acids having acidic side chains (e.g., aspartic acid, glutamic acid), amino acids having uncharged polar side chains (e.g., , glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, Tryptophan), amino acids having nonpolar side chains (e.g., alanine, valine, leucine , isoleucine, proline, phenylalanine, methionine), amino acids having β-branched side chains (e.g., threonine, valine, isoleucine) and amino acids having aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Therefore, one or more amino acid residues within the BBM can be replaced with other amino Acid residues from the same side chain family, and the modified BBM can be tested, for example, for binding to a target molecule and / or for efficient Heterodimerization and / or effector function.

[0051] Bispecific antibody: As used herein, the term "bispecific antibody" refers to a small antibody fragment having two antigen-binding sites, typically formed by pairing of scFv chains. Each scFv contains a heavy-chain variable domain (VH ) linked to a light-chain variable domain (VL) in the same polypeptide chain (VH-VL, where VH is either N-terminal or C-terminal relative to VL). Different from a typical scFv in which VH and VL on the same polypeptide chain are separated by a linker that allows VH and VL to pair to form an antigen-binding domain, a bispecific antibody typically contains a linker that is too short to allow pairing between VH and VL domains on the same chain, such that the VH and VL domains pair with complementary domains on another chain to form two antigen- binding sites. Bispecific antibodies are described in further detail, for example, in European Patent No. 404,097; International Publication No. WO 93 / 11161; and Hollinger et al., 1993, Proc.

[0052] Natl. Acad. Sci. USA 90:6444-6448. dsFv: The term "dsFv" refers to a disulfide-stabilized Fv fragment. In a dsFv, VH and VL are linked by an interdomain disulfide bond. To generate such a molecule, one amino acid in the framework region of VH and VL is mutated to cysteine, which then forms a stable interchain disulfide bond. Typically, position 44 in VH and position 100 in VL are mutated to cysteine. Please refer to 189, DOI: 10.1007 / 978-3-642-01147-4_14 The term dsFv encompasses both molecules known as dsFv (where VH and VL are linked by an interchain disulfide bond rather than a linker peptide) or scdsFv (where VH and VL are linked by a linker as well as an interchain disulfide bond). The term dsFv encompasses both molecules known as dsFv (where VH and VL are linked by an interchain disulfide bond rather than a linker peptide) or scdsFv (where VH and VL are linked by a linker as well as an interchain disulfide bond). The term dsFv encompasses both molecules known as dsFv (where VH and VL are linked by an interchain disulfide bond rather than a linker peptide) or scdsFv (where VH and VL are linked by a linker as well as an interchain disulfide bond). The term dsFv encompasses both molecules known as dsFv (where VH and VL are linked by an interchain disulfide bond rather than a linker peptide) or scdsFv (where VH and VL are linked by a linker as well as an interchain disulfide bond).

[0053] Epitope: An epitope or antigenic determinant is the part of an antigen that is recognized by an antibody or other antigen-binding moiety described herein. An epitope can be linear or conformational. Epitope: An epitope or antigenic determinant is the part of an antigen that is recognized by an antibody or other antigen-binding moiety described herein. An epitope can be linear or conformational. Epitope: An epitope or antigenic determinant is the part of an antigen that is recognized by an antibody or other antigen-binding moiety described herein. An epitope can be linear or conformational.

[0054] Effector function: The term "effector function" generally refers to the activity of an antibody molecule mediated by binding through domains of the antibody other than the antigen-binding domain, typically mediated by the binding of effector molecules. Effector functions include, for example, complement-mediated effector functions mediated by the binding of complement C1 components to the antibody. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and be involved in autoimmune hypersensitivity. Effector functions also include Fc receptor (FcR)-mediated effector functions, which can be triggered upon binding of the constant domain of the antibody to an Fc receptor (FcR). Binding of the antibody to an Fc receptor on the cell surface can cause many important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental passage, and regulation of immunoglobulin production. The effector functions of an antibody are determined by effector molecules such as Fc receptors or complement components. Effector function: The term "effector function" generally refers to the activity of an antibody molecule mediated by binding through domains of the antibody other than the antigen-binding domain, typically mediated by the binding of effector molecules. Effector functions include, for example, complement-mediated effector functions mediated by the binding of complement C1 components to the antibody. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and be involved in autoimmune hypersensitivity. Effector functions also include Fc receptor (FcR)-mediated effector functions, which can be triggered upon binding of the constant domain of the antibody to an Fc receptor (FcR). Binding of the antibody to an Fc receptor on the cell surface can cause many important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental passage, and regulation of immunoglobulin production. The effector functions of an antibody are determined by effector molecules such as Fc receptors or complement components. Effector function: The term "effector function" generally refers to the activity of an antibody molecule mediated by binding through domains of the antibody other than the antigen-binding domain, typically mediated by the binding of effector molecules. Effector functions include, for example, complement-mediated effector functions mediated by the binding of complement C1 components to the antibody. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and be involved in autoimmune hypersensitivity. Effector functions also include Fc receptor (FcR)-mediated effector functions, which can be triggered upon binding of the constant domain of the antibody to an Fc receptor (FcR). Binding of the antibody to an Fc receptor on the cell surface can cause many important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental passage, and regulation of immunoglobulin production. The effector functions of an antibody are determined by effector molecules such as Fc receptors or complement components. Effector function: The term "effector function" generally refers to the activity of an antibody molecule mediated by binding through domains of the antibody other than the antigen-binding domain, typically mediated by the binding of effector molecules. Effector functions include, for example, complement-mediated effector functions mediated by the binding of complement C1 components to the antibody. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and be involved in autoimmune hypersensitivity. Effector functions also include Fc receptor (FcR)-mediated effector functions, which can be triggered upon binding of the constant domain of the antibody to an Fc receptor (FcR). Binding of the antibody to an Fc receptor on the cell surface can cause many important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental passage, and regulation of immunoglobulin production. The effector functions of an antibody are determined by effector molecules such as Fc receptors or complement components. Effector function: The term "effector function" generally refers to the activity of an antibody molecule mediated by binding through domains of the antibody other than the antigen-binding domain, typically mediated by the binding of effector molecules. Effector functions include, for example, complement-mediated effector functions mediated by the binding of complement C1 components to the antibody. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and be involved in autoimmune hypersensitivity. Effector functions also include Fc receptor (FcR)-mediated effector functions, which can be triggered upon binding of the constant domain of the antibody to an Fc receptor (FcR). Binding of the antibody to an Fc receptor on the cell surface can cause many important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental passage, and regulation of immunoglobulin production. The effector functions of an antibody are determined by effector molecules such as Fc receptors or complement components. Effector function: The term "effector function" generally refers to the activity of an antibody molecule mediated by binding through domains of the antibody other than the antigen-binding domain, typically mediated by the binding of effector molecules. Effector functions include, for example, complement-mediated effector functions mediated by the binding of complement C1 components to the antibody. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and be involved in autoimmune hypersensitivity. Effector functions also include Fc receptor (FcR)-mediated effector functions, which can be triggered upon binding of the constant domain of the antibody to an Fc receptor (FcR). Binding of the antibody to an Fc receptor on the cell surface can cause many important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental passage, and regulation of immunoglobulin production. The effector functions of an antibody are determined by effector molecules such as Fc receptors or complement components. Effector function: The term "effector function" generally refers to the activity of an antibody molecule mediated by binding through domains of the antibody other than the antigen-binding domain, typically mediated by the binding of effector molecules. Effector functions include, for example, complement-mediated effector functions mediated by the binding of complement C1 components to the antibody. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and be involved in autoimmune hypersensitivity. Effector functions also include Fc receptor (FcR)-mediated effector functions, which can be triggered upon binding of the constant domain of the antibody to an Fc receptor (FcR). Binding of the antibody to an Fc receptor on the cell surface can cause many important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental passage, and regulation of immunoglobulin production. The effector functions of an antibody are determined by effector molecules such as Fc receptors or complement components. Effector function: The term "effector function" generally refers to the activity of an antibody molecule mediated by binding through domains of the antibody other than the antigen-binding domain, typically mediated by the binding of effector molecules. Effector functions include, for example, complement-mediated effector functions mediated by the binding of complement C1 components to the antibody. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and be involved in autoimmune hypersensitivity. Effector functions also include Fc receptor (FcR)-mediated effector functions, which can be triggered upon binding of the constant domain of the antibody to an Fc receptor (FcR). Binding of the antibody to an Fc receptor on the cell surface can cause many important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental passage, and regulation of immunoglobulin production. The effector functions of an antibody are determined by effector molecules such as Fc receptors or complement components. Effector function: The term "effector function" generally refers to the activity of an antibody molecule mediated by binding through domains of the antibody other than the antigen-binding domain, typically mediated by the binding of effector molecules. Effector functions include, for example, complement-mediated effector functions mediated by the binding of complement C1 components to the antibody. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and be involved in autoimmune hypersensitivity. Effector functions also include Fc receptor (FcR)-mediated effector functions, which can be triggered upon binding of the constant domain of the antibody to an Fc receptor (FcR). Binding of the antibody to an Fc receptor on the cell surface can cause many important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental passage, and regulation of immunoglobulin production. The effector functions of an antibody are determined by effector molecules such as Fc receptors or complement components. Effector function: The term "effector function" generally refers to the activity of an antibody molecule mediated by binding through domains of the antibody other than the antigen-binding domain, typically mediated by the binding of effector molecules. Effector functions include, for example, complement-mediated effector functions mediated by the binding of complement C1 components to the antibody. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and be involved in autoimmune hypersensitivity. Effector functions also include Fc receptor (FcR)-mediated effector functions, which can be triggered upon binding of the constant domain of the antibody to an Fc receptor (FcR). Binding of the antibody to an Fc receptor on the cell surface can cause many important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental passage, and regulation of immunoglobulin production. The effector functions of an antibody are determined by effector molecules such as Fc receptors or complement components. Effector function: The term "effector function" generally refers to the activity of an antibody molecule mediated by binding through domains of the antibody other than the antigen-binding domain, typically mediated by the binding of effector molecules. Effector functions include, for example, complement-mediated effector functions mediated by the binding of complement C1 components to the antibody. Complement activation is important in the opsonization and lysis of cellular pathogens. Complement activation can also stimulate inflammatory responses and be involved in autoimmune hypersensitivity. Effector functions also include Fc receptor (FcR)-mediated effector functions, which can be triggered upon binding of the constant domain of the antibody to an Fc receptor (FcR). Binding of the antibody to an Fc receptor on the cell surface can cause many important and diverse biological responses, including phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, ADCC, ADCP, release of inflammatory mediators, placental passage, and regulation of immunoglobulin production. The effector functions of an antibody are determined by effector molecules such as Fc receptors or complement components. Modified, for example, by modifying the affinity of the antibody for the effector molecule, such as enhancing or reducing it. It can be. The binding affinity is generally changed by modifying the effector molecule binding site, in which case it is appropriate to identify the site of interest and modify at least a part of this site in a suitable way. It is appropriate to modify at least a part of this site in a suitable way. Modification of the binding site in the antibody for the effector molecule does not necessarily substantially modify the overall binding affinity, but it is also conceivable that the geometric nature of the interaction can be modified so as to inactivate the effector mechanism as in non-productive binding. It is also conceivable that the geometric nature of the interaction can be modified so as to inactivate the effector mechanism as in non-productive binding. The effector function can also be further considered to be modified by modifying sites that do not directly participate in effector molecule binding but participate in the performance of the effector function in other ways. The effector function can also be further considered to be modified by modifying sites that do not directly participate in effector molecule binding but participate in the performance of the effector function in other ways. The effector function can also be further considered to be modified by modifying sites that do not directly participate in effector molecule binding but participate in the performance of the effector function in other ways.

[0055] Fab: As used herein, "Fab" or "Fab region" means a polypeptide region containing the VH, CH1, VL, and CL immunoglobulin domains. These terms can refer to this region alone or this region in relation to an antigen-binding molecule. These terms can refer to this region alone or this region in relation to an antigen-binding molecule. These terms can refer to this region alone or this region in relation to an antigen-binding molecule.

[0056] The Fab domain is formed by the association of the CH1 domain bound to the VH domain with the CL domain bound to the VL domain. The VH domain pairs with the VL domain to form the Fv region, and the CH1 domain pairs with the CL domain to further stabilize the binding module. The disulfide bond between the two constant domains can further stabilize the Fab domain. The VH domain pairs with the VL domain to form the Fv region, and the CH1 domain pairs with the CL domain to further stabilize the binding module. The VH domain pairs with the VL domain to form the Fv region, and the CH1 domain pairs with the CL domain to further stabilize the binding module. The disulfide bond between the two constant domains can further stabilize the Fab domain. The disulfide bond between the two constant domains can further stabilize the Fab domain.

[0057] The Fab region can be produced by proteolytic cleavage of the immunoglobulin molecule (using an enzyme such as papain, for example) or by recombinant expression. In native immunoglobulin molecules ​​ Fab is a polypeptide that binds to two different polypeptide chains (e.g., VH-CH1 on one chain). The Fab region is typically formed by two It is typically expressed recombinantly on one polypeptide chain, although single-chain Fabs are also available. Contemplated herein.

[0058] Fc region: As used herein, the term "Fc region" or "Fc chain" refers to A polypeptide that includes the CH2-CH3 domains of an IgG molecule and, in some cases, includes a hinge. In the EU numbering for human IgG1, the CH2-CH3 domains are , amino acids 231 to 447, and the hinge is 216 to 230. The definition of the region is amino acids 231 to 447 (CH2-CH3) or 216 to 447 ( The related "Fc fragment" includes both the Fc domain and the Fc region (hinge-CH2-CH3) or fragments thereof. "Fragments" contain fewer amino acids from either or both the N-terminus and C-terminus. Although it is possible to perform chromatographic analysis, standard size-based methods (e.g., non-denaturing chromatography, The dimers can be detected using size exclusion chromatography (HPLC). The human IgG Fc region is particularly referred to in this disclosure as Useful, it may be an Fc region from human IgG1, IgG2 or IgG4.

[0059] Fc domain: The term "Fc domain" refers to a pair of related Fc regions. Fc regions dimerize to generate an Fc domain. Two Fc regions in an Fc domain are identical to each other (e.g., Fc domains referred to herein as "Fc homodimers") or may be different (such as the Fc domain, referred to herein as "Fc heterodimer").

[0060] Fv: The terms "Fv", "Fv fragment", or "Fv region" refer to a region containing the VL and VH domains (VH-VL dimer) of an antibody fragment that is tightly non-covalently associated. In this form, the three CDRs of each variable domain interact to define a target binding site . Often, the six CDRs confer target binding specificity to the antigen-binding molecule. However, in some cases, a single variable domain (or half of the Fv containing only three CDRs specific for the target) may also have the ability to recognize and bind to the target. In native immunoglobulin molecules, the VH and VL of the Fv are on separate polypeptide chains but can be engineered as a single-chain Fv (scFv). This term also includes Fvs that are engineered by the introduction of disulfide bonds for additional stability. The reference herein to the VH-VL dimer is not intended to indicate any particular form. For example, in scFv, the VH can be N-terminal or C-terminal to the VL (with the VH and VL typically linked by a linker as described herein).

[0061] The reference herein to the VH-VL dimer is not intended to indicate any particular form. For example, in scFv, the VH can be N-terminal or C-terminal to the VL (with the VH and VL typically linked by a linker as described herein).

[0062] Half-antibody: The term "half-antibody" refers to a molecule that contains at least one ABD or ABD chain and can associate with another molecule containing an ABD or ABD chain, for example, by disulfide bridging or molecular interactions (such as the knob-in-hole interaction between Fc heterodimers). A half-antibody can be a single polypeptide chain or two or more polypeptide chains (e.g., the two polypeptides of Fab ). ​​​​In one embodiment, the half antibody comprises an Fc region.

[0063] An example of a half antibody is a molecule that contains the heavy and light chains of an antibody (e.g., an IgG antibody). Another example of the present invention is a method for the preparation of a polypeptide comprising a first polypeptide comprising a VL domain and a CL domain, and a VH domain a second polypeptide comprising a CH1 domain, a hinge region, a CH2 domain and a CH3 domain; and a peptide, where the VL and VH domains form the ABD. Yet another example of an antibody is a polypeptide comprising an scFv domain, a CH2 domain and a CH3 domain. It is a peptide.

[0064] A half antibody can include two or more ABDs, for example, a half antibody can include (in order from N-terminus to C-terminus) 2) comprising an scFv domain, a CH2 domain, a CH3 domain and another scFv domain nothing.

[0065] A half antibody is an ABD that forms a complete ABD when associated with another ABD chain in another half antibody. It may also include a BD strand.

[0066] Thus, a BBM may comprise one, more typically two or even three or more half antibodies. , a half antibody may comprise one or more ABDs or ABD chains.

[0067] In some BBMs, the first half antibody is associated with a second half antibody, e.g., In other BBMs, the first half antibody is heterodimerized, e.g., by disulfide bridges. Alternatively, the second half antibody may be covalently linked to the second half antibody by chemical cross-linking. One half antibody has both covalent and non-covalent interactions, e.g., disulfide bridges and knob-binding sites. It associates with the second half antibody through in-hole interactions.

[0068] The term "half-antibody" is intended for illustrative purposes only and does not imply a particular form or method of manufacture. Descriptions of half-antibodies such as "first" half-antibody, "second" half-antibody, "left" half-antibody, "right" half-antibody, etc. are for convenience and illustrative purposes only. For the hole:knob-into-hole, the "hole" is indented from the boundary of the first Fc chain and thus stabilizes the Fc heterodimer, thereby, for example, acting more favorably on Fc heterodimer formation than on Fc homodimer formation, and is positioned at least one amino acid side chain that can be positioned at the complementary "knob" at the adjacent boundary of the second Fc chain.

[0069] relates to. For the hole:knob-into-hole, the "hole" is indented from the boundary of the first Fc chain and thus stabilizes the Fc heterodimer, thereby, for example, acting more favorably on Fc heterodimer formation than on Fc homodimer formation, and is positioned at least one amino acid side chain that can be positioned at the complementary "knob" at the adjacent boundary of the second Fc chain. refers to.

[0070] Host cell or recombinant host cell: The term "host cell" or "recombinant host cell" refers to a cell that has been genetically engineered, for example, by the introduction of a heterologous nucleic acid. Such terms are intended to refer not only to a particular cell of interest but also to the progeny of such a cell. It should be understood that due to either a mutation or environmental influence, such modifications may be present in subsequent generations, and such progeny may not actually be identical to the parental cell, but are still included within the scope of the term "host cell" as used herein. A host cell may transiently carry a heterologous nucleic acid on an extrachromosomal heterologous expression vector or stably, for example, by integration of the heterologous nucleic acid into the host cell genome. For the purpose of expressing an antigen-binding molecule, host cells include, for example, simian kidney cells (COS, such as COS-1, COS-7 ), HEK293, baby hamster kidney (BHK, such as BHK21), Chinese hamster ovary (CHO, such as CHO-K1), murine myeloma cells (such as NS0, Sp2 / 0), insect cells (such as Sf9, Sf21), yeast cells (such as Saccharomyces cerevisiae, Pichia pastoris), and plant cells. Hamster ovary (CHO), NSO, PerC6, BSC-1, human hepatocellular carcinoma cells (e.g., Hep G2), SP2 / 0, HeLa, Madin-Darby bovine kidney (MDB K), myeloma and lymphoma cells or derivatives and / or modified mutants thereof, etc., can be cell lines derived from mammals or having mammalian-like characteristics. Modified mutants include, for example, glycosylation profile-modified and / or site-specific integration site derivatives.

