Anti-BCMA antibody

Abstract

Antibodies and antigen-binding fragments thereof that bind to B cell maturation antigen (BCMA), and methods of using the same are provided.

Description

Technical Field

[0001] The present disclosure relates to novel antibodies that bind to B cell maturation antigen (BCMA), antigen-binding fragments thereof, and methods of using the same.

Background Art

[0002] B cell maturation antigen (BCMA) is a member of the tumor necrosis factor receptor (TNFR) family and is expressed on cells of the B cell lineage. BCMA expression is highest in terminally differentiated B cells and is involved in mediating the survival of plasma cells for maintaining long-term humoral immunity. The expression of BCMA is associated with a number of cancers and plasma cell malignancies such as multiple myeloma (MM). RNA has been ubiquitously detected in multiple myeloma cells, and BCMA protein has been detected on the surface of plasma cells from multiple myeloma patients by multiple researchers. Therefore, BCMA is being studied as a potential therapeutic target for multiple myeloma.

[0003] Accordingly, there is a need in the art for compositions that can be used in methods for treating multiple myeloma.

Summary of the Invention

Problems to be Solved by the Invention

[0004] The specification of the subject matter provides anti-BCMA antibodies and antigen-binding fragments thereof.

Means for Solving the Problems

[0005] In one aspect, there is provided an antibody or an antigen-binding fragment thereof that specifically binds to BCMA, comprising an antibody heavy chain variable (VH) domain and an antibody light chain variable (VL) domain, wherein the VH domain comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFSNFGMH (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of VIWSDETNR (SEQ ID NO: 2), and a CDR-H3 sequence comprising the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3), and the VL domain comprises CX 1 SSTGX2 VTPX 3 X 4 YAN (SEQ ID NO: 25) (where X 1 is R or A, and X 2 is T or A, and X 3 is S or G, and X 4 is N or Y) amino acid sequence-containing CDR-L1 sequence, DNNX 5 X 6 PP (SEQ ID NO: 26) (where X 5 is S, I, or N, and X 6 is R or K) amino acid sequence-containing CDR-L2 sequence, and ALX7X8GX9QWV (SEQ ID NO: 27) (where X 7 is W or Y, and X 8 is F or Y, and X 9 is N or G) amino acid sequence-containing CDR-L3 sequence.

[0006] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a VH domain comprising a CDR-H1 sequence having the amino acid sequence of GFTFSNFGMH (SEQ ID NO: 1), a CDR-H2 sequence having the amino acid sequence of VIWSDETNR (SEQ ID NO: 2), and a CDR-H3 sequence having the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3), and a VL domain comprising a CDR-L1 sequence having the amino acid sequence of CASSTGTVTPSNYAN (SEQ ID NO: 4), CRSSTGTVTPSNYAN (SEQ ID NO: 5), CASSTGAVTPSNYAN (SEQ ID NO: 6), or CASSTGAVTPGYYAN (SEQ ID NO: 7), a CDR-L2 sequence having the amino acid sequence of DNNSRPP (SEQ ID NO: 9), DNNIKPP (SEQ ID NO: 10), or DNNNKPP (SEQ ID NO: 11), and a CDR-L3 sequence having the amino acid sequence of ALWFGNQWV (SEQ ID NO: 13), ALWYGGQWV (SEQ ID NO: 14), or ALYYGGQWV (SEQ ID NO: 15).

[0007] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a VH domain that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16, and a VL domain that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24.

[0008] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain antibody that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16, and a light chain antibody that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 24.

[0009] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 16, and a VL domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 23, and SEQ ID NO: 24.

[0010] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain antibody comprising the amino acid sequence of SEQ ID NO: 16, and a light chain antibody comprising the amino acid sequence of SEQ ID NO: 24.

[0011] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a VH domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSNFGMH (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of VIWSDETNR (SEQ ID NO: 2), and a CDR-H3 sequence comprising the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3), and a VL domain comprising a CDR-L1 sequence comprising the amino acid sequence of CASSTGTVTPSNYAN (SEQ ID NO: 4), a CDR-L2 sequence comprising the amino acid sequence of DNNSRPP (SEQ ID NO: 9), and a CDR-L3 sequence comprising the amino acid sequence of ALWFGNQWV (SEQ ID NO: 13).

[0012] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16, and a light chain that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 18.

[0013] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 16, and a light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0014] In certain exemplary embodiments, the antibody or antigen-binding fragment comprises a VH domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSNFGMH (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of VIWSDETNR (SEQ ID NO: 2), and a CDR-H3 sequence comprising the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3), and a VL domain comprising a CDR-L1 sequence comprising the amino acid sequence of CRSSTGTVTPSNYAN (SEQ ID NO: 5), a CDR-L2 sequence comprising the amino acid sequence of DNNSRPP (SEQ ID NO: 9), and a CDR-L3 sequence comprising the amino acid sequence of ALWFGNQWV (SEQ ID NO: 13).

[0015] In certain exemplary embodiments, the antibody or antigen-binding fragment comprises a heavy chain that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16, and a light chain that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 19.

[0016] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 16, and a light chain comprising the amino acid sequence of SEQ ID NO: 19.

[0017] In certain exemplary embodiments, the antibody or antigen-binding fragment comprises a VH domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSNFGMH (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of VIWSDETNR (SEQ ID NO: 2), and a CDR-H3 sequence comprising the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3), and a VL domain comprising a CDR-L1 sequence comprising the amino acid sequence of CASSTGTVTPSNYAN (SEQ ID NO: 4), a CDR-L2 sequence comprising the amino acid sequence of DNNSRPP (SEQ ID NO: 9), and a CDR-L3 sequence comprising the amino acid sequence of ALWFGNQWV (SEQ ID NO: 13).

[0018] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy antibody chain that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16 and a light antibody chain that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 20.

[0019] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy antibody chain comprising the amino acid sequence of SEQ ID NO: 16 and a light antibody chain comprising the amino acid sequence of SEQ ID NO: 20.

[0020] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a VH domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSNFGMH (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of VIWSDETNR (SEQ ID NO: 2), and a CDR-H3 sequence comprising the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3), and a VL domain comprising a CDR-L1 sequence comprising the amino acid sequence of CASSTGAVTPSNYAN (SEQ ID NO: 6), a CDR-L2 sequence comprising the amino acid sequence of DNNIKPP (SEQ ID NO: 10), and a CDR-L3 sequence comprising the amino acid sequence of ALWYGGQWV (SEQ ID NO: 14).

[0021] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain antibody that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16, and a light chain antibody that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 21.

[0022] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain antibody comprising the amino acid sequence of SEQ ID NO: 16, and a light chain antibody comprising the amino acid sequence of SEQ ID NO: 21.

[0023] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a VH domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSNFGMH (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of VIWSDETNR (SEQ ID NO: 2), and a CDR-H3 sequence comprising the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3), and a VL domain comprising a CDR-L1 sequence comprising the amino acid sequence of CASSTGAVTPGYYAN (SEQ ID NO: 7), a CDR-L2 sequence comprising the amino acid sequence of DNNNKPP (SEQ ID NO: 11), and a CDR-L3 sequence comprising the amino acid sequence of ALYYGGQWV (SEQ ID NO: 15).

[0024] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain antibody that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16, and a light chain antibody that is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 23.

[0025] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a heavy chain antibody comprising the amino acid sequence of SEQ ID NO: 16, and a light chain antibody comprising the amino acid sequence of SEQ ID NO: 23.

[0026] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises a VH domain comprising a CDR-H1 sequence having the amino acid sequence of GFTFSNFGMH (SEQ ID NO: 1), a CDR-H2 sequence having the amino acid sequence of VIWSDETNR (SEQ ID NO: 2), and a CDR-H3 sequence having the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3), and a VL domain comprising a CDR-L1 sequence having the amino acid sequence of CASSTGTVTPSNYAN (SEQ ID NO: 4), a CDR-L2 sequence having the amino acid sequence of DNNSRPP (SEQ ID NO: 9), and a CDR-L3 sequence having the amino acid sequence of ALWFGNQWV (SEQ ID NO: 13).

[0027] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is a chimeric antibody or a humanized antibody or antigen-binding fragment thereof.

[0028] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof.

[0029] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof.

[0030] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is a multispecific antibody.

[0031] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof comprises one or more full-length antibody heavy chains comprising an Fc region.

[0032] In certain exemplary embodiments, the Fc region is a human IgG1 Fc region.

[0033] In certain exemplary embodiments, the Fc region is a human IgG4 Fc region.

[0034] In certain exemplary embodiments, provided herein is a pharmaceutical composition comprising the antibody or antigen-binding fragment of the present disclosure and a pharmaceutically acceptable carrier.

[0035] In certain exemplary embodiments, an isolated nucleic acid molecule encoding an antibody or an antigen-binding fragment thereof is provided herein.

[0036] In certain exemplary embodiments, an expression vector comprising a nucleic acid molecule is provided herein.

