WO2023019398A1 - Anticorps ciblant bcma, récepteurs antigéniques chimériques et leurs utilisations - Google Patents

Anticorps ciblant bcma, récepteurs antigéniques chimériques et leurs utilisations Download PDF

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WO2023019398A1
WO2023019398A1 PCT/CN2021/112798 CN2021112798W WO2023019398A1 WO 2023019398 A1 WO2023019398 A1 WO 2023019398A1 CN 2021112798 W CN2021112798 W CN 2021112798W WO 2023019398 A1 WO2023019398 A1 WO 2023019398A1
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seq
amino acid
nos
antigen
cdr3
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PCT/CN2021/112798
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English (en)
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Yangbing Zhao
Wei Pan
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Utc Therapeutics (Shanghai) Co., Ltd.
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Priority to PCT/CN2021/112798 priority Critical patent/WO2023019398A1/fr
Priority to CN202180005555.3A priority patent/CN116745325A/zh
Publication of WO2023019398A1 publication Critical patent/WO2023019398A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/461—Cellular immunotherapy characterised by the cell type used
    • A61K39/4611—T-cells, e.g. tumor infiltrating lymphocytes [TIL], lymphokine-activated killer cells [LAK] or regulatory T cells [Treg]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/463—Cellular immunotherapy characterised by recombinant expression
    • A61K39/4631—Chimeric Antigen Receptors [CAR]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • A61K39/464411—Immunoglobulin superfamily
    • A61K39/464412—CD19 or B4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/46—Cellular immunotherapy
    • A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
    • A61K39/4643—Vertebrate antigens
    • A61K39/4644—Cancer antigens
    • A61K39/464402—Receptors, cell surface antigens or cell surface determinants
    • A61K39/464416—Receptors for cytokines
    • A61K39/464417—Receptors for tumor necrosis factors [TNF], e.g. lymphotoxin receptor [LTR], CD30
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
    • C12N5/06—Animal cells or tissues; Human cells or tissues
    • C12N5/0602—Vertebrate cells
    • C12N5/0634—Cells from the blood or the immune system
    • C12N5/0636—T lymphocytes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2510/00—Genetically modified cells

Definitions

  • the present invention relates to molecular biology, cell biology, and immuno-oncology.
  • provided herein include anti-BCMA antibodies, chimeric antigen receptors (CARs) comprising such anti-BCMA antibodies ( “BCMA CARs” ) , genetically engineered immune effector cells expressing such BCMA CARs, and uses thereof in treating tumors or cancers.
  • CARs chimeric antigen receptors
  • BCMA CARs chimeric antigen receptors
  • BCMA CARs genetically engineered immune effector cells expressing such BCMA CARs
  • BCMA B-cell maturation antigen
  • CARs BCMA-binding chimeric antigen receptors
  • antibodies or antigen-binding fragments thereof that specifically binds BCMA comprising: (a) a light chain variable region (VL) comprising (1) a light chain CDR1 (VL CDR1) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-10; (2) a light chain CDR2 (VL CDR2) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-21; and (3) a light chain CDR3 (VL CDR3) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-32; or a variant thereof having up to about 5 amino acid substitutions, additions, and/or deletions in the VL CDRs; and/or (b) a heavy chain variable region (VH) comprising (1) a heavy chain CDR1 (VH CDR1) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 33-43; (2) a heavy chain CDR2 (VH
  • the VL CDR1, CDR2 and CDR3 have (1) the amino acid sequences of SEQ ID NOs: 1, 11, and 22, respectively; (2) the amino acid sequences of SEQ ID NOs: 2, 12, and 23, respectively; (3) the amino acid sequences of SEQ ID NOs: 3, 13, and 24, respectively; (4) the amino acid sequences of SEQ ID NOs: 4, 14, and 24, respectively; (5) the amino acid sequences of SEQ ID NOs: 5, 15, and 25, respectively; (6) the amino acid sequences of SEQ ID NOs: 6, 16, and 26, respectively; (7) the amino acid sequences of SEQ ID NOs: 7, 17, and 27, respectively; (8) the amino acid sequences of SEQ ID NOs: 8, 18, and 28, respectively; (9) the amino acid sequences of SEQ ID NOs: 2, 19, and 29, respectively; (10) the amino acid sequences of SEQ ID NOs: 2, 20, and 30, respectively; (11) the amino acid sequences of SEQ ID NOs: 9, 21, and 31, respectively; or (12
  • the VL CDR1, CDR2, and CDR3 have the amino acid sequences of SEQ ID NOs: 1, 11, and 22, respectively; and/or the VH CDR1, CDR2, and CDR3 have the amino acid sequences of SEQ ID NOs: 33, 44, and 56, respectively; (2) the VL CDR1, CDR2, and CDR3 have the amino acid sequences of SEQ ID NOs: 2, 12, and 23, respectively; and/or the VH CDR1, CDR2, and CDR3 have the amino acid sequences of SEQ ID NOs: 34, 45, and 57, respectively; (3) the VL CDR1, CDR2, and CDR3 have the amino acid sequences of SEQ ID NOs: 3, 13, and 24, respectively; and/or the VH CDR1, CDR2, and CDR3 have the amino acid sequences of SEQ ID NOs: 35, 46, and 58, respectively; (4) the VL CDR1, CDR2, and CDR3 have the amino acid sequences of
  • the antibodies and antigen-binding fragments provided herein comprise a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2 and a VH CDR3, wherein (a) the VL CDR1, CDR2 and CDR3 have the amino acid sequences of SEQ ID NOs: 4, 14, and 24, respectively; and (b) the VH CDR1, CDR2 and CDR3 have the amino acid sequences of SEQ ID NOs: 36, 47, and 59, respectively.
  • the antibodies and antigen-binding fragments provided herein comprise a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2 and a VH CDR3, wherein (a) the VL CDR1, CDR2 and CDR3 have the amino acid sequences of SEQ ID NOs: 8, 18, and 28, respectively; and (b) the VH CDR1, CDR2 and CDR3 have the amino acid sequences of SEQ ID NOs: 39, 51, and 63, respectively.
  • the antibodies and antigen-binding fragments provided herein comprise a VL CDR1, a VL CDR2, a VL CDR3, a VH CDR1, a VH CDR2 and a VH CDR3, wherein (a) the VL CDR1, CDR2 and CDR3 have the amino acid sequences of SEQ ID NOs: 2, 20, and 30, respectively; and (b) the VH CDR1, CDR2 and CDR3 have the amino acid sequences of SEQ ID NOs: 41, 53, and 65, respectively.
  • antibodies or antigen-binding fragments thereof that specifically binds BCMA e.g., human BCMA
  • BCMA e.g., human BCMA
  • the antibodies and antigen-binding fragments provided herein comprise a VL and a VH, wherein the VL and VH have (1) the amino acid sequences of SEQ ID NOs: 68 and 80, respectively; (2) the amino acid sequences of SEQ ID NOs: 69 and 81, respectively; (3) the amino acid sequences of SEQ ID NOs: 70 and 82, respectively; (4) the amino acid sequences of SEQ ID NOs: 71 and 83, respectively; (5) the amino acid sequences of SEQ ID NOs: 72 and 84, respectively; (6) the amino acid sequences of SEQ ID NOs: 73 and 85, respectively; (7) the amino acid sequences of SEQ ID NOs: 74 and 86, respectively; (8) the amino acid sequences of SEQ ID NOs: 75 and 87, respectively; (9) the amino acid sequences of SEQ ID NOs: 76 and 88, respectively; (10) the amino acid sequences of SEQ ID NOs: 77 and 89, respectively; (11) the amino acid sequences of S
  • the antibodies and antigen-binding fragments provided herein comprise a VL and a VH, wherein the VL and VH have the amino acid sequences of SEQ ID NOs: 71 and 83, respectively. In some embodiments, the antibodies and antigen-binding fragments provided herein comprise a VL and a VH, wherein the VL and VH have the amino acid sequences of SEQ ID NOs: 75 and 87, respectively. In some embodiments, the antibodies and antigen-binding fragments provided herein comprise a VL and a VH, wherein the VL and VH have the amino acid sequences of SEQ ID NOs: 77 and 89, respectively.
  • antibodies or antigen-binding fragments thereof that specifically binds BCMA e.g., human BCMA
  • BCMA e.g., human BCMA
  • the antibodies and antigen-binding fragments provided herein comprise (1) a VL comprising VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 68, and/or a VH comprising VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 80; (2) a VL comprising VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 69, and/or a VH comprising VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 81; (3) a VL comprising VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 70, and/or a VH comprising VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 82; (4) a VL comprising
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 71
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 83
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 75
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 87.
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 77
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 89.
  • antibodies or antigen-binding fragments that compete with an antibody or antigen-binding fragment described herein for binding to BCMA.
  • the antibody or antigen-binding fragment provided herein is a monoclonal antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment provided herein is a bispecific or multispecific antibody. In some embodiments, the antibody provided herein is a Bi-specific T-cell engager (BiTE) . In some embodiments, the antibody provided herein is selected from the group consisting of an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody.
  • the antibody or antigen-binding fragment provided herein is selected from the group consisting of a Fab, a Fab’ , a F (ab’) 2, a Fv, a scFv, a (scFv) 2, a single domain antibody (sdAb) , and a heavy chain antibody (HCAb) .
  • the antibody or antigen-binding fragment provided herein is a scFv.
  • the antibody or antigen-binding fragment provided herein is a chimeric antibody or antigen-binding fragment, a humanized antibody or antigen-binding fragment, or a human antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment provided herein is a human antibody or antigen-binding fragment.
  • polynucleotides encoding the antibody or antigen-binding fragment described herein.
  • the polynucleotide is a messenger RNA (mRNA) .
  • mRNA messenger RNA
  • vectors comprising the polynucleotide described herein.
  • host cells comprising the polynucleotide described herein or vectors described herein.
  • Chimeric Antigen Receptors that specifically bind BCMA, comprising, from N-terminus to C-terminus: (a) a BCMA-binding domain that comprises an antibody or antigen-binding fragment described herein; (b) a transmembrane domain; and (c) a cytoplasmic domain.
  • the transmembrane domain is derived from CD8, CD28, CD3 ⁇ , CD4, 4-1BB, OX40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, BTLA, TCR ⁇ chain, TCR ⁇ chain, or TCR ⁇ chain, CD3 ⁇ , CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, or CD154.
  • the transmembrane domain comprises CD8 transmembrane region or CD28 transmembrane region.
  • the cytoplasmic domain comprises a signaling domain derived from CD3 ⁇ , FcR ⁇ , Fc ⁇ RIIa, FcR ⁇ , CD3 ⁇ , CD3 ⁇ , CD5, CD22, CD79a, CD79b, DAP10, DAP12, or any combination thereof.
  • the cytoplasmic domain further comprises a co-stimulatory domain derived from CD28, 4-1BB (CD137) , OX40, ICOS, DAP10, 2B4, CD27, CD30, CD40, CD2, CD7, LIGHT, GITR, TLR, DR3, CD43, or any combination thereof.
  • the cytoplasmic domain comprises a CD3 ⁇ signaling domain and a 4-1BB co-stimulatory domain.
  • the cytoplasmic domain comprises a CD3 ⁇ signaling domain and a CD28 co-stimulatory domain.
  • the CARs provided herein further comprise a CD8 hinge between the antibody or antigen-binding fragment and the transmembrane domain.
  • CAR that specifically binds BCMA comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 131-142.
  • polynucleotides encoding a CAR described herein.
  • the polynucleotide is a mRNA.
  • vectors comprising a polynucleotide described herein or a vector described herein.
  • the cell provided herein is an immune effector cell.
  • the cell is derived from a cell isolated from peripheral blood or bone marrow.
  • the cell is derived from a cell differentiated in vitro from a stem or progenitor cell selected from the group consisting of a T cell progenitor cell, a hematopoietic stem and progenitor cell, a hematopoietic multipotent progenitor cell, an embryonic stem cell, and an induced pluripotent cell.
  • the cell is a T cell or a NK cell.
  • the cell is a cytotoxic T cell, a helper T cell, a gamma delta T, a CD4+/CD8+ double positive T cell, a CD4+ T cell, a CD8+ T cell, a CD4/CD8 double negative T cell, a CD3+ T cell, a naive T cell, an effector T cell, a helper T cell, a memory T cell, a regulator T cell, a Th0 cell, a Th1 cell, a Th2 cell, a Th3 (Treg) cell, a Th9 cell, a Th17 cell, a Th ⁇ helper cell, a Tfh cell, a stem memory TSCM cell, a central memory TCM cell, an effector memory TEM cell, or an effector memory TEMRA cell.
  • the cell is a cytotoxic T cell.
  • PBMC peripheral blood mononuclear cells
  • PBL peripheral blood leukocytes
  • TIL tumor infiltrating lymphocytes
  • CIK cytokine-induced killer cells
  • LAK lymphokine-activated killer cells
  • MILs marrow infiltrate lymphocytes
  • compositions comprising a therapeutically effective amount of the antibody or antigen-binding fragment described herein, and a pharmaceutically acceptable carrier. In some embodiments, provided herein are pharmaceutical compositions comprise a therapeutically effective amount of the cell or cell population described herein, and a pharmaceutically acceptable carrier.
  • provided herein are uses of the antibody or antigen-binding fragment described herein, the cell or population of cells described herein, or the pharmaceutical composition described herein in cancer treatment. In some embodiments, provided herein are use of the antibody or antigen-binding fragment described herein, the cell or population of cells described herein, or the pharmaceutical composition described herein for the preparation of a medicament for the treatment of cancer. In some embodiments, the cell, population of cells, or pharmaceutical composition is used in combination with an additional therapy.
  • provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the antibody or antigen-binding fragment of described herein, or the pharmaceutical composition described herein.
  • provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the cell or cell population described herein.
  • the population of cells is autologous to the subject.
  • the methods provided herein further comprise obtaining T cells from the subject.
  • the methods provided herein further comprise administering an additional therapy to the subject.
  • the subject is a human.
  • the cancer is a BCMA-expressing cancer.
  • the cancer is a solid tumor or a hematological cancer.
  • the cancer is a B cell malignancy.
  • the cancer is a lymphoma, a leukemia, or a plasma cell malignancy.
  • the caner is multiple myeloma (MM) , Waldenstrom macroglobulinemia, Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.
  • the caner is MM.
  • the MM is non-secretory multiple myeloma, or smoldering multiple myeloma.
  • the cell is selected from the group consisting of a T cell, an NK cell, an NKT cell, a macrophage, a neutrophil, and a granulocyte cell.
  • the polynucleotide is transferred via electroporation.
  • the polynucleotide is transferred via viral transduction.
  • the methods provided herein comprise using a lentivirus, a retrovirus, an adenovirus, or an adeno-associated virus for the viral transduction.
  • the polynucleotide is transferred using a transposon system.
  • the transposon system is Sleeping Beauty or PiggyBac.
  • the polynucleotide is transferred using gene-editing.
  • the polynucleotide is transferred using a CRISPR-Cas system, a ZFN system, or a TALEN system.
  • FIGs. 1A-1B provides flow cytometry data of anti-BCMA CAR-T cells stained with CD19-Fc (FIG. 1A) or BCMA-Fc (FIG. 1B) .
  • FIG. 2A provides the frequencies of CAR+ cells of the T cells transduced with the designated BCMA CARs.
  • FIG. 2B provides the Medium Fluorescence Intensity ( “MFI” ) of CAR expression in T cells transduced with the designated BCMA CARs.
  • MFI Medium Fluorescence Intensity
  • FIG. 3 provides the frequencies of CAR+ CD8 cells of the T cells transduced with the designated BCMA CARs.
  • FIG. 4 provides the phenotype of designated CART cells characterized by CCR7 expression and CD45RO expression.
  • FIGs. 5A-5B provide the expression of BCMA in tumor lines.
  • FIG. 5A provides the FACS results.
  • FIG. 5B provides the relative expression levels as compared to A549 cells.
  • FIGs. 6A-6B provide ELISA results showing the production of INF- ⁇ and IL-2 by designated CART cells
  • FIG. 6A shows INF- ⁇ production.
  • FIG. 6B shows IL-2 production.
  • FIGs. 7A-7D provide results of the tumor killing assay showing the cytolytic activities of designated CART cells against Jeko-1 cells at different E (T cells) : T (tumor cells) ratio.
  • FIG. 7A :
  • FIGs. 8A-8E provide results of the tumor killing assay showing the cytolytic activities of designated CART cells against RPMI-8226 cells.
  • BCMA B-Cell Maturation Protein
  • TNFRSF17 Tumor Necrosis Factor Receptor Superfamily Member 17
  • BCMA is preferentially expressed in mature B lymphocytes and plays important roles for B cell development and autoimmune response.
  • BCMA has been shown to specifically bind to the tumor necrosis factor (ligand) superfamily, member 13b (TNFSF13B/TALL-1/BAFF) , and to lead to NF-kappaB and MAPK8/JNK activation.
  • ligand tumor necrosis factor
  • TNFSF13B/TALL-1/BAFF tumor necrosis factor
  • MAPK8/JNK activation BCMA has also been shown to bind to various TRAF family members and transduce signals for cell survival and proliferation.
  • MM multiple myeloma
  • MM is a hematologic malignancy characterized by the uncontrolled proliferation of plasma cells in the bone marrow. About 160,000 new cases are diagnosed, and 110,000 patients die every year in the world. This disease is incurable, although the survival rates are increasing with the development of new therapeutic approaches.
  • the present disclosure provides novel antibodies, including antigen-binding fragments that specifically bind BCMA (e.g., human BCMA) . Further, the present disclosure also provides chimeric antigen receptors (CARs) that comprise such antibodies or antigen-binding fragments that specifically bind BCMA (e.g., human BCMA) , as well as engineered immune effector cells (e.g., T cells) and populations of cells that recombinantly express a CAR (e.g., CARTs) that specifically binds BCMA (e.g., human BCMA) .
  • CARs chimeric antigen receptors
  • Pharmaceutical compositions comprising a therapeutically effective amount of such antibodies or antigen-binding fragments, and pharmaceutical compositions comprising a therapeutically effective amount of cells or population of cells are also disclosed herein. Also disclosed herein are uses of such pharmaceutical compositions for treating diseases and disorders relating to BCMA expression (e.g., BCMA expressing cancer) and related methods of treatment.
  • BCMA antigen-binding fragments that specifically bind BCMA
  • the term “BCMA” includes any variants or isoforms of BCMA which are naturally expressed by cells. Accordingly, antibodies described herein can cross-react with BCMA from species other than human (e.g., cynomolgus BCMA) . Alternatively, the antibodies can be specific for human BCMA and do not exhibit any cross-reactivity with other species. BCMA or any variants and isoforms thereof, can either be isolated from cells or tissues which naturally express them or be recombinantly produced using well-known techniques in the art and/or those described herein.
  • antibody and its grammatical equivalents as used herein refer to an immunoglobulin molecule that recognizes and specifically binds a target, such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination of any of the foregoing, through at least one antigen-binding site wherein the antigen-binding site is usually within the variable region of the immunoglobulin molecule.
  • a target such as a protein, polypeptide, peptide, carbohydrate, polynucleotide, lipid, or a combination of any of the foregoing.
  • the term encompasses intact polyclonal antibodies, intact monoclonal antibodies, single-domain antibodies (sdAbs; e.g., camelid antibodies, alpaca antibodies) , single-chain Fv (scFv) antibodies, heavy chain antibodies (HCAbs) , light chain antibodies (LCAbs) , multispecific antibodies, bispecific antibodies, monospecific antibodies, monovalent antibodies, and any other modified immunoglobulin molecule comprising an antigen-binding site (e.g., dual variable domain immunoglobulin molecules) as long as the antibodies exhibit the desired biological activity.
  • Antibodies also include, but are not limited to, mouse antibodies, camel antibodies, chimeric antibodies, humanized antibodies, and human antibodies.
  • An antibody can be any of the five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, or subclasses (isotypes) thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2) , based on the identity of their heavy-chain constant domains referred to as alpha, delta, epsilon, gamma, and mu, respectively.
  • the term “antibody” as used herein include “antigen-binding fragment” of intact antibodies.
  • the term “antigen-binding fragment” as used herein refers to a portion or fragment of an intact antibody that is the antigenic determining variable region of an intact antibody.
  • antigen-binding fragments include, but are not limited to, Fab, Fab', F (ab’) 2, Fv, linear antibodies, single chain antibody molecules (e.g., scFv) , heavy chain antibodies (HCAbs) , light chain antibodies (LCAbs) , disulfide-linked scFv (dsscFv) , diabodies, tribodies, tetrabodies, minibodies, dual variable domain antibodies (DVD) , single variable domain antibodies (sdAbs; e.g., camelid antibodies, alpaca antibodies) , and single variable domain of heavy chain antibodies (VHH) , and bispecific or multispecific antibodies formed from antibody fragments.
  • scFv single chain antibody molecules
  • HCAbs heavy chain antibodies
  • LCAbs light chain antibodies
  • dsscFv disulfide-linked scFv
  • VHH single variable domain of heavy chain antibodies
  • humanized antibody refers to forms of non-human (e.g., murine) antibodies that are specific immunoglobulin chains, chimeric immunoglobulins, or fragments thereof that contain minimal non-human sequences.
  • humanized antibodies are human immunoglobulin.
  • the Fv framework region residues of a human immunoglobulin are replaced with the corresponding residues in an antibody from a non-human species.
  • residues of the CDRs are replaced by residues from the CDRs of a non-human species (e.g., mouse, rat, hamster, camel) that have the desired specificity, affinity, and/or binding capability.
  • humanized antibody can be further modified by the substitution of additional residues either in the Fv framework region and/or within the replaced non-human residues to refine and optimize antibody specificity, affinity, and/or binding capability.
  • human antibody refers to an antibody produced by a human or an antibody having an amino acid sequence corresponding to an antibody produced by a human made using any of the techniques known in the art.
  • the term “heavy chain” when used in reference to an antibody refers to a polypeptide chain of about 50-70 kDa, wherein the amino-terminal portion includes a variable region of about 120 to 130 or more amino acids and a carboxy-terminal portion that includes a constant region.
  • the constant region can be one of five distinct types, referred to as alpha (a) , delta ( ⁇ ) , epsilon ( ⁇ ) , gamma ( ⁇ ) and mu ( ⁇ ) , based on the amino acid sequence of the heavy chain constant region.
  • the distinct heavy chains differ in size: ⁇ , ⁇ and ⁇ contain approximately 450 amino acids, while ⁇ and ⁇ contain approximately 550 amino acids.
  • heavy chains When combined with a light chain, these distinct types of heavy chains give rise to five well known classes of antibodies, IgA, IgD, IgE, IgG and IgM, respectively, including four subclasses of IgG, namely IgGl, IgG2, IgG3 and IgG4.
  • a heavy chain can be a human heavy chain.
  • light chain when used in reference to an antibody refers to a polypeptide chain of about 25 kDa, wherein the amino-terminal portion includes a variable region of about 100 to about 110 or more amino acids and a carboxy-terminal portion that includes a constant region.
  • the approximate length of a light chain is 211 to 217 amino acids.
  • Light chain amino acid sequences are well known in the art.
  • a light chain can be a human light chain.
  • variable domain refers to a portion of the light or heavy chains of an antibody that is generally located at the amino-terminal of the light or heavy chain and has a length of about 120 to 130 amino acids in the heavy chain and about 100 to 110 amino acids in the light chain, and are used in the binding and specificity of each particular antibody for its particular antigen.
  • the variable domains differ extensively in sequence between different antibodies. The variability in sequence is concentrated in the CDRs while the less variable portions in the variable domain are referred to as framework regions (FR) .
  • FR framework regions
  • the CDRs of the light and heavy chains are primarily responsible for the interaction of the antibody with antigen. Numbering of amino acid positions used herein is according to the EU Index, as in Kabat et al. (1991) Sequences of proteins of immunological interest. (U.S. Department of Health and Human Services, Washington, D.C. ) 5thed.
  • a variable region can be a human variable region.
  • a CDR refers to one of three hypervariable regions (H1, H2 or H3) within the non-framework region of the immunoglobulin (Ig or antibody) VH ⁇ -sheet framework, or one of three hypervariable regions (L1, L2 or L3) within the non-framework region of the antibody VL ⁇ -sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by a variety of methods/systems. These systems and/or definitions have been developed and refined over years and include Kabat, Chothia, IMGT, AbM, and Contact.
  • Kabat defines the regions of most hypervariability within the antibody variable (V) domains (Kabat et al, J. Biol. Chem. 252: 6609-6616 (1977) ; Kabat, Adv. Prot. Chem. 32: 1-75 (1978) ) .
  • the Chothia definition is based on the location of the structural loop regions, which defines CDR region sequences as those residues that are not part of the conserved ⁇ -sheet framework, and thus are able to adapt different conformations (Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987) ) . Both terminologies are well recognized in the art.
  • the IMGT system is based on sequence variability and location within the structure of the variable regions.
  • the AbM definition is a compromise between Kabat and Chothia.
  • the Contact definition is based on analyses of the available antibody crystal structures.
  • Software programs e.g., abYsis
  • abYsis are available and known to those of skill in the art for analysis of antibody sequence and determination of CDRs.
  • the positions of CDRs within a canonical antibody variable domain have been determined by comparison of numerous structures (Al-Lazikani et al, J. Mol. Biol. 273: 927-948 (1997) ; Morea et al, Methods 20: 267-279 (2000) ) .
  • CDRs defined according to either the Kabat (hypervariable) or Chothia (structural) designations are set forth in the table below.
  • One or more CDRs also can be incorporated into a molecule either covalently or noncovalently to make it an immunoadhesin.
  • An immunoadhesin can incorporate the CDR (s) as part of a larger polypeptide chain, can covalently link the CDR (s) to another polypeptide chain, or can incorporate the CDR (s) noncovalently.
  • the CDRs permit the immunoadhesin to bind to a particular antigen of interest.
  • the CDR regions can be analyzed by, for example, abysis website ( http: //abysis. org/ ) .
  • a CDR, or individual specified CDRs e.g., VL CDR1, VL CDR2, VL CDR3 , of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) complementary determining region as defined by any of the aforementioned schemes, or other known schemes.
  • a particular CDR e.g., a VH CDR3
  • a CDR has a sequence of the corresponding CDR (e.g., CDR-H3) within the variable region, as defined by any of the aforementioned schemes, or other known schemes.
  • specific CDR sequences are specified, although it is understood that a provided antibody can include CDRs as described according to any of the other aforementioned numbering schemes or other numbering schemes known to a skilled artisan.
  • FR or individual specified FR e.g., VH FRl, VH FR2, VH FR3, VH FR4
  • VH FRl, VH FR2, VH FR3, VH FR4 a FR or individual specified FR (s) (e.g., VH FRl, VH FR2, VH FR3, VH FR4) , of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) framework region as defined by any of the known schemes.
  • epitope and “antigenic determinant” are used interchangeably herein an refer to the site on the surface of a target molecule to which an antibody or antigen-binding fragment binds, such as a localized region on the surface of an antigen.
  • the target molecule can comprise, a protein, a peptide, a nucleic acid, a carbohydrate, or a lipid.
  • An epitope having immunogenic activity is a portion of a target molecule that elicits an immune response in an animal.
  • An epitope of a target molecule having antigenic activity is a portion of the target molecule to which an antibody binds, as determined by any method well known in the art, including, for example, by an immunoassay.
  • Antigenic epitopes need not necessarily be immunogenic. Epitopes often consist of chemically active surface groupings of molecules such as amino acids or sugar side chains and have specific three dimensional structural characteristics as well as specific charge characteristics.
  • epitope includes linear epitopes and conformational epitopes.
  • a region of a target molecule e.g., a polypeptide
  • contributing to an epitope can be contiguous amino acids of the polypeptide or the epitope can come together from two or more non-contiguous regions of the target molecule.
  • the epitope may or may not be a three-dimensional surface feature of the target molecule.
  • Epitopes formed from contiguous amino acids are typically retained upon protein denaturing, whereas epitopes formed by tertiary folding (also referred to as conformational epitopes) are typically lost upon protein denaturing.
  • An epitope typically includes at least 3, and more usually, at least 5, 6, 7, or 8-10 amino acids in a unique spatial conformation.
  • binding moiety e.g., antibody
  • SPR e.g., Biacore
  • a specific reaction will be at least twice background signal or noise and can be more than 10 times background.
  • a binding moiety that specifically binds a target molecule can bind the target molecule at a higher affinity than its affinity for a different molecule.
  • a binding moiety that specifically binds a target molecule can bind the target molecule with an affinity that is at least 20 times greater, at least 30 times greater, at least 40 times greater, at least 50 times greater, at least 60 times greater, at least 70 times greater, at least 80 times greater, at least 90 times greater, or at least 100 times greater, than its affinity for a different molecule.
  • a binding moiety that specifically binds a particular target molecule binds a different molecule at such a low affinity that binding cannot be detected using an assay described herein or otherwise known in the art.
  • “specifically binds” means, for instance, that a binding moiety binds a molecule target with a K D of about 0.1 mM or less.
  • “specifically binds” means that a polypeptide or molecule binds a target with a K D of at about 10 ⁇ M or less or about 1 ⁇ M or less.
  • “specifically binds” means that a polypeptide or molecule binds a target with a K D of at about 0.1 ⁇ M or less, about 0.01 ⁇ M or less, or about 1 nM or less. Because of the sequence identity between homologous proteins in different species, specific binding can include a polypeptide or molecule that recognizes a protein or target in more than one species. Likewise, because of homology within certain regions of polypeptide sequences of different proteins, specific binding can include a polypeptide or molecule that recognizes more than one protein or target. It is understood that, in some embodiments, a binding moiety (e.g., antibody) that specifically binds a first target may or may not specifically bind a second target.
  • a binding moiety e.g., antibody
  • binding does not necessarily require (although it can include) exclusive binding, i.e., binding to a single target.
  • a binding moiety e.g., antibody
  • an antibody can, in some embodiments, specifically bind more than one target.
  • an antibody can, in certain instances, comprise two identical antigen-binding sites, each of which specifically binds the same epitope on two or more proteins.
  • an antibody can be bispecific and comprise at least two antigen-binding sites with differing specificities.
  • binding affinity generally refers to the strength of the sum total of noncovalent interactions between a binding moiety and a target molecule (e.g., antigen) .
  • the binding of a binding moiety and a target molecule is a reversible process, and the affinity of the binding is typically reported as an equilibrium dissociation constant (K D ) .
  • K D is the ratio of a dissociation rate (k off or k d ) to the association rate (k on or k a ) .
  • K D is the ratio of a dissociation rate (k off or k d ) to the association rate (k on or k a ) .
  • the lower the K D of a binding pair the higher the affinity.
  • a variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present disclosure. Specific illustrative embodiments include the following.
  • the “K D ” or “K D value” can be measured by assays known in the art, for example by a binding assay.
  • the K D may be measured in a radiolabeled antigen binding assay (RIA) (Chen, et al., (1999) J. Mol Biol 293: 865-881) .
