B cell maturation antigen (BCMA) chimeric antigen receptor invariant natural killer T cells and their uses

Abstract

The present disclosure is based at least in part on the discovery of novel BCMA antibodies or antigen-binding fragments thereof, and generally, genetically modified cells (e.g., iNKT cells, CAR T cells, etc.) expressing chimeric antigen receptors comprising anti-BCMA antibodies or antigen-binding fragments thereof exhibit improved properties, including increased binding to BCMA, killing of BCMA-expressing cancer cells in vitro and in vivo, and enhanced persistence in treated subjects.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 63 / 422,916, filed November 4, 2022, the entire contents of which are incorporated herein by reference.

[0002] Electronic Sequence Listing Reference The contents of the electronic sequence listing (A132770003WO00-SEQ-LJG.xml, size: 202,613 bytes, created on November 3, 2023) are incorporated herein by reference in their entirety. [Background technology]

[0003] B-cell maturation antigen (BCMA) is a tumor necrosis factor receptor (TNFR) member expressed on the surface of B-cell lineage cells. BCMA expression is associated with several types of cancer, autoimmune diseases, and infectious diseases. Cancers with increased BCMA expression include hematological cancers such as multiple myeloma (MM), Hodgkin's lymphoma and non-Hodgkin's lymphoma, various leukemias, and glioblastoma. Chimeric antigen receptor (CAR) proteins and CAR cells (e.g., CAR T cells or CAR iNKT cells) that target BCMA have previously been reported. Summary of the Invention

[0004] The present disclosure is based on novel BCMA antibodies or antigen-binding fragments thereof, and genetically engineered cells (e.g., iNKT cells, CAR T cells, etc.) expressing chimeric antigen receptors comprising anti-BCMA antibodies or antigen-binding fragments thereof. In some embodiments, the compositions described herein exhibit improved properties, including increased binding to BCMA, killing of BCMA-expressing cancer cells in vitro and in vivo, and enhanced persistence in subjects receiving the compositions to the previously described anti-BCMA binding molecules. Aspects of the present disclosure relate to methods for treating certain cancers (e.g., BCMA-expressing cancers) by administering the compositions described herein to a subject in need thereof.

[0005] In some aspects, the present disclosure provides invariant natural killer T (iNKT) cells engineered to express a chimeric antigen receptor comprising a B-cell maturation antigen (BCMA) binding site and IL-15.

[0006] In some embodiments, the IL-15 is soluble IL-15. In some embodiments, the IL-15 is human IL-15.

[0007] In some embodiments, the iNKT cells kill BCMA-expressing cells. In some embodiments, the iNKT cells directly kill BCMA-expressing cells. In some embodiments, the iNKT cells indirectly kill BCMA-expressing cells.

[0008] In some embodiments, the iNKT cells retain their response to CD1d and / or NK receptor ligands.

[0009] In some embodiments, the iNKT cells comprise a CAR having any one of the anti-BCMA antibodies shown in Table 3. In some embodiments, the iNKT cells comprise a CAR having any one of the CARs shown in Table 4.

[0010] In some aspects, the disclosure provides a method for killing a cell, the method comprising contacting the cell with an iNKT cell engineered to express a chimeric antigen receptor comprising a B-cell maturation antigen (BCMA) binding site and IL-15.

[0011] In some aspects, the disclosure provides a method for treating a tumor in a subject, the method comprising administering to a subject having or suspected of having cancer said iNKT cells engineered to express a chimeric antigen receptor comprising a B-cell maturation antigen (BCMA) binding site and IL-15.

[0012] In some aspects, the disclosure provides a method for reducing tumor growth, the method comprising contacting said cancer in a subject with said iNKT cells engineered to express a chimeric antigen receptor comprising a B-cell maturation antigen (BCMA) binding site and IL-15.

[0013] In some embodiments, the tumor cells express BCMA. In some embodiments, the administration of the iNKT cells results in a reduction of tumor burden relative to the tumor burden in the subject prior to the administration. In some embodiments, the administration of the iNKT cells results in resistance to T cell depletion, enhanced tissue homing of anti-BCMA iNKT cells, selective cytotoxicity against M2 macrophages, and / or stimulation of dendritic cell maturation.

[0014] In some embodiments, the subject does not undergo lymphodepletion prior to administration of the iNKT cells engineered to express a chimeric antigen receptor comprising a B-cell maturation antigen (BCMA) binding site and IL-15.

[0015] In some aspects, the present disclosure provides antibodies or antigen-binding fragments that specifically bind to an amino acid sequence having at least 85% identity to SEQ ID NOs: 38-48.

[0016] In some embodiments, the antibody specifically binds to the amino acid sequences set forth in SEQ ID NOs: 38-48.

[0017] In some aspects, the disclosure provides an antibody or antigen-binding fragment comprising a heavy chain variable region having the sequence set forth in any one of SEQ ID NOs: 7, 12, 19, or 21.

[0018] In some embodiments, the antibody comprises a heavy chain variable region having the sequence set forth in SEQ ID NO: 7, 12, 19, or 21, and a light chain variable region having the sequence set forth in SEQ ID NO: 8, 10, 13, 15, or 22.

[0019] In some embodiments, the antibody comprises (i) a heavy chain variable region having the sequence set forth in SEQ ID NO: 7 and a light chain variable region having the sequence set forth in SEQ ID NO: 8, (ii) a heavy chain variable region having the sequence set forth in SEQ ID NO: 7 and a light chain variable region having the sequence set forth in SEQ ID NO: 10, (iii) a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and a light chain variable region having the sequence set forth in SEQ ID NO: 13, (iv) a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and a light chain variable region having the sequence set forth in SEQ ID NO: 15, (v) a heavy chain variable region having the sequence set forth in SEQ ID NO: 7 and a light chain variable region having the sequence set forth in SEQ ID NO: 13, (vi) a heavy chain variable region having the sequence set forth in SEQ ID NO: 7 and a light chain variable region having the sequence set forth in SEQ ID NO: 15, (vii) a heavy chain variable region having the sequence set forth in SEQ ID NO: 19 and a light chain variable region having the sequence set forth in SEQ ID NO: 10, or (viii) a heavy chain variable region having the sequence set forth in SEQ ID NO: 21 and a light chain variable region having the sequence set forth in SEQ ID NO: 22.

[0020] In some aspects, the disclosure provides an antibody or antigen-binding fragment comprising a variable heavy chain region comprising a complementarity determining region 3 (CDRH3) having the sequence set forth in SEQ ID NO: 3 or 33.

[0021] In some embodiments, the antibody or antigen-binding fragment further comprises a variable light chain region having a complementarity-determining region 3 (CDRL3) having the sequence set forth in any one of SEQ ID NOs: 6, 29, 30, or 36.

[0022] In some aspects, the disclosure provides an antibody or antigen-binding fragment comprising six complementarity determining regions (CDRs), which are CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, wherein (i) CDRH1 comprises the sequence set forth in SEQ ID NO: 1, CDRH2 comprises the sequence set forth in SEQ ID NO: 2, CDRH3 comprises the sequence set forth in SEQ ID NO: 3, CDRL1 comprises the sequence set forth in SEQ ID NO: 4, CDRL2 comprises the sequence set forth in SEQ ID NO: 5, and CDRL3 comprises the sequence set forth in SEQ ID NO: 6; and (ii) CDRH1 comprises the sequence set forth in SEQ ID NO: 1, and the CDRs H2 comprises the sequence set forth in SEQ ID NO:2, CDRH3 comprises the sequence set forth in SEQ ID NO:3, CDRL1 comprises the sequence set forth in SEQ ID NO:4, CDRL2 comprises the sequence set forth in SEQ ID NO:5, and CDRL3 comprises the sequence set forth in SEQ ID NO:6, (iii) CDRH1 comprises the sequence set forth in SEQ ID NO:25, CDRH2 comprises the sequence set forth in SEQ ID NO:27, CDRH3 comprises the sequence set forth in SEQ ID NO:3, CDRL1 comprises the sequence set forth in SEQ ID NO:4, CDRL2 comprises the sequence set forth in SEQ ID NO:24, and CDRL3 comprises the sequence set forth in SEQ ID NO:30, and (iv) CDRH1 comprises the sequence set forth in SEQ ID NO: (v) CDRH1 comprises the sequence set forth in SEQ ID NO: 1, CDRH2 comprises the sequence set forth in SEQ ID NO: 2, CDRH3 comprises the sequence set forth in SEQ ID NO: 3, CDRL1 comprises the sequence set forth in SEQ ID NO: 4, CDRL2 comprises the sequence set forth in SEQ ID NO: 24, and CDRL3 comprises the sequence set forth in SEQ ID NO: 29; (v) CDRH1 comprises the sequence set forth in SEQ ID NO: 1, CDRH2 comprises the sequence set forth in SEQ ID NO: 2, CDRH3 comprises the sequence set forth in SEQ ID NO: 3, CDRL1 comprises the sequence set forth in SEQ ID NO: 4, CDRL2 comprises the sequence set forth in SEQ ID NO: 24, and CDRL3 comprises the sequence set forth in SEQ ID NO: 30 (vi) CDRH1 comprises the sequence set forth in SEQ ID NO: 1, CDRH2 comprises the sequence set forth in SEQ ID NO: 2, CDRH3 comprises the sequence set forth in SEQ ID NO: 3, CDRL1 comprises the sequence set forth in SEQ ID NO: 4, CDRL2 comprises the sequence set forth in SEQ ID NO: 24, and CDRL3 comprises the sequence set forth in SEQ ID NO: 29, (vii) CDRH1 comprises the sequence set forth in SEQ ID NO: 26, CDRH2 comprises the sequence set forth in SEQ ID NO: 28, CDRH3 comprises the sequence set forth in SEQ ID NO: 3, CDRL1 comprises the sequence set forth in SEQ ID NO: 4, and CDRL2 comprises the sequence set forth in SEQ ID NO: 24,CDRL3 comprises the sequence set forth in SEQ ID NO:6, or (viii) CDRH1 comprises the sequence set forth in SEQ ID NO:31, CDRH2 comprises the sequence set forth in SEQ ID NO:32, CDRH3 comprises the sequence set forth in SEQ ID NO:33, CDRL1 comprises the sequence set forth in SEQ ID NO:34, CDRL2 comprises the sequence set forth in SEQ ID NO:35, and CDRL3 comprises the sequence set forth in SEQ ID NO:36.

[0023] In some embodiments, the antibody or antigen-binding fragment is chimeric.

[0024] In some embodiments, the antibody or antigen-binding fragment is humanized.

[0025] In some embodiments, the antibody or antigen-binding fragment is a single-chain variable fragment (scFv). In some embodiments, the scFv comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9, 11, 14, 16, 17, 18, 20, or 23.

[0026] In some aspects, the present disclosure provides isolated nucleic acids encoding the antibodies or antigen-binding fragments described herein.

[0027] In some embodiments, the isolated nucleic acid comprises a sequence set forth in any one of SEQ ID NOs: 49-64. In some embodiments, the isolated nucleic acid comprises a sequence set forth in any one of SEQ ID NOs: 65-72.

[0028] In some aspects, the present disclosure provides a vector comprising an isolated nucleic acid described herein. In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is a lentiviral vector. In some embodiments, the lentiviral vector comprises a sequence set forth in any one of SEQ ID NOs: 73-80.

[0029] In some aspects, the present disclosure provides a host cell comprising an antibody or antigen-binding fragment, isolated nucleic acid, or vector described herein. In some embodiments, the cell is a mammalian cell, a bacterial cell, a yeast cell, or an insect cell. In some embodiments, the cell is a hybridoma cell.

[0030] In some aspects, the present disclosure provides a chimeric antigen receptor (CAR) comprising an anti-BCMA antigen-binding fragment (e.g., an anti-BCMA scFv) described herein.

[0031] In some embodiments, the CAR further comprises a hinge region, hi some embodiments, the hinge region comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:82.

[0032] In some embodiments, the CAR further comprises a transmembrane domain, hi some embodiments, the transmembrane domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:83.

[0033] In some embodiments, the CAR further comprises a cytoplasmic domain, hi some embodiments, the cytoplasmic domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:84.

[0034] In some embodiments, the CAR comprises a costimulatory domain, hi some embodiments, the costimulatory domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:85.

[0035] In some embodiments, the CAR comprises the amino acid sequence of any one of SEQ ID NOs: 86-93.

[0036] In some aspects, the present disclosure provides an immune cell comprising an anti-BCMA CAR described herein. In some embodiments, the immune cell is a natural killer (NK) cell or a T cell. In some embodiments, the immune cell is an invariant natural killer T cell (iNKT cell).

[0037] In some embodiments, the immune cells are engineered to express one or more immunomodulatory gene products, hi some embodiments, the one or more immunomodulatory gene products include IL-15, IL-12, CD40L, or 4-1BB.

[0038] In some aspects, the present disclosure provides a pharmaceutical composition comprising an anti-BCMA antibody or antigen-binding fragment, or immune cell described herein, and a pharmaceutically acceptable excipient.

[0039] In some aspects, the disclosure provides methods for killing a cell, the methods comprising contacting the cell with an anti-BCMA antibody or antigen-binding fragment, immune cell, or pharmaceutical composition described herein.

[0040] In some aspects, the disclosure provides methods of treating cancer in a subject, the methods comprising administering to a subject having or suspected of having cancer an immune cell or pharmaceutical composition described herein.

[0041] In some aspects, the disclosure provides methods for reducing tumor growth, the methods comprising contacting said tumor in a subject with an anti-BCMA antibody or antigen-binding fragment, immune cell, or pharmaceutical composition described herein.

[0042] In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer is a blood cancer. In some embodiments, the blood cancer is leukemia or lymphoma. In some embodiments, the cancer is multiple myeloma.

[0043] In some embodiments, the administration is via injection.

[0044] In some embodiments, the subject does not undergo lymphodepletion prior to administration of the iNKT cells.

[0045] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate certain embodiments and, together with the specification, serve to provide non-limiting examples of certain aspects of the compositions and methods disclosed herein. [Brief explanation of the drawings]

[0046] [Figure 1] FIG. 1 is a schematic diagram showing how iNKT cells target tumor cells via direct and indirect mechanisms. [Figure 2] 1 shows a schematic diagram of exemplary anti-BCMA-CAR-iNKT cells. The anti-BCMA-CAR iNKT cells shown are also engineered to secrete IL-15. [Figure 3] A schematic overview of the screening process for anti-BCMA CAR iNKT cells is shown. [Figure 4] FIG. 1 shows a schematic diagram of a conventional phage campaign to select BCMA binders. [Figure 5] 1 shows an outline of a mammalian screening strategy to identify highly functional BCMA CARs. [Figure 6] Representative data for the binding affinity of exemplary anti-BCMA scFvs F6 and F1 are shown. [Figure 7A] Representative data from epitope mapping of BCMA CAR candidates is shown. [Figure 7B] Representative data from epitope mapping of BCMA CAR candidates are shown. Figure 7A shows loss of binding to BCMA mutants (accessible amino acids are mutated to alanine to map the epitope of anti-BCMA CAR candidates) compared to wild-type BCMA by Biacore. Figure 7B shows a 3D structure showing the binding site of F6G-Var2 to BCMA based on Figure 7A (Asp15, Leu17, Leu18 at the top, Arg27, Thr32, and Leu35 at the bottom). [Figure 8A] Representative data from an anti-BCMA-CAR iNKT cell-mediated cytotoxicity assay are shown. [Figure 8B] Representative data from an anti-BCMA-CAR iNKT cell-mediated cytotoxicity assay are shown. [Figure 8C] Representative data from an anti-BCMA-CAR iNKT cell-mediated cytotoxicity assay are shown. [Figure 8D] Representative data from an anti-BCMA-CAR iNKT cell-mediated cytotoxicity assay are shown. [Figure 8E] Representative data from an anti-BCMA-CAR iNKT cell-mediated cytotoxicity assay are shown. [Figure 8F] Representative data from an anti-BCMA-CAR iNKT cell-mediated cytotoxicity assay are shown. [Figure 8G] Representative data from an anti-BCMA-CAR iNKT cell-mediated cytotoxicity assay are shown. [Figure 8H] Representative data from an anti-BCMA-CAR iNKT cell-mediated cytotoxicity assay are shown. [Figure 8I]Representative data from anti-BCMA-CAR iNKT cell-mediated cytotoxicity assays are shown. Figure 8A shows a schematic of the cytotoxicity assay with iNKT cells transiently transfected with BCMA-CAR. Figures 8B-8H show target cell killing by iNKT cells expressing various BCMA-CAR candidates or the clinical benchmark bb2121. The legend for Figure 8B applies to Figures 8B-8H. Figure 8I shows the level of endogenous BCMA expression in each tumor line as assessed by flow cytometry (bottom right). K562 cells stably transfected with wild-type or BCMA were also included in the assay. [Figure 9A] An example of an accelerated drug discovery (ADD) approach to affinity matured F6G is shown. [Figure 9B] An example of an accelerated drug discovery (ADD) approach to affinity matured F6G is shown. [Figure 9C] An example of an accelerated drug discovery (ADD) approach to affinity-matured F6G is shown. Figure 9A shows a schematic of the CDR positions that underwent mutagenesis. Figure 9B shows the affinity KD(M) values ​​of the mutant scFvs that bind to the BCMA antigen. The sequences shown are GYYMH (SEQ ID NO: 1), NPNSGN (SEQ ID NO: 105), QWEPL (SEQ ID NO: 106), DALPKKYTY (SEQ ID NO: 107), EDTKRPS (SEQ ID NO: 5), and LSTDPTGQ (SEQ ID NO: 108). Figure 9C shows individual Biacore sensorgrams of the E to Y substitution at position 49 of CDRL2. [Figure 10A] Representative data of affinity maturation of F6G with a phage library are shown. [Figure 10B] Representative data of affinity maturation of F6G with a phage library are shown. [Figure 10C] Representative data of affinity maturation of F6G with a phage library are shown. [Figure 10D]Representative data are shown for affinity maturation of F6G using a phage library. Figure 10A shows a schematic of the phage display affinity maturation library strategy. CDR amino acids marked with "x" were mutated to any other amino acid to generate the library. Figure 10B shows the library was used for phage panning and subsequent mammalian display. Figure 10C shows representative data for target cell killing by iNKT cells expressing various BCMA-CAR candidates or the clinical benchmark (bb2121). Figure 10D shows representative data showing that cytotoxicity against BCMA-negative K562 cells was negligible and similar to bb2121, and activation was negligible and similar to bb2121 for most of the candidates tested. [Figure 11] Representative data of the binding kinetics of F6 variants are shown: affinity-matured clones showed a 10-fold improvement in affinity compared to the original F6 clone and an almost 50-fold improvement in affinity compared to germline F6G. [Figure 12] Representative data of the kinetics of other known anti-BCMA CARs compared to F6G-Var2 are shown. [Figure 13A] Representative data of anti-BCMA-CAR iNKT cell-mediated tumor cell killing is shown. [Figure 13B] Representative data of anti-BCMA-CAR iNKT cell-mediated tumor cell killing is shown. [Figure 13C] Representative data of anti-BCMA-CAR iNKT cell-mediated tumor cell killing is shown. [Figure 13D] Representative data of anti-BCMA-CAR iNKT cell-mediated tumor cell killing is shown. [Figure 13E] Representative data of anti-BCMA-CAR iNKT cell-mediated tumor cell killing is shown. [Figure 13F] Representative data of anti-BCMA-CAR iNKT cell-mediated tumor cell killing is shown. [Figure 13G]Representative data are shown for anti-BCMA-CAR iNKT cell-mediated tumor cell killing. Figures 13A-13C show flow cytometry analysis of RFP expression, indicating CAR expression and antigen binding to BCMA-APCs, in BCMA-CAR iNKTs from two iNKT donors. Figure 13D shows the BCMA expression level on each tumor cell line assessed by flow cytometry. The left peak indicates isotype staining, and the right peak indicates BCMA expression. Figure 13E shows the percentage of dead target cells after 24 hours of coculture of the iNKT cells in Figure 13A with tumor cell lines endogenously expressing BCMA or K562 at three different effector-to-target ratios. Figure 13F shows the percentage of CD69 / CD25-coexpressing iNKT cells after coculture with BCMA-expressing target cells or K562 cells. Figure 13G shows the percentage of 4-1BB-expressing iNKT cells after coculture with BCMA-expressing target cells or K562 cells. [Figure 14]