[0037] In certain exemplary embodiments, a host cell comprising a nucleic acid molecule is provided herein. In certain exemplary embodiments, a host cell comprising an expression vector is provided herein. In certain exemplary embodiments, a host cell that is a mammalian cell is provided herein.

[0038] In certain exemplary embodiments, a method for producing an antibody or an antigen-binding fragment thereof, comprising culturing a host cell under suitable conditions and recovering the antibody or an antigen-binding fragment thereof, is provided herein.

[0039] In certain exemplary embodiments, a method for treating or preventing a disease or disorder, comprising administering to a subject in need thereof a pharmaceutical composition provided herein, is provided herein.

[0040] In certain exemplary embodiments, a method for treating or preventing cancer, comprising administering to a subject in need thereof a pharmaceutical composition provided herein, is provided herein.

[0041] In certain exemplary embodiments, a method for treating or preventing a plasma cell disorder, comprising administering to a subject in need thereof a pharmaceutical composition provided herein, is provided herein.

[0042] In certain exemplary embodiments, a method for treating multiple myeloma in a subject, comprising administering to a subject in need thereof an antibody or an antigen-binding fragment thereof, is provided herein.

[0043] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is for use as a medicament.

[0044] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is for use in a method for the treatment or prevention of a disease or disorder.

[0045] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is for use in a method for the treatment or prevention of cancer.

[0046] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is for use in a method for the treatment or prevention of multiple myeloma.

[0047] In certain exemplary embodiments, the antibody or antigen-binding fragment thereof is for use in a method for the treatment or prevention of plasmacytic malignancies.

[0048] The foregoing summary of the present disclosure is non-limiting, and other features and advantages of the disclosed antigen-binding proteins and methods will be apparent from the following brief description of the drawings, the detailed description of the disclosure, and the claims.

[0049] The foregoing and other features and advantages of the invention will be more fully understood from the following detailed description of exemplary embodiments taken in conjunction with the accompanying drawings. This patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Patent Office upon request and payment of the necessary fee.

Brief Description of the Drawings

[0050]

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DETAILED DESCRIPTION OF THE INVENTION

[0051] Before describing the present disclosure, it should be understood that this disclosure is not limited to the specific methods and experimental conditions described, and such methods and conditions may change. Since the scope of the present disclosure is limited only by the appended claims, it should also be understood that the terms used herein are for the purpose of describing specific embodiments only and are not intended to be limiting.

[0052] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0053] Any methods and materials similar or equivalent to those described herein can be used in the practice of this disclosure, but exemplary methods and materials are described herein. All publications mentioned herein are hereby incorporated by reference in their entirety as if fully set forth herein.

[0054] As used herein, the term "BCMA" refers to B cell maturation antigen. BCMA (also known as TNFRSF17, BCM, or CD269) is a member of the tumor necrosis factor receptor (TNFR) family and is mainly expressed on terminally differentiated B cells, such as memory B cells and plasma cells. Its ligands are called B cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL) of the TNF family. BCMA is involved in mediating the survival of plasma cells for maintaining long-term humoral immunity. The BCMA gene is encoded on chromosome 16 and produces a 994-nucleotide primary mRNA transcript (NCBI accession NM_001192.2) encoding a 184-amino acid protein (NP_001183.2). A second antisense transcript derived from the BCMA locus has been described, which may play a role in regulating BCMA expression. (Laabi Y. et al., Nucleic Acids Res., 1994, 22:1147-1154). Additional transcript variants have been described with unknown significance (Smirnova A S et al. Mol Immunol., 2008, 45(4):1179-1183). A second isoform, also known as TV4, has been identified (Uniprot identifier Q02223-2). As used herein, "BCMA" includes mutations, such as point mutations, fragments, insertions, deletions of the full-length wild-type BCMA, and splice variants.

[0055] As used herein, the terms "antibody" or "antigen-binding protein" refer to immunoglobulin molecules that specifically bind to or are immunologically reactive with an antigen or epitope (e.g., the BCMA antigen or epitope), including both polyclonal and monoclonal antibodies, as well as functional antibody fragments thereof, which include, but are not limited to, fragment antigen-binding (Fab) fragments, F(ab’) 2 fragments, Fab’ fragments, Fv fragments, recombinant IgG (rIgG) fragments, single-chain variable fragments (scFv), and single-domain antibody (e.g., sdAb, sdFv, nanobody) fragments. The term "antibody" includes immunoglobulins in genetically engineered forms or modified forms by other means, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, meditope-enabled antibodies, heteroconjugate antibodies (e.g., bispecific antibodies, diabodies, triabodies, tetra-bodies, tandem di-scFv, tandem tri-scFv), and the like. Unless otherwise indicated, the term "antibody" should be understood to encompass its functional antibody fragments. As used herein, the term "functional antibody fragment" refers to an antibody fragment that has at least 80%, at least 85%, at least 90%, or at least 95% of the affinity of the antibody from which the fragment is derived.

[0056] As used herein, the terms "complementary determining region" or "CDR" refer to the amino acid sequences within the antibody variable regions that confer antigen specificity and binding affinity. Generally, each heavy-chain variable region has three CDRs (CDR-H1, CDR-H2, CDR-H3), and each light-chain variable region has three CDRs (CDR-L1, CDR-L2, CDR-L3). The "framework region" or "FR" is known in the art to refer to the non-CDR portions of the variable regions of the heavy and light chains. Generally, each heavy-chain variable region has four FRs (FR-H1, FR-H2, FR-H3, and FR-H4), and each light-chain variable region has four FRs (FR-L1, FR-L2, FR-L3, and FR-L4).

[0057] The exact amino acid sequence boundaries of a given CDR or FR can be readily determined using any of several well-known schemes, including those described by Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. ("Kabat" numbering scheme), Al-Lazikani et al. (1997) JMB 273, 927-948 ("Chothia" numbering scheme), MacCallum et al., J. Mol. Biol. 262:732-745 (1996), "Antibody-antigen interactions: Contact analysis and binding site topography," J. Mol. Biol. 262, 732-745. ("Contact" numbering scheme), Lefranc M P et al., "IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains," Dev Comp Immunol, 2003 January;27(1):55-77 ("IMGT" numbering scheme), and Honegger A and Pluckthun A, "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool," J Mol Biol, 2001 Jun. 8;309(3):657-70, (AHo numbering scheme).

[0058] The boundaries of a given CDR or FR can vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignment, and the Chothia scheme is based on structural information. The numbering of both the Kabat and Chothia schemes is based on the most common antibody region sequence lengths, accommodated by inserted characters, such as "30a", and deletions appear in some antibodies. The two schemes place specific insertions and deletions ("indels") at different positions, resulting in different numberings. The contact scheme is based on the analysis of complex crystal structures and is similar to the Chothia numbering scheme in many respects.

[0059] A given antibody or region thereof, such as the "CDR" or "complementary determining region" of its variable region, or an individual designated CDR (e.g., "CDR-H1", "CDR-H2", "CDR-H3"), should be understood to encompass the complementary determining region defined (or specified) by any of the known schemes. Similarly, a given antibody or region thereof, such as the "FR" or "framework region" of its variable region, or an individual designated FR (e.g., "FR-H1", "FR-H2"), should be understood to encompass the framework region defined (or specified) by any of the known schemes. In some examples, a scheme for the identification of a particular CDR or FR, such as the CDR defined by IMGT, Kabat, Chothia, AbM, or the contact method, is specified. In other cases, a particular amino acid sequence of the CDR or FR is given. Unless otherwise specified, all specific CDR amino acid sequences described in this disclosure are IMGT CDRs. However, alternative CDRs defined by other schemes, such as those determined by abYsis Key Annotation (Website: abysis.org / abysis / sequence_input / key_annotation / key_annotation.cgi), are also encompassed by this disclosure.

[0060] As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human mAbs of the disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by in vitro random or site-directed mutagenesis, or somatic mutations in vivo), such as in CDRs, particularly CDR3. However, the term "human antibody" as used herein is not intended to include mAbs in which CDR sequences derived from the germline of another mammalian species (e.g., mouse) are grafted onto human FR sequences. The term includes antibodies recombinantly produced in a non-human mammal or in cells of a non-human mammal. The term is not intended to include antibodies isolated from or generated in a human subject.

[0061] As used herein, the term "multispecific antigen-binding molecule" refers to bispecific, trispecific, or multispecific antigen-binding molecules, and antigen-binding fragments thereof. A multispecific antigen-binding molecule can be specific for different epitopes of one target polypeptide or can contain antigen-binding domains specific for epitopes of multiple target polypeptides. A multispecific antigen-binding molecule can be a single multifunctional polypeptide or can be a multimeric complex of two or more polypeptides that are covalently or noncovalently associated with each other. The term "multispecific antigen-binding molecule" includes antibodies of the present disclosure that can be linked to another functional molecule, such as another peptide or protein, or co-expressed with another functional molecule. For example, an antibody or fragment thereof can be functionally linked (e.g., by chemical conjugation, gene fusion, noncovalent association, or another method) to one or more other molecular entities, such as a protein or fragment thereof, to generate a bispecific or multispecific antigen-binding molecule having a second binding specificity. According to the present disclosure, the term "multispecific antigen-binding molecule" also includes bispecific, trispecific, or multispecific antibodies, or antigen-binding fragments thereof. In certain exemplary embodiments, an antibody of the present disclosure is functionally linked to another antibody or antigen-binding fragment thereof to generate a bispecific antibody having a second binding specificity.