  • the K D or K D value may also be measured by using surface plasmon resonance assays by Biacore, using, for example, a BIAcoreTM-2000 or a BIAcoreTM-3000 BIAcore, Inc., Piscataway, NJ) , or by biolayer interferometry using, for example, the OctetQK384 system (ForteBio, Menlo Park, CA) .
  • variant refers to a different protein or polypeptide having one or more (such as, for example, about 1 to about 25, about 1 to about 20, about 1 to about 15, about 1 to about 10, or about 1 to about 5) amino acid substitutions, deletions, and/or additions as compared to the reference protein or reference polypeptide.
  • the changes to an amino acid sequence can be amino acid substitutions.
  • the changes to an amino acid sequence can be conservative amino acid substitutions.
  • a functional fragment or a functional variant of a protein or polypeptide maintains the basic structural and functional properties of the reference protein or polypeptide.
  • polypeptide, ” “peptide, ” “protein, ” and their grammatical equivalents as used interchangeably herein refer to polymers of amino acids of any length, which can be linear or branched. It can include unnatural or modified amino acids or be interrupted by non-amino acids.
  • a polypeptide, peptide, or protein can also be modified with, for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification.
  • polynucleotide, ” “nucleic acid, ” and their grammatical equivalents as used interchangeably herein mean polymers of nucleotides of any length and include DNA and RNA.
  • the nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase.
  • nucleotide, % “identity, ” and their grammatical equivalents as used herein in the context of two or more polynucleotides or polypeptides refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity.
  • the percent identity can be measured using sequence comparison software or algorithms or by visual inspection. Various algorithms and software that can be used to obtain alignments of amino acid or nucleotide sequences are well-known in the art.
  • two polynucleotides or polypeptides provided herein are substantially identical, meaning they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%nucleotide or amino acid residue identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection.
  • identity exists over a region of the amino acid sequences that is at least about 10 residues, at least about 20 residues, at least about 40-60 residues, at least about 60-80 residues in length or any integral value there between. In some embodiments, identity exists over a longer region than 60-80 residues, such as at least about 80-100 residues, and in some embodiments the sequences are substantially identical over the full length of the sequences being compared, such as the coding region of a target protein or an antibody. In some embodiments, identity exists over a region of the nucleotide sequences that is at least about 10 bases, at least about 20 bases, at least about 40-60 bases, at least about 60-80 bases in length or any integral value there between.
  • identity exists over a longer region than 60-80 bases, such as at least about 80-1000 bases or more, and in some embodiments the sequences are substantially identical over the full length of the sequences being compared, such as a nucleotide sequence encoding a protein of interest.
  • vector refers to a vehicle that is used to carry genetic material (e.g., a polynucleotide sequence) , which can be introduced into a host cell, where it can be replicated and/or expressed.
  • vectors applicable for use include, for example, expression vectors, plasmids, phage vectors, viral vectors, episomes and artificial chromosomes, which can include selection sequences or markers operable for stable integration into a host cell’s chromosome. Additionally, the vectors can include one or more selectable marker genes and appropriate expression control sequences.
  • Selection control sequences can include constitutive and inducible promoters, transcription enhancers, transcription terminators, and the like which are well known in the art.
  • both polynucleotides can be inserted, for example, into a single expression vector or in separate expression vectors.
  • the encoding polynucleotides can be operationally linked to one common expression control sequence or linked to different expression control sequences, such as one inducible promoter and one constitutive promoter.
  • polynucleotides into a host cell can be confirmed using methods well known in the art. It is understood by those skilled in the art that the polynucleotides are expressed in a sufficient amount to produce a desired product (e.g., an anti-BCMA antibody or antigen-binding fragment as described herein) , and it is further understood that expression levels can be optimized to obtain sufficient expression using methods well known in the art.
  • a desired product e.g., an anti-BCMA antibody or antigen-binding fragment as described herein
  • chimeric antigen receptor refers to an artificially constructed hybrid protein or polypeptide containing a binding moiety (e.g., an antibody) linked to immune cell (e.g., T cell) signaling or activation domains.
  • CARs are synthetic receptors that retarget T cells to tumor surface antigens (Sadelain et al., Nat. Rev. Cancer 3 (l) : 35-45 (2003) ; Sadelain et al., Cancer Discovery 3 (4) : 388-398 (2013) ) .
  • CARs can provide both antigen binding and immune cell activation functions onto an immune cell such as a T cell.
  • CARs have the ability to redirect T-cell specificity and reactivity toward a selected target in a non-MHC-restricted manner, exploiting the antigen-binding properties of monoclonal antibodies.
  • the non-MHC-restricted antigen recognition can give T-cells expressing CARs the ability to recognize an antigen independent of antigen processing, thus bypassing a mechanism of tumor escape.
  • genetic engineering or its grammatical equivalents when used in reference to a cell is intended to mean alteration of the genetic materials of the cell that is not normally found in a naturally occurring cell. Genetic alterations include, for example, modifications introducing expressible polynucleotides, other additions, mutations/alterations, deletions and/or other functional disruption of the cell’s genes. Such modifications can be done in, for example, coding regions and functional fragments thereof of a gene. Additional modifications can be done in, for example, non-coding regulatory regions in which the modifications alter expression of a gene.
  • transfer, ” “transduce, ” “transfect, ” and their grammatical equivalents as used herein refer to a process by which an exogenous polynucleotide is introduced into the host cell.
  • a “transferred, ” “transfected, ” or “transduced” cell is one which has been transferred, transduced, or transfected with an exogenous polynucleotide.
  • the cell includes the primary subject cell and its progeny.
  • a polynucleotide can be “transferred” into a host cell using any type of approaches known in the art, including, e.g., a chemical method, a physical method, or a biological method.
  • a polynucleotide is commonly “transduced” into a host cell using a virus.
  • a polynucleotide is commonly “transfected” into a host cell using a non-viral approach.
  • the term “encode” and its grammatical equivalents refer to the inherent property of specific sequences of nucleotides in a polynucleotide or a nucleic acid, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom.
  • a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein.
  • nucleotide sequence encoding an amino acid sequence includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. Nucleotide sequences that encode proteins and RNA can include introns.
  • a polypeptide, peptide, protein, antibody, polynucleotide, vector, cell, or composition which is “isolated” is a polypeptide, peptide, protein, antibody, polynucleotide, vector, cell, or composition which is in a form not found in nature.
  • Isolated polypeptides, peptides, proteins, antibodies, polynucleotides, vectors, cells, or compositions include those which have been purified to a degree that they are no longer in a form in which they are found in nature.
  • a polypeptide, peptide, protein, antibody, polynucleotide, vector, cell, or composition which is isolated is substantially pure.
  • Immune effector cell and its grammatical equivalents as used herein and understood in the art refer to cells that are of hematopoietic origin and play a direct role in the immune response against a target, such as a pathogen, a cancer cell, or a foreign substance.
  • Immune effector cells include T cells, B cell, natural killer (NK) cells, NKT cells, macrophages, granulocytes, neutrophils, eosinophils, mast cells, and basophils.
  • the term “treat” and its grammatical equivalents refer to an action that reduces the severity of the cancer or tumor, or retards or slows the progression of the cancer or tumor, including (a) inhibiting the growth, or arresting development of the cancer or tumor, (b) causing regression of the cancer or tumor, or (c) delaying, ameliorating or minimizing one or more symptoms associated with the presence of the cancer or tumor.
  • administer and its grammatical equivalents as used herein refer to the act of delivering, or causing to be delivered, a therapeutic or a pharmaceutical composition to the body of a subject by a method described herein or otherwise known in the art.
  • the therapeutic can be a compound, a polypeptide, an antibody, a cell, or a population of cells.
  • Administering a therapeutic or a pharmaceutical composition includes prescribing a therapeutic or a pharmaceutical composition to be delivered into the body of a subject.
  • Exemplary forms of administration include oral dosage forms, such as tablets, capsules, syrups, suspensions; injectable dosage forms, such as intravenous (IV) , intramuscular (IM) , or intraperitoneal (IP) ; transdermal dosage forms, including creams, jellies, powders, or patches; buccal dosage forms; inhalation powders, sprays, suspensions, and rectal suppositories.
  • oral dosage forms such as tablets, capsules, syrups, suspensions
  • injectable dosage forms such as intravenous (IV) , intramuscular (IM) , or intraperitoneal (IP)
  • transdermal dosage forms including creams, jellies, powders, or patches
  • buccal dosage forms inhalation powders, sprays, suspensions, and rectal suppositories.
  • an effective amount, ” “therapeutically effective amount, ” and their grammatical equivalents as used herein refer to the administration of an agent to a subject, either alone or as a part of a pharmaceutical composition and either in a single dose or as part of a series of doses, in an amount that is capable of having any detectable, positive effect on any symptom, aspect, or characteristics of a disease, disorder or condition when administered to the subject.
  • the therapeutically effective amount can be ascertained by measuring relevant physiological effects. The exact amount required vary from subject to subject, depending on the age, weight, and general condition of the subject, the severity of the condition being treated, the judgment of the clinician, and the like. An appropriate “effective amount” in any individual case can be determined by one of ordinary skill in the art using routine experimentation.
  • pharmaceutically acceptable carrier or “pharmaceutically acceptable excipient” refers to a material that is suitable for drug administration to an individual along with an active agent without causing undesirable biological effects or interacting in a deleterious manner with any of the other components of the pharmaceutical composition.
  • subject refers to any animal (e.g., a mammal) , including, but not limited to, humans, non-human primates, canines, felines, rodents, and the like, which is to be the recipient of a particular treatment.
  • a subject can be a human.
  • a subject can have a particular disease or condition.
  • autologous refers to any material derived from the same individual to which it is later to be re-introduced into the individual.
  • allogeneic refers to a graft derived from a different animal of the same species.
  • ranges throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
  • GenBank numbers GI numbers and/or SEQ ID NOS. It is understood that one skilled in the art can readily identify homologous sequences by reference to sequence sources, including but not limited to GenBank (ncbi. nlm. nih. gov/genbank/) and EMBL (embl. org/) .
  • the antibody is an IgA, IgD, IgE, IgG, or IgM antibody. In some embodiments, the antibody is an IgA antibody. In some embodiments, the antibody is an IgD antibody. In some embodiments, the antibody is an IgE antibody. In some embodiments, the antibody is an IgG antibody. In some embodiments, the antibody is an IgM antibody. In some embodiments, the antibodies provided herein can be an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments, the antibody is an IgG1 antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG4 antibody.
  • antigen-binding fragments of an anti-BCMA antibody can be a single domain antibody (sdAb) , a heavy chain antibody (HCAb) , a Fab, a Fab’ , a F (ab’) 2 , a Fv, a single-chain variable fragment (scFv) , or a (scFv) 2 .
  • the antigen-binding fragment of an anti-BCMA antibody is a single domain antibody (sdAb) .
  • the antigen-binding fragment of an anti-BCMA antibody is a heavy chain antibody (HCAb) .
  • the antigen-binding fragment of an anti-BCMA antibody is a Fab. In some embodiments, the antigen-binding fragment of an anti-BCMA antibody is a Fab’ . In some embodiments, the antigen-binding fragment of an anti-BCMA antibody is a F (ab’) 2 . In some embodiments, the antigen-binding fragment of an anti-BCMA antibody is a Fv. In some embodiments, the antigen-binding fragment of an anti-BCMA antibody is a scFv. In some embodiments, the antigen-binding fragment of an anti-BCMA antibody is a disulfide-linked scFv [ (scFv) 2 ] . In some embodiments, the antigen-binding fragment of an anti-BCMA antibody is a diabody (dAb) .
  • dAb diabody
  • the anti-BCMA antibodies or antigen-binding fragments provided herein comprise recombinant antibodies or antigen-binding fragments. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments provided herein comprise monoclonal antibodies or antigen-binding fragments. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments provided herein comprise polyclonal antibodies or antigen-binding fragments. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments provided herein comprise camelid (e.g., camels, dromedary and llamas) antibodies or antigen-binding fragments.
  • camelid e.g., camels, dromedary and llamas
  • the anti-BCMA antibodies or antigen-binding fragments provided herein comprise chimeric antibodies or antigen-binding fragments. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments provided herein comprise humanized antibodies or antigen-binding fragments. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments provided herein comprise human antibodies or antigen-binding fragments. In some embodiments, provided herein are anti-BCMA human scFvs.
  • the anti-BCMA antibodies or antigen-binding fragments provided herein are isolated. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments provided herein are substantially pure.
  • the anti-BCMA antibody or antigen-binding fragment provided herein comprises a multispecific antibody or antigen-binding fragment. In some embodiments, the anti-BCMA antibody or antigen-binding fragment provided herein comprises a bispecific antibody or antigen-binding fragment. In some embodiments, provided herein is a Bi-specific T-cell engager (BiTE) .
  • BiTEs are bispecific antibodies that bind to a T cell antigen (e.g., CD3) and a tumor antigen. BiTEs have been shown to induce directed lysis of target tumor cells and thus provide great potential therapies for cancers and other disorders. In some embodiments, provided herein are BiTEs that specifically bind CD3 and BCMA. In some embodiments, the BiTEs comprises an anti-BCMA antibody or antigen-binding fragment provided herein. In some embodiments, the BiTEs comprises an anti-BCMA scFv provided herein.
  • the anti-BCMA antibody or antigen-binding fragment provided herein comprises a monovalent antigen-binding site. In some embodiments, an anti-BCMA antibody or antigen-binding fragment comprises a monospecific binding site. In some embodiments, an anti-BCMA antibody or antigen-binding fragment comprises a bivalent binding site.
  • an anti-BCMA antibody or antigen-binding fragment is a monoclonal antibody or antigen-binding fragment.
  • Monoclonal antibodies can be prepared by any method known to those of skill in the art. One exemplary approach is screening protein expression libraries, e.g., phage or ribosome display libraries. Phage display is described, for example, in Ladner et al., U.S. Patent No. 5,223,409; Smith (1985) Science 228: 1315-1317; and WO 92/18619.
  • recombinant monoclonal antibodies are isolated from phage display libraries expressing variable regions or CDRs of a desired species. Screening of phage libraries can be accomplished by various techniques known in the art.
  • monoclonal antibodies are prepared using hybridoma methods known to one of skill in the art. For example, using a hybridoma method, a mouse, rat, rabbit, hamster, or other appropriate host animal, is immunized as described above. In some embodiments, lymphocytes are immunized in vitro. In some embodiments, the immunizing antigen is a human protein or a fragment thereof. In some embodiments, the immunizing antigen is a human protein or a fragment thereof.
  • lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol.
  • the hybridoma cells are selected using specialized media as known in the art and unfused lymphocytes and myeloma cells do not survive the selection process.
  • Hybridomas that produce monoclonal antibodies directed to a chosen antigen can be identified by a variety of methods including, but not limited to, immunoprecipitation, immunoblotting, and in vitro binding assays (e.g., flow cytometry, FACS, ELISA, SPR (e.g., Biacore) , and radioimmunoassay) .
  • the clones may be subcloned by limiting dilution or other techniques.
  • the hybridomas can be propagated either in in vitro culture using standard methods or in vivo as ascites tumors in an animal.
  • the monoclonal antibodies can be purified from the culture medium or ascites fluid according to standard methods in the art including, but not limited to, affinity chromatography, ion-exchange chromatography, gel electrophoresis, and dialysis.
  • monoclonal antibodies are made using recombinant DNA techniques as known to one skilled in the art.
  • the polynucleotides encoding an antibody are isolated from mature B-cells or hybridoma cells, such as by RT-PCR using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequence is determined using standard techniques.
  • the isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors which produce the monoclonal antibodies when transfected into host cells such as E. coli, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin proteins.
  • a monoclonal antibody is modified by using recombinant DNA technology to generate alternative antibodies.
  • the constant domains of the light chain and heavy chain of a mouse monoclonal antibody are replaced with the constant regions of a human antibody to generate a chimeric antibody.
  • the constant regions are truncated or removed to generate a desired antibody fragment of a monoclonal antibody.
  • site-directed or high-density mutagenesis of the variable region (s) is used to optimize specificity and/or affinity of a monoclonal antibody.
  • an anti-BCMA antibody or antigen-binding fragment is a humanized antibody or antigen-binding fragment.
  • Various methods for generating humanized antibodies are known in the art. Methods are known in the art for achieving high affinity binding with humanized antibodies. A non-limiting example of such a method is hypermutation of the variable region and selection of the cells expressing such high affinity antibodies (affinity maturation) .
  • the specified antigen e.g., recombinant BCMA or an epitope thereof
  • a non-human animal e.g., a rodent.
  • rodent antigen-binding fragments e.g., mouse antigen-binding fragments
  • rodent antigen-binding fragments can be generated and isolated using methods known in the art and/or disclosed herein.
  • a mouse can be immunized with an antigen (e.g., recombinant BCMA or an epitope thereof) .
  • an anti-BCMA antibody or antigen-binding fragment is a human antibody or antigen-binding fragment.
  • Human antibodies can be prepared using various techniques known in the art. In some embodiments, human antibodies are generated from immortalized human B lymphocytes immunized in vitro. In some embodiments, human antibodies are generated from lymphocytes isolated from an immunized individual. In any case, cells that produce an antibody directed against a target antigen can be generated and isolated. In some embodiments, a human antibody is selected from a phage library, where that phage library expresses human antibodies. Alternatively, phage display technology can be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable region gene repertoires from unimmunized donors.
  • human antibodies are produced in transgenic mice that contain human immunoglobulin loci. Upon immunization these mice are capable of producing the full repertoire of human antibodies in the absence of endogenous immunoglobulin production.
  • CDR sequences defined herein are generally based on a combination of Kabat and Chothia definitions. However, it is understood that reference to a heavy chain CDR or CDRs and/or a light chain CDR or CDRs of a specific antibody encompass all CDR definitions as known to those of skill in the art.
  • Anti-BCMA antibodies or antigen-binding fragments provided herein include the followings clones: BCMA21, BCMA22, BCMA23, BCMA24, BCMA27, BCMA28, BCMA30, BCMA31, BCMA32, BCMA33, BCMA34, and BCMA35. The sequence features are described below.
  • anti-BCMA antibodies or antigen-binding fragments provided herein comprise one, two, three, four, five, and/or six CDRs of any one of the antibodies described herein.
  • anti-BCMA antibodies or antigen-binding fragments provided herein comprise a VL comprising one, two, and/or three, VL CDRs from Table 1.
  • anti-BCMA antibodies or antigen-binding fragments provided herein comprise a VH comprising one, two, and/or three VH CDRs from Table 2.
  • anti-BCMA antibodies or antigen-binding fragments provided herein comprise one, two, and/or three VL CDRs from Table 1 and one, two, and/or three VH CDRs from Table 2.
  • an anti-BCMA antibody or antigen-binding fragment thereof comprises a humanized antibody or antigen-binding fragment.
  • an anti-BCMA antibody or antigen-binding fragment thereof comprises a VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2, and/or VH CDR3 from an antibody or antigen-binding fragment described herein.
  • an anti-BCMA antibody or antigen-binding fragment thereof comprises a variant of an anti-BCMA antibody or antigen-binding fragment described herein.
  • a variant of an anti-BCMA antibody or antigen-binding fragment comprises one to 30 amino acid substitutions, additions, and/or deletions in the anti-BCMA antibody or antigen-binding fragment. In some embodiments, a variant of an anti-BCMA antibody or antigen-binding fragment comprises one to 25 amino acid substitutions, additions, and/or deletions in the anti-BCMA antibody or antigen-binding fragment. In some embodiments, a variant of an anti-BCMA antibody or antigen-binding fragment comprises one to 20 substitutions, additions, and/or deletions in the anti-BCMA antibody or antigen-binding fragment.
  • a variant of an anti-BCMA antibody or antigen-binding fragment comprises one to 15 substitutions, additions, and/or deletions in the anti-BCMA antibody or antigen-binding fragment. In some embodiments, a variant of an anti-BCMA antibody or antigen-binding fragment comprises one to 10 substitutions, additions, and/or deletions in the anti-BCMA antibody or antigen-binding fragment. In some embodiments, a variant of an anti-BCMA antibody or antigen-binding fragment comprises one to five conservative amino acid substitutions, additions, and/or deletions in the anti-BCMA antibody or antigen-binding fragment.
  • a variant of an anti-BCMA antibody or antigen-binding fragment comprises one to three amino acid substitutions, additions, and/or deletions in the anti-BCMA antibody or antigen-binding fragment.
  • the amino acid substitutions, additions, and/or deletions are conservative amino acid substitutions.
  • the conservative amino acid substitution (s) is in a CDR of the antibody or antigen-binding fragment.
  • the conservative amino acid substitution (s) is not in a CDR of the antibody or antigen-binding fragment.
  • the conservative amino acid substitution (s) is in a framework region of the antibody or antigen-binding fragment.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising a light chain variable region (VL) comprising (1) a light chain CDR1 (VL CDR1) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-10; (2) a light chain CDR2 (VL CDR2) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-21; or (3) a light chain CDR3 (VL CDR3) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-32; or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions, and/or deletions in the VL CDRs. In some embodiments, the variant has about 5 amino acid substitutions, additions, and/or deletions in the VL CDRs.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising a VL comprising (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-10; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-21; and (3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-32; or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions, and/or deletions in the VL CDRs. In some embodiments, the variant has up to about 5 amino acid substitutions, additions, and/or deletions in the VL CDRs.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising a heavy chain variable region (VH) comprising (1) a heavy chain CDR1 (VH CDR1) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 33-43; (2) a heavy chain CDR2 (VH CDR2) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 44-55; or (3) a heavy chain CDR3 (VH CDR3) having an amino acid sequence selected from the group consisting of SEQ ID NOs: 56-67; or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions, and/or deletions in the VH CDRs. In some embodiments, the variant has up about 5 amino acid substitutions, additions, and/or deletions in the VH CDRs.
  • VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 33-43
  • VH CDR2 having an amino acid sequence selected
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising a VH comprising (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 33-43; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 44-55; and (3) a VH CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 56-67; or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acid substitutions, additions, and/or deletions in the VH CDRs. In some embodiments, the variant has up about 5 amino acid substitutions, additions, and/or deletions in the VH CDRs.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL comprising (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-10; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-21; and (3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-32; or a variant thereof having up to about 5 amino acid substitutions, additions, and/or deletions in the VL CDRs; and (b) a VH comprising (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 33-43; (2) a VH CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 44-55; and (3) a VH CDR3 having an amino acid sequence selected from the
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, wherein the VL comprises VL CDR1, CDR2 and CDR3 having the amino acid sequences of (1) SEQ ID NOs: 1, 11, and 22, respectively; (2) SEQ ID NOs: 2, 12, and 23, respectively; (3) SEQ ID NOs: 3, 13, and 24, respectively; (4) SEQ ID NOs: 4, 14, and 24, respectively; (5) SEQ ID NOs: 5, 15, and 25, respectively; (6) SEQ ID NOs: 6, 16, and 26, respectively; (7) SEQ ID NOs: 7, 17, and 27, respectively; (8) SEQ ID NOs: 8, 18, and 28, respectively; (9) SEQ ID NOs: 2, 19, and 29, respectively; (10) SEQ ID NOs: 2, 20, and 30, respectively; (11) SEQ ID NOs: 9, 21, and 31, respectively; or (12) SEQ ID NOs: 10, 14, and 32, respectively; or a variant thereof having up to about 3, about 5, about 8, about 10, about 12, or about 15 amino acids
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, wherein the VH comprises VH CDR1, CDR2 and CDR3 having the amino acid sequences of (1) SEQ ID NOs: 33, 44, and 56, respectively; (2) SEQ ID NOs: 34, 45, and 57, respectively; (3) SEQ ID NOs: 35, 46, and 58, respectively; (4) SEQ ID NOs: 36, 47, and 59, respectively; (5) SEQ ID NOs: 37, 48, and 60, respectively; (6) SEQ ID NOs: 38, 49, and 61, respectively; (7) SEQ ID NOs: 35, 50, and 62, respectively; (8) SEQ ID NOs: 39, 51, and 63, respectively; (9) SEQ ID NOs: 40, 52, and 64, respectively; (10) SEQ ID NOs: 41, 53, and 65, respectively; (11) SEQ ID NOs: 42, 54, and 66,
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL and a VH.
  • the VL and VH are connected by a linker.
  • the linker can be a flexible linker or a rigid linker.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL and a VH
  • the VL comprises VL CDR1, CDR2 and CDR3 having the amino acid sequences of (1) SEQ ID NOs: 1, 11, and 22, respectively; (2) SEQ ID NOs: 2, 12, and 23, respectively; (3) SEQ ID NOs: 3, 13, and 24, respectively; (4) SEQ ID NOs: 4, 14, and 24, respectively; (5) SEQ ID NOs: 5, 15, and 25, respectively; (6) SEQ ID NOs: 6, 16, and 26, respectively; (7) SEQ ID NOs: 7, 17, and 27, respectively; (8) SEQ ID NOs: 8, 18, and 28, respectively; (9) SEQ ID NOs: 2, 19, and 29, respectively; (10) SEQ ID NOs: 2, 20, and 30, respectively; (11) SEQ ID NOs: 9, 21, and 31, respectively; or (12) SEQ ID NOs: 10, 14, and 32, respectively; or a variant thereof having up to about 5 amino acid substitutions
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL and a VH, wherein the VL comprises VL CDR1, CDR2 and CDR3 and the VH comprises VH CDR1, CDR2 and CDR3, and wherein the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2 and VH CDR3 have the amino acid sequences of (1) SEQ ID NOs: 1, 11, 22, 33, 44, and 56, respectively; (2) SEQ ID NOs: 2, 12, 23, 34, 45, and 57, respectively; (3) SEQ ID NOs: 3, 13, 24, 35, 46, and 58, respectively; (4) SEQ ID NOs: 4, 14, 24, 36, 47, and 59, respectively; (5) SEQ ID NOs: 5, 15, 25, 37, 48, and 60, respectively; (6) SEQ ID NOs: 6, 16, 26, 38, 49, and 61, respectively; (7) SEQ ID NOs: 7, 17, 27,
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 1, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 11, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 22.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 1, 11, and 22, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 33, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 44, or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 56.
  • the VH can have VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 33, 44, and 56, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 1, 11, and 22, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 33, 44, and 56, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 2, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 12, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 23.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 2, 12, and 23, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 34, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 45, or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 57.
  • the VH can have VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 34, 45, and 57, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ NOs: 2, 12, and 23, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 34, 45, and 57, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 3, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 13, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 24.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 3, 13, and 24, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 35, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 46, or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 58.
  • the VH can have VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 35, 46, and 58, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 3, 13, and 24, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 35, 46, and 58, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 4, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 14, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 24.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 4, 14, and 24, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 36, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 47, or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 59.
  • the VH can have VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 36, 47, and 59, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 4, 14, and 24, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 36, 47, and 59, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 5, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 15, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 25.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 5, 15, and 25, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 37, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 48, or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 60.
  • the VH can have VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 37, 48, and 60, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 5, 15, and 25, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 37, 48, and 60, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 6, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 16, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 26.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 6, 16, and 26, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 38, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 49, or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 61.
  • the VH can have VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 38, 49, and 61, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 6, 16, and 26, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 38, 49, and 61, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 7, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 17, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 27.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 7, 17, and 27, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 35, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 50, or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 62.
  • the VH can have VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 35, 50, and 62, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 7, 17, and 27, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 35, 50, and 62, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 8, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 18, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 28.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 8, 18, and 28, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 39, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 51, or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 63.
  • the VH can have VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 39, 51, and 63, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 8, 18, and 28, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 39, 51, and 63, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 2, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 19, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 29.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 2, 19, and 29, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 40, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 52, or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 64.
  • the VH can have VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 40, 52, and 64, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 2, 19, and 29, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 40, 52, and 64, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 2, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 20, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 30.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 2, 20, and 30, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 2, 20, and 30, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 41, 53, and 65, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 9, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 21, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 31.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 9, 21, and 31, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 42, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 54, or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 66.
  • the VH can have VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 42, 54, and 66, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 9, 21, and 31, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 42, 54, and 66, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VL, comprising (1) a VL CDR1 having the amino acid sequence of SEQ ID NO: 10, (2) a VL CDR2 having the amino acid sequence of SEQ ID NO: 14, or (3) a VL CDR3 having the amino acid sequence of SEQ ID NO: 32.
  • the VL can have VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 10, 14, and 32, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) having a VH, comprising (1) a VH CDR1 having the amino acid sequence of SEQ ID NO: 43, (2) a VH CDR2 having the amino acid sequence of SEQ ID NO: 55, or (3) a VH CDR3 having the amino acid sequence of SEQ ID NO: 67.
  • the VH can have VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 43, 55, and 67, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL that comprises VL CDR1, VL CDR2, and VL CDR3 having the amino acid sequences of SEQ ID NOs: 10, 14, and 32, respectively; and (b) a VH that comprises VH CDR1, VH CDR2, and VH CDR3 having the amino acid sequences of SEQ ID NOs: 43, 55, and 67, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising a VL having 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 100%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising a VH having 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 100%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91.
  • VLs light chain variable regions
  • VHs heavy chain variable region
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising: (a) a VL having 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 100%sequence identity sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79; and (b) a VH having 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 100%sequence identity sequence identity to an amino acid sequence selected from the group consisting
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 68.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 68.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 68. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 68. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 68. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL having the amino acid sequence of SEQ ID NO: 68.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 69.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 69.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 69. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 69. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 69. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising a VL having the amino acid sequence of SEQ ID NO: 69.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 70.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 70.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 70. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 70. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 70. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL having the amino acid sequence of SEQ ID NO: 70.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 71.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 71.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 71. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 71. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 71. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL having the amino acid sequence of SEQ ID NO: 71.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 72.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 72.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 72. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 72. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 72. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL having the amino acid sequence of SEQ ID NO: 72.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 73.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 73.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 73. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 73. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 73. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL having the amino acid sequence of SEQ ID NO: 73.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 74.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 74.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 74. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 74. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 74. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL having the amino acid sequence of SEQ ID NO: 74.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 75.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 75.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 75. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 75. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 75. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL having the amino acid sequence of SEQ ID NO: 75.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 76.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 76.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 76. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 76. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 76. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL having the amino acid sequence of SEQ ID NO: 76.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 77.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 77.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 77. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 77. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 77. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL having the amino acid sequence of SEQ ID NO: 77.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 78.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 78.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 78. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 78. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 78. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL having the amino acid sequence of SEQ ID NO: 78.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL, wherein the VL has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 79.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 85%sequence identity to SEQ ID NO: 79.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 90%sequence identity to SEQ ID NO: 79. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 95%sequence identity to SEQ ID NO: 79. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VL having at least 98%sequence identity to SEQ ID NO: 79. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL having the amino acid sequence of SEQ ID NO: 79.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 80.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 80.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 80. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 80. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 80. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 80.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 81.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 81.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 81. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 81. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 81. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 81.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 82.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 82.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 82. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 82. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 82. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 82.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 83.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 83.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 83. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 83. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 83. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 83.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 84.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 84.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 84. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 84. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 84. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 84.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 85.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 85.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 85. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 85. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 85. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 85.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 86.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 86.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 86. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 86. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 86. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 86.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 87.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 87.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 87. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 87. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 87. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 87.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 88.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 88.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 88. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 88. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 88. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 88.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 89.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 89.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 89. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 89. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 89. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 89.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 90.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 90.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 90. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 90. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 90. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 90.