[0039] Figure 1 shows a sequence alignment of the heavy and light chain variable regions of F6G variants. The heavy chain sequences shown are consensus (SEQ ID NO: 7), F6G-Var5 (SEQ ID NO: 7), F6G-Var3 (SEQ ID NO: 12), F6G-Var2 (SEQ ID NO: 12), F6G-Var6 (SEQ ID NO: 19), F6G-Var4 (SEQ ID NO: 7), and F6G-Var1 (SEQ ID NO: 7). The light chain sequences shown are consensus (SEQ ID NO: 109), F6G-Var6 (SEQ ID NO: 109), F6G-Var1 (SEQ ID NO: 109), F6G-Var5 (SEQ ID NO: 110), F6G-Var3 (SEQ ID NO: 110), F6G-Var2 (SEQ ID NO: 111), and F6G-Var4 (SEQ ID NO: 111). [Figure 15] Representative data of predicted immunogenicity of F6G variants are shown. [Figure 16] An overview of the stable CAR-iNKT generation process (left) and flow cytometry assessment of the purity and quantity of BCMA CAR-iNKT cells (right) are shown. [Figure 17] 1 shows flow cytometry analysis of anti-BCMA CAR IL-15 iNKT cells generated by lentiviral transduction and antigen-mediated CAR enrichment. [Figure 18A]Representative data are shown from an in vitro cytotoxicity assay of BCMA-CAR iNKT cells with or without IL-15 armoring, challenged with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as non-transduced iNKT cells, were used as controls. [Figure 18B] Representative data are shown from an in vitro cytotoxicity assay of BCMA-CAR iNKT cells with or without IL-15 armoring, challenged with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as non-transduced iNKT cells, were used as controls. [Figure 18C] Representative data are shown from an in vitro cytotoxicity assay of BCMA-CAR iNKT cells with or without IL-15 armoring, challenged with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as non-transduced iNKT cells, were used as controls. [Figure 18D] Representative data are shown from an in vitro cytotoxicity assay of BCMA-CAR iNKT cells with or without IL-15 armoring, challenged with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as non-transduced iNKT cells, were used as controls. [Figure 18E] Representative data are shown from an in vitro cytotoxicity assay of BCMA-CAR iNKT cells with or without IL-15 armoring, challenged with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as non-transduced iNKT cells, were used as controls. [Figure 18F]Representative data are shown from an in vitro cytotoxicity assay of BCMA-CAR iNKT cells with or without IL-15 armoring, challenged with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as non-transduced iNKT cells, were used as controls. [Figure 18G] Representative data are shown from an in vitro cytotoxicity assay of BCMA-CAR iNKT cells with or without IL-15 armoring, challenged with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as non-transduced iNKT cells, were used as controls. [Figure 18H] Representative data are shown from an in vitro cytotoxicity assay of BCMA-CAR iNKT cells with or without IL-15 armoring, challenged with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as non-transduced iNKT cells, were used as controls. [Figure 18I] Representative data are shown from an in vitro cytotoxicity assay of BCMA-CAR iNKT cells with or without IL-15 armoring, challenged with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as non-transduced iNKT cells, were used as controls. [Figure 18J] Representative data are shown from an in vitro cytotoxicity assay of BCMA-CAR iNKT cells with or without IL-15 armoring, challenged with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as non-transduced iNKT cells, were used as controls. [Figure 18K]Representative data are shown from an in vitro cytotoxicity assay of BCMA-CAR iNKT cells with or without IL-15 armoring, challenged with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as non-transduced iNKT cells, were used as controls. [Figure 18L] Representative data from in vitro cytotoxicity assays of BCMA-CAR iNKT cells, with or without IL-15 armoring, are shown, following challenge with a BCMA-expressing multiple myeloma tumor line. bb2121 IL-15 iNKT cells and anti-CD19 CAR IL-15 iNKT cells, as well as untransduced iNKT cells, were used as controls. Figures 18A-18F show the results of the cytotoxicity assay of iNKT cells from donor 1. Figures 18G-18L show representative cytotoxicity assay data for iNKT cells from donor 2. Sample legends are shown between Figures 18A and 18B. [Figure 19A] Representative data for antigen-specific activation of BCMA-CAR-IL-15 iNKT cells are shown. [Figure 19B] Representative data for antigen-specific activation of BCMA-CAR-IL-15 iNKT cells are shown. [Figure 19C] Representative data for antigen-specific activation of BCMA-CAR-IL-15 iNKT cells are shown. [Figure 19D] Representative data are shown for antigen-specific activation of BCMA-CAR-IL-15 iNKT cells. Figures 19A-19B show antigen-specific activation of BCMA-CAR-IL-15 iNKT cells from donor 1. Figures 19C-19D show antigen-specific activation of BCMA-CAR-IL-15 iNKT cells from donor 2. [Figure 20A] Representative data are shown regarding increased IFN-γ production by BCMA-CAR-IL-15 iNKT cells upon challenge with BCMA-expressing tumor lines. [Figure 20B]Representative data are shown regarding increased IFN-γ production by BCMA-CAR-IL-15 iNKT cells upon challenge with a BCMA-expressing tumor line. Figure 20A shows increased IFN-γ production by BCMA-CAR-IL-15 iNKT cells from donor 1 upon challenge with a BCMA-expressing tumor line. Figure 20B shows IFN-γ production by BCMA-CAR-IL-15 iNKT cells from donor 1 upon challenge with a BCMA-expressing tumor line. [Figure 21A] Representative data are shown demonstrating that IL-15 production increases the in vivo persistence of anti-BCMA CAR iNKT cells in the blood. [Figure 21B] Representative data are shown demonstrating that IL-15 production increases the in vivo persistence of anti-BCMA CAR iNKT cells in the bone marrow. [Figure 21C] Representative data are shown demonstrating that IL-15 production increases the in vivo persistence of anti-BCMA CAR iNKT cells in the liver. [Figure 21D] Representative data are shown demonstrating that IL-15 production increases the in vivo persistence of anti-BCMA CAR iNKT cells in the spleen. [Figure 21E] Representative data are shown demonstrating that IL-15 production increases the in vivo persistence of anti-BCMA CAR iNKT cells in the lung. [Figure 22A] Representative data are shown demonstrating that adoptive cell transfer of BCMA-CAR-IL-15 iNKT cells delays engraftment of multiple myeloma MM1.s tumors in xenografted mice. [Figure 22B] Representative data are shown demonstrating that adoptive cell transfer of BCMA-CAR-IL-15 iNKT cells delays engraftment of multiple myeloma MM1.s tumors in xenografted mice. [Figure 22C] Representative data are shown demonstrating that adoptive cell transfer of BCMA-CAR-IL-15 iNKT cells delays engraftment of multiple myeloma MM1.s tumors in xenografted mice. [Figure 22D]Representative data are shown demonstrating that adoptive cell transfer of BCMA-CAR-IL-15 iNKT cells delays engraftment of multiple myeloma MM1.s tumors in xenografted mice. [Figure 22E] Representative data are shown demonstrating that adoptive cell transfer of BCMA-CAR-IL-15 iNKT cells delays engraftment of multiple myeloma MM1.s tumors in xenografted mice. [Figure 22F] Representative data are shown demonstrating that adoptive cell transfer of BCMA-CAR-IL-15 iNKT cells delays engraftment of multiple myeloma MM1.s tumors in xenografted mice. [Figure 22G] Representative data are shown demonstrating that adoptive cell transfer of BCMA-CAR-IL-15 iNKT cells delays engraftment of multiple myeloma MM1.s tumors in xenografted mice. [Figure 22H]Representative data are shown demonstrating that adoptive cell transfer of BCMA-CAR-IL-15 iNKT cells delays the engraftment of multiple myeloma MM1.s tumors in xenografted mice. Figures 22A-22B show that BCMA-CAR-IL-15 iNKT cells delayed tumor engraftment 3 weeks after adoptive transfer. Figure 22C shows a Kaplan-Meier survival graph demonstrating significantly improved survival in mice treated with BCMA-CAR-IL-15 iNKT cells compared to CD19-IL-15 CAR iNKT cell and untreated mice. Figure 22D shows that mice treated with BCMA-CAR-IL-15 iNKT cells did not exhibit multiple myeloma- or IL-15-related (F6G-Var2 IL-15 iNKT cell vs. F6G-Var2 iNKT cell cohort) toxicity or weight loss. Figures 22E-22F show flow cytometry analysis and quantification of bone marrow tissue from all mice showing that samples at both harvested time points showed little / few GFP-positive MM1.s transfections, indicating significant tumor control. Figures 22G-22H show flow cytometry analysis of bone marrow demonstrating persistence of BCMA-CAR-IL-15 at both harvested time points. IL-15 expressed in F6G-Var2 IL-15 demonstrates the benefit of IL-15 expression in iNKT persistence at early time points compared to non-IL-15-expressing F6G-Var2. DETAILED DESCRIPTION OF THE INVENTION

[0047] The present disclosure is based, at least in part, on novel BCMA antibodies or antigen-binding fragments thereof. In some aspects, the present disclosure also relates to chimeric antigen receptors (CARs) comprising the anti-BCMA antibodies or antigen-binding fragments described herein, and immune cells (e.g., iNKT cells, T cells, NK cells, etc.) expressing such CARs. In some embodiments, the immune cells (e.g., iNKT cells, T cells, NK cells, etc.) are engineered to secrete IL-15, which has been observed to promote the persistence of the immune cells described herein in a subject. Also provided are uses of the anti-BCMA antibodies or antigen-binding fragments, and / or immune cells expressing the anti-BCMA antigen-binding fragments, for killing cancer cells (e.g., cancer cells expressing BCMA) and / or treating cancer (e.g., BCMA-positive cancer). As further described in the Examples, cells expressing anti-BCMA antibodies and / or CARs comprising the anti-BCMA antibodies described herein exhibit improved properties, including increased binding to BCMA, killing of BCMA-expressing cancer cells in vitro and in vivo, and increased persistence in subjects to whom the composition is administered (e.g., compared to subjects receiving other CAR T cell therapies or anti-BCMA antibody therapies).

[0048] The foregoing and other aspects, implementations, operations, functions, features, and embodiments of the present teachings can be more fully understood from the following description taken in conjunction with the accompanying drawings.

[0049] I. Definition Section headings are provided for convenience and should not be construed as limiting the disclosure, for example, terms are defined throughout the specification as well as in the section entitled "Definitions."

[0050] Administration: As used herein, the terms "administering" or "administration" mean providing a therapeutic agent or composition thereof to a subject in a physiologically and / or pharmacologically useful manner (e.g., to treat a condition in the subject).

[0051] Affinity matured antibody: As used herein, "affinity matured antibody" refers to an antibody that has one or more modifications made to one or more CDRs that result in an improved affinity (i.e., KD, kd, or ka) of the antibody for a target antigen compared to a parent antibody lacking the modification(s). In some embodiments, the affinity matured antibody has nanomolar or even picomolar affinity for the target antigen. Various procedures for generating affinity matured antibodies, including screening combinatorial antibody libraries generated using biodisplay, are known in the art. For example, Marks et al., BioTechnology, 10:779-783 (1992) describes affinity maturation by shuffling VH and VL domains. Random mutagenesis of CDR and / or framework residues is described in Barbas et al., Proc. Nat. Acad. Sci. USA, 91:3809-3813 (1994), Schier et al., Gene, 169:147-155 (1995), Yelton et al., J. Immunol., 155:1994-2004 (1995), Jackson et al., J. Immunol., 154(7):3310-3319 (1995), and Hawkins et al., J. Mol. Biol., 226:889-896 (1992). Selective mutagenesis positions and selective mutations at contact positions with activity-enhancing amino acid residues or hypermutation positions are described in U.S. Patent No. 6,914,128 B1.

[0052] Antibody: As used herein, the term "antibody" or "antibodies" refers to a polypeptide that contains at least one immunoglobulin variable domain or at least one antigenic determinant, e.g., a paratope, that specifically binds to an antigen. Examples of antibodies include monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, heteroconjugate antibodies, antibody-drug conjugates, single domain antibodies, monovalent antibodies, single-chain antibodies or single-chain Fvs (scFvs), camelized antibodies, affibodies, Fab fragments, F(ab')2 fragments, disulfide-linked Fvs (sdFvs), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), and antigen-binding fragments of any of the above. In some embodiments, the antibody is a full-length antibody further comprising the constant regions of an immunoglobulin heavy chain and an immunoglobulin light chain. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. However, in some embodiments, the antibody is a Fab fragment, F(ab')2 fragment, Fv fragment, or scFv fragment. In some embodiments, the antibody is a nanobody derived from a camelid antibody or a nanobody derived from a shark antibody. In some embodiments, the antibody is a diabody. In some embodiments, the antibody comprises a framework having germline sequences from a species (e.g., human germline sequences). In some embodiments, the antibody comprises a heavy (H) chain variable region (abbreviated herein as VH) and / or a light (L) chain variable region (abbreviated herein as VL). In some embodiments, the VH comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any of the heavy chain variable domains described herein.In some embodiments, the VL comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 95%, 98%, or at least 99% identical to any of the light chain variable domains described herein. In some embodiments, the antibody comprises a constant domain, e.g., an Fc region. An immunoglobulin constant domain refers to a heavy chain constant domain or a light chain constant domain. The amino acid sequences of human IgG heavy and light chain constant domains and their functional mutations are known. In another embodiment, the antibody comprises a heavy chain constant domain selected from the group consisting of IgG, IgG1, IgG2, IgG2A, IgG2B, IgG2C, IgG3, IgG4, IgA1, IgA2, IgD, IgM, and IgE constant domains. With respect to the heavy chain, in some embodiments, the heavy chain of the antibodies described herein can be an alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In some embodiments, the heavy chain of an antibody described herein can comprise an alpha (α), delta (Δ), epsilon (ε), gamma (γ), or mu (μ) heavy chain. In certain embodiments, an antibody described herein comprises the CH1, CH2, and / or CH3 domain of human gamma 1. In some embodiments, the amino acid sequence of the VH domain comprises the amino acid sequence of a human gamma (γ) heavy chain constant region, such as any amino acid sequence known in the art. Non-limiting examples of human constant region sequences are described in the art, see, for example, U.S. Pat. No. 5,693,780 and Kabat EA et al., (1991). In some embodiments, the antibody is modified, for example, by glycosylation, phosphorylation, sumoylation, and / or methylation. In some embodiments, the antibody is a glycosylated antibody, to which one or more sugar or carbohydrate molecules are attached. In some embodiments, one or more sugar or carbohydrate molecules are attached to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypionation (GPI anchor attachment), and / or phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans.In some embodiments, the one or more sugar or carbohydrate molecules comprise a mannose unit, a glucose unit, an N-acetylglucosamine unit, or a phospholipid unit.

[0053] Approximately: As used herein, the term "approximately" or "about," when applied to one or more values ​​of interest, refers to a value similar to a stated reference value. In certain embodiments, the term "approximately" or "about," unless otherwise stated or otherwise clear from the context, refers to a range of values ​​that fall within 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less in either direction (greater or less) of the stated reference value (except where such number exceeds 100% of possible values).

[0054] B-cell maturation antigen (BCMA): Human BCMA is a 184-amino acid protein encoded by the TNFRSF17 gene, a member of the TNF receptor superfamily. BCMA is expressed in mature B lymphocytes and may be important in B-cell development and autoimmune responses. This receptor has been shown to specifically bind to tumor necrosis factor (ligand) superfamily member 13b (TNFSF13B / TALL-1 / BAFF), leading to activation of NF-kappa B and MAPK8 / JNK. This receptor also binds to various TRAF family members and may therefore transduce signals for cell survival and proliferation.

[0055] Binding affinity: As used herein, "binding affinity" generally refers to the strength of the sum of non-covalent interactions between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an epitope). Unless otherwise indicated, as used herein, "binding affinity" refers to the intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair. The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K D Affinity can be expressed by, but not limited to, the equilibrium dissociation constant (K D), and the equilibrium association constant (K A ) can be measured and / or expressed in several ways known in the art. D is k オフ / k オン It is calculated from the quotient of K A is k オン / k オフ It is calculated from the quotient of k オン k refers to the binding rate constant of an antibody to an epitope, for example. オフ refers, for example, to the dissociation rate constant of an antibody to an epitope.

[0056] Binding affinity (or binding specificity) can be determined by a variety of methods, including equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance (SPR), fluorescence-activated cell sorting (FACS), or spectroscopy (e.g., using a fluorescence assay). Exemplary conditions for assessing binding affinity are in HBS-P buffer (10 mM HEPES pH 7.4, 150 mM NaCl, 0.005% (v / v) surfactant P20) and PBS buffer (10 mM PO4-3, 137 mM NaCl, and 2.7 mM KCl). Using these techniques, the concentration of bound protein can be measured as a function of target protein concentration. The concentration of bound protein ([bound]) is generally related to the concentration of free target protein ([free]) by the following equation: [Bound]=[Free] / (Kd+[Free])

[0057] Not necessarily K A It is not necessary to make an exact determination of K, but it is sufficient to obtain a quantitative measure of affinity, as determined using methods such as, for example, ELISA or FACS analysis, and the K A and therefore can be used in comparisons to obtain a qualitative measure of affinity, such as determining whether a higher affinity is, for example, 2-fold higher, or to obtain an inference of affinity, for example, by activity in a functional assay (e.g., an in vitro or in vivo assay).

[0058] CDR: As used herein, the term "CDR" refers to a complementarity-determining region within an antibody variable sequence. A typical antibody molecule contains a heavy chain variable region (VH) and a light chain variable region (VL), which are usually involved in antigen binding. The VH and VL regions can be further subdivided into regions of hypervariability known as "complementarity-determining regions" ("CDRs"), interspersed with more conserved regions known as "framework regions" ("FRs"). Each VH and VL is typically composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of the framework regions and CDRs can be precisely identified using methodologies known in the art, for example, by the Kabat definition, the IMGT definition, the Chothia definition, the AbM definition, and / or the contact definition, all of which are well known in the art.For example, Kabat, EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242, IMGT®, the international ImMunoGeneTics information system (registered trademark) http: / / www.imgt.org, Lefranc, M.-P. et al., Nucleic Acids. Res.,27:209-212(1999), Ruiz,M.et al.,Nucleic Acids Res.,28:219-221(2000),Lefranc,M.-P.,Nucleic Acids Res.,29:207-209(2001),Lefranc,M.-P.,Nucleic Acids Res.,31:307-310(2003), Lefranc, M.-P. et al.,In Silico Biol.,5,0006(2004)[Epub],5:45-60(2005),Lefranc,M.-P.et al.,Nucleic Acids Res.,33:D593-597(2005),Lefranc,M.-P.et al.,Nucleic Acids Res.,37:D1006-1012(2009), Lefranc,M.-P.et al.,Nucleic Acids Res.,43:D413-422(2015),Chothia et al.,(1989)Nature 342:877,Chothia,C.et al. (1987) J. Mol. Biol. 196:901-917, Al-lazikani et al. al (1997) J. Molec. Biol. 273:927-948, and Almagro, J. Mol. Recognit. 17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. As used herein, CDRs may refer to CDRs defined by any method known in the art.Two antibodies having the same CDRs means that the two antibodies have the same amino acid sequence of their CDRs as determined by the same method, for example, the Kabat definition.

[0059] Typically, there are three CDRs in each heavy and light chain variable region, designated CDR1, CDR2, and CDR3 for each variable region. As used herein, the term "CDR set" refers to a group of three CDRs occurring in a single variable region capable of binding to an antigen. The exact boundaries of these CDRs are defined differently in different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Subportions of the CDRs may be designated L1, L2, and L3, or H1, H2, and H3, with "L" and "H" indicating the light chain and heavy chain regions, respectively. These regions may also be referred to as Chothia CDRs, whose boundaries overlap with the Kabat CDRs. Other boundaries defining CDRs that overlap with the Kabat CDRs are described by (FASEB J. 9:133-139 (1995)) and MacCallum (J Mol Biol 262(5):732-45 (1996)). Still other CDR boundary definitions may not strictly adhere to any of the above systems, but overlap with the Kabat CDRs, provided they are shortened or extended in light of predictions or experimental results that indicate that particular residues, groups of residues, or entire CDRs do not significantly affect antigen binding. The methods for use herein may utilize CDRs defined according to any of these systems.

[0060] The CDRs of an antibody may have different amino acid sequences if different definition systems are used (e.g., the IMGT definition, the Kabat definition, or the Chothia definition). In these definition systems, each amino acid in a given antibody sequence (e.g., the VH or VL sequence of an anti-BCMA antibody listed in Table 3) is assigned a number, and the number or numbers corresponding to the heavy chain and light chain CDRs are shown in Table 1. The CDRs of the anti-BCMA antibodies provided herein (e.g., the CDRs of any of the anti-BCMA antibodies listed in Table 3) are defined according to the Kabat definition. One of skill in the art would be able to derive the CDR sequences using the different numbering systems of the anti-BCMA antibodies shown in Table 3. [Table 1] 1 IMGT (registered trademark), the international ImMunoGeneTics information system (registered trademark), imgt.org, Lefranc, M.-P. et al., Nucleic Acids Res., 27:209-212 (1999) 2 Kabat et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242 3 Chothia et al., J. Mol. Biol. 196:901-917 (1987))

[0061] Chimeric Antigen Receptor: As used herein, "chimeric antigen receptor" or "CAR" refers to an engineered receptor that specifically binds an antigen (e.g., BCMA) or other ligand or molecule on an immune effector cell (e.g., T cell, NK cell, NKT cell, iNKT cell). A chimeric antigen receptor typically comprises at least an extracellular ligand-binding domain or portion capable of specifically binding to an antigen, and an intracellular domain comprising one or more signaling and / or costimulatory domains.