[0062] As used herein, the terms "specifically binds", "specifically binding", "binding specificity", or "specifically recognized" refer to an antigen-binding protein or an antigen-binding fragment thereof that exhibits significant affinity for an antigen (e.g., the BCMA antigen) and does not exhibit significant cross-reactivity with targets that are not the BCMA protein. As used herein, the term "affinity" refers to the strength of the interaction between the antigen-binding site of an antigen-binding protein or an antigen-binding fragment thereof and the epitope to which it binds. In certain exemplary embodiments, affinity is measured by surface plasmon resonance (SPR), for example, on a Biacore instrument. As will be readily understood by those skilled in the art, antigen-binding protein affinity can be reported as the dissociation constant (KD) in molar concentration (M). The antigen-binding proteins or antigen-binding fragments thereof of the present disclosure have KD values in the range of about 10 -6 M to about 10 -12 M (i.e., the low micromolar to picomolar range), about 10 -7 M to 10 -11 M, about 10 -8 M to about 10 -10 M, about 10 -9 M. In certain embodiments, the antigen-binding protein or an antigen-binding fragment thereof has a binding affinity of about 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, or 10 -12 M. In certain embodiments, the antigen-binding protein or an antigen-binding fragment thereof has a binding affinity in the range of about 10 -7 M to about 10 -9 M (nanomolar range).

[0063] Specific binding can be determined according to means recognized in any art for determining such binding. In some embodiments, specific binding is determined by a competitive binding assay (e.g., ELISA) or a Biacore assay. In certain embodiments, the assay is performed at about 20 °C, 25 °C, 30 °C, or 37 °C.

[0064] As used herein, "administering" or "administration" refers to the act of injecting or otherwise physically delivering a substance that exists outside the body (e.g., an isolated binding polypeptide provided herein) to a patient by, but not limited to, the lung (e.g., inhalation), mucosa (e.g., intranasal), intradermal, intravenous, intramuscular delivery, and / or any other physical delivery method described herein or known in the art. When a disease or its symptoms are being managed or treated, administration of the substance is typically carried out after the onset of the disease or its symptoms. When a disease or its symptoms are being prevented, administration of the substance is typically carried out before the onset of the disease or its symptoms and may be continued chronically to delay or reduce the appearance or degree of disease-related symptoms.

[0065] As used herein, the term "composition" is intended to encompass a product that optionally contains specific components (e.g., an isolated binding polypeptide provided herein) in optionally more specific amounts, as well as any product that directly or indirectly results from an optionally more specific amount combination of specific components.

[0066] "Effective amount" means an amount of an active pharmaceutical agent (e.g., an isolated binding polypeptide of the present disclosure) sufficient to effect a desired physiological outcome in an individual in need of the agent. The effective amount can vary among individuals depending on the health and physical condition of the individual being treated, the taxonomic group of the individual being treated, the formulation of the composition, the assessment of the individual's disease state, and other relevant factors.

[0067] As used herein, the terms "subject" and "patient" are used interchangeably. As used herein, a subject can be a non - primate (e.g., cow, pig, horse, cat, dog, rat, etc.) or a primate (e.g., monkey and human). In certain embodiments, the term "subject" as used herein refers to a vertebrate such as a mammal. Mammals include, but are not limited to, humans, non - human primates, wildlife, farm animals, sport animals, and pets.

[0068] As used herein, the term "therapy" refers to any protocol, method, and / or agent that can be used for the prevention, management, treatment, and / or amelioration of a disease or a symptom associated therewith. In some embodiments, the term "therapy" refers to any protocol, method, and / or agent that can be used for the modulation of an immune response against an infection or a symptom associated therewith in a subject. In some embodiments, the terms "therapies" and "therapy" refer to biological therapies, supportive therapies, and / or other therapies known to those of skill in the art, such as medical practitioners, useful for the prevention, management, treatment, and / or amelioration of a disease or a symptom associated therewith. In other embodiments, the terms "therapies" and "therapy" refer to biological therapies, supportive therapies, and / or other therapies known to those of skill in the art, such as medical practitioners, useful for the modulation of an immune response against an infection or a symptom associated therewith in a subject.

[0069] As used herein, the terms "treat," "treatment," and "treating" refer to a decrease or improvement in the progression, severity, and / or duration of a disease or a symptom associated therewith resulting from the administration of one or more therapies (including, but not limited to, the administration of one or more prophylactic or therapeutic agents, such as the administration of the isolated binding polypeptides provided herein). The term "treating" as used herein can also refer to changing the course of a disease in a subject being treated. Therapeutic effects of treatment include, but are not limited to, prevention of the occurrence or recurrence of a disease, alleviation of symptoms, reduction of the direct or indirect pathological effects of a disease, reduction in the rate of disease progression, improvement or palliation of a disease state, and remission or improvement of prognosis.

[0070] The term "about" or "approximately" means within about 20% of a given value or range, such as within about 10% of, within about 5% of, or within about 1% of.

[0071] Anti-BCMA antibody In one aspect, the disclosure provides an antibody or an antigen-binding fragment thereof having binding specificity for BCMA.

[0072] Exemplary anti-BCMA antibodies or antigen-binding fragments thereof CDRs are listed in Table 1 below. Exemplary anti-BCMA antibodies or variable heavy (VH) and variable light (VL) domains of antigen-binding fragments thereof are listed in Table 2 below.

[0073] [Table 1]

[0074] [Table 2]

[0075] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSNFGMH (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of VIWSDETNR (SEQ ID NO: 2), and a CDR-H3 sequence comprising the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3), and a VL domain comprising a CDR-L1 sequence comprising the amino acid sequence of CX 1 SSTGX 2 VTPX 3 X 4 YAN (SEQ ID NO: 25) (where X 1 is R or A, X 2 is T or A, X 3 is S or G, X 4 is N or Y), a CDR-L2 sequence comprising the amino acid sequence of DNNX 5 X 6 PP (SEQ ID NO: 26) (where X 5 is S, I, or N, X 6 is R or K), and a CDR-L3 sequence comprising the amino acid sequence of ALX7X8GX9QWV (SEQ ID NO: 27) (where X 7 is W or Y, X 8 is F or Y, X 9 is N or G).

[0076] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSNFGMH (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of VIWSDETNR (SEQ ID NO: 2), and a CDR-H3 sequence comprising the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3), and a VL domain comprising a CDR-L1 sequence comprising the amino acid sequence of CASSTGTVTPSNYAN (SEQ ID NO: 4), CRSSTGTVTPSNYAN (SEQ ID NO: 5), CASSTGAVTPSNYAN (SEQ ID NO: 6), or CASSTGAVTPGYYAN (SEQ ID NO: 7), a CDR-L2 sequence comprising the amino acid sequence of DNNSRPP (SEQ ID NO: 9), DNNIKPP (SEQ ID NO: 10), or DNNNKPP (SEQ ID NO: 11), and a CDR-L3 sequence comprising the amino acid sequence of ALWFGNQWV (SEQ ID NO: 13), ALWYGGQWV (SEQ ID NO: 14), or ALYYGGQWV (SEQ ID NO: 15).

[0077] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSNFGMH (SEQ ID NO: 1), a CDR-H2 sequence comprising the amino acid sequence of VIWSDETNR (SEQ ID NO: 2), and a CDR-H3 sequence comprising the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3), and a VL domain comprising a CDR-L1 sequence comprising the amino acid sequence of CASSTGTVTPSNYAN (SEQ ID NO: 4), a CDR-L2 sequence comprising the amino acid sequence of DNNSRPP (SEQ ID NO: 9), and a CDR-L3 sequence comprising the amino acid sequence of ALWFGNQWV (SEQ ID NO: 13).

[0078] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH domain that is at least about 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more identical to the amino acid sequence of SEQ ID NO: 16, and a VL domain that is at least about 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more identical to the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO: 24.

[0079] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH domain that is at least about 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more identical to the amino acid sequence of SEQ ID NO: 16, and a VL domain that is at least about 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or more identical to the amino acid sequence of SEQ ID NO: 24.

[0080] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 16 and a VL domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 23, and SEQ ID NO: 24.

[0081] In certain exemplary embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises an antibody heavy chain comprising the amino acid sequence of SEQ ID NO: 16 and an antibody light chain comprising the amino acid sequence of SEQ ID NO: 2.

[0082] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is a chimeric antibody or a humanized antibody or antigen-binding fragment thereof. In certain embodiments, the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof.

[0083] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is a monoclonal antibody or antigen-binding fragment thereof.