  • BCMA e.g., human BCMA
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH has at least 80%, 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%, or at least 99%sequence identity to SEQ ID NO: 91.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 85%sequence identity to SEQ ID NO: 91.
  • the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 90%sequence identity to SEQ ID NO: 91. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 95%sequence identity to SEQ ID NO: 91. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a VH having at least 98%sequence identity to SEQ ID NO: 91. In some embodiments, provided herein are antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH having the amino acid sequence of SEQ ID NO: 91.
  • BCMA e.g., human BCMA
  • the anti-BCMA antibodies or antigen-binding fragments thereof can comprise a combination of any VL disclosed herein and any VH disclosed herein.
  • the VL and VH are connected by a linker.
  • the linker can be a flexible linker or a rigid linker.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL and a VH, wherein the VL has the amino acid sequence of SEQ ID NO: 68, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91.
  • the VL has the amino acid sequence of SEQ ID NO: 69, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91.
  • the VL has the amino acid sequence of SEQ ID NO: 70, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91.
  • the VL has the amino acid sequence of SEQ ID NO: 71, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91. In some embodiments, the VL has the amino acid sequence of SEQ ID NO: 72, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91. In some embodiments, the VL has the amino acid sequence of SEQ ID NO: 73, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91. In some embodiments, the VL has the amino acid sequence of SEQ ID NO: 74, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91.
  • the VL has the amino acid sequence of SEQ ID NO: 75, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91. In some embodiments, the VL has the amino acid sequence of SEQ ID NO: 76, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91. In some embodiments, the VL has the amino acid sequence of SEQ ID NO: 77, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91. In some embodiments, the VL has the amino acid sequence of SEQ ID NO: 78, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91. In some embodiments, the VL has the amino acid sequence of SEQ ID NO: 79, and the VH has an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL and a VH, wherein the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 80.
  • the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 81.
  • the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 82.
  • the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 83. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 84. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 85.
  • the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 86. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 87. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 88.
  • the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 89. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 90. In some embodiments, the VL has an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79, and the VH has the amino acid sequence of SEQ ID NO: 91.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL and a VH, wherein the VL and VH have the amino acid sequences of SEQ ID NOs: 68 and 80, respectively.
  • the VL and VH have the amino acid sequences of SEQ ID NOs: 69 and 81, respectively.
  • the VL and VH have the amino acid sequences of SEQ ID NOs: 70 and 82, respectively.
  • the VL and VH have the amino acid sequences of SEQ ID NOs: 71 and 83, respectively.
  • the VL and VH have the amino acid sequences of SEQ ID NOs: 72 and 84, respectively. In some embodiments, the VL and VH have the amino acid sequences of SEQ ID NOs: 73 and 85, respectively. In some embodiments, the VL and VH have the amino acid sequences of SEQ ID NOs: 74 and 86, respectively. In some embodiments, the VL and VH have the amino acid sequences of SEQ ID NOs: 75 and 87, respectively. In some embodiments, the VL and VH have the amino acid sequences of SEQ ID NOs: 76 and 88, respectively. In some embodiments, the VL and VH have the amino acid sequences of SEQ ID NOs: 77 and 89, respectively. In some embodiments, the VL and VH have the amino acid sequences of SEQ ID NOs: 78 and 90, respectively. In some embodiments, the VL and VH have the amino acid sequences of SEQ ID NOs: 79 and 91, respectively.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising (a) a VL comprising VL CDRs 1, 2, and 3 from a VL having an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79; and/or (b) a VH comprising VH CDRs 1, 2, and 3 from a VH having an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA comprising a VL, wherein the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 68.
  • the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 69.
  • the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 70.
  • the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 71.
  • the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 72. In some embodiments, the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 73. In some embodiments, the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 74. In some embodiments, the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 75. In some embodiments, the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 76.
  • the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 77. In some embodiments, the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 78. In some embodiments, the VL comprises VL CDRs 1, 2, and 3 from a VL having the amino acid sequence of SEQ ID NO: 79.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VH, wherein the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 80.
  • the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 81.
  • the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 82.
  • the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 83.
  • the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 84. In some embodiments, the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 85. In some embodiments, the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 86. In some embodiments, the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 87. In some embodiments, the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 88.
  • the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 89. In some embodiments, the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 90. In some embodiments, the VH comprises VH CDRs 1, 2, and 3 from a VH having the amino acid sequence of SEQ ID NO: 91.
  • antibodies or antigen-binding fragments thereof that specifically bind BCMA (e.g., human BCMA) comprising a VL and a VH, wherein the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 68, and the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 80.
  • BCMA e.g., human BCMA
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 68
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 80.
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 69
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 81
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 70
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 82.
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 71
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 83
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 72
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 84.
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 73
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 85
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 74
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 86.
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 75
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 87
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 76
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 88.
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 77
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 89
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 78
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 90.
  • the VL comprises VL CDR1, CDR2, and CDR3 from a VL having the amino acid sequence of SEQ ID NO: 79
  • the VH comprises VH CDR1, CDR2, and CDR3 from a VH having the amino acid sequence of SEQ ID NO: 91.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA21 (SEQ ID NO: 116) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 116.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA21 (SEQ ID NO: 68) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA21 (SEQ ID NO: 80) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA21.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA21 (SEQ ID NO: 68) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA21 (SEQ ID NO: 80) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA21, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA21.
  • the BCMA21 variant can have a VL that is a variant of the VL of BCMA21 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 68.
  • the BCMA21 variant can have a VH that is a variant of the VH of BCMA21 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 80.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA21 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA21 has up to 3 conservative amino acid substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA22 (SEQ ID NO: 117) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 117.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA22 (SEQ ID NO: 69) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA22 (SEQ ID NO: 81) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA22.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA22 (SEQ ID NO: 69) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA22 (SEQ ID NO: 81) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA22, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA22.
  • the BCMA22 variant can have a VL that is a variant of the VL of BCMA22 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 69.
  • the BCMA22 variant can have a VH that is a variant of the VH of BCMA22 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 81.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA22 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA22 has up to 3 conservative amino acid substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA23 (SEQ ID NO: 118) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 118.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA23 (SEQ ID NO: 70) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA23 (SEQ ID NO: 82) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA23.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA23 (SEQ ID NO: 70) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA23 (SEQ ID NO: 82) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA23, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA23.
  • the BCMA23 variant can have a VL that is a variant of the VL of BCMA23 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 70.
  • the BCMA23 variant can have a VH that is a variant of the VH of BCMA23 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 82.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA23 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA23 has up to 3 conservative amino acid substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA24 (SEQ ID NO: 119) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 119.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA24 (SEQ ID NO: 71) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA24 (SEQ ID NO: 83) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA24.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA24 (SEQ ID NO: 71) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA24 (SEQ ID NO: 83) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA24, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA24.
  • the BCMA24 variant can have a VL that is a variant of the VL of BCMA24 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 71.
  • the BCMA24 variant can have a VH that is a variant of the VH of BCMA24 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 83.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA24 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA24 has up to 3 conservative amino acid substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA27 (SEQ ID NO: 120) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 120.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA27 (SEQ ID NO: 72) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA27 (SEQ ID NO: 84) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA27.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA27 (SEQ ID NO: 72) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA27 (SEQ ID NO: 84) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA27, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA27.
  • the BCMA27 variant can have a VL that is a variant of the VL of BCMA27 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 72.
  • the BCMA27 variant can have a VH that is a variant of the VH of BCMA27 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 84.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA27 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA27 has up to 3 conservative amino acid substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA28 (SEQ ID NO: 121) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 121.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA28 (SEQ ID NO: 73) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA28 (SEQ ID NO: 85) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA28.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA28 (SEQ ID NO: 73) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA28 (SEQ ID NO: 85) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA28, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA28.
  • the BCMA28 variant can have a VL that is a variant of the VL of BCMA28 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 73.
  • the BCMA28 variant can have a VH that is a variant of the VH of BCMA28 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 85.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA28 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA28 has up to 3 conservative amino acid substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA30 (SEQ ID NO: 122) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 122.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA30 (SEQ ID NO: 74) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA30 (SEQ ID NO: 86) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA30.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA30 (SEQ ID NO: 74) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA30 (SEQ ID NO: 86) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA30, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA30.
  • the BCMA30 variant can have a VL that is a variant of the VL of BCMA30 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 74.
  • the BCMA30 variant can have a VH that is a variant of the VH of BCMA30 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 86.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA30 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA30 has up to 3 conservative amino acid substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA31 (SEQ ID NO: 123) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 123.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA31 (SEQ ID NO: 75) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA31 (SEQ ID NO: 87) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA31.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA31 (SEQ ID NO: 75) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA31 (SEQ ID NO: 87) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA31, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA31.
  • the BCMA31 variant can have a VL that is a variant of the VL of BCMA31 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 75.
  • the BCMA31 variant can have a VH that is a variant of the VH of BCMA31 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 87.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA31 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA31 has up to 3 conservative amino acid substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA32 (SEQ ID NO: 124) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 124.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA32 (SEQ ID NO: 76) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA32 (SEQ ID NO: 88) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA32.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA32 (SEQ ID NO: 76) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA32 (SEQ ID NO: 88) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA32, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA32.
  • the BCMA32 variant can have a VL that is a variant of the VL of BCMA32 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 76.
  • the BCMA32 variant can have a VH that is a variant of the VH of BCMA32 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 88.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA32 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA32 has up to 3 conservative amino acid substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA33 (SEQ ID NO: 125) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 125.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA33 (SEQ ID NO: 77) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA33 (SEQ ID NO: 89) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA33.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA33 (SEQ ID NO: 77) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA33 (SEQ ID NO: 89) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA33, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA33.
  • the BCMA33 variant can have a VL that is a variant of the VL of BCMA33 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 77.
  • the BCMA33 variant can have a VH that is a variant of the VH of BCMA33 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 89.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA33 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA33 has up to 3 conservative amino acid substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA34 (SEQ ID NO: 126) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 126.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA34 (SEQ ID NO: 78) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA34 (SEQ ID NO: 90) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA34.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA34 (SEQ ID NO: 78) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA34 (SEQ ID NO: 90) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA34, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA34.
  • the BCMA34 variant can have a VL that is a variant of the VL of BCMA34 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 78.
  • the BCMA34 variant can have a VH that is a variant of the VH of BCMA34 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 90.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA34 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA34 has up to 3 conservative amino acid substitutions.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is the scFv designated as BCMA35 (SEQ ID NO: 127) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has an amino acid sequence that is at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%identical to SEQ ID NO: 127.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL from BCMA35 (SEQ ID NO: 79) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH from BCMA35 (SEQ ID NO: 91) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have both a VL and a VH from BCMA35.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VL that comprises VL CDRs 1, 2, and 3 from the VL from BCMA35 (SEQ ID NO: 79) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein has a VH that comprises VH CDRs 1, 2, and 3 from the VH from BCMA35 (SEQ ID NO: 91) .
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein can have a VL comprising VL CDRs 1, 2, and 3 and a VH comprising VH CDRs 1, 2, and 3 from the VL and VH of BCMA35, respectively.
  • the anti-BCMA antibody or antigen-binding fragment thereof provided herein is a variant of BCMA35.
  • the BCMA35 variant can have a VL that is a variant of the VL of BCMA35 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 79.
  • the BCMA35 variant can have a VH that is a variant of the VH of BCMA35 having up to about 5 amino acid substitutions, additions, and/or deletions in SEQ ID NO: 91.
  • the amino acid substitutions, additions, and/or deletions can be in the VH CDRs or VL CDRs. In some embodiments, the amino acid substitutions, additions, and/or deletions are not in the CDRs.
  • the variant of BCMA35 has up to about 5 conservative amino acid substitutions. In some embodiments, the variant of BCMA35 has up to 3 conservative amino acid substitutions.
  • antibodies or antigen-binding fragments that compete with the antibody or antigen-binding fragment provided above for binding to BCMA (e.g., human BCMA) .
  • Antibodies that “compete with another antibody for binding to a target” refer to antibodies that inhibit (partially or completely) the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, can be determined using known competition experiments, e.g., surface plasmon resonance (SPR) analysis.
  • SPR surface plasmon resonance
  • an anti-BCMA antibody or antigen-binding fragment competes with, and inhibits binding of another antibody or antigen-binding fragment to BCMA by at least 50%, 60%, 70%, 80%, 90%or 100%.
  • Competition assays can be conducted as described, for example, in Ed Harlow and David Lane, Cold Spring Harb Protoc; 2006; doi: l0. H0l/pdb. prot4277 or in Chapter 11 of “Using Antibodies” by Ed Harlow and David Lane, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, USA 1999.
  • provided herein are antibodies or antigen-binding fragments that compete with BCMA21 for binding to BCMA. In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with BCMA22 for binding to BCMA. In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with BCMA23 for binding to BCMA. In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with BCMA24 for binding to BCMA. In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with BCMA27 for binding to BCMA. In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with BCMA28 for binding to BCMA.
  • provided herein are antibodies or antigen-binding fragments that compete with BCMA30 for binding to BCMA. In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with BCMA31 for binding to BCMA. In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with BCMA32 for binding to BCMA. In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with BCMA33 for binding to BCMA. In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with BCMA34 for binding to BCMA. In some embodiments, provided herein are antibodies or antigen-binding fragments that compete with BCMA35 for binding to BCMA.
  • the present disclosure further contemplates additional variants and equivalents that are substantially homologous to the recombinant, monoclonal, chimeric, humanized, and human antibodies, or antibody fragments thereof, described herein.
  • it is desirable to modulate biological properties of the antibody including but not limited to, specificity, thermostability, expression level, effector function (s) , glycosylation, immunogenicity, and/or solubility.
  • amino acid changes may alter post-translational processes of an antibody, such as changing the number or position of glycosylation sites or altering membrane anchoring characteristics.
  • Variations can be a substitution, deletion, or insertion of one or more nucleotides encoding the antibody or polypeptide that results in a change in the amino acid sequence as compared with the native antibody or polypeptide sequence.
  • amino acid substitutions are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine, e.g., conservative amino acid replacements.
  • Insertions or deletions can be in the range of about 1 to 5 amino acids.
  • the substitution, deletion, or insertion includes less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions relative to the parent molecule.
  • variations in the amino acid sequence that are biologically useful and/or relevant can be determined by systematically making insertions, deletions, or substitutions in the sequence and testing the resulting variant proteins for activity as compared to the parent protein.
  • the constant region (s) of an antibody mediates several effector functions and these effector functions can vary depending on the isotype of the antibody.
  • binding of the C1 component of complement to the Fc region of IgG or IgM antibodies (bound to antigen) activates the complement system.
  • Activation of complement is important in the opsonization and lysis of cell pathogens.
  • the activation of complement also stimulates the inflammatory response and can be involved in autoimmune hypersensitivity.
  • the Fc region of an antibody can bind a cell expressing a Fc receptor (FcR) .
  • Fc receptors which are specific for different classes of antibody, including IgG (gamma receptors) , IgE (epsilon receptors) , IgA (alpha receptors) and IgM (mu receptors) . Binding of antibody to Fc receptors on cell surfaces triggers a number of important and diverse biological responses including engulfment and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (called antibody-dependent cell cytotoxicity or ADCC) , release of inflammatory mediators, placental transfer, and control of immunoglobulin production.
  • IgG gamma receptors
  • IgE epsilon receptors
  • IgA alpha receptors
  • IgM mi receptors
  • anti-BCMA antibody or antigen-binding fragment described herein comprise at least one constant region of a human IgA antibody. In some embodiments, anti-BCMA antibody or antigen-binding fragment described herein comprise at least one constant region of a human IgD antibody. In some embodiments, anti-BCMA antibody or antigen-binding fragment described herein comprise at least one constant region of a human IgE antibody. In some embodiments, anti-BCMA antibody or antigen-binding fragment described herein comprise at least one constant region of a human IgG antibody. In some embodiments, anti-BCMA antibody or antigen-binding fragment described herein comprise at least one constant region of a human IgM antibody.
  • anti-BCMA antibody or antigen-binding fragment described herein comprise at least one constant region of a human IgG1 antibody. In some embodiments, anti-BCMA antibody or antigen-binding fragment described herein comprise at least one constant region of a human IgG2 antibody. In some embodiments, anti-BCMA antibody or antigen-binding fragment described herein comprise at least one constant region of a human IgG3 antibody. In some embodiments, anti-BCMA antibody or antigen-binding fragment described herein comprise at least one constant region of a human IgG4 antibody.
  • the antibodies comprise modifications to one or more of the three heavy chain constant regions (CH1, CH2 or CH3) and/or to the light chain constant region (CL) .
  • the heavy chain constant region of the modified antibodies comprises at least one human constant region.
  • the heavy chain constant region of the modified antibodies comprises more than one human constant region.
  • modifications to the constant region comprise additions, deletions, or substitutions of one or more amino acids in one or more regions.
  • one or more regions are partially or entirely deleted from the constant regions of the modified antibodies.
  • a deleted constant region is replaced by a short amino acid spacer that provides some of the molecular flexibility typically imparted by the absent constant region.
  • a modified antibody comprises a CH3 domain directly fused to the hinge region of the antibody.
  • a modified antibody comprises a peptide spacer inserted between the hinge region and modified CH2 and/or CH3 domains.
  • an anti-BCMA antibody or antigen-binding fragment comprises a Fc region.
  • the Fc region is fused via a hinge.
  • the hinge can be an IgG1 hinge, an IgG2 hinge, or an IgG3 hinge.
  • the amino acid sequences of the Fc region of human IgG1, IgG2, IgG3, and IgG4 are known to those of ordinary skill in the art.
  • Fc regions with amino acid variations have been identified in native antibodies.
  • the modified antibodies e.g., modified Fc region
  • the deletion or inactivation (through point mutations or other means) of a constant region reduces Fc receptor binding of the modified antibody as it circulates.
  • the constant region modifications reduce the immunogenicity of the antibody.
  • the constant region modifications increase the serum half-life of the antibody.
  • the constant region modifications reduce the serum half-life of the antibody.
  • the constant region modifications decrease or remove ADCC and/or complement dependent cytotoxicity (CDC) of the antibody.
  • specific amino acid substitutions in a human IgG1 Fc region with corresponding IgG2 or IgG4 residues reduce effector functions (e.g., ADCC and CDC) in the modified antibody.
  • an antibody does not have one or more effector functions (e.g., “effectorless” antibodies) .
  • the antibody has no ADCC activity and/or no CDC activity.
  • the antibody does not bind an Fc receptor and/or complement factors.
  • the antibody has no effector function (s) .
  • the constant region modifications increase or enhance ADCC and/or CDC of the antibody.
  • the constant region is modified to eliminate disulfide linkages or oligosaccharide moieties.
  • the constant region is modified to add/substitute one or more amino acids to provide one or more cytotoxin, oligosaccharide, or carbohydrate attachment sites.
  • an anti-BCMA antibody or antigen-binding fragment comprises a variant Fc region that is engineered with substitutions at specific amino acid positions as compared to a native Fc region.
  • an anti-BCMA antibody or antigen-binding fragment described herein comprises an IgG1 heavy chain constant region that comprises one or more amino acid substitutions selected from the group consisting of K214R, L234A, L235E, G237A, D356E, and L358M, per EU numbering.
  • the IgG1 heavy chain constant region comprises one or more amino acid substitutions selected from the group consisting of K214R, L234A, L235E, G237A, A330S, P331S, D356E, and L358M, per EU numbering. In some embodiments, the IgG1 heavy chain constant region comprises one or more amino acid substitutions selected from the group consisting of K214R, C226S, C229S, and P238S, per EU numbering. In some embodiments, the IgG1 heavy chain constant region comprises one or more amino acid substitutions selected from the group consisting of K214R, D356E, and L358M, per EU numbering.
  • the IgG1 heavy chain constant region comprises one or more amino acid substitutions selected from the group consisting of S131C, K133R, G137E, G138S, Q196K, I199T, N203D, K214R, C226S, C229S, and P238S, per EU numbering.
  • variants can include addition of amino acid residues at the amino-and/or carboxyl-terminal end of the antibody or polypeptide.
  • the length of additional amino acids residues can range from one residue to a hundred or more residues.
  • a variant comprises an N-terminal methionyl residue.
  • the variant comprises an additional polypeptide/protein (e.g., Fc region) to create a fusion protein.
  • a variant is engineered to be detectable and may comprise a detectable label and/or protein (e.g., a fluorescent tag or an enzyme) .
  • variant antibodies or antigen-binding fragments described herein can be generated using methods known in the art, including but not limited to, site-directed mutagenesis, alanine scanning mutagenesis, and PCR mutagenesis.
  • a variant of an anti-BCMA antibody or antigen-binding fragment disclosed herein can retain the ability to bind BCMA to a similar extent, the same extent, or to a higher extent, as the parent antibody or antigen-binding fragment.
  • the variant can be at least about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%or more identical in amino acid sequence to the parent antibody or antigen-binding fragment.
  • a variant of an anti-BCMA antibody or antigen-binding fragment comprises the amino acid sequence of the parent anti-BCMA antibody or antigen-binding fragment with one or more conservative amino acid substitution. Conservative amino acid substitutions are known in the art and include amino acid substitutions in which one amino acid having certain physical and/or chemical properties is exchanged for another amino acid that has the same or similar chemical or physical properties.
  • a variant of an anti-BCMA antibody or antigen-binding fragment comprises the amino acid sequence of the parent antibody or antigen-binding fragment with one or more non-conservative amino acid substitutions.
  • a variant of an anti-BCMA antibody or antigen-binding fragment comprises the amino acid sequence of the parent binding antibody or antigen-binding fragment with one or more non-conservative amino acid substitution, wherein the one or more non-conservative amino acid substitutions do not interfere with or inhibit one or more biological activities of the variant (e.g., BCMA binding) .
  • the one or more conservative amino acid substitutions and/or the one or more non-conservative amino acid substitutions can enhance a biological activity of the variant, such that the biological activity of the functional variant is increased as compared to the parent binding moiety.
  • the variant can have 1, 2, 3, 4, or 5 amino acid substitutions in the CDRs (e.g., VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) of the binding moiety.
  • VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 amino acid substitutions in the CDRs (e.g., VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3) of the binding moiety.
  • anti-BCMA antibodies or antigen-binding fragments described herein are chemically modified naturally or by intervention.
  • the anti-BCMA antibodies or antigen-binding fragments have been chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, and/or linkage to a cellular ligand or other protein. Any of numerous chemical modifications can be carried out by known techniques.
  • the anti-BCMA antibodies or antigen- binding fragments can comprise one or more analogs of an amino acid (including, for example, unnatural amino acids) , as well as other modifications known in the art.
  • an anti-BCMA antibody or antigen-binding fragment binds BCMA (e.g., human BCMA) with a dissociation constant (K D ) of about 1 ⁇ M or less, about 100 nM or less, about 40 nM or less, about 20 nM or less, about 10 nM or less, about 1 nM or less, about 0.1 nM or less, 50 pM or less, 10 pM or less, or 1 pM or less.
  • an anti-BCMA antibody or antigen-binding fragment binds BCMA (e.g., human BCMA) with a K D of about 20 nM or less.
  • an anti-BCMA antibody or antigen-binding fragment binds BCMA (e.g., human BCMA) with a K D of about 10 nM or less. In some embodiments, an anti-BCMA antibody or antigen-binding fragment binds BCMA (e.g., human BCMA) with a K D of about 1 nM or less. In some embodiments, an anti-BCMA antibody or antigen-binding fragment binds BCMA (e.g., human BCMA) with a K D of about 0.5 nM or less. In some embodiments, an anti-BCMA antibody or antigen-binding fragment binds BCMA (e.g., human BCMA) with a K D of about 0.1 nM or less.
  • an anti-BCMA antibody or antigen-binding fragment binds BCMA (e.g., human BCMA) with a K D of about 50 pM or less. In some embodiments, an anti-BCMA antibody or antigen-binding fragment binds BCMA (e.g., human BCMA) with a K D of about 25 pM or less. In some embodiments, an anti-BCMA antibody or antigen-binding fragment binds BCMA (e.g., human BCMA) with a K D of about 10 pM or less. In some embodiments, an anti-BCMA antibody or antigen-binding fragment binds BCMA (e.g., human BCMA) with a K D of about 1 pM or less.
  • the dissociation constant of the binding agent (e.g., an antibody) for BCMA is the dissociation constant determined using a BCMA protein immobilized on a Biacore chip and the binding agent flowed over the chip.
  • the dissociation constant of the binding agent (e.g., an antibody) for BCMA is the dissociation constant determined using the binding agent captured by an anti-human IgG antibody on a Biacore chip and soluble BCMA flowed over the chip.
  • anti-BCMA antibodies or antigen-binding fragments of the present disclosure can be analyzed for their physical, chemical and/or biological properties by various methods known in the art.
  • an anti-BCMA antibody is tested for its ability to bind BCMA (e.g., human BCMA) .
  • Binding assays include, but are not limited to, SPR (e.g., Biacore) , ELISA, and FACS.
  • antibodies can be evaluated for solubility, stability, thermostability, viscosity, expression levels, expression quality, and/or purification efficiency.
  • Epitope mapping is a method of identifying the binding site, region, or epitope on a target protein where an antibody binds.
  • a variety of methods are known in the art for mapping epitopes on target proteins. These methods include mutagenesis, including but not limited to, shotgun mutagenesis, site-directed mutagenesis, and alanine scanning; domain or fragment scanning; peptide scanning (e.g., Pepscan technology) ; display methods (e.g., phage display, microbial display, and ribosome/mRNA display) ; methods involving proteolysis and mass spectroscopy; and structural determination (e.g., X-ray crystallography and NMR) .
  • anti-BCMA antibodies or antigen-binding fragments described herein are characterized by assays including, but not limited to, N-terminal sequencing, amino acid analysis, HPLC, mass spectrometry, ion exchange chromatography, and papain digestion.
  • an anti-BCMA antibody or antigen-binding fragment is conjugated to a cytotoxic agent or moiety.
  • an anti-BCMA antibody or antigen-binding fragment is conjugated to a cytotoxic agent to form an ADC (antibody-drug conjugate) .
  • the cytotoxic moiety is a chemotherapeutic agent including, but not limited to, methotrexate, adriamycin/doxorubicin, melphalan, mitomycin C, chlorambucil, duocarmycin, daunorubicin, pyrrolobenzodiazepines (PBDs) , or other intercalating agents.
  • the cytotoxic moiety is a microtubule inhibitor including, but not limited to, auristatins, maytansinoids (e.g., DM1 and DM4) , and tubulysins.
  • the cytotoxic moiety is an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof, including, but not limited to, diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S) , Momordica charantia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin
  • an anti-BCMA antibody or antigen-binding fragment described herein is conjugated to a detectable substance or molecule that allows the agent to be used for diagnosis and/or detection.
  • a detectable substance can include, but is not limited to, enzymes, such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and acetylcholinesterase; prosthetic groups, such as biotin and flavine (s) ; fluorescent materials, such as, umbelliferone, fluorescein, fluorescein isothiocyanate (FITC) , rhodamine, tetramethylrhodamine isothiocyanate (TRITC) , dichlorotriazinylamine fluorescein, dansyl chloride, cyanine (Cy3) , and phycoerythrin; bioluminescent materials, such as luciferase; radioactive materials, such as 212 Bi, 14 C, 57 Co, 51 Cr
  • An anti-BCMA antibody or antigen-binding fragment described herein can be attached to a solid support.
  • Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene.
  • an immobilized anti-BCMA antibody or antigen-binding fragment is used in an immunoassay.
  • an immobilized anti-BCMA antibody or antigen-binding fragment is used in purification of the target antigen (e.g., human BCMA) .
  • the anti-BCMA antibodies or antigen-binding fragments described herein can be used as part of a chimeric antigen receptor (CAR) or a T-Cell Receptor (TCR) that can be expressed in an immune effector cell for cancer treatment.
  • CAR chimeric antigen receptor
  • TCR T-Cell Receptor
  • CARs and TCRs that specifically bind BCMA (e.g., human BCMA) , immune effector cells that express such CARs or TCRs, and the uses of such cells.
  • TCRs T cell receptors
  • BCMA TCR BCMA TCR
  • TCRs are antigen-specific molecules that are responsible for recognizing antigenic peptides presented in the context of a product of the MHC on the surface of APCs or any nucleated cells. This system endows T cells, via their TCRs, with the potential ability to recognize the entire array of intracellular antigens expressed by a cell (including virus proteins) that are processed into short peptides, bound to an intracellular MHC molecule, and delivered to the surface as a peptide-MHC complex.
  • This system allows foreign protein (e.g., mutated cancer antigen or virus protein) or aberrantly expressed protein to serve a target for T cells (e.g., Davis and Bjorkman (1988) Nature, 334, 395-402; Davis et al. (1998) Annu Rev Immunol, 16, 523-544) .
  • foreign protein e.g., mutated cancer antigen or virus protein
  • aberrantly expressed protein e.g., mutated cancer antigen or virus protein
  • the interaction of a TCR and a peptide-MHC complex can drive the T cell into various states of activation, depending on the affinity (or dissociation rate) of binding.
  • the TCR recognition process allows a T cell to discriminate between a normal, healthy cell and, for example, one that has become transformed via a virus or malignancy, by providing a diverse repertoire of TCRs, wherein there is a high probability that one or more TCRs will be present with a binding affinity for the foreign peptide bound to an MHC molecule that is above the threshold for stimulating T cell activity (Manning and Kranz (1999) Immunology Today, 20, 417-422) .
  • T cells have evolved a co-receptor system in which the cell surface molecules CD4 and CD8 bind to the MHC molecules (class II and class I, respectively) and synergize with the TCR in mediating signaling activity.
  • Directed evolution can be used to generate TCRs with higher affinity for a specific peptide-MHC complex.
  • Methods that can be used include yeast display (Holler et al. (2003) Nat Immunol, 4, 55-62; Holler et al. (2000) Proc Natl Acad Sci U S A, 97, 5387-92) , phage display (Li et al. (2005) Nat Biotechnol, 23, 349-54) , and T cell display (Chervin et al. (2008) J Immunol Methods, 339, 175-84) . All three approaches involve engineering, or modifying, a TCR that exhibits the normal, low affinity of the wild-type TCR, to increase the affinity for the cognate peptide-MHC complex (the original antigen that the T cells were specific for) .
  • TCRs comprising an anti-BCMA antibody or antigen-binding fragment described herein.