[0071] Humanization: The term "humanized" form of a non-human (e.g., mouse) antibody refers to a chimeric antibody containing the minimal sequence derived from non-human immunoglobulin. In most cases, a humanized antibody is a human immunoglobulin (recipient antibody) in which the residues derived from the hypervariable regions of the recipient are replaced with residues from the hypervariable regions of a non-human species such as mouse, rat, rabbit, or non-human primate (donor antibody) that have the desired specificity, affinity, and capacity. In some cases, the framework region (FR) residues of the human immunoglobulin are replaced with the corresponding non-human residues. Further, a humanized antibody may contain residues not found in the recipient antibody or donor antibody. These modifications are made to further improve the performance of the antibody. Generally, a humanized antibody contains substantially all of at least one, typically two variable domains, where all or substantially all of the hypervariable loops correspond to those of the non-human immunoglobulin, and all or substantially all of the FRs are those of the human immunoglobulin lo sequence. A humanized antibody optionally also contains at least a portion of the Low immunogenicity and thus provides a therapeutic effect in certain situations. Humanized antibodies can be generated using well-known methods. For example, Hwang et al., 2005, Methods 36:35; Queen et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:10029-10033; Jones et al., 1986, Nature 321:522-25, 1986; Riechmann et al., 1988, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-36; Orlandi et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:3833-3837; U.S. Patent No. 5,225,539; No. 5,530,101; No. 5,585,089; No. 5,693,761; No. 5,693,762; and No. 6,180,370; and WO 90 / 07861 pamphlet. See also the following reviews and the references cited therein: Presta, 1992, Curr. Op. Struct. Biol. 2:593-596; Vaswani and Hamilton, 1998, Ann. Allergy, Asthma & Immunol. 1:105-115; Harris, 1995, Biochem. Soc. Transactions 23:1035-1038; Hurle and Gross, 1994, Curr. Op. Biotech. 5:428-433. known methods can be used. For example, Hwang et al., 2005, Methods 36:35; Queen et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:10029-10033; Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1988, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-36; Orlandi et al., 1989, Proc. Natl. Acad. Sci. U.S.A. 86: 3833-3837; U.S. Patent No. 5,225,539; No. 5,530,101; No. 5,585,089; No. 5,693,761; No. 5, 693,762; and No. 6,180,370; and WO 90 / 07861 pamphlet. See also the following reviews and the references cited therein: Presta, 1992, Curr. Op. Struct. Biol. 2:593- 596; Vaswani and Hamilton, 1998, Ann. Allergy, Asthma & Immunol. 1:105-115; Harris, 1995, Biochem. Soc. Transactions 23:1035-1038; Hurle and Gross, 1994, Curr. Op. Biotech. 5:428-433. 3833-3837; U.S. Patent No. 5,225,539; No. 5,530,101; No. 5,585,089; No. 5,693,761; No. 5, 693,762; and No. 6,180,370; and WO 90 / 07861 pamphlet. See also the following reviews and the references cited therein: Presta, 1992, Curr. Op. Struct. Biol. 2:593- 596; Vaswani and Hamilton, 1998, Ann. Allergy, Asthma & Immunol. 1:105-115; Harris, 1995, Biochem. Soc. Transactions 23:1035-1038; Hurle and Gross, 1994, Curr. Op. Biotech. 5:428-433. 596; Vaswani and Hamilton, 1998, Ann. Allergy, Asthma & Immunol. 1:105-115; Harris, 1995, Biochem. Soc. Transactions 23:1035-1038; Hurle and Gross, 1994, Curr. Op. Biotech. 5:428-433. 1994, Curr. Op. Biotech. 5:428-433. 1994, Curr. Op. Biotech. 5:428-433. 1994, Curr. Op. Biotech. 5:428-433. 1994, Curr. Op. Biotech. 5:428-433.

[0072] Human antibodies: As used herein, the term "human antibody" refers to the framework It includes antibodies having variable regions in which both the κ and CDR regions are derived from human-derived sequences. Fur thermore, when the antibody includes a constant region, the constant region is also derived from such human sequences, such as human germline sequences or mutant human germline sequences or, for example, antibody-containing consensus framework sequences derived from human framework sequence analysis as described in Knappik et al., 2000, J Mol Biol 296, 57-86. The structure and position of immunoglobulin variable domains, such as CDRs, can be defined using well-known numbering schemes, such as the Kabat numbering scheme, the Chothia numbering scheme, or any combination of Kabat and Chothia (see, for example, Lazikan i et al., 1997, J.Mol.Bio.273:927 948; Kab at et al., 1991, Sequences of Proteins of I mmunological Interest, 5th edit., NIH Publ ication no.91-3242 U.S.Department of Hea lth and Human Services; Chothia et al., 19 87, J.Mol.Biol.196:901-917; Chothia et al. 1989, Nature 342:877-883). Human antibodies can include amino acid residues not encoded by human sequences (e.g., mutations introduced by in vitro random or site-directed mutagenesis or somatic mutations in vivo or conservative substitutions to promote stability or production). However,

[0073] ​​​In addition, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, are grafted onto human framework sequences.

[0074] In combination: As used herein, administered "in combination" means that two (or more) different therapeutic agents are delivered to a subject during the course of the subject's disease, e.g., two or more therapeutic agents are delivered after the subject has been diagnosed with the disease and before the disease has been cured or removed or the treatment has been stopped for another reason.

[0075] Knob: In the context of knob-into-hole, a "knob" protrudes from the interface of the first Fc chain and is thus positionable at a complementary "hole" at the interface with the second Fc chain so as to stabilize the Fc heterodimer and thereby act preferentially on Fc heterodimer formation over, for example, Fc homodimer formation. It refers to at least one amino acid side chain.

[0076] Knob and hole (or knob-into-hole): One mechanism of Fc heterodimerization is referred to in the art as "knob and hole", or "knob-in-hole", or "knob-into-hole". These terms refer to amino acid mutations that create a steric effect that preferentially acts on the formation of Fc heterodimers over Fc homodimers, as described, for example, in Ridgway et al., 1996, Protein Engineering 9(7):617; Atwell et al., 1997, J. Mol. Biol. 270:26; and U.S. Patent No. 8,216,805. · In-hole mutations can be combined with other methods to improve dimerization, as described, for example, in Section 7.4.1.6.

[0077] Monoclonal antibody: As used herein, the term "monoclonal antibody" refers to a polypeptide comprising an antibody, antibody fragment, molecule (including BBM), etc., derived from the same genetic source.

[0078] Monovalent: As used herein in connection with an antigen-binding molecule, the term "monovalent" refers to an antigen-binding molecule having a single antigen-binding domain.

[0079] Multispecific binding molecule: The term "multispecific binding molecule" or "MBM" refers to an antigen-binding molecule that specifically binds to at least two antigens and contains two or more ABDs. ABDs can each independently be an antibody fragment (e.g., scFv, Fab, nanobody), a ligand or a non-antibody-derived binder (e.g., fibronectin, finomer, DARPin). )

[0080] Mutation or modification: In connection with the primary amino acid sequence of a polypeptide, the terms "modification" and "mutation" refer to amino acid substitutions, insertions and / or deletions in the polypeptide sequence compared to a reference polypeptide. Further, the term "modification" further encompasses modifications to amino acid residues, for example, by chemical conjugation (e.g., of a drug or polyethylene glycol moiety) or post-translational modification (e.g., glycosylation).

[0081] Nucleic acid: The term "nucleic acid" is used herein synonymously with the term "polynucleotide". used herein to refer to deoxyribonucleotides or ribonucleotides in either single-stranded or double-stranded form, and polymers thereof. The term includes synthetic, natural, and non-natural nucleic acids having binding characteristics similar to those of the reference nucleic acid and being metabolized in a manner similar to the reference nucleotide, and includes nucleic acids containing known nucleotide analogs or modified backbone residues or linkages. Examples of such analogs include, but are not limited to, phosphorothioates, phosphoramidates, methylphosphonates, chiral-methylphosphonates, 2-O-methyl ribonucleotides, and peptide-nucleic acids (PNA). Unless otherwise indicated, a particular nucleic acid sequence includes not only the explicitly recited sequence but also conservatively modified variants (e.g., degenerate codon substitutions) of that nucleic acid sequence and complementary sequences. Specifically, as detailed below, degenerate codon substitutions can be achieved by substituting the third position of one or more selected (or all) codons with mixed bases and / or deoxyinosine residues (Batzer et al., (1991) Nucleic Acid Res. 19:5081; Ohtsuka et al., (1985) J. Biol. Chem. 260:2605-2608; and Rossolini et al., (1994) Mol. Cell. Probes 8:91-98). Operably linked: The term "operably linked" refers to a functional relationship between two or more peptides or polypeptide domains or nucleic acid (e.g., DNA) segments. In the context of a fusion protein or other polypeptide, the term "operably linked" refers to...

[0082] ... ... ... ... ... ... ... ... ...

[0083] ... ... ... A language means that two or more amino acid segments are linked so as to produce a functional polypeptide. For example, in relation to an antigen-binding molecule, separate ABMs (or chains of ABMs) can be operably linked via a peptide linker sequence. In relation to a nucleic acid encoding a fusion protein, such as a polypeptide chain of an antigen-binding molecule, "operably linked" means that two nucleic acids are linked such that the amino acid sequences encoded by the two nucleic acids remain in-frame. In relation to transcriptional regulation, the term refers to the functional relationship of a transcriptional regulatory sequence to a transcriptional sequence. For example, a promoter or enhancer sequence is operably linked to a coding sequence if it stimulates or regulates the transcription of the coding sequence in an appropriate host cell or other expression system.

[0084] Polypeptides and Proteins: The terms "polypeptide" and "protein" are used interchangeably herein to refer to a polymer of amino acid residues. The term includes amino acid polymers in which one or more amino acid residues are artificial chemical mimics of the corresponding natural amino acids, as well as natural and non-natural amino acid polymers. Further, the term includes amino acid polymers derivatized, for example, by one or more side chain or terminal synthetic derivatization, glycosylation, PEGylation, circular permutation, cyclization, linkage to other molecules, fusion to proteins or protein domains, and addition of peptide tags or labels.

[0085] Recognize: As used herein, the term "recognize" refers to an ABD that finds and interacts with (e.g., binds to) its epitope. ​

[0086] Sequence identity: The sequence identity between two similar sequences (e.g., antibody variable domains) is Sm ith, T.F. & Waterman, M.S. (1981) “Comparison Of Biosequences”, Adv. Appl. Math. 2:482 [local identity algorithm]; Needleman, S.B. & Wunsch, C.D. (197 0) “A General Method Applicable To the Se arch For Similarities In Amino Acid Sequ ence Of Two Proteins”, J. Mol. Biol. 48:443 identity alignment algorithm], Pearson, W.R. & Lipman, D.J . (1988) “Improved Tools For Biological Se quence Comparison”, Proc. Natl. Acad. Sci. (U . S.A.) 85:2444 [similarity search method]; or Altschul, S.F. e t al, (1990) “Basic Local Alignment Search Tool“, J. Mol. Biol. 215:403 - 10, “BLAST” alg orithm (see blast.ncbi.nlm.nih.gov / Blast.cgi ). It can be measured by algorithms such as those described above. When using any of the above algorithms, the default parameters (window length, gap penalty , etc.) are used. In one embodiment, the sequence identity is performed using the BLAST algorithm with default parameters.

[0087] Optionally, identity is determined over a region of at least about 50 nucleotides (or for peptides or polypeptides, at least about 10 amino acids) in length, or in some cases over a region of 100 - 500 or 1000 or more nucleotides (or 20, 50, 200 or more amino acids) in length. In certain embodiments identity is determined over a defined domain, such as the VH or VL of an antibody. Unless otherwise specified, sequence identity between two sequences is determined over the full length of the shorter of the two sequences .. Single-chain Fab or scFab: The terms "single-chain Fab" and "scFab" refer to polypeptides comprising an antibody heavy-chain variable domain (VH), an antibody constant domain 1 (CH1), an antibody light-chain variable domain (VL), an antibody light-chain constant domain (CL), and a linker, such that the VH and VL are associated with each other and the CH1 and CL are associated with each other. In certain embodiments

[0088] the antibody domains and linker have one of the following orders from the N-terminus to the C-terminus: a) VH-CH1-linker-VL-CL, b) VL-CL-linker-VH-CH1, c) VH-CL-linker-VL-CH1 or d) VL-CH1-linker-VH-CL The linker can be a polypeptide of at least 30 amino acids, such as 32 - 50 amino acids. The single-chain Fab is stabilized by a native disulfide bond between the CL domain and the CH1 domain .. .. .. .. .. ..

[0089] Simultaneous or concurrent delivery: In certain embodiments delivery of one therapeutic agent is overlapping with respect to administration with delivery of a second therapeutic agent is still being performed when delivery begins. This is sometimes referred to in this specification as "simultaneous" or "simultaneous delivery". In embodiments in either case, the therapeutic agent is more effective for combination administration. For example, a second therapeutic agent is more effective, e.g., is seen with a second therapeutic agent having fewer equivalent effects, or the second therapeutic agent reduces symptoms more than is seen when the second therapeutic agent is administered without the first therapeutic agent, or a similar situation is seen with the first therapeutic agent. In certain embodiments, delivery is such that the reduction of symptoms or other parameters associated with the disease are greater than can be observed with one therapeutic agent delivered without the other. The effects of the two therapeutic agents can be partially additive, fully additive, or more than additive. Delivery can be such that the effect of the first therapeutic agent being delivered is still detectable when the second therapeutic agent is delivered.

[0090] Single-chain Fv or scFv: As used herein, "single-chain Fv" or "scFv" generally refers to a variable heavy-chain domain covalently attached to a variable light-chain domain using an ABD linker as described herein to form an scFv or scFv domain. The scFv domain can be in either the N-terminal to C-terminal orientation (VH-linker-VL or VL-linker-VH). For an overview of scFv, see Plueckthun in the Pharmacology of Monoclonal Antibodies, vol. 113, Rosenberg and Moore eds., (1994) Springer-Verlag, New York, pp. 269-315. See.​​​​​ 。

[0091] Specifically (or selectively) bind: The term "specifically (or selectively ) bind" refers to a binding reaction that determines the presence of a homologous antigen or epi tope in a heterogeneous population of proteins and other biological substances. The antigen-binding molecule or ABD of the present disclosure typically has a dissociation rate constant (KD) (ko -2 f / kon) of less than 5×10 -2 M, less than 10 -3 M, less than 5×10 -3 M, less than 10 10 -4 M, less than 10 -4 M, less than 5×10 -5 M, less than 10 -5 M, less than 5×10 -6 M, less than 10 -6 M, less than 5×10 -7 M, less than 10 -7 M, less than 5×10 -8 M, 10 -8 M, less than 5×10 -9 M, less than 10 -9 M or less, and binds to the target antigen with an affinity that is at least 2-fold higher (more typically, at least 20-fold, at least 50-fold or at least 100-fold) than its affinity for binding to a non-specific antigen (e.g., HSA). The binding affinity can be measured using a Biacore, SPR or BLI assay. The term "specifically bind" does not exclude cross-reactivity between different species. For example, an antigen-binding module (e.g., the antigen-binding fragment of an antibody) that "specifically binds" to an antigen from one species can also "specifically bind" to the corresponding antigen in one or more other species. Thus

[0092] ​​​That is, such cross-species reactivity itself does not change the classification of the antigen-binding module as a "specific" binder. In certain embodiments, an antigen-binding domain that specifically binds to a human antigen has cross-species reactivity with one or more non-human mammalian species, such as primate species (e.g., cynomolgus monkey (Macaca fascicularis), rhesus monkey (Macaca mulatta), and pig-tailed macaque (Macaca nemestrina)), or rodent species, such as mouse (Mus musculus). In other embodiments, the antigen-binding domain does not have cross-species reactivity. Mainly, it has cross-species reactivity with one or more non-human mammalian species, such as primate species (e.g., cynomolgus monkey (Macaca fascicularis), rhesus monkey (Macaca mulatta), and pig-tailed macaque (Macaca nemestrina)), or rodent species, such as mouse (Mus musculus). In other embodiments, the antigen-binding domain does not have cross-species reactivity. Mainly, it has cross-species reactivity with one or more non-human mammalian species, such as primate species (e.g., cynomolgus monkey (Macaca fascicularis), rhesus monkey (Macaca mulatta), and pig-tailed macaque (Macaca nemestrina)), or rodent species, such as mouse (Mus musculus). In other embodiments, the antigen-binding domain does not have cross-species reactivity. Mainly, it has cross-species reactivity with one or more non-human mammalian species, such as primate species (e.g., cynomolgus monkey (Macaca fascicularis), rhesus monkey (Macaca mulatta), and pig-tailed macaque (Macaca nemestrina)), or rodent species, such as mouse (Mus musculus). In other embodiments, the antigen-binding domain does not have cross-species reactivity. Mainly, it has cross-species reactivity with one or more non-human mammalian species, such as primate species (e.g., cynomolgus monkey (Macaca fascicularis), rhesus monkey (Macaca mulatta), and pig-tailed macaque (Macaca nemestrina)), or rodent species, such as mouse (Mus musculus). In other embodiments, the antigen-binding domain does not have cross-species reactivity. Mainly, it has cross-species reactivity with one or more non-human mammalian species, such as primate species (e.g., cynomolgus monkey (Macaca fascicularis), rhesus monkey (Macaca mulatta), and pig-tailed macaque (Macaca nemestrina)), or rodent species, such as mouse (Mus musculus). In other embodiments, the antigen-binding domain does not have cross-species reactivity. Mainly, it has cross-species reactivity with one or more non-human mammalian species, such as primate species (e.g., cynomolgus monkey (Macaca fascicularis), rhesus monkey (Macaca mulatta), and pig-tailed macaque (Macaca nemestrina)), or rodent species, such as mouse (Mus musculus). In other embodiments, the antigen-binding domain does not have cross-species reactivity.