[0084] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is an anti-BCMA antibody-drug conjugate.

[0085] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is a monospecific antibody.

[0086] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is a bispecific antibody.

[0087] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is a trispecific antibody.

[0088] In certain embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is a multispecific antibody.

[0089] Immune cell engager The anti-BCMA antigen-binding proteins of the present disclosure can exist in an immune cell-engaging format. An immune cell engager is an antigen-binding protein comprising at least one binding domain capable of binding to a cell surface protein of an immune cell and at least one binding domain for a distinct cell surface protein (e.g., a surface protein on a tumor cell such as BCMA). A binding domain specific for a cell surface protein of an immune cell can specifically recruit immune cells to the target tumor cells to be eliminated. Examples of immune cells that can be recruited include, but are not limited to, T cells, B cells, natural killer (NK) cells, natural killer T (NKT) cells, neutrophil cells, monocytes, and macrophages. Examples of surface proteins that can be used to recruit immune cells include, but are not limited to, CD3, TCRa, TCRp, CD16, NKG2D, CD89, CD64, and CD32a.

[0090] Expression of the antigen-binding protein In one aspect, polynucleotides encoding the binding proteins (e.g., antigen-binding proteins and antigen-binding fragments thereof) disclosed herein are provided. Also provided are methods of making binding proteins comprising expressing these polynucleotides.

[0091] The polynucleotides encoding the binding proteins disclosed herein are typically inserted into an expression vector for introduction into a host cell that can be used to produce the desired amount of the binding protein. Accordingly, in certain aspects, the present disclosure provides expression vectors comprising the polynucleotides disclosed herein and host cells comprising these vectors and polynucleotides.

[0092] The term "vector" or "expression vector" is used herein to mean a vector used in accordance with the present disclosure as a vehicle for introducing and expressing a desired gene in a cell. As is known to those skilled in the art, such vectors can be readily selected from the group consisting of plasmids, phages, viruses, and retroviruses. Generally, vectors compatible with the present disclosure include a selectable marker, appropriate restriction sites for facilitating cloning of the desired gene, and the ability to invade and / or replicate in eukaryotic or prokaryotic cells.

[0093] For the purposes of the present disclosure, a number of expression vector systems can be used. For example, one class of vectors utilizes DNA elements derived from animal viruses such as bovine papillomavirus, polyomavirus, adenovirus, vaccinia virus, baculovirus, retroviruses (RSV, MMTV or MOMLV), or SV40 virus. Others involve the use of polycistronic systems with internal ribosome binding sites. Additionally, cells in which the DNA has been integrated into the chromosome can be selected by introducing one or more markers that enable the selection of transfected host cells. The markers can provide prototrophy for auxotrophic hosts, biocide resistance (e.g., antibiotics), or resistance to heavy metals such as copper. The selectable marker gene can be introduced into the same cell either directly ligated to the DNA sequence to be expressed or by cotransformation. Additional elements may also be required for optimal synthesis of mRNA. These elements can include signal sequences, splice signals, and transcriptional promoters, enhancers, and termination signals. In some embodiments, the cloned variable region genes are inserted into an expression vector together with the heavy chain constant region gene and the light chain constant region gene (e.g., human constant region genes) synthesized as described above.

[0094] In other embodiments, the binding protein can be expressed using a polycistronic construct. In such an expression system, multiple gene products of interest, such as the heavy and light chains of an antibody, can be produced from a single polycistronic construct. These systems advantageously provide relatively high levels of polypeptide in eukaryotic host cells using an internal ribosome entry site (IRES). Suitable IRES sequences are described in U.S. Patent No. 6,193,980, which is hereby incorporated by reference in its entirety for all purposes. Those skilled in the art will understand that such expression systems can be used to effectively produce the full range of polypeptides disclosed herein for immediate application.

[0095] More generally, once a vector or DNA sequence encoding a binding protein, such as an antibody or fragment thereof, is prepared, the expression vector can be introduced into a suitable host cell. That is, the host cell can be transformed. Introduction of the plasmid into the host cell can be accomplished by a variety of techniques well known to those skilled in the art. These techniques include, but are not limited to, transfection (including electroporation and electrophoresis), protoplast fusion, calcium phosphate precipitation, cell fusion with enveloped DNA, microinjection, and infection with intact virus. See Ridgway, A.A.G., "Mammalian Expression Vectors," Chapter 24.2, pp. 470 - 472 in Vectors, Rodriguez and Denhardt, Eds. (Butterworths, Boston, Mass. 1988). Introduction of the plasmid into the host can be by electroporation. The transformed cells are cultured under conditions appropriate for production of the light and heavy chains and assayed for synthesis of the heavy chain protein and / or light chain protein. Exemplary assay techniques include enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA), fluorescence-activated cell sorter analysis (FACS), immunohistochemistry, and the like.

[0096] As used herein, the term "transformation" refers broadly to the introduction of DNA into a recipient host cell that changes the genotype. Along the same lines, "host cell" refers to a cell that has been constructed using recombinant DNA techniques and transformed with a vector encoding at least one heterologous gene. In the context of describing the process of isolating a polypeptide from a recombinant host, the terms "cell" and "cell culture" are used interchangeably to denote the source of the antibody, unless otherwise specified. In other words, the recovery of a polypeptide from a "cell" can mean from spin-down whole cells, from the supernatant of a lysed cell culture, or from a cell culture broth containing both the medium and the suspended cells.

[0097] In one embodiment, the host cell line used for antibody expression is of mammalian origin. One of ordinary skill in the art can determine the particular host cell line most suitable for the desired gene product to be expressed therein. Exemplary host cell lines include, but are not limited to, DG44 and DUXB11 (Chinese hamster ovary line, DHFR minus), HELA (human cervical carcinoma), CV-1 (monkey kidney line), COS (a derivative of CV-1 having SV40 T antigen), R1610 (Chinese hamster fibroblast), BALBC / 3T3 (mouse fibroblast), HEK (human kidney line), SP2 / O (mouse myeloma), BFA-1c1BPT (bovine endothelial cell), RAJI (human lymphocyte), 293 (human kidney). In one embodiment, the cell line provides altered glycosylation of the antibody expressed therefrom, e.g., afucosylation (e.g., PER.C6® (Crucell) or FUT8-knockout CHO cell line (POTELLIGENT® cell) (Biowa, Princeton, N.J.)). In one embodiment, NS0 cells can be used. CHO cells are particularly useful. Host cell lines are typically available from commercial services, e.g., American Tissue Culture Collection, or from the authors of public literature.

[0098] In vitro production enables scale-up for obtaining large amounts of the desired polypeptide. Techniques for culturing mammalian cells under tissue culture conditions are known in the art and include, for example, homogeneous suspension culture in an airlift reactor or a continuous stirred reactor, or, for example, culturing cells immobilized or trapped within hollow fibers, within microcapsules, on agarose microbeads, or on a ceramic cartridge. If necessary and / or desired, the polypeptide solution can be purified by conventional chromatography methods, such as gel filtration, ion exchange chromatography, chromatography on DEAE-cellulose, and / or (immuno)affinity chromatography.

[0099] The genes encoding the binding proteins featured in the present disclosure can be expressed in non-mammalian cells such as bacterial cells, yeast cells, or plant cells. In this context, it will be understood that various unicellular microorganisms other than mammals, such as bacteria, can also be transformed, i.e., these microorganisms can be grown by culture or fermentation. Bacteria capable of transformation include members of the Enterobacteriaceae such as strains of Escherichia coli or Salmonella, the Bacillaceae such as Bacillus subtilis, Pneumococcus, Streptococcus, and Haemophilus influenzae. Furthermore, it will be understood that when expressed in bacteria, the binding protein will be part of inclusion bodies. In some embodiments, the binding protein is then isolated, purified, and assembled into a functional molecule. In some embodiments, the binding proteins of the present disclosure are expressed in bacterial host cells. In some embodiments, the bacterial host cells are transformed with an expression vector containing a nucleic acid molecule encoding the binding protein of the present disclosure.

[0100] In addition to prokaryotes, eukaryotic microorganisms can also be used. Saccharomyces cerevisiae, or common baker's yeast, is the most commonly used among eukaryotic microorganisms, but many other strains are commonly available. In the case of expression in Saccharomyces, plasmid YRp7, for example (Stinchcomb et al., Nature, 282:39 (1979); Kingsman et al., Gene, 7:141 (1979); Tschemper et al., Gene, 10:157 (1980)) is commonly used. This plasmid already contains the TRP1 gene that provides a selectable marker for yeast mutant strains lacking the ability to grow on tryptophan, such as ATCC number 44076 or PEP4-1 (Jones, Genetics, 85:12 (1977)). Subsequently, the presence of the trpl lesion as a characteristic of the yeast host cell genome provides an effective environment for detecting transformation by growth in the absence of tryptophan.