  • the anti-BCMA antibody or antigen-binding fragment can be any anti-BCMA antibody or antigen-binding fragment described herein.
  • the TCRs provided herein can comprise an anti-BCMA antibody or antigen-binding fragment having a VL and a VH, wherein the VL comprises VL CDR1, CDR2 and CDR3 and the VH comprises VH CDR1, CDR2 and CDR3, and wherein the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2 and VH CDR3 have the amino acid sequences of (1) SEQ ID NOs: 1, 11, 22, 33, 44, and 56, respectively; (2) SEQ ID NOs: 2, 12, 23, 34, 45, and 57, respectively; (3) SEQ ID NOs: 3, 13, 24, 35, 46, and 58, respectively; (4) SEQ ID NOs: 4, 14, 24, 36, 47, and 59, respectively; (5) SEQ ID NOs: 5, 15, 25, 37, 48, and 60, respectively; (6) SEQ ID NOs: 6, 16, 26, 38, 49, and 61, respectively; (7) SEQ ID NOs: 7, 17, 27,
  • the TCRs provided herein can comprise an anti-BCMA antibody or antigen-binding fragment that is the scFv designated as BCMA21, BCMA22, BCMA23, BCMA24, BCMA27, BCMA28, BCMA30, BCMA31, BCMA32, BCMA33, BCMA34, or BCMA35.
  • the TCRs provided herein can comprise BCMA24.
  • the TCRs provided herein can comprise BCMA31.
  • the TCRs provided herein can comprise BCMA33.
  • the TCRs provided herein comprise an alpha ( ⁇ ) chain and a beta ( ⁇ ) chain.
  • the constant region of TCR ⁇ chain and ⁇ chain are encoded by TRAC and TRBC, respectively.
  • a human TRAC can have an amino acid sequence corresponding to UniProtKB/Swiss-Prot No.: P01848.2 (Accession: P01848.2 GI: 1431906459) .
  • a human TRBC can have an amino acid sequence corresponding to the GenBank sequence ALC78509.1 (Accession: ALC78509.1 GI: 924924895) .
  • the TCRs provided herein comprise a TCR ⁇ chain comprising an anti-BCMA antibody or antigen-binding fragment provided herein. In some embodiments, the TCRs provided herein comprise a TCR ⁇ chain comprising an anti-BCMA antibody or antigen-binding fragment provided herein. In some embodiments, the TCR comprises a gamma chain ( ⁇ ) and a delta ( ⁇ ) chain. The constant region of TCR ⁇ chain and ⁇ chain are encoded by encoded by TRGC and TRDC, respectively.
  • a human TRGC can have an amino acid sequence corresponding to UniProtKB/Swiss-Prot: P0CF51.1 (Accession: P0CF51.1 GI: 294863156) , or an amino acid sequence corresponding to UniProtKB/Swiss-Prot: P03986.2 (Accession: P03986.2 GI: 1531253869) .
  • a human TRDC can have an amino acid sequence corresponding to the UniProtKB/Swiss-Prot: B7Z8K6.2 (Accession: B7Z8K6.2 GI: 294863191) .
  • the TCRs provided herein comprise a TCR ⁇ chain comprising an anti-BCMA antibody or antigen-binding fragment provided herein.
  • the TCRs provided herein comprise a TCR ⁇ chain comprising an anti-BCMA antibody or antigen-binding fragment provided herein.
  • CARs are engineered receptors that provide both antigen binding and immune effector cell activation functions.
  • CARs can be used to graft the specificity of an antibody, such as a monoclonal antibody, onto an immune effector cell such as a T cell, a NK cell, or a macrophage.
  • CARs can retarget immune effector cells (e.g., T cells) to tumor surface antigens in HLA-independent manner (Sadelain et al., Nat. Rev. Cancer. 3 (1) : 35-45 (2003) ; Sadelain et al., Cancer Discovery 3 (4) : 388-398 (2013) ; Rafiq and Brentjens (2016) . Nat Rev Clin Oncol 13 (6) : 370-383) .
  • the typical structure of a CAR molecule includes an extracellular antigen-binding domain (e.g., scFv) , a transmembrane domain (TM) and an intracellular signaling domain.
  • the extracellular antigen-binding domain of a CAR is usually derived from a monoclonal antibody (mAb) or from receptors or their ligands.
  • mAb monoclonal antibody
  • Antigen binding by the CARs triggers phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the intracellular domain, initiating a signaling cascade required for cytolysis induction, cytokine secretion, and proliferation.
  • CAR-expressing T cells ( “CART” s) can be classified into three generations according to the presence of intracellular co-stimulatory signals.
  • CARs that specifically binds BCMA ( “BCMA CAR” ) .
  • the CAR can be a “first generation, ” “second generation” or “third generation” CAR (see, for example, Sadelain et al., Cancer Discov. 3 (4) : 388-398 (2013) ; Jensen et al., Immunol. Rev. 257: 127-133 (2014) ; Sharpe et al., Dis. Model Mech. 8 (4) : 337-350 (2015) ; June et al (2016) , Science 359 (6382) : 1361-1365) .
  • First generation CARs are typically composed of an extracellular antigen binding domain, for example, a single-chain variable fragment (scFv) , fused to a transmembrane domain, which is fused to a cytoplasmic/intracellular domain of the T cell receptor chain.
  • scFv single-chain variable fragment
  • First generation CARs typically have the intracellular domain from the CD3 ⁇ -chain, which is the primary transmitter of signals from endogenous T cell receptors (TCRs) .
  • TCRs endogenous T cell receptors
  • First generation CARs can provide de novo antigen recognition and cause activation of both CD4 + and CD8 + T cells through their CD3 ⁇ chain signaling domain in a single fusion molecule, independent of HLA-mediated antigen presentation.
  • “Second-generation” CARs comprise a cancer antigen-binding domain fused to an intracellular signaling domain capable of activating immune effector cells such as T cells and a co-stimulatory domain designed to augment immune effector cell, such as T cell, potency and persistence (Sadelain et al., Cancer Discov. 3: 388-398 (2013) ) .
  • CAR design can therefore combine antigen recognition with signal transduction, two functions that are physiologically borne by two separate complexes, the TCR heterodimer and the CD3 complex.
  • “Second generation” CARs include an intracellular domain from various co-stimulatory receptors, for example, CD28, 4-1BB, ICOS, OX40, and the like, in the cytoplasmic tail of the CAR to provide additional signals to the cell. “Second generation” CARs provide both co-stimulation, for example, by CD28 or 4-1BB domains, and activation, for example, by a CD3 ⁇ signaling domain. Studies have indicated that “Second Generation” CARs can improve the anti-tumor activity of T cells.
  • B-ALL B-cell precursor acute lymphoblastic leukemia
  • B-cell Non-Hodgkin Lymphoma B-cell Non-Hodgkin Lymphoma.
  • “Third generation” CARs provide multiple co-stimulation, for example, by comprising both CD28 and 4-1BB domains, and activation, for example, by comprising a CD3 ⁇ activation domain.
  • CARs that specifically binds BCMA, comprising, from N-terminus to C-terminus: (a) a BCMA binding domain comprising an anti-BCMA antibody or antigen-binding fragment provided herein, (b) a transmembrane domain, and (c) a cytoplasmic domain.
  • the anti-BCMA antibody or antigen-binding fragment can be any anti-BCMA antibody or antigen-binding fragment described herein.
  • the CARs provided herein can comprise an anti-BCMA antibody or antigen-binding fragment having a VL and a VH, wherein the VL comprises VL CDR1, CDR2 and CDR3 and the VH comprises VH CDR1, CDR2 and CDR3, and wherein the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2 and VH CDR3 have the amino acid sequences of (1) SEQ ID NOs: 1, 11, 22, 33, 44, and 56, respectively; (2) SEQ ID NOs: 2, 12, 23, 34, 45, and 57, respectively; (3) SEQ ID NOs: 3, 13, 24, 35, 46, and 58, respectively; (4) SEQ ID NOs: 4, 14, 24, 36, 47, and 59, respectively; (5) SEQ ID NOs: 5, 15, 25, 37, 48, and 60, respectively; (6) SEQ ID NOs: 6, 16, 26, 38, 49, and 61, respectively; (7) SEQ ID NOs: 7, 17, 27,
  • the CARs provided herein can comprise an anti-BCMA antibody or antigen-binding fragment that is the scFv designated as BCMA21, BCMA22, BCMA23, BCMA24, BCMA27, BCMA28, BCMA30, BCMA31, BCMA32, BCMA33, BCMA34, or BCMA35.
  • the CARs provided herein can comprise BCMA24.
  • the CARs provided herein can comprise BCMA31.
  • the CARs provided herein can comprise BCMA33.
  • the transmembrane domain of the CARs provided herein comprises a hydrophobic alpha helix that spans at least a portion of the membrane. Different transmembrane domains result in different receptor stability. After antigen recognition, receptors cluster and a signal is transmitted to the cell.
  • the transmembrane domain of the CAR provided herein can be derived from a protein or polypeptide that is naturally expressed in an immune effector cell.
  • a transmembrane domain derived from a protein or polypeptide means that the transmembrane domain comprises the entire transmembrane region of the protein or polypeptide, or a fragment thereof.
  • the CAR provided herein can have a transmembrane domain derived from CD8, CD28, CD3 ⁇ , CD4, 4-1BB, OX40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, BTLA, T-cell receptor (TCR) ⁇ chain, TCR ⁇ chain, or TCR ⁇ chain, CD3 ⁇ , CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD154, or other polypeptides expressed in the immune effector cell.
  • TCR T-cell receptor
  • the transmembrane domain of CARs provided herein comprises the transmembrane region of CD8, CD28, CD3 ⁇ , CD4, 4-1BB, OX40, ICOS, CTLA-4, PD-1, LAG-3, 2B4, BTLA, T-cell receptor (TCR) ⁇ chain, TCR ⁇ chain, or TCR ⁇ chain, CD3 ⁇ , CD45, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD154, or other polypeptides expressed in the immune effector cell.
  • the transmembrane domain of CARs provided herein is derived from CD8. In some embodiments, the transmembrane domain comprises the transmembrane region of CD8. In some embodiments, the transmembrane domain is derived from CD28. In some embodiments, the transmembrane domain comprises the transmembrane region of CD28. In some embodiments, the transmembrane domain is derived from CD3 ⁇ . In some embodiments, the transmembrane domain comprises the transmembrane region of CD3 ⁇ . In some embodiments, the transmembrane domain is derived from CD4. In some embodiments, the transmembrane domain comprises the transmembrane region of CD4.
  • the transmembrane domain is derived from 4-1BB. In some embodiments, the transmembrane domain comprises the transmembrane region of 4-1BB. In some embodiments, the transmembrane domain is derived from OX40. In some embodiments, the transmembrane domain comprises the transmembrane region of OX40. In some embodiments, the transmembrane domain is derived from ICOS. In some embodiments, the transmembrane domain comprises the transmembrane region of ICOS. In some embodiments, the transmembrane domain is derived from CTLA-4. In some embodiments, the transmembrane domain comprises the transmembrane region of CTLA-4.
  • the transmembrane domain is derived from PD-1. In some embodiments, the transmembrane domain comprises the transmembrane region of PD-1. In some embodiments, the transmembrane domain is derived from LAG-3. In some embodiments, the transmembrane domain comprises the transmembrane region of LAG-3. In some embodiments, the transmembrane domain is derived from 2B4. In some embodiments, the transmembrane domain comprises the transmembrane region of 2B4. In some embodiments, the transmembrane domain is derived from BTLA. In some embodiments, the transmembrane domain comprises the transmembrane region of BTLA.
  • the transmembrane domain is derived from TCR ⁇ chain. In some embodiments, the transmembrane domain comprises the transmembrane region of TCR ⁇ chain. In some embodiments, the transmembrane domain is derived from TCR ⁇ chain. In some embodiments, the transmembrane domain comprises the transmembrane region of TCR ⁇ chain. In some embodiments, the transmembrane domain is derived from TCR ⁇ chain. In some embodiments, the transmembrane domain comprises the transmembrane region of TCR ⁇ chain. In some embodiments, the transmembrane domain is derived from CD3 ⁇ . In some embodiments, the transmembrane domain comprises the transmembrane region of CD3 ⁇ .
  • the transmembrane domain is derived from CD45. In some embodiments, the transmembrane domain comprises the transmembrane region of CD45. In some embodiments, the transmembrane domain is derived from CD5. In some embodiments, the transmembrane domain comprises the transmembrane region of CD5. In some embodiments, the transmembrane domain is derived from CD8. In some embodiments, the transmembrane domain comprises the transmembrane region of CD8. In some embodiments, the transmembrane domain is derived from CD9. In some embodiments, the transmembrane domain comprises the transmembrane region of CD9. In some embodiments, the transmembrane domain is derived from CD16.
  • the transmembrane domain comprises the transmembrane region of CD16. In some embodiments, the transmembrane domain is derived from CD22. In some embodiments, the transmembrane domain comprises the transmembrane region of CD22. In some embodiments, the transmembrane domain is derived from CD33. In some embodiments, the transmembrane domain comprises the transmembrane region of CD33. In some embodiments, the transmembrane domain is derived from CD37. In some embodiments, the transmembrane domain comprises the transmembrane region of CD37. In some embodiments, the transmembrane domain is derived from CD64.
  • the transmembrane domain comprises the transmembrane region of CD64. In some embodiments, the transmembrane domain is derived from CD80. In some embodiments, the transmembrane domain comprises the transmembrane region of CD80. In some embodiments, the transmembrane domain is derived from CD86. In some embodiments, the transmembrane domain comprises the transmembrane region of CD86. In some embodiments, the transmembrane domain is derived from CD134. In some embodiments, the transmembrane domain comprises the transmembrane region of CD134. In some embodiments, the transmembrane domain is derived from CD154. In some embodiments, the transmembrane domain comprises the transmembrane region of CD154. Exemplary transmembrane domains are described below in more detail.
  • a short oligo-or polypeptide linker preferably between 2 and 10 amino acids in length can form the linkage between the transmembrane domain and the cytoplasmic signaling domain of the CAR.
  • a glycine-serine doublet provides a particularly suitable linker.
  • Cytoplasmic domains of CARs provided herein can contain a signaling domain that functions in the immune effector cell expressing the CAR.
  • a signaling domain can be, for example, derived from CD3 ⁇ , Fc receptor ⁇ , Fc ⁇ RIIa, FcR ⁇ (Fc ⁇ R1b) , CD3 ⁇ , CD3 ⁇ , CD3 ⁇ , CD79a, CD79b, DAP10, or DAP12.
  • a signaling domain can also be a combination of signaling domains derived from molecules selected from CD3 ⁇ , Fc receptor ⁇ , Fc ⁇ RIIa, FcR ⁇ (Fc ⁇ R1b) , CD3 ⁇ , CD3 ⁇ , CD3 ⁇ , CD79a, CD79b, DAP10, and DAP12.
  • a signaling domain derived from a protein or polypeptide refers to the domain of the protein or polypeptide that is responsible for activating the immune effector cell (e.g., a T cell) , or a fragment thereof that retains its activation function.
  • the signaling domain induces persistence, trafficking and/or effector functions in the transduced immune effector cells such as T cells (Sharpe et al., Dis. Model Mech. 8: 337-350 (2015) ; Finney et al., J. Immunol. 161: 2791-2797 (1998) ; Krause et al., J. Exp. Med. 188: 619-626 (1998) ) .
  • the signaling domain of a protein or polypeptide can be the intracellular domain of the protein or polypeptide.
  • the signaling domain comprises the intracellular domain of CD3 ⁇ , FcR ⁇ , Fc ⁇ RIIa, FcR ⁇ , CD3 ⁇ , CD3 ⁇ , CD3 ⁇ , CD5, CD22, CD79a, CD79b, DAP10, DAP12, or any combination thereof.
  • the cytoplasmic domain of CARs provided herein comprises a signaling domain derived from CD3 ⁇ . In some embodiments, the signaling domain comprises the intracellular domain of CD3 ⁇ . In some embodiments, the cytoplasmic domain comprises a signaling domain derived from FcR ⁇ . In some embodiments, the signaling domain comprises the intracellular domain of FcR ⁇ . In some embodiments, the cytoplasmic domain comprises a signaling domain derived from Fc ⁇ RIIa. In some embodiments, the signaling domain comprises the intracellular domain of Fc ⁇ RIIa. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from FcR ⁇ . In some embodiments, the signaling domain comprises the intracellular domain of FcR ⁇ .
  • the cytoplasmic domain comprises a signaling domain derived from CD3 ⁇ . In some embodiments, the signaling domain comprises the intracellular domain of CD3 ⁇ . In some embodiments, the cytoplasmic domain comprises a signaling domain derived from CD3 ⁇ . In some embodiments, the signaling domain comprises the intracellular domain of CD3 ⁇ . In some embodiments, the cytoplasmic domain comprises a signaling domain derived from CD3 ⁇ . In some embodiments, the signaling domain comprises the intracellular domain of CD3 ⁇ . In some embodiments, the cytoplasmic domain comprises a signaling domain derived from CD5. In some embodiments, the signaling domain comprises the intracellular domain of CD5. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from CD22.
  • the signaling domain comprises the intracellular domain of CD22. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from CD79a. In some embodiments, the signaling domain comprises the intracellular domain of CD79a. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from CD79b. In some embodiments, the signaling domain comprises the intracellular domain of CD79b. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from DAP10. In some embodiments, the signaling domain comprises the intracellular domain of DAP10. In some embodiments, the cytoplasmic domain comprises a signaling domain derived from DAP12. In some embodiments, the signaling domain comprises the intracellular domain of DAP12. Exemplary signaling domains are described below in more detail.
  • the cytoplasmic domain of CARs provided herein further comprises a co-stimulatory domain. In some embodiments, the cytoplasmic domain of CARs provided herein further comprises two co-stimulatory domains. Such a co-stimulatory domain can provide increased activation of an immune effector cell (e.g., T cell) .
  • a co-stimulatory signaling domain can be derived from, for example, CD28, 4-1BB (CD137) , OX40, ICOS, DAP10, 2B4, CD27, CD30, CD40, CD2, CD7, LIGHT, TIGIT, GITR, TLR, DR3, or CD43.
  • a co-stimulatory domain derived from a protein or polypeptide refers to the domain of the protein or polypeptide that is responsible for providing increased activation of an immune effector cell (e.g., T cell) , or a fragment thereof that retains its activation function.
  • the co-stimulatory domain of CARs provided herein comprises the intracellular domain of CD28, 4-1BB (CD137) , OX40, ICOS, DAP10, 2B4, CD27, CD30, CD40, CD2, CD7, LIGHT, TIGIT, GITR, TLR, DR3, or CD43.
  • the cytoplasmic domain of CARs provided herein comprises a co-stimulatory domain derived from CD28.
  • the co-stimulatory domain comprises the intracellular domain of CD28. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from 4-1BB. In some embodiments, the co-stimulatory domain comprises the intracellular domain of 4-1BB. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from OX40. In some embodiments, the co-stimulatory domain comprises the intracellular domain of OX40. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from ICOS. In some embodiments, the co-stimulatory domain comprises the intracellular domain of ICOS.
  • the cytoplasmic domain comprises a co-stimulatory domain derived from DAP10. In some embodiments, the co-stimulatory domain comprises the intracellular domain of DAP10. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from 2B4. In some embodiments, the co-stimulatory domain comprises the intracellular domain of 2B4. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from CD27. In some embodiments, the co-stimulatory domain comprises the intracellular domain of CD27. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from CD30. In some embodiments, the co-stimulatory domain comprises the intracellular domain of CD30.
  • the cytoplasmic domain comprises a co-stimulatory domain derived from CD40. In some embodiments, the co-stimulatory domain comprises the intracellular domain of CD40. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from CD2. In some embodiments, the co-stimulatory domain comprises the intracellular domain of CD2. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from CD7. In some embodiments, the co-stimulatory domain comprises the intracellular domain of CD7. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from LIGHT. In some embodiments, the co-stimulatory domain comprises the intracellular domain of LIGHT.
  • the cytoplasmic domain comprises a co-stimulatory domain derived from TIGIT. In some embodiments, the co-stimulatory domain comprises the intracellular domain of TIGIT. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from GITR. In some embodiments, the co-stimulatory domain comprises the intracellular domain of GITR. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from TLR. In some embodiments, the co-stimulatory domain comprises the intracellular domain of TLR. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from DR3. In some embodiments, the co-stimulatory domain comprises the intracellular domain of DR3. In some embodiments, the cytoplasmic domain comprises a co-stimulatory domain derived from CD43. In some embodiments, the co-stimulatory domain comprises the intracellular domain of CD43. Exemplary co-stimulatory domains are described below in more detail.
  • CARs comprising an intracellular domain that comprises a co-stimulatory domain derived from 4-1BB, ICOS or DAP-10 have been described previously (see U.S. 7,446,190, which is incorporated herein by reference, which also describes representative sequences for 4-1BB, ICOS and DAP-10) .
  • the cytoplasmic domain of a CAR can comprise two co-stimulatory domains derived from two co-stimulatory receptors, such as CD28 and 4-1BB (see Sadelain et al., Cancer Discov. 3 (4) : 388-398 (2013) ) , or CD28 and OX40, or other combinations of co-stimulatory ligands, as disclosed herein.
  • the extracellular domain of a CAR can be fused to a leader or a signal peptide that directs the nascent protein into the endoplasmic reticulum and subsequent translocation to the cell surface. It is understood that, once a polypeptide containing a signal peptide is expressed at the cell surface, the signal peptide has generally been proteolytically removed during processing of the polypeptide in the endoplasmic reticulum and translocation to the cell surface. Thus, a polypeptide such as a CAR is generally expressed at the cell surface as a mature protein lacking the signal peptide, whereas the precursor form of the polypeptide includes the signal peptide.
  • a signal peptide or leader can be essential if a CAR is to be glycosylated and/or anchored in the cell membrane.
  • the signal sequence or leader is a peptide sequence generally present at the N-terminus of newly synthesized proteins that directs their entry into the secretory pathway.
  • the signal peptide is covalently joined to the N-terminus of the extracellular antigen-binding domain of a CAR as a fusion protein.
  • Any suitable signal peptide as are well known in the art, can be applied to a CAR to provide cell surface expression in an immune cell (see Gierasch Biochem. 28: 923-930 (1989) ; von Heijne, J. Mol. Biol. 184 (1) : 99–105 (1985) ) .
  • Particularly useful signal peptides can be derived from cell surface proteins naturally expressed in the immune cell provided herein, including any of the signal peptides of the polypeptides disclosed herein. Thus, any suitable signal peptide can be utilized to direct a CAR to be expressed at the cell surface of an immune effector cell provided herein.
  • a CAR can also comprise a spacer region or sequence that links the domains of the CAR to each other.
  • a spacer can be included between a signal peptide and an antigen binding domain, between the antigen binding domain and the transmembrane domain, between the transmembrane domain and the intracellular domain, and/or between domains within the intracellular domain, for example, between a stimulatory domain and a co-stimulatory domain.
  • the spacer region can be flexible enough to allow interactions of various domains with other polypeptides, for example, to allow the antigen binding domain to have flexibility in orientation in order to facilitate antigen recognition.
  • the spacer region can be, for example, the hinge region from an IgG, the CH 2 CH 3 (constant) region of an immunoglobulin, and/or portions of CD3 (cluster of differentiation 3) or some other sequence suitable as a spacer.
  • a CAR disclosed herein comprises a hinge domain that connects the BCMA binding domain and the transmembrane domain.
  • the hinge domain comprises human CD8 hinge domain.
  • the hinge domain comprises human CD28 hinge domain.
  • CD3 ⁇ comprises 3 Immune-receptor-Tyrosine-based-Activation-Motifs (ITAMs) , and transmits an activation signal to the cell, for example, a cell of the lymphoid lineage such as a T cell, after antigen is bound.
  • a CD3 ⁇ polypeptide can have an amino acid sequence corresponding to the sequence having GenBank No. NP_932170 (NP_932170.1, GI: 37595565; see below) , or fragments thereof.
  • a CD3 ⁇ signaling domain has an amino acid sequence of amino acids 52 to 164 of the CD3 ⁇ polypeptide sequence provided below, or a fragment thereof that is sufficient for signaling activity.
  • a CAR can have a transmembrane domain derived from CD3 ⁇ .
  • the transmembrane domain can comprise the transmembrane region of CD3 ⁇ (e.g., amino acids 31 to 51 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a signaling domain derived from CD3 ⁇ .
  • a signaling domain of CD3 ⁇ can comprise the intracellular domain of CD3 ⁇ (e.g., amino acids 52 to 164 of the sequence below) , or a fragment thereof. It is understood that sequences of CD3 ⁇ that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • FcR ⁇ Activating types of IgG receptor Fc ⁇ Rs form multimeric complexes including the Fc receptor common ⁇ chain (FcR ⁇ ) that contains an intracellular tyrosine-based activating motif (ITAM) , whose activation triggers oxidative bursts, cytokine release, phagocytosis, antibody-dependent cell-mediated cytotoxicity, and degranulation.
  • FcR ⁇ polypeptide can have an amino acid sequence corresponding to the sequence having NCBI Reference Sequence: NP_004097.1 (GI: 4758344) , provided below, or fragments thereof.
  • a CAR can comprise a transmembrane domain derived from FcR ⁇ .
  • the transmembrane domain of the CAR comprises the transmembrane region of FcR ⁇ (e.g., amino acids 24 to 44 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a signaling domain derived from FcR ⁇ .
  • the signaling domain comprises the intracellular domain of FcR ⁇ (e.g., amino acids 45 to 86 of the sequence below) , or a fragment thereof. It is understood that sequences of FcR ⁇ that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • FcR ⁇ e.g., amino acids 45 to 86 of the sequence below
  • Fc ⁇ RIIa is a cell surface receptor found on phagocytic cells such as macrophages and neutrophils, and is involved in the process of phagocytosis and clearing of immune complexes. By binding to IgG it initiates cellular responses against pathogens and soluble antigens. Fc ⁇ RIIa also promotes phagocytosis of opsonized antigens.
  • An Fc ⁇ RIIa polypeptide can have an amino acid sequence corresponding to the sequence having NCBI Reference Sequence: NP_001129691.1, provided below, or fragments thereof.
  • a CAR can comprise a transmembrane domain derived from Fc ⁇ RIIa.
  • the transmembrane domain of the CAR comprises the transmembrane region of Fc ⁇ RIIa (e.g., amino acids 218 to 240 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a signaling domain derived from Fc ⁇ RIIa.
  • the signaling domain comprises the intracellular domain of Fc ⁇ RIIa (e.g., amino acids 241 to 317 of the sequence below) , or a fragment thereof. It is understood that sequences of Fc ⁇ RIIa that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • FcR ⁇ (Fc ⁇ R1b) is a high affinity receptor that binds to the Fc region of immunoglobulins epsilon. Aggregation of FcR ⁇ by multivalent antigens is required for the full mast cell response, including the release of preformed mediators (such as histamine) by degranulation and de novo production of lipid mediators and cytokines. FcR ⁇ also mediates the secretion of important lymphokines. Binding of allergen to receptor-bound IgE leads to cell activation and the release of mediators responsible for the manifestations of allergy.
  • An FcR ⁇ polypeptide can have an amino acid sequence corresponding to the sequence having NCBI Reference Sequence: NP_000130.1, provided below, or fragments thereof.
  • the cytoplasmic domain of a CAR can comprise a signaling domain derived from FcR ⁇ .
  • the signaling domain comprises an intracellular domain of FcR ⁇ (e.g., amino acids 1 to 59, 118 to 130, or 201 to 244 of the sequence below, or a combination thereof) , or a fragment thereof. It is understood that sequences of FcR ⁇ that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD3 ⁇ T-cell surface glycoprotein CD3 gamma chain
  • CD3 ⁇ is part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.
  • ITAMs immunoreceptor tyrosine-based activation motifs
  • CD3 ⁇ plays an essential role in the dynamic regulation of TCR expression at the cell surface.
  • a CD3 ⁇ polypeptide can have an amino acid sequence corresponding to the sequence having NCBI Reference Sequence: NP_004097.1 (GI: 4758344) , provided below, or fragments thereof.
  • a CAR can comprise a transmembrane domain derived from CD3 ⁇ .
  • the transmembrane domain of the CAR comprises the transmembrane region of CD3 ⁇ (e.g., amino acids 117 to 137 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a signaling domain derived from CD3 ⁇ .
  • the signaling domain comprises the intracellular domain of CD3 ⁇ (e.g., amino acids 138 to 182 of the sequence below) , or a fragment thereof. It is understood that sequences of CD3 ⁇ that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD3 ⁇ T-cell surface glycoprotein CD3 delta chain
  • CD3 ⁇ is part of the TCR-CD3 complex present on T-lymphocyte cell surface that plays an essential role in adaptive immune response.
  • CD3 ⁇ contains immunoreceptor tyrosine-based activation motifs (ITAMs) in its cytoplasmic domain.
  • ITAMs immunoreceptor tyrosine-based activation motifs
  • CD3 ⁇ plays an essential role in thymocyte differentiation and participates in correct intracellular TCR-CD3 complex assembly and surface expression.
  • CD3 ⁇ interacts with CD4 and CD8 and thus serves to establish a functional link between the TCR and coreceptors CD4 and CD8, which is needed for activation and positive selection of CD4 or CD8 T-cells.
  • a CD3 ⁇ polypeptide can have an amino acid sequence corresponding to the sequence having NCBI Reference Sequence: NP_000723.1, provided below, or fragments thereof. See NCBI Reference Sequence: NP_000723.1 for reference to domains within CD3 ⁇ , for example, signal peptide, amino acids 1 to 21; extracellular domain, amino acids 22 to 105; transmembrane region, amino acids 106 to 126; intracellular domain, amino acids 127 to 171.
  • a CAR can comprise a transmembrane domain derived from CD3 ⁇ .
  • the transmembrane domain of the CAR comprises the transmembrane region of CD3 ⁇ (e.g., amino acids 106 to 126 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a signaling domain derived from CD3 ⁇ .
  • the signaling domain comprises the intracellular domain of CD3 ⁇ (e.g., amino acids 127 to 171 of the sequence below) , or a fragment thereof. It is understood that sequences of CD3 ⁇ that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD3 ⁇ T-cell surface glycoprotein CD3 epsilon chain
  • T-lymphocyte cell surface CD3 ⁇ contains immunoreceptor tyrosine-based activation motifs (ITAMs) in its cytoplasmic domain.
  • ITAMs immunoreceptor tyrosine-based activation motifs
  • CD3 ⁇ plays an essential role in correct T-cell development.
  • CD3 ⁇ initiates the TCR-CD3 complex assembly by forming the two heterodimers CD3 ⁇ /CD3 ⁇ and CD3 ⁇ /CD3 ⁇ .
  • a CD3 ⁇ polypeptide can have an amino acid sequence corresponding to the sequence having NCBI Reference Sequence: NP_000724.1, provided below, or fragments thereof. See NCBI Reference Sequence: NP_000724.1 for reference to domains within CD3 ⁇ , for example, signal peptide, amino acids 1 to 22; extracellular domain, amino acids 23 to 126; transmembrane region, amino acids 127 to 152; intracellular domain, amino acids 153 to 207.