[0093] Subject: The term "subject" includes humans and non-human animals. Non-human animals include all vertebrate animals, such as non-human primates, sheep, dogs, cows, chickens, amphibians, and reptiles, as well as mammals and non-mammals. Unless otherwise specified, the terms "patient" or "subject" are used interchangeably herein. Subject: The term "subject" includes humans and non-human animals. Non-human animals include all vertebrate animals, such as non-human primates, sheep, dogs, cows, chickens, amphibians, and reptiles, as well as mammals and non-mammals. Unless otherwise specified, the terms "patient" or "subject" are used interchangeably herein. Subject: The term "subject" includes humans and non-human animals. Non-human animals include all vertebrate animals, such as non-human primates, sheep, dogs, cows, chickens, amphibians, and reptiles, as well as mammals and non-mammals. Unless otherwise specified, the terms "patient" or "subject" are used interchangeably herein. Subject: The term "subject" includes humans and non-human animals. Non-human animals include all vertebrate animals, such as non-human primates, sheep, dogs, cows, chickens, amphibians, and reptiles, as well as mammals and non-mammals. Unless otherwise specified, the terms "patient" or "subject" are used interchangeably herein.

[0094] Tandem of VH domains: As used herein, the term "tandem of VH domains (or VHs)" refers to a series of VH domains consisting of multiple identical VH domains of an antibody. Each of the VH domains has its C-terminus linked to the N-terminus of another VH domain, with or without a linker, except for the last one at the end of the tandem. The tandem has at least two VH domains and, in certain embodiments of the BBM, has 3, 4, 5, 6, 7, 8, 9, or 10 VH domains. The tandem of VHs can be produced by recombinant methods, with or without a linker, that allow them to be made as a single polypeptide chain. Tandem of VH domains: As used herein, the term "tandem of VH domains (or VHs)" refers to a series of VH domains consisting of multiple identical VH domains of an antibody. Each of the VH domains has its C-terminus linked to the N-terminus of another VH domain, with or without a linker, except for the last one at the end of the tandem. The tandem has at least two VH domains and, in certain embodiments of the BBM, has 3, 4, 5, 6, 7, 8, 9, or 10 VH domains. The tandem of VHs can be produced by recombinant methods, with or without a linker, that allow them to be made as a single polypeptide chain. Tandem of VH domains: As used herein, the term "tandem of VH domains (or VHs)" refers to a series of VH domains consisting of multiple identical VH domains of an antibody. Each of the VH domains has its C-terminus linked to the N-terminus of another VH domain, with or without a linker, except for the last one at the end of the tandem. The tandem has at least two VH domains and, in certain embodiments of the BBM, has 3, 4, 5, 6, 7, 8, 9, or 10 VH domains. The tandem of VHs can be produced by recombinant methods, with or without a linker, that allow them to be made as a single polypeptide chain. Tandem of VH domains: As used herein, the term "tandem of VH domains (or VHs)" refers to a series of VH domains consisting of multiple identical VH domains of an antibody. Each of the VH domains has its C-terminus linked to the N-terminus of another VH domain, with or without a linker, except for the last one at the end of the tandem. The tandem has at least two VH domains and, in certain embodiments of the BBM, has 3, 4, 5, 6, 7, 8, 9, or 10 VH domains. The tandem of VHs can be produced by recombinant methods, with or without a linker, that allow them to be made as a single polypeptide chain. Tandem of VH domains: As used herein, the term "tandem of VH domains (or VHs)" refers to a series of VH domains consisting of multiple identical VH domains of an antibody. Each of the VH domains has its C-terminus linked to the N-terminus of another VH domain, with or without a linker, except for the last one at the end of the tandem. The tandem has at least two VH domains and, in certain embodiments of the BBM, has 3, 4, 5, 6, 7, 8, 9, or 10 VH domains. The tandem of VHs can be produced by recombinant methods, with or without a linker, that allow them to be made as a single polypeptide chain. Tandem of VH domains: As used herein, the term "tandem of VH domains (or VHs)" refers to a series of VH domains consisting of multiple identical VH domains of an antibody. Each of the VH domains has its C-terminus linked to the N-terminus of another VH domain, with or without a linker, except for the last one at the end of the tandem. The tandem has at least two VH domains and, in certain embodiments of the BBM, has 3, 4, 5, 6, 7, 8, 9, or 10 VH domains. The tandem of VHs can be produced by recombinant methods, with or without a linker, that allow them to be made as a single polypeptide chain. Tandem of VH domains: As used herein, the term "tandem of VH domains (or VHs)" refers to a series of VH domains consisting of multiple identical VH domains of an antibody. Each of the VH domains has its C-terminus linked to the N-terminus of another VH domain, with or without a linker, except for the last one at the end of the tandem. The tandem has at least two VH domains and, in certain embodiments of the BBM, has 3, 4, 5, 6, 7, 8, 9, or 10 VH domains. The tandem of VHs can be produced by recombinant methods, with or without a linker, that allow them to be made as a single polypeptide chain. (For example, as described in Section 7.4.3) can be used to combine the coding nucleic acids of each VH domain in the desired order. The N -terminus of the first VH domain in the tandem is defined as the N-terminus of the tandem, while the C-terminus of the last VH domain in the tandem is defined as the C-terminus of the tandem.

[0095] Tandem of VL domains: As used herein, the term "tandem of VL domains (or VL )" refers to a series of VL domains consisting of multiple identical VL domains of an antibody. Each of the VL domains has its C-terminus linked to the N-terminus of another VL, with or without a linker, except for the last one at the end of the tandem. The tandem has at least two VL domains and, in certain embodiments of the BBM, has 3, 4, 5, 6, 7, 8, 9 or 10 VL domains. The tandem of VLs can be generated by combining the coding nucleic acids of each VL domain in the desired order using a recombinant method with or without a linker (e.g., , as described in Section 7.4.3) that allows them to be made as a single polypeptide chain. The N-terminus of the first VL domain in the tandem is defined as the N-terminus of the tandem, while the C-terminus of the last VL domain in the tandem is defined as the C-terminus of the tandem.

[0096] Target antigen: As used herein, the term "target antigen" means a molecule that is non-covalently, reversibly and specifically bound by an antigen-binding domain.

[0097] Tetravalent: As used herein in relation to an antigen-binding molecule (e.g., a BBM), the term " The term "tetravalent" refers to an antigen-binding molecule having four ABDs. The antigen-binding molecules of the present disclosure, which are BBMs, are bispecific and specifically bind to BCMA and a second antigen, such as a component of the TCR complex. In certain embodiments, the tetravalent BBMs generally have two ABDs that specifically bind to BCMA and two ABDs that specifically bind to a second antigen, such as a component of the TCR complex, respectively. However, other configurations are contemplated, whereby three ABDs specifically bind to one antigen (e.g., BCMA) and one ABD specifically binds to a different antigen (e.g., a component of the TCR complex). Examples of the tetravalent configuration are schematically shown in FIGS. 1AA-1AG.

[0098] Therapeutically effective amount: "Therapeutically effective amount" refers to an amount effective at the dosage and for the period required to achieve the desired therapeutic result.

[0099] Treat, treatment, treating: As used herein, the terms "treat," "treatment," and "treating" refer to a decrease or amelioration in the progression, severity, and / or duration of a proliferative disease and / or an improvement in one or more symptoms (e.g., one or more distinguishable symptoms) of a proliferative disease resulting from the administration of one or more antigen-binding molecules. In certain embodiments, the terms "treat," "treatment," and "treating" refer to an improvement in at least one measurable physical parameter of a proliferative disease, such as tumor growth, that may not necessarily be identifiable by the patient. In other embodiments, the terms "treat," "treatment," and "treating" refer to inhibition of the progression of a proliferative disease, physically, e.g., by stabilization of a physical parameter, physiologically, e.g., by stabilization of a distinguishable symptom, or both, e.g., by stabilization of a physical parameter and a distinguishable symptom. ​​​​​​​​​​​ refers to. In other embodiments, the terms "treating", "treatment" and "treatment" refer to a decrease or stabilization in tumor size or the number of cancerous cells.

[0100] Tumor: The term "tumor" is used interchangeably herein with the term "cancer", e.g., both terms include solid and liquid, e.g., diffuse or circulating tumors. As used herein, the terms "cancer" or "tumor" include pre - malignant as well as malignant cancers and tumors.

[0101] Trivalent: When used herein in connection with an antigen - binding molecule (e.g., BBM), the term "trivalent" refers to an antigen - binding molecule having three ABDs. The antigen - binding molecules of the present disclosure that are BBMs are bispecific and specifically bind to BCMA and a second antigen, e.g., a component of the TCR complex. Thus, a trivalent BBM has two ABDs that bind to one antigen (e.g., BCMA) and one ABD that binds to a different antigen (e.g., a component of the TCR complex). Examples of the trivalent form are schematically shown in FIGS. 1G - 1Z.

[0102] Variable region: As used herein, the "variable region" or "variable domain" means a region of an immunoglobulin that contains one or more Ig domains substantially encoded by any of the Vκ, Vλ and / or VH genes that make up the κ, λ and heavy - chain immunoglobulin loci, respectively, and contains CDRs that confer antigen specificity. A "variable heavy - chain domain" can pair with a "variable light - chain domain" to form an antigen - binding domain ("ABD"). Further, each variable domain has the following order: FR1 - CDR1 - FR2 - CDR2 - FR . Three hypervariable regions (the "complementarity-determining regions", "CDRs") arranged from the amino terminus to the carboxy terminus in 3-CDR3-FR4 region (for the variable heavy chain domain, CDR-H1, C DR-H2, CDR-H3 and for the variable light chain domain, CDR-L1, CDR-L2 , CDR-L3) and four framework (FR) regions.

[0103] Vector: The term "vector" is intended to refer to a polynucleotide molecule capable of transporting another polynucleotide linked thereto. One type of vector is a "plasmid", which refers to a circular double-stranded DNA loop into which additional DNA segments can be ligated. Another type of vector is a viral vector wherein additional DNA segments can be ligated into the viral genome. Certain vectors are capable of self-replication within the host cells into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of the host cell upon introduction into the host cell and thereby replicated along with the host genome. Furthermore, certain vectors are capable of inducing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply "expression vectors"). Generally, expression vectors useful in recombinant DNA technology are often in the form of plasmids. Since plasmids are the most commonly used form of vectors, in this specification, "plasmid" and "vector" may be used synonymously. However, in some cases, they may have different meanings depending on the context. Furthermore, certain vectors are capable of inducing the expression of genes to which they are operably linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply "expression vectors"). Generally, expression vectors useful in recombinant DNA technology are often in the form of plasmids. Since plasmids are the most commonly used form of vectors, in this specification, "plasmid" and "vector" may be used synonymously. However, in some cases, they may have different meanings depending on the context. In addition, the present disclosure encompasses other forms of expression vectors such as viral vectors (e.g., replication-defective retroviruses, adenoviruses, and adeno-associated viruses) that perform equivalent functions.

[0104] VH: The term "VH" refers to the variable region of the immunoglobulin heavy chain of an antibody, including the heavy chain of Fv, scFv, dsFv, or Fab.

[0105] VL: The term "VL" refers to the variable region of the immunoglobulin light chain of an antibody, including the light chain of Fv, scFv, dsFv, or Fab.

[0106] VH-VL or VH-VL pair: With reference to the VH-VL pair, regardless of whether on the same polypeptide chain or on different polypeptide chains, the terms "VH-VL" and "VH-VL pair" are used for convenience and are not intended to indicate any specific orientation, except where the context indicates otherwise. Thus, an scFv containing "VH-VL" or "VH-VL pair" can have VH and VL domains in any orientation, for example, from the VH N-terminus to VL or from the VL N-terminus to VH.

[0107] 7.2. BCMA Binding Molecules In one aspect, the present disclosure provides BCMA binding molecules that include monospecific and multispecific molecules that bind to human BCMA. In certain embodiments, the BCMA binding molecule is a monospecific binding molecule. For example, the monospecific binding molecule can be an antibody or an antigen-binding fragment thereof (e.g., an antibody fragment, scFv, dsFv, Fv, Fab, scFab, (Fab')2, or a single-domain antibody (SDAB)). In other embodiments, BC The MA-binding molecule is a multi-specific (e.g., bispecific) BCMA-binding molecule (e.g., a bispecific antibody). In certain embodiments, the BCMA-binding molecule is a chimeric or humanized monoclonal antibody.

[0108] Chimeric and / or humanized antibodies can be produced in non-human subjects or engineered to minimize the immune response in human patients against antibodies obtained from the expression of non-human antibody genes. A chimeric antibody contains non-human animal antibody variable regions and human antibody constant regions. Such antibodies retain the epitope-binding specificity of the original monoclonal antibody but may be less immunogenic when administered to humans and thus more likely to be tolerated by patients. For example, one or all (e.g., one, two, or three) of the variable regions of the light chain and / or one or all (e.g., one, two, or three) of the variable regions of the heavy chain of a mouse antibody (e.g., a mouse monoclonal antibody) can be linked to human constant regions such as, without limitation, an IgG1 human constant region. Chimeric monoclonal antibodies can be produced by known recombinant DNA techniques. For example, the gene encoding the constant region of a non-human antibody molecule can be replaced with a gene encoding a human constant region (see PCT Publication No. PCT / US86 / 02269 to Robinson et al.; European Patent Application No. 184,187 to Akira et al.; or European Patent Application No. 171,496 to Taniguchi, M.). Further suitable techniques that can be used to generate chimeric antibodies are described, for example, in U.S. Patent Nos. 4,816,567; 4,978,775; 4,975,369; and 4,816,397. ​​​​​​​​​​​​​​​

[0109] The chimeric or humanized antibodies of the present disclosure and antigen-binding fragments thereof can be prepared based on the sequences of murine monoclonal antibodies. The DNA encoding the heavy and light chain immunoglobulins is obtained from the murine hybridoma of interest and can be engineered to include non-murine (e.g., human) immunoglobulin sequences using standard molecular biology techniques. For example, to generate a chimeric antibody, the murine variable regions can be linked to human constant regions using known methods (see, e.g., U.S. Patent No. 4,816,567 to Cabilly et al.). To generate a humanized antibody, the murine CDR regions can be inserted into a human framework using known methods. See, for example, U.S. Patent No. 5, 225,539 to Winter and U.S. Patent Nos. 5,530,101 to Queen et al.; 5,585,089; 5,693,762 and 6,180,370. Humanized antibodies can be prepared by CDR grafting (see, e.g., European Patent No. 239,400; International Publication No. WO 91 / 09967; and U.S. Patent Nos. 5,225, 539, 5,530,101 and 5,585,089), veneering or resurfacing (see, e.g., European Patent Nos. 592,106 and 519,596; Padlan, 1991, Molecular Immunology, 28(4 / 5):489-498; Studnicka et al., 1994 ).

[0110] ,Protein Engineering, 7(6):805-814; and Rogu ska et al., 1994, PNAS, 91:969-973 (see also), Chain shuffling (e.g., see U.S. Patent No. 5, 565,332), and for example, U.S. Patent Application Publication No. 2005 / 0 042664, U.S. Patent Application Publication No. 2005 / 0048617, U.S. Patent No. 6,407,213, U.S. Patent No. 5,766,886, International Publication No. WO 93 / 17105, Tan et al., J. Immunol., 169:1119-25 (2002), Caldas et al., Prote in Eng., 13(5):353-60 (2000), Morea et al., Methods, 20(3):267-79 (2000), Baca et al., J . Biol. Chem., 272(16):10678-84 (1997), Rogus ka et al., Protein Eng., 9(10):895-904 (199 6), Couto et al., Cancer Res., 55(23 Supp): 5973s-5977s (1995), Couto et al., Cancer Re s., 55(8):1717-22 (1995), Sandhu J S, Gene, 1 50(2):409-10 (1994) and Pedersen et al., J. Mo l. Biol., 235(3):959-73 (1994), and can be produced using a variety of known techniques including, but not limited to, those disclosed in these. In many cases, framework residues in the framework region are used to modify, e.g., improve, antigen binding by CDR s, e.g., to improve antigen binding. are replaced with the corresponding residues derived from the donor antibody. These framework substitutions, e.g., conservative substitutions, are identified by well-known methods, e.g., modeling the interaction of CDRs with framework residues to identify framework residues important for antigen binding and comparing sequences to identify abnormal frameworks at specific positions. (See, e.g., U.S. Patent No. 5,585,089 to Queen et al.; and Riechmann et al , 1988, Nature, 332:323). As provided herein, a humanized antibody or antibody fragment can comprise one or more CDRs and framework regions from a non-human immunoglobulin molecule, where the amino acid residues comprising the framework are entirely or mostly derived from the germline. Multiple techniques for humanizing antibodies or antibody fragments are well known and involve replacing the CDR sequences of rodent CDRs or the corresponding sequences of human antibodies, i.e., CDR grafting, according to the methods of Winter and co-workers (Jones et al., Nature, 321:522-525 (1986 ); Riechmann et al., Nature, 332:323-327 (19 88); Verhoeyen et al., Science, 239:1534-15

[0111] 36 (1988)), i.e., replacing the CDR sequences of rodent CDRs or the corresponding sequences of human antibodies, i.e., CDR grafting (European Patent No. 239,400 specification; PCT Publication No. WO 91 / 09967 pamphlet; and U.S. Patent No. 4 ,816,567; No. 6,331,415; No. 5,225,539 ; No. 5,530,101; No. 5,585,089; No. 6 ​​​​​​​​,548,640 specification) can be substantially carried out by. Such humanized antibodies and anti- In the body fragment, a substantially smaller portion than the intact human variable domain is replaced with the corresponding sequence from a non-human species . The humanized antibody often has several CDR residues and in some cases Several framework (FR) residues are replaced with residues from similar sites of rodent antibodies . Humanization of antibodies and antibody fragments can also be achieved by veneering Glu or resurfacing (European Patent No. 592,106; European Patent No. 519,5 96; Padlan, 1991, Molecular Immunology, 28(4 / 5):489-498; Studnicka et al., Protein Engineering, 7(6):805-814(1994); and Rogusk a et al., PNAS, 91:969-973(1994)) or chain shuffling Fring (U.S. Patent No. 5,565,332 specification).

[0112] The selection of human variable domains for both the light and heavy chains used to produce humanized antibodies Will reduce antigenicity. According to the so-called "best-fit" method , the sequences of the variable domains of rodent antibodies are screened against the entire library of known human variable domain sequences . Next, the human sequence closest to the rodent sequence is recognized as the human framework (FR) for the humanized antibody (Sims et al ., J. Immunol., 151:2296(1993); Chothia et a l., J. Mol. Biol., 196:901(1987)). Another method is the light chain or Heavy chain, or A particular framework derived from the consensus sequences of all human antibodies of a particular subgroup of heavy chains is used. The same framework can be used for several different humanized antibodies (see, e.g., Nicholson et al., Mol. Immunol. 34(16 - 17 ):1157 - 1165(1997); Carter et al., Proc. Nat l. Acad. Sci. USA, 89:4285(1992); Presta et a l., J. Immunol., 151:2623(1993). In one embodiment, all four framework regions of a framework region, e.g., the heavy chain variable region are derived from the VH4_4 - 59 germline sequence. In one embodiment, the framework region can include, e.g., 1, 2, 3, 4, or 5 modifications, e.g., substitutions, e.g., conservative substitutions, from the amino acids in the corresponding mouse sequence . In one embodiment, all four framework regions of a framework region, e.g., the light chain variable region are derived from the VK3_1.25 germline sequence. In one embodiment, the framework region can include, e.g., 1, 2, 3, 4, or 5 modifications, e.g., substitutions, e.g., conservative substitutions, from the amino acids in the corresponding mouse sequence .