[0101] Methods of administering antigen-binding proteins Methods for preparing and administering an antigen-binding protein (e.g., an anti-BCMA antibody or an antigen-binding fragment thereof disclosed herein) to a subject are well known to those skilled in the art or can be readily determined by those skilled in the art. The route of administration of the antigen-binding proteins of the present disclosure can be oral, parenteral, inhalation, or topical. As used herein, the term parenteral includes intravenous administration, intraarterial administration, intraperitoneal administration, intramuscular administration, subcutaneous administration, rectal administration, or vaginal administration. All of these administration forms are clearly contemplated within the scope of the present disclosure, but the administration form will be a liquid for injection, particularly a liquid for intravenous injection, intraarterial injection, or infusion. Usually, a suitable pharmaceutical composition for injection may contain a buffer (e.g., acetic acid, phosphate, or citrate buffer), a surfactant (e.g., polysorbate), and optionally a stabilizer (e.g., human albumin), etc. However, in other ways consistent with the teachings herein, the modified antibody can be delivered directly to the site of the harmful cell population, thereby increasing the exposure of the diseased tissue to the therapeutic agent.

[0102] Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions, or suspensions, including saline and buffered media. In the compositions and methods of the present disclosure, pharmaceutically acceptable carriers include, but are not limited to, 0.01-0.1 M or 0.05 M phosphate buffer, or 0.8% saline. Other common parenteral vehicles include sodium phosphate solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils. Intravenous vehicles include fluids and nutrient supplements, electrolyte supplements, for example, those based on Ringer's dextrose, etc. Preservatives and other additives such as, for example, antimicrobial agents, antioxidants, chelating agents, and inert gases may also be present. More specifically, pharmaceutical compositions suitable for injection include sterile aqueous solutions (water-soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In such cases, the composition must be sterile and must be fluid to the extent that it can be easily injected. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyols (for example, glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0103] Prevention of microbial activity can be achieved by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like. Isotonic agents such as sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride can also be included in the composition. Delaying agents such as aluminum monostearate and gelatin can be included in the composition to provide for long-term absorption of the injectable composition.

[0104] In any case, the sterile injectable solution can be prepared by incorporating the active compound (e.g., a conjugated polypeptide modified by a polypeptide alone or in combination with other active agents) in the required amounts in a suitable solvent, together with one or a combination of the ingredients enumerated herein, as required, followed by filtration sterilization. Generally, dispersions are prepared by incorporating the active compound in a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the methods of preparation typically include vacuum drying and freeze drying, whereby powders of the active ingredient and any additional desired ingredients are obtained from their previously sterile filtered solutions. Preparations for injection are processed to fill containers such as ampoules, bags, bottles, syringes, or vials and are sealed under sterile conditions according to methods known in the art. Further, the preparations can be packaged and sold in the form of kits such as those described in co-pending U.S. patent applications Ser. No. 09 / 259,337 and Ser. No. 09 / 259,338, each of which is incorporated herein by reference. Such manufactured products can include a label or package insert indicating that the associated composition is useful for treating subjects afflicted with or predisposed to an autoimmune disorder or a neoplastic disorder.

[0105] The effective dosage of the compositions of the present disclosure for the treatment of the above-described conditions varies depending on many different factors, including the means of administration, the target site, the physiological state of the patient, whether the patient is human or an animal, other pharmaceuticals being administered, and whether the treatment is prophylactic or therapeutic. Typically, the patient is human, although non-human mammals, including transgenic mammals, can also be treated. To optimize safety and efficacy, the therapeutic dosage can be titrated using conventional methods known to those of skill in the art.

[0106] In the case of passive immunization with an antigen-binding protein, the dosage can include, for example, about 0.0001 to 100 mg / kg of host body weight, more typically 0.01 to 5 mg / kg (e.g., 0.02 mg / kg, 0.25 mg / kg, 0.5 mg / kg, 0.75 mg / kg, 1 mg / kg, 2 mg / kg, etc.). For example, the dosage can be 1 mg / kg body weight or 10 mg / kg body weight, or within the range of 1 to 10 mg / kg, for example at least 1 mg / kg. Intermediate dosages within the above ranges are also considered to be within the scope of the present disclosure. Such dosages can be administered to the subject daily, every other day, weekly, or according to any other schedule determined by empirical analysis. Exemplary treatments involve administration in multiple doses over an extended period, for example, at least 6 months. Additional exemplary treatment regimens involve administration once every two weeks, once a month, or once every three to six months. Exemplary dosing schedules include 1 to 10 mg / kg or 15 mg / kg on consecutive days, 30 mg / kg every other day, or 60 mg / kg weekly. In some methods, two or more antigen-binding proteins having different binding specificities are administered simultaneously, in which case the dosage of each antigen-binding protein administered falls within the indicated range.

[0107] The antigen-binding proteins described herein can be administered on multiple occasions. The intervals between single doses may be weekly, monthly, or yearly. Also, the intervals may be irregular as directed by measuring the blood levels of the modified binding polypeptide or antigen in the patient. In some methods, the dosage is adjusted to achieve plasma modified antigen-binding protein concentrations of 1 - 1000 μg / ml and in some methods 25 - 300 μg / ml. Alternatively, the antigen-binding protein can be administered as a sustained release formulation, in which case it is necessary to administer it less frequently. For antigen-binding proteins, the dosage and frequency vary according to the half-life of the antigen-binding protein in the patient. Generally, humanized antibodies exhibit the longest half-life, followed by chimeric antibodies and non-human antibodies.

[0108] The dosage and frequency of administration can vary depending on whether the treatment is prophylactic or therapeutic. For prophylactic use, the composition containing the present antigen-binding protein or a cocktail thereof is administered to patients who are not already in a diseased state in order to enhance the patient's resistance. Such an amount is defined as a "prophylactically effective dose". In this use, the exact amount depends again on the patient's health status and general immunity, but generally ranges from 0.1 - 25 mg per dose, particularly 0.5 - 2.5 mg per dose. Over a long period, relatively low doses are administered at relatively low frequency intervals. Some patients continue treatment for the remainder of their lifespan. For therapeutic use, relatively high doses (e.g., an antibody of about 1 - 400 mg / kg per dose, a dosage of 5 - 25 mg is more commonly used for radioimmunoconjugates, and higher doses are used for cytotoxic-drug modified antibodies) may be required at relatively short intervals until the progression of the disease is reduced or terminated, or until the patient shows partial or complete improvement of the disease symptoms. Thereafter, a prophylactic regimen can be administered to the patient.

[0109] The antigen-binding proteins described herein can optionally be administered in combination with other agents that are effective in the treatment of disorders or conditions that require treatment (e.g., prophylactic or therapeutic). The present disclosure's90 The effective single therapeutic dosage (i.e., therapeutically effective amount) of the Y-labeled antibody ranges from about 5 to about 75 mCi, for example from about 10 to about 40 mCi. 131 The effective single therapeutic non-myeloablative dosage of the I-modified antibody ranges from about 5 to about 70 mCi, for example from about 5 to about 40 mCi. 131 The effective single therapeutic ablation dosage of the I-labeled antibody (i.e., which may require autologous bone marrow transplantation) ranges from about 30 to about 600 mCi, for example less than about 50 to about 500 mCi. In combination with chimeric antibodies, due to the long circulating half-life against mouse antibodies, 131 The effective single therapeutic non-myeloablative dosage of the I-labeled chimeric antibody ranges from about 5 to about 40 mCi, for example less than about 30 mCi. For example, 111 The imaging criterion for In label is typically less than about 5 mCi.

[0110] The antigen-binding protein can be administered as described immediately above, but in other embodiments, it must be emphasized that the antigen-binding protein can be administered to healthy patients in other ways as a first-line therapy. In such embodiments, the antigen-binding protein can be administered to patients with normal or average red marrow reserves and / or patients who have not received and are not receiving one or more other therapies. As used herein, the administration of a modified antibody or fragment thereof in combination with or in combination with an adjuvant therapy means the sequential, simultaneous, coexistent, parallel, coexistent, or concurrent administration or application of that therapy and the disclosed antibody. One of ordinary skill in the art will understand that the time of administration or application of the various components of the combined therapy regimen can be adjusted to enhance the overall effect of the treatment. One of ordinary skill in the art (e.g., an experienced oncology specialist) will be able to readily determine an effective combination therapy regimen without undue experimentation based on the selected adjuvant therapy and the teachings of this specification.

[0111] As previously discussed, the antigen-binding proteins, immunoreactive fragments or recombinants of the present disclosure can be administered in a pharmaceutically effective amount for the in vivo treatment of mammalian disorders. In this regard, it will be understood that the disclosed antigen-binding proteins are formulated to facilitate administration and promote the stability of the active agent.

[0112] The pharmaceutical compositions according to the present disclosure typically contain a pharmaceutically acceptable non-toxic sterile carrier such as physiological saline, non-toxic buffers, preservatives, etc. For the purposes of the present application, a pharmaceutically effective amount of a modified antigen-binding protein, immunoreactive fragment or recombinant thereof conjugated or non-conjugated to a therapeutic agent is maintained to achieve effective binding to the antigen and achieve a benefit, for example, to improve the symptoms of a disease or disorder or to detect a substance or cell. In the case of tumor cells, the modified binding polypeptide can typically interact with selected immunoreactive antigens on the tumor cells or immunoreactive cells, resulting in an increase in the death of those cells. Of course, the pharmaceutical compositions of the present disclosure can be administered in single or multiple doses to provide a pharmaceutically effective amount of the modified binding polypeptide.