  • a CAR can comprise a transmembrane domain derived from CD3 ⁇ .
  • the transmembrane domain of the CAR comprises the transmembrane region of CD3 ⁇ (e.g., amino acids 127 to 152 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a signaling domain derived from CD3 ⁇ .
  • the signaling domain comprises the intracellular domain of CD3 ⁇ (e.g., amino acids 153 to 207 of the sequence below) , or a fragment thereof. It is understood that sequences of CD3 ⁇ that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD79a B-cell antigen receptor complex-associated protein alpha chain
  • CD79b B-cell antigen receptor complex-associated protein alpha chain
  • BCR B-cell antigen receptor complex
  • CD79a stimulates SYK autophosphorylation and activation.
  • CD79a also binds to BLNK, bringing BLNK into proximity with SYK and allowing SYK to phosphorylate BLNK, and interacts with and increases activity of some Src-family tyrosine kinases.
  • a CD79a polypeptide can have an amino acid sequence corresponding to the sequence having NCBI Reference Sequence: NP_001774.1, provided below, or fragments thereof. See NCBI Reference Sequence: NP_001774.1 for reference to domains within CD79a, for example, signal peptide, amino acids 1 to 32; extracellular domain, amino acids 33 to 143; transmembrane region, amino acids 144 to 165; intracellular domain, amino acids 166 to 226.
  • a CAR can comprise a transmembrane domain derived from CD79a.
  • the transmembrane domain of the CAR comprises the transmembrane region of CD79a (e.g., amino acids 144 to 165 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a signaling domain derived from CD79a.
  • the signaling domain comprises the intracellular domain of CD79a (e.g., amino acids 166 to 226 of the sequence below) , or a fragment thereof. It is understood that sequences of CD79a that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD79b B-cell antigen receptor complex-associated protein beta chain
  • BCR B-cell antigen receptor complex
  • a CD79b polypeptide can have an amino acid sequence corresponding to the sequence having NCBI Reference Sequence: NP_000617.1, provided below, or fragments thereof.
  • a CAR can comprise a transmembrane domain derived from CD79b.
  • the transmembrane domain of the CAR comprises the transmembrane region of CD79b (e.g., amino acids 160 to 180 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a signaling domain derived from CD79b.
  • the signaling domain comprises the intracellular domain of CD79b (e.g., amino acids 181 to 229 of the sequence below) , or a fragment thereof. It is understood that sequences of CD79b that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • DAP10 also referred to as hematopoietic cell signal transducer, is a signaling subunit that associates with a large family of receptors in hematopoietic cells.
  • a DAP10 polypeptide can have an amino acid sequence corresponding to the sequence having GenBank No. NP_055081.1 (GI: 15826850) , provided below, or fragments thereof. See GenBank NP_055081 for reference to domains within DAP10, for example, signal peptide, amino acids 1 to 18; extracellular domain, amino acids 19 to 48; transmembrane region, amino acids 49 to 69; intracellular domain, amino acids 70 to 93.
  • the cytoplasmic domain of a CAR can comprise a signaling domain derived from DAP10.
  • the signaling domain comprises the intracellular domain of DAP10 (e.g., amino acids 70 to 93 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain comprises a co-stimulatory domain derived from DAP10.
  • the co-stimulatory domain comprises the intracellular domain of DAP10 (e.g., amino acids 70 to 93 of the sequence below) , or a fragment thereof. It is understood that sequences of DAP10 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • DAP12 is found in cells of the myeloid lineage, such as macrophages and granulocytes, where it associates, for instance, with the triggering receptor expressed on myeloid cell members (TREM) and MDL1 (myeloid DAP12-associating lectin 1/CLEC5A) , both involved in inflammatory responses against pathogens like viruses and bacteria.
  • TAM myeloid cell members
  • MDL1 myeloid DAP12-associating lectin 1/CLEC5A
  • DAP12 is expressed in NK cells and associates with activating receptors such as the C-type lectin receptor NKG2C, the natural cytotoxicity receptor NKp44, and the short-tailed KIR3DS1 and KIR2DS1/2/5, respectively.
  • NGK2C is the dominant activating NK cell receptor for controlling CMV infection in both humans and mice. It was found that a DAP12-containing CAR generated sufficient activating signals in NK cells upon cross-linking with its Ag. et al., J Immunol 194: 3201-12 (2015) .
  • a DAP12 polypeptide can have an amino acid sequence corresponding to the sequence having GenBank No. AAD09437.1 (GI: 2905996) , provided below, or fragments thereof. See GenBank No.
  • the cytoplasmic domain of a CAR can comprise a signaling domain derived from DAP12.
  • the signaling domain comprises the intracellular domain of DAP12 (e.g., amino acids 62 to 113 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain comprises a co-stimulatory domain derived from DAP12.
  • the co-stimulatory domain comprises the intracellular domain of DAP12 (e.g., amino acids 62 to 113 of the sequence below) , or a fragment thereof. It is understood that sequences of DAP12 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD28 Cluster of Differentiation 28
  • CD28 is a protein expressed on T cells that provides co-stimulatory signals for T cell activation and survival.
  • CD28 is the receptor for CD80 (B7.1) and CD86 (B7.2) proteins.
  • a CD28 polypeptide can have an amino acid sequence corresponding to the sequence having GenBank No. P10747 (P10747.1, GI: 115973) or NP_006130 (NP_006130.1, GI: 5453611) , as provided below, or fragments thereof.
  • a CAR can comprise a hinge domain derived from CD28 (e.g., amino acids 114 to 152 of the sequence below, or a fragment thereof) .
  • a CAR can comprise a transmembrane domain derived from CD28.
  • the transmembrane domain of the CAR comprises the transmembrane region of CD28 (e.g., amino acids 153 to 179 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from CD28.
  • the co-stimulatory domain comprises the intracellular domain of CD28 (e.g., amino acids 180 to 220 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from CD28, a co-stimulatory signaling domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of CD28 and comprises amino acids 153 to 220 of CD28.
  • a CAR can comprise three domains derived from CD28, a transmembrane domain, a hinge domain and a co-stimulatory signaling domain.
  • a CAR comprises amino acids 114 to 220 of CD28. It is understood that sequences of CD28 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • 4-1BB also referred to as tumor necrosis factor receptor superfamily member 9, can act as a tumor necrosis factor (TNF) ligand and have stimulatory activity.
  • a 4-1BB polypeptide can have an amino acid sequence corresponding to the sequence having GenBank No. P41273 (P41273.1, GI: 728739) or NP_001552 (NP_001552.2, GI: 5730095) or fragments thereof. See GenBank NP_001552 for reference to domains within 4-1BB, for example, signal peptide, amino acids 1 to 17; extracellular domain, amino acids 18 to 186; transmembrane domain, amino acids 187 to 213; intracellular domain, amino acids 214 to 255.
  • a CAR can comprise a transmembrane domain derived from 4-1BB.
  • the transmembrane domain of the CAR comprises the transmembrane region of 4-1BB (e.g., amino acids 187 to 213 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from 4-1BB.
  • the co-stimulatory domain comprises the intracellular domain of 4-1BB (e.g., amino acids 214 to 255 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from 4-1BB, a co-stimulatory signaling domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of 4-1BB and comprises amino acids 187 to 255 of 4-1BB. It is understood that sequences of 4-1BB that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • OX40 also referred to as tumor necrosis factor receptor superfamily member 4 precursor or CD134, is a member of the TNFR-superfamily of receptors.
  • An OX40 polypeptide can have an amino acid sequence corresponding to the sequence having GenBank No. P43489 (P43489.1, GI: 1171933) or NP_003318 (NP_003318.1, GI: 4507579) , provided below, or fragments thereof. See GenBank NP_003318 for reference to domains within OX40, for example, signal peptide, amino acids 1 to 28; extracellular domain, amino acids 29 to 214; transmembrane domain, amino acids 215 to 235; intracellular domain, amino acids 236 to 277.
  • a CAR can comprise a transmembrane domain derived from OX40.
  • the transmembrane domain of the CAR comprises the transmembrane region of OX40 (e.g., amino acids 215 to 235 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from OX40.
  • the co-stimulatory domain comprises the intracellular domain of OX40 (e.g., amino acids 236 to 277 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from OX40, a co-stimulatory signaling domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of OX40 and comprises amino acids 215 to 277 of OX40.
  • ICOS Inducible T-cell co-stimulator precursor
  • CD278 is a CD28-superfamily co-stimulatory receptor that is expressed on activated T cells.
  • An ICOS polypeptide can have an amino acid sequence corresponding to the sequence having GenBank No. NP_036224 (NP_036224.1, GI: 15029518) , provided below, or fragments thereof. See GenBank NP_036224 for reference to domains within ICOS, for example, signal peptide, amino acids 1 to 20; extracellular domain, amino acids 21 to 140; transmembrane domain, amino acids 141 to 161; intracellular domain, amino acids 162 to 199.
  • a CAR can comprise a transmembrane domain derived from ICOS.
  • the transmembrane domain of the CAR comprises the transmembrane region of ICOS (e.g., amino acids 141 to 161 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from ICOS.
  • the co-stimulatory domain comprises the intracellular domain of ICOS (e.g., amino acids 162 to 199 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from ICOS, a co-stimulatory signaling domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of ICOS and comprises amino acids 141 to 199 of ICOS. It is understood that sequences of ICOS that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • 2B4 2B4 (CD244) is a co-stimulatory receptor expressed on both NK cells and CD8+ T cells. It targets a non-MHC like molecule (CD48) expressed on hematopoietic cells, including B and T cells, as well as on activated monocytes and granulocytes. Activation of 2B4 by binding of its ligand on target cells leads to NK (or T cell) activation, and target killing.
  • a 2B4 polypeptide can have an amino acid sequence corresponding to the sequence having Accession No: Q9BZW8.2 (NP_001160135.1; GI: 47605541) , provided below, or fragments thereof.
  • a CAR can comprise a transmembrane domain derived from 2B4.
  • the transmembrane domain of the CAR comprises the transmembrane region of 2B4 (e.g., amino acids 230 to 250 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from 2B4.
  • the co-stimulatory domain comprises the intracellular domain of 2B4 (e.g., amino acids 251 to 370 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from 2B4, a co-stimulatory signaling domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of 2B4 and comprises amino acids 230 to 370 of 2B4. It is understood that sequences of 2B4 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD27 (TNFRSF7) is a transmembrane receptor expressed on subsets of human CD8+ and CD4+ T-cells, NKT cells, NK cell subsets and hematopoietic progenitors and induced in FOXP3+ CD4 T-cells and B cell subsets.
  • TNFRSF7 TNFRSF7
  • Previously studies have found that CD27 can either actively provide costimulatory signals that improve human T-cell survival and anti-tumor activity in vivo. (See Song and Powell; Oncoimmunology 1, no. 4 (2012) : 547-549) .
  • a CD27 polypeptide can have an amino acid sequence corresponding to the sequence having UniProtKB/Swiss-Prot No.: P26842.2 (GenBank NP_001233.1; GI: 269849546) , provided below, or fragments thereof. See GenBank NP_001233 for reference to domains within CD27, for example, signal peptide, amino acids 1 to 19; extracellular domain, amino acids 20 to 191; transmembrane domain, amino acids 192 to 212; intracellular domain, amino acids 213 to 260.
  • a CAR can comprise a transmembrane domain derived from CD27.
  • the transmembrane domain of the CAR comprises the transmembrane region of CD27 (e.g., amino acids 192 to 212 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from CD27.
  • the co-stimulatory domain comprises the intracellular domain of CD27 (e.g., amino acids 213 to 260 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from CD27, a co-stimulatory signaling domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of CD27 and comprises amino acids 192 to 260 of CD27. It is understood that sequences of CD27 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD30 and its ligand are members of the tumor necrosis factor receptor (TNFR) and tumor necrosis factor (TNF) superfamilies, respectively.
  • TNFR tumor necrosis factor receptor
  • TNF tumor necrosis factor
  • CD30 in many respects, behaves similarly to Ox40 and enhances proliferation and cytokine production induced by TCR stimulation.
  • a CD30 polypeptide can have an amino acid sequence corresponding to the sequence having GenBank No.: AAA51947.1 (GenBank NP_001234.3; GI: 180096) , provided below, or fragments thereof.
  • a CAR can comprise a transmembrane domain derived from CD30.
  • the transmembrane domain of the CAR comprises the transmembrane region of CD30 (e.g., amino acids 386 to 406 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from CD30.
  • the co-stimulatory domain comprises the intracellular domain of CD30 (e.g., amino acids 407 to 595 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from CD30, a co-stimulatory signaling domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of CD30 and comprises amino acids 386 to 595 of CD30. It is understood that sequences of CD30 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD40 is a 48 kD transmembrane glycoprotein surface receptor that is a member of the Tumor Necrosis Factor Receptor superfamily (TNFRSF) .
  • TNFRSF Tumor Necrosis Factor Receptor superfamily
  • Exemplary amino acid sequences of human CD40 are described (see, e.g., Accession: ALQ33424.1, GenBank NP_001241.1, GI: 957949089) , CD40 was initially characterized as a co-stimulatory receptor expressed on APCs that played a central role in B and T cell activation.
  • the ligand for CD40, CD154 also known as TRAP, T-BAM, CD40 Ligand or CD40L
  • CD40L is a type II integral membrane protein.
  • a CAR can comprise a transmembrane domain derived from CD40.
  • the transmembrane domain of the CAR comprises the transmembrane region of CD40 (e.g., amino acids 194 to 215 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from CD40.
  • the co-stimulatory domain comprises the intracellular domain of CD40 (e.g., amino acids 216 to 277 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from CD40, a co-stimulatory signaling domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of CD40 and comprises amino acids 194 to 277 of CD40. It is understood that sequences of CD40 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD2 The engagement of the CD2 molecule by its ligand CD58 co-stimulates proliferation, cytokine production, and effector function in this T cells, especially the CD28-deficient T cells subset.
  • CD58 is broadly expressed on APCs including dendritic cells. Engagement of CD2 amplifies TCR signals in CD28 - CD8 + T cells, demonstrating that the CD2–CD58 interaction has a genuine costimulatory effect.
  • CD2 signals could promote the control of viral infection by CD28 - CD8 + T cells, but they could also contribute to the continuous expansion of CD28 - CD8 + T cells during chronic stimulation by persistent Ag. (Judith Leitner J et al., Immunol, 2015, 195 (2) 477-487) .
  • a CD2 polypeptide can have an amino acid sequence corresponding to the sequence having Accession: NP_001758.2 GI: 156071472, provided below, or fragments thereof. See GenBank NP_001758.2 for reference to domains within CD2, for example, signal peptide, amino acids 1 to 24; extracellular domain, amino acids 25 to 209; transmembrane domain, amino acids 210 to 235; intracellular domain, amino acids 236 to 351.
  • a CAR can comprise a transmembrane domain derived from CD2.
  • the transmembrane domain of the CAR comprises the transmembrane region of CD2 (e.g., amino acids 210 to 235 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from CD2.
  • the co-stimulatory domain comprises the intracellular domain of CD2 (e.g., amino acids 236 to 351 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from CD2, a co-stimulatory domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of CD2 and comprises amino acids 210 to 351 of CD2. It is understood that sequences of CD2 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • LIGHT TNF superfamily member 14 (also known as LTg, CD258, HVEML, LIGHT) is a co-stimulatory receptor involved in cellular immune responses. LIGHT can function as a costimulatory factor for the activation of lymphoid cells and as a deterrent to infection by herpesvirus. LIGHT has been shown to stimulate the proliferation of T cells, and trigger apoptosis of various tumor cells. LIGHT is found in T cells and stromal cells. LIGHT is expressed on immature dendritic cells (DCs) generated from human PBMCs.
  • DCs dendritic cells
  • a LIGHT polypeptide can have an amino acid sequence corresponding to the sequence provided below (Accession: NP_001363816.1 GI: 1777376047) , or fragments thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from LIGHT.
  • the co-stimulatory domain comprises the intracellular domain of LIGHT (e.g., amino acids 1 to 37 of the sequence below) , or a fragment thereof. It is understood that sequences of LIGHT that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • GITR TNF receptor superfamily member 18 also known as TNFRSF18, AITR, GITR; CD357; GITR-D; ENERGEN
  • GITR TNF receptor superfamily member 18 has been shown to have increased expression upon T-cell activation. Stimulation of T cells through GITR has been shown to enhance immunity to tumors and viral pathogens, and to exacerbate autoimmune disease. The effects of stimulation through GITR are generally thought to be caused by attenuation of the effector activity of immunosuppressive CD4+CD25+ regulatory T (TReg) cells. (Shevach, E. and Stephens, G. Nat Rev Immunol 6, 613–618 (2006) ) .
  • a GITR polypeptide can have an amino acid sequence corresponding to the sequence provided below (Accession: AAI52382.1, GenBank NP_004186.1, GI: 158931986) , or fragments thereof. See GenBank NP_004186.1 for reference to domains within GITR, for example, signal peptide, amino acids 1 to 25; extracellular domain, amino acids 26 to 162; transmembrane domain, amino acids 163 to 183; intracellular domain, amino acids 184 to 241.
  • a CAR can comprise a transmembrane domain derived from GITR.
  • the transmembrane domain of the CAR comprises the transmembrane region of GITR (e.g., amino acids 163 to 183 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from GITR.
  • the co-stimulatory domain comprises the intracellular domain of GITR (e.g., amino acids 184 to 241 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from GITR, a co-stimulatory signaling domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of GITR and comprises amino acids 163 to 241 of GITR. It is understood that sequences of GITR that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • DR3 TNF receptor superfamily member 25 (also known as DR3, TR3, DDR3, LARD, APO-3, TRAMP, WSL-1, GEF720, WSL-LR, PLEKHG5, or TNFRSF12) is expressed preferentially in the tissues enriched in lymphocytes, and it plays a role in regulating lymphocyte homeostasis.
  • This receptor has been shown to stimulate NF-kappa B activity and regulate cell apoptosis. The signal transduction of this receptor is mediated by various death domain containing adaptor proteins. Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported, most of which are potentially secreted molecules.
  • a DR3 polypeptide can have an amino acid sequence corresponding to the sequence provided below (Accession: Accession: Accession: AAI17190.1, GenBank NP_003781.1 GI: 109658976) , or fragments thereof. See GenBank NP_003781.1 for reference to domains within DR3, for example, signal peptide, amino acids 1 to 24; extracellular domain, amino acids 25 to 199; transmembrane domain, amino acids 200 to 220; intracellular domain, amino acids 221 to 417.
  • a CAR can comprise a transmembrane domain derived from DR3.
  • the transmembrane domain of the CAR comprises the transmembrane region of DR3 (e.g., amino acids 200 to 220 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from DR3.
  • the co-stimulatory domain comprises the intracellular domain of DR3 (e.g., amino acids 221 to 417 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from DR3, a co-stimulatory signaling domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of DR3 and comprises amino acids 200 to 417 of DR3. It is understood that sequences of DR3 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD43 CD43 (also known as SPN sialophorin, LSN, GALGP, GPL115) is a highly sialylated glycoprotein that functions in antigen-specific activation of T cells, and is found on the surface of thymocytes, T lymphocytes, monocytes, granulocytes, and some B lymphocytes. It contains a mucin-like extracellular domain, a transmembrane region and a carboxy-terminal intracellular region. In stimulated immune effector cells, proteolytic cleavage of the extracellular domain occurs in some cell types, releasing a soluble extracellular fragment.
  • a CD43 polypeptide can have an amino acid sequence corresponding to the sequence provided below (GenBank NP_003114.1, Accession: EAW80016.1 GI: 119600422) , or fragments thereof. See GenBank NP_003114.1 for reference to domains within CD43, for example, signal peptide, amino acids 1 to 19; extracellular domain, amino acids 20 to 253; transmembrane domain, amino acids 254 to 276; intracellular domain, amino acids 277 to 400.
  • a CAR can comprise a transmembrane domain derived from CD43.
  • the transmembrane domain of the CAR comprises the transmembrane region of CD43 (e.g., amino acids 254 to 276 of the sequence below) , or a fragment thereof.
  • the cytoplasmic domain of a CAR can comprise a co-stimulatory domain derived from CD43.
  • the co-stimulatory domain comprises the intracellular domain of CD43 (e.g., amino acids 277 to 400 of the sequence below) , or a fragment thereof.
  • a CAR can comprise two domains derived from CD43, a co-stimulatory signaling domain and a transmembrane domain.
  • a CAR has an amino acid sequence comprising the transmembrane domain and the intracellular domain of CD43 and comprises amino acids 254 to 400 of CD43. It is understood that sequences of CD43 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD4 Cluster of differentiation 4
  • T-cell surface glycoprotein CD4 is a glycoprotein found on the surface of immune cells such as T helper cells, monocytes, macrophages, and dendritic cells.
  • a CAR can comprise a transmembrane domain derived from CD4.
  • CD4 exists in various isoforms. It is understood that any isoform can be selected to achieve a desired function.
  • Exemplary isoforms include isoform 1 (NP_000607.1, GI: 10835167) , isoform 2 (NP_001181943.1, GI: 303522479) , isoform 3 (NP_001181944.1, GI: 303522485; or NP_001181945.1, GI: 303522491; or NP_001181946.1, GI: 303522569) , and the like.
  • One exemplary isoform sequence, isoform 1 is provided below.
  • a CAR can comprise a transmembrane domain derived from CD4.
  • the transmembrane domain of the CAR comprises the transmembrane region of CD4 (e.g., amino acids 397 to 418 of the sequence below) , or a fragment thereof. It is understood that additional sequence of CD4 beyond the transmembrane domain of amino acids 397 to 418 can be included in a CAR, if desired. It is further understood that sequences of CD4 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • CD8 Cluster of differentiation 8
  • TCR T cell receptor
  • CD8 binds to a major histocompatibility complex (MHC) molecule and is specific for the class I MHC protein.
  • MHC major histocompatibility complex
  • a CAR can comprise a transmembrane domain derived from CD8.
  • a CD8 polypeptide can have an amino acid sequence corresponding to the sequence having GenBank No. NP_001139345.1 (GI: 225007536) , as provided below, or fragments thereof.
  • a CAR can comprise a hinge domain derived from CD8.
  • the hinge domain can comprise amino acids 137 to 182 of the CD8 polypeptide provided below.
  • a CAR can comprise a transmembrane domain derived from CD8.
  • the transmembrane domain of the CAR comprises the transmembrane region of CD8 (e.g., amino acids 183 to 203 of the sequence below) , or a fragment thereof.
  • a CAR can comprise amino acids 137 to 203 of the CD8 polypeptide provided below.
  • a CAR can comprise amino acids 137 to 209 of the CD8 polypeptide provided below. It is understood that additional sequence of CD8 beyond the hinge domain of amino acids 137 to 182 and the transmembrane domain of amino acids 183 to 203 can be included in a CAR, if desired. It is further understood that sequences of CD8 that are shorter or longer than a specific delineated domain can be included in a CAR, if desired.
  • a CAR disclosed herein can comprise, from N-terminus to the C-terminus, an anti-BCMA antibody or antigen-binding fragment (e.g., scFvs disclosed herein) , a hinge (e.g., CD8 hinge or CD28 hinge) , a transmembrane region (e.g., CD8 transmembrane region or CD28 transmembrane region) , a costimulatory domain (e.g., the intracellular domain of 4-1BB, CD28, or both) , and a signaling domain (e.g., the T cell signaling domain of CD3 ⁇ ) .
  • an anti-BCMA antibody or antigen-binding fragment e.g., scFvs disclosed herein
  • a hinge e.g., CD8 hinge or CD28 hinge
  • a transmembrane region e.g., CD8 transmembrane region or CD28 transmembrane region
  • costimulatory domain e.g.
  • polynucleotides that encode a polypeptide e.g., an anti-BCMA antibody or antigen-binding fragment or a CAR that specifically binds BCMA
  • polynucleotide that encode a polypeptide encompasses a polynucleotide which includes only coding sequences for the polypeptide as well as a polynucleotide which includes additional coding and/or non-coding sequences.
  • the polynucleotides of the disclosure can be in the form of RNA or in the form of DNA.
  • DNA can be cDNA, genomic DNA, or synthetic DNA, and can be double-stranded or single-stranded. Single stranded DNA can be the coding strand or non-coding (anti-sense) strand.
  • the polynucleotides of the disclosure can be mRNA.
  • polynucleotides encode any anti-BCMA antibody or antigen-binding fragment disclosed herein.
  • the polynucleotides provided herein encode an anti-BCMA antibody or antigen-binding fragment comprising (a) a VL comprising (1) a VL CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-10; (2) a VL CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 11-21; and (3) a VL CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 22-32; or a variant thereof having up to about 5 amino acid substitutions, additions, and/or deletions in the VL CDRs; and/or (b) a VH comprising (1) a VH CDR1 having an amino acid sequence selected from the group consisting of SEQ ID NOs: 33-43; (2) a VH CDR2 having an amino
  • the polynucleotides provided herein encode an anti-BCMA antibody or antigen-binding fragment comprising (a) a VL having at least 85%, at least 90%, at least 95%, at least 98%, or 100%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79; and/or (b) a VH having at least 85%, at least 90%, at least 95%, at least 98%, or 100%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91.
  • the polynucleotides can be in the form of DNA.
  • the polynucleotides can be in the form of mRNA.
  • the polynucleotides provided herein encode an anti-BCMA antibody or antigen-binding fragment disclosed herein comprising a VL and a VH, wherein the VL comprises VL CDR1, CDR2 and CDR3 and the VH comprises VH CDR1, CDR2 and CDR3, and wherein the VL CDR1, VL CDR2, VL CDR3, VH CDR1, VH CDR2 and VH CDR3 have the amino acid sequences of (1) SEQ ID NOs: 1, 11, 22, 33, 44, and 56, respectively; (2) SEQ ID NOs: 2, 12, 23, 34, 45, and 57, respectively; (3) SEQ ID NOs: 3, 13, 24, 35, 46, and 58, respectively; (4) SEQ ID NOs: 4, 14, 24, 36, 47, and 59, respectively; (5) SEQ ID NOs: 5, 15, 25, 37, 48, and 60, respectively; (6) SEQ ID NOs: 6, 16, 26, 38, 49, and 61, respectively; (7) SEQ ID NOs: 7, 17, 27, 35
  • the polynucleotides provided herein encode an anti-BCMA antibody or antigen-binding fragment disclosed herein comprising a VL and a VH, wherein the VL and VH have the amino acid sequences of (1) SEQ ID NOs: 68 and 80, respectively; (2) SEQ ID NOs: 69 and 81, respectively; (3) SEQ ID NOs: 70 and 82, respectively; (4) SEQ ID NOs: 71 and 83, respectively; (5) SEQ ID NOs: 72 and 84, respectively; (6) SEQ ID NOs: 73 and 85, respectively; (7) SEQ ID NOs: 74 and 86, respectively; (8) SEQ ID NOs: 75 and 87, respectively; (9) SEQ ID NOs: 76 and 88, respectively; (10) SEQ ID NOs: 77 and 89, respectively; (11) SEQ ID NOs: 78 and 90, respectively; or (12) SEQ ID NOs: 79 and 91, respectively.
  • the polynucleotides can be in
  • the VL and VH are connected by a linker.
  • the linker can be a flexible linker or a rigid linker.
  • the linker has the amino acid sequence of GGGGSGGGGSGGGGS (SEQ ID NO: 158) .
  • the polynucleotides provided herein encode an anti-BCMA antibody or antigen-binding fragment disclosed herein comprising a VL having at least 85%, at least 90%, at least 95%, at least 98%, or 100%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79. In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen-binding fragment disclosed herein comprising a VL having an amino acid sequence selected from the group consisting of SEQ ID NOs: 68-79.
  • the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 68. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 69. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 70. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 71.
  • the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 72. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 73. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 74. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 75.
  • the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 76. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 77. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 78. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VL having the amino acid sequence of SEQ ID NO: 79.
  • the polynucleotides provided herein have a nucleotide sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%identical to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 92-103. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 92.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 93. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 94. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 95.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 96. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 97. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 98.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 99. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 100. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 101.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 102. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 103. Also provided is a polynucleotide that hybridizes to a polynucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NOs: 92-103. In some embodiments, the hybridization is under conditions of high stringency as is known to those skilled in the art.
  • the polynucleotides can be in the form of DNA.
  • the polynucleotides can be in the form of mRNA.
  • the polynucleotides provided herein encode an anti-BCMA antibody or antigen-binding fragment disclosed herein comprising a VH having at least 85%, at least 90%, at least 95%, at least 98%, or 100%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91. In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen-binding fragment disclosed herein comprising a VH having an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-91.
  • the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 80. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 81. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 82. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 83.
  • the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 84. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 85. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 86. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 87.
  • the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 88. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 89. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 90. In some embodiments, the polynucleotides encode an anti-BCMA antibody or antigen-binding fragment comprising a VH having the amino acid sequence of SEQ ID NO: 91.
  • the polynucleotides provided herein have a nucleotide sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%identical to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 104-115. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 104.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 105. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 106. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 107.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 108. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 109. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 110.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 111. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 112. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 113.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 114. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 115. Also provided is a polynucleotide that hybridizes to a polynucleotide having a nucleotide sequence selected from the group consisting of SEQ ID NOs: 104-115. In some embodiments, the hybridization is under conditions of high stringency as is known to those skilled in the art.
  • the polynucleotides can be in the form of DNA.
  • the polynucleotides can be in the form of mRNA.
  • the present disclosure also provides variants of the polynucleotides described herein, wherein the variants encode, for example, fragments, analogs, and/or derivatives of an anti-BCMA antibody or antigen-binding fragment disclosed herein.
  • the present disclosure provides a polynucleotide having a nucleotide sequence at least about 80%identical, at least about 85%identical, at least about 90%identical, at least about 95%identical, at least about 96%identical, at least about 97%identical, at least about 98%identical, or at least about 99%identical to a polynucleotide sequence encoding an anti-BCMA antibody or antigen-binding fragment described herein.
  • the polynucleotides provided herein encode an anti-BCMA antibody or antigen-binding fragment that is the scFv designated as BCMA21, BCMA22, BCMA23, BCMA24, BCMA27, BCMA28, BCMA30, BCMA31, BCMA32, BCMA33, BCMA34, or BCMA35. In some embodiments, the polynucleotides provided herein encode an anti-BCMA antibody or antigen-binding fragment having the amino acid sequence selected from the group consisting of SEQ ID NOs: 116-127.
  • polynucleotides that encode the TCRs disclosed herein are also polynucleotides that encode the TCRs disclosed herein.
  • polynucleotides that encode a TCR ⁇ chain that comprises an anti-BCMA antibody or antigen-binding fragment described herein are also polynucleotides that encode a TCR ⁇ chain that comprises an anti-BCMA antibody or antigen-binding fragment described herein.