[0113] In certain embodiments, the BCMA binding molecule includes a heavy chain variable region from a particular germline heavy chain immunoglobulin gene and / or a light chain variable region from a particular germline light chain immunoglobulin gene . For example, such antibodies can include or consist of human antibodies that include a heavy or light chain variable region that is a "product" of or "derived from" a particular germline sequence . Human antibodies that are "products" of or "derived from" germline immunoglobulin sequences can include or consist of human antibodies . The amino acid sequence of the body is compared with the amino acid sequence of the germline immunoglobulin, and the sequence closest to (i.e., having the highest identity %) the sequence of the human antibody is identified (using the methods outlined herein). For example, it can be identified by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). In some cases, the humanized antibody may have an amino acid sequence that is at least 95, 96, 97, 98 or 99% or at least 96%, 97%, 98% or 99% identical to the amino acid sequence encoded by the germline immunoglobulin gene. Typically, a humanized antibody derived from a specific germline sequence shows 10 to 20 or fewer amino acid differences from the amino acid sequence encoded by the germline immunoglobulin gene (before the introduction of any skews, pI, and ablation mutations herein; i.e., the number of mutations is generally low before the introduction of the mutations of the present disclosure). In some cases, the humanized antibody may show 5 or fewer or 4, 3, 2 or 1 or fewer amino acid differences from the amino acid sequence encoded by the germline immunoglobulin gene (again, before the introduction of any skews, pI, and ablation mutations herein; i.e., the number of mutations is generally low before the introduction of the mutations of the present disclosure). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). and can be identified, for example, by selecting the germline immunoglobulin sequence. A human antibody that is a "product of" or "derived from" a specific germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, natural somatic mutations or intentional introduction of site-specific mutations. However, a humanized antibody typically has an amino acid sequence that is at least 90% identical to the amino acid sequence encoded by the germline immunoglobulin gene and contains amino acid residues that identify the antibody as being derived from the human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences).

[0114] In one embodiment, the parental antibody is affinity matured. For example, as described in U.S. Patent Application No. 11 / 004,590, structure-based methods can be used for humanization and affinity maturation. Wu et al., 1999, J. Mol. Biol. 294: 151-162; Baca et al., 1997, J. Biol. Chem. 272 (16):10678-10684; Rosok et al., 1996, J. Bio l. Chem. 271(37):22611-22618; Rader et al., 1998, Proc. Natl. Acad. Sci. USA 95:8910-8915 ; Krauss et al., 2003, Protein Engineering 16(10):753-759, and methods based on selection, including but not limited to these, can be used to humanize and / or affinity mature the antibody variable region. Other humanization methods, including but not limited to those described in U.S. Patent No. 09 / 810,510; Tan et al., 2002, J. Im munol. 169:1119-1125; De Pascalis et al., 2 002, J. Immunol. 169:3076-3084, may include grafting only a portion of the CDRs.

[0115] In certain embodiments, the BCMA-binding molecule comprises an ABD that is a Fab. The Fab domain can be produced by proteolytic cleavage of an immunoglobulin molecule using an enzyme such as papain or by recombinant expression. The Fab domain is typically bound to the VL domain It includes a CH1 domain bound to a VH domain that pairs with the CL domain obtained. In wild-type immune globulins, the VH domain pairs with the VL domain to form the Fv region, and the CH1 domain pairs with the CL domain to further stabilize the binding module. The disulfide bond between the two constant domains can further stabilize the Fab domain. In certain embodiments, the BCMA binding molecule comprises an ABD that is an scFab. In one embodiment, the antibody domains and linkers in the scFab fragment are in one of the following orders from the N-terminus to the C-terminus: a) VH-CH1-linker-VL-CL, or b) V

[0116] L-CL-linker-VH-CH1. In some cases, VL-CL-linker-V H-CH1 is used. In another embodiment, the antibody domains and linkers in the scFab fragment are in one of the following orders from the N terminus to the C-terminus: a) VH-CL-linker-VL-CH1 or b) VL-CH1-linker-VH-CL.

[0117] Optionally, in the scFab fragment, in addition to the native disulfide bond between the CL-domain and the CH1 domain, the antibody heavy chain variable domain (VH) and the antibody light chain variable domain (VL) are also disulfide-stabilized by the introduction of disulfide bonds between the following positions: i) position 44 of the heavy chain variable domain and position 10 0 of the light chain variable domain, ii) position 105 of the heavy chain variable domain and position 43 of the light chain variable domain, or iii) heavy chain variable

[0118] domain position 101 and light chain variable domain position 100 (numbering according to Kabat's EU index).

[0119] ​​​​​ Such further disulfide stabilization of the scFab fragment is achieved by introducing a disulfide bond between the variable domains VH and VL of the single-chain Fab fragment. Techniques for introducing non-natural disulfide cross-links for stabilization of single-chain Fv are described, for example , in WO 94 / 029350, Rajagopal et al., 1997, Prot. Engin. 10: 1453-59; Kobayashi et al., 1998, Nuclear Medicine & Biology, 25: 387 -393; and Schmidt, et al., 1999, Oncogene 18: 1 711-1721. In one embodiment, an optional disulfide bond between the variable domains of the scFab fragment is between position 44 of the heavy-chain variable domain and position 100 of the light-chain variable domain. In one embodiment, an optional disulfide bond between the variable domains of the scFab fragment is between position 105 of the heavy-chain variable domain and position 4 3 of the light-chain variable domain (numbering according to the Kabat EU index). In certain embodiments, the BCMA binding molecule comprises an ABD that is an scFv. The single-chain Fv antibody fragment contains the VH and VL domains of the antibody in a single polypeptide chain and can be expressed as a single-chain polypeptide, retaining the antigenicity of the intact antibody from which it is derived. Generally, an scFv polypeptide further comprises a polypeptide linker between the VH and VL domains that allows the scFv to form the desired

[0120] structure for target binding. Examples of linkers suitable for linking the VH and VL chains of scFV are described in Section 7.4.3 . The single-chain Fv antibody fragment contains the VH and VL domains of the antibody in a single polypeptide chain and can be expressed as a single-chain polypeptide, retaining the antigenicity of the intact antibody from which it is derived. Generally, an scFv polypeptide further comprises a polypeptide linker between the VH and VL domains that allows the scFv to form the desired structure for target binding. Examples of linkers suitable for linking the VH and VL chains of scFV are described in Section 7.4.3 . The single-chain Fv antibody fragment contains the VH and VL domains of the antibody in a single polypeptide chain and can be expressed as a single-chain polypeptide, retaining the antigenicity of the intact antibody from which it is derived. Generally, an scFv polypeptide further comprises a polypeptide linker between the VH and VL domains that allows the scFv to form the desired The ABD linker identified in the section, for example, any of the linkers shown as L1 to L58 is any one of them.

[0121] Unless otherwise specified, when used herein, scFv can have VL and VH variable regions in either order with respect to the N-terminus and C-terminus of the polypeptide, and the scFv can contain VL-linker-VH or VH-linker-VL. For the N-terminus and C-terminus of the polypeptide, and the scFv can contain VL-linker-VH or VH-linker-VL. For the N-terminus and C-terminus of the polypeptide, and the scFv can contain VL-linker-VH or VH-linker-VL.

[0122] To generate the scFv-encoding nucleic acid, the VH and VL-encoding DNA fragments are operably linked to another fragment encoding a linker, for example, any of the linkers described in Section 7.4.3 (such as the amino acid sequence (Gly4~Ser)3 (SEQ ID NO: 1)), so that the VH and VL regions are linked by a flexible linker and the VH and VL sequences can be expressed as a continuous single-chain protein (see, for example, Bird et al., 1988, Science 242:423-426; Hu ston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., 1990, Natu re 348:552-554). ston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; McCafferty et al., 1990, Natu re 348:552-554). 85:5879-5883; McCafferty et al., 1990, Natu re 348:552-554).

[0123] The BCMA-binding molecule can also include an ABD that is an Fv, dsFv, (Fab’)2, single-domain antibody (SDAB ), VH or VL domain, or a camelid VHH domain (also called nanobody). ), VH or VL domain, or a camelid VHH domain (also called nanobody).

[0124] The BCMA-binding molecule is a single VH or VL domain that exhibits sufficient affinity for BCMA. It may include a single-domain antibody composed of . In one embodiment, the single-domain antibody is a camelid VHH domain (see, for example, Riechmann, 1999, Jour nal of Immunological Methods 231:25-38; see International Publication No. 94 / 04678 pamphlet).

[0125] Tables 1A-1 to 1P (collectively "Table 1") list the sequences of exemplary BCMA-binding sequences that may be included in the BCMA-binding molecule.

[0126]

Table 1

[0127]

Table 2

[0128]

Table 3

[0129]

Table 4

[0130]

Table 5

[0131]

Table 6

[0132]

Table 7

[0133]

Table 8

[0134]

Table 9

[0135]

Table 10

[0136]

Table 11

[0137]

Table 12

[0138]

Table 13

[0139]

Table 14

[0140]

Table 15

[0141]

Table 16

[0142]

Table 17

[0143]

Table 18

[0144]

Table 19

[0145]

Table 20

[0146]

Table 21

[0147]

Table 22

[0148]

Table 23

[0149]

Table 24

[0150]

Table 25

[0151]

Table 26

[0152]

Table 27

[0153]

Table 28

[0154]

Table 29

[0155]

Table 30

[0156]

Table 31

[0157]

Table 32

[0158]

Table 33

[0159]

Table 34

[0160]

Table 35

[0161]

Table 36

[0162]

Table 37

[0163]

Table 38

[0164]

Table 39

[0165] [Table 40]

[0166] [Table 41]

[0167] [Table 42]

[0168] [Table 43]

[0169] [Table 44]

[0170] Tables 1A-1 to 1B-2 show the CDR sequences of exemplary BCMA binding molecules described in the Examples. The CDR consensus sequences derived from the columns are listed. Kabat CDR sequences of exemplary BCMA binding molecules. thia CDR sequence, exemplary IMGT CDR sequence of BCMA binding molecule, exemplary B Combination of Kabat and Chothia CDR sequences of CMA binding molecules, exemplary BCM A combination of Kabat and IMGT CDR sequences of binding molecules and exemplary BCMA binding molecules The sequences include those based on a combination of the Chothia and IMGT CDR sequences. The specific CDR sequences of the exemplary BCMA binding molecules described herein are listed in Tables 1C1-1N-2. They are provided. Exemplary VL and VH sequences are listed in Tables 1O-1 and 1O-2, respectively. Exemplary scFv sequences are listed in Table 1P.

[0171] In certain embodiments, the BCMA binding molecule comprises a light chain CDR having the amino acid sequence of any one of the CDR consensus sequences listed in Table 1A-1 or Table 1B-1. In certain embodiments, the disclosure provides a BCMA binding molecule comprising one, two, three or more light chain CDRs selected from (or alternatively consisting of) the light chain CDRs described in Table 1A-1 or Table 1B-1. In certain embodiments, the disclosure provides a BCMA binding molecule comprising one, two, three or more light chain CDRs selected from (or alternatively consisting of) the light chain CDRs described in Table 1A-1 or Table 1B-1. In certain embodiments, the disclosure provides a BCMA binding molecule comprising one, two, three or more light chain CDRs selected from (or alternatively consisting of) the light chain CDRs described in Table 1A-1 or Table 1B-1. In certain embodiments, the disclosure provides a BCMA binding molecule comprising one, two, three or more light chain CDRs selected from (or alternatively consisting of) the light chain CDRs described in Table 1A-1 or Table 1B-1.

[0172] In certain embodiments, the BCMA binding molecule comprises a heavy chain CDR having the amino acid sequence of any one of the heavy chain CDRs listed in Table 1A-2 or Table 1B-2. In certain embodiments, the disclosure provides a BCMA binding molecule comprising one, two, three or more heavy chain CDRs selected from (or alternatively consisting of) the heavy chain CDRs described in Table 1A-2 or Table 1B-2. In certain embodiments, the disclosure provides a BCMA binding molecule comprising one, two, three or more heavy chain CDRs selected from (or alternatively consisting of) the heavy chain CDRs described in Table 1A-2 or Table 1B-2. In certain embodiments, the disclosure provides a BCMA binding molecule comprising one, two, three or more heavy chain CDRs selected from (or alternatively consisting of) the heavy chain CDRs described in Table 1A-2 or Table 1B-2. In certain embodiments, the disclosure provides a BCMA binding molecule comprising one, two, three or more heavy chain CDRs selected from (or alternatively consisting of) the heavy chain CDRs described in Table 1A-2 or Table 1B-2.

[0173] In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C1 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C2 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C3 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C2 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C2 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C3 described in Tables 1A-1 and 1A-2. , and includes CDR-H1, CDR-H2, and CDR-H3 sequences. In certain embodiments, B The CMA-binding molecule includes the CDR-L1, CDR- L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C4 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C5 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C6 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C7 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C8 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C9 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C10 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C11 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C10 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C11 described in Tables 1A-1 and 1A-2. In certain embodiments, the BCMA-binding molecule The antibody comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C12 as set forth in Tables 1A-1 and 1A-2.

[0174] In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C13 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C14 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C15 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C16 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C17 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C18 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C19 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C20 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C21 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C22 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C23 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of C24 as set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule ​​​​and the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences set forth in Tables 1B-1 and 1B-2 . In certain embodiments, the BCMA-binding molecule comprises the C DR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences of C21 set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences of C22 set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C23 set forth in Tables 1B-1 and 1B-2. In certain embodiments , the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C24 set forth in Tables 1B-1 and 1B-2 . In certain embodiments, the BCMA-binding molecule comprises the C DR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences of C25 set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences of C26 set forth in Tables 1B-1 and 1B-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2, and CDR-H3 sequences of C27 set forth in Tables 1B-1 and 1B-2. In certain embodiments , the BCMA-binding molecule comprises the CDR-L1, comprising CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences .

[0175] In certain embodiments, the BCMA binding molecule is selected from Table 1C-1, Table 1D-1, Table 1E-1, Table 1F-1, Table 1G-1, Table 1H-1, Table 1I-1, Table 1J-1, Table 1K-1(a), Table 1K-1(b), Table 1L-1, Table 1M-1, Table 1N-1(a) or Table 1N-1(b) and comprises a light chain CDR having the amino acid sequence of any one of the CDRs listed therein. In certain embodiments, the disclosure provides a BCMA binding molecule comprising one, two, three or more light chain CDRs selected from (or alternatively consisting of) the light chain CDRs described in Table 1C-1, Table 1D-1, Table 1E-1, Table 1F-1, Table 1G-1 , Table 1H-1, Table 1I-1, Table 1J-1, Table 1K-1(a), Table 1K-1(b), Table 1L -1, Table 1M-1, Table 1N-1(a) and Table 1N-1(b).

[0176] In certain embodiments, the BCMA binding molecule is selected from Table 1C-2, Table 1D-2, Table 1E-2, Table 1F-2, Table 1G-2, Table 1H-2, Table 1I-2, Table 1J-2, Table 1K-2, Table 1L- 2, Table 1M-2 or Table 1N-2 and comprises a heavy chain CDR having the amino acid sequence of any one of the heavy chain CDRs listed therein. In certain embodiments, the disclosure provides a BCMA binding molecule comprising one, two, three or more heavy chain CDRs selected from (or alternatively consisting of) the heavy chain CDRs described in Table 1C-2, Table 1D-2 , Table 1E-2, Table 1F-2, Table 1G-2, Table 1H-2, Table 1I-2, Table 1J-2, Table 1K -2, Table 1L-2, Table 1M-2 and Table 1N-2.

[0177] ​​​​​In certain embodiments, the BCMA binding molecule comprises a VL domain having the amino acid sequence of any of the VL domains set forth in Table 1O-1. Other BCMA binding molecules are mutated, but in the VL domain, have at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity to the VL domain shown in the sequences set forth in Table 1O-1 and may contain amino acids having such identity. In certain embodiments, the BCMA binding molecule comprises a VH domain having the amino acid sequence of any of the VH domains set forth in Table 1O-2. Other BCMA binding molecules are mutated, but in the VH domain, have at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity to the VH domain shown in the sequences set forth in Table 1O-2 and may contain amino acids having such identity. Other BCMA binding molecules are mutated, but in the CDR regions, have at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity to the CDR sequences set forth in Table 1 and contain amino acids having such identity. In certain embodiments, such BCMA binding molecules contain mutant amino acid sequences in which 1, 2, 3, 4, or 5 or fewer amino acids are mutated in the CDR regions when compared to the CDR sequences set forth in Table 1. Other BCMA binding molecules comprise VH and / or VL domains having amino acid sequences that have at least 80, 85, 90, 95, 96, 97, 98, or 99 percent identity to the VH and / or VL sequences set forth in Table 1. In certain embodiments, the BCMA binding molecule

[0178]

[0179]

[0180] ​​​​​​​​​​​​​​One, two, three, four, or five or fewer amino acids while retaining substantially the same therapeutic activity, which are mutated when compared to the VH and / or VL domains shown in the sequences listed in Table 1 and include VH and / or VL domains.

[0181] The VH and VL sequences (amino acid sequences and nucleotide sequences encoding the amino acid sequences) can be "mixed and matched" to create other BCMA-binding molecules. Such "mixed and matched" BCMA-binding molecules can be tested using known binding assays (e.g., ELISA, the assays described in the Examples). When the chains are mixed and matched, the VH sequence from a particular VH / VL pairing should be replaced with a substantially similar VH sequence and the VL sequence from a particular VH / VL pairing should be replaced with a substantially similar VL sequence.

[0182] Accordingly, in one embodiment, the disclosure provides a BCMA-binding molecule having a variable heavy chain (VH) comprising an amino acid sequence selected from any one of the VH sequences listed in Table 1-O2; and a variable light chain (VL) comprising the amino acid sequence listed in Table 1-O1.

[0183] In another embodiment, the disclosure provides a BCMA-binding molecule comprising CDR-H1, CDR-H2, C DR-H3, CDR-L1, CDR-L2, and CDR-L3 listed in Table 1 or any combination thereof.

[0184] In certain embodiments, the BCMA-binding molecule has CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CD of AB1 as shown in Tables 1C-1 and 1C-2. It comprises an R-H3 sequence. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB1 shown in Tables 1D-1 and 1D -2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB1 shown in Tables 1E-1 and 1E-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB1 shown in Tables 1F-1 and 1F-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB1 shown in Tables 1G-1 and 1G-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB1 shown in Tables 1H-1 and 1H-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1C-1 and 1C-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1D-1 and 1D-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1E-1 and 1E-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1F-1 and 1F-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1G-1 and 1G-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1H-1 and 1H-2 .