[0113] Along the scope of the present disclosure, the antigen-binding proteins of the present disclosure can be administered to humans or other animals according to the aforementioned treatment methods in an amount sufficient to produce a therapeutic or prophylactic effect. The antigen-binding proteins of the present disclosure can be administered to such humans or other animals in conventional dosage forms prepared by combining the antibodies of the present disclosure with conventional pharmaceutically acceptable carriers or diluents according to known techniques. It will be recognized by those skilled in the art that the form and properties of the pharmaceutically acceptable carrier or diluent are determined by the amount of the active ingredient with which it is combined, the route of administration, and other well-known variables. Those skilled in the art will further understand that cocktails containing one or more of the binding polypeptides described in the present disclosure can be shown to be particularly effective.

[0114] The biological activity of the pharmaceutical composition as defined herein can be determined, for example, by a cytotoxicity assay as described in the following examples, WO 99 / 54440 pamphlet, or Schlereth et al. (Cancer Immunol. Immunother. 20 (2005), 1 - 12). As used herein, "efficacy" or "in vivo efficacy" refers to the response to therapy with the pharmaceutical composition of the present invention, for example, using standardized NCI response criteria. The success or in vivo efficacy of therapy using the pharmaceutical composition of the present invention refers to the efficacy of the composition for its intended purpose, i.e., the ability of the composition to cause its desired effect, i.e., depletion of pathological cells, such as tumor cells. In vivo efficacy can be monitored by established standard methods for each disease entity, including but not limited to white blood cell count, differential, fluorescence-activated cell sorting, bone marrow aspiration. In addition, various disease-specific clinical chemistry parameters and other established standard methods can be used. Furthermore, computerized tomography, X-ray, magnetic resonance imaging (e.g., for response evaluation based on the National Cancer Institute criteria [Cheson B D, Horning S J, Coiffier B, Shipp M A, Fisher R I, Connors J M, Lister T A, Vose J, Grillo-Lopez A, Hagenbeek A, Cabanillas F, Klippensten D, Hiddemann W, Castellino R, Harris N L, Armitage J O, Carter W, Hoppe R, Canellos G P. Report of an international workshop to standardize response criteria for non-Hodgkin's lymphoma. The NCI supported the International Working Group. J Clin Oncol. 1999 April;17(4):1244]), positron emission tomography scan, white blood cell count, differential, fluorescence-activated cell sorting, bone marrow aspiration, lymph node biopsy / tissue, and various lymphoma-specific clinical chemistry parameters (e.g., lactate dehydrogenase) and other established standard methods can be used.

Example

[0115] The following examples are set forth to provide a complete disclosure and description to those skilled in the art of how to make and use the methods and compositions embraced in the present invention and are not intended to limit the scope which the inventors regard as their invention. Efforts have been made to ensure the accuracy of the numerical values (e.g., amounts, temperatures, etc.) used, but some experimental errors and deviations should be accounted for. Unless otherwise indicated, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric pressure.

[0116] Example 1. Anti-BCMA Antibody Generation of Anti-Human BCMA Antibody A cohort of 15 eight-week-old female Trianni human Ig transgenic mice were implanted subcutaneously with estradiol pellets and injected with 100 μg of anti-mouse CD25 antibody 3 weeks later. One week later, all mice were primed with an intraperitoneal administration of approximately 5×10 6 (5 million) 300.19 cells overexpressing human BCMA in PBS without adjuvant. This was followed by three immunizations with the extracellular domain (ECD) of human BCMA conjugated to diphtheria toxin A (DTA) protein and two immunizations with the ECD of cynomolgus monkey conjugated to diphtheria toxin A (DTA) protein in Sigma adjuvant. To evaluate the immune response, anti-BCMA specific IgG titers in the blood were measured by ELISA after the last immunization using the human BCMA-ECD protein as the antigen. Mice expressing high anti-BCMA antibody titers (1:100,000 or higher) were selected for hybridoma generation. These mice were boosted with a combination of the ECD domains of human and cynomolgus monkey BCMA-DTA proteins in PBS without adjuvant 4 days prior to sacrificing the mice to harvest the spleens in preparation for fusion.

[0117] The process of hybridoma fusion and generation was performed according to the following established protocol (Yale J Biol Med, 1981, 54(5)387 - 402) and Gefter et al. (Somatic Cell Genet, 1977, 3(2)231 - 236). A single cell suspension of splenocytes was mixed with F0 myeloma cells at a ratio of 5:1 in 50 ml conical polypropylene tubes, and the cells were washed twice with serum - free IMDM. To this, 1 mL of polyethylene glycol 1500 (PEG) (Roche Applied Science, Indianapolis, IN) was pre - heated at 37°C and slowly added to the cell pellet over approximately 1 minute while gently rocking the tube. The cells were incubated in PEG for 1 minute, followed by the addition of 1 mL of serum - free IMDM dropped onto the pellet over 30 seconds, and then 9 mL of serum - free IMDM was added to the pellet for 1 minute. The tubes were centrifuged at 350×g for 10 minutes at room temperature and the supernatant was aspirated. The pellet was resuspended in IMDM (Hyclone) supplemented with 200 mL of filtered - complete hybridoma production medium, 10% FBS (HyClone), 1× non - essential amino acids (Gibco), 1 mM sodium pyruvate (Gibco), 1× penicillin - streptomycin (Gibco), hybridoma fusion and cloning factor (Roche), and 1× HAT (Sigma). The cells were transferred to T - 150 suspension cell flasks and stored in an incubator at 37°C, 7% CO 2 2.

[0118] The next day, the cells in the T - 150 flasks were centrifuged and the supernatant was removed. The cells were carefully transferred to hybridoma semi - solid selection and cloning medium (Molecular Devices) containing FITC - conjugated anti - mouse IgG (Molecular Devices). The cells were gently mixed and the semi - solid medium was seeded into six - well plates at 2 mL / well. These plates were incubated at 37°C, 7% CO 2Incubated with. After incubation for about 10 days, the hybridoma-secreted antibody reacts with FITC-conjugated anti-mouse IgG, creating a green halo surrounding the hybridoma. These hybridomas were detected by Clonepix (Molecular devices), and single colonies were picked into the wells of multiple 96-well plates. The 96-well plates containing the cloned hybridomas were incubated further at 37 °C, 7% CO 2 for an additional 10 days.

[0119] Anti-BCMA antibody sequence The heavy chain variable region is described as follows:

Chemical formula

[0120] The parental light chain variable region is described as follows:

Chemical formula

[0121] The light chain variable region of variant 1 is described as follows:

Chemical formula

[0122] The light chain variable region of Variant 2 is described as follows:

Chemical formula

[0123] The light chain variable region of Variant 3 is described as follows:

Chemical formula

[0124] The light chain variable region of Variant 4 is described as follows:

Chemical formula

[0125] The light chain variable region of Variant 5 is described as follows: [Chemical formula] The underlined residue sections are CDR1, 2, and 3. CDR-L1 is described as CASSTGAVTSGYYAN (SEQ ID NO: 8). CDR-L2 is described as DNNIKPS (SEQ ID NO: 12). CDR-L3 is described as ALYYGGQWV (SEQ ID NO: 15).

[0126] The light chain variable region of Variant 6 is described as follows: [Chemical formula] The underlined residue sections are CDR1, 2, and 3. CDR-L1 is described as CASSTGTVTPSNYAN (SEQ ID NO: 4). CDR-L2 is described as DNNSRPP (SEQ ID NO: 9). CDR-L3 is described as ALWFGNQWV (SEQ ID NO: 13).

[0127] The light chain variable region of Variant 7 is described as follows: [Chemical formula] The underlined residue sections are CDR1, 2, and 3. CDR-L1 is described as CASSTGTVTPSNYAN (SEQ ID NO: 4). CDR-L2 is described as DNNSRPP (SEQ ID NO: 9). CDR-L3 is described as ALWFGNQWV (SEQ ID NO: 13).

[0128] Example 2. Expression and Purification of Anti-BCMA Antibody Expi293F (trademark) cells were subcultured until the cell density reached about 3 - 5×10 6 viable cells / mL. The cells were then [2.5 - 3×10] 6Seeded at a final density of 6 viable cells / mL and then grown overnight. The cells were then diluted to a final density of 3×10

[0129] Plasmid DNA was diluted with OPTI-PLEX™ Complexation Buffer (or OPTI-MEM™ I Medium) to a total plasmid DNA concentration of approximately 1.0 μg / mL. EXPIFECTAMINE™ 293 Reagent was diluted with OPTI-PLEX™ Complexation Buffer (or OPTI-MEM™ I Medium). Both solutions were incubated at room temperature for 5 minutes. The diluted EXPIFECTAMINE™ 293 Reagent was added to the diluted plasmid DNA, the solution was mixed, and the solution containing the EXPIFECTAMINE™ 293 / Plasmid DNA complex was incubated at room temperature for 10 - 20 minutes. The complex was gently transferred to Expi293F™ cells while gently swirling during addition, and then the cells were incubated in a 37°C incubator with a relative humidity of 80% or more and 8% CO 2 in an orbital shaker.