  • polynucleotides that encode a TCR ⁇ chain that comprises an anti-BCMA antibody or antigen-binding fragment described herein.
  • the polynucleotides can be in the form of DNA.
  • the polynucleotides can be in the form of mRNA.
  • polynucleotides that encode the CARs disclosed herein.
  • polynucleotides encoding CARs that specifically binds BCMA comprising, from N-terminus to C-terminus: (a) a BCMA binding domain comprising an anti-BCMA antibody or antigen-binding fragment provided herein, (b) a transmembrane domain, and (c) a cytoplasmic domain.
  • the transmembrane and cytoplasmic domains can be any transmembrane and cytoplasmic domains disclosed herein.
  • polynucleotides that encode the CARs that specifically binds BCMA comprising, from N-terminus to C-terminus: (a) a BCMA binding domain comprising an anti-BCMA scFv provided herein, (b) a transmembrane domain comprising the CD28 transmembrane region, and (c) a cytoplasmic domain comprising a CD3 ⁇ signaling domain and a 4-1BB co-stimulatory domain.
  • the polynucleotides can be in the form of DNA.
  • the polynucleotides can be in the form of mRNA.
  • the polynucleotides provided herein encode an anti-BCMA CAR having at least 85%, at least 90%, at least 95%, at least 98%, or 100%sequence identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 131-142. In some embodiments, the polynucleotides provided herein encode an anti-BCMA CAR having an amino acid sequence selected from the group consisting of SEQ ID NOs: 131-142. In some embodiments, the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 131.
  • the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 132. In some embodiments, the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 133. In some embodiments, the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 134. In some embodiments, the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 135. In some embodiments, the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 136.
  • the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 137. In some embodiments, the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 138. In some embodiments, the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 139. In some embodiments, the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 140. In some embodiments, the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 141. In some embodiments, the polynucleotides provided herein encode an anti-BCMA CAR having the amino acid sequence of SEQ ID NO: 142.
  • the polynucleotides provided herein have a nucleotide sequence at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%identical to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 143-154. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 143.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 144. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 145. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 146.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 147. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 148. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 149.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 150. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 151. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 152.
  • the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 153. In some embodiments, the polynucleotides provided herein have a nucleotide sequence at least 85%, at least 90%, at least 95%, at least 99%, or 100%identical to SEQ ID NO: 154. Also provided is a polynucleotide that hybridizes to a polynucleotide encoding an amino acid sequence selected from SEQ ID NOs: 143-154. In some embodiments, the hybridization is under conditions of high stringency as is known to those skilled in the art.
  • a polynucleotide having a nucleotide sequence at least about 95%identical to a polynucleotide sequence means that the nucleotide sequence of the polynucleotide is identical to a reference sequence except that the polynucleotide sequence can include up to five point mutations per each 100 nucleotides of the reference nucleotide sequence.
  • a polynucleotide having a nucleotide sequence at least 95%identical to a reference nucleotide sequence up to 5%of the nucleotides in the reference sequence can be deleted or substituted with another nucleotide, or a number of nucleotides up to 5%of the total nucleotides in the reference sequence can be inserted into the reference sequence.
  • These mutations of the reference sequence can occur at the 5’ or 3’ terminal positions of the reference nucleotide sequence or anywhere between those terminal positions, interspersed either individually among nucleotides in the reference sequence or in one or more contiguous groups within the reference sequence.
  • the polynucleotide variants can contain alterations in the coding regions, non-coding regions, or both.
  • a polynucleotide variant contains alterations which produce silent substitutions, additions, or deletions, but does not alter the properties or activities of the encoded polypeptide.
  • a polynucleotide variant comprises silent substitutions that results in no change to the amino acid sequence of the polypeptide (due to the degeneracy of the genetic code) .
  • Polynucleotide variants can be produced for a variety of reasons, for example, to optimize codon expression for a particular host (e.g., change codons in the human mRNA to those preferred by a bacterial host such as E. coli) .
  • a polynucleotide variant comprises at least one silent mutation in a non-coding or a coding region of the sequence.
  • a polynucleotide variant is produced to modulate or alter expression (or expression levels) of the encoded polypeptide. In some embodiments, a polynucleotide variant is produced to increase expression of the encoded polypeptide. In some embodiments, a polynucleotide variant is produced to decrease expression of the encoded polypeptide. In some embodiments, a polynucleotide variant has increased expression of the encoded polypeptide as compared to a parental polynucleotide sequence. In some embodiments, a polynucleotide variant has decreased expression of the encoded polypeptide as compared to a parental polynucleotide sequence.
  • a polynucleotide comprises the coding sequence for a polypeptide (e.g., a CAR or an antibody) fused in the same reading frame to a polynucleotide which aids in expression and secretion of a polypeptide from a host cell (e.g., a leader sequence which functions as a secretory sequence for controlling transport of a polypeptide) .
  • a host cell e.g., a leader sequence which functions as a secretory sequence for controlling transport of a polypeptide
  • the polypeptide can have the leader sequence cleaved by the host cell to form a “mature” form of the polypeptide.
  • a polynucleotide comprises the coding sequence for a polypeptide (e.g., a CAR or an antibody) fused in the same reading frame to a marker or tag sequence.
  • a marker sequence is a hexa-histidine tag (HIS-tag) that allows for efficient purification of the polypeptide fused to the marker.
  • a marker sequence is a hemagglutinin (HA) tag derived from the influenza hemagglutinin protein when a mammalian host (e.g., COS-7 cells) is used.
  • the marker sequence is a FLAG TM tag.
  • a marker can be used in conjunction with other markers or tags.
  • a polynucleotide is isolated. In some embodiments, a polynucleotide is substantially pure.
  • vectors and cells comprising the polynucleotides described herein are also provided.
  • vectors comprising a polynucleotide provided herein.
  • the vectors can be expression vectors.
  • vectors provided herein comprise a polynucleotide encoding an anti-BCMA antibody or antigen-binding fragment described herein.
  • vectors provided herein comprise a polynucleotide encoding a polypeptide that is part of an anti-BCMA antibody or antigen-binding fragment described herein.
  • vectors provided herein comprise a polynucleotide encoding a CAR or TCR described herein.
  • vectors provided herein comprise a polynucleotide encoding a polypeptide that is part of a CAR or TCR described herein.
  • recombinant expression vectors which can be used to amplify and express a polynucleotide encoding a CAR/TCR described herein that specifically binds BCMA or an anti-BCMA antibody or antigen-binding fragment described herein.
  • a recombinant expression vector can be a replicable DNA construct that includes synthetic or cDNA-derived DNA fragments encoding a CAR/TCR or a polypeptide chain of an anti-BCMA antibody, operatively linked to suitable transcriptional and/or translational regulatory elements derived from mammalian, microbial, viral or insect genes.
  • a viral vector is used.
  • DNA regions are “operatively linked” when they are functionally related to each other.
  • a promoter is operatively linked to a coding sequence if it controls the transcription of the sequence; or a ribosome binding site is operatively linked to a coding sequence if it is positioned so as to permit translation.
  • structural elements intended for use in certain expression systems include a leader sequence enabling extracellular secretion of translated protein by a host cell.
  • a polypeptide in situations where recombinant protein is expressed without a leader or transport sequence, a polypeptide can include an N-terminal methionine residue.
  • Useful expression vectors for eukaryotic hosts include, for example, vectors comprising expression control sequences from SV40, bovine papilloma virus, adenovirus, and cytomegalovirus.
  • Useful expression vectors for bacterial hosts include known bacterial plasmids, such as plasmids from E. coli, including pCR1, pBR322, pMB9 and their derivatives, and wider host range plasmids, such as M13 and other filamentous single-stranded DNA phages.
  • a CAR/TCR described herein or an anti-BCMA antibody or antigen-binding fragment described herein is expressed from one or more vectors.
  • Suitable host cells for expression include prokaryotes, yeast cells, insect cells, or higher eukaryotic cells under the control of appropriate promoters.
  • Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts, as well as methods of protein production, including antibody production are well-known in the art.
  • suitable mammalian host cell lines include, but are not limited to, COS-7 (monkey kidney-derived) , L-929 (murine fibroblast-derived) , C127 (murine mammary tumor-derived) , 3T3 (murine fibroblast-derived) , CHO (Chinese hamster ovary-derived) , HeLa (human cervical cancer-derived) , BHK (hamster kidney fibroblast-derived) , HEK-293 (human embryonic kidney-derived) cell lines and variants thereof.
  • COS-7 monkey kidney-derived
  • L-929 murine fibroblast-derived
  • C127 murine mammary tumor-derived
  • 3T3 murine fibroblast-derived
  • CHO Choinese hamster ovary-derived
  • HeLa human cervical cancer-derived
  • BHK hamster kidney fibroblast-derived
  • HEK-293 human embryonic kidney-derived
  • Mammalian expression vectors can comprise non-transcribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5’ or 3’ flanking non-transcribed sequences, and 5’ or 3’ non-translated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences.
  • expression of recombinant proteins in insect cell culture systems e.g., baculovirus
  • Baculovirus systems for production of heterologous proteins in insect cells are well-known to those of skill in the art.
  • host cells comprising the polypeptides described herein, polynucleotides encoding polypeptides described herein, or vectors comprising such polynucleotides.
  • host cells comprising a vector comprising a polynucleotide disclosed herein.
  • host cells provided herein comprise a vector comprising a polynucleotide encoding an anti-BCMA antibody or antigen-binding fragment described herein.
  • host cells provided herein comprise a vector comprising a polynucleotide encoding a polypeptide that is part of an anti-BCMA antibody or antigen-binding fragment described herein.
  • host cells provided herein comprise a polynucleotide encoding an anti-BCMA antibody or antigen-binding fragment described herein. In some embodiments, the cells produce the anti-BCMA antibodies or antigen-binding fragments described herein. In some embodiments, host cells provided herein comprise a vector comprising a polynucleotide encoding a CAR or TCR described herein. In some embodiments, host cells provided herein comprise a vector comprising a polynucleotide molecule encoding a polypeptide that is part of a CAR or TCR described herein. In some embodiments, host cells provided herein comprise a polynucleotide encoding a CAR or TCR described herein. In some embodiments, the host cells produce the BCMA CARs or TCR described herein.
  • cells comprising the polynucleotides disclosed herein.
  • cells comprising a polynucleotide that encodes a polypeptide disclosed herein.
  • cells comprising a vector having a polynucleotide disclosed herein.
  • the polypeptide can be an anti-BCMA antibody or antigen-binding fragment.
  • the polypeptide can be BCMA CAR.
  • the polypeptide can be a BCMA TCR.
  • cells provided herein are immune effector cells.
  • the immune effector cells are selected from the group consisting of T cells, B cell, natural killer (NK) cells, NKT cells, macrophages, granulocytes, neutrophils, eosinophils, mast cells, and basophils.
  • the immune effector cells provided herein are selected from the group consisting of T cells, NK cells, NKT cells, macrophages, neutrophils, and granulocytes.
  • the immune effector cell provided herein is a T cell.
  • the immune effector cell provided herein is an NK cell.
  • the immune effector cell provided herein is an NKT cell.
  • the immune effector cell provided herein is a macrophage.
  • the immune effector cell provided herein is a neutrophil.
  • the immune effector cell provided herein is a granulocyte.
  • the immune effector cells provided herein can be genetically engineered. In some embodiments, the genetically engineered immune effector cells provided herein are isolated. In some embodiments, the genetically engineered immune effector cells provided herein are substantially pure.
  • immune effector cells recombinantly expressing a polypeptide (e.g., an antibody or a CAR) disclosed herein.
  • a polypeptide e.g., an antibody or a CAR
  • immune effector cells e.g., T cells
  • a polynucleotide encoding a polypeptide (e.g., an antibody or a CAR) disclosed herein, or a vector having a polynucleotide disclosed herein.
  • immune effector cells e.g., T cells
  • immune effector cells comprising a polynucleotide that encodes an anti-BCMA antibody or antigen-binding fragment disclosed herein.
  • immune effector cells e.g., T cells
  • immune effector cells comprising a polynucleotide that encodes a BCMA CAR disclosed herein.
  • immune effector cells e.g., T cells
  • immune effector cells e.g., T cells
  • BCMA CAR e.g., BCMA CART cell
  • immune effector cells comprising a polynucleotide that encodes a BCMA TCR disclosed herein.
  • immune effector cells e.g., T cells
  • immune effector cells recombinantly expressing a BCMA TCR disclosed herein (e.g., BCMA TCRT cell) .
  • the immune effector cell provided herein is a T cell.
  • the T cell can be a cytotoxic T cell, a helper T cell, or a gamma delta T, a CD4+/CD8+ double positive T cell, a CD4+ T cell, a CD8+ T cell, a CD4/CD8 double negative T cell, a CD3+ T cell, a naive T cell, an effector T cell, a cytotoxic T cell, a helper T cell, a memory T cell, a regulator T cell, a Th0 cell, a Th1 cell, a Th2 cell, a Th3 (Treg) cell, a Th9 cell, a Th17 cell, a Th ⁇ helper cell, a Tfh cell, a stem memory TSCM cell, a central memory TCM cell, an effector memory TEM cell, an effector memory TEMRA cell, or a gamma delta T cell.
  • the T cell is a cytotoxic T cell,
  • genetically engineered cells provided herein are derived from cells isolated from a subject.
  • a genetically engineered cell that is “derived from” a source cell means that the genetically engineered cell is obtained by taking the source cell and genetically manipulating the source cell.
  • the source cell can be from a natural source.
  • the source cell can be a primary cell isolated from a subject.
  • the subject can be an animal or a human.
  • the source cell can also be a cell that has undergone passages or genetically manipulation in vitro.
  • genetically engineered cells provided herein are derived from cells isolated from a human.
  • Immune effector cells e.g., T cells
  • T cells can be obtained from many sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors.
  • T cell lines available in the art can be used.
  • genetically engineered cells provided herein are derived from cells isolated from peripheral blood.
  • genetically engineered cells provided herein are derived from cells isolated from bone marrow.
  • genetically engineered cells provided herein are derived from cells isolated from peripheral blood mononuclear cells (PBMC) .
  • PBMC peripheral blood mononuclear cells
  • genetically engineered cells provided herein are derived from cells differentiated in vitro from a stem or progenitor cell.
  • the stem or progenitor cell is selected from the group consisting of a T cell progenitor cell, a hematopoietic stem and progenitor cell, a hematopoietic multipotent progenitor cell, an embryonic stem cell, and an induced pluripotent cell.
  • genetically engineered cells provided herein are derived from cells differentiated in vitro from a T cell progenitor cell.
  • genetically engineered cells provided herein are derived from cells differentiated in vitro from a hematopoietic stem and progenitor cell.
  • genetically engineered cells provided herein are derived from cells differentiated in vitro from a hematopoietic multipotent progenitor cell. In some embodiments, genetically engineered cells provided herein are derived from cells differentiated in vitro from an embryonic stem cell. In some embodiments, genetically engineered cells provided herein are derived from cells differentiated in vitro from an induced pluripotent cell.
  • a population of cells comprising a cell disclosed herein.
  • the cells disclosed herein can comprise a polynucleotide that encodes a polypeptide disclosed herein or recombinantly express a polypeptide disclosed herein.
  • the polypeptide can be an anti-BCMA antibody or antigen-binding fragment, a BCMA CAR, or a BCMA TCR.
  • the population of cells can be a homogenous population of cells.
  • the population of cells can be a heterogeneous population of cells. In some embodiments, the population of cells can be a heterogeneous population of cells comprising any combination of the cells disclosed herein.
  • the population of cells are derived from peripheral blood mononuclear cells (PBMC) , peripheral blood leukocytes (PBL) , tumor infiltrating lymphocytes (TIL) , cytokine-induced killer cells (CIK) , lymphokine-activated killer cells (LAK) , or marrow infiltrate lymphocytes (MILs) .
  • PBMC peripheral blood mononuclear cells
  • PBL peripheral blood leukocytes
  • TIL tumor infiltrating lymphocytes
  • CIK cytokine-induced killer cells
  • LAK lymphokine-activated killer cells
  • MILs marrow infiltrate lymphocytes
  • the population of cells provided herein are derived from PBMC.
  • the population of cells provided herein are derived from PBL.
  • the population of cells provided herein are derived from TIL.
  • the population of cells provided herein are derived from CIK.
  • the population of cells provided herein are derived from LAK. In some embodiments, the population of cells provided herein are derived from MILs. The population of cells can be genetically engineered to recombinantly expressing a polypeptide (e.g., an antibody or a CAR) disclosed herein. In some embodiments, provided herein are population of cells comprising a polynucleotide encoding a polypeptide (e.g., an antibody or a CAR) disclosed herein, or a vector having a polynucleotide disclosed herein. In some embodiments, provided herein are population of cells comprising a polynucleotide that encodes an anti-BCMA antibody or antigen-binding fragment disclosed herein.
  • provided herein are population of cells recombinantly expressing an anti-BCMA antibody or antigen-binding fragment disclosed herein.
  • population of cells comprising a polynucleotide that encodes a BCMA CAR disclosed herein.
  • population of cells recombinantly expressing a BCMA CAR disclosed herein e.g., BCMA CART cell
  • population of cells comprising a polynucleotide that encodes a BCMA TCR disclosed herein.
  • provided herein are population of cells recombinantly expressing a BCMA TCR disclosed herein (e.g., BCMA TCRT cell) .
  • compositions comprising the anti-BCMA antibodies or antigen-binding fragments disclosed herein.
  • pharmaceutical compositions comprising the genetically engineered immune effector cells disclosed herein.
  • the pharmaceutical composition comprises a therapeutically effective amount of the anti-BCMA antibodies or antigen-binding fragments disclosed herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a therapeutically effective amount of genetically engineered cells disclosed herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions are useful in immunotherapy.
  • the pharmaceutical compositions are useful in immuno-oncology.
  • the pharmaceutical compositions are useful in inhibiting tumor growth in a subject (e.g., a human patient) .
  • the pharmaceutical compositions are useful in treating cancer in a subject (e.g., a human patient) .
  • the pharmaceutical compositions provided herein comprise anti-BCMA antibodies or antigen-binding fragments provided herein.
  • the anti-BCMA antibodies or antigen-binding fragments can be present at various concentrations.
  • the pharmaceutical compositions provided herein comprise soluble anti-BCMA antibodies or antigen-binding fragments provided herein at 1-1000 mg/ml.
  • the pharmaceutical compositions comprise soluble anti-BCMA antibodies or antigen-binding fragments provided herein at 10-500 mg/ml, 10-400 mg/ml, 10-300 mg/ml, 10-200 mg/ml, 10-100 mg/ml, 20-100 mg/ml, or 50-100 mg/ml.
  • the pharmaceutical compositions provided herein comprise anti-BCMA antibodies or antigen-binding fragments provided herein at about 10 mg/ml, about 20 mg/ml, about 30 mg/ml, about 40 mg/ml, about 50 mg/ml, about 60 mg/ml, about 70 mg/ml, about 80 mg/ml, about 90 mg/ml, about 100 mg/ml, about 120 mg/ml, about 150 mg/ml, about 180 mg/ml, about 200 mg/ml, about 300 mg/ml, about 500 mg/ml, about 800 mg/ml, or about 1000 mg/ml.
  • compositions comprising genetically engineered immune effector cells can comprise a purified population of cells.
  • T cells genetically engineered immune effector cells
  • Those skilled in the art can readily determine the percentage of cells in a cell population using various well-known methods, as described herein.
  • the ranges of purity in cell populations comprising genetically engineered cells provided herein can be from about 20%to about 25%, from about 25%to about 30%, from about 30%to about 35%, from about 35%to about 40%, from about 40%to about 45%, from about 45%to about 50%, from about 55%to about 60%, from about 65%to about 70%, from about 70%to about 75%, from about 75%to about 80%, from about 80%to about 85%; from about 85%to about 90%, from about 90%to about 95%, or from about 95 to about 100%.
  • the ranges of purity in cell populations comprising immune effector cells provided herein can be from about 20%to about 30%, from about 20%to about 50%, from about 20%to about 80%, from about 20%to about 100%, from about 50%to about 80%, or from about 50%to about 100%. Dosages can be readily adjusted by those skilled in the art; for example, a decrease in purity may require an increase in dosage.
  • kits for preparation of pharmaceutical compositions having the anti-BCMA antibodies or antigen-binding fragments disclosed herein comprising the anti-BCMA antibodies or antigen-binding fragments disclosed herein and a pharmaceutically acceptable carrier in one or more containers.
  • the kits can comprise anti-BCMA antibodies or antigen-binding fragments disclosed herein for administration to a subject.
  • the kits comprise instructions regarding the preparation and/or administration of the anti-BCMA antibodies or antigen-binding fragments.
  • kits for preparation of immune effector cells e.g., T cells
  • the kits comprise one or more vectors for generating a genetically engineered cell, such as a T cell, that expresses the anti-BCMA antibodies or antigen-binding fragments disclosed herein.
  • the kits can be used to generate genetically engineered immune effector cells (e.g., T cells) from autologous or non-autologous cells to be administered to a compatible subject.
  • the kits can comprise immune effector cells disclosed herein for administration to a subject.
  • the kits comprise the immune effector cells disclosed herein in one or more containers.
  • the kits comprise instructions regarding the preparation and/or administration of the immune effector cells.
  • a pharmaceutical composition comprising anti-BCMA antibodies or antigen-binding fragments or cells provided herein wherein the composition is suitable for local administration.
  • local administration comprises intratumoral injection, peritumoral injection, juxtatumoral injection, intralesional injection and/or injection into a tumor draining lymph node, or essentially any tumor-targeted injection where the antitumor agent is expected to leak into primary lymph nodes adjacent to targeted solid tumor.
  • compositions provided herein include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion) .
  • the active ingredient i.e., anti-BCMA antibodies or antigen-binding fragments or immune effector cells provided herein
  • the pharmaceutical composition or formulation disclosed herein comprises: (a) anti-BCMA antibodies or antigen-binding fragments disclosed herein; (b) a buffering agent; (c) a stabilizing agent; (d) a salt; (e) a bulking agent; and/or (f) a surfactant.
  • the pharmaceutical composition or formulation is stable for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 1 year, at least 2 years, at least 3 years, at least 5 years or more.
  • the pharmaceutical composition or formulation is stable when stored at 4°C, 25°C, or 40°C.
  • Buffering agents useful in the pharmaceutical compositions or formulations disclosed herein can be a weak acid or base used to maintain the acidity (pH) of a solution near a chosen value after the addition of another acid or base.
  • Suitable buffering agents can maximize the stability of the pharmaceutical formulations by maintaining pH control of the formulation. Suitable buffering agents can also ensure physiological compatibility or optimize solubility. Rheology, viscosity and other properties can also depend on the pH of the formulation.
  • Common buffering agents include, but are not limited to, histidine, citrate, succinate, acetate and phosphate.
  • a buffering agent comprises histidine (e.g., L-histidine) with isotonicity agents and potentially pH adjustment with an acid or a base known in the art.
  • the buffering agent is L-histidine.
  • the pH of the formulation is maintained between about 2 and about 10, or between about 4 and about 8.
  • Stabilizing agents are added to a pharmaceutical product to stabilize that product. Such agents can stabilize proteins in different ways. Common stabilizing agents include, but are not limited to, amino acids such as glycine, alanine, lysine, arginine, or threonine, carbohydrates such as glucose, sucrose, trehalose, rafftnose, or maltose, polyols such as glycerol, mannitol, sorbitol, cyclodextrins or destrans of any kind and molecular weight, or PEG. In some embodiments, the stabilizing agent is chosen to maximize the stability of FIX polypeptide in lyophilized preparations. In certain embodiments, the stabilizing agent is sucrose and/or arginine.
  • Bulking agents can be added to a pharmaceutical composition or formulation to add volume and mass to the product, thereby facilitating precise metering and handling thereof.
  • Common bulking agents include, but are not limited to, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, or magnesium stearate.
  • Surfactants are amphipathic substances with lyophilic and lyophobic groups.
  • a surfactant can be anionic, cationic, zwitterionic, or nonionic.
  • nonionic surfactants include, but are not limited to, alkyl ethoxylate, nonylphenol ethoxylate, amine ethoxylate, polyethylene oxide, polypropylene oxide, fatty alcohols such as cetyl alcohol or oleyl alcohol, cocamide MEA, cocamide DEA, polysorbates, or dodecyl dimethylamine oxide.
  • the surfactant is polysorbate 20 or polysorbate 80.
  • compositions disclosed herein can further comprise one or more of a buffer system, a preservative, a tonicity agent, a chelating agent, a stabilizer and/or a surfactant, as well as various combinations thereof.
  • a buffer system a preservative, a tonicity agent, a chelating agent, a stabilizer and/or a surfactant, as well as various combinations thereof.
  • preservatives, isotonic agents, chelating agents, stabilizers and surfactants in pharmaceutical compositions is well-known to the skilled person. Reference may be made to Remington: The Science and Practice of Pharmacy , 19 th edition, 1995.
  • the pharmaceutical composition is an aqueous formulation.
  • aqueous formulation is typically a solution or a suspension, but can also include colloids, dispersions, emulsions, and multi-phase materials.
  • aqueous formulation is defined as a formulation comprising at least 50%w/w water.
  • aqueous solution is defined as a solution comprising at least 50 %w/w water
  • aqueous suspension is defined as a suspension comprising at least 50 %w/w water.
  • the pharmaceutical compositions disclosed herein are freeze-dried, to which the physician or the patient adds solvents and/or diluents prior to use.
  • compositions disclosed herein can also include a pharmaceutically acceptable antioxidant.
  • pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA) , butylated hydroxytoluene (BHT) , lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA) , sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butyl
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like) , and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • 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.
  • compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms can be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It can also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions described herein is contemplated.
  • a pharmaceutical composition or formulation can comprise a preservative or can be devoid of a preservative. Supplementary active compounds can be incorporated into the compositions.
  • compositions or formulations typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like) , and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • compositions can include isotonic agents, for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein.
  • some methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the amount of active ingredient which can be combined with a carrier material in the pharmaceutical compositions or formulations disclosed herein can vary.
  • the amount of active ingredient which can be combined with a carrier material is the amount that produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.01 percent to about ninety-nine percent of active ingredient, from about 0.1 percent to about 70 percent, or from about 1 percent to about 30 percent of active ingredient in combination with a pharmaceutically acceptable carrier.
  • compositions disclosed herein can be prepared with carriers that protect the active ingredient against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and poly lactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. See. e.g., Sustained and Controlled Release Drug Delivery Systems , J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • the anti-BCMA antibodies or antigen-binding fragments or immune effector cells (e.g., T cells) described herein can be formulated to ensure proper distribution in vivo.
  • the blood-brain barrier (BBB) excludes many highly hydrophilic compounds.
  • the activate ingredient described herein cross the BBB (if desired, e.g., for brain cancers)
  • they can be formulated, for example, in liposomes.
  • liposomes see, e.g., U.S. Patents 4,522,811; 5,374,548; and 5,399,331.
  • the liposomes can comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery (see, e.g., V.V. Ranade (1989) J. Clin. Pharmacol. 29: 685) .
  • exemplary targeting moieties include folate or biotin (see, e.g., U.S. Patent 5,416,016 to Low et al) mannosides (Umezawa et al, (1988) Biochem. Biophys. Res. Commun. 153: 1038) ; antibodies (P. G. Bloeman et al. (1995) FEBS Lett. 357: 140; M. Owais et al. (1995) Antimicrob. Agents Chemother.
  • the present disclosure also provides methods of uses of the anti-BCMA antibodies or antigen-binding fragments, BCMA CARs, BCMA TCRs, polynucleotides encoding such anti-BCMA antibodies or antigen-binding fragments and BCMA CARs/TCRs, vectors comprising such polynucleotides, BCMA CAR/TCR-expressing cells or pharmaceutical compositions having such cells disclosed herein in treating cancer.
  • the anti-BCMA antibodies or antigen-binding fragments and the BCMA CAR/TCR-expressing cells disclosed herein can specifically target BCMA expressing cancer cells in vivo, thereby delivering their therapeutic effect of eliminating, lysing and/or killing cancer cells.
  • the methods include administering a therapeutically effective amount of the anti-BCMA antibodies or antigen-binding fragments disclosed herein to a subject in need thereof. In some embodiments, the methods include administering a therapeutically effective amount of BCMA CAR-expressing immune effector cells disclosed herein to a subject in need thereof. In one embodiment, the methods can include administering a therapeutically effective amount of BCMA CARTs disclosed herein to a subject in need thereof.
  • provided herein are methods of treating tumor or cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the anti-BCMA antibodies or antigen-binding fragments disclosed herein.
  • methods of treating tumor or cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the anti-BCMA antibodies or antigen-binding fragments disclosed herein.
  • provided herein are uses of the anti-BCMA antibodies or antigen-binding fragments provided herein for the preparation of a medicament for the treatment of tumor or cancer.
  • provided herein are methods of treating tumor or cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the immune effector cells (e.g., BCMA CARTs) disclosed herein.
  • a therapeutically effective amount of the immune effector cells e.g., BCMA CARTs
  • uses of the immune effector cells disclosed herein e.g., BCMA CARTs
  • a population of cells comprising the immune effector cell disclosed herein is used in the treatment.
  • the population of cells can be homogenous.
  • the population of cells can be heterogenous.
  • provided herein are methods of treating tumor or cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition disclosed herein.
  • provided herein are uses of the pharmaceutical composition disclosed herein in treatment of tumor or cancer.
  • provided herein are uses of the pharmaceutical composition provided herein for the preparation of a medicament for the treatment of tumor or cancer.
  • the active ingredients i.e., the anti-BCMA antibodies or antigen-binding fragments or the immune effector cells provided herein
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions described herein, the route of administration, the time of administration, the rate of excretion, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • the anti-BCMA antibodies or antigen-binding fragments can be administered as a sustained release formulation, in which case less frequent administration is required. Dosage and frequency vary depending on the half-life of the anti-BCMA antibodies or antigen-binding fragments in the patient. In therapeutic applications, a relatively high dosage at relatively short intervals is sometimes required until progression of the disease is reduced or terminated, and until the patient shows partial or complete amelioration of symptoms of disease.
  • immune effector cells provided herein that recombinantly express the BCMA CARs or TCRs disclosed herein can be used in the therapeutic methods disclosed herein.
  • the cells provided herein can be administered as a dose based on cells per kilogram (cells/kg) of body weight of the subject to which the cells are administered.
  • the cell doses can be in the range of about 10 4 to about 10 10 cells/kg of body weight, for example, about 10 5 to about 10 9 , about 10 5 to about 10 8 , about 10 5 to about 10 7 , or about 10 5 to 10 6 cells/kg of body weight, depending on the mode and location of administration.
  • a higher dose is used than in regional administration, where the immune effector cells are administered in the region of a tumor.