[0062] In some embodiments, the extracellular ligand-binding domain of the CAR is in the form of a binding protein, a small molecule, a peptide, a targeting agent, an agonist, or an antagonist. In some embodiments, the binding protein is an antibody, an antigen-binding fragment of an antibody (e.g., an scFv), a ligand, a cytokine, or a receptor. In some embodiments, the antigen-binding fragment is an scFv (e.g., an scFv that targets BCMA).

[0063] In some embodiments, the extracellular ligand-binding domain is in the form of a single-chain variable fragment (scFv) derived from an antibody (e.g., a monoclonal antibody) and confers specificity for a particular epitope or antigen (e.g., an epitope or antigen that is preferentially present on the surface of cells such as cancer cells or other disease-causing cells or particles).

[0064] In some embodiments, the CAR comprises an intracellular signaling domain. The intracellular signaling domain is a cytoplasmic domain that transmits an activation signal to the cell after binding of the extracellular domain. The intracellular signaling domain can be any intracellular signaling domain of interest known in the art. Such cytoplasmic signaling domains include, but are not limited to, CD3ζ. In some embodiments, the intracellular domain also comprises one or more intracellular costimulatory domains, such as those described herein, that transmit a costimulatory signal that promotes cell proliferation, cell survival, and / or cytokine secretion after binding of the extracellular domain. Such intracellular costimulatory domains include, but are not limited to, any costimulatory domain disclosed herein or known in the art, such as CD27, CD28, CD8, 4-1BB (CD137), OX40, CD30, CD40, CD127, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand that specifically binds with CD83, N1, N6, or any combination thereof. Additional suitable costimulatory domains are described in PCT International Application No. PCT / US2017 / 055133, which is incorporated herein by reference in its entirety. In some embodiments, the costimulatory domain is 4-1BB (CD137). In some embodiments, the chimeric antigen receptor further comprises additional structural elements, including a transmembrane domain connected to the extracellular ligand-binding domain via a hinge or linking sequence. The transmembrane domain can be derived from any membrane-associated or transmembrane protein. For example, the transmembrane polypeptide can be a CD protein, such as a subunit of the T cell receptor (i.e., the α, β, γ, or ζ polypeptide that constitutes the CD3 complex), the IL2 receptor p55 (α chain), p75 (β chain), or γ chain, a subunit chain of an Fc receptor (e.g., Fcγ receptor III), or the CD8 α chain. Alternatively, the transmembrane domain can be synthetic and comprise primarily hydrophobic residues, such as leucine and valine. In some embodiments, the CAR comprises a CD8 transmembrane domain.Hinge region refers to any oligo- or polypeptide that functions to link the transmembrane domain to the extracellular ligand-binding domain. For example, the hinge region can contain up to 300 amino acids, 10-100 amino acids, and 25-50 amino acids. The hinge region can be derived from all or a portion of a natural molecule, such as all or a portion of the extracellular region of CD8, CD4, or CD28, or all or a portion of an antibody constant region. Alternatively, the hinge region can be a synthetic sequence corresponding to a natural hinge sequence, or a completely synthetic hinge sequence. In some embodiments, the hinge domain can comprise a portion of the human CD8 α chain, FcγRIIIa receptor, or IgG1. In some embodiments, the CAR comprises a CD8 hinge region.

[0065] CDR-grafted antibody: The term "CDR-grafted antibody" refers to an antibody that comprises heavy and light chain variable region sequences from one species, but in which the sequences of one or more of the VH and / or VL CDR regions have been replaced with CDR sequences from another species, e.g., an antibody having murine heavy and light chain variable regions in which the murine CDR (e.g., CDR3) has been replaced with a human CDR sequence.

[0066] Chimeric antibody: The term "chimeric antibody" refers to an antibody that contains heavy and light chain variable region sequences from one species and constant region sequences from another species, e.g., an antibody in which murine heavy and light chain variable regions are linked to human constant regions.

[0067] Complementary: As used herein, the term "complementary" refers to the ability to precisely pair two nucleotides or two sets of nucleotides. In particular, complementary is a term that characterizes the degree of hydrogen bond pairing that binds two nucleotides or two sets of nucleotides. For example, if a base at one position of an oligonucleotide can hydrogen bond with a base at the corresponding position of a target nucleic acid (such as mRNA), the bases are considered to be complementary to each other at that position. Base pairing can include both standard Watson-Crick base pairing and non-Watson-Crick base pairing (e.g., wobble base pairing and Hoogsteen base pairing). For example, in some embodiments, for complementary base pairing, adenosine-type bases (A) are complementary to thymidine-type bases (T) or uracil-type bases (U), cytosine-type bases (C) are complementary to guanosine-type bases (G), and universal bases such as 3-nitropyrrole or 5-nitroindole can hybridize to and are considered complementary to any A, C, U, or T. Inosine (I) is also considered in the art to be a universal base and is considered complementary to any A, C, U, or T.

[0068] Conservative amino acid substitution: As used herein, "conservative amino acid substitution" refers to an amino acid substitution that does not alter the relative charge or size characteristics of the protein in which the amino acid substitution is made. Variants can be prepared according to methods for modifying polypeptide sequences known to those skilled in the art. For example, such methods can be found in references that summarize such methods, such as Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Fourth Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2012, or Current Protocols in Molecular Biology, F.M.A.usubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative amino acid substitutions include substitutions between amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.

[0069] Costimulatory domain: As used herein, "costimulatory domain" refers to a polypeptide domain that, upon activation, transmits an intracellular growth and / or cell survival signal. Activation of a costimulatory domain may occur following homodimerization of two costimulatory domain polypeptides. Activation may also occur, for example, following activation of a construct (e.g., a chimeric antigen receptor or an inducible regulatory construct) that includes the costimulatory domain. Generally, costimulatory domains can be derived from transmembrane costimulatory receptors, particularly the intracellular portion of a costimulatory receptor. Non-limiting examples of costimulatory polypeptides include, but are not limited to, 4-1BB, CD28, ICOS, OX-40, and CD27, as well as other costimulatory domains further described herein. In some embodiments, the CAR described herein comprises a 4-1BB costimulatory domain.

[0070] Costimulatory signal: As used herein, a "costimulatory signal" refers to an intracellular signal induced by a costimulatory domain that promotes cell proliferation, expansion of a cell population in vitro and / or in vivo, promotes cell survival, regulates cytokine secretion (e.g., upregulation or downregulation), and / or regulates the production and / or secretion of other immunomodulatory molecules. In some embodiments, a costimulatory signal is induced following homodimerization of two costimulatory domain polypeptides. In some embodiments, a costimulatory signal is induced following activation of a construct (e.g., a chimeric antigen receptor or an inducible regulatory construct) comprising a costimulatory domain.

[0071] Cross-reactivity: As used herein and in the context of targeting agents (e.g., antibodies), the term "cross-reactivity" refers to a property of a targeting agent that can specifically bind to two or more antigens of a similar type or class (e.g., multiple homologous, paralogous, or orthologous antigens) with similar affinity or avidity. For example, in some embodiments, an antibody that is cross-reactive to a similar type or class of human antigen and a non-human primate antigen (e.g., human BCMA and non-human primate BCMA) can bind to the human antigen and the non-human primate antigen with similar affinity or avidity. In some embodiments, the antibody is cross-reactive to a similar type or class of human antigen and a rodent antigen. In some embodiments, the antibody is cross-reactive to a similar type or class of rodent antigen and a non-human primate antigen. In some embodiments, the antibody is cross-reactive to a human antigen, a non-human primate antigen, and a similar type or class of rodent antigen.

[0072] Effective amount: As used herein, "effective amount" refers to the amount of each active agent (e.g., an anti-BCMA antibody), alone or in combination with one or more other active agents, required to confer a therapeutic effect on a subject. In some embodiments, the therapeutic effect includes, but is not limited to, a reduction in tumor size, eradication of a tumor, or alleviation of symptoms associated with a tumor.

[0073] Epitope: As used herein, "epitope" is a term used in the art and refers to a localized region of an antigen (e.g., a peptide or peptide-MHC complex) to which an antibody or chimeric antigen receptor can bind. In certain embodiments, the epitope to which an antibody or chimeric antigen receptor binds can be determined by, for example, NMR spectroscopy, X-ray diffraction crystallography, ELISA assays, hydrogen / deuterium exchange coupled with mass spectrometry (e.g., liquid chromatography electrospray mass spectrometry), flow cytometry analysis, mutagenesis mapping (e.g., site-directed mutagenesis mapping), and / or structural modeling. In the case of X-ray crystallography, crystallization may be achieved using any of the methods known in the art (e.g., Giege R et al., (1994) Acta Crystallogr D Biol Crystallogr 50(Pt 4):339-350; McPherson A (1990) Eur J Biochem 189:1-23; Chayen NE (1997) Structure 5:1269-1274; McPherson A (1976) J Biol Chem 251:6300-6303, which are incorporated herein in their entireties).Antibody:antigen crystals may be studied using well-known X-ray diffraction techniques and refined using computer software such as X-PLOR (Yale University, 1992, distributed by Molecular Simulations, Inc.; see, e.g., Meth Enzymol (1985) volumes 114 & 115, eds. Wyckoff HW et al., US2004 / 0014194) and BUSTER (Bricogne G (1993) Acta Crystallogr D Biol Crystallogr 49(Pt 1):37-60; Bricogne G (1997) Meth Enzymol 276A:361-423, ed. Carter CW, Roversi P et al., (2000) Acta Crystallogr D Biol Crystallogr 56(Pt 10):1316-1323), the entire contents of which are incorporated herein by reference. Mutagenesis mapping studies can be accomplished using any method known to those of skill in the art. See, for example, Champe M et al., (1995) J Biol Chem 270:1388-1394 and Cunningham BC & Wells JA (1989) Science 244:1081-1085, which are incorporated herein by reference in their entireties for a description of mutagenesis techniques, including alanine scanning mutagenesis techniques. In a specific embodiment, the epitope of the antigen is determined using alanine scanning mutagenesis studies. In a specific embodiment, the epitope of the antigen is determined using hydrogen / deuterium exchange coupled with mass spectrometry.

[0074] Framework: As used herein, the term "framework" or "framework sequence" refers to the remaining sequence of a variable region excluding the CDRs. Because the exact definition of a CDR sequence can be determined by different systems, the meaning of a framework sequence can be interpreted accordingly. The six CDRs (CDR-L1, CDR-L2, and CDR-L3 of the light chain and CDR-H1, CDR-H2, and CDR-H3 of the heavy chain) also divide the framework regions on the light and heavy chains into four subregions (FR1, FR2, FR3, and FR4) on each chain, with CDR1 located between FR1 and FR2, CDR2 located between FR2 and FR3, and CDR3 located between FR3 and FR4. Without specifying a particular subregion as FR1, FR2, FR3, or FR4, framework regions referred to by others represent the combined FRs within the variable region of a single native immunoglobulin chain. As used herein, FR refers to one of the four subregions, and FR refers to two or more of the four subregions that make up a framework region. Human heavy and light chain acceptor sequences are known in the art. In one embodiment, acceptor sequences known in the art may be used in the antibodies disclosed herein.

[0075] Human antibody: As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may include, for example, amino acid residues in the CDRs, particularly CDR3, that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). The term "human antibody," as used herein, is also not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.

[0076] Humanized antibody: The term "humanized antibody" refers to an antibody that contains heavy and light chain variable region sequences from a non-human species (e.g., mouse), but does not contain V H and / or V LThis refers to an antibody in which at least a portion of its sequence has been altered to be more "human-like," i.e., to resemble human germline variable sequences more closely. One type of humanized antibody is a CDR-grafted antibody, in which human CDR sequences are introduced into non-human VH and VL sequences to replace the corresponding non-human CDR sequences. In one embodiment, humanized anti-BCMA antibodies and antigen-binding fragments thereof are provided. Such antibodies may be produced by obtaining a murine anti-BCMA monoclonal antibody using conventional hybridoma technology, such as that disclosed in PCT Publication No. WO 2005 / 123126 A2 to Kasaian et al., followed by humanization using in vitro genetic engineering. In some embodiments, a humanized antibody comprises a human immunoglobulin (recipient antibody) in which residues from the recipient's complementarity-determining regions (CDRs) are replaced by residues from the CDRs of a non-human species (donor antibody), such as mouse, rat, or rabbit, having the desired specificity, affinity, and capacity. In some embodiments, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues found neither in the recipient antibody nor in the imported CDR or framework sequences, but are included to further refine and optimize antibody performance. Generally, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, with all or substantially all of the CDRs corresponding to those of a non-human antibody and all or substantially all of the framework regions corresponding to those of the relevant human consensus sequence. A humanized antibody will also optimally comprise at least a portion of an immunoglobulin constant region or domain (Fc), typically that of a human immunoglobulin. The antibody may have an altered Fc region, as described in WO 99 / 58572. Other forms of humanized antibodies have one or more (1, 2, 3, 4, 5, 6) CDRs that are altered relative to the original antibody, also referred to as one or more CDRs "derived from" one or more CDRs from the original antibody. Humanized antibodies may also be affinity matured.

[0077] Invariant Natural Killer Cells (iNKT): As used herein, the terms "invariant natural killer T cells," or "invariant NKT cells," "iNKT cells," or "type I NKT cells" refer to a population of T lymphocytes expressing a conserved, semi-invariant TCR specific for lipid antigens (Ags) restricted to the monomorphic MHC class I-associated molecule CD1d. Natural killer T cells (NKT cells) were originally characterized in mice as T cells expressing both a TCR and the C-type lectin NK receptor, NK1.1 (NKR-P1a-c or CD161). Invariant NKT (iNKT) cells express a semi-invariant αβ TCR (e.g., formed by the invariant TRAV11-TRAJ18 rearrangement in mice (4) or the homologous invariant TRAV10-TRAJ18 chains in humans) and pair with a limited set of diverse Vβ chains, primarily TRBV1, TRBV29, or TRBV13 in mice (6) and TRBV25 in humans (see, e.g., Dellabona et al., An invariant V alpha 24-J alpha Q / V beta 11 T cell receptor is expressed in all individuals by clonally expanded CD4-8- T cells. J Exp Med. (1994) 180:1171-1084). In some embodiments, the semi-invariant TCR recognizes exogenous and endogenous lipid antigen Ags presented by the monomorphic MHC class I-associated molecule CD1d (see, e.g., Brennan et al., Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol. (2013) 13:101-17.10.1038).In some embodiments, exogenous lipid antigens include the prototypical α-galactosylceramide (α-GalCer) (Kawano et al., CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science. (1997) 278:1626-9.10.1126), and multiple bacterial-derived antigens can activate iNKT cells.

[0078] iNKT cells undergo a distinct developmental pathway compared to T cells to acquire innate effector functions already present in the thymus. Thymic iNKT cells express markers typically upregulated by peripheral effector / memory T cells, such as CD44 and CD69, along with distinctive NK differentiation markers such as NK1.1 (in some mouse genetic backgrounds and CD161 in humans), CD122 (IL-2R / IL-15R β chain), CD94 / NKG2, and Ly49 (AJ), as well as a broad range of TH1 / 2 / 17 effector cytokines. In some embodiments, once they migrate to the periphery, iNKT cells form tissue-resident populations that monitor cellular integrity, rapidly respond to local injury and inflammation, and initiate cellular responses of the innate and adaptive immune responses. In some embodiments, the anti-BCMA CAR iNKT cells are Th1 iNKT cells, Th2 iNKT cells, Th17 iNKT cells, or a combination thereof.

[0079] In some embodiments, iNKT cells have been shown to play a role in various diseases by establishing Th1- or Th2-based immune responses due to their ability to rapidly produce IFNγ, IL-4, or both. In bacterial and viral infections, iNKT cells typically aid in early pathogen control by establishing productive Th1 responses. Both mouse and human studies have demonstrated the role of iNKT cells in diseases associated with excessive Th1 responses, such as type 1 diabetes and chronic obstructive pulmonary disease. Furthermore, iNKT cells have also been shown to suppress Th1 responses and promote tolerance-inducing responses to grafts. For example, after hematopoietic stem cell transplantation, the presence of iNKT cells is a predictor of survival due to reduced graft-versus-host disease (GvHD) in patients and preclinical models.

[0080] In some aspects, iNKT cells infiltrate tumors and play an important role in immune surveillance against tumors (e.g., solid tumors and / or hematopoietic malignancies) (see, e.g., Wolf et al., Novel Approaches to Exploiting Invariant NKT Cells in Cancer Immunotherapy, Front Immunol. 2018 Mar. 2;9:384). In some cases, iNKT cells may be an attractive platform for adoptive cellular immunotherapy of cancer compared to conventional T cells. In some embodiments, iNKT cells can directly kill cancer cells (e.g., CD1d-expressing cancer cells). In some embodiments, iNKT cells can restrict immunosuppressive myelomonocytic cell populations in the tumor microenvironment (TME) (e.g., via recognition of CD1d cognate) and promote anti-tumor responses (e.g., regardless of CD1d expression on cancer cells). In some embodiments, iNKT cells have the ability to suppress graft-versus-host disease (GvHD) without affecting anti-tumor responses. Because the CD1d molecule is identical in all individuals, they can be adoptively transferred across the MHC barrier without the risk of alloreactivity. In other embodiments, iNKT cells can acquire a second antigen specificity by expressing a recombinant TCR and / or chimeric antigen receptor (CAR) specific for a tumor-associated antigen, allowing them to directly target antigen-expressing cancer cells while maintaining their CD1d-dependent functions. In some embodiments, iNKT cells can be used for ready-to-use adoptive cell therapy without donor restrictions, enabling simultaneous targeting of cancer cells and the suppressive microenvironment. Compared to conventional αβ T cells, iNKT cell adoptive immunotherapy offers advantages, including, but not limited to, the following: (i) they can control the tumor microenvironment (TME); (ii) they can be directed against cancer cells by engineering tumor-specific CARs and / or TCRs while maintaining their restrictive control over the TME; and (iii) they are not alloreactive and are not limited to a monotypic CD1d molecule, allowing them to be used immediately without donor restrictions.

[0081] Isolated antibody: As used herein, an "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds to BCMA is substantially free of antibodies that specifically bind to antigens other than BCMA). Additionally, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0082] Percent identity: The determination of "percent identity" or "percent identity" between two sequences (e.g., amino acid sequences or nucleic acid sequences) can be achieved using a mathematical algorithm. A specific, non-limiting example of a mathematical algorithm utilized for comparing two sequences is the algorithm of Karlin S & Altschul SF (1990) PNAS 87:2264-2268, modified as in Karlin S & Altschul SF (1993) PNAS 90:5873-5877, each of which is incorporated herein by reference in its entirety. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Altschul SF et al., (1990) J Mol Biol 215:403, which are incorporated herein by reference in their entirety. BLAST nucleotide searches are performed with the NBLAST nucleotide program parameters set, for example, score=100, word length=12, to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed with the XBLAST program parameters set, e.g., score=50, word length=3, to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul SF et al., (1997) Nucleic Acids Res 25:3389-3402, incorporated herein by reference in its entirety. Alternatively, PSI BLAST can be used to perform an iterated search that detects distant relationships between molecules. When utilizing Id. BLAST, Gapped BLAST, and PSI Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used (see, e.g., the National Center for Biotechnology Information (NCBI) on the worldwide web at ncbi.nlm.nih.gov).Another specific, non-limiting example of a mathematical algorithm utilized for comparing sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17, incorporated herein by reference in its entirety. Such an algorithm is incorporated into the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When utilizing the ALIGN program for comparing amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used.

[0083] The percent identity between two sequences can be determined using techniques similar to those described above, with or without allowing gaps. In calculating percent identity, typically only exact matches are counted.

[0084] Recombinant antibody: As used herein, the term "recombinant human antibody" refers to any human antibody (as described in more detail herein) that is prepared, expressed, generated, or isolated by recombinant means, such as an antibody expressed using a recombinant expression vector transfected into a host cell; an antibody isolated from a recombinant combinatorial human antibody library (Hoogenboom HR, (1997) TIB Tech. 15:62-70; Azzazy H., and Highsmith WE, (2002) Clin. Biochem. 35:425-445; Gavilondo JV, and Larrick JW (2002) BioTechniques 29:128-145; Hoogenboom H., and Chames P. (2000) Immunology Today 21:371-378); an antibody isolated from an animal (e.g., a mouse) that is transgenic for human immunoglobulin genes (e.g., Taylor, LD, et al. (1992) Nucl. Acids Res. 20:6287-6295; Kellermann SA., and Green LL (2002) Current Opinion in Biotechnology 13:593-597; Little M. et al (2000) Immunology Today 21:364-370), or any other means including splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies are subjected to in vitro mutagenesis (or, when animals transgenic for human Ig sequences are used, in vivo somatic mutagenesis) to thereby modify the V and constant regions of the recombinant antibody. H Area and V L The amino acid sequence of the region is human germline V H Sequence and V LWhile derived from and related to the sequence, the sequence may not naturally occur in the human antibody germline repertoire in vivo. One embodiment of the present disclosure provides fully human antibodies capable of binding to human BCMA, which can be generated using techniques well known in the art, including, but not limited to, using human Ig phage libraries such as those disclosed in Jermutus et al., PCT Publication No. WO 2005 / 007699 A2.