[0185] . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1C-1 and 1C-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1D-1 and 1D-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1E-1 and 1E-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1F-1 and 1F-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1G-1 and 1G-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1H-1 and 1H-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1I-1 and 1I-2 The CMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1G-1 and 1G-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1C-1 and 1C-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB2 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA-binding molecule

[0186] comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1G-1 and 1G-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1G-1 and 1G-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1G-1 and 1G-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1G-1 and 1G-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1G-1 and 1G-2. It includes the DR-H3 sequence. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of R1F2 shown in Tables 1H-1 and 1 H-2.

[0187] In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF03 shown in Tables 1C-1 and 1C-2. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, CDR-L3, CD R-H1, CDR-H2, and CDR-H3 sequences of PALF03 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, CDR-L3, CD R-H1, CDR-H2, and CDR-H3 sequences of PALF03 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR- L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF03 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences of PALF03 shown in Tables 1G-1 and 1G- 2. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1 CDR-H2, and CDR-H3 sequences of PALF03 shown in Tables 1H-1 and 1H- 2. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, C DR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF03 shown in Tables 1H-1 and 1H-2.

[0188] In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and The BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of LF04. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CD R-H1, CDR-H2, and CDR-H3 sequences of PALF04 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR- L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF04 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences of PALF04 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences of PALF04 shown in Tables 1G-1 and 1G- 2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, C

[0189] DR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF04 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF05 shown in Tables 1C-1 and 1C-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CD R-H1, CDR-H2, and CDR-H3 sequences of PALF05 shown in Tables 1D-1 and The binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF05 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF05 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF05 shown in Tables 1G-1 and 1G-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF05 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1C-1 and 1C-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1E-1 and 1E-2. The binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF05 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF05 shown in Tables 1G-1 and 1G-2. The binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF05 shown in Tables 1G-1 and 1G-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF05 shown in Tables 1H-1 and 1H-2. The binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF05 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1C-1 and 1C-2.

[0190] In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1C-1 and 1C-2. The binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1C-1 and 1C-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1D-1 and 1D-2. The binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1E-1 and 1E-2. The binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1F-1 and 1F-2. The binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF06 shown in Tables 1E-1 and 1E-2. - It contains the -H3 sequence. In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1 of PALF06 shown in Tables 1G-1 and 1G- 2, and the CDR-H2 and CDR-H3 sequences. In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, C DR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF06 shown in Tables 1H-1 and 1H-2.

[0191] In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF07 shown in Tables 1C-1 and 1C-2. In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CD R-H1, CDR-H2 and CDR-H3 sequences of PALF07 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR- L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF07 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR -H3 sequences of PALF07 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR -H3 sequences of PALF07 shown in Tables 1G-1 and 1G- 2, and the CDR-H2 and CDR-H3 sequences. In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, C It includes DR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences.

[0192] In certain embodiments, the BCMA binding molecule is the PA shown in Tables 1C-1 and 1C-2 It includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of LF08. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CD R-H1, CDR-H2 and CDR-H3 sequences of PALF08 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF08 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF08 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR -H3 sequences of PALF08 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR -H3 sequences of PALF08 shown in Tables 1G-1 and 1G- 2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2 and CDR-H3 sequences of PALF08 shown in Tables 1H-1 and 1H-2. It includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences.

[0193] In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR sequences of PALF09 shown in Tables 1C-1 and 1C-2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and The CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 shown in Figure 1D-2 are included. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 shown in Tables 1G-1 and 1G- 2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 shown in Tables 1G-1 and 1G- 2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF09 shown in Tables 1H-1 and 1H-2.

[0194] In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 shown in Tables 1C-1 and 1C-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF12 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule is PALF12 as shown in Tables 1F-1 and 1F-2 and includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences thereof. In certain embodiments, the BCMA binding molecule is PALF12 as shown in Tables 1G-1 and 1G- 2 and includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences thereof. In certain embodiments, the BCMA binding molecule is PALF12 as shown in Tables 1H-1 and 1H-2 and includes the CDR-L1, CDR-L2, C DR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences thereof.

[0195] In certain embodiments, the BCMA binding molecule is PALF13 as shown in Tables 1C-1 and 1C-2 and includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences thereof. In certain embodiments, the BCMA binding molecule is PALF13 as shown in Tables 1D-1 and 1D-2 and includes the CDR-L1, CDR-L2, CDR-L3, CD R-H1, CDR-H2, and CDR-H3 sequences thereof. In certain embodiments, the BCMA binding molecule is PALF13 as shown in Tables 1E-1 and 1E-2 and includes the CDR-L1, CDR- L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences thereof. In certain embodiments, the BCMA binding molecule is PALF13 as shown in Tables 1F-1 and 1F-2 and includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences thereof. In certain embodiments, the BCMA binding molecule is PALF13 as shown in Tables 1G-1 and 1G- 2 and includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences thereof. In certain embodiments, the BCMA binding molecule is PALF13 as shown in Tables 1G-1 and 1G- 2 and includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , and includes CDR-H2 and CDR-H3 sequences. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, C DR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF13 shown in Tables 1H-1 and 1H-2.

[0196] In certain embodiments, the BCMA binding molecule is the PA shown in Tables 1C-1 and 1C-2 LF14's CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences. In certain embodiments, the BCMA binding molecule is the one shown in Tables 1D-1 and 1D-2 PALF14's CDR-L1, CDR-L2, CDR-L3, CD R-H1, CDR-H2, and CDR-H3 sequences. In certain embodiments, BCMA The binding molecule includes the CDR-L1, CDR- L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF14 shown in Tables 1E-1 and 1E-2. In certain Embodiments, the BCMA binding molecule is the PALF14 shown in Tables 1F-1 and 1F-2 's CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences. In certain embodiments, the BCMA binding molecule is the one shown in Tables 1G-1 and 1G- 2 PALF14's CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, C DR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF14 shown in Tables 1H-1 and 1H-2.

[0197] In certain embodiments, the BCMA binding molecule is the PA shown in Tables 1C-1 and 1C-2 It includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of LF15. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CD R-H1, CDR-H2 and CDR-H3 sequences of PALF15 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR- L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF15 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR -H3 sequences of PALF15 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2 and CDR-H3 sequences of PALF15 shown in Tables 1G-1 and 1G- 2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, C

[0198] DR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF15 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF16 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA-binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CD R-H1, CDR-H2 and CDR-H3 sequences of PALF16 shown in Tables 1D-1 and The binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF16 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences of PALF16 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences of PALF16 shown in Tables 1G-1 and 1G-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences of PALF16 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences of PALF16 shown in Tables 1H-1 and 1H-2.

[0199] In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF17 shown in Tables 1C-1 and 1C-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PALF17 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences of PALF17 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -H3 sequences of PALF17 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR -It contains the -H3 sequence. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1 shown in Tables 1G-1 and 1G- , CDR-H2 and CDR-H3 sequences of PALF17. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, C DR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF17 shown in Tables 1H-1 and 1H-2.

[0200] In certain embodiments, the BCMA-binding molecule is the PA shown in Tables 1C-1 and 1C-2 LF18's CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, CDR-L3, CD shown in Tables 1D-1 and 1D-2 of PALF18's CDR-H1, CDR-H2 and CDR-H3 sequences. In certain embodiments, BCMA The binding molecule is the CDR-L1, CDR- L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF18 shown in Tables 1E-1 and 1E-2. In certain embodiments the BCMA-binding molecule is the PALF18 shown in Tables 1F-1 and 1F-2 's CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR -H3 sequences. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1 shown in Tables 1G-1 and 1G- 2 of PALF18's CDR-H2 and CDR-H3 sequences. In certain embodiments, the BCMA-binding molecule is the CDR-L1, CDR-L2, C It includes DR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences.

[0201] In certain embodiments, the BCMA binding molecule is the PA shown in Tables 1C-1 and 1C-2 It includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of LF19. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CD R-H1, CDR-H2 and CDR-H3 sequences of PALF19 shown in Tables 1D-1 and 1D-2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF19 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF19 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR -H3 sequences of PALF19 shown in Tables 1G-1 and 1G- 2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1 CDR-H2 and CDR-H3 sequences of PALF19 shown in Tables 1H-1 and 1H-2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, C DR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF19 shown in Tables 1H-1 and 1H-2.

[0202] In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR sequences of PALF20 shown in Tables 1C-1 and 1C-2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF20 shown in FIGS. 1D-2 include. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR- L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of PALF20 shown in Tables 1E-1 and 1E-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR -H3 sequences of PALF20 shown in Tables 1F-1 and 1F-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR -H3 sequences of PALF20 shown in Tables 1G-1 and 1G- 2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR -H3 sequences of PALF20 shown in Tables 1H-1 and 1H-2.

[0203] In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CD R-H3 sequences of AB3 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CD R-H3 sequences of AB3 shown in Tables 1J-1 and 1J -2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CD R-H3 sequences of AB3 shown in Tables 1K-1 and 1K-2. In certain embodiments, B The CMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB3 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB3 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB3 shown in Tables 1N-1 and 1N-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1J-1 and 1J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1N-1 and 1N-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB3 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB3 shown in Tables 1N-1 and 1N-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB3 shown in Tables 1N-1 and 1N-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB3 shown in Tables 1N-1 and 1N-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of AB3 shown in Tables 1N-1 and 1N-2.

[0204] In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1J-1 and 1J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1J-1 and 1J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of PI-61 shown in Tables 1N-1 and 1N-2. -1 and the CDR-L1, CDR-L2, CDR-L3, including the CDR-H1, CDR-H2 and CDR-H3 sequences of PI-61 shown in 1N-2.

[0205] In certain embodiments, the BCMA binding molecule is the H2 / L2-22 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H 2 and CDR-H3 sequences shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule is the H2 / L2-22 CDR-L1, CDR-L2, CDR-L 3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Tables 1J- 1 and 1J-2. In certain embodiments, the BCMA binding molecule is the H2 / L2-22 CDR-L 1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA binding molecule is the H2 / L2-22 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR -H2 and CDR-H3 sequences shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA binding molecule is the H2 / L2-22 CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Tables 1 M-1 and 1M-2. In certain embodiments the BCMA binding molecule is the H2 / L2-22 CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Tables 1N-1 and 1N-2. In certain embodiments the BCMA binding molecule is the H2 / L2-22 CDR -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences.

[0206] In certain embodiments, the BCMA binding molecule is the H2 The CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-88 are included. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L 3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-88 shown in Table 1J- 1 and 1J-2. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-88 shown in Table 1K-1 and 1K-2 . In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-88 shown in Table 1L-1 and 1L-2 and is included. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR -H2 and CDR-H3 sequences of H2 / L2-88 shown in Table 1M-1 and 1M-2 . In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-88 shown in Table 1 N-1 and 1N-2 . In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-88 shown in Table 1N-1 and 1N-2 and is included. In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-88 shown in Table 1 N-1 and 1N-2 and is included.

[0207] In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-36 shown in Table 1I-1 and 1I-2 . In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H 2 and CDR-H3 sequences of H2 / L2-36 shown in Table 1J- 1 and 1J-2. In certain embodiments, The BCMA-binding molecule comprises the CDR-L of H2 / L2-36 shown in Table 1 K-1 and 1K-2 1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR -H2 and CDR-H3 sequences of H2 / L2-36 shown in Table 1 L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-36 shown in Table 1 M-1 and 1M-2. In certain embodiments the BCMA-binding molecule comprises the CDR -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-36 shown in Table 1 N-1 and 1N-2 In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-34 shown in Table 1 I-1 and 1I-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-34 shown in Table 1 J-1 and 1J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-34 shown in Table 1 K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-34 shown in Table 1 L-1 and 1L-2

[0208] In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-34 shown in Table 1 I-1 and 1I-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H 2 and CDR-H3 sequences of H2 / L2-34 shown in Table 1 J- 1 and 1J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L 3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-34 shown in Table 1 K-1 and 1K-2. In certain embodiments the BCMA-binding molecule comprises the CDR-L 1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-34 shown in Table 1 K-1 and 1K-2 In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-34 shown in Table 1 L-1 and 1L-2 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR -H2 and CDR-H3 sequences. In certain embodiments, the BCMA binding molecule is shown in Table 1 CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-34 shown in M-1 and 1M-2. In certain embodiments the BCMA binding molecule is CDR of H2 / L2-34 shown in Table 1 N-1 and 1N-2 -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences including.

[0209] In certain embodiments, the BCMA binding molecule is CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H 2 and CDR-H3 sequences of H2 / L2-68 shown in Table 1 I-1 and 1I-2. In certain embodiments, the BCMA binding molecule is CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H 2 and CDR-H3 sequences of H2 / L2-68 shown in Table 1 J- 1 and 1J-2. In certain embodiments, the BCMA binding molecule is CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-68 shown in Table 1 K-1 and 1K-2. In certain embodiments the BCMA binding molecule is CDR-L 1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-68 shown in Table 1 K-1 and 1K-2 including. In certain embodiments, the BCMA binding molecule is CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR -H2 and CDR-H3 sequences of H2 / L2-68 shown in Table 1 L-1 and 1L-2. In certain embodiments, the BCMA binding molecule is shown in Table 1 -H2 and CDR-H3 sequences. In certain embodiments, the BCMA binding molecule is CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-68 shown in M-1 and 1M-2. In certain embodiments the BCMA binding molecule is CDR of H2 / L2-68 shown in Table 1 N-1 and 1N-2 -L1, CDR-L2, CDR -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are included.

[0210] In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H 2 and CDR-H3 sequences of H2 / L2-18 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L 3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-18 shown in Tables 1J- 1 and 1J-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L 3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-18 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA binding molecule has the CDR-L 1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-18 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR -H2 and CDR-H3 sequences of H2 / L2-18 shown in Tables 1 M-1 and 1M-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-18 shown in Tables 1 N-1 and 1N-2. In certain embodiments, the BCMA binding molecule has the CDR -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-18 shown in Tables 1 N-1 and 1N-2.

[0211] In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H 2 and CDR-H3 sequences of H2 / L2-47 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H It includes 2 and the CDR-H3 sequence. In certain embodiments, the BCMA binding molecule is shown in Table 1J- the CDR-L1, CDR-L2, CDR-L 3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-47 shown in 1 and 1J-2. In certain embodiments, the BCMA binding molecule is the CDR-L 1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-47 shown in Table 1K-1 and 1K-2 It includes. In certain embodiments, the BCMA binding molecule is shown in Table 1L-1 and 1L-2 the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR -H2 and CDR-H3 sequences of H2 / L2-47. In certain embodiments, the BCMA binding molecule is Table 1 the CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-47 shown in M-1 and 1M-2. In certain embodiments the BCMA binding molecule is the CDR of H2 / L2-47 shown in Table 1N-1 and 1N-2 -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences It includes.

[0212] In certain embodiments, the BCMA binding molecule is the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H 2 and CDR-H3 sequences of H2 / L2-20 shown in Table 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule is Table 1J- the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-20 shown in 1 and 1J-2. In certain embodiments, the CDR-L1, CDR-L2, CDR-L 3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-20 shown in 3 and 1J-2. In certain embodiments, the BCMA binding molecule is the CDR-L 1. Comprising the CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR -H2, and CDR-H3 sequences of H2 / L2-20 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-20 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA-binding molecule comprises the CDR -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-20 shown in Tables 1N-1 and 1N-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1J-1 and 1J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the

[0213] CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H 2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1J-1 and 1J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1J-1 and 1J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L 3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1J-1 and 1J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H -H2, and CDR-H3 sequences of H2 / L2-80 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the It includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-80 shown in M-1 and 1M-2. In certain embodiments , the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H2 / L2-80 shown in Table 1N-1 and 1N-2 . In certain embodiments , the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1I-1 and 1I-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1J-1 and 1J-2 of H2 / L2-83

[0214] . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1K-1 and 1K-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1L-1 and 1L-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1M-1 and 1M-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1N-1 and 1N-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1N-1 and 1N-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1K-1 and 1K-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1L-1 and 1L-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1M-1 and 1M-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1N-1 and 1N-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1M-1 and 1M-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1N-1 and 1N-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1N-1 and 1N-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1N-1 and 1N-2 of H2 / L2-83 . In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences shown in Table 1N-1 and 1N-2 of H2 / L2-83 It includes columns.

[0215] In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences of H3-1 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences of H3-1 shown in Tables 1J-1 and 1 J-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences of H3-1 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-1 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3 -1 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences of H3-1 shown in Tables 1N-1 and 1 N-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences of H3-1 shown in Tables 1N-1 and 1N-2.

[0216] In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences of H3-2 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences of H3-2 shown in Tables 1J-1 and 1 J-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1 and includes CDR-H2 and CDR-H3 sequences. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-2 shown in Tables 1K-1 and 1K-2. In certain embodiments the BCMA binding molecule includes the CDR-L1 of H3-2 shown in Tables 1L-1 and 1L-2 , CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences . In certain embodiments, the BCMA binding molecule includes the H3 shown in Tables 1M-1 and 1M-2 -2 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and C DR-H3 sequences. In certain embodiments, the BCMA binding molecule includes the CDR-L1 of H3-2 shown in Tables 1N-1 and 1 N-2, CDR-L2, CDR-L3, CDR-H1 , CDR-H2 and CDR-H3 sequences.

[0217] In certain embodiments, the BCMA binding molecule includes the H3 shown in Tables 1I-1 and 1I-2 -3 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and C DR-H3 sequences. In certain embodiments, the BCMA binding molecule includes the CDR-L1 of H3-3 shown in Tables 1J-1 and 1 J-2, CDR-L2, CDR-L3, CDR-H1 , CDR-H2 and CDR-H3 sequences. In certain embodiments, the BCMA binding molecule includes the CDR-L1 of H3-3 shown in Tables 1K-1 and 1K-2, CDR-L2, CDR -L3, CDR-H1, CDR-H2 and CDR-H3 sequences. In certain embodiments the BCMA binding molecule includes the CDR-L1 of H3-3 shown in Tables 1L-1 and 1L-2 , CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-3 shown in Tables 1M-1 and 1M-2. -3 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and C In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-3 shown in Tables 1N-1 and 1N-2. N-2 CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2 and CDR-H3 sequences.

[0218] In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-4 shown in Tables 1I-1 and 1I-2. -4 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and C In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-4 shown in Tables 1J-1 and 1J-2. J-2 CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2 and CDR-H3 sequences. In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-4 shown in Tables 1K-1 and 1K-2. -L3, CDR-H1, CDR-H2 and CDR-H3 sequences. In certain embodiments the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-4 shown in Tables 1L-1 and 1L-2. CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-4 shown in Tables 1M-1 and 1M-2. -4 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and C In certain embodiments, the BCMA-binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-4 shown in Tables 1N-1 and 1N-2. N-2 CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2 and CDR-H3 sequences.

[0219] In certain embodiments, the BCMA binding molecule has the H3 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1 CDR-H2, and CDR-H3 sequences of H3-5 shown in Tables 1J-1 and 1 J-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-5 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-5 shown in Tables 1L-1 and 1L-2 . In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-5 shown in Tables 1M-1 and 1M-2 . In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences of H3 -5 shown in Tables 1N-1 and 1 N-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences of H3-5 shown in Tables 1N-1 and 1N-2.