  • the precise determination of what would be considered an effective dose can be based on factors individual to each subject, including their size, age, sex, weight, and condition of the particular subject, as described above. Dosages can be readily determined by those skilled in the art based on the disclosure herein and knowledge in the art.
  • anti-BCMA antibodies or antigen-binding fragments, immune effector cells, and pharmaceutical compositions provided herein can be administered to a subject by any methods known in the art, including, but not limited to, pleural administration, intravenous administration, subcutaneous administration, intranodal administration, intratumoral administration, intramuscular administration, intradermal administration, intrathecal administration, intrapleural administration, intraperitoneal administration, intracranial administration, spinal or other parenteral routes of administration, for example by injection or infusion, or direct administration to the thymus.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion.
  • subcutaneous administration is adopted.
  • intravenous administration is adopted.
  • oral administration is adopted.
  • the cells provided herein can be delivered regionally to a tumor using well known methods, including but not limited to, hepatic or aortic pump; limb, lung or liver perfusion; in the portal vein; through a venous shunt; in a cavity or in a vein that is nearby a tumor, and the like.
  • the cells provided herein can be administered systemically.
  • the cells are administered regionally at the site of a tumor.
  • the cells can also be administered intratumorally, for example, by direct injection of the cells at the site of a tumor and/or into the tumor vasculature.
  • administration is preferably by intrapleural administration (see Adusumilli et al., Science Translational Medicine 6 (261) : 261ra151 (2014) ) .
  • One skilled in the art can select a suitable mode of administration based on the type of cancer and/or location of a tumor to be treated.
  • the cells can be introduced by injection or catheter.
  • the cells are pleurally administered to the subject in need, for example, using an intrapleural catheter.
  • expansion and/or differentiation agents can be administered to the subject prior to, during or after administration of cells to increase production of the cells provided herein in vivo.
  • Proliferation of the cells provided herein is generally done ex vivo, prior to administration to a subject, and can be desirable in vivo after administration to a subject (see Kaiser et al., Cancer Gene Therapy 22: 72-78 (2015) ) .
  • Cell proliferation should be accompanied by cell survival to permit cell expansion and persistence, such as with T cells.
  • BCMA-associated diseases or disorders include hematologic malignancies such as multiple myeloma, Waldenstrom macroglobulinemia, as well as both Hodgkin’s and non-Hodgkin’s lymphomas. See Coquery et al., Crit Rev Immunol., 2012, 32 (4) : 287-305 for a review of BCMA.
  • the BCMA-associated disease or disorder is a B cell-related disorder. In some embodiments, the BCMA-associated disease or disorder is glioblastoma, lymphomatoid granulomatosis, post-transplant lymphoproliferative disorder, an immunoregulatory disorder, heavy-chain disease, primary or immunocyte-associated amyloidosis, or monoclonal gammopathy of undetermined significance.
  • BCMA is expressed on malignant cells and cancers.
  • the cancer is a solid tumor.
  • the cancer is a hematopoietic cancer.
  • the cancer is a B cell malignancy.
  • the cancer is a lymphoma, a leukemia, or a plasma cell malignancy.
  • Lymphomas contemplated herein include, but are not limited to, Burkitt lymphoma (e.g., endemic Burkitt's lymphoma or sporadic Burkitt’s lymphoma) , non-Hodgkin's lymphoma (NHL) , Hodgkin's lymphoma, Waldenstrom macroglobulinemia, follicular lymphoma, small non-cleaved cell lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT) , marginal zone lymphoma, splenic lymphoma, nodal monocytoid B cell lymphoma, immunoblastic lymphoma, large cell lymphoma, diffuse mixed cell lymphoma, pulmonary B cell angiocentric lymphoma, small lymphocytic lymphoma, primary mediastinal B cell lymphoma, lymphoplasmacytic lymphoma (LPL) , or mantle cell lymphoma (MCL)
  • plasma cell malignancies including, but not limited to, multiple myeloma (MM) and plasmacytoma.
  • MM multiple myeloma
  • plasmacytoma plasmacytoma
  • the anti-BCMA antibodies or antigen-binding fragments, the immune effector cells, or the pharmaceutical compositions provided herein can be used to treat MM.
  • the MM to be treated is non-secretory MM.
  • the MM is smoldering MM.
  • the disease or condition is relapsed and/or refractory multiple myeloma (R/R MM) .
  • a BCMA-expressing cancer include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell cancer, melanoma, myeloma (e.g., multiple myeloma) , stomach cancer, brain cancer, lung cancer, pancreatic cancer, cervical cancer, ovarian cancer, liver
  • the methods include identifying a subject who has, is suspected to have, or is at risk for developing a BCMA-associated disease or disorder.
  • identifying a subject who has, is suspected to have, or is at risk for developing a BCMA-associated disease or disorder are provided.
  • a subject can be screened for the presence of a disease or disorder associated with elevated BCMA expression, such as a BCMA-expressing cancer.
  • the methods include screening for or detecting the presence of a BCMA-associated disease, e.g., a tumor.
  • a sample can be obtained from a patient suspected of having a disease or disorder associated with elevated BCMA expression and assayed for the expression level of BCMA.
  • a subject who tests positive for a BCMA-associated disease or disorder can be selected for treatment by the present methods, and can be administered a therapeutically effective amount of the anti-BCMA antibodies or antigen-binding fragments, the immune effector cells, or the pharmaceutical compositions provided herein.
  • An anti-tumor effect can be manifested by a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in the number of metastases, an increase in life expectancy, or amelioration of various physiological symptoms associated with the cancerous condition.
  • An anti-tumor effect can also be manifested by the ability of the cells or pharmaceutical compositions provided herein in prevention of the occurrence of tumor in the first place.
  • an “anti-tumor effect” can be manifested by the reduction in cancer-induced immunosuppression.
  • Clinical improvement comprises decreased risk or rate of progression or reduction in pathological consequences of the cancer or tumor.
  • a method of treating cancer can include any effect that ameliorates a sign or symptom associated with cancer.
  • signs or symptoms include, but are not limited to, reducing tumor burden, including inhibiting growth of a tumor, slowing the growth rate of a tumor, reducing the size of a tumor, reducing the number of tumors, eliminating a tumor, all of which can be measured using routine tumor imaging techniques well known in the art.
  • Other signs or symptoms associated with cancer include, but are not limited to, fatigue, pain, weight loss, and other signs or symptoms associated with various cancers.
  • the methods or uses provided herein can reduce tumor burden.
  • administration of the anti-BCMA antibodies or antigen-binding fragments, cells or pharmaceutical compositions disclosed herein can reduce the number of tumor cells, reduce tumor size, and/or eradicate the tumor in the subject.
  • Methods for monitoring patient response to administration of a pharmaceutical composition disclosed herein are known in the art and can be employed in accordance with methods disclosed herein.
  • a therapeutically effective amount of the anti-BCMA antibodies or antigen-binding fragments, cells or pharmaceutical compositions disclosed herein is administered to a subject in need of cancer treatment.
  • the subject can be a mammal.
  • the subject is a human.
  • these individuals have no clinically measurable tumor. However, they are suspected of being at risk for progression of the disease, either near the original tumor site, or by metastases.
  • This group can be further subdivided into high-risk and low-risk individuals. The subdivision is made on the basis of features observed before or after the initial treatment. These features are known in the clinical arts and are suitably defined for different types of cancers.
  • Features typical of high-risk subgroups are those in which the tumor has invaded neighboring tissues, or who show involvement of lymph nodes.
  • the subject has persistent or relapsed disease, e.g., following treatment with another BCMA-specific antibody and/or BCMA CART and/or other therapy, including chemotherapy, radiation, and/or hematopoietic stem cell transplantation (HSCT) , e.g., allogeneic HSCT or autologous HSCT.
  • HSCT hematopoietic stem cell transplantation
  • the administration effectively treats the subject despite the subject having become resistant to another BCMA-targeted therapy.
  • the subject has not relapsed but is determined to be at risk for relapse, such as at a high risk of relapse, and thus the compound or composition is administered prophylactically, e.g., to reduce the likelihood of or prevent relapse.
  • the subject is one that is eligible for a transplant, such as is eligible for a hematopoietic stem cell transplantation (HSCT) , e.g., allogeneic HSCT or autologous HSCT.
  • HSCT hematopoietic stem cell transplantation
  • the subject has not previously received a transplant, despite being eligible, prior to administration of the BCMA-binding molecules, including the anti-BCMA antibodies or antigen-binding fragments, the immune effector cells, or the pharmaceutical compositions provided herein.
  • the subject is one that is not eligible for a transplant, such as is not eligible for a hematopoietic stem cell transplantation (HSCT) , e.g., allogenic HSCT or autologous HSCT.
  • HSCT hematopoietic stem cell transplantation
  • the methods provided herein include adoptive cell therapy, whereby genetically engineered immune effector cells expressing the provided recombinant receptors comprising a BCMA-binding molecule (e.g., BCMA CARs provided herein) are administered to subjects. Such administration can promote activation of the cells (e.g., T cell activation) in a BCMA-targeted manner, such that the cells of the disease or disorder are targeted for destruction.
  • the provided methods and uses include methods and uses for adoptive cell therapy.
  • the methods include administration of the cells or a composition containing the cells to a subject such as one having, or at risk for, or suspected of having the disease, condition or disorder.
  • the cells, populations, and compositions are administered to a subject having the particular disease or condition to be treated, e.g., via adoptive cell therapy, such as adoptive T cell therapy.
  • adoptive cell therapy such as adoptive T cell therapy.
  • the cells or compositions are administered to the subject, such as a subject having or at risk for the disease or condition.
  • the methods thereby treat, e.g., ameliorate one or more symptom of the disease or condition, such as by lessening tumor burden in a BCMA-expressing cancer.
  • the cell therapy e.g., adoptive cell therapy, e.g., adoptive T cell therapy
  • the cells are isolated and/or otherwise prepared from the subject who is to receive the cell therapy, or from a sample derived from such a subject.
  • the cells are derived from a subject, e.g., patient, in need of a treatment and the cells, following isolation and processing are administered to the same subject.
  • the cell therapy e.g., adoptive cell therapy, e.g., adoptive T cell therapy
  • the cells are isolated and/or otherwise prepared from a subject other than a subject who is to receive or who ultimately receives the cell therapy, e.g., a first subject.
  • the cells then are administered to a different subject, e.g., a second subject, of the same species.
  • the first and second subjects are genetically identical.
  • the first and second subjects are genetically similar.
  • the second subject expresses the same HLA class or supertype as the first subject.
  • Anti-BCMA antibodies or antigen-binding fragments, cells, or pharmaceutical compositions provided herein can be administered with medical devices known in the art.
  • a needleless hypodermic injection device can be used, such as the devices disclosed in U.S. Patent Nos. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824; or 4,596,556.
  • Examples of well-known implants and modules for use described herein include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No.
  • Combination therapy using agents with different mechanisms of action can result in additive or synergetic effects.
  • Combination therapy can allow for a lower dose of each agent than is used in monotherapy, thereby reducing toxic side effects and/or increasing the therapeutic index of the agent disclosed herein.
  • Combination therapy can decrease the likelihood that resistant cancer cells will develop.
  • the additional therapy results in an increase in the therapeutic index of the cells or pharmaceutical compositions described herein.
  • the additional therapy results in a decrease in the toxicity and/or side effects of cells or pharmaceutical compositions described herein.
  • the anti-BCMA antibodies or antigen-binding fragments, cells, or pharmaceutical compositions described herein can be administered in combination with an additional therapy.
  • the additional therapy can be surgical resection, radiotherapy, or chemotherapy.
  • the additional therapy can be administered prior to, concurrently with, or subsequent to administration of the anti-BCMA antibodies or antigen-binding fragments, cells, or pharmaceutical compositions described herein.
  • Combined administration can include co-administration, either in a single pharmaceutical formulation or using separate formulations, or consecutive administration in either order but generally within a time period such that all active agents can exert their biological activities simultaneously.
  • a person skilled in the art can readily determine appropriate regimens for administering a pharmaceutical composition described herein and an additional therapy in combination, including the timing and dosing of an additional agent to be used in a combination therapy, based on the needs of the subject being treated.
  • Polynucleotides provided herein can be prepared, manipulated, and/or expressed using any of the well-established techniques known and available in the art.
  • Many vectors can be used. Examples of vectors are plasmid, autonomously replicating sequences, and transposable elements. Exemplary transposon systems such as Sleeping Beauty and PiggyBac can be used, which can be stably integrated into the genome (e.g., Ivics et al., Cell, 91 (4) : 501–510 (1997) ; et al., (2007) Nucleic Acids Research. 35 (12) : e87) .
  • Additional exemplary vectors include, without limitation, plasmids, phagemids, cosmids, artificial chromosomes such as yeast artificial chromosome (YAC) , bacterial artificial chromosome (BAC) , or P1-derived artificial chromosome (PAC) , bacteriophages such as lambda phage or M13 phage, and animal viruses.
  • artificial chromosomes such as yeast artificial chromosome (YAC) , bacterial artificial chromosome (BAC) , or P1-derived artificial chromosome (PAC)
  • bacteriophages such as lambda phage or M13 phage
  • animal viruses include, without limitation, retrovirus (including lentivirus) , adenovirus, adeno-associated virus, herpesvirus (e.g., herpes simplex virus) , poxvirus, baculovirus, papillomavirus, and papovavirus (e.g., SV40) .
  • expression vectors are pClneo vectors (Promega) for expression in mammalian cells; pLenti4/V5-DEST TM , pLenti6/V5-DEST TM , and pLenti6.2/V5-GW/lacZ (Invitrogen) for lentivirus-mediated gene transfer and expression in mammalian cells.
  • the vector is an episomal vector or a vector that is maintained extrachromosomally.
  • episomal vector refers to a vector that is able to replicate without integration into host’s chromosomal DNA and without gradual loss from a dividing host cell also meaning that said vector replicates extrachromosomally or episomally.
  • the vector is engineered to harbor the sequence coding for the origin of DNA replication or “ori” from a lymphotrophic herpes virus or a gamma herpesvirus, an adenovirus, SV40, a bovine papilloma virus, or a yeast, specifically a replication origin of a lymphotrophic herpes virus or a gamma herpesvirus corresponding to oriP of EBV.
  • the lymphotrophic herpes virus may be Epstein Barr virus (EBV) , Kaposi's sarcoma herpes virus (KSHV) , Herpes virus saimiri (HS) , or Marek's disease virus (MDV) .
  • Epstein Barr virus (EBV) and Kaposi's sarcoma herpes virus (KSHV) are also examples of a gamma herpesvirus.
  • the host cell comprises the viral replication transactivator protein that activates the replication.
  • “Expression control sequences, ” “control elements, ” or “regulatory sequences” present in an expression vector are those non-translated regions of the vector-origin of replication, selection cassettes, promoters, enhancers, translation initiation signals (Shine Dalgarno sequence or Kozak sequence) introns, a polyadenylation sequence, 5' and 3' untranslated regions-which interact with host cellular proteins to carry out transcription and translation.
  • Such elements can vary in their strength and specificity.
  • any number of suitable transcription and translation elements including ubiquitous promoters and inducible promoters can be used.
  • Illustrative ubiquitous expression control sequences that can be used in present disclosure include, but are not limited to, a cytomegalovirus (CMV) immediate early promoter, a viral simian virus 40 (SV40) promoter (e.g., early or late) , a Moloney murine leukemia virus (MoMLV) LTR promoter, a Rous sarcoma virus (RSV) LTR, a herpes simplex virus (HSV) (thymidine kinase) promoter, H5, P7.5, and P11 promoters from vaccinia virus, an elongation factor 1-alpha (EF1a) promoter, early growth response 1 (EGR1) , ferritin H (FerH) , ferritin L (FerL) , Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) , eukaryotic translation initiation factor 4A1 (EIF4A1) , heat shock 70kDa protein 5 (H
  • inducible promoters/systems include, but are not limited to, steroid-inducible promoters such as promoters for genes encoding glucocorticoid or estrogen receptors (inducible by treatment with the corresponding hormone) , metallothionine promoter (inducible by treatment with various heavy metals) , MX-1 promoter (inducible by interferon) , the “GeneSwitch” mifepristone-regulatable system (Sirin et al., 2003, Gene, 323: 67) , the cumate inducible gene switch (WO 2002/088346) , tetracycline-dependent regulatory systems, etc.
  • steroid-inducible promoters such as promoters for genes encoding glucocorticoid or estrogen receptors (inducible by treatment with the corresponding hormone)
  • metallothionine promoter inducible by treatment with various heavy metals
  • MX-1 promoter inducible by interfer
  • MOLECULAR CLONING A LABORATORY MANUAL, Second Edition, Cold Spring Harbor Laboratory Press; Sambrook et al. (2001) MOLECULAR CLONING: A LABORATORY MANUAL, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY; Ausubel et al., CURRENT PROTOCOLS IN MOLECULAR BIOLOGY, John Wiley &Sons (1987 and annual updates) ; CURRENT PROTOCOLS IN IMMUNOLOGY, John Wiley &Sons (1987 and annual updates) Gait (ed. ) (1984) OLIGONUCLEOTIDE SYNTHESIS: A PRACTICAL APPROACH, IRL Press; Eckstein (ed.
  • polypeptides described herein can be produced and isolated using methods known in the art.
  • Peptides can be synthesized, in whole or in part, using chemical methods (see, e.g., Caruthers (1980) . Nucleic Acids Res. Symp. Ser. 215; Horn (1980) ; and Banga, A. K., THERAPEUTIC PEPTIDES AND PROTEINS, FORMULATION, PROCESSING AND DELIVERY SYSTEMS (1995) Technomic Publishing Co., Lancaster, PA) .
  • Peptide synthesis can be performed using various solid phase techniques (see, e.g., Roberge, Science 269: 202 (1995) ; Merrifield, Methods. Enzymol. 289: 3 (1997) ) and automated synthesis may be achieved, e.g., using the ABI 431A Peptide Synthesizer (Perkin Elmer) in accordance with the manufacturer’s instructions. Peptides can also be synthesized using combinatorial methodologies. Synthetic residues and polypeptides can be synthesized using a variety of procedures and methodologies known in the art (see, e.g., ORGANIC SYNTHESES COLLECTIVE VOLUMES, Gilman, et al.
  • Modified peptides can be produced by chemical modification methods (see, for example, Belousov, Nucleic Acids Res. 25: 3440 (1997) ; Frenkel, Free Radic. Biol. Med. 19: 373 (1995) ; and Blommers, Biochemistry 33: 7886 (1994) ) .
  • Peptide sequence variations, derivatives, substitutions and modifications can also be made using methods such as oligonucleotide-mediated (site-directed) mutagenesis, alanine scanning, and PCR based mutagenesis. Site-directed mutagenesis (Carter et al., Nucl.
  • a recombinant expression vector is used to express a polynucleotide encoding a polypeptide described herein.
  • a recombinant expression vector can be a replicable DNA construct that includes synthetic or cDNA-derived DNA fragments encoding a polypeptide operatively linked to suitable transcriptional and/or translational regulatory elements derived from mammalian, microbial, viral or insect genes.
  • coding sequences of polypeptides disclosed herein can be ligated into such expression vectors for their expression in mammalian cells.
  • a viral vector is used.
  • DNA regions are “operatively linked” when they are functionally related to each other.
  • a promoter is operatively linked to a coding sequence if it controls the transcription of the sequence; or a ribosome binding site is operatively linked to a coding sequence if it is positioned so as to permit translation.
  • structural elements intended for use in yeast expression systems include a leader sequence enabling extracellular secretion of translated protein by a host cell.
  • a polypeptide in situations where recombinant protein is expressed without a leader or transport sequence, a polypeptide can include an N-terminal methionine residue.
  • Suitable host cells for expression include prokaryotes, yeast cells, insect cells, or higher eukaryotic cells under the control of appropriate promoters.
  • Appropriate cloning and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts, as well as methods of protein production, including antibody production are well-known in the art.
  • Useful expression vectors for bacterial hosts include known bacterial plasmids, such as plasmids from E. coli, including pCR1, pBR322, pMB9 and their derivatives, and wider host range plasmids, such as M13 and other filamentous single-stranded DNA phages.
  • Useful expression vectors for eukaryotic hosts include, for example, vectors comprising expression control sequences from SV40, bovine papilloma virus, adenovirus, and cytomegalovirus.
  • suitable mammalian host cell lines include, but are not limited to, COS-7 (monkey kidney-derived) , L-929 (murine fibroblast-derived) , C127 (murine mammary tumor-derived) , 3T3 (murine fibroblast-derived) , CHO (Chinese hamster ovary-derived) , HeLa (human cervical cancer-derived) , BHK (hamster kidney fibroblast-derived) , HEK-293 (human embryonic kidney-derived) cell lines and variants thereof.
  • Mammalian expression vectors can comprise non-transcribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5’ or 3’ flanking non-transcribed sequences, and 5’ or 3’ non-translated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences.
  • expression of recombinant proteins in insect cell culture systems e.g., baculovirus
  • Baculovirus systems for production of heterologous proteins in insect cells are well-known to those of skill in the art.
  • anti-BCMA antibodies and antigen-binding fragments thereof that include but are not limited to monoclonal antibodies, polyclonal antibodies, synthetic antibodies, human antibodies, humanized antibodies, and antigen-binding fragments thereof.
  • Human antibodies can be made by a variety of methods known in the art including phage display methods using antibody libraries derived from human immunoglobulin sequences, including improvements to these techniques. See, also, U.S. Pat. Nos. 4,444,887 and 4,716,111; and PCT publications WO 98/46645, WO 98/50433, WO 98/24893, WO98/16654, WO 96/34096, WO 96/33735, and WO 91/10741; each of which is incorporated herein by reference in its entirety.
  • a human antibody can also be an antibody wherein the heavy and light chains are encoded by a nucleotide sequence derived from one or more sources of human DNA.
  • Human antibodies can also be produced using transgenic mice which are incapable of expressing functional endogenous immunoglobulins, but which can express human immunoglobulin genes.
  • the human heavy and light chain immunoglobulin gene complexes can be introduced randomly or by homologous recombination into mouse embryonic stem cells.
  • the human variable region, constant region, and diversity region can be introduced into mouse embryonic stem cells in addition to the human heavy and light chain genes.
  • the mouse heavy and light chain immunoglobulin genes may be rendered non-functional separately or simultaneously with the introduction of human immunoglobulin loci by homologous recombination.
  • the modified embryonic stem cells are expanded and microinjected into blastocysts to produce chimeric mice.
  • the chimeric mice are then bred to produce homozygous offspring which express human antibodies.
  • the transgenic mice are immunized in the normal fashion with a selected antigen, e.g., all or a portion of a polypeptide of the invention.
  • anti-BCMA antibodies directed against the human BCMA antigen can be obtained from the immunized, transgenic mice using conventional hybridoma technology.
  • the human immunoglobulin transgenes harbored by the transgenic mice rearrange during B cell differentiation, and subsequently undergo class switching and somatic mutation.
  • IgG, IgA, IgM and IgE antibodies including, but not limited to, IgG1 (gamma 1) and IgG3.
  • IgG1 gamma 1
  • IgG3 IgG3
  • companies such as Abgenix, Inc. (Freemont, Calif. ) and Genpharm (San Jose, Calif. ) can be engaged to provide human antibodies directed against a selected antigen using technology similar to that described above.
  • Human antibodies can also be derived from phage-display libraries (Hoogenboom et al., J. Mol. Biol., 227: 381 (1991) ; Marks et al., J. Mol. Biol., 222: 581-597 (1991) ; Vaughan et al., Nature Biotech., 14: 309 (1996) ) .
  • Phage display technology McCafferty et al., Nature, 348: 552-553 (1990)
  • V immunoglobulin variable
  • antibody V domain genes are cloned in-frame into either a major or minor coat protein gene of a filamentous bacteriophage, such as M13 or fd, and displayed as functional antibody fragments on the surface of the phage particle.
  • a filamentous bacteriophage such as M13 or fd
  • the filamentous particle contains a single-stranded DNA copy of the phage genome
  • selections based on the functional properties of the antibody also result in selection of the gene encoding the antibody exhibiting those properties.
  • the phage mimics some of the properties of the B cell.
  • Phage display can be performed in a variety of formats; for their review see, e.g., Johnson and Chiswell, Current Opinion in Structural Biology 3: 564-571 (1993) .
  • V-gene segments can be used for phage display.
  • Clackson et al., Nature, 352: 624-628 (1991) isolated a diverse array of anti-oxazolone antibodies from a small random combinatorial library of V genes derived from the spleens of unimmunized mice.
  • a repertoire of V genes from unimmunized human donors can be constructed and antibodies to a diverse array of antigens (including self-antigens) can be isolated essentially following the techniques described by Marks et al., J. Mol. Biol., 222: 581-597 (1991) , or Griffith et al., EMBO J., 12: 725-734 (1993) .
  • Marks et al. J. Mol. Biol., 222: 581-597 (1991)
  • Griffith et al. EMBO J., 12: 725-734 (1993) .
  • Human antibodies can also be generated by in vitro activated B cells (see, U.S. Pat. Nos. 5,567,610 and 5,229,275, each of which is incorporated herein by reference in its entirety) . Human antibodies can also be generated in vitro using hybridoma techniques such as, but not limited to, that described by Roder et al. (Methods Enzymol., 121: 140-167 (1986) ) .
  • a non-human antibody is humanized, where specific sequences or regions of the antibody are modified to increase similarity to an antibody naturally produced in a human.
  • the antigen binding domain portion is humanized.
  • a humanized antibody can be produced using a variety of techniques known in the art, including but not limited to, CDR-grafting (see, e.g., European Patent No. EP 239, 400; International Publication No. WO 91/09967; and U.S. Pat. Nos. 5,225,539, 5,530,101, and 5,585,089, each of which is incorporated herein in its entirety by reference) , veneering or resurfacing (see, e.g., European Patent Nos.
  • framework residues in the framework regions can be substituted with the corresponding residue from the CDR donor antibody to alter, preferably improve, antigen binding.
  • These framework substitutions are identified by methods well-known in the art, e.g., by modeling of the interactions of the CDR and framework residues to identify framework residues important for antigen binding and sequence comparison to identify unusual framework residues at particular positions. (See, e.g., Queen et al., U.S. Pat. No. 5,585,089; and Riechmann et al., 1988, Nature, 332: 323, which are incorporated herein by reference in their entireties. )
  • humanized antibody has one or more amino acid residues introduced into it from a source which is nonhuman. These nonhuman amino acid residues are often referred to as “import” residues, which are typically taken from an “import” variable domain. Thus, humanized antibodies comprise one or more CDRs from nonhuman immunoglobulin molecules and framework regions from human.
  • humanized chimeric antibodies substantially less than an intact human variable domain has been substituted by the corresponding sequence from a nonhuman species.
  • humanized antibodies are typically human antibodies in which some CDR residues and possibly some FR residues are substituted by residues from analogous sites in rodent antibodies.
  • variable domains both light and heavy
  • the choice of human variable domains, both light and heavy, to be used in making the humanized antibodies is to reduce antigenicity.
  • sequence of the variable domain of a rodent antibody is screened against the entire library of known human variable-domain sequences.
  • the human sequence which is closest to that of the rodent is then accepted as the human framework (FR) for the humanized antibody (Sims et al., J. Immunol., 151: 2296 (1993) ; Chothia et al., J. Mol. Biol., 196: 901 (1987) , the contents of which are incorporated herein by reference herein in their entirety) .
  • FR human framework
  • Another method uses a particular framework derived from the consensus sequence of all human antibodies of a particular subgroup of light or heavy chains.
  • the same framework may be used for several different humanized antibodies (Carter et al., Proc. Natl. Acad. Sci. USA, 89: 4285 (1992) ; Presta et al., J. Immunol., 151: 2623 (1993) , the contents of which are incorporated herein by reference herein in their entirety) .
  • Antibodies can be humanized with retention of high affinity for the target antigen and other favorable biological properties.
  • humanized antibodies can be prepared by a process of analysis of the parental sequences and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are commonly available and are familiar to those skilled in the art. Computer programs are available which illustrate and display probable three-dimensional conformational structures of selected candidate immunoglobulin sequences. Inspection of these displays permits analysis of the likely role of the residues in the functioning of the candidate immunoglobulin sequence, i.e., the analysis of residues that influence the ability of the candidate immunoglobulin to bind the target antigen. In this way, FR residues can be selected and combined from the recipient and import sequences so that the desired antibody characteristic, such as increased affinity for the target antigen, is achieved. In general, the CDR residues are directly and most substantially involved in influencing antigen binding.
  • a humanized antibody retains a similar antigenic specificity as the original antibody, for example, the ability to bind human BCMA antigen.
  • affinity and/or specificity of binding of the antibody for a particular antigen can be increased using methods of “directed evolution, ” as described by Wu et al., J. Mol. Biol., 294: 151 (1999) , the contents of which are incorporated herein by reference herein in their entirety.
  • provided herein is a genetically engineered immune effector cell that comprises a polynucleotide encoding a BCMA CAR or TCR disclosed herein. In some embodiments, provided herein is a genetically engineered immune effector cell that recombinantly expresses a BCMA CAR or TCR disclosed herein. In some embodiments, provided herein is a genetically engineered immune effector cell that comprises a vector comprising a polynucleotide encoding a BCMA CAR or TCR disclosed herein. In some embodiments, the immune effector cells are T cells.
  • one or more polynucleotides encoding the BCMA CAR or TCR is introduced into the target cell using a suitable expression vector.
  • the target immune effector cells e.g., T cells
  • the genetically engineered cells can also express the anti-BCMA antibodies or antigen-binding fragments disclosed herein.
  • kits for genetically engineering an immune effector cell by transferring a polynucleotide provided herein into the cell using a non-viral delivery system.
  • the BCMA CAR or TCR encoding polynucleotide can be mRNA, which allows transient expression and the self-elimination of the immune effector cells expressing such BCMA CAR or TCR.
  • Physical methods for introducing a polynucleotide into a host cell include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, and the like.
  • RNA electroporation can be used (Van Driessche et al.
  • the methods can further include preparing the mRNA by in vitro transcribing the polynucleotides described herein.
  • methods of genetically engineering an immune effector cell by transferring a polynucleotide encoding anti-BCMA antibodies or antigen-binding fragments disclosed herein into the cell using electroporation.
  • methods of genetically engineering an immune effector cell by transferring a polynucleotide encoding BCMA CARs or TCRs disclosed herein into the cell using electroporation.
  • DNA transfection and transposon can be used.
  • the Sleeping Beauty system or PiggyBac system is used (e.g., Ivics et al., Cell, 91 (4) : 501-510 (1997) ; et al. (2007) Nucleic Acids Research. 35 (12) : e87) .
  • Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes.
  • An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle) .
  • a polynucleotide encoding a BCMA CAR or TCR disclosed herein can be cloned into a suitable vector, and introduced into the target cell using well known molecular biology techniques (see Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, MD (1999) ) .
  • Any vector suitable for expression in a cell, particularly a human cell can be used.
  • the vectors contain suitable expression elements such as promoters that provide for expression of the encoded nucleic acids in the target cell.