[0085] Single-chain variable fragment (scFv): As used herein, the term "single-chain variable fragment (scFv)" refers to a fusion protein of the variable regions of the heavy (VH) and light (VL) chains of an immunoglobulin linked by a short linker peptide. The linker refers to a peptide or short oligopeptide sequence used to link the two subunits into a single polypeptide. The linker may have a sequence found in a naturally occurring protein or may be an artificial sequence not found in any naturally occurring protein. The linker may be flexible, lack secondary structure, and tend to form specific three-dimensional structures under physiological conditions. In some embodiments, the linker is a glycine-rich linker. In some embodiments, the linker is serine- or threonine-rich. In some embodiments, an scFv is a fusion protein in which the N-terminus of the VH is linked to the C-terminus of the VL. In some embodiments, an scFv is a fusion protein in which the N-terminus of the VL is linked to the C-terminus of the VH. An scFv retains the specificity of the original immunoglobulin despite the removal of the constant regions and the introduction of the linker. In some embodiments, scFvs can be generated to facilitate phage display. In some embodiments, scFvs can be generated directly from subcloned heavy and light chains from hybridomas. ScFvs have a variety of uses, including flow cytometry, immunohistochemistry, and as the antigen-binding domain of chimeric antigen receptors.

[0086] Specific Binds: As used herein, the terms "specifically binds" or "specific binding" refer to the ability of a molecule to bind to a binding partner with a degree of affinity or avidity that can be used to distinguish the binding partner from an appropriate control in a binding assay or other binding context. With respect to an antibody, the term "specifically binds" refers to the ability of the antibody to bind to a particular antigen, relative to an appropriate reference antigen or antigens, with an affinity or avidity that can be used to distinguish the particular antigen from other antigens, e.g., that allows preferential targeting to particular cells, e.g., cancer cells, via binding to the antigen, as described herein. In some embodiments, the K of an antibody that binds to a target D is at least about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10-10M, 10 -11 M, 10 -12 M, 10 -13 The antibody specifically binds to the target if M is less than or equal to M. In some embodiments, the antibody specifically binds to BCMA.

[0087] Subject: As used herein, "subject" refers to a mammal. In some embodiments, the subject is a non-human primate or rodent. In some embodiments, the subject is a human. In some embodiments, the subject is a patient, e.g., a human patient having or suspected of having a disease. In some embodiments, the subject is a human patient having or suspected of having cancer (e.g., a BCMA-expressing cancer) or other disease associated with aberrant BCMA expression or activity.

[0088] Treatment: As used herein, the terms "treat" or "treatment" refer to the application or administration of a composition comprising one or more active agents (e.g., anti-BCMA antibodies) to a subject with a target disease or disorder (e.g., cancer), a symptom of a disease / disorder (e.g., tumor growth, tumor metastasis, fatigue, weight change including unintentional weight loss or gain, pain, fever, non-healing wounds, persistent cough or hoarseness, abnormal bleeding, or anemia), or a predisposition to a disease / disorder (e.g., cancer), for the purpose of curing, healing, alleviating, mitigating, altering, treating, ameliorating, or affecting the disease (e.g., cancer), a symptom of the disease (e.g., tumor growth, tumor metastasis, fatigue, weight change including unintentional weight loss or gain, pain, fever, non-healing wounds, persistent cough or hoarseness, abnormal bleeding, or anemia), or a predisposition to the disease or disorder. Alleviating a target disease / disorder includes delaying or preventing the onset or progression of the disease, or reducing the severity of the disease.

[0089] II. Anti-BCMA Antibodies or Antigen-Binding Fragments Thereof In some aspects, the present disclosure provides antibodies or antigen-binding fragments specific for B-cell maturation antigen (BCMA). In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof provided herein are antibodies that bind to BCMA with high specificity and affinity. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof described herein specifically bind to an extracellular epitope of BCMA or an epitope exposed by the antibody. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof provided herein specifically bind to BCMA from humans, non-human primates, mice, rats, etc. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof provided herein bind to human BCMA. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof described herein specifically bind to an epitope on human BCMA (e.g., the human BCMA set forth in SEQ ID NO: 103 or 104). In some embodiments, the described anti-BCMA antibodies or antigen-binding fragments thereof bind to a fragment of human BCMA (e.g., the human BCMA set forth in SEQ ID NO: 103 or 104). In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof described herein bind to a fragment of BCMA (e.g., human BCMA set forth in SEQ ID NO: 103 or 104) that is about 5 to about 184 amino acids, about 10 to about 184 amino acids, about 20 to about 184 amino acids, about 30 to about 150 amino acids, about 30 to about 120 amino acids, about 30 to about 100 amino acids, about 30 to about 90 amino acids, about 30 to about 80 amino acids, about 30 to about 60 amino acids, about 30 to about 50 amino acids, about 40 to about 80 amino acids, or about 40 to about 60 amino acids in length. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof described herein bind to a fragment comprising a consecutive number of amino acids from a human BCMA protein (e.g., human BCMA set forth in SEQ ID NO: 103 or 104).In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof described herein bind to a fragment comprising at least 5, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 110, at least 120, at least 130, at least 140, at least 150, at least 160, at least 170, or at least 180 consecutive amino acids of a human BCMA protein (e.g., a human BCMA set forth in SEQ ID NO: 103 or 104). In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof described herein bind to a fragment having an amino acid sequence that has up to 5 amino acids, up to 4 amino acids, up to 3 amino acids, up to 2 amino acids, or up to 1 amino acid that differs from a fragment of a human BCMA protein (e.g., a human BCMA set forth in SEQ ID NO: 103 or 104). Exemplary human BCMA amino acid sequences are shown in NP_001183 (SEQ ID NO: 103) or BAB60895 (SEQ ID NO: 104).

[0090] An exemplary BCMA amino acid sequence is shown in SEQ ID NO: 103 (NP_001183): MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR

[0091] An exemplary BCMA amino acid sequence is shown in SEQ ID NO: 104 (BAB60895): MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKISSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR

[0092] Exemplary BCMA epitopes are shown in Table 2. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof described herein bind to an epitope having an amino acid sequence that is at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, 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% identical to any one of SEQ ID NOs: 38-48. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof described herein bind to an epitope having an amino acid sequence that differs from any one of SEQ ID NOs: 38-48 by at most 1 amino acid, at most 2 amino acids, at most 3 amino acids, at most 4 amino acids, at most 5 amino acids, at most 6 amino acids, at most 7 amino acids, at most 8 amino acids, at most 9 amino acids, or at most 10 amino acids. [Table 2]

[0093] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof has a nucleotide sequence of at least about 10 -4 M, 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13For example, an anti-BCMA antibody or antigen-binding fragment thereof of the present disclosure specifically binds to a BCMA protein (e.g., a human BCMA epitope set forth in any one of SEQ ID NOs: 38-48) with a binding affinity (e.g., as indicated by a KD) of 5 pM to 500 nM, 10 pM to 450 nM, 20 pM to 400 nM, 30 pM to 350 nM, 40 pM to 300 nM, 50 pM to 250 nM, 60 pM to 200 nM, 70 pM to 750 nM, 80 pM to 850 nM, 90 pM to 100 nM, 100 pM to 1200 nM, 120 pM to 1400 nM, 140 pM to 1600 nM, 160 pM to 1800 nM, 180 pM to 200 nM, 180 pM to 2200 nM, 180 pM to 2400 nM, 180 pM to 2600 nM, 180 pM to 2800 nM, 180 pM to 2900 nM, 180 pM to 300 nM, 180 pM to 3200 nM, 180 pM to 350 nM, 180 pM to 3200 nM, 180 pM to 290 ... It can bind with an affinity of 0 pM to 150 nM, 80 pM to 100 nM, 80 pM to 90 nM, 90 pM to 80 nM, 100 pM to 70 nM, 200 pM to 60 nM, 300 pM to 50 nM, 400 pM to 40 nM, 500 pM to 30 nM, 600 pM to 20 nM, 700 pM to 10 nM, 800 pM to 5 nM, or 900 pM to 2 nM.

[0094] The present disclosure also includes antibodies that compete with any of the antibodies described herein for binding to a BCMA protein (e.g., a human BCMA epitope set forth in any one of SEQ ID NOs: 38-48) and have an affinity of 100 nM or less (e.g., 80 nM or less, 50 nM or less, 20 nM or less, 10 nM or less, 500 pM or less, 50 pM or less, or 5 pM or less). The affinity and binding kinetics of anti-BCMA antibodies or antigen-binding fragments thereof can be tested using any suitable method, including, but not limited to, biosensor technology (e.g., OCTET or BIACORE). In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof described herein bind to BCMA with a KD in the sub-nanomolar range.

[0095] Non-limiting examples of anti-BCMA antibodies are shown in Table 3. [Table 3] JPEG2025542567000005.jpg251164JPEG2025542567000006.jpg250165JPEG2025542567000007.jpg17111 0JPEG2025542567000008.jpg171110JPEG2025542567000009.jpg255165JPEG2025542567000010.jpg27164

[0096] In some embodiments, an anti-BCMA antibody or antigen-binding fragment thereof of the present disclosure comprises one or more of the heavy chain CDR (e.g., CDRH1, CDRH2, or CDRH3) amino acid sequences from any one of the anti-BCMA antibodies selected from Table 3. In some embodiments, an anti-BCMA antibody or antigen-binding fragment thereof of the present disclosure comprises CDRH1, CDRH2, and CDRH3 provided for any one of the antibodies selected from Table 3. In some embodiments, an anti-BCMA antibody or antigen-binding fragment thereof of the present disclosure comprises one or more of the light chain CDR (e.g., CDRL1, CDRL2, or CDRL3) amino acid sequences from any one of the anti-BCMA antibodies selected from Table 3. In some embodiments, an anti-BCMA antibody or antigen-binding fragment thereof of the present disclosure comprises CDRL1, CDRL2, and CDRL3 provided for any one of the anti-BCMA antibodies selected from Table 3.

[0097] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 as provided for any one of the anti-BCMA antibodies selected from Table 3. In some embodiments, the heavy and light chain CDR3 domains of an antibody may play a particularly important role in the binding specificity / affinity of the antibody to the antigen. Thus, the anti-BCMA antibody, or antigen-binding fragment thereof, may comprise at least the heavy and / or light chain CDR3 of any one of the anti-BCMA antibodies selected from Table 3.

[0098] Also within the scope of the present disclosure are functional variants of any of the exemplary anti-BCMA antibodies or antigen-binding fragments thereof disclosed herein. Functional variants may contain one or more amino acid residue mutations in the VH and / or VL, or one or more heavy chain CDRs and / or one or more light chain CDRs, compared to a reference antibody, but may retain substantially similar binding and biological activity (e.g., substantially similar binding affinity, binding specificity, inhibitory activity, anti-inflammatory activity, or a combination thereof) as the reference antibody.

[0099] In some embodiments, any of the anti-BCMA antibodies or antigen-binding fragments thereof of the present disclosure have one or more CDR (e.g., heavy chain CDR or light chain CDR) sequences substantially similar to any of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 sequences from any of the anti-BCMA antibodies selected from Table 3. In some embodiments, the position of one or more CDRs along the VH (e.g., CDRH1, CDRH2, or CDRH3) and / or VL (e.g., CDRL1, CDRL2, or CDRL3) regions of an antibody described herein can be varied by one, two, three, four, five, or six amino acid positions, so long as specific binding to BCMA (e.g., human BCMA) is maintained (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, etc., of the binding of the original antibody from which it is derived is substantially maintained). For example, in some embodiments, the positions defining the CDRs of the antibodies described herein can be altered by shifting the N-terminal and / or C-terminal boundaries of the CDR by 1, 2, 3, 4, 5, or 6 amino acids relative to any one CDR position of the antibodies described herein, so long as specific binding to BCMA (e.g., human BCMA) is maintained (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, etc., of the binding of the original antibody from which it is derived is substantially maintained). In another embodiment, the length of one or more CDRs along the VH (e.g., CDRH1, CDRH2, or CDRH3) and / or VL (e.g., CDRL1, CDRL2, or CDRL3) regions of an antibody described herein can be varied (e.g., shortened or lengthened) by one, two, three, four, five or more amino acids, so long as specific binding to BCMA (e.g., human BCMA) is maintained (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, etc., of the binding of the original antibody from which it is derived is substantially maintained).

[0100] Thus, in some embodiments, CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and / or CDRL3 of an anti-BCMA antibody or antigen-binding fragment thereof may be shortened by one, two, three, four, five or more amino acids than one or more of the CDRs described herein (e.g., a CDR from any of the anti-BCMA antibodies selected from Table 3), provided that specific binding to BCMA (e.g., human BCMA) is maintained (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, etc., of the binding of the original antibody from which it is derived is substantially maintained). In some embodiments, CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and / or CDRL3 of an anti-BCMA antibody or antigen-binding fragment thereof may be one, two, three, four, five or more amino acids longer than one or more of the CDRs described herein (e.g., a CDR from any of the anti-BCMA antibodies selected from Table 3), provided that specific binding to BCMA (e.g., human BCMA) is maintained (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, etc., of the binding of the original antibody from which it is derived is substantially maintained). In some embodiments, the amino portion of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and / or CDRL3 of an anti-BCMA antibody or antigen-binding fragment thereof may be extended by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (e.g., a CDR from any of the anti-BCMA antibodies selected from Table 3), provided that specific binding to BCMA (e.g., human BCMA) is maintained (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, etc. relative to the binding of the original antibody from which it is derived is substantially maintained).In some embodiments, the carboxy portion of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and / or CDRL3 of an anti-BCMA antibody or antigen-binding fragment thereof may be extended by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (e.g., a CDR from any of the anti-BCMA antibodies selected from Table 3), provided that specific binding to BCMA (e.g., human BCMA) is maintained (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, etc. relative to the binding of the original antibody from which it is derived is substantially maintained). In some embodiments, the amino portion of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 of an anti-BCMA antibody or antigen-binding fragment thereof may be shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (e.g., a CDR from any of the anti-BCMA antibodies selected from Table 3), provided that specific binding to BCMA (e.g., human BCMA) is maintained (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, etc., of the binding of the original antibody from which it is derived is substantially maintained). In some embodiments, the carboxy portion of CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 of an anti-BCMA antibody or antigen-binding fragment thereof may be shortened by one, two, three, four, five or more amino acids compared to one or more of the CDRs described herein (e.g., a CDR from any of the anti-BCMA antibodies selected from Table 3), provided that specific binding to BCMA (e.g., human BCMA) is maintained (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, etc., of the binding of the original antibody from which it is derived is substantially maintained). Any method can be used to determine whether specific binding to BCMA (e.g., human BCMA), for example, using binding assays and conditions described in the art.

[0101] In some examples, the anti-BCMA antibody or antigen-binding fragment thereof comprises one or more CDR (e.g., heavy chain CDR or light chain CDR) sequences substantially similar to any one of the anti-BCMA antibodies selected from Table 3. For example, the antibody may comprise one or more CDR sequence(s) from any of the anti-BCMA antibodies selected from Table 3 that comprise up to five, four, three, two, or one amino acid residue mutations compared to the corresponding CDR region in any one of the CDRs provided herein (e.g., a CDR from any of the anti-BCMA antibodies selected from Table 3), so long as specific binding to BCMA (e.g., human BCMA) is maintained (e.g., is substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% relative to the binding of the original antibody from which it was derived). In some embodiments, any of the amino acid mutations in any of the CDRs provided herein may be conservative mutations. Conservative mutations can be introduced into the CDRs at positions where the residues are unlikely to be involved in interactions with the BCMA protein (e.g., human BCMA), for example, as determined based on a crystal structure.

[0102] Some aspects of the present disclosure provide anti-BCMA antibodies comprising one or more of the heavy chain variable (VH) domains and / or light chain variable (VL) domains provided herein. In some embodiments, any of the VH domains provided herein comprise one or more of the heavy chain CDR sequences (e.g., CDRH1, CDRH2, and CDRH3) provided herein, e.g., any of the heavy chain CDR sequences provided in any one of the anti-BCMA antibodies selected from Table 3. In some embodiments, any of the VL domains provided herein comprise one or more of the CDR-L sequences (e.g., CDRL1, CDRL2, and CDRL3) provided herein, e.g., any of the light chain CDR sequences provided in any one of the anti-BCMA antibodies selected from Table 3.

[0103] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof includes any antibody comprising the heavy chain variable domain and / or the light chain variable domain of any one of the anti-BCMA antibodies selected from Table 3, and variants thereof. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof includes any antibody comprising the heavy chain variable pair and light chain variable pair of any of the anti-BCMA antibodies selected from Table 3.

[0104] Aspects of the present disclosure provide anti-BCMA antibodies or antigen-binding fragments thereof comprising heavy chain variable (VH) and / or light chain variable (VL) domain amino acid sequences homologous to any of those described herein. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH or VL that is at least 75% (e.g., at least 80%, at least 85%, 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%) identical to the VH and / or any VL of any one of the anti-BCMA antibodies selected from Table 3. In some embodiments, the homologous VH and / or VL amino acid sequences do not vary within any of the CDR sequences provided herein. For example, in some embodiments, a degree of sequence variation (e.g., at least 80%, at least 85%, 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%) may occur within the VH and / or VL sequences, excluding any of the CDR sequences provided herein. In some embodiments, any of the anti-BCMA antibodies or antigen-binding fragments thereof provided herein comprise VH and VL sequences that comprise framework sequences that are at least 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the framework sequences of any anti-BCMA antibody selected from Table 3. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutation) compared to the VH of any of the anti-BCMA antibodies listed in Table 3.Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL of any one of the anti-BCMA antibodies listed in Table 3.

[0105] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is a humanized antibody (e.g., a humanized variant comprising one or more CDRs of Table 3). In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises the same CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 as shown in Table 3, and comprises a humanized VH and / or a humanized VL. In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is a humanized variant comprising one or more amino acid substitutions compared to any one of the VHs listed in Table 3 (e.g., in the VH framework regions) and / or one or more amino acid substitutions compared to any one of the VLs listed in Table 3 (e.g., in the VL framework regions).

[0106] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 8.

[0107] In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 5, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0108] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, and CDRH3 that collectively comprise five or fewer amino acid mutations (e.g., five, four, three, two, or one or fewer amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 1, CDRH2 having the amino acid sequence of SEQ ID NO: 2, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. As used anywhere in this disclosure, "collectively" means that the total number of amino acid mutations in all three heavy chain CDRs is within a defined range. Alternatively, or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2, and CDRL3 that collectively comprise five or fewer amino acid mutations (e.g., five, four, three, two, or one or fewer amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 5, and CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0109] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to a CDRH1 having the amino acid sequence of SEQ ID NO:1, a CDRH2 having the amino acid sequence of SEQ ID NO:2, and a CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:5, and CDRL3 having the amino acid sequence of SEQ ID NO:6.

[0110] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 1; a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 2; and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof includes a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 5, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0111] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH having the amino acid sequence of SEQ ID NO: 7. Alternatively, or additionally, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL having the amino acid sequence of SEQ ID NO: 8.

[0112] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 8.

[0113] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO:8.

[0114] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 10.

[0115] In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0116] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 1, CDRH2 having the amino acid sequence of SEQ ID NO: 2, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0117] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to a CDRH1 having the amino acid sequence of SEQ ID NO:1, a CDRH2 having the amino acid sequence of SEQ ID NO:2, and a CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:24 and CDRL3 having the amino acid sequence of SEQ ID NO:6.

[0118] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 1; a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 2; and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof includes a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0119] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH having the amino acid sequence of SEQ ID NO: 7. Alternatively, or additionally, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL having the amino acid sequence of SEQ ID NO: 10.

[0120] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, in some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 10.

[0121] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 10.

[0122] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 13.

[0123] In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 25, a CDRH2 having the amino acid sequence of SEQ ID NO: 27, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 25, a CDRH2 having the amino acid sequence of SEQ ID NO: 27, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0124] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 25, CDRH2 having the amino acid sequence of SEQ ID NO: 27, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0125] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to a CDRH1 having the amino acid sequence of SEQ ID NO:25, a CDRH2 having the amino acid sequence of SEQ ID NO:27, and a CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:24 and CDRL3 having the amino acid sequence of SEQ ID NO:30.

[0126] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 25; a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 27; and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof includes a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0127] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH having the amino acid sequence of SEQ ID NO: 12. Alternatively, or additionally, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL having the amino acid sequence of SEQ ID NO: 13.

[0128] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 12. Alternatively or additionally, in some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 13.

[0129] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 13.

[0130] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 15.

[0131] In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 25, a CDRH2 having the amino acid sequence of SEQ ID NO: 27, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 25, a CDRH2 having the amino acid sequence of SEQ ID NO: 27, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0132] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 25, CDRH2 having the amino acid sequence of SEQ ID NO: 27, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0133] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to a CDRH1 having the amino acid sequence of SEQ ID NO:25, a CDRH2 having the amino acid sequence of SEQ ID NO:27, and a CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:24 and CDRL3 having the amino acid sequence of SEQ ID NO:29.

[0134] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 25; a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 27; and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof includes a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4; a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24; and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0135] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH having the amino acid sequence of SEQ ID NO: 12. Alternatively, or additionally, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL having the amino acid sequence of SEQ ID NO: 15.