[0220] In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences of H3 -6 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences of H3-6 shown in Tables 1J-1 and 1 and comprises CDR-H2 and CDR-H3 sequences. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-6 shown in Tables 1K-1 and 1K-2. In certain embodiments the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-6 shown in Tables 1L-1 and 1L-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3 -6 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2 and CDR-H3 sequences of H3-6 shown in Tables 1N-1 and 1 N-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2 and CDR-H3 sequences of H3-6 shown in Tables 1N-1 and 1

[0221] In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3 -7 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-7 shown in Tables 1J-1 and 1 J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-7 shown in Tables 1K-1 and 1K-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-7 shown in Tables 1L-1 and 1L-2 . In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-7 shown in Tables 1L-1 and 1L-2 ​ In certain embodiments, the BCMA binding molecule has the H3 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA binding molecule has the H3 CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences shown in Tables 1N-1 and 1

[0222] In certain embodiments, the BCMA binding molecule has the H3 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule has the H3 CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences shown in Tables 1J-1 and 1 J-2. In certain embodiments, the BCMA binding molecule has the H3 CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2, and CDR-H3 sequences shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA binding molecule has the H3 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences shown in Tables 1L-1 and 1L-2 In certain embodiments, the BCMA binding molecule has the H3 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA binding molecule has the H3 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences shown in Tables 1N-1 and 1

[0223] In certain embodiments, the BCMA binding molecule has H3 CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences as set forth in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule has CDR-L1, CDR-L2, CDR-L3, CDR-H1 CDR-H2, and CDR-H3 sequences of H3-9 as set forth in Tables 1J-1 and 1 J-2. In certain embodiments, the BCMA binding molecule has CDR-L1, CDR-L2, CDR -L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-9 as set forth in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA binding molecule has CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-9 as set forth in Tables 1L-1 and 1L-2 . In certain embodiments, the BCMA binding molecule has CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences of H3-9 as set forth in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA binding molecule has CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and C DR-H3 sequences of H3-9 as set forth in Tables 1N-1 and 1 N-2. In certain embodiments, the BCMA binding molecule has CDR-L1, CDR-L2, CDR-L3, CDR-H1 , CDR-H2, and CDR-H3 sequences of H3-9 as set forth in Tables 1N-1 and 1N-2.

[0224] In certain embodiments, the BCMA binding molecule has CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3 -10 as set forth in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule has CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-10 as set forth in Tables 1J-1 and It includes H1, CDR-H2, and CDR-H3 sequences. In certain embodiments, BCMA binding molecules include the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-10 shown in Tables 1K-1 and 1K-2. In certain embodiments the BCMA binding molecule includes the CDR -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-10 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2, and CDR-H3 sequences of H3-10 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2, and CDR-H3 sequences of H3-10 shown in Tables 1N -1 and 1N-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3,

[0225] In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-11 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-11 shown in Tables 1J-1 and 1J-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR- H1, CDR-H2, and CDR-H3 sequences of H3-11 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA binding molecule includes the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-11 shown in Tables 1L-1 and 1L-2. In certain embodiments the BCMA binding molecule includes the CDR -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences are included. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2 and CDR-H3 sequences of H3-11 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-11 shown in Tables 1N-1 and 1N-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-11 shown in Tables 1N-1 and 1N-2.

[0226] In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 shown in Tables 1J-1 and 1J-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA binding molecule comprises the CDR -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 shown in Tables 1L-1 and 1L-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2 and CDR-H3 sequences of H3-12 shown in Tables 1N-1 and 1N-2. In certain embodiments, the BCMA binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, -1 and the CDR-L1, CDR-L2, CDR-L3, comprising the CDR-H1, CDR-H2 and CDR-H3 sequences of H3-12 shown in 1N-2.

[0227] In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-13 shown in Tables 1I-1 and 1I-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-13 shown in Tables 1J-1 and 1J-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR- H1, CDR-H2 and CDR-H3 sequences of H3-13 shown in Tables 1K-1 and 1K-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-13 shown in Tables 1K-1 and 1K-2. In certain embodiments the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 of H3-13 shown in Tables 1L-1 and 1L-2 sequences. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-13 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2 and CDR-H3 sequences of H3-13 shown in Tables 1M-1 and 1M-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 of H3-13 shown in Tables 1N -1 and 1N-2. In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-13 shown in Tables 1N-1 and 1N-2.

[0228] In certain embodiments, the BCMA binding molecule has the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2 and CDR-H3 sequences of H3-14 shown in Tables 1I-1 and 1I-2. It includes a CDR-H3 sequence. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-14 shown in Table 1J-1 and 1J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-14 shown in Table 1K-1 and 1K-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-14 shown in Table 1L-1 and 1L-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-14 shown in Table 1M-1 and 1M-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-14 shown in Table 1N-1 and 1N-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-14 shown in Table 1N-1 and 1N-2.

[0229] In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-15 shown in Table 1I-1 and 1I-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-15 shown in Table 1J-1 and 1J-2. In certain embodiments, the BCMA-binding molecule comprises the CDR-L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences of H3-15 shown in Table 1K-1 and It includes CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences. In certain embodiments the BCMA-binding molecule includes the CDRs of H3-15 shown in Tables 1L-1 and 1L-2 -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences In certain embodiments, the BCMA-binding molecule includes the CDRs of H3-15 shown in Tables 1M-1 and 1M-2 -L1, CDR-L2, CDR-L3, CDR-H1, CDR- H2, and CDR-H3 sequences. In certain embodiments, the BCMA-binding molecule includes the CDRs of H3-15 shown in Tables 1N -1 and 1N-2 -L1, CDR-L2, CDR-L3, CDR-H1, CDR-H2, and CDR-H3 sequences.

[0230] In certain embodiments, the BCMA-binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of AB1 described in Tables 1O-1 and 1O-2. In certain embodiments, BCMA the binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of AB2 described in Tables 1O-1 and 1O-2. In certain embodiments, the BCMA-binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of R1F2 described in Tables 1O-1 and 1O -2. In certain embodiments, the BCMA-binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of PALF03 described in Tables 1O-1 and 1O -2. In certain embodiments, the BCMA-binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of PALF04 described in Tables 1O-1 and 1O-2. In certain embodiments, the BCMA-binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of PALF05 described in Tables 1O-1 and 1O-2. In certain embodiments the BCMA-binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of PALF05 described in Tables 1O-1 and 1O-. In certain embodiments the BCMA-binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of PALF05 described in Tables 1O-1 and 1O-2. In certain embodiments In one state, the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of PALF06 as described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of PALF07 as described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of PALF08 as described in Table 1O-1 and Table 1O -2. In certain embodiments, the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of PALF0 9 as described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of PALF12 as described in Table 1O-1 and Table 1O -2. In certain embodiments, the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of PALF 14 as described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of PALF15 as described in Table 1O-1 and Table 1O -2. In certain embodiments, the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of PALF16 as described in Table 1O-1 and Table 1O -2. In certain embodiments, the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of PAL F17 as described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of PALF18 as described in Table 1O-1 and It includes the light chain variable sequence and / or heavy chain variable sequence of PALF19 described in Table 1O-2. A In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of PALF20 described in Table 1O-1 and Table 1O-2. In certain embodiments, BCM A binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of AB3 described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of AB3 described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of PI-61 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of H3-1 described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of H3-2 described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of H3-3 described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of H3-4 described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of H3-5 described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of H3-6 described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of H3-7 described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of H3-7 described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of H3-6 described in Table 1O-1 and Table 1O-2. In certain embodiments, BCM A binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of H3-7 described in Table 1O-1 and Table 1O-2. In certain embodiments, the BCMA binding molecule includes the light chain variable sequence and / or heavy chain variable sequence of H3-7 described in Table 1O-1 and Table 1O-2. It comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-8 described in 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-9 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-10 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-11 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-12 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-13 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-14 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-15 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-16 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-17 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-18 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-19 described in Table 1O-1 and Table 1O-2. In certain embodiments the BCMA binding molecule comprises the light chain variable sequence and / or the heavy chain variable sequence of H3-20 described in Table 1O-1 and Table 1O-2.

[0231] In certain embodiments, the BCMA binding molecule comprises the scFv sequence of H2 / L2-88 described in Table 1P. In certain embodiments, the BCMA binding molecule comprises the scFv sequence of H2 / L2-36 described in Table 1P. In certain embodiments, the BCMA binding molecule comprises the scFv sequence of H2 / L2-34 described in Table 1P. In certain embodiments, the BCMA binding molecule comprises the scFv sequence of H2 / L2-68 described in Table 1P. In certain embodiments, the BCMA binding molecule comprises the scFv sequence of H2 / L2-18 described in Table 1P. sequence. It includes an array. In certain embodiments, the BCMA binding molecule is H2 / L as described in Table 1P and includes the scFv sequence of 2-47. In certain embodiments, the BCMA binding molecule is in Table 1P and includes the scFv sequence of H2 / L2-20 described therein. In certain embodiments, the BCMA binding molecule includes the scFv sequence of H2 / L2-80 described in Table 1P. In certain embodiments the BCMA binding molecule includes the scFv sequence of H2 / L2-83 described in Table 1P .

[0232] Considering that each BCMA binding molecule binds to BCMA and the antigen binding specificity is mainly provided by the CDR-H1 , CDR-H2, CDR-H3, CDR-L1, CDR-L2 and CDR-L3 regions, the CDR-H1, CDR-H2, CDR-H3, CDR -L1, CDR-L2 and CDR-L3 sequences can be "mixed and matched". Such "mixed and matched" BCMA binding molecules can be tested using known binding assays and those described in the examples (e.g., ELISA). When the VH CDR sequences are mixed and matched, the CDR-H1, CDR-H2 and / or CD R-H3 sequences from a particular VH sequence should be replaced with structurally similar CDR sequences. Similarly, when the VL CDR sequences are mixed and matched, the CDR-L1, CDR -L2 and / or CDR-L3 sequences from a particular VL sequence should be replaced with structurally similar CDR sequences . New VH and VL sequences can be created by replacing one or more VH and / or VL CDR region sequences with structurally similar sequences from the CD R sequences shown herein for the monoclonal antibodies or other BCMA binding molecules of the present disclosure, which will be understood by those skilled in the art to be possible. ​ It will become readily apparent.

[0233] In certain embodiments, the BCMA binding molecule comprises a VL sequence selected from the VL sequences set forth in Table 1O-1 and a VH sequence selected from the VH sequences set forth in Table 1O-2. In certain embodiments, the BCMA binding molecule comprises a CDR-H1 sequence selected from the CDR-H1 sequences set forth in Table 1A-2, Table 1B-2, Table 1C-2, Table 1D-2, Table 1E-2, Table 1F-2, Table 1G-2, Table 1H-2, Table 1I-2, Table 1J-2 Table 1K-2, Table 1L-2, Table 1M-2, and Table 1N-2; a CDR-H2 sequence selected from the CDR-H2 sequences set forth in Table 1A-2, Table 1B-2, Table 1C-2, Table 1D-2, Table 1E-2, Table 1F-2, Table 1G-2, Table 1H-2, Table 1I-2, Table 1J-2, Table 1K-2 Table 1L-2, Table 1M-2, and Table 1N-2; a CDR-H3 sequence selected from the CDR-H3 sequences set forth in Table 1A-2, Table 1B-2, Table 1C-2, Table 1D-2, Table 1E-2, Table 1F-2, Table 1G-2, Table 1H-2, Table 1I-2, Table 1J-2, Table 1K-2, Table 1L-2 Table 1M-2, and Table 1N-2; a CDR-L1 sequence selected from the CDR-L1 sequences set forth in Table 1A-1, Table 1B-1, Table 1C-1, Table 1D-1, Table 1E-1, Table 1F-1, Table 1G-1, Table 1H-1, Table 1I-1, Table 1J-1, Table 1K-1(a), Table 1K-1(b) Table 1L-1, Table 1M-1, Table 1N-1(a), and Table 1N-1(b); and a CDR-L2 sequence selected from the CDR-L2 sequences set forth in Table 1A-1, Table 1B-1, Table 1C-1, Table 1D-1, Table 1E-1, Table 1F-1, Table 1G-1, Table 1H-1, Table 1I-1, Table 1J-1 Table 1K-1(a), Table 1K-1(b), Table 1L-1, Table 1M-1, Table 1N-1(a), and Table 1N-1(b). a CDR-L1 sequence selected from the CDR-L1 sequences set forth in Table 1A-1, Table 1B-1, Table 1C-1, Table 1D-1, Table 1E-1, Table 1F-1, Table 1G-1, Table 1H-1, Table 1I-1, Table 1J-1 Table 1K-1(a), Table 1K-1(b), Table 1L-1, Table 1M-1, Table 1N-1(a), and a CDR-L2 sequence selected from the CDR-L2 sequences set forth in Table 1N-1(b); and and a CDR-L3 sequence selected from the CDR-L3 sequences set forth in Table 1A-1, Table 1B-1, Table 1C-1, Table 1D-1, Table 1E-1, Table 1F-1, Table 1 G-1, Table 1H-1, Table 1I-1, Table 1J-1, Table 1K-1(a), Table 1K-1(b), Table 1L-1, Table 1M-1, Table 1N-1(a) and Table 1N-1(b). The BCMA binding molecule may be fused or chemically conjugated (including both covalent and non-covalent conjugation) to a heterologous protein or polypeptide (or a fragment thereof, such as a polypeptide of at least 10, at least 20, at least 30, at least 40, at least 50

[0234] amino acids). For example, the BCMA binding molecule may be directly or indirectly fused to a detectable protein, such as an enzyme or a fluorescent protein, such as those described in Section 7.10. Methods for fusing or conjugating a protein, polypeptide or peptide to an antibody or an antibody fragment are known and can be used to fuse or conjugate a protein or polypeptide to the BCMA binding molecules of the present disclosure. For example, U.S. Patent Nos. 5,336,603, 5,622,929 5,359,046, 5,349,053, 5, 447,851 and 5,112,946; European Patent Nos. 307,43 4 and 367,166; International Publication No. WO 96 / 04 ​​​​​​​​388 and WO 91 / 06570; Ashkena zi et al.,(1991)Proc.Natl.Acad.Sci.USA 8 8:10535-10539;Zheng et al.,(1995)J.Immun ol.154:5590-5600; and Vil et al., (1992) Proc. See Natl. Acad. Sci. USA 89:11337-11341 .

[0235] Further BCMA binding molecules have been generated using gene-shuffling, motif-shuffling, Exon-shuffling and / or codon-shuffling (collectively referred to as "DNA shuffling") DNA shuffling can be performed by the technique of "shuffling" (also known as "shuffling"). or fragments thereof (e.g., molecules with higher affinity and lower dissociation rates). Generally, the present invention can be used to modify the activity of a polypeptide (or a fragment thereof). Specification No. 605,793, Specification No. 5,811,238, No. 5,830,721 Specification, Patent Nos. 5,834,252 and 5,837,458; Pat ten et al.,(1997)Curr.Opinion Biotechnol .8:724-33;Harayama,(1998)Trends Biotechn. ol.16(2):76-82;Hansson et al.,(1999)J.Mo l.Biol.287:265-76; and Lorenzo and Blasco, ( 1998) Biotechniques 24(2):308-313. The BCMA binding molecules or fragments thereof described herein may be modified to - Random mutagenesis by error-prone PCR, random nucleotide insertion, or other methods can be modified by being subjected to. The polynucleotide encoding the fragment of the BCMA-binding molecule described herein can be recombined with one or more components of one or more heterologous molecules, motifs, sections, parts, domains, fragments, etc.

[0236] Furthermore, the BCMA-binding molecule can be fused to a marker sequence such as a peptide to facilitate purification. In certain embodiments, the marker amino acid sequence is, among others, in particular, the tag provided in the pQE vector (QIAGEN, Inc., 9259 Eton Av enue, Chatsworth, CA, 91311), such as the hexahistidine peptide (SEQ ID NO: 603), many of which are commercially available. Gentz et al. , (1989) Proc. Natl. Acad. Sci. USA 86:821-824 As described in, for example, hexahistidine (SEQ ID NO: 603) provides convenient purification of the fusion protein . Other peptide tags useful for purification include, but are not limited to , hemagglutinin ("HA") tag corresponding to the epitope derived from the influenza hemagglutinin protein (Wilson et al., (1984) Cell 37:767 ) and the "flag" tag.

[0237] 7.3. Antigen-binding main of the multispecific binding molecule Typically, one or more ABDs of the MBM comprise an immunoglobulin-based antigen-binding domain, for example, the sequence or derivative of an antibody fragment as described in Section 7.2. This The antibody fragments and derivatives thereof typically include the CDRs of the antibody and may include larger fragments and derivatives thereof, such as Fab, scFab, Fv, and scFv.

[0238] 7.3.1. Immunoglobulin-based ABDs 7.3.1.1. Fab In certain embodiments, the MBM includes one or more ABDs that are, for example, Fab domains as described in Section 7.2.

[0239] In the MBMs of the present disclosure, Fab heterodimerization techniques are used to enable proper association of Fab domains belonging to the same ABD and to minimize aberrant pairing of Fab domains belonging to different ABDs. Advantageously, for example, the Fab heterodimerization techniques shown in Table 2 below can be used.

[0240] [Table 45]

[0241] Thus, in certain embodiments, proper association between the two polypeptides of the Fab is promoted, for example, by exchanging the VL and VH domains of the Fab as described in WO 2009 / 080251 pamphlet, or by exchanging the CH1 and CL domains with each other.

[0242] Proper Fab pairing can also be achieved by introducing one or more amino acid modifications into the CH1 domain and one or more amino acid modifications into the CL domain of the Fab, and / or by introducing one or more amino acid modifications into the VH domain and one or more amino acid modifications into the VL domain. ​Fab components preferentially pair with each other over other Fab components. Thus, the amino acids that are modified are typically part of the VH:VL and CH1:CL boundaries. do.

[0243] In one embodiment, one or more amino acid modifications are indicated by the Kabat numbering of the residues. As shown in Fig. 1, the conserved frames of the variable (VH, VL) and constant (CH1, CL) domains are Almagro, 2008, Frontiers In Bioscience 13:1619-1633, Kabat, Chothia and and framework residue definitions based on the IMGT numbering scheme are provided.

[0244] In one embodiment, the VH and CH1 and / or VL and CL domains are introduced The modifications are complementary to each other. Complementarity at the heavy and light chain interface is due to steric and hydrophobic contacts. This can be achieved based on electrostatic / charge interactions or any combination of different interactions. Complementarity between protein surfaces allows for lock-and-key mating, knob-into-hole, protrusion and The properties of the vacancies, donors and acceptors have been widely described in the literature. This suggests the nature of the structural and chemical match between the two interacting surfaces.