  • the vector is a gamma retroviral vector.
  • the vector is an SGF retroviral vector such as an SGF ⁇ -retroviral vector, which is Moloney murine leukemia-based retroviral vector.
  • SGF vectors have been described previously (see, for example, Wang et al., Gene Therapy 15: 1454-1459 (2008) ) .
  • cells can optionally be activated to increase transduction efficiency (see Parente-Pereira et al., J. Biol. Methods 1 (2) e7 (doi 10.14440/jbm. 2014.30) (2014) ; Movassagh et al., Hum. Gene Ther. 11: 1189-1200 (2000) ; Rettig et al., Mol. Ther.
  • amphotropic virus-producing cell lines are known, including, but not limited to, PA12 (Miller et al., Mol. Cell. Biol. 5: 431-437 (1985) ) ; PA317 (Miller et al., Mol. Cell. Biol. 6: 2895-2902 (1986) ) ; and CRIP (Danos et al., Proc. Natl. Acad. Sci. USA 85: 6460-6464 (1988) ) .
  • Non-amphotropic particles are suitable too, for example, particles pseudotyped with VSVG, RD114 or GALV envelope and any other known in the art (Relander et al., Mol. Therap. 11: 452-459 (2005) ) .
  • Possible methods of transduction also include direct co-culture of the cells with producer cells (for example, Bregni et al., Blood 80: 1418-1422 (1992) ) , or culturing with viral supernatant alone or concentrated vector stocks with or without appropriate growth factors and polycations (see, for example, Xu et al., Exp. Hemat. 22: 223-230 (1994) ; Hughes, et al. J. Clin. Invest. 89: 1817-1824 (1992) ) .
  • viral vectors that can be used include, for example, adenoviral, lentiviral, and adeno-associated viral vectors, vaccinia virus, a bovine papilloma virus derived vector, or a herpes virus, such as Epstein-Barr Virus (see, for example, Miller, Hum. Gene Ther. 1 (1) : 5-14 (1990) ; Friedman, Science 244: 1275-1281 (1989) ; Eglitis et al., BioTechniques 6: 608-614 (1988) ; Tolstoshev et al., Current Opin. Biotechnol.
  • Epstein-Barr Virus see, for example, Miller, Hum. Gene Ther. 1 (1) : 5-14 (1990) ; Friedman, Science 244: 1275-1281 (1989) ; Eglitis et al., BioTechniques 6: 608-614 (1988) ; Tolstoshev et al., Current Opin. Biotechno
  • Retroviral vectors are particularly well developed and have been used in clinical settings (Rosenberg et al., N. Engl. J. Med.
  • the chosen vector exhibits high efficiency of infection and stable expression (see, for example, Cayouette et al., Human Gene Therapy 8: 423-430 (1997) ; Kido et al., Current Eye Research 15: 833-844 (1996) ; Bloomer et al., J. Virol. 71: 6641-6649 (1997) ; Naldini et al., Science 272: 263-267 (1996) ; and Miyoshi et al., Proc. Natl. Acad. Sci. U.S.A. 94: 10319-10323 (1997) ) .
  • the vectors used herein employ suitable promoters for expression in a particular host cell.
  • the promoter can be an inducible promoter or a constitutive promoter.
  • the promoter of an expression vector provides expression in a stem cell, such as a hematopoietic stem cell.
  • the promoter of an expression vector provides expression in an immune effector cell, such as a T cell.
  • Non-viral vectors can be used as well, so long as the vector contains suitable expression elements for expression in the target cell.
  • Some vectors, such as retroviral vectors can integrate into the host genome.
  • provided herein are methods of genetically engineering an immune effector cell by transferring a polynucleotide provided herein into the cell using gene-editing.
  • targeted integration can be implemented using technologies such as a nuclease, transcription activator-like effector nucleases (TALENs) , Zinc-finger nucleases (ZFNs) , clustered regularly interspaced short palindromic repeats (CRISPRs) , homologous recombination, non-homologous end joining, microhomology-mediated end joining, homology-mediated end joining and the like (Gersbach et al., Nucl. Acids Res. 39: 7868-7878 (2011) ;ouvreva, et al.
  • TALENs transcription activator-like effector nucleases
  • ZFNs Zinc-finger nucleases
  • CRISPRs clustered regularly interspaced short palindromic repeats
  • a zinc-finger nuclease consists of a DNA recognition domain and a non-specific endonuclease.
  • the DNA recognition domain consists of a series of Cys2-His2 zinc-finger proteins linked in series, and each zinc-finger unit includes about 30 amino acids for specifically binding to DNA.
  • the non-specific endonuclease is a FokI endonuclease which forms a dimer to cleave the DNA.
  • methods provided herein use a TALEN system.
  • TALEN is a transcription activator-like effector nuclease.
  • the TALE protein is a core component of a DNA binding domain, and generally consists of a plurality of basic repeat units linked in series. The designed and combined series of units can specifically recognize a DNA sequence and cleave a specific DNA sequence by coupling the FokI endonuclease.
  • methods provided herein use a CRISPR-Cas system.
  • the CRISPR-Cas system can be a CRISPR-Cas9 system.
  • CRISPR/Cas system is a nuclease system consisting of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR binding proteins (i.e., Cas proteins) , which can cleave nearly all genomic sequences adjacent to protospacer-adjacent motifs (PAM) in eukaryocytes (Cong et al. Science 2013.339: 819-823) .
  • CRISPR clustered regularly interspaced short palindromic repeats
  • Cas proteins CRISPR binding proteins
  • CRISPR/Cas system is used to refer collectively to transcripts involving CRISPR-related ( “Cas” ) genes, as well as other elements involving the expression thereof or directing the activity thereof, including sequences encoding a Cas gene, tracr (trans-activated CRISPR) sequences (for example, tracrRNA or active partial tracrRNA) , tracr pairing sequences (in the background of an endogenous CRISPR system, cover “direct repeats” and processed partial direct repeats) , guide sequences, or other sequences from the CRISPR locus and transcripts.
  • tracr trans-activated CRISPR sequences
  • tracr pairing sequences in the background of an endogenous CRISPR system, cover “direct repeats” and processed partial direct repeats
  • guide sequences or other sequences from the CRISPR locus and transcripts.
  • the CRISPR system is characterized as an element that facilitates the formation of a CRISPR complex at a site of a target sequence (also called a protospacer in the endogenous CRISPR system) .
  • Cas protein include Cas1, Cas1B, Cas2, Cas3, Cas4, Cas5, Cas6, Cas7, Cas8, Cas9 (also known as Csn1 and Csx12) , Cas10, Csy1, Csy2, Csy3, Cse1, Cse2, Csc1, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmr1, Cmr3, Cmr4, Cmr5, Cmr6, Csb1, Csb2, Csb3, Csx17, Csx14, Csx10, Csx16, CsaX, Csx3, Csx1, Csx15, Csf1, Csf2, C
  • the Cas protein is a Cas9 protein (Gasiunas, Barrangou et al. 2012; Jinek, Chylinski et al. 2012; Deltcheva, Chylinski et al. 2011; Makarova, Grishin et al. (2006) ) .
  • Amino acid sequences of the Cas9 protein are known in the art. Exemplary sequences can be found, for example, in the SwissProt database under the accession number Q99ZW2, in the UniProt database under the number A1IQ68, Q03LF7, or J7RUA5.
  • the vectors and constructs can optionally be designed to include a reporter.
  • the vector can be designed to express a reporter protein, which can be useful to identify cells comprising the vector or polynucleotides provided on the vector, such as polynucleotides that have integrated into the host chromosome.
  • the reporter can be expressed as a bicistronic or multicistronic expression construct with the anti-BCMA antibody or antigen-binding fragment or the BCMA CAR or TCR.
  • reporter proteins include, but are not limited to, fluorescent proteins, such as mCherry, green fluorescent protein (GFP) , blue fluorescent protein, for example, EBFP, EBFP2, Azurite, and mKalama1, cyan fluorescent protein, for example, ECFP, Cerulean, and CyPet, and yellow fluorescent protein, for example, YFP, Citrine, Venus, and YPet.
  • fluorescent proteins such as mCherry, green fluorescent protein (GFP) , blue fluorescent protein, for example, EBFP, EBFP2, Azurite, and mKalama1
  • cyan fluorescent protein for example, ECFP, Cerulean, and CyPet
  • yellow fluorescent protein for example, YFP, Citrine, Venus, and YPet.
  • Assays can be used to determine the transduction efficiency using routine molecular biology techniques. If a marker has been included in the construct, such as a fluorescent protein, gene transfer efficiency can be monitored by FACS analysis to quantify the fraction of transduced (for example, GFP + ) immune effector cells, such as T cells, and/or by quantitative PCR. Using a well-established cocultivation system (Gade et al., Cancer Res. 65: 9080-9088 (2005) ; Gong et al., Neoplasia 1: 123-127 (1999) ; Latouche et al., Nat. Biotechnol. 18: 405-409 (2000) ) it can be determined whether fibroblast AAPCs expressing cancer antigen (vs.
  • T cells transduced immune effector cells
  • a CAR cell supernatant LUMINEX (Austin TX) assay for IL-2, IL-4, IL-10, IFN- ⁇ , TNF- ⁇ , and GM-CSF)
  • T cell proliferation by carboxyfluorescein succinimidyl ester (CFSE) labeling
  • CFSE carboxyfluorescein succinimidyl ester
  • T cell survival by Annexin V staining
  • the influence of CD80 and/or 4-1BBL on T cell survival, proliferation, and efficacy can be evaluated.
  • T cells can be exposed to repeated stimulation by cancer antigen positive target cells, and it can be determined whether T cell proliferation and cytokine response remain similar or diminished with repeated stimulation.
  • the cancer antigen CAR constructs can be compared side by side under equivalent assay conditions. Cytotoxicity assays with multiple E: T ratios can be conducted using chromium-release assays.
  • Immune effector cells provided herein can be obtained from a subject.
  • Sources for the immune effector cells provided herein include, but are not limited to, peripheral blood, umbilical cord blood, bone marrow, or other sources of hematopoietic cells.
  • Immune effector cells e.g., T cells
  • T cells can be obtained from a number of sources, including peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors.
  • cell lines available in the art can be used.
  • Immune effector cells provided herein can be isolated by methods well known in the art, including commercially available isolation methods (see, for example, Rowland-Jones et al., LYMPHOCYTES: A PRACTICAL APPROACH, Oxford University Press, New York (1999) ) .
  • isolation methods see, for example, Rowland-Jones et al., LYMPHOCYTES: A PRACTICAL APPROACH, Oxford University Press, New York (1999) ) .
  • Various methods for isolating immune effector cells have been described previously, and can be used, including but not limited to, using peripheral donor lymphocytes (Sadelain et al., Nat. Rev.
  • immune effector cells e.g., T cells
  • T cells can be obtained from a unit of blood collected from a subject using any techniques known to the skilled artisan, such as Ficoll TM separation.
  • cells from the circulating blood of an individual are obtained by apheresis.
  • the apheresis product typically contains lymphocytes, including T cells, monocytes, granulocytes, B cells, other nucleated white blood cells, red blood cells, and platelets.
  • the cells collected by apheresis can be washed to remove the plasma fraction and to place the cells in an appropriate buffer or media for subsequent processing steps.
  • the cells are washed with phosphate buffered saline (PBS) .
  • the wash solution lacks calcium and may lack magnesium or may lack many if not all divalent cations. Initial activation steps in the absence of calcium lead to magnified activation.
  • a washing step can be accomplished by methods known to those in the art, such as by using a semi-automated “flow-through” centrifuge (for example, the Cobe 2991 cell processor, the Baxter CytoMate, or the Haemonetics Cell Saver 5) according to the manufacturer's instructions.
  • the cells can be resuspended in a variety of biocompatible buffers, such as, for example, Ca 2+ -free, Mg 2+ -free PBS, PlasmaLyte A, or other saline solution with or without buffer.
  • buffers such as, for example, Ca 2+ -free, Mg 2+ -free PBS, PlasmaLyte A, or other saline solution with or without buffer.
  • the undesirable components of the apheresis sample can be removed, and the cells directly resuspended in culture media.
  • T cells are isolated from peripheral blood lymphocytes by lysing the red blood cells and depleting the monocytes, for example, by centrifugation through a PERCOLL TM gradient or by counterflow centrifugal elutriation.
  • a specific subpopulation of T cells such as CD3 + , CD28 + , CD4 + , CD8 + , CD45RA + , and CD45RO + T cells, can be further isolated by positive or negative selection techniques.
  • T cells are isolated by incubation with anti-CD3/anti-CD28 (i.e., 3 ⁇ 28) -conjugated beads, such as M-450 CD3/CD28 T, for a time period sufficient for positive selection of the desired T cells.
  • the time period is about 30 minutes. In a further embodiment, the time period ranges from 30 minutes to 36 hours or longer and all integer values there between. In a further embodiment, the time period is at least 1, 2, 3, 4, 5, or 6 hours. In yet another preferred embodiment, the time period is 10 to 24 hours. In one preferred embodiment, the incubation time period is 24 hours. For isolation of T cells from patients with leukemia, use of longer incubation times, such as 24 hours, can increase cell yield. Longer incubation times may be used to isolate T cells in any situation where there are few T cells as compared to other cell types, such in isolating tumor infiltrating lymphocytes (TIL) from tumor tissue or from immune-compromised individuals.
  • TIL tumor infiltrating lymphocytes
  • T cells can be preferentially selected for or against at culture initiation or at other time points during the process.
  • subpopulations of T cells can be preferentially selected for or against at culture initiation or at other desired time points.
  • the skilled artisan would recognize that multiple rounds of selection can also be used in the context of this invention.
  • Various techniques can be employed to separate the cells to enrich for desired immune effector cells. For instance, negative selection methods can be used to remove cells that are not the desired immune effector cells. Additionally, positive selection methods can be used to isolate or enrich for desired immune effector cells or precursor cells thereof, or a combination of positive and negative selection methods can be employed. Monoclonal antibodies (MAbs) are particularly useful for identifying markers associated with particular cell lineages and/or stages of differentiation for both positive and negative selections.
  • a particular type of cell is to be isolated, for example, a particular type of T cell
  • various cell surface markers or combinations of markers including but not limited to, CD3, CD4, CD8, CD34 (for hematopoietic stem and progenitor cells) and the like, can be used to separate the cells, as is well known in the art (see Kearse, T CELL PROTOCOLS: DEVELOPMENT AND ACTIVATION, Humana Press, Totowa NJ (2000) ; De Libero, T CELL PROTOCOLS, Vol. 514 of Methods in Molecular Biology, Humana Press, Totowa NJ (2009) ) .
  • enrichment of a T cell population by negative selection can be accomplished with a combination of antibodies directed to surface markers unique to the negatively selected cells.
  • One method is cell sorting and/or selection via negative magnetic immunoadherence or flow cytometry that uses a cocktail of monoclonal antibodies directed to cell surface markers present on the cells negatively selected.
  • a monoclonal antibody cocktail typically includes antibodies to CD14, CD20, CD11b, CD16, HLA-DR, and CD8.
  • it may be desirable to enrich for or positively select for regulatory T cells which typically express CD4 + , CD25 + , CD62L hi , GITR + , and FoxP3 + .
  • T regulatory cells are depleted by anti-C25 conjugated beads or other similar method of selection.
  • Procedures for separation of immune effector cells include, but are not limited to, density gradient centrifugation, coupling to particles that modify cell density, magnetic separation with antibody-coated magnetic beads, affinity chromatography; cytotoxic agents joined to or used in conjunction with a monoclonal antibody (mAb) , including, but not limited to, complement and cytotoxins, and panning with an antibody attached to a solid matrix, for example, a plate or chip, elutriation, flow cytometry, or any other convenient technique (see, for example, Recktenwald et al., CELL SEPARATION METHODS AND APPLICATIONS, Marcel Dekker, Inc., New York (1998) ) .
  • mAb monoclonal antibody
  • the immune effector cells used in methods provided herein can be substantially pure cells or can be a polyclonal population.
  • a polyclonal population can be enriched for a desired immune effector cell. Such an enrichment can take place prior to or after genetically engineering the cells to express a BCMA CAR or TCR provided herein, as desired.
  • the immune effector cells can be autologous or non-autologous to the subject to which they are administered in the methods of treatment disclosed herein.
  • Autologous cells are isolated from the subject to which the engineered cells are to be administered.
  • the cells can be obtained by leukapheresis, where leukocytes are selectively removed from withdrawn blood, made recombinant, and then retransfused into the donor.
  • allogeneic cells from a non-autologous donor that is not the subject can be used.
  • the cells are typed and matched for human leukocyte antigen (HLA) to determine an appropriate level of compatibility, as is well known in the art.
  • HLA human leukocyte antigen
  • the cells can optionally be cryopreserved after isolation and/or genetic engineering, and/or expansion of genetically engineered cells (see Kaiser et al., supra, 2015) ) .
  • Methods for cyropreserving cells are well known in the art (see, for example, Freshney, CULTURE OF ANIMAL CELLS: A MANUAL OF BASIC TECHNIQUES, 4th ed., Wiley-Liss, New York (2000) ; Harrison and Rae, GENERAL TECHNIQUES OF CELL CULTURE, Cambridge University Press (1997) ) .
  • isolated immune effector cells are genetically engineered ex vivo for recombinant expression of a polypeptide (e.g., CAR or TCR) .
  • isolated immune effector cells are genetically engineered ex vivo for recombinant expression of a BCMA CAR or TCR.
  • immune effector cells provided herein are obtained by in vitro sensitization, wherein the sensitization can occur before or after the immune effector cells are genetically engineered to recombinantly express a polypeptide disclosed herein.
  • the sensitized immune effector cells such T cells, are isolated from in vivo sources, it will be self-evident that genetic engineering occurs of the already-sensitized immune effector cells.
  • a blood sample or an apheresis product is taken from a generally healthy subject.
  • a blood sample or an apheresis is taken from a generally healthy subject who is at risk of developing a disease, but who has not yet developed a disease, and the cells of interest are isolated and frozen for later use.
  • the T cells can be expanded, frozen, and used at a later time.
  • samples are collected from a patient shortly after diagnosis of a particular disease as described herein but prior to any treatments.
  • the cells are isolated from a blood sample or an apheresis from a subject prior to any number of relevant treatment modalities, including but not limited to treatment with agents such as natalizumab, efalizumab, antiviral agents, chemotherapy, radiation, immunosuppressive agents, such as cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3 antibodies, cytoxan, fludarabine, cyclosporin, FK506, rapamycin, mycophenolic acid, steroids, FR901228, and irradiation.
  • agents such as natalizumab, efalizumab, antiviral agents, chemotherapy, radiation, immunosuppressive agents, such as cyclosporin, azathioprine, methotrexate, mycophenolate, and FK506, antibodies, or other immunoablative agents such as CAMPATH, anti-CD3
  • the cells are isolated for a patient and frozen for later use in conjunction with (e.g., before, simultaneously or following) bone marrow or stem cell transplantation, T cell ablative therapy using either chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT) , cyclophosphamide, or antibodies such as OKT3 or CAMPATH.
  • chemotherapy agents such as, fludarabine, external-beam radiation therapy (XRT) , cyclophosphamide, or antibodies such as OKT3 or CAMPATH.
  • XRT external-beam radiation therapy
  • cyclophosphamide cyclophosphamide
  • antibodies such as OKT3 or CAMPATH.
  • the cells are isolated prior to and can be frozen for later use for treatment following B-cell ablative therapy such as agents that react with CD20, e.g., Rituxan.
  • T cells are obtained from a patient directly following treatment.
  • the quality of T cells obtained can be optimal or improved for their ability to expand ex vivo.
  • these cells may be in a preferred state for enhanced engraftment and in vivo expansion.
  • blood cells including T cells, NK cells, or other immune effector cells of the hematopoietic lineage, during this recovery phase.
  • mobilization for example, mobilization with GM-CSF
  • conditioning regimens can be used to create a condition in a subject wherein repopulation, recirculation, regeneration, and/or expansion of particular cell types is favored, especially during a defined window of time following therapy.
  • Illustrative cell types include T cells, B cells, dendritic cells, and other cells of the immune system.
  • the immune effector cells disclosed herein can be subjected to conditions that favor maintenance or expansion of cells as well known in the art.
  • the immune effector cells disclosed herein can optionally be expanded prior to or after ex vivo genetic engineering. Expansion of the cells is particularly useful to increase the number of cells for administration to a subject. Such methods for expansion of cells are well known in the art (see e.g., Kaiser et al., Cancer Gene Therapy 22: 72-78 (2015) ; Wolfl et al., Nat. Protocols 9: 950-966 (2014) ) .
  • the cells can optionally be cryopreserved after isolation and/or genetic engineering, and/or expansion of genetically engineered cells (see Kaiser et al., supra, 2015) ) .
  • Methods for cyropreserving cells are well known in the art (see, for example, Freshney, Culture of Animal Cells: A Manual of Basic Techniques, 4th ed., Wiley-Liss, New York (2000) ; Harrison and Rae, General Techniques of Cell Culture, Cambridge University Press (1997) ) .
  • the T cells provided herein can be expanded by contact with a surface having attached thereto an agent that stimulates a CD3/TCR complex associated signal and a ligand that stimulates a co-stimulatory receptor on the surface of the T cells.
  • T cell populations can be stimulated as described herein, such as by contact with an anti-CD3 antibody, or antigen-binding fragment thereof, or an anti-CD2 antibody immobilized on a surface, or by contact with a protein kinase C activator (e.g., bryostatin) in conjunction with a calcium ionophore.
  • a ligand that binds the accessory molecule is used for co-stimulation of an accessory molecule on the surface of the T cells.
  • a population of T cells can be contacted with an anti-CD3 antibody and an anti-CD28 antibody, under conditions appropriate for stimulating proliferation of the T cells.
  • an anti-CD3 antibody and an anti-CD28 antibody can be used as can other methods commonly known in the art (Berg et al., Transplant Proc. 30 (8) : 3975- 3977, 1998; Haanen et al., J. Exp. Med. 190 (9) : 13191328, 1999; Garland et al., J. Immunol Meth. 227 (1-2) : 53-63, 1999) .
  • the invention is generally disclosed herein using affirmative language to describe the numerous embodiments.
  • the invention also specifically includes embodiments in which particular subject matter is excluded, in full or in part, such as substances or materials, method steps and conditions, protocols, procedures, assays or analysis.
  • the invention is generally not expressed herein in terms of what the invention does not include, aspects that are not expressly included in the invention are nevertheless disclosed herein.
  • Primary human lymphocytes Primary human lymphocytes .
  • Primary human CD4+ T cells and CD8+ T cells were isolated from healthy volunteer donors. T cells were stimulated with anti-CD3/CD28 Dynabeads (Life Technologies, Grand Island, NY) and cultured in the R10 medium (RPMI-1640 medium supplemented with 10%fetal bovine serum, 1%HEPES, 1%GutaMAX, 1%penicillin and streptomycin, 1%MEM NEAA, and 1%sodium pyruvate) supplemented with 100 IU/mL IL-2.
  • R10 medium RPMI-1640 medium supplemented with 10%fetal bovine serum, 1%HEPES, 1%GutaMAX, 1%penicillin and streptomycin, 1%MEM NEAA, and 1%sodium pyruvate
  • Cell lines The following cell lines were cultured in R10 medium and used in related experiments: Nalm6 (human leukemia cells) , Jeko1 (human lymphoma cells) , RPMI-8226 (human myeloma cells) , Raji (human lymphoma cells) , THP1 (human leukemia cells) , HCC70 (human breast cancer cells) , 786-O (human renal cell carcinoma cells) , SH-SY5Y (human neuroblastoma cells) , A549ESO (human lung cancer cells) , SKOV3 (human ovarian cancer cells) , PC3 (human prostate cancer cells) , H226 (human lung carcinoma cells) , ASPC1 (human pancreatic tumor cells) , Caski (human cervical cancer cells) , and K562 (human leukemia cells) .
  • Nalm6 human leukemia cells
  • Jeko1 human lymphoma cells
  • RPMI-8226 human myeloma cells
  • Raji
  • Lentivirus production and transduction Lentiviral vectors were produced from HEK293T cells transfected with transfer plasmids and packaging plasmids pRSV. REV, pMD2. G and pMDLg. pRRE. Lentiviral vectors were harvested after 24 and 48 hours and concentrated by ultracentrifugation.
  • Electroporation of BCMA31 BBz and LACO mRNA .
  • mRNA was added to 0.1 ml T cells (1 ⁇ 108 cells/ml) that were washed twice and resuspended with OPTI-MEM. Electroporation was performed in a 0.2 cm cuvette with a BTX830 (Harvard Apparatus BTX) at 500 V and 0.7 ms.
  • Tumor killing assay using IncuCyte real-time cell analyzer Tumor cells and T cells were washed with R10 medium twice, and then were resuspended in R10 medium. Both tumor cells and CAR+ T cells were seeded at 10,000 cells/well in a 96 well flat-bottom plate. Total integrated intensity was recorded every 4 hours.
  • ELISA 0.1 million of CAR-T cells and 0.1 million of tumor cells were co-cultured at 37 °C for 24 h, then the supernatant was collected and the ELISA assay was performed to measure IL-2 and IFN ⁇ secretion levels following the instruction manual of ELISA kits (R&D Systems) .
  • CD107a assay CAR-T cells and tumor cells were mixed at a ratio of 1: 2. CD107 antibody was added to the medium. One hour after coculture, GolgiStop solution was added. After 3 more hours, the cells were stained by CD3-BV421 and CD8-APC antibodies and were analyzed by flow cytometry.
  • Anti-BCMA antibodies were prepared using fully human antibody phage display library following the steps below:
  • mpELISA screening after three round selection, 480 phage-infected bacterial colonies were selected for monoclonal phage ELISA (mpELISA) screening. Phage supernatant was generated from individual bacterial clones and tested for the binding to BCMA-Fc protein. The supernatant was incubated with pre-blocked Maxisorp plate coated with 2 ⁇ g/ml BCMA-6His protein. After three washes, 100 ⁇ l/well of HRP-conjugated anti-M13 antibody diluted 1: 5000 in blocking buffer (5% milk+1%BSA in 1 ⁇ PBS) was added and incubate for 60 min at RT.
  • anti-BCMA scFv (s) were constructed into a bicistronic lentiviral CAR expression vector, which contained an IRES-truncated EGFR (tEGFR) expressing cassette.
  • Lentivirus was generated by transient transfection in 293T cells, then purified and concentrated by ultra-centrifuge. T cells were transduced with CAR lentivirus to generate CAR-T cells, and cultured for another 10 days.
  • CAR-T cells were collected and stained with 5 ⁇ g/ml CD19-Fc protein (Ctrl Fc protein) or BCMA-Fc recombinant protein at 4 °C for 30 min. After washing, the CAR-T cells were stained with anti-human IgG Fc and anti-EGFR mAb. Sample was analyzed by flow cytometry. As shown, T cells expressing CARs comprising the following anti-BCMA scFv (s) showed binding to BCMA-Fc (FIG. 1B) and were selected for further studies: BCMA21, BCMA22, BCMA23, BCMA24, BCMA27, BCMA28, BCMA30, BCMA31, BCMA32, BCMA33, BCMA34, and BCMA35.
  • FIGs. 2A and 2B show the frequencies of CAR+ T cells and their expression levels (Mean Fluorescence Intensity; “MFI” ) , respectively.
  • MFI Green Fluorescence Intensity
  • BCMA31 #10; SEQ ID NO: 138
  • BCMA33 #12; SEQ ID NO: 140
  • FIG. 3 shows comparable frequencies of CAR+ CD8 cells among tested CARTs.
  • FIG. 4 shows the phenotypes of CART cells. The frequencies of T cell population (CD45RO-; CCR7+) in BCMA27 (#7) , BCMA31 (#10) and BCMA33 (#12) T cells were higher than those in other samples, indicating these T cells were less differentiated.
  • FIGs. 5A and 5B different tumor cell lines were examined for the expression of BCMA by FACS staining (FIG. 5A) and RT-PCR (FIG. 5B) .
  • BCMA expression was detected in Jeko-1 (low level) , Raji (intermediate level) and RPMI-8226 cells (high level) by FACS staining.
  • RT-PCR analysis showed it was expressed, albeit at a very low level.
  • the CART cells were cocultured with Jeko-1 cells and RPMI-8226 tumor cells.
  • the production of INF- ⁇ and IL-2 were examined.
  • FIGs. 6A (INF- ⁇ ) and 6B (IL-2) of the 12 CARTs that we generated, BCMA23 (#5; SEQ ID NO: 133) , BCMA24 (#6; SEQ ID NO: 134) , BCMA27 (#7; SEQ ID NO: 135) , BCMA31 (#10; SEQ ID NO: 138) , and BCMA33 (#12; SEQ ID NO: 140) produced more cytokines than the others, including NBC10 and B38M CAR T cells.
  • BCMA23 (#5) , BCMA24 (#6) , BCMA31 (#10) , and BCMA33 (#12) CART cells showed different levels of cytotoxicity against Jeko-1 cells, with BCMA31 (#10) being the highest, which efficiently eliminated Jeko-1.
  • BCMA21 (#3 SEQ ID NO: 131) , BCMA22 (#4; SEQ ID NO: 132) , BCMA23 (#5; SEQ ID NO: 133) , BCMA24 (#6; SEQ ID NO: 134) , BCMA27 (#7; SEQ ID NO: 135) , BCMA31 (#10; SEQ ID NO: 138) , BCMA33 (#12; SEQ ID NO: 140) , BCMA4 (#13; SEQ ID NO: 141) , and BCMA35 (#14; SEQ ID NO: 142) showed different levels of cytotoxicity against RPMI-8226 cells, of which BCMA21 (#3) , BCMA23 (#5) , BCMA24 (#6) , BCMA27 (#7) , BCMA31 (#10) , and BCMA33 (#12) efficiently eliminated RPMI-8226 cells.

Abstract

La présente divulgation concerne des anticorps anti-BCMA et des fragments de liaison à l'antigène, des récepteurs antigéniques chimériques (" CAR ") comprenant ces anticorps anti-BCMA et des fragments de liaison à l'antigène (" CAR BCMA ") et des cellules effectrices immunitaires génétiquement modifiées comprenant de telles CAR BCMA. La divulgation concerne également des polynucléotides codant pour les anticorps anti-BCMA et des fragments de liaison à l'antigène et des CAR BCMA. La divulgation concerne en outre des compositions comprenant des anticorps anti-BCMA et des fragments de liaison à l'antigène et des CAR BCMA. La présente divulgation concerne par ailleurs l'utilisation des anticorps anti-BCMA et des fragments de liaison à l'antigène et des cellules effectrices immunitaires génétiquement modifiées comprenant de tels CAR BCMA dans le traitement du cancer.
PCT/CN2021/112798 2021-08-16 2021-08-16 Anticorps ciblant bcma, récepteurs antigéniques chimériques et leurs utilisations WO2023019398A1 (fr)

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