[0136] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 12. Alternatively or additionally, in some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 15.

[0137] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 15.

[0138] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 13.

[0139] In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0140] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 1, CDRH2 having the amino acid sequence of SEQ ID NO: 2, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0141] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to a CDRH1 having the amino acid sequence of SEQ ID NO:1, a CDRH2 having the amino acid sequence of SEQ ID NO:2, and a CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:24 and CDRL3 having the amino acid sequence of SEQ ID NO:30.

[0142] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 1; a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 2; and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof includes a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0143] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH having the amino acid sequence of SEQ ID NO: 7. Alternatively, or additionally, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL having the amino acid sequence of SEQ ID NO: 13.

[0144] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, in some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 13.

[0145] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 13.

[0146] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 15.

[0147] In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0148] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 1, CDRH2 having the amino acid sequence of SEQ ID NO: 2, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0149] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to a CDRH1 having the amino acid sequence of SEQ ID NO:1, a CDRH2 having the amino acid sequence of SEQ ID NO:2, and a CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:24 and CDRL3 having the amino acid sequence of SEQ ID NO:29.

[0150] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 1; a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 2; and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof includes a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4; a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24; and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0151] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH having the amino acid sequence of SEQ ID NO: 7. Alternatively, or additionally, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL having the amino acid sequence of SEQ ID NO: 15.

[0152] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, in some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 15.

[0153] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 7. Alternatively, or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 15.

[0154] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 19. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 10.

[0155] In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 26, a CDRH2 having the amino acid sequence of SEQ ID NO: 28, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 26, a CDRH2 having the amino acid sequence of SEQ ID NO: 28, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0156] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 26, CDRH2 having the amino acid sequence of SEQ ID NO: 28, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0157] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to a CDRH1 having the amino acid sequence of SEQ ID NO:26, a CDRH2 having the amino acid sequence of SEQ ID NO:28, and a CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:24 and CDRL3 having the amino acid sequence of SEQ ID NO:6.

[0158] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 26; a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 28; and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof includes a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0159] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH having the amino acid sequence of SEQ ID NO: 19. Alternatively, or additionally, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL having the amino acid sequence of SEQ ID NO: 10.

[0160] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 19. Alternatively or additionally, in some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 10.

[0161] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 19. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 10.

[0162] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 21. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 22.

[0163] In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 33. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 31, a CDRH2 having the amino acid sequence of SEQ ID NO: 32, and a CDRH3 having the amino acid sequence of SEQ ID NO: 33. In some embodiments, according to the Kabat definition system, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 31, a CDRH2 having the amino acid sequence of SEQ ID NO: 32, a CDRH3 having the amino acid sequence of SEQ ID NO: 33, a CDRL1 having the amino acid sequence of SEQ ID NO: 34, a CDRL2 having the amino acid sequence of SEQ ID NO: 35, and a CDRL3 having the amino acid sequence of SEQ ID NO: 36.

[0164] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 31, CDRH2 having the amino acid sequence of SEQ ID NO: 32, and CDRH3 having the amino acid sequence of SEQ ID NO: 33. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 34, CDRL2 having the amino acid sequence of SEQ ID NO: 35, and CDRL3 having the amino acid sequence of SEQ ID NO: 36.

[0165] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRH1 having the amino acid sequence of SEQ ID NO: 31, CDRH2 having the amino acid sequence of SEQ ID NO: 32, and CDRH3 having the amino acid sequence of SEQ ID NO: 33. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO: 34, CDRL2 having the amino acid sequence of SEQ ID NO: 35 and CDRL3 having the amino acid sequence of SEQ ID NO: 36.

[0166] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 31; a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 32; and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 33. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof includes a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 34, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 35, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 36.

[0167] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH having the amino acid sequence of SEQ ID NO: 21. Alternatively, or additionally, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL having the amino acid sequence of SEQ ID NO: 22.

[0168] In some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 21. Alternatively or additionally, in some embodiments, the anti-BCMA antibody, or antigen-binding fragment thereof, comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 22.

[0169] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VH having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 21. Alternatively or additionally, the anti-BCMA antibody or antigen-binding fragment thereof comprises a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 22.

[0170] The anti-BCMA antibodies or antigen-binding fragments thereof described herein can be in any antibody format, including, but not limited to, intact (i.e., full-length) antibodies, antigen-binding fragments thereof (Fab, F(ab'), F(ab')2, Fv), single-chain antibodies (e.g., scFv), bispecific antibodies, or nanobodies. In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof described herein are single-chain variable fragments (scFv). In some embodiments, the anti-BCMA antibodies or antigen-binding fragments thereof described herein are scFv-FAB (e.g., scFv fused to a portion of a constant region).

[0171] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises the VL domain and / or VH domain of any one of the anti-BCMA antibodies selected from Table 3, and comprises a constant region having the amino acid sequence of the constant region of an IgG, IgE, IgM, IgD, IgA, or IgY immunoglobulin molecule, of any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2), or of any subclass (e.g., IgG2a and IgG2b). Non-limiting examples of human constant region sequences are described in the art, see, for example, Kabat EA et al. (1991), supra. Other antibody heavy and light chain constant regions are well known in the art, such as those provided in the IMGT database (imgt.org) or vbase2.org / vbstat.php, both of which are incorporated herein by reference.

[0172] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof is a single-chain variable fragment (scFv). In some embodiments, the anti-BCMA scFv comprises the VH and VL of any one of the anti-BCMA antibodies selected from Table 3. In some embodiments, the VH and VL of the anti-BCMA scFv are linked together by a linker. In some embodiments, the linker can be about 2-10 amino acids, 5-20 amino acids, 10-30 amino acids, 20-50 amino acids, 40-60 amino acids, 60-80 amino acids, or more than 80 amino acids in length. In some embodiments, the linker may comprise a sequence substantially comprising glycine and serine. An exemplary linker sequence is GGGGSGGGGSGGGAS (SEQ ID NO: 81). In some embodiments, linkers may include, but are not limited to, those contained in U.S. Patent Nos. 8,445,251 and 9,434,931. In some embodiments, the anti-BCMA antibody comprises a linker between the VH and VL, wherein the linker comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:81.

[0173] In some embodiments, the anti-BCMA scFv comprises a VH and a VL, and the C-terminus of the VH is joined to the N-terminus of the VL via a linker (e.g., the linker set forth in SEQ ID NO: 81). In some embodiments, the anti-BCMA scFv comprises a VH and a VL, and the C-terminus of the VL is joined to the N-terminus of the VH via a linker (e.g., the linker set forth in SEQ ID NO: 81).

[0174] In some embodiments, the anti-BCMA scFv comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH of any of the anti-BCMA antibodies listed in Table 3. Alternatively or additionally, the anti-BCMA scFv comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH of any of the anti-BCMA antibodies listed in Table 3. In some embodiments, the anti-BCMA scFv comprises a VH having an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH of any of the anti-BCMA antibodies listed in Table 3. Alternatively or additionally, the anti-BCMA scFv comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH of any of the anti-BCMA antibodies listed in Table 3.

[0175] In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to any of the anti-BCMA scFvs listed in Table 3. In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to any of the anti-BCMA scFvs listed in Table 3.

[0176] In some embodiments, the anti-BCMA scFv comprises a VH having the amino acid sequence of SEQ ID NO: 7, and / or a VL having the amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-BCMA scFv comprises a VH that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7, and / or a VL that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 8. In some embodiments, the anti-BCMA scFv comprises a VH having an amino acid sequence at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH set forth in SEQ ID NO:7, and / or a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO:8.

[0177] In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the scFv amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the anti-BCMA scFv comprises the amino acid sequence of SEQ ID NO: 9.

[0178] In some embodiments, the anti-BCMA scFv comprises a VH having the amino acid sequence of SEQ ID NO: 7, and / or a VL having the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-BCMA scFv comprises a VH that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7, and / or a VL that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 10. In some embodiments, the anti-BCMA scFv comprises a VH having an amino acid sequence at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH set forth in SEQ ID NO: 7, and / or a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 10.

[0179] In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the scFv amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the anti-BCMA scFv comprises the amino acid sequence of SEQ ID NO: 11.

[0180] In some embodiments, the anti-BCMA scFv comprises a VH having the amino acid sequence of SEQ ID NO: 12, and / or a VL having the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-BCMA scFv comprises a VH that contains no more than 20 amino acid mutations compared to the VH set forth in SEQ ID NO: 12 (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations), and / or a VL that contains no more than 20 amino acid mutations compared to the VL set forth in SEQ ID NO: 13 (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations). In some embodiments, the anti-BCMA scFv comprises a VH having an amino acid sequence at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH set forth in SEQ ID NO: 12, and / or a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 13.

[0181] In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the scFv amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the anti-BCMA scFv comprises the amino acid sequence of SEQ ID NO: 14.

[0182] In some embodiments, the anti-BCMA scFv comprises a VH having the amino acid sequence of SEQ ID NO: 12, and / or a VL having the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-BCMA scFv comprises a VH that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 12, and / or a VL that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 15. In some embodiments, the anti-BCMA scFv comprises a VH having an amino acid sequence at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VH set forth in SEQ ID NO: 12, and / or a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 15.

[0183] In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the scFv amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the anti-BCMA scFv comprises the amino acid sequence of SEQ ID NO: 16.

[0184] In some embodiments, the anti-BCMA scFv comprises a VH having the amino acid sequence of SEQ ID NO: 7, and / or a VL having the amino acid sequence of SEQ ID NO: 13. In some embodiments, the anti-BCMA scFv comprises a VH that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7, and / or a VL that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 13. In some embodiments, the anti-BCMA scFv comprises a VH having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 7, and / or a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 13.

[0185] In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the scFv amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the anti-BCMA scFv comprises the amino acid sequence of SEQ ID NO: 17.

[0186] In some embodiments, the anti-BCMA scFv comprises a VH having the amino acid sequence of SEQ ID NO: 7, and / or a VL having the amino acid sequence of SEQ ID NO: 15. In some embodiments, the anti-BCMA scFv comprises a VH that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7, and / or a VL that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 15. In some embodiments, the anti-BCMA scFv comprises a VH having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 7, and / or a VL having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 15.

[0187] In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that is at least 80% identical (e.g., at least 80%, at least 85%, 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%) to the scFv amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, the anti-BCMA scFv comprises the amino acid sequence of SEQ ID NO: 18.

[0188] In some embodiments, the anti-BCMA scFv comprises a VH having the amino acid sequence of SEQ ID NO: 19, and / or a VL having the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-BCMA scFv comprises a VH that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 19, and / or a VL that contains no more than 20 amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 10. In some embodiments, the anti-BCMA scFv comprises a VH having an amino acid sequence at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 19, and / or a VL having an amino acid sequence at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to the VL set forth in SEQ ID NO: 10.

[0189] In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that is at least 80% (e.g., 80%, 85%, 90%, 95%, 98%, or 99%) identical to the scFv amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the anti-BCMA scFv comprises the amino acid sequence of SEQ ID NO: 20.

[0190] In some embodiments, the anti-BCMA scFv comprises a VH having the amino acid sequence of SEQ ID NO: 21, and / or a VL having the amino acid sequence of SEQ ID NO: 22. In some embodiments, the anti-BCMA scFv comprises a VH that contains no more than 20 amino acid mutations compared to the VH set forth in SEQ ID NO: 21 (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations), and / or a VL that contains no more than 20 amino acid mutations compared to the VL set forth in SEQ ID NO: 22 (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations). In some embodiments, the anti-BCMA scFv comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO:21, and / or a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO:22.

[0191] In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the scFv amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the anti-BCMA scFv comprises the amino acid sequence of SEQ ID NO: 23.

[0192] In some embodiments, any of the anti-BCMA antibodies or antigen-binding fragments described herein are modified, for example, via glycosylation, phosphorylation, sumoylation, and / or methylation. In some embodiments, the anti-BCMA antibody or antigen-binding fragment is a glycosylated antibody that is conjugated to one or more sugar or carbohydrate molecules. In some embodiments, the one or more sugar or carbohydrate molecules are conjugated to the antibody via N-glycosylation, O-glycosylation, C-glycosylation, glypionation (GPI anchor attachment), and / or phosphoglycosylation. In some embodiments, the one or more sugar or carbohydrate molecules are monosaccharides, disaccharides, oligosaccharides, or glycans. In some embodiments, the one or more sugar or carbohydrate molecules are branched oligosaccharides or branched glycans. In some embodiments, the one or more sugar or carbohydrate molecules comprise a mannose unit, a glucose unit, an N-acetylglucosamine unit, an N-acetylgalactosamine unit, a galactose unit, a fucose unit, or a phospholipid unit. In some embodiments, there are about 1-10, about 1-5, about 5-10, about 1-4, about 1-3, or about 2 sugar molecules. In some embodiments, the glycosylated antibody is fully or partially glycosylated. In some embodiments, the antibody is glycosylated by chemical or enzymatic means. In some embodiments, the antibody is glycosylated in vitro or intracellularly, which may optionally be due to a deficiency of an enzyme in the N- or O-glycosylation pathway, e.g., a glycosyltransferase. In some embodiments, the antibody is functionalized with a sugar or carbohydrate molecule as described in International Patent Application Publication WO2014065661, published May 1, 2014, and entitled "Modified antibody, antibody-conjugate and process for the preparation thereof."

[0193] In some embodiments, conservative mutations can be introduced into an antibody sequence (e.g., a CDR or framework sequence) at positions where the residue is unlikely to be involved in interactions with the target antigen (e.g., BCMA), as determined, for example, based on a crystal structure.

[0194] In some embodiments, any one of the anti-BCMA antibodies or antigen-binding fragments described herein may comprise a signal peptide in the heavy and / or light chain sequence (e.g., an N-terminal signal peptide). In some embodiments, the anti-BCMA antibody or antigen-binding fragment described herein comprises any one of the VH and VL sequences, any one of the IgG heavy and light chain sequences, or any one of the scFv sequences described herein (e.g., any one of the scFvs set forth in SEQ ID NOs: 9, 11, 14, 16, 17, 18, 20, or 23), and further comprises a single peptide (e.g., an N-terminal signal peptide).

[0195] II. Anti-BCMA Chimeric Antigen Receptor The present disclosure also provides chimeric antigen receptors (CARs) comprising, at least in part, an extracellular ligand-binding domain. In some embodiments, the selection of the ligand-binding domain depends on the type and number of ligands defining the surface of the target cell. For example, the ligand-binding domain may be selected to recognize one or more ligands that act as cell surface markers on target cells associated with a particular disease state. Thus, cell surface markers that may act as ligands for the ligand-binding domain in a CAR of the present disclosure include, for example, those associated with viral, bacterial, and parasitic infections, autoimmune diseases, and, more preferably, cancer cells. In some embodiments, a CAR of the present disclosure is engineered to target one or more tumor antigens of interest by engineering a desired ligand-binding site that specifically binds to one or more antigens on tumor cells. In the context of the present disclosure, "tumor antigen" refers to an antigen common to or characteristic of a particular hyperproliferative disorder, such as cancer. Generally, a CAR of the present disclosure (e.g., an anti-BCMA CAR) comprises at least an extracellular domain and an intracellular domain. In some embodiments, the extracellular domain comprises a target-specific binding element (e.g., an scFv that specifically binds BCMA), otherwise referred to herein as a ligand-binding domain (also referred to herein as an antigen-binding domain). In some embodiments, the extracellular domain is an antigen-binding domain or a portion thereof. In some embodiments, the extracellular ligand-binding domain is a Fab. In some embodiments, the extracellular ligand-binding domain is an scFv. In some embodiments, the extracellular ligand-binding domain of a CAR described herein comprises an antigen-binding fragment that specifically binds BCMA (e.g., human BCMA). In some embodiments, the extracellular ligand-binding domain of a CAR described herein comprises any one of a BCMA antibody or antigen-binding fragment thereof (e.g., an anti-BCMA scFv).

[0196] In some embodiments, the anti-BCMA CAR of the present disclosure has a cytotoxicity of at least about 10 -4 M, 10 -5 M, 10 -6 M, 10-7 M, 10 -8 M, 10 -9 M, 10 -10 M, 10 -11 M, 10 -12 M, 10 -13 The anti-BCMA CAR comprises an extracellular ligand-binding domain that specifically binds to BCMA with a binding affinity (e.g., as indicated by a KD) of 5 pM to 500 nM, 10 pM to 450 nM, 20 pM to 400 nM, 30 pM to 350 nM, 40 pM to 300 nM, 50 pM to 250 nM, 60 pM to 200 nM, 70 pM to 150 nM, 80 pM to 150 nM, 90 pM to 150 nM, 10 ... The antibody can bind with an affinity of 800 pM to 100 nM, 80 pM to 90 nM, 90 pM to 80 nM, 100 pM to 70 nM, 200 pM to 60 nM, 300 pM to 50 nM, 400 pM to 40 nM, 500 pM to 30 nM, 600 pM to 20 nM, 700 pM to 10 nM, 800 pM to 5 nM, or 900 pM to 2 nM.

[0197] The present disclosure also includes CARs that compete with any of the CARs described herein for binding to BCMA protein (e.g., a human cell surface BCMA epitope set forth in any one of SEQ ID NOs: 38-48) and have an affinity of 100 nM or less (e.g., 80 nM or less, 50 nM or less, 20 nM or less, 10 nM or less, 500 pM or less, 50 pM or less, or 5 pM or less). The affinity and binding kinetics of anti-BCMA CARs can be tested using any suitable method, including, but not limited to, biosensor technology (e.g., OCTET or BIACORE). In some embodiments, the anti-BCMA CARs described herein have a K in the sub-nanomolar range. D binds to BCMA.

[0198] In some embodiments, an anti-BCMA CAR of the disclosure comprises one or more of the heavy chain CDR (e.g., CDRH1, CDRH2, or CDRH3) amino acid sequences from any one of the anti-BCMA antibodies selected from Table 3. In some embodiments, an anti-BCMA CAR of the disclosure comprises CDRH1, CDRH2, and CDRH3 provided for any one of the antibodies selected from Table 3. In some embodiments, an anti-BCMA CAR of the disclosure comprises one or more of the light chain CDR (e.g., CDRL1, CDRL2, or CDRL3) amino acid sequences from any one of the anti-BCMA antibodies selected from Table 3. In some embodiments, an anti-BCMA CAR of the disclosure comprises CDRL1, CDRL2, and CDRL3 provided for any one of the anti-BCMA antibodies selected from Table 3.

[0199] In some embodiments, an anti-BCMA CAR comprises CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 as provided for any one of the anti-BCMA antibodies selected from Table 3. In some embodiments, the heavy and light chain CDR3 domains of an antibody may play a particularly important role in the binding specificity / affinity of the antibody to its antigen. Thus, an anti-BCMA CAR may comprise at least the heavy and / or light chain CDR3 of any one of the anti-BCMA antibodies selected from Table 3.

[0200] In some embodiments, any of the anti-BCMA CARs of the present disclosure have one or more CDR (e.g., heavy chain CDR or light chain CDR) sequences substantially similar to any of the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and / or CDRL3 sequences from one of the anti-BCMA antibodies selected from Table 3. In some embodiments, the position of one or more CDRs along the VH (e.g., CDRH1, CDRH2, or CDRH3) and / or VL (e.g., CDRL1, CDRL2, or CDRL3) regions of a chimeric antigen receptor described herein can be varied by one, two, three, four, five, or six amino acid positions, so long as specific binding to BCMA (e.g., human BCMA) is maintained (e.g., at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, etc., of the binding of the original antibody from which it is derived is substantially maintained).

[0201] In some examples, an anti-BCMA CAR comprises one or more CDR (e.g., heavy chain CDR or light chain CDR) sequences that are substantially similar to any one of the anti-BCMA antibodies selected from Table 3. For example, an anti-BCMA CAR may comprise one or more CDR sequence(s) from any of the anti-BCMA antibodies selected from Table 3 that comprise up to five, four, three, two, or one amino acid residue mutations compared to the corresponding CDR region in any one of the CDRs provided herein (e.g., a CDR from any of the anti-BCMA antibodies selected from Table 3), so long as specific binding to BCMA (e.g., human BCMA) is maintained (e.g., is substantially maintained by at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% relative to the binding of the original antibody from which it is derived).

[0202] Some aspects of the present disclosure provide anti-BCMA CARs comprising one or more of the heavy chain variable (VH) domains and / or light chain variable (VL) domains provided herein. In some embodiments, any of the VH domains provided herein comprise one or more of the heavy chain CDR sequences (e.g., CDRH1, CDRH2, and CDRH3) provided herein, e.g., any of the heavy chain CDR sequences provided in any one of the anti-BCMA antibodies selected from Table 3. In some embodiments, any of the VL domains provided herein comprise one or more of the CDR-L sequences (e.g., CDRL1, CDRL2, and CDRL3) provided herein, e.g., any of the light chain CDR sequences provided in any one of the anti-BCMA antibodies selected from Table 3.

[0203] In some embodiments, the anti-BCMA CAR comprises any antibody comprising the heavy chain variable domain and / or the light chain variable domain of any one of the anti-BCMA antibodies selected from Table 3, and variants thereof. In some embodiments, the anti-BCMA CAR comprises the heavy chain variable and light chain variable pair of any anti-BCMA antibody selected from Table 3.