[0130] EXPIFECTAMINE™ 293 Transfection Enhancer 1 and EXPIFECTAMINE™ 293 Transfection Enhancer 2 were added to the transfection flask approximately 18 - 22 hours after transfection while gently swirling the flask during addition, and then the flask was immediately returned to the 37°C incubator on an orbital shaker platform with a relative humidity of 80% or more and 8% CO 2 in it.

[0131] The protein-containing culture supernatant was harvested between approximately 5 - 7 days after transfection.

[0132] Purification The antibody was purified using an mAb Select Sure column (GE number 11-0034-95, 16 mm × 25 mm). Before loading onto the column, the antibody solution was filtered through a 0.2 μm PES filter unit to remove any particles. The following buffers were used during purification: Buffer A: 0.2 M NaOH; Buffer B: 20 mM sodium phosphate, 150 mM NaCl pH 7.2 (or PBS 1X); Buffer C: 50 mM sodium citrate (dihydrate), pH 3.5; Buffer D: 50 mM succinic acid; and Buffer E: 20% ethanol. The antibody was purified using the following protocol: 1) The mAb Select Sure column was sanitized with 6 column volumes (CV) of Buffer A for a contact time of 15 minutes (15 minutes at 2 mL / min); 2) The column was rinsed with 5 CV of MilliQ water; 3) The column was equilibrated with 15 CV of Buffer B. Before loading the antibody, 0.5 mL of conditioned media was collected and stored; 4) The antibody was loaded onto the column; 5) The column was washed with 6 CV of Buffer B; 6) The antibody was eluted using 6 CV of Buffer C, and the eluate was neutralized with 1 / 10 volume of 600 mM dibasic sodium phosphate or Tris pH 10; 7) The column was stripped using 6 CV of Buffer D and neutralized by adding 1 / 10 volume of 600 mM sodium phosphate or Tris pH 10; 8) The column was cleaned using 10 CV of Buffer A; 9) The column was rinsed with 5 CV of MilliQ water; 10) The column was re-equilibrated with 10 CV of Buffer V; 11) The column was washed with 10 CV of Buffer E and stored at 4°C.

[0133] The volume of the eluate was reduced to approximately 0.5 mL - 2 mL using an MWCO Millipore concentrator: a) Approximately 2 mL of DPBS was added to the concentrator to wet the membrane, and the concentrator was centrifuged for approximately 1 minute, and the liquid was discarded; b) The eluate was added to the concentrator and centrifuged to pass the liquid through the membrane. This was repeated to reduce the volume to approximately 0.5 mL - 2 mL.

[0134] The buffer exchange into DPBS was carried out using a GE PD-10 column or a THERMO SCIENTIFIC™ ZEBA™ column: a) the column was cut diagonally to allow better dripping, the cap was removed and the liquid was drained; b) DPBS (5 mL) was added to the column and this was repeated a total of 4 times through the column; c) the entire concentrated sample was loaded into the column by filter sterilization and flushed through. The bottom of the MWCO filter was rinsed and any excess antibody was collected; d) DPBS was added to bring the volume up to 2 mL and the column was completely loaded; e) a 15 mL conical tube was placed under the column and 4 mL DPBS was added to the column for elution. The eluate was concentrated using an MWCO Millipore concentrator and the concentration of the antibody was determined using a NANODROP™ UV-Vis spectrophotometer.

[0135] Example 3. Cross-reactivity of the Clone CA10 variant against human and cynomolgus BCMA proteins A solution of BCMA antigen (biotinylated BCMA antigen at 2 μg / mL or 1 mg / mL when using streptavidin-coated plates) was prepared in phosphate-buffered saline (PBS). The antigen solution was added to a 96-well plate (50 μL / well) and incubated overnight at 4°C. The plate was blocked with PBSA (PBS containing 1% BSA) at 250 μL / well for 2 hours at 37°C and then washed three times with 200 μL / well of phosphate-buffered saline (PBS). Hybridoma supernatant (50 μL) or purified test or control (positive and negative) antibody at 1 mg / mL (50 μL) was added per well in a 96-well plate and incubated for 1 hour at room temperature. The plate was washed three times with 200 μL / well of PBS and then a goat anti-mouse peroxidase (HRP) conjugated secondary antibody diluted 1:5,000 in PBSA (50 μL / well) was added and incubated for 1 hour at room temperature. The plate was then washed three times with 200 μL / well of PBS. Tetramethylbenzidine dihydrochloride (TMB) substrate was prepared by mixing both solution A and solution B (1:1) in a 15 mL conical tube and then 50 μL of the substrate was added to the wells. The color was developed for 1 - 5 minutes and then 50 μL of stop solution was added to each well. Absorbance was read using a SpectraMax (Molecular Devices) at 450 nm.

[0136] Among the antibody clones showing BCMA-specific binding, clone CA10_parent (CA10_V2_parent) showed strong binding (Figure 3). Variants 1 - 4, variant 6, and variant 7 all had binding similar to that of the parental antibody. However, variant 5 (CA10_PE_V5) lost binding compared to the other variants (Figure 3).

[0137] Example 4. Binding of anti-BCMA mAb antibody to BCMA protein on the surface of HEK or MM1R cells Cell staining for flow cytometry HEK 293 cells or MM1R cells (0.5×10 6) was aliquoted into separate FACS tubes and labeled as unstained, test samples or positive controls. Hybridoma supernatant (20 μL) or purified CA10 or positive control (1 μg / mL, 5 μL) was added to the cells and incubated on ice for 30 minutes. Cells were washed by adding 3 mL of 1XPBX / 5% FBS (FACS buffer) and centrifuged at 1500 rpm for 5 - 7 minutes (450 xg). The supernatant was poured off and the cells were gently vortexed to mix. 50 μL of a 1:500 dilution of FITC-conjugated goat anti-human (or mouse) H+L specific secondary antibody was added to the cells and the cells were incubated at 4°C for 30 minutes on ice or in the dark. FACS buffer (3 mL) was added and the cells were washed at 1500 rpm for 5 - 7 minutes. The supernatant was discarded and the cells were resuspended in 150 - 200 μL of FACS buffer. Cells were acquired on a BD FACS Canto and data were analyzed using Flojo V10 software.

[0138] Variants 1 - 4, Variant 6, and Variant 7 all had binding to BCMA protein similar to that of the CA10_parent (CA10_V2_parent) antibody in both HEK293 cells and MM1R cells (Figures 4 and 5A - 5B). Variant 5 did not show binding to BCMA protein on HEK293 cells and MM1R cells.

[0139] Example 5. Antibody and antigen protein interactions and affinity constants determined by surface plasmon resonance measurements 1X HBS-EP+ was prepared in MilliQ water, filtered, and degassed. BIACORE™ T100 was primed with 1X HBS-EP+. Immobilized chip Protein A CM was used with the BIACORE™ control software.

[0140] The antibody was diluted to 20 μg / mL in HBS-EP+. Seven 1:1 serial dilutions of the antigen (final concentration 80 nM) were prepared, and 1X HBS-EP+ was used as the 0 nM control. 1X HBS-EP+ was used for the injection start, and HCl (12 mM) was used for regeneration. Samples were run and the data were analyzed using BIACORE™ T100 software.

[0141]

Table 3

[0142]

Table 4

[0143] Calculations used in the preparation of the antigen dilutions:

Number

[0144]

Table 5

[0145] Calculations used in the preparation of the antibody dilutions:

Number

[0146] Variants 1, 2, 6, and 7 showed similar affinities to the CA10_parent (CA10 WT) antibody for both human BCMA protein and cynomolgus monkey BCMA protein (Figures 6-9). Variant 3 showed a similar affinity to the parental antibody for human BCMA protein but a low affinity for cellular BCMA. Both variants 4 and 5 lost their affinities for human BCMA protein and canino BCMA protein.

Claims

1. An antibody or antigen-binding fragment thereof that specifically binds to B cell maturation antigen (BCMA), comprising an antibody heavy chain variable (VH) domain and an antibody light chain variable (VL) domain, The aforementioned VH domain, CDR-H1 sequence containing the amino acid sequence of GFTFFSNFGMH (SEQ ID NO: 1); The CDR-H2 sequence containing the amino acid sequence of VIWSDETNR (SEQ ID NO: 2); and The CDR-H3 sequence includes the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3); The aforementioned VL domain, CX 1 SSTGX 2 VTPX 3 X 4 YAN (Sequence No. 25) (where X 1 is R or A, X 2 is T or A, X 3 is S or G, X 4 The CDR-L1 sequence contains the amino acid sequence of N or Y; DNNX 5 X 6 PP (SEQ ID NO: 26) (where X 5 is S, I, or N, and X 6 is R or K) amino acid sequence-containing CDR-L2 sequence; and ALX 7 X 8 GX 9 QWV (Sequence No. 27) (where X 7 is W or Y, and X 8 is F or Y, and X 9 An antibody or its antigen-binding fragment comprising a CDR-L3 sequence containing an amino acid sequence (which is N or G).