[0245] In one embodiment, the one or more modifications introduced are novel modifications spanning the boundaries of the Fab components. In one embodiment, one or more of the modifications introduced are in the Fab structure. Exemplary substitutions are described in WO 2014 / 023363 and WO 2014 / 023363. As described in International Publication No. 150973 and International Publication No. 2014 / 082179 It is listed.

[0246] In one embodiment, the Fab domain comprises a 192E substitution in the CH1 domain and C 114A and 137K substitutions in the L domain, which introduce an ionic bridge between the CH1 and CL domains (see Golay et al., 2016, J Immunol 196 :3199-211).

[0247] In one embodiment, the Fab domain comprises 143Q and 188V substitutions in the CH1 domain and 113T and 176V substitutions in the CL domain, which serve to swap the hydrophobic and polar contact regions between the CH1 and CL domains (see Golay et al., 2016, J Immunol 196:3199-211).

[0248] In one embodiment, the Fab domain comprises modifications in some or all of the VH, CH1, VL, CL domains to introduce orthogonal Fab boundaries that facilitate the proper assembly of Fab domains (Lewis et al., 2014 Nature Biot echnology 32:191-198). In one embodiment, 39K, 62E modifications are introduced into the VH domain, H172A, F174G modifications are introduced into the CH1 domain, 1R, 38D, (36F) modifications are introduced into the VL domain, and L135Y, S17 6W modifications are introduced into the CL domain. In another embodiment, 39Y modification is introduced into the VH dom ain and 38R modification is introduced into the VL domain.

[0249]

[0249] The Fab domain replaces the native CH1:CL disulfide bond with a modified disulfide bond modified to enhance the efficiency of Fab component pairing. For example, engineered disulfide bonds can be introduced by introducing 126C into the CH1 domain and 121C into the CL domain (see Mazor et al., 2015, MAbs 7:377-89).

[0250] The Fab domain can also be modified by replacing the CH1 and CL domains with another domain that promotes proper assembly. For example, Wu et al., 2015 , MAbs 7:364-76 describes replacing the CH1 domain of the α T cell receptor with a constant domain, replacing the CL domain of the T cell receptor with a β domain, and introducing 38 D modifications into the VL domain and 39K modifications into the VH domain, and combining additional charge-charge interactions between the VL and VH domains with these domain replacements.

[0251] The MBM can include, for example, one or more ABDs as a single-chain Fab fragment as described in Section 7.2.

[0252] 7.3.1.2. scFv In certain embodiments, the MBM includes, for example, one or more ABDs as an scFv as described in Section 7.2.

[0253] 7.3.1.3. Other immunoglobulin-based ABDs The MBM can also include ABDs having an immunoglobulin format other than Fab or scFv, such as Fv, dsFv, (Fab’)2, single-domain antibodies (SDAB), VH or VL domains, or camelid VHH domains (also called nanobodies). do.

[0254] ABDs consist of a single VH or VL domain that exhibits sufficient affinity for the target. In an embodiment, the single domain antibody may be a single domain antibody comprising a Camelidae VH H domain (e.g., Riechmann, 1999, Journal of immunological Methods 231:25-38; International Publication No. 94 / 0 (See Brochure No. 4678).

[0255] 7.3.2. Non-immunoglobulin-based ABD In certain embodiments, the MBM comprises a non-antibody scaffold protein (such as an engineered ankyrin ligand). DARPin, Avimer (short for avidity multimer), Anti Cullin / lipocalin, Centrin, Kunitz domain, Adnexin, Affilin, Affilin Phytin (also known as nanophytin), knottin, pronectin, versabody , Duocalin and Finomer), ligands, receptors, It includes one or more ABDs derived from cytokines or chemokines.

[0256] Non-immunoglobulin scaffolds that can be used in MBM include those described by Mintz and C rea,2013,Bioprocess International 11(2): Tables 3 and 4 of pp. 40-48; Vazquez-Lombardi et al., 2015 ,Drug Discovery Today 20(10):1271-83,Figure 1, Table 1 and Figure I; Skrlec et al., 2015, Trends in Biot Those listed in Table 1 and Box 2 of Echnology 33(7):408-18 include. Mintz and Crea, 2013, Bioprocess In ternational 11(2): 40-48, Tables 3 and 4; Vazquez-Lo mbardi et al., 2015, Drug Discovery Today 20(10): 1271-83, Figure 1, Table 1 and Figure I; Skrlec et al., 2 015, Trends in Biotechnology 33(7): 408-18 The content of Table 1 and Box 2 in (collectively referred to as the "substrate disclosure") is incorporated herein by reference . In certain embodiments, the substrate disclosure is incorporated by reference for what they disclose regarding annexin . In another embodiment, the substrate disclosure is incorporated by reference for what they disclose regarding avimer . In another embodiment, the substrate disclosure is incorporated by reference for what they disclose regarding affibody . In yet another embodiment, the substrate disclosure is incorporated by reference for what they disclose regarding anticalin . In yet another embodiment, the substrate disclosure is incorporated by reference for what they disclose regarding DARPin . In yet another embodiment, the substrate disclosure is incorporated by reference for what they disclose regarding knotted domain . In yet another embodiment, the substrate disclosure is incorporated by reference for what they disclose regarding notch . In yet another embodiment, the substrate disclosure is incorporated by reference for what they disclose regarding pronectin . In yet another embodiment, the substrate disclosure is incorporated by reference for what they disclose regarding nanofitin . In yet another embodiment, the substrate disclosure is incorporated by reference for what they disclose regarding pronectin . In yet another embodiment, the substrate disclosure is incorporated by reference for what they disclose regarding nanofitin . In yet another embodiment, the substrate disclosure is incorporated by reference for what they disclose regarding nanofitin is incorporated by reference for those that do. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Affilin. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Adnectin. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding ABD. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Adhirons. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Affimers. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Alphabodies. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Almadillo repeat proteins. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Atrimers / Tetranectins. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Orbodies / OB-folds. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Centyrins. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Repobodies. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Anticalins. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Atimers. is incorporated by reference for what they disclose regarding Affilin. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Adnectin. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding ABD. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Adhirons. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Affimers. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Alphabodies. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Almadillo repeat proteins. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Atimers / Tetranectins. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Orbodies / OB-folds. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Centyrins. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Repobodies. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Anticalins. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Atimers. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Centyrins. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Repobodies. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Anticalins. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Atimers. In yet another embodiment, the disclosure of the scaffold is incorporated by reference for what they disclose regarding Atimers. 。In yet another embodiment, the disclosure of the scaffolds is incorporated by reference for those that they disclose regarding bicyclic peptides. In yet another embodiment, the disclosure of the scaffolds is incorporated by reference for those that they disclose regarding cys-knots. In yet another embodiment, the disclosure of the scaffolds is incorporated by reference for those that they disclose regarding Fn3 scaffolds (including adnectin, centyrin, prolynectin and Tn3). 。In one embodiment, the ABD can be a designed ankyrin repeat protein (“DARPin”). DARPins are antibody mimetic proteins that typically exhibit highly specific and high affinity target protein binding. They are typically recombinantly engineered and derived from natural ankyrin proteins, and consist of at least three, usually four or five repeat motifs of these proteins. Their molecular weights are approximately 14 or 18 kDa (kilodaltons) for four or five repeat DARPins respectively. Examples of DARPins can be found, for example, in U.S. Patent No. 7,417,130. Multispecific binding molecules comprising DARPin binding modules and immunoglobulin-based binding modules are disclosed, for example, in U.S. Patent Application Publication No. 2015 / 0030596 A1. 。In yet another embodiment, the ABD can be an affibody. Affibodies are well-known affinity proteins based on a 58 amino acid residue protein domain derived from one of the IgG-binding domains of staphylococcal protein A. 。In one embodiment, the ABD can be a designed ankyrin repeat protein (“DARPin”). DARPins are antibody mimetic proteins that typically exhibit highly specific and high affinity target protein binding. They are typically recombinantly engineered and derived from natural ankyrin proteins, and consist of at least three, usually four or five repeat motifs of these proteins. Their molecular weights are approximately 14 or 18 kDa (kilodaltons) for four or five repeat DARPins respectively. Examples of DARPins can be found, for example, in U.S. Patent No. 7,417,130. Multispecific binding molecules comprising DARPin binding modules and immunoglobulin-based binding modules are disclosed, for example, in U.S. Patent Application Publication No. 2015 / 0030596 A1. 。In yet another embodiment, the disclosure of the scaffolds is incorporated by reference for those that they disclose regarding Fn3 scaffolds (including adnectin, centyrin, prolynectin and Tn3).

[0257] 。In one embodiment, the ABD can be a designed ankyrin repeat protein (“DARPin”). 。DARPins are antibody mimetic proteins that typically exhibit highly specific and high affinity target protein binding. 。They are typically recombinantly engineered and derived from natural ankyrin proteins, and consist of at least three, usually four or five repeat motifs of these proteins. 。Their molecular weights are approximately 14 or 18 kDa (kilodaltons) for four or five repeat DARPins respectively. Examples of DARPins can be found, for example, in U.S. Patent No. 7,417,130. Multispecific binding molecules comprising DARPin binding modules and immunoglobulin-based binding modules are disclosed, for example, in U.S. Patent Application Publication No. 2015 / 0030596 A1. 。In yet another embodiment, the ABD can be an affibody. Affibodies are well-known affinity proteins based on a 58 amino acid residue protein domain derived from one of the IgG-binding domains of staphylococcal protein A. 。In one embodiment, the ABD can be a designed ankyrin repeat protein (“DARPin”). 。DARPins are antibody mimetic proteins that typically exhibit highly specific and high affinity target protein binding. Their molecular weights are approximately 14 or 18 kDa (kilodaltons) for four or five repeat DARPins respectively. Examples of DARPins can be found, for example, in U.S. Patent No. 7,417,130. Multispecific binding molecules comprising DARPin binding modules and immunoglobulin-based binding modules are disclosed, for example, in U.S. Patent Application Publication No. 2015 / 0030596 A1. 。They are typically recombinantly engineered and derived from natural ankyrin proteins, and consist of at least three, usually four or five repeat motifs of these proteins. Their molecular weights are approximately 14 or 18 kDa (kilodaltons) for four or five repeat DARPins respectively. Examples of DARPins can be found, for example, in U.S. Patent No. 7,417,130. Multispecific binding molecules comprising DARPin binding modules and immunoglobulin-based binding modules are disclosed, for example, in U.S. Patent Application Publication No. 2015 / 0030596 A1. 。Multispecific binding molecules comprising DARPin binding modules and immunoglobulin-based binding modules are disclosed, for example, in U.S. Patent Application Publication No. 2015 / 0030596 A1.

[0258] 。In yet another embodiment, the ABD can be an affibody. Affibodies are well-known 。and are affinity proteins based on a 58 amino acid residue protein domain derived from one of the IgG-binding domains of staphylococcal protein A. 。In yet another embodiment, the ABD can be an affibody. Affibodies are well-known 。and are affinity proteins based on a 58 amino acid residue protein domain derived from one of the IgG-binding domains of staphylococcal protein A.

[0259] In another embodiment, the ABD can be an anticalin. Anticalins are well-known and refer to another antibody mimetic technology, where the binding specificity is derived from lipocalin . Anticalins can also be formatted as a dual-targeting protein called a duocalin .

[0260] In another embodiment, the ABD can be a bispecific antibody fragment. Bispecific antibody fragments are well-known and refer to another antibody mimetic technology. They are small proteins of 3 to 5 kDa with a high disulfide density scaffold that replaces the hydrophobic core of a typical protein and has more than 15% cysteine .

[0261] Other non-immunoglobulin ABDs include "A" domain oligomers (also known as avimers) (see, for example, U.S. Patent Application Publication No. 2005 / 0164301, No. 2005 / 0048512, and No. 2004 / 017576), Fn3-based protein scaffolds (see, for example, U.S. Patent Application Publication No. 2003 / 017 0753), VASP polypeptides, pancreatic polypeptide (a PP), tetranectin (based on CTLD3), affilins (based on γB-crystallin / ubiquitin), knottins, SH3 domains, PDZ domains, tenascins, neocarzinostatin, protein A domains, lipocalins, transferrins and kunitz domains. In one aspect, ABDs useful for constructing MBMs include a fibronectin-based scaffold exemplified in WO 2011 / 130324.

[0262] Furthermore, in certain embodiments, the ABD comprises a ligand-binding domain or a receptor-binding domain of a receptor of the ligand.

[0263] 7.3.3.TCR ABD The MBM contains an ABD that specifically binds to BCMA and at least one ABD specific for a different antigen, such as a component of the TCR complex The TCR is typically a highly variable alpha (α) and beta (β) chain that is expressed as part of a complex with non-mutated CD3 chain molecules, a disulfide-linked membrane-anchored heterodimeric protein consisting of T cells that express this receptor are called α:β (or αβ) T cells, although a small number of T cells express a different receptor and are formed by variable gamma (γ) and delta (δ) chains and are called γδ T cells.

[0264] In one embodiment, the MBM contains an ABD that specifically binds to CD3.

[0265] 7.3.3.1.CD3 ABD The MBM may contain an ABD that specifically binds to CD3. The term "CD3" refers to a group of three differentiated coreceptors of the T cell receptor (or a coreceptor complex or the polypeptide chains of the coreceptor complex). The amino acid sequences of the polypeptide chains of human CD3 are shown in NCBI A ccession P04234, P07766, and P09693. C The CD3 protein may also include variants. The CD3 protein may also include fragments. The CD3 protein also includes post-translational modifications of the CD3 amino acid sequence. Post-translational modifications include, but are not limited to N-linked and O-linked glycosylation.

[0266] In one embodiment, the MBM is an ABD that is an anti-CD3 antibody (e.g., as described in U.S. Patent Application Publication No. 2016 / 0355600, International Publication No. 2014 / 110601 Pamph let and International Publication No. 2014 / 145806 Pamphlet) or may include its antigen-binding domain. Exemplary anti-CD3 VH , VL, and scFV sequences that can be used in the MBM are shown in Table 3A.

[0267]

Table 46

[0268]

Table 47

[0269]

Table 48

[0270]

Table 49

[0271]

Table 50

[0272]

Table 51

[0273] The Kabat numbering scheme (Kabat et al, 1991, Sequence s of Proteins of Immunological Interest, 5 thEd.Public Health Service,National In stitutes of Health,Bethesda,Md.),Chothia numbering scheme (Al-Lazikani et al.,1997,J.Mol.B iol 273:927-948) and the combination of Kabat and Chothia numbering The CDR sequences of several CD3 binders defined by are shown in Tables 3B - 3D, respectively. respectively.

[0274] [Table 52]

[0275] [Table 53]

[0276] [Table 54]

[0277] [Table 55]

[0278] [Table 56]

[0279] [Table 57]

[0280] [Table 58]

[0281] [Table 59]

[0282]

Table 60

[0283]

Table 61

[0284]

Table 62

[0285]

Table 63

[0286]

Table 64

[0287]

Table 65

[0288]

Table 66

[0289]

Table 67

[0290]

Table 68

[0291]

Table 69

[0292]

Table 70

[0293]

Table 71

[0294]

Table 72

[0295] In certain embodiments, the MBM can include a CD3 ABD that includes any one of CDR CD3-1 to CD3-127 as defined by Kabat numbering (e.g., as set forth in Table 3B). In other embodiments, the MBM can include a CD3 ABD that includes any one of CDR CD3-1 to CD3-127 as defined by Chothia numbering (e.g., as set forth in Table 3C). In yet other embodiments, the MBM can include a CD3 ABD that includes any one of CDR CD3-1 to CD3-127 as defined by a combination of Kabat and Chothia numbering (e.g., as set forth in Table 3D). In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-1. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-2. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-3. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-4. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-5.

[0296] In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-1. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-2. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-3. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-4. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-5. It includes the CDR sequences of 6. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-7. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-8 . In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-9. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-10. In certain embodiments it has, the CD3 ABD includes the CDR sequences of CD3-11. In certain embodiments, C D3 ABD includes the CDR sequences of CD3-12. In certain embodiments, CD3 A BD includes the CDR sequences of CD3-13. In certain embodiments, the CD3 ABD is including the CDR sequences of CD3-14. In certain embodiments, the CD3 ABD is CD3- including the CDR sequences of 15. In certain embodiments, the CD3 ABD is including the C DR sequences of CD3-16. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-17. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-18. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-19. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-20. In certain embodiments it has, the CD3 ABD includes the CDR sequences of CD3-21. In certain embodiments, C D3 ABD includes the CDR sequences of CD3-22. In certain embodiments, CD3 A BD includes the CDR sequences of CD3-23. In certain embodiments, the CD3 ABD is including the CDR sequences of CD3-24. In certain embodiments, the CD3 ABD is CD3- including the CDR sequences of 25. In certain embodiments, the CD3 ABD is including the C In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-27. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-28. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-29. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-30. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-31. The D3 ABD comprises the CDR sequences of CD3-32. The BD comprises the CDR sequences of CD3-33. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-34. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-36. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-37. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-38. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-39. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-40. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-41. The D3 ABD comprises the CDR sequences of CD3-42. The BD comprises the CDR sequences of CD3-43. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-44. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-46. In one embodiment, the CD3 ABD comprises the CDR sequences of CD3-47. It includes. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-48. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-49. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-50. In certain embodiments it includes the CDR sequences of CD3-51. In certain embodiments, the C D3 ABD includes the CDR sequences of CD3-52. In certain embodiments, the CD3 A BD includes the CDR sequences of CD3-53. In certain embodiments, the CD3 ABD is including the CDR sequences of CD3-54. In certain embodiments, the CD3 ABD is including the CDR sequences of CD3-55. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-56. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-57. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-58. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3- 59. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-60. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-61. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-62. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-63. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-64. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-65. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-66. In certain It includes. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-68. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-69. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-70. In certain embodiments it includes the CDR sequences of CD3-71. In certain embodiments, the C D3 ABD includes the CDR sequences of CD3-72. In certain embodiments, the CD3 A BD includes the CDR sequences of CD3-73. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-74. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-75. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-76. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-77. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-78. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-79. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-80. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-81. In certain embodiments, the C D3 ABD includes the CDR sequences of CD3-82. In certain embodiments, the CD3 A BD includes the CDR sequences of CD3-83. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-84. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-85. In certain embodiments, the CD3 ABD includes the CDR sequences of CD3-86. In certain embodiments, the CD3 ABD In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-89. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-90. In certain embodiments the CD3 ABD comprises the CDR sequences of CD3-91. In certain embodiments, the C D3 ABD comprises the CDR sequences of CD3-92. In certain embodiments, the CD3 A BD comprises the CDR sequences of CD3-93. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-94. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-95. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-96. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-97. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-98. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-99. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-100. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-101. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-102. In certain embodiments, the CD 3 ABD comprises the CDR sequences of CD3-103. In certain embodiments, the CD3 A BD comprises the CDR sequences of CD3-104. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-105. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-106. In certain embodiments, the CD3 ABD comprises the CDR sequences of CD3-107. In certain embodiments, the CD3 ABD It includes a CDR sequence. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-109. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-110 In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-111. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-112. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-113. In certain embodiments the CD3 ABD includes the CDR sequence of CD3-114. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-115. In certain embodiments, the C D3 ABD includes the CDR sequence of CD3-116. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-117. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-118. In certain embodiments, the CD3 ABD includes the C DR sequence of CD3-119. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3- 120. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-121 In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-122 In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-123 In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-124 . In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-125. In certain embodiments, the CD3 ABD includes the CDR sequence of CD3-126. In certain embodiments the CD3 ABD includes the CDR sequence of CD3-127.