[0204] Aspects of the present disclosure provide anti-BCMA CARs comprising heavy chain variable (VH) and / or light chain variable (VL) domain amino acid sequences homologous to any of those described herein. In some embodiments, the anti-BCMA CAR comprises a VH or VL that is at least 75% (e.g., at least 80%, at least 85%, 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%) identical to the VH and / or any VL of any one of the anti-BCMA antibodies selected from Table 3. In some embodiments, the homologous VH and / or VL amino acid sequences of the anti-BCMA CAR are unchanged within any of the CDR sequences provided herein. For example, in some embodiments, a degree of sequence variation (e.g., 75%, 80%, 85%, 90%, 95%, 98%, or 99%) may occur within the VH and / or VL sequences of an anti-BCMA CAR, excluding any of the CDR sequences described herein. In some embodiments, any of the anti-BCMA CARs provided herein comprises VH and VL sequences that comprise framework sequences that are at least 75%, 80%, 85%, 90%, 95%, 98%, or 99% identical to the framework sequences of any anti-BCMA antibody selected from Table 3. In some embodiments, the anti-BCMA CAR comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH of any of the anti-BCMA antibodies listed in Table 3. Alternatively or additionally, the anti-BCMA CAR comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL of any one of the anti-BCMA antibodies listed in Table 3.

[0205] In some embodiments, the anti-BCMA CAR comprises a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 that are the same as those shown in Table 3, and comprises a humanized VH and / or a humanized VL. In some embodiments, the anti-BCMA CAR is a humanized variant that comprises one or more amino acid substitutions compared to any one of the VHs listed in Table 3 (e.g., in the VH framework regions) and / or one or more amino acid substitutions compared to any one of the VLs listed in Table 3 (e.g., in the VL framework regions).

[0206] In some embodiments, the anti-BCMA CAR comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 8.

[0207] In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 5, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0208] In some embodiments, an anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 1, CDRH2 having the amino acid sequence of SEQ ID NO: 2, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, an anti-BCMA CAR comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 5, and CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0209] In some embodiments, the anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRH1 having the amino acid sequence of SEQ ID NO:1, CDRH2 having the amino acid sequence of SEQ ID NO:2, and CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA CAR comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:5, and CDRL3 having the amino acid sequence of SEQ ID NO:6.

[0210] In some embodiments, the anti-BCMA CAR comprises a CDRH1 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 1; a CDRH2 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 2; and / or a CDRH3 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA CAR comprises a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 5, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0211] In some embodiments, the anti-BCMA CAR comprises a VH having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL having the amino acid sequence of SEQ ID NO: 8.

[0212] In some embodiments, the anti-BCMA CAR comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 8.

[0213] In some embodiments, the anti-BCMA CAR comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 8.

[0214] In some embodiments, the anti-BCMA CAR comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 10.

[0215] In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0216] In some embodiments, an anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 1, CDRH2 having the amino acid sequence of SEQ ID NO: 2, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, an anti-BCMA CAR comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0217] In some embodiments, the anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRH1 having the amino acid sequence of SEQ ID NO:1, CDRH2 having the amino acid sequence of SEQ ID NO:2, and CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA CAR comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:24 and CDRL3 having the amino acid sequence of SEQ ID NO:6.

[0218] In some embodiments, the anti-BCMA CAR comprises a CDRH1 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 1; a CDRH2 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 2; and / or a CDRH3 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA CAR comprises a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0219] In some embodiments, the anti-BCMA CAR comprises a VH having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL having the amino acid sequence of SEQ ID NO: 10.

[0220] In some embodiments, the anti-BCMA CAR comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 10.

[0221] In some embodiments, the anti-BCMA CAR comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 10.

[0222] In some embodiments, the anti-BCMA CAR comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA CAR comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 13.

[0223] In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 25, a CDRH2 having the amino acid sequence of SEQ ID NO: 27, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 25, a CDRH2 having the amino acid sequence of SEQ ID NO: 27, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0224] In some embodiments, an anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 25, CDRH2 having the amino acid sequence of SEQ ID NO: 27, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, an anti-BCMA CAR comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0225] In some embodiments, the anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRH1 having the amino acid sequence of SEQ ID NO: 25, CDRH2 having the amino acid sequence of SEQ ID NO: 27, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA CAR comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0226] In some embodiments, the anti-BCMA CAR comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 25; a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 27; and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA CAR comprises a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0227] In some embodiments, the anti-BCMA CAR comprises a VH having the amino acid sequence of SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA CAR comprises a VL having the amino acid sequence of SEQ ID NO: 13.

[0228] In some embodiments, the anti-BCMA CAR comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA CAR comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 13.

[0229] In some embodiments, the anti-BCMA CAR comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA CAR comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 13.

[0230] In some embodiments, the anti-BCMA CAR comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA CAR comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 15.

[0231] In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 25, a CDRH2 having the amino acid sequence of SEQ ID NO: 27, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 25, a CDRH2 having the amino acid sequence of SEQ ID NO: 27, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0232] In some embodiments, an anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 25, CDRH2 having the amino acid sequence of SEQ ID NO: 27, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, an anti-BCMA CAR comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0233] In some embodiments, the anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRH1 having the amino acid sequence of SEQ ID NO: 25, CDRH2 having the amino acid sequence of SEQ ID NO: 27, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA CAR comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:24 and CDRL3 having the amino acid sequence of SEQ ID NO:29.

[0234] In some embodiments, the anti-BCMA CAR comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 25; a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 27; and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA CAR comprises a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0235] In some embodiments, the anti-BCMA CAR comprises a VH having the amino acid sequence of SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA CAR comprises a VL having the amino acid sequence of SEQ ID NO: 15.

[0236] In some embodiments, the anti-BCMA CAR comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA CAR comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 15.

[0237] In some embodiments, the anti-BCMA CAR comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 12. Alternatively or additionally, the anti-BCMA CAR comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 15.

[0238] In some embodiments, the anti-BCMA CAR comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 13.

[0239] In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0240] In some embodiments, an anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 1, CDRH2 having the amino acid sequence of SEQ ID NO: 2, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, an anti-BCMA CAR comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0241] In some embodiments, the anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRH1 having the amino acid sequence of SEQ ID NO:1, CDRH2 having the amino acid sequence of SEQ ID NO:2, and CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA CAR comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0242] In some embodiments, the anti-BCMA CAR comprises a CDRH1 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 1; a CDRH2 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 2; and / or a CDRH3 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA CAR comprises a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 30.

[0243] In some embodiments, the anti-BCMA CAR comprises a VH having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL having the amino acid sequence of SEQ ID NO: 13.

[0244] In some embodiments, the anti-BCMA CAR comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 13.

[0245] In some embodiments, the anti-BCMA CAR comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 13.

[0246] In some embodiments, the anti-BCMA CAR comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 15.

[0247] In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0248] In some embodiments, an anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 1, CDRH2 having the amino acid sequence of SEQ ID NO: 2, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, an anti-BCMA CAR comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0249] In some embodiments, the anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRH1 having the amino acid sequence of SEQ ID NO:1, CDRH2 having the amino acid sequence of SEQ ID NO:2, and CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA CAR comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:24 and CDRL3 having the amino acid sequence of SEQ ID NO:29.

[0250] In some embodiments, the anti-BCMA CAR comprises a CDRH1 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 1; a CDRH2 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 2; and / or a CDRH3 that has three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA CAR comprises a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 29.

[0251] In some embodiments, the anti-BCMA CAR comprises a VH having the amino acid sequence of SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL having the amino acid sequence of SEQ ID NO: 15.

[0252] In some embodiments, the anti-BCMA CAR comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 15.

[0253] In some embodiments, the anti-BCMA CAR comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 7. Alternatively or additionally, the anti-BCMA CAR comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 15.

[0254] In some embodiments, the anti-BCMA CAR comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 19. Alternatively or additionally, the anti-BCMA CAR comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 10.

[0255] In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 26, a CDRH2 having the amino acid sequence of SEQ ID NO: 28, and a CDRH3 having the amino acid sequence of SEQ ID NO: 3. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 26, a CDRH2 having the amino acid sequence of SEQ ID NO: 28, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0256] In some embodiments, an anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 26, CDRH2 having the amino acid sequence of SEQ ID NO: 28, and CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, an anti-BCMA CAR comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g., no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 4, CDRL2 having the amino acid sequence of SEQ ID NO: 24, and CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0257] In some embodiments, the anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRH1 having the amino acid sequence of SEQ ID NO:26, CDRH2 having the amino acid sequence of SEQ ID NO:28, and CDRH3 having the amino acid sequence of SEQ ID NO:3. Alternatively or additionally, the anti-BCMA CAR comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO:4, CDRL2 having the amino acid sequence of SEQ ID NO:24 and CDRL3 having the amino acid sequence of SEQ ID NO:6.

[0258] In some embodiments, the anti-BCMA CAR comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 26, a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 28, and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 3. Alternatively or additionally, the anti-BCMA CAR comprises a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 6.

[0259] In some embodiments, the anti-BCMA CAR comprises a VH having the amino acid sequence of SEQ ID NO: 19. Alternatively or additionally, the anti-BCMA CAR comprises a VL having the amino acid sequence of SEQ ID NO: 10.

[0260] In some embodiments, the anti-BCMA CAR comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 19. Alternatively or additionally, the anti-BCMA CAR comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 10.

[0261] In some embodiments, the anti-BCMA CAR comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 19. Alternatively or additionally, the anti-BCMA CAR comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 10.

[0262] In some embodiments, the anti-BCMA CAR comprises a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of SEQ ID NO: 21. Alternatively or additionally, the anti-BCMA CAR comprises a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of SEQ ID NO: 22.

[0263] In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH3 having the amino acid sequence of SEQ ID NO: 33. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 31, a CDRH2 having the amino acid sequence of SEQ ID NO: 32, and a CDRH3 having the amino acid sequence of SEQ ID NO: 33. In some embodiments, according to the Kabat definition system, the anti-BCMA CAR comprises a CDRH1 having the amino acid sequence of SEQ ID NO: 31, a CDRH2 having the amino acid sequence of SEQ ID NO: 32, a CDRH3 having the amino acid sequence of SEQ ID NO: 33, a CDRL1 having the amino acid sequence of SEQ ID NO: 34, a CDRL2 having the amino acid sequence of SEQ ID NO: 35, and a CDRL3 having the amino acid sequence of SEQ ID NO: 36.

[0264] In some embodiments, an anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that collectively comprise no more than five amino acid mutations (e.g. no more than five, four, three, two, or one amino acid mutations) compared to CDRH1 having the amino acid sequence of SEQ ID NO: 31, CDRH2 having the amino acid sequence of SEQ ID NO: 32, and CDRH3 having the amino acid sequence of SEQ ID NO: 33. Alternatively or additionally, an anti-BCMA CAR comprises CDRL1, CDRL2, and CDRL3 that collectively comprise no more than five amino acid mutations (e.g. no more than five, four, three, two, or one amino acid mutations) compared to CDRL1 having the amino acid sequence of SEQ ID NO: 34, CDRL2 having the amino acid sequence of SEQ ID NO: 35, and CDRL3 having the amino acid sequence of SEQ ID NO: 36.

[0265] In some embodiments, the anti-BCMA CAR comprises CDRH1, CDRH2, and CDRH3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRH1 having the amino acid sequence of SEQ ID NO: 31, CDRH2 having the amino acid sequence of SEQ ID NO: 32, and CDRH3 having the amino acid sequence of SEQ ID NO: 33. Alternatively or additionally, the anti-BCMA CAR comprises CDRL1, CDRL2 and CDRL3 that are at least 80% (e.g., at least 80%, at least 85%, 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%) identical to CDRL1 having the amino acid sequence of SEQ ID NO: 34, CDRL2 having the amino acid sequence of SEQ ID NO: 35, and CDRL3 having the amino acid sequence of SEQ ID NO: 36.

[0266] In some embodiments, the anti-BCMA CAR comprises a CDRH1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH1 having the amino acid sequence of SEQ ID NO: 31; a CDRH2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH2 having the amino acid sequence of SEQ ID NO: 32; and / or a CDRH3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRH3 having the amino acid sequence of SEQ ID NO: 33. Alternatively or additionally, the anti-BCMA CAR comprises a CDRL1 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL1 having the amino acid sequence of SEQ ID NO: 34, a CDRL2 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL2 having the amino acid sequence of SEQ ID NO: 35, and / or a CDRL3 having three or fewer amino acid mutations (e.g., three, two, or one or fewer amino acid mutations) compared to a CDRL3 having the amino acid sequence of SEQ ID NO: 36.

[0267] In some embodiments, the anti-BCMA CAR comprises a VH having the amino acid sequence of SEQ ID NO: 21. Alternatively or additionally, the anti-BCMA CAR comprises a VL having the amino acid sequence of SEQ ID NO: 22.

[0268] In some embodiments, the anti-BCMA CAR comprises a VH that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VH set forth in SEQ ID NO: 21. Alternatively or additionally, the anti-BCMA CAR comprises a VL that contains 20 or fewer amino acid mutations (e.g., no more than 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid mutations) compared to the VL set forth in SEQ ID NO: 22.

[0269] In some embodiments, the anti-BCMA CAR comprises a VH having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH set forth in SEQ ID NO: 21. Alternatively or additionally, the anti-BCMA CAR comprises a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VL set forth in SEQ ID NO: 22.

[0270] The anti-BCMA antibodies or antigen-binding fragments thereof described herein can be grafted into chimeric antigen receptors, including, but not limited to, antigen-binding fragments thereof (e.g., Fab, F(ab'), F(ab')2, Fv), single chain antibodies (e.g., scFv), bispecific antibodies, or nanobodies. In some embodiments, the anti-BCMA CARs described herein comprise a single chain variable fragment (scFv) as the extracellular ligand-binding domain.

[0271] In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain comprising a single-chain variable fragment (scFv). In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain comprising the VH and VL of any one of the anti-BCMA scFvs selected from Table 3. In some embodiments, the VH and VL of the anti-BCMA CAR are joined together by a linker. In some embodiments, the linker can be about 2-10 amino acids, 5-20 amino acids, 10-30 amino acids, 20-50 amino acids, 40-60 amino acids, 60-80 amino acids, or more than 80 amino acids in length. In some embodiments, the linker may comprise a sequence substantially comprising glycine and serine. An exemplary linker sequence is GGGGSGGGGSGGGAS (SEQ ID NO: 81). In some embodiments, linkers may include, but are not limited to, those contained in U.S. Patent Nos. 8,445,251 and 9,434,931. In some embodiments, the anti-BCMA CAR comprises a linker between the VH and VL, wherein the linker comprises an amino acid sequence that is at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO:81.

[0272] In some embodiments, the anti-BCMA CAR comprises an extracellular ligand binding domain having an scFv comprising a VH and a VL, wherein the C-terminus of the VH is joined to the N-terminus of the VL via a linker (e.g., the linker set forth in SEQ ID NO: 81). In some embodiments, the anti-BCMA CAR comprises an extracellular ligand binding domain having an scFv comprising a VH and a VL, wherein the C-terminus of the VL is joined to the N-terminus of the VH via a linker (e.g., the linker set forth in SEQ ID NO: 81).

[0273] In some embodiments, the anti-BCMA CAR comprises an extracellular ligand binding domain having an scFv comprising a VH that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH of any of the anti-BCMA antibodies listed in Table 3. Alternatively or additionally, the anti-BCMA CAR comprises an extracellular ligand binding domain having an scFv comprising a VL that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the VH of any of the anti-BCMA antibodies listed in Table 3. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand binding domain having an scFv that comprises a VH with an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH of any of the anti-BCMA antibodies listed in Table 3. Alternatively or additionally, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising a VL having an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the VH of any of the anti-BCMA antibodies listed in Table 3.

[0274] In some embodiments, the anti-BCMA CAR comprises an extracellular ligand binding domain having an scFv comprising an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to any of the anti-BCMA scFvs listed in Table 3. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand binding domain having an scFv comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to any of the anti-BCMA scFvs listed in Table 3.

[0275] In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-scFv amino acid sequence set forth in SEQ ID NO: 9. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising the amino acid sequence of SEQ ID NO:9.

[0276] In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-scFv amino acid sequence set forth in SEQ ID NO: 11. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising the amino acid sequence of SEQ ID NO:11.

[0277] In some embodiments, the anti-BCMA scFv comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv that comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-scFv amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising the amino acid sequence of SEQ ID NO: 14.

[0278] In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-scFv amino acid sequence set forth in SEQ ID NO: 16. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising the amino acid sequence of SEQ ID NO: 16.

[0279] In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-scFv amino acid sequence set forth in SEQ ID NO: 17. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising the amino acid sequence of SEQ ID NO: 17.

[0280] In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-scFv amino acid sequence set forth in SEQ ID NO: 18. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising the amino acid sequence of SEQ ID NO: 18.

[0281] In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-scFv amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising the amino acid sequence of SEQ ID NO: 20.

[0282] In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the scFv amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-scFv amino acid sequence set forth in SEQ ID NO: 23. In some embodiments, the anti-BCMA CAR comprises an extracellular ligand-binding domain having an scFv comprising the amino acid sequence of SEQ ID NO: 23.

[0283] In some embodiments, the anti-BCMA CAR further comprises a hinge sequence. In some embodiments, the hinge region is a CD8 hinge region. An exemplary amino acid sequence of a CD8 hinge region is set forth below in SEQ ID NO: 82. TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD

[0284] In some embodiments, the anti-BCMA CAR comprises a CD8 hinge region having the amino acid sequence set forth in SEQ ID NO: 82, or a variant thereof. In some embodiments, the anti-BCMA CAR comprises a hinge region having an amino acid sequence that is at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 82. In some embodiments, the hinge region can be any suitable hinge region known in the art, such as the hinge region described in Guedan et al., Engineering and Design of Chimeric Antigen Receptors, Mol Ther Methods Clin Dev. 2019 Mar 15;12:145-156, for example, a hinge region derived from IgG1, IgG2, IgG4, CD28, CD8, or a hybrid thereof.

[0285] In some embodiments, the anti-BCMA CAR further comprises a transmembrane domain linking the extracellular ligand-binding domain with the intracellular signaling and costimulatory domain. Regarding the transmembrane domain, the CAR can be designed to include a transmembrane domain fused to the extracellular domain (e.g., the antigen-binding domain) of the CAR. As long as the domain is capable of anchoring the CAR containing the domain to the cell membrane, any transmembrane domain is contemplated for use herein. In some embodiments, a transmembrane domain that naturally associates with one of the domains in the CAR is used. In some cases, the transmembrane domain may be selected or modified by amino acid substitution to avoid binding of such domain to the transmembrane domain of the same or a different surface membrane protein and minimize interaction with other members of the receptor complex. Those skilled in the art will appreciate that a complete transmembrane domain or a portion thereof may be implemented using a cytoplasmic domain or a portion thereof. The transmembrane domain may be derived from either natural or synthetic sources. If the source is natural, the domain may be derived from any membrane-bound or transmembrane protein. In some embodiments, the transmembrane domain may be synthetic, in which case it comprises primarily hydrophobic residues such as leucine and valine. Preferably, a triplet of phenylalanine, tryptophan, and valine is found at each end of the synthetic transmembrane domain. Optionally, a short oligo- or polypeptide linker, preferably 2-10 amino acids in length, may form the bond between the transmembrane domain and the cytoplasmic signaling domain of the CAR. A glycine-serine doublet provides a particularly suitable linker.

[0286] In some embodiments, the transmembrane domain is a CD8 transmembrane domain. An exemplary amino acid sequence of a CD8 transmembrane domain is set forth below in SEQ ID NO:83. IYIWAPLAGTCGVLLLSLVITLYC

[0287] In some embodiments, the anti-BCMA CAR comprises a CD8 transmembrane domain having the amino acid sequence set forth in SEQ ID NO: 83, or a variant thereof. In some embodiments, the anti-BCMA CAR comprises a transmembrane domain having an amino acid sequence that is at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 83. In some embodiments, the transmembrane domain can be any suitable transmembrane domain known in the art, for example, a transmembrane domain derived from TCRα, TCRβ, TCRζ, CD3ζ, CD3ε, CD3γ, CD3δ, CD4, CD5, CD8, CD9, CD16, CD22, CD28, CD32, CD33, CD34, CD37, CD45, CD64, CD80, CD86, CD134, CD137, CD154, or inducible T-cell costelia (ICOS). However, transmembrane domains are contemplated for use herein, so long as the domain is capable of anchoring a CAR, including the extracellular domain, to a cell membrane. Transmembrane domains can be identified using any method known in the art or described herein, for example, by using the UniProt database.