2. The aforementioned VH domain, CDR-H1 sequence containing the amino acid sequence of GFTFFSNFGMH (SEQ ID NO: 1); The CDR-H2 sequence containing the amino acid sequence of VIWSDETNR (SEQ ID NO: 2); and The CDR-H3 sequence includes the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3); The aforementioned VL domain, CDR-L1 sequences containing the amino acid sequences of CASSTGTVTPSNYAN (SEQ ID NO: 4), CRSSTGTVTPSNYAN (SEQ ID NO: 5), CASSTGAVTPSNYAN (SEQ ID NO: 6), or CASSTGAVTPGYYAN (SEQ ID NO: 7); CDR-L2 sequences containing the amino acid sequences of DNNSRPP (SEQ ID NO: 9), DNNIKPP (SEQ ID NO: 10), or DNNNNKPP (SEQ ID NO: 11); and ALWFGNQWV (SEQ ID NO: 13), ALWYGGQWV (SEQ ID NO: 14), or ALY The antibody or antigen-binding fragment thereof according to claim 1, comprising a CDR-L3 sequence containing the amino acid sequence of YGGQWV (SEQ ID NO: 15).

3. The VH domain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16; The VL domain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 23, or SEQ ID NO:

24. Optionally, The VH domain comprises the amino acid sequence of SEQ ID NO: 16; The antibody or antigen-binding fragment thereof according to claim 1, wherein the VL domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 23, and SEQ ID NO:

24.

4. The antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 16; The antibody or antigen-binding fragment thereof according to claim 3, wherein the antibody light chain comprises the amino acid sequence of SEQ ID NO:

24.

5. The aforementioned VH domain, CDR-H1 sequence containing the amino acid sequence of GFTFFSNFGMH (SEQ ID NO: 1); The CDR-H2 sequence containing the amino acid sequence of VIWSDETNR (SEQ ID NO: 2); and The CDR-H3 sequence includes the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3); The aforementioned VL domain, CDR-L1 sequence containing the amino acid sequence of CASSTGTVTPSNYAN (SEQ ID NO: 4); The CDR-L2 sequence containing the amino acid sequence of DNNSRPP (SEQ ID NO: 9); and The antibody or antigen-binding fragment thereof according to claim 1, comprising a CDR-L3 sequence containing the amino acid sequence of ALWFGNQWV (SEQ ID NO: 13).

6. The antibody heavy chain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16; The antibody light chain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO:

18. Optionally, The antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 16; The antibody or antigen-binding fragment thereof according to claim 5, wherein the antibody light chain comprises the amino acid sequence of SEQ ID NO:

18.

7. The aforementioned VH domain, CDR-H1 sequence containing the amino acid sequence of GFTFFSNFGMH (SEQ ID NO: 1); The CDR-H2 sequence containing the amino acid sequence of VIWSDETNR (SEQ ID NO: 2); and The CDR-H3 sequence includes the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3); The aforementioned VL domain, CDR-L1 sequence containing the amino acid sequence of CRSSTGTVTPSNYAN (SEQ ID NO: 5); The CDR-L2 sequence containing the amino acid sequence of DNNSRPP (SEQ ID NO: 9); and The antibody or antigen-binding fragment thereof according to claim 1, comprising a CDR-L3 sequence containing the amino acid sequence of ALWFGNQWV (SEQ ID NO: 13).

8. The antibody heavy chain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16; The antibody or antigen-binding fragment thereof according to claim 7, wherein the antibody light chain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO:

19.

9. The aforementioned VH domain, CDR-H1 sequence containing the amino acid sequence of GFTFFSNFGMH (SEQ ID NO: 1); The CDR-H2 sequence containing the amino acid sequence of VIWSDETNR (SEQ ID NO: 2); and The CDR-H3 sequence includes the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3); The aforementioned VL domain, CDR-L1 sequence containing the amino acid sequence of CASSTGTVTPSNYAN (SEQ ID NO: 4); The CDR-L2 sequence containing the amino acid sequence of DNNSRPP (SEQ ID NO: 9); and The antibody or antigen-binding fragment thereof according to claim 1, comprising a CDR-L3 sequence containing the amino acid sequence of ALWFGNQWV (SEQ ID NO: 13).

10. The antibody heavy chain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16; The antibody or antigen-binding fragment thereof according to claim 9, wherein the antibody light chain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO:

20.

11. The aforementioned VH domain, CDR-H1 sequence containing the amino acid sequence of GFTFFSNFGMH (SEQ ID NO: 1); The CDR-H2 sequence containing the amino acid sequence of VIWSDETNR (SEQ ID NO: 2); and The CDR-H3 sequence includes the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3); The aforementioned VL domain, CDR-L1 sequence containing the amino acid sequence of CASSTGAVTPSNYAN (SEQ ID NO: 6); CDR-L2 sequence containing the amino acid sequence of DNNIKPP (SEQ ID NO: 10); and The antibody or antigen-binding fragment thereof according to claim 1, comprising a CDR-L3 sequence containing the amino acid sequence of ALWYGGQWV (SEQ ID NO: 14).

12. The antibody heavy chain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16; The antibody or antigen-binding fragment according to claim 11, wherein the antibody light chain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO:

21.

13. The aforementioned VH domain, CDR-H1 sequence containing the amino acid sequence of GFTFFSNFGMH (SEQ ID NO: 1); The CDR-H2 sequence containing the amino acid sequence of VIWSDETNR (SEQ ID NO: 2); and The CDR-H3 sequence includes the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3); The aforementioned VL domain, CDR-L1 sequence containing the amino acid sequence CASSTGAVTPGYYAN (SEQ ID NO: 7); CDR-L2 sequence containing the amino acid sequence DNNNKPP (SEQ ID NO: 11); and The antibody or antigen-binding fragment thereof according to claim 1, comprising a CDR-L3 sequence containing the amino acid sequence ALYYGGQWV (SEQ ID NO: 15).

14. The antibody heavy chain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO: 16; The antibody or antigen-binding fragment according to claim 13, wherein the antibody light chain is at least about 90% identical or at least 95% identical to the amino acid sequence of SEQ ID NO:

23.

15. The aforementioned VH domain, CDR-H1 sequence containing the amino acid sequence of GFTFFSNFGMH (SEQ ID NO: 1); The CDR-H2 sequence containing the amino acid sequence of VIWSDETNR (SEQ ID NO: 2); and The CDR-H3 sequence includes the amino acid sequence of DQQYCSSDSCFTWFDP (SEQ ID NO: 3); The aforementioned VL domain, CDR-L1 sequence containing the amino acid sequence of CASSTGTVTPSNYAN (SEQ ID NO: 4); The CDR-L2 sequence containing the amino acid sequence of DNNSRPP (SEQ ID NO: 9); and The antibody or antigen-binding fragment thereof according to claim 1, comprising a CDR-L3 sequence containing the amino acid sequence of ALWFGNQWV (SEQ ID NO: 13).

16. The antibody or its antigen-binding fragment is a chimeric antibody or a humanized antibody or its antigen-binding fragment, or The antibody or antigen-binding fragment according to claim 1, wherein the antibody or antigen-binding fragment thereof is a human antibody or antigen-binding fragment thereof.

17. The antibody or antigen-binding fragment according to claim 1, wherein the antibody or antigen-binding fragment thereof is a multispecific antibody.

18. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 17, for use as a pharmaceutical product.

19. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 17, for use in a method for treating or preventing a disease or disorder.

20. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 17, for use in a method for treating or preventing cancer.

21. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 17, for use in a method for the treatment or prevention of multiple myeloma.

22. An antibody or antigen-binding fragment thereof according to any one of claims 1 to 17, for use in a method for the treatment or prevention of plasma cell malignancies.

23. A pharmaceutical composition comprising an antibody or an antigen-binding fragment thereof according to any one of claims 1 to 17.

24. An isolated nucleic acid molecule comprising a nucleotide sequence encoding the binding protein according to any one of claims 1 to 17.

25. An expression vector comprising the nucleic acid molecule described in claim 24.

26. A host cell comprising the nucleic acid molecule described in claim 24.

27. A host cell comprising the expression vector described in claim 25.

28. The host cell according to claim 27, wherein the cell is a mammalian cell.

29. A method for producing an antibody or antigen-binding fragment thereof according to any one of claims 1 to 17, comprising culturing a host cell according to any one of claims 26 to 28 under suitable conditions, and recovering the antibody or antigen-binding fragment thereof.

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