[0297] The MBM may include any one complete heavy chain and light chain variable sequences of CD3-1 to CD3-127 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-1 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-1 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-2 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-3 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-4 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-5 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-6 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-7 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-8 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-9 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-10 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-11 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-12 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-13 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-14 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-15 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-16 In certain embodiments, the MBM includes a CD3 ABD including the VH and VL sequences of CD3-17 In one form, the MBM comprises a CD3 ABD comprising the VH and VL sequences of CD3-16 . In certain embodiments, the MBM comprises a CD3 A BD comprising the VH and VL sequences of CD3-17 . In certain embodiments, the MBM comprises a CD3 ABD comprising the VH and VL sequences of CD3-18 . In certain embodiments, the MBM comprises a CD3 ABD comprising the VH and VL sequences of CD3-19 . In certain embodiments, the MBM comprises a CD3 ABD comprising the VH and VL sequences of CD3-21 . In certain embodiments, the MBM comprises a CD3 ABD comprising the VH and VL sequences of CD3-22 . In certain embodiments, the MBM comprises a CD3 ABD comprising the VH and VL sequences of CD3-24 . In certain embodiments, the MBM comprises a CD3 A BD comprising the VH and VL sequences of CD3-25 . In certain embodiments, the MBM comprises a CD3 ABD comprising the VH and VL sequences of CD3-26 . In certain embodiments, the MBM comprises a CD3 ABD comprising the VH and VL

[0298] In addition to the CDR sets described in Tables 3B-3D (i.e., the sets of six CDRs for each of CD3-1 to CD3-127 ), the present disclosure provides variant CDR sets. In one embodiment , the set of six CDRs is at least one of a Biacore, surface plasmon resonance (SPR) and / or BLI (Biolayer Interferometry, e.g., Octet assay) assay When measured by, the CD3 ABD is still capable of binding to the target antigen As long as it can have 1, 2, 3, 4, or 5 amino acid changes from the CDR sets described in Tables 3B - 3D It can have.

[0299] In addition to the variable heavy and variable light chain domains disclosed in Table 3A that form the ABD to CD3 The present disclosure provides mutant VH and VL domains. In one embodiment, the mutant V H and VL domains are measured by at least one of Biacore, surface plasmon resonance (SPR) and / or BL I (Biolayer interferometry, such as Octet assay) assay. As long as the ABD is still capable of binding to the target antigen when measured By, it can have 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid changes from the VH and VL domain sets described in Table 3A, respectively. In another embodiment, Biacore, surface Plasmon resonance (SPR) and / or BLI (Biolayer interferometry, such as Octet Assay) assay. As long as the ABD is still capable of binding to the target antigen when measured by at least one of the assays The mutant VH and VL are at least 90, 95, 97, 98, or 99% identical to the respective VH or VL disclosed in Table 3A as long as they are still capable of binding to the target antigen When. In certain embodiments, the antigen - binding domain that specifically binds to human CD3 is non - immunoglobulin

[0300] Based and instead is derived from one of the non - antibody scaffold proteins, such as those described in Section 7.3.2 In one embodiment, the antigen - binding domain that specifically binds to human CD3 is from International Publication No. WO 2017 / 013136 pamphlet As described. In one embodiment, the antigen - binding domain that specifically binds to human CD3 Is specifically bound to, and is derived from one of the non - antibody scaffold proteins described in Section 7.3.2 of the present application It contains Affilin-144160 described in the pamphlet. Affilin-144160 is and has the following amino acid sequence. MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQ QWLWFAGKQLEDGRTLSDYNIQKESTLKLWLVDKAAMQIF VYTRTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLI WAGKQLEDGRTLSDYNIALESGLHLVLRLRAA (SEQ ID NO: 415 )

[0301] 7.3.3.2. TCR-α / β ABD The MBM may contain an ABD that specifically binds to the TCR-α chain, TCR-β chain, or TCR-αβ dimer. Exemplary anti-TCR-α / β antibodies are known (e.g., U.S. Patent Application Publication No. 2012 / 0034221; Borst et al., 1990, Hu m Immunol. 29(3):175-88 (describing antibody BMA031)) . See . The VH, VL, and Kabat CDR sequences of antibody BMA031 are shown in Table 4 .

[0302]

Table 73

[0303] In one embodiment, the TCR ABD may contain the CDR sequences of antibody BMA031. In other embodiments, the TCR ABD may contain the VH and VL sequences of antibody BMA031 .

[0304] 7.3.3.3. TCR-γ / δ ABD The MBM may contain an ABD that specifically binds to the TCR-γ chain, TCR-δ chain, or TCR-γδ dimer. It may contain BD. Exemplary anti-TCR-γ / δ antibodies are known (see, for example, U.S. Patent No. 5 ,980,892 (describing δTCS1 produced by a hybridoma deposited with the ATCC under accession number HB 9578)). See).

[0305] 7.4. Connector In some cases, the BCMA-binding molecule may, for example, as a fusion protein without a linker, be a pair of ABDs or ABD chains directly linked to each other (e.g., the VH-CH1 or VL-CL components of a Fab). It is conceivable that it may contain. For example, the BCMA-binding molecule contains a connector portion that links individual ABDs or ABD chains. The use of the connector portion can improve target binding, for example, by increasing the flexibility of the ABDs within the BCMA-binding molecule, thereby reducing steric hindrance. The ABDs or ABD chains can be linked to each other via, for example, an Fc domain (each Fc domain represents a pair of associated Fc regions) and / or an ABD linker. The use of the Fc domain typically requires the use of a hinge region as a connector for the ABDs or ABD chains for optimal antigen binding. Thus, the term "connector" includes, but is not limited to, an Fc region, an Fc domain, and a hinge region.

[0306] The connector can be selected or modified, for example, to increase or decrease the biological half-life of the BCMA-binding molecule. For example, to decrease the biological half-life, a BCMA-binding molecule containing a fragment has reduced Staphylococcyl protein A (SpA) binding compared to native Fc-hinge region SpA binding, so that one or more ​​​​​​​​​​​The amino acid mutations above can be introduced into the CH2-CH3 domain boundary region of the Fc-hinge fragment This method is described in more detail in U.S. Patent No. 6,165,745 to Ward et al. Alternatively, the BCMA binding molecule can be modified to increase its biological half-life For example, as described in U.S. Patent No. 6,277, 375 to Ward, one or more of the following mutations: T252L, T254S, T25 6F can be introduced. Alternatively, to increase the biological half-life, Pre As described in U.S. Patent Nos. 5,869,046 and 6,121,022 to Sta et al. Specification, the BCMA binding molecule can be modified within the CH1 or CL region to include a salvage receptor binding epitope taken from two loops of the CH2 domain of the Fc region of IgG Alternatively, the BCMA binding molecule can be modified within the CH1 or CL region to include a salvage receptor binding epitope taken from two loops of the CH2 domain of the Fc region of IgG region.

[0307] Examples of the Fc domain (formed by the pairing of two Fc regions), hinge region, and ABD linker are described in Sections 7.4.1, 7.4.2, and 7.4.3, respectively. Examples of the Fc domain (formed by the pairing of two Fc regions), hinge region, and ABD linker are described in Sections 7.4.1, 7.4.2, and 7.4.3, respectively.

[0308] 7.4.1. Fc Domain The BCMA binding molecule can include an Fc domain derived from any suitable species. In one embodiment the Fc domain is derived from the human Fc domain.

[0309] The Fc domain can be derived from an antibody of any suitable class, including IgA (including subclasses IgA1 and IgA2), IgD, IgE , IgG (including subclasses IgG1, IgG2, IgG3, and IgG4), and IgM . In one embodiment, the Fc domain is derived from IgG1, IgG2, IgG3, or IgG4. In one embodiment, the Fc domain In is derived from IgG1. In one embodiment, the Fc domain is derived from IgG4. from.

[0310] In natural antibodies, the Fc regions are typically identical, but for the purpose of generating a multispecific binding molecule, such as the MBM of the present disclosure, the Fc regions may advantageously be different to allow for heterodimerization, as described in Section 7.4.1.5 below.

[0311] Typically, each Fc region comprises or consists of two or three heavy chain constant domains. .

[0312] In natural antibodies, the Fc regions of IgA, IgD and IgG consist of two heavy chain constant domains (CH2 and CH3), and the heavy chain Fc regions of IgE and IgM consist of three heavy chain constant domains (CH2, CH3 and CH4). These dimerize to form the Fc domain.

[0313] In the present disclosure, the Fc region may comprise heavy chain constant domains derived from one or more different classes of antibodies, such as one, two or three different classes.

[0314] In one embodiment, the Fc region comprises the CH2 and CH3 domains derived from IgG1. include.

[0315] In one embodiment, the Fc region comprises the CH2 and CH3 domains derived from IgG2. include.

[0316] In one embodiment, the Fc region comprises the CH2 and CH3 domains derived from IgG3. include.

[0317] ​​In one embodiment, the Fc region comprises CH2 and CH3 domains derived from IgG4. It includes.

[0318] In one embodiment, the Fc region comprises a CH4 domain derived from IgM. IgM The CH4 domain is typically located at the C-terminus of the CH3 domain.

[0319] In one embodiment, the Fc region comprises CH2 and CH3 domains derived from IgG and a CH4 domain derived from IgM.

[0320] It will be understood that the heavy chain constant domains used to generate the Fc region for the BCMA-binding molecules of the present disclosure may include variants of the natural constant domains described above. Such variants may contain one or more amino acid changes compared to the wild-type constant domain. In one example, the Fc region of the present disclosure comprises at least one constant domain that differs in sequence from the wild-type constant domain. The variant constant domain may be longer or shorter than the wild-type constant domain. It will be understood that. For example, the variant constant domain is at least 60% identical or similar to the wild-type constant domain. In another example, the variant constant domain is at least 70% identical or similar. In another example, the variant constant domain is at least 75% identical or similar. In another example, the variant constant domain is at least 80% identical or similar. In another example the variant constant domain is at least 85% identical or similar. In another example the variant constant domain is at least 90% identical or similar. In another example the variant constant domain is at least 95% identical or similar. In another example the variant constant domain is at least 90% identical or similar. In another example the variant constant domain is at least 95% identical or similar. Another In the example, the mutant constant domain is at least 99% identical or similar . Exemplary Fc mutants are described in Sections 7.4.1.1 to 7.4.1.5 below .

[0321] IgM and IgA are naturally present in humans as covalently linked multimers of a common H2L2 antibody unit . IgM exists as a pentamer when incorporating the J chain, or as a hexamer when lacking the J chain . IgA exists in monomeric and dimeric forms . The heavy chains of IgM and IgA have an 18-amino acid extension to the C-terminal constant domain, known as the tail . The tail contains cysteine residues that form disulfide bonds between heavy chains in the polymer and is thought to play an important role in polymerization . The tail also contains glycosylation sites. In certain embodiments, the BCMA-binding molecules of the present disclosure do not contain a tail . .

[0322] The Fc domain incorporated into the BCMA-binding molecules of the present disclosure may include one or more modifications that alter one or more functional properties of the protein, such as serum half-life, complement binding, Fc receptor binding, and / or antibody-dependent cell cytotoxicity . Further, the BCMA-binding molecules may be chemically modified (e.g., one or more chemical moieties may be attached to the BCMA-binding molecules) or may be modified to alter one or more functional properties of the BCMA-binding molecules, such as by modifying its glycosylation . . . .

[0323] The effector functions of antibody molecules include, for example, complement-mediated effector functions mediated by the binding of the C1 component of complement to the antibody . Complement activation results in the opsonization of pathogens and is important in direct lysis. Furthermore, it stimulates the inflammatory response by recruiting and activating phagocytic cells at the site of complement activation. Effector functions include Fc receptor (FcR)-mediated effector functions, which can be induced upon binding of the constant domain of an antibody to an Fc receptor (FcR). Cross-linking mediated by the antigen-antibody complex of Fc receptors on the surface of effector cells causes phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (referred to as antibody-dependent cell-mediated cytotoxicity or ADCC), release of inflammatory mediators, placental passage, and regulation of immunoglobulin production, causing many important and diverse biological responses. and activating them. Effector functions include Fc receptor (Fc R)-mediated effector functions, which can be induced upon binding of the constant domain of an antibody to an Fc receptor (FcR). Cross-linking mediated by the antigen-antibody complex of Fc receptors on the surface of effector cells causes phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (referred to as antibody-dependent cell-mediated cytotoxicity or ADCC), release of inflammatory mediators, placental passage, and regulation of immunoglobulin production, causing many important and diverse biological responses. Cross-linking mediated by the antigen-antibody complex of Fc receptors on the surface of effector cells causes phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (referred to as antibody-dependent cell-mediated cytotoxicity or ADCC), release of inflammatory mediators, placental passage, and regulation of immunoglobulin production, causing many important and diverse biological responses. Cross-linking mediated by the antigen-antibody complex of Fc receptors on the surface of effector cells causes phagocytosis and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (referred to as antibody-dependent cell-mediated cytotoxicity or ADCC), release of inflammatory mediators, placental passage, and regulation of immunoglobulin production, causing many important and diverse biological responses. Cross-linking ...

Claims

Use of a BCMA-binding molecule that specifically binds to human BCMA in the manufacture of a medicament for the treatment of an autoimmune disease associated with high expression of BCMA, wherein the BCMA-binding molecule is (a) CDR-L1, CDR-L2 and CDR-L3 sequences respectively set forth in SEQ ID NOs: 26, 102 and 110 and CDR-H1, CDR-H2 and CDR-H3 sequences respectively set forth in SEQ ID NOs: 188, 112 and 49, according to the combined definition of Kabat and Chothia, (b) CDR-L1, CDR-L2 and CDR-L3 sequences respectively set forth in SEQ ID NOs: 26, 102 and 110 and CDR-H1, CDR-H2 and CDR-H3 sequences respectively set forth in SEQ ID NOs: 39, 112 and 49, according to the definition of Kabat, (c) CDR-L1, CDR-L2 and CDR-L3 sequences respectively set forth in SEQ ID NOs: 27, 31 and 136 and CDR-H1, CDR-H2 and CDR-H3 sequences respectively set forth in SEQ ID NOs: 138, 140 and 49, according to the definition of Chothia, or (d) CDR-L1, CDR-L2 and CDR-L3 sequences respectively set forth in SEQ ID NOs: 28, 154 and 110 and CDR-H1, CDR-H2 and CDR-H3 sequences respectively set forth in SEQ ID NOs: 162, 165 and 51, according to the definition of IMGT comprising the use. Use according to claim 1, wherein the BCMA-binding molecule comprises a light chain variable sequence comprising the amino acid sequence of SEQ ID NO: 200 and a heavy chain variable sequence comprising the amino acid sequence of SEQ ID NO:

224. Use according to claim 1 or claim 2, wherein the BCMA-binding molecule comprises an antibody, an antibody fragment, scFv, dsFv, Fv, Fab, scFab, or (Fab')2. Use according to any one of claims 1 to 3, wherein the BCMA-binding molecule is a multispecific binding molecule. Use according to claim 4, wherein the BCMA-binding molecule is a bispecific binding molecule (BBM). Use according to claim 5, wherein the BBM is (a) an antigen-binding domain 1 (ABD1) that specifically binds to BCMA; and (b) an antigen-binding domain 2 (ABD2) that specifically binds to a component of the human T cell receptor (TCR) complex comprising the use. **Claim 7**: The use according to claim 6, wherein ABD1 is capable of binding to BCMA simultaneously with ABD2 binding to a component of the human TCR complex. **Claim 8**: The use according to claim 6 or claim 7, wherein ABD1 is an antibody, antibody fragment, scFv, dsFv, Fv, Fab, scFab, or (Fab’)2. **Claim 9**: The use according to any one of claims 6 - 8, wherein ABD2 is an antibody, antibody fragment, scFv, dsFv, Fv, Fab, scFab, (Fab’)2, single domain antibody (SDAB), VH or VL domain, or camelid VHH domain. **Claim 10**: The use according to any one of claims 6 - 9, wherein the component of the TCR complex is CD3, and optionally, ABD2 is an anti - CD3 antibody or its antigen - binding domain, and optionally, ABD2 comprises any one CDR sequence of CD3 - 1 to CD3 - 127. **Claim 11**: The use according to any one of claims 5 - 10, wherein the BCMA - binding molecule is bivalent, trivalent, or tetravalent. **Claim 12**: The use according to claim 1, wherein the BCMA - binding molecule is (a) a first polypeptide comprising (i) a first heavy - chain constant domain comprising a first Fc region; (ii) an scFv comprising the amino acid sequence of SEQ ID NO: 294, covalently bound to the N - terminus of the first Fc region by a hinge the first polypeptide; (b) a second polypeptide comprising (i) a heavy - chain variable domain; (ii) a second heavy - chain constant domain comprising a second Fc region the second polypeptide; and (c) a third polypeptide comprising a light - chain constant domain and a light - chain variable domain wherein A. the first and second Fc regions form an Fc domain; B. the first and second Fc regions have a set of amino acid substitutions comprising S364K / E357Q: L368D / K370S; C. the first and / or second Fc regions comprise the amino acid substitutions E223P, L234V, L235A, G236del, and S267K; D. the first and / or second Fc regions comprise the amino acid substitutions N208D, Q295E, N384D, Q418E, and N421D; and E. the light - chain variable domain and the heavy - chain variable domain comprise the light - chain variable domain and heavy - chain variable domain sequences of SEQ ID NO: 200 and SEQ ID NO: 224, respectively. The use according to claim 13, wherein the BCMA binding molecule comprises a first polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 509; a second polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 510; and a third polypeptide having an amino acid sequence comprising the amino acid sequence of SEQ ID NO: 504 and the use thereof. The use according to any one of claims 1 to 13, wherein the autoimmune disease is systemic lupus erythematosus (SLE), Sjögren's syndrome, scleroderma, rheumatoid arthritis (RA), juvenile idiopathic arthritis, graft-versus-host disease, dermatomyositis, type 1 diabetes, Hashimoto's thyroiditis, Graves' disease, Addison's disease, celiac disease, Crohn's disease, pernicious anemia, pemphigus vulgaris, vitiligo, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, giant cell arteritis, myasthenia gravis, multiple sclerosis (MS) (e.g., relapsing-remitting MS (RRMS)), glomerulonephritis, Goodpasture's syndrome, bullous pemphigoid, ulcerative colitis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, antiphospholipid antibody syndrome, narcolepsy, sarcoidosis or Wegener's granulomatosis.

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