[0288] In some embodiments, the anti-BCMA CAR further comprises an intracellular (or cytoplasmic) domain. In some embodiments, the intracellular domain of the CAR is responsible for activating at least one of the normal effector functions of the immune cell in which the CAR is placed. The term "effector function" refers to a specialized function of a cell (e.g., an iNKT cell). The effector function of a cell (e.g., an iNKT cell) may be, for example, cytolytic activity or helper activity, including cytokine secretion. Thus, the term "intracellular signaling domain" refers to a portion of a protein that transmits an effector function signal and instructs the cell to perform a specialized function. Typically, the entire intracellular signaling domain can be used, but in many cases, it is not necessary to use the entire domain. To the extent that a truncated portion of the intracellular signaling domain is used, such a truncated portion may be used in place of the intact domain, so long as it transmits the effector function signal. Thus, the term intracellular signaling domain is meant to include any truncated portion of the intracellular signaling domain sufficient to transmit the effector function signal. In certain embodiments, the intracellular (or cytoplasmic) domain of the chimeric antigen receptor disclosed herein may include, but is not limited to, a 4-1bb intracellular domain, an OX40 intracellular domain, a CD30 intracellular domain, a CD40 intracellular domain, an ICOS intracellular domain, an LFA-1 intracellular domain, a CD2 intracellular domain, a CD3ζ intracellular domain, a CD3γ intracellular domain, a CD3δ intracellular domain, a CD3ε intracellular domain, and a CD7 intracellular domain, as well as a CD22 intracellular domain. In some embodiments, an anti-BCMA CAR comprises a CD3ζ intracellular domain. An exemplary amino acid sequence of a CD3ζ intracellular domain is set forth below in SEQ ID NO:84. RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

[0289] In some embodiments, the anti-BCMA CAR comprises a CD3 intracellular domain having the amino acid sequence set forth in SEQ ID NO: 84, or a variant thereof. In some embodiments, the anti-BCMA CAR comprises an intracellular domain having an amino acid sequence that is at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 84.

[0290] In some embodiments, the intracellular domain further comprises one or more intracellular costimulatory domains, such as those described herein, that transduce costimulatory signals that promote cell proliferation, cell survival, and / or cytokine secretion after binding of the extracellular domain. In some embodiments, such intracellular costimulatory domains include, but are not limited to, any costimulatory domain disclosed herein or known in the art, including, but not limited to, CD28, ICOS, 4-1BB, OX40, or CD27. In some embodiments, the anti-BCMA CAR comprises a 4-1BB costimulatory domain. An exemplary amino acid sequence of a 4-1BB costimulatory domain is set forth below in SEQ ID NO:85. KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL

[0291] In some embodiments, the anti-BCMA CAR comprises a 4-1BB costimulatory domain having the amino acid sequence set forth in SEQ ID NO: 85, or a variant thereof. In some embodiments, the anti-BCMA CAR comprises a 4-1BB costimulatory domain having an amino acid sequence that is at least 70%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 85.

[0292] The intracellular signaling domain of the chimeric antigen receptor of the present disclosure is responsible for activating at least one of the normal effector functions and / or proliferation and cell survival pathways of the cell in which the CAR is placed.

[0293] It is understood that the chimeric antigen receptors disclosed herein can include domains having the sequences disclosed herein (e.g., extracellular domains, transmembrane domains, intracellular (cytoplasmic) domains, costimulatory domains, signaling domains, or any combination thereof), or variants thereof, or fragments of any one or more of the domains disclosed herein (e.g., variants and / or fragments that retain functions necessary for chimeric antigen receptor activity).

[0294] In some embodiments, exemplary anti-BCMA CAR amino acid sequences are shown in Table 4. [Table 4] JPEG2025542567000012.jpg254160JPEG2025542567000013.jpg254160JPEG2025542567000014.jpg156159

[0295] In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 86. In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 86. In some embodiments, the anti-BCMA CAR comprises the amino acid sequence of SEQ ID NO:86.

[0296] In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 87. In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 87. In some embodiments, the anti-BCMA CAR comprises the amino acid sequence of SEQ ID NO: 87.

[0297] In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 88. In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 88. In some embodiments, the anti-BCMA CAR comprises the amino acid sequence of SEQ ID NO: 88.

[0298] In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 89. In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 89. In some embodiments, the anti-BCMA CAR comprises the amino acid sequence of SEQ ID NO: 89.

[0299] In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 90. In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 90. In some embodiments, the anti-BCMA CAR comprises the amino acid sequence of SEQ ID NO: 90.

[0300] In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 91. In some embodiments, the anti-BCMA CAR comprises the amino acid sequence of SEQ ID NO: 91.

[0301] In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the anti-BCMA CAR comprises the amino acid sequence of SEQ ID NO:92.

[0302] In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that contains 20 or fewer amino acid mutations (e.g., 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 or fewer amino acid mutations) compared to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 93. In some embodiments, the anti-BCMA CAR comprises an amino acid sequence that is at least 80% (e.g., at least 80%, at least 85%, 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%) identical to the anti-BCMA CAR amino acid sequence set forth in SEQ ID NO: 93. In some embodiments, the anti-BCMA CAR comprises the amino acid sequence of SEQ ID NO:93.

[0303] III. Genetically modified cells expressing anti-BCMA chimeric antigen receptors and methods for their production The present disclosure also provides genetically modified cells comprising at least one anti-BCMA antibody or antigen-binding fragment thereof, or at least one anti-BCMA CAR disclosed herein.

[0304] In some embodiments, cells can be genetically modified to express any one of the chimeric antigen receptors described herein. In some embodiments, the genetically modified cells described herein are eukaryotic cells. In some embodiments, the genetically modified cells comprising a CAR described herein (e.g., an anti-BCMA CAR) are human cells. In some embodiments, the genetically modified cells comprising a CAR described herein (e.g., an anti-BCMA CAR) are immune cells. In some embodiments, in the genetically modified cells, the CAR (e.g., an anti-BCMA CAR) is an immune cell (e.g., a T cell, such as a cytotoxic T lymphocyte and a regulatory T cell, an NK cell, an NKT cell, such as an invariant NKT cell, a macrophage, a monocyte, a neutrophil, an eosinophil, or any combination thereof). In some embodiments, the genetically modified immune cell is an iNKT cell modified to express one or more of the anti-BCMA CARs described herein.

[0305] In some embodiments, the disclosure provides a population of genetically modified immune cells (e.g., iNKT cells) comprising an anti-BCMA CAR described herein. In some embodiments, the disclosure provides a population of genetically modified immune cells (e.g., iNKT cells) comprising an anti-BCMA CAR having a heavy chain variable domain (VH) CDRH1, CDRH2, and CDRH3 having the amino acid sequence of any one of SEQ ID NOs: 7, 12, 19, or 21, and / or a light chain variable domain (VL) CDRL1, CDRL2, and CDRL3 having the amino acid sequence of any one of SEQ ID NOs: 8, 10, 13, 15, or 22.

[0306] In some embodiments, the disclosure provides populations of genetically modified immune cells (e.g., iNKT cells), the populations comprising: (i) an anti-BCMA CAR comprising a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 5, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6; (ii) an anti-BCMA CAR comprising a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6; and (iii) an anti-BCMA CAR comprising a CDRH1 having the amino acid sequence of SEQ ID NO: 25, a CDRH2 having the amino acid sequence of SEQ ID NO: 27, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 30. (iv) an anti-BCMA CAR comprising a CDRH1 having the amino acid sequence of SEQ ID NO: 25, a CDRH2 having the amino acid sequence of SEQ ID NO: 27, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 29; (v) an anti-BCMA CAR comprising a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 30; and (vi) an anti-BCMA CAR comprising a CDRH1 having the amino acid sequence of SEQ ID NO: 1, a CDRH2 having the amino acid sequence of SEQ ID NO: 2, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 29.a CAR; (vii) an anti-BCMA CAR comprising a CDRH1 having the amino acid sequence of SEQ ID NO: 26, a CDRH2 having the amino acid sequence of SEQ ID NO: 28, a CDRH3 having the amino acid sequence of SEQ ID NO: 3, a CDRL1 having the amino acid sequence of SEQ ID NO: 4, a CDRL2 having the amino acid sequence of SEQ ID NO: 24, and a CDRL3 having the amino acid sequence of SEQ ID NO: 6, or (viii) an anti-BCMA CAR comprising a CDRH1 having the amino acid sequence of SEQ ID NO: 31, a CDRH2 having the amino acid sequence of SEQ ID NO: 32, a CDRH3 having the amino acid sequence of SEQ ID NO: 33, a CDRL1 having the amino acid sequence of SEQ ID NO: 34, a CDRL2 having the amino acid sequence of SEQ ID NO: 35, and a CDRL3 having the amino acid sequence of SEQ ID NO: 36.

[0307] In some embodiments, the present disclosure provides a population of genetically modified immune cells (e.g., iNKT cells), the population comprising: (i) an anti-BCMA CAR comprising a VH having the amino acid sequence of SEQ ID NO: 7 and / or a VL having the amino acid sequence of SEQ ID NO: 8; (ii) an anti-BCMA CAR comprising a VH having the amino acid sequence of SEQ ID NO: 7 and / or a VL having the amino acid sequence of SEQ ID NO: 10; (iii) an anti-BCMA CAR comprising a VH having the amino acid sequence of SEQ ID NO: 12 and / or a VL having the amino acid sequence of SEQ ID NO: 13; (iv) an anti-BCMA CAR comprising a VH having the amino acid sequence of SEQ ID NO: 12 and / or a VL having the amino acid sequence of SEQ ID NO: 15; (v) an anti-BCMA CAR comprising a VH having the amino acid sequence of SEQ ID NO: 7 and / or a VL having the amino acid sequence of SEQ ID NO: 13; and (vi) an anti-BCMA CAR comprising a VH having the amino acid sequence of SEQ ID NO: 7 and / or a VL having the amino acid sequence of SEQ ID NO: 15. and (vii) an anti-BCMA CAR comprising a VH having the amino acid sequence of SEQ ID NO: 19 and / or a VL having the amino acid sequence of SEQ ID NO: 10, or (viii) an anti-BCMA CAR comprising a VH having the amino acid sequence of SEQ ID NO: 21 and / or a VL having the amino acid sequence of SEQ ID NO: 22.

[0308] In some embodiments, the present disclosure provides a population of genetically modified immune cells (e.g., iNKT cells) comprising an anti-BCMA CAR, which comprises an scFv as an extracellular ligand-binding domain comprising the amino acid sequence of any one of SEQ ID NOs: 9, 11, 14, 16, 17, 18, 20, or 23.

[0309] In some embodiments, the present disclosure provides a population of genetically modified immune cells (e.g., iNKT cells) comprising an anti-BCMA CAR, which comprises an scFv as an extracellular ligand-binding domain comprising the amino acid sequence of any one of SEQ ID NOs: 9, 11, 14, 16, 17, 18, 20, or 23.

[0310] In some embodiments, the present disclosure provides a population of genetically modified immune cells (e.g., iNKT cells) comprising an anti-BCMA CAR having the amino acid sequence of any one of SEQ ID NOs: 86-93.

[0311] In some embodiments, the genetically modified cells (e.g., iNKT cells) are armored CAR-expressing cells that have been engineered to express another molecule (e.g., a cytokine or ligand) that can enhance one or more properties of the genetically modified cells (e.g., survival / persistence, immune interactions with other cells such as macrophages and / or dendritic cells, disruption of the immunosuppressive tumor microenvironment). The genetically modified cells (e.g., iNKT cells) can be engineered to express any suitable armor molecule known in the art, for example, those described in Yeku et al., "Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumor efficacy," Biochem Soc Trans. 2016 Apr. 15;44(2):412-418; Hawkins et al., "Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy," Biologics. 2021;15:95-105). Non-limiting examples of armor molecules include IL-15, IL-2, IL-12, CD40L, 4-1BBL, IL-18, IL-7, IL-33, dominant negative TGF-β receptor II (dnTGF-βRII), constitutively active Akt (caAkt), hybrid IL-4 / IL-7 receptor, checkpoint inhibitors such as anti-PD1 antibodies, nanobodies targeting CD47, or bispecific T cell engagers (BiTEs).

[0312] In some embodiments, genetically modified cells expressing a CAR described herein (e.g., an anti-BCMA CAR) are also engineered to express IL-15. In some embodiments, genetically modified cells expressing a CAR described herein (e.g., an anti-BCMA CAR) are also engineered to express secreted IL-15 (sIL-15). The role of IL-15 in enhancing the expansion and function of T cells and natural killer T cells (e.g., iNKT cells) has been previously described (see, e.g., Lin et al., Interleukin-15 enhances the expansion and function of natural killer T cells from adult peripheral and umbilical cord blood, Cytokine. 2015 December;76(2):348-355; Battram et al., IL-15 Enhances the Persistence and Function of BCMA-Targeting CAR-T Cells Compared to IL-2 or IL-15 / IL-7 by Limiting CAR-T Cell Dysfunction and Differentiation; Cancers (Basel). 2021 July;13(14):3534). Numerous cell types, such as macrophages and dendritic cells, have been shown to produce IL-15. Upon release, IL-15 stimulates CD8+ T cells and NK cells, enhancing their proliferation and cytotoxicity. Administration of IL-15 to mice has been shown to enhance the antitumor activity of adoptively transferred CD8+ tumor-reactive T cells, suggesting that IL-15 can promote the antitumor activity of CAR T cell therapy. CAR T cells further engineered to secrete IL-15 have been shown to enhance tumor cytotoxicity in vitro and in vivo compared to CAR-only T cells, and to increase T cell expansion upon antigen recognition in vitro. Furthermore, IL-15 enables T cell persistence after tumor clearance while increasing antigen-independent T cell proliferation.We also found that secretion of IL-15 provided greater protection against tumor reinfection in vivo than CAR T cells that do not secrete IL-15. Certain previous studies have used a membrane-tethered form of IL-15 and found it promotes CAR T cells to express a memory phenotype. These data indicate that IL-15 can enhance CAR T cell function within the tumor microenvironment and provide long-term CAR T cell-mediated immunity against cancer antigens.

[0313] In some embodiments, the present disclosure is based, at least in part, on the discovery of using secreted IL-15 as an "armor molecule" for genetically modified immune cells (e.g., iNKT cells) that express an anti-BCMA CAR. In some embodiments, secreted IL-15 enhances the persistence of genetically modified immune cells (e.g., iNKT cells) in the tumor microenvironment (e.g., relative to the persistence of other modified cells that do not produce armor molecules such as IL-15).

[0314] In some embodiments, the nucleic acid encoding the CAR (such as an anti-BCMA CAR) is a multicistronic vector that encodes the CAR as well as secreted IL-15. An exemplary IL-15 coding sequence is shown below in SEQ ID NO:94. ATGCGGATCTCCAAGCCCCACCTCCGAAGCATCAGTATCCAGTGTTATCTGTGCCTTCTTCTGAATTCCCATTTTTTGACAGAGGCAGGAATTCATGTATTCATATTGGGTTGTTTCTCCGCGGGCTTCCTAAAACCGAAGCTAACTGGGTTAATGTCATTTCAGATCTGAAGAAAATTGAAGATCTTATTCAATCAATGCATATCGACGCGACCTTGTACACGGAGAGTGATGTCCACCCG AGCTGCAAGGTAACGGCCATGAAATGCTTCTTGCTGGAATTGCAGGTAATTAGTCTTGAGAGTGGAGATGCGTCTATACACGACACCGTAGAGAATCTCATTATTTTGGCGAACAATTCTCTCAGCAGTAACGGCAATGTTACTGAATCAGGATGTAAGGAGTGTGAAGAGCTGGAAGAAAAGAACATTAAGGAATTTTTGCAGAGCTTCGTACATATCGTCCAAATGTTCATAAATACAAGC

[0315] In some embodiments, the nucleic acid encoding the CAR further comprises a nucleic acid sequence that is at least 60%, at least 70%, at least 75%, at least 80%, at least 85%, 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% identical to the amino acid sequence of SEQ ID NO:94.

[0316] In some embodiments, the multicistronic vector comprises two or more expression cassettes encoding one or more anti-BCMA CARs and sIL-15.

[0317] In some embodiments, the multicistronic expression construct comprises expression cassettes arranged in various ways. For example, in some embodiments, multicistronic expression constructs are provided in which a first expression cassette (e.g., an expression cassette encoding an anti-BCMA CAR, or a portion thereof) is arranged adjacent to a second expression cassette (e.g., an expression cassette encoding sIL-15). In some embodiments, the first expression cassette (e.g., an expression cassette encoding an anti-BCMA CAR, or a portion thereof) is arranged 5' to the second expression cassette (e.g., an expression cassette encoding sIL-15). For example, in some embodiments, the first expression cassette (e.g., an expression cassette encoding an anti-BCMA CAR, or a portion thereof) is arranged 3' to the second expression cassette (e.g., an expression cassette encoding sIL-15). Multicistronic vectors have been previously described, for example, in Shaimardanova et al., Production and Application of Multicistronic Constructs for Various Human Disease Therapies, Pharmaceuticals 2019, 11, 580. In some embodiments, the multicistor vector comprises a nucleic acid sequence encoding a self-cleaving 2A peptide between a first expression cassette (e.g., an expression cassette encoding an anti-BCMA CAR, or a portion thereof) and a second expression cassette (e.g., an expression cassette encoding sIL-15). In some embodiments, the self-cleaving 2A peptide is a P2A peptide. In some embodiments, the self-cleaving 2A peptide is a T2A peptide. In some embodiments, the multicistor vector comprises a nucleic acid sequence encoding an internal ribosome entry site (IRES) between the first expression cassette (e.g., an expression cassette encoding an anti-BCMA CAR, or a portion thereof) and a second expression cassette (e.g., an expression cassette encoding sIL-15).

[0318] In some embodiments, a nucleic acid sequence encoding sIL-15 (e.g., the sIL-15 coding sequence set forth in SEQ ID NO: 94) is delivered to the cells in a separate construct from the construct encoding the CAR. In some embodiments, the cells already expressed secreted IL-15 (e.g., engineered to express sIL-15) prior to receiving the nucleic acid construct encoding the CAR (e.g., an anti-BCMA CAR).

[0319] Also provided herein are cells (e.g., iNKT cells) comprising a nucleic acid molecule encoding a chimeric antigen receptor disclosed herein. In some embodiments, the nucleic acid molecule encoding a CAR (e.g., an anti-BCMA CAR) described herein is present within (i.e., integrated into) the genome of the genetically modified cell, or alternatively, is not integrated into the genome of the cell. In some embodiments, when the nucleic acid molecule encoding the CAR (e.g., an anti-BCMA CAR) is not integrated into the genome, the nucleic acid molecule is present in the genetically modified cell within a recombinant DNA construct, within mRNA, within a viral genome, or within another nucleic acid that is not integrated into the genome of the cell.

[0320] In one embodiment, the genetically modified cell (e.g., iNKT cell) contains a nucleic acid molecule encoding a chimeric antigen receptor (e.g., an anti-BCMA CAR) disclosed herein located within the genome of the cell. In other embodiments, the genetically modified cell (e.g., iNKT cell) contains a nucleic acid molecule encoding a chimeric antigen receptor (e.g., an anti-BCMA CAR) disclosed herein located within the endogenous T cell receptor alpha gene of the cell.

[0321] In some embodiments, the present invention includes an isolated nucleic acid comprising the sequence of a CAR (e.g., an anti-BCMA CAR), the sequence comprising a nucleic acid sequence of an extracellular ligand-binding domain operably linked to a nucleic acid sequence of a transmembrane domain and a cytoplasmic domain. Nucleic acid sequences encoding the desired molecule can be obtained using standard techniques, such as by screening libraries from cells expressing the gene, by deriving from a vector known to contain the gene, or by directly isolating from cells and tissues containing them, using recombinant methods known in the art. Alternatively, the gene of interest can be produced synthetically rather than cloned. The present invention also provides vectors into which the DNA of the present invention is inserted. Vectors derived from retroviruses, such as lentiviruses, are suitable tools for achieving long-term gene transfer because they allow long-term, stable integration of the transgene and its propagation in daughter cells. Lentiviral vectors have the additional advantage over vectors derived from oncoretroviruses, such as murine leukemia viruses, in that they can transduce non-proliferating cells, such as hepatocytes. They also have the additional advantage of low immunogenicity. In another embodiment, the desired CAR can be expressed in cells by a transposon.

[0322] Briefly, expression of a natural or synthetic nucleic acid encoding a CAR is typically achieved by operably linking a nucleic acid encoding a CAR polypeptide (e.g., an anti-BCMA CAR), or a portion thereof, to a promoter and incorporating the construct into an expression vector (e.g., a lentiviral vector). The vector is suitable for replication and integration into eukaryotes. Typical cloning vectors contain transcription and translation terminators, initiation sequences, and promoters useful for regulating expression of the desired nucleic acid sequence. The expression vectors of the present disclosure can also be used for nucleic acid immunization and gene therapy using standard gene delivery protocols. Methods for gene delivery are known in the art. See, e.g., U.S. Patent Nos. 5,399,346, 5,580,859, and 5,589,466, which are incorporated herein in their entireties.

[0323] Nucleic acids can be cloned into several types of vectors, including, but not limited to, plasmids, viral vectors, phagemids, phage derivatives, animal viruses, and cosmids. Vectors of particular interest include expression vectors, replication vectors, probe generation vectors, and sequencing vectors.

[0324] Furthermore, the expression vector can be provided to cells in the form of a viral vector. Viral vector technology is well known in the art and is described, for example, in Sambrook et al. (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York) and other virology and molecular biology manuals. Viruses useful as vectors include, but are not limited to, retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, and lentiviruses. In general, a suitable vector contains a functional origin of replication in at least one organism, a promoter sequence, an appropriate restriction endonuclease site, and one or more selectable markers (e.g., WO01 / 96584, WO01 / 29058, and U.S. Patent No. 6,326,193).

[0325] Many virus-based systems have been developed for gene transfer into mammalian cells.For example, lentivirus provides a convenient platform for gene delivery system.Selected gene can be inserted into vector and packaged into lentiviral particles using techniques known in the art.Then, recombinant virus can be isolated and delivered to target cells either in vivo or ex vivo.Several lentiviral systems are known in the art.

[0326] In some embodiments, the vectors described herein further comprise a promoter operably linked to the nucleic acid encoding a CAR (e.g., an anti-BCMA CAR) described herein. Non-limiting examples of suitable promoters include the cytomegalovirus (CMV) promoter, the elongation factor-1 alpha (EF-1α) promoter, the simian virus 40 (SV40) early promoter, the mouse mammary tumor virus (MMTV), the human immunodeficiency virus (HIV) long terminal repeat (LTR) promoter, the MoMuLV promoter, the avian leukosis virus promoter, the Epstein-Barr virus immediate early promoter, the Rous sarcoma virus promoter, and human gene promoters such as, but not limited to, the actin promoter, the myosin promoter, the hemoglobin promoter, and the creatine kinase promoter. In some embodiments, the promoter is the EF-1α promoter. Additionally, the present disclosure also contemplates the use of inducible promoters. The use of inducible promoters provides a molecular switch that can turn on expression of an operably linked polynucleotide sequence when such expression is desired or turn off expression when expression is not desired. Examples of inducible promoters include, but are not limited to, metallothionine promoters, glucocorticoid promoters, progesterone promoters, and tetracycline promoters.

[0327] To assess the expression of a CAR polypeptide or a portion thereof, the expression vector introduced into the cells can also contain either a selectable marker gene or a reporter gene, or both, to facilitate the identification and selection of expressing cells from a population of cells subjected to transfection or infection via a viral vector. In other aspects, the selectable marker can be carried on a separate piece of DNA and used in a co-transfection procedure. Both the selectable marker and the reporter gene can be flanked by appropriate regulatory sequences to enable expression in the host cell. Useful selectable markers include, for example, antibiotic resistance genes, such as the kanamycin resistance gene, and fluorescent genes, such as GFP, YFP, and RFP. In some embodiments, the reporter gene or selectable marker gene is omitted from the CAR polypeptide used in the treatments described herein.

[0328] Methods for introducing and expressing genes into cells are known in the art. In the context of expression vectors, vectors can be easily introduced into host cells, such as mammalian, bacterial, yeast, or insect cells, by any method in the art. For example, expression vectors can be introduced into host cells by physical, chemical, or biological means. Physical methods for introducing polynucleotides into host cells include calcium phosphate precipitation, lipofection, particle bombardment, microinjection, electroporation, etc. Methods for producing cells containing vectors and / or exogenous nucleic acids are well known in the art. See, for example, Sambrook et al. (2001, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory, New York). A preferred method for introducing polynucleotides into host cells is calcium phosphate transfection. Biological methods for introducing a polynucleotide of interest into host cells include the use of DNA and RNA vectors. Viral vectors, and particularly retroviral vectors, have become the most widely used method for inserting genes into mammalian, e.g., human, cells. Other viral vectors can be derived from lentiviruses, poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, etc. See, e.g., U.S. Patent Nos. 5,350,674 and 5,585,362.

[0329] Chemical means for introducing polynucleotides into host cells include colloidal dispersion systems such as macromolecular complexes, nanocapsules, microspheres, beads, and lipid 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., artificial membrane vesicle). When a non-viral delivery system is used, an exemplary delivery vehicle is a liposome. The use of lipid formulations is contemplated for the introduction of nucleic acids into host cells (in vitro, ex vivo, or in vivo). In another embodiment, the nucleic acid can be associated with a lipid. Lipid-associated nucleic acids may be encapsulated within the aqueous interior of liposomes, interspersed within the lipid bilayer of liposomes, attached to liposomes via a linking molecule associated with both the liposome and the oligonucleotide, entrapped within liposomes, complexed with liposomes, dispersed in a solution containing lipids, mixed with lipids, combined with lipids, contained as a suspension in lipids, contained in micelles, complexed with micelles, or otherwise associated with lipids. Lipid, lipid / DNA, or lipid / expression vector-associated compositions are not limited to any particular structure in solution. For example, they may exist as bilayer structures, micelles, or in "collapsed" structures. They may also simply be interspersed in solution, or in some cases, form aggregates that are not uniform in size or shape. Lipids are fatty substances that can be naturally occurring or synthetic lipids. For example, lipids include the fatty droplets that occur naturally in the cytoplasm, as well as a class of compounds that contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, aminoalcohols, and aldehydes.

[0330] Regardless of the method used to introduce exogenous nucleic acid into host cells or otherwise expose cells to inhibitors of the present invention, various assays can be performed to confirm the presence of the recombinant DNA sequence within the host cells. Such assays include "molecular biological" assays well known to those of skill in the art, such as Southern blotting, Northern blotting, RT-PCR, and PCR, as well as "biochemical" assays, such as immunological means (ELISAs and Western blots) or the assays described herein to detect the presence or absence of specific peptides to identify agents within the scope of the present invention.

[0331] In some embodiments, the nucleic acid sequences encoding the anti-BCMA antibody or antigen-binding fragment thereof, BCMA CAR, and lentiviral vector sequences are shown in Table 5. [Table 5] JPEG2025542567000016.jpg254168JPEG2025542567000017.jpg254168JPEG2025542567000018.jpg254168JPEG2025542567000019.jpg254168JPEG2025542567000020.jpg254168JPEG2025542567000021.jpg254168JPEG2025542567000022.jpg254168JPEG2025542567000023.jpg254168JPEG2025542567000024.jpg254168JPEG2025542567000025.jpg254168JPEG2025542567000026.jpg254168JPEG2025542567000027.jpg254168JPEG2025542567000028.jpg254168JPEG2025542567000029.jpg254168JPEG2025542567000030.jpg254168JPEG2025542567000031.jpg254168JPEG2025542567000032.jpg254168JPEG2025542567000033.jpg254168JPEG2025542567000034.jpg254168JPEG2025542567000035.jpg254168JPEG2025542567000036.jpg254168JPEG2025542567000037.jpg254168JPEG2025542567000038.jpg254168JPEG2025542567000039.jpg254168JPEG2025542567000040.jpg254168JPEG2025542567000041.jpg254168JPEG2025542567000042.jpg254168JPEG2025542567000043.jpg254168JPEG2025542567000044.jpg254168JPEG2025542567000045.jpg254168JPEG2025542567000046.jpg254168JPEG2025542567000047.jpg254168JPEG2025542567000048.jpg254168JPEG2025542567000049.jpg254168JPEG2025542567000050.jpg254168JPEG2025542567000051.jpg254168JPEG2025542567000052.jpg254168JPEG2025542567000053.jpg254168JPEG2025542567000054.jpg254168JPEG2025542567000055.jpg254168JPEG2025542567000056.jpg254168JPEG2025542567000057.jpg254168JPEG2025542567000058.jpg254168JPEG2025542567000059.jpg254168JPEG2025542567000060.jpg254168JPEG2025542567000061.jpg254168JPEG2025542567000062.jpg254168JPEG2025542567000063.jpg254168JPEG2025542567000064.jpg254168JPEG2025542567000065.jpg254168JPEG2025542567000066.jpg254168JPEG2025542567000067.jpg254168JPEG2025542567000068.jpg254168JPEG2025542567000069.jpg254168JPEG2025542567000070.jpg254168JPEG2025542567000071.jpg254168JPEG2025542567000072.jpg254168JPEG2025542567000073.jpg254168JPEG2025542567000074.jpg254168JPEG2025542567000075.jpg254168JPEG2025542567000076.jpg254168JPEG2025542567000077.jpg254168JPEG2025542567000078.jpg254168JPEG2025542567000079.jpg254168JPEG2025542567000080.jpg254168JPEG2025542567000081.jpg254168JPEG2025542567000082.jpg254168JPEG2025542567000083.jpg254168JPEG2025542567000084.jp g254168JPEG2025542567000085.jpg254168JPEG2025542567000086.jpg254168JPEG2025542567000087.jpg2 54168JPEG2025542567000088.jpg254168JPEG2025542567000089.jpg254168JPEG2025542567000090.jpg254 168JPEG2025542567000091.jpg254168JPEG2025542567000092.jpg254168JPEG2025542567000093.jpg53166.

[0332] In some embodiments, single chain antibodies (e.g., anti-BCMA scFvs) can be prepared via recombinant techniques by linking a nucleotide sequence encoding a heavy chain variable region with a nucleotide sequence encoding a light chain variable region, preferably incorporating a flexible linker between the two variable regions.

[0333] In some embodiments, the anti-BCMA antibody or antigen-binding fragment thereof comprises (i) a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 49 and / or a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 57; (ii) a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 57; 50, and / or a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 58; (iii) a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 51; %, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 59, and / or a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 59; (iv) a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 52; 60%, (v) nucleic acids that are at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 60; (vi) nucleic acids that are at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 53; and / or nucleic acids that are at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 61;(vi) a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 54, and / or is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 62; (vii) a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 55; 63, and / or a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 63, or (viii) a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 56. 5%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to a nucleic acid and / or a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 64.

[0334] In some embodiments, the anti-BCMA scFv is produced by expressing a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to any one of SEQ ID NOs: 66-72.

[0335] In some embodiments, the anti-BCMA CAR is expressed by a cell (e.g., an iNKT cell) by delivering to the cell a nucleic acid that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to any one of SEQ ID NOs: 95-102.

[0336] In some embodiments, the present disclosure also provides a vector (e.g., a lentiviral vector) for expressing an anti-BCMA CAR in a cell (e.g., an iNKT cell). In some embodiments, the lentiviral vector comprises a nucleic acid sequence that is at least 60% (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%) identical to any one of SEQ ID NOs: 73-80.

[0337] In some aspects, the present disclosure also provides methods for preparing a population of immune cells (e.g., iNKT cells) that express a CAR (e.g., an anti-BCMA CAR). The initial population of immune cells can be obtained from any source, such as peripheral blood mononuclear cells (PBMCs), bone marrow, or tissue such as the spleen, lymph nodes, thymus, or tumor tissue. Suitable sources for obtaining the desired type of cells will be apparent to one of skill in the art. In some embodiments, the population of immune cells (e.g., iNKT cells) is derived from PBMCs. In some embodiments, a blood sample or apheresis is taken from a generally healthy subject. In some embodiments, a blood sample or apheresis is taken from a generally healthy subject who is at risk of developing a disease but has not yet developed the disease, and the cells of interest are isolated and frozen for later use. In some embodiments, the iNKT cells may be expanded, frozen, and used at a later time. In certain embodiments, the sample is collected from the patient shortly after diagnosis of a particular disease, prior to treatment, as described herein. In further embodiments, the cells are isolated from a blood sample or apheresis from the subject prior to any number of relevant therapies, including, but not limited to, treatment with drugs such as natalizumab, efalizumab, antivirals, chemotherapy, radiation therapy, and immunosuppressants such as cyclosporine, azathioprine, methotrexate, mycophenolic acid, FK506, antibodies, or other immunoablative agents such as CAMPATH®, anti-CD3 antibodies, cytoxan, fludarabine, cyclosporine, FK506, rapamycin, mycophenolic acid, steroids, FR901228, and radiation therapy. These drugs inhibit the calcium-dependent phosphatase calcineurin (cyclosporine and FK506) or inhibit p70S6 kinase, which is important in growth factor-induced signal transduction (rapamycin) (Liu et al., Cell 66:807-815, 1991; Henderson et al., Immun. 73:316-321, 1991; Bierer et al., Curr. Opin. Immun. 5:763-773, 1993).In further embodiments, cells are isolated for a patient and frozen for later use in combination with (e.g., before, simultaneously with, or after) T cell ablative therapy using either bone marrow or stem cell transplant, chemotherapy agents such as fludarabine, external beam radiation therapy (XRT), cyclophosphamide, or antibodies such as OKT3 or CAMPATH®. In some embodiments, blood samples or apheresis are taken from healthy donors, and iNKT cells isolated from third-party healthy donors are "ready to use," as described, for example, in Li et al., Off-the-shelf third-party HSC-engineered iNKT cells for ameliorating GvHD while preserving GvL effect in the treatment of blood cancers, iScience. 2022 Sep 16;25(9):104859.

[0338] In some embodiments, the initial population of iNKT cells is purified from PBMCs using any suitable method known in the art (e.g., FACS or MACS). In some embodiments, the initial population of iNKT cells is stimulated with α-galactosylceramide (α-Galcer) or any modified glycolipid thereof, as described in Zhang et al., α-Galcer and iNKT Cell-Based Cancer Immunotherapy: Realizing the Therapeutic Potentials, Front Immunol. 2019 Jun 6; 10:1126; Schafer et al., iNKT cell stimulation by glycolipid ligands modified from α-galactosylceramide results in differential interleukin-2 secretion profiles, J Immunol May 1, 2019, 202(1 Supplement) 177.1) for activation and expansion. In some embodiments, iNKT cells are transduced with any one of the lentiviral vectors described herein to express an anti-BCMA CAR (e.g., any one of the anti-BCMA CARs described herein). In some embodiments, after transduction, more than 1%, more than 2%, more than 5%, more than 8%, more than 10%, more than 12%, or more than 15%, more than 18%, more than 20%, more than 22%, more than 25%, more than 28%, or more than 30% of the iNKT cells express the anti-BCMA CAR. In some embodiments, after transduction, the iNKT cells are further stimulated and expanded. In some embodiments, the further stimulation and expansion comprises stimulating the iNKT cells expressing the anti-BCMA CAR with feeders carrying BCMA.The feeder can be any suitable feeder cell known in the art, for example, a feeder cell or a cell-derived membrane vesicle (Ukrainskaya et al., Antigen-Specific Stimulation and Expansion of CAR-T Cells Using Membrane Vesicles as Target Cell Surrogates, Small. 2021 Nov;17(45):e2102643). In some embodiments, the feeder is a feeder cell (e.g., K562 feeder cell, major histocompatibility complex class I chain-related protein A (MICA) feeder cell, or membrane-bound IL-21 human B lymphoblastoid cell line 721.221 (hereinafter 221)-based feeder (221-mIL-21) cell). In some embodiments, the feeder cell is a K562 feeder cell. Expansion of NK cells using genetically engineered K562 feeder cells has been previously described, see, e.g., Phan et al., Expansion of NK Cells Using Genetically Engineered K562 Feeder Cells, Natural Killer Cells pp 167-174. In some embodiments, the K562 cells are transfected with anti-BCMA The engineered K562 cells are irradiated prior to co-culture with CAR-expressing iNKT cells. In some embodiments, the engineered K562 cells express BCMA on the cell surface. In some embodiments, after co-culture with feeder cells, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 92%, at least 95%, at least 98%, at least 99% or more of the iNKT cells express the anti-BCMA CAR.

[0339] IV. Therapeutic uses In some embodiments, the present disclosure includes cells (e.g., iNKT cells) modified to express a CAR that combines an antigen recognition domain (e.g., an anti-BCMA scFv), a transmembrane domain (e.g., a CD8 transmembrane domain), and a cytoplasmic domain (e.g., the intracellular domain of CD3-zeta, CD28, OX40, 4-1BB, or any combination thereof). Thus, in some embodiments, the introduced immune cells (e.g., iNKT cells) elicit a CAR-mediated immune response (e.g., a T cell response) and / or an innate immune response (e.g., an NK cell response) in a subject. In some embodiments, the present disclosure provides for the use of a CAR to redirect the specificity of primary iNKT cells to a tumor antigen. Thus, in some embodiments, the present invention also provides a method for stimulating an iNKT cell-mediated immune response against a target cell population or tissue in a mammal, the method comprising administering to the mammal a plurality of iNKT cells expressing a CAR (e.g., an anti-BCMA CAR), wherein the CAR comprises a binding moiety that specifically interacts with a predetermined target (e.g., BCMA), e.g., a zeta chain moiety comprising the intracellular domain of human CD3 zeta, and a costimulatory signaling region. In some embodiments, the present disclosure includes a type of cell therapy in which iNKT cells are genetically modified to express a CAR, and the iNKT cells expressing the CAR (e.g., an anti-BCMA CAR) are infused into a recipient in need thereof. The infused cells can kill tumor cells in the recipient. Unlike antibody therapy, CAR iNKT cells can replicate in vivo, allowing for long-term persistence that can result in sustained tumor control. In some embodiments, unlike CAR T therapy, subjects receiving an iNKT cell composition do not receive lymph node transplantation prior to receiving the iNKT cells.

[0340] In some embodiments, the present disclosure provides cells (e.g., iNKT cells) modified to express a CAR (e.g., an anti-BCMA CAR) and a cytokine (e.g., sIL-15). In some embodiments, the secretion of IL-15 by iNKT cells expressing an anti-BCMA CAR enhances the persistence of iNKT cells in a subject (e.g., relative to a subject administered a CAR that does not express an armor molecule such as IL-15).

[0341] Without wishing to be bound by a particular theory, the anti-tumor immune response elicited by CAR-modified iNKT cells can be an innate immune response or an adaptive immune response. In some embodiments, the CAR-mediated immune response can be part of an adoptive immunotherapy approach in which the CAR-modified iNKT cells induce an immune response specific to the antigen-binding site in the CAR. For example, BCMA-specific CAR iNKT cells elicit a specific immune response against cells expressing BCMA. In some embodiments, the BCMA-specific CAR iNKT cells described herein kill cancer cells. In some embodiments, the BCMA-specific CAR iNKT cells described herein reduce tumor burden. In some embodiments, the BCMA-specific CAR iNKT cells described herein recruit other immune cells to the tumor microenvironment to kill cancer. In some embodiments, the antigen-binding domain in a CAR of the present disclosure targets a tumor antigen (e.g., BCMA) for the treatment of cancer. In some embodiments, the antigen-binding site portion of a CAR of the present disclosure is designed to treat a specific cancer (e.g., a BCMA-expressing cancer), such as multiple myeloma.

[0342] The CAR-modified iNKT cells of the present disclosure may also serve as a type of vaccine for ex vivo immunization and / or in vivo therapy in mammals. Preferably, the mammal is a human.

[0343] In some embodiments, the iNKT cells described herein may be used to treat and prevent diseases (e.g., cancer) that occur in immunocompromised individuals, such as individuals suffering from cancer. In particular, iNKT cells expressing an anti-BCMA CAR of the present disclosure are used to treat multiple myeloma. In certain embodiments, iNKT cells expressing an anti-BCMA CAR of the present disclosure are used to treat patients at risk of developing multiple myeloma.

[0344] In some embodiments, iNKT cells expressing an anti-BCMA CAR of the present disclosure, or compositions comprising such cells, may be used or administered to a subject in need thereof to provide anti-tumor immunity, treat or prevent cancer, treat or prevent an autoimmune condition, or treat or prevent an allergic condition. In some embodiments, the cancer is a BCMA-expressing cancer. In some embodiments, the cancer is multiple myeloma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, or glioblastoma. In some embodiments, the autoimmune condition is myasthenia gravis, systemic lupus erythematosus, rheumatoid arthritis, pemphigus, psoriasis, inflammatory bowel disease, celiac disease, pernicious anemia, idiopathic thrombocytopenic purpura, scleroderma, Graves' disease, Sjögren's syndrome, Goodpasture's syndrome, or type 1 diabetes. In some embodiments, the allergic condition is anaphylaxis, asthma, food allergy, stinging insect allergy, drug allergy, allergic rhinitis, urticaria, angioedema, eczema, atopic dermatitis, contact dermatitis, and eosinophilic esophagitis.

[0345] In some embodiments, iNKT cells expressing an anti-BCMA CAR of the present disclosure may be administered as a composition (e.g., a pharmaceutical composition) alone or in combination with a diluent and / or other components, such as IL-2 or other cytokines or cell populations. Briefly, pharmaceutical compositions of the present invention may include a target cell population described herein in combination with one or more pharmaceutically or physiologically acceptable carriers, diluents, or excipients. Such compositions may include a buffer, such as neutral buffered saline or phosphate buffered saline; carbohydrates and proteins, such as glucose, mannose, sucrose, or dextran, mannitol; polypeptides or amino acids, such as glycine; antioxidants; chelating agents, such as EDTA or glutathione; adjuvants (e.g., aluminum hydroxide); and preservatives.

[0346] The pharmaceutical compositions of the present invention may be administered in a manner appropriate for the disease to be treated (or prevented). The amount and frequency of administration will depend on factors such as the patient's condition and the severity of the patient's disease, but appropriate doses may be determined through clinical trials. In some embodiments, the compositions of the present disclosure are formulated for intravenous administration.

[0347] When an "immunologically effective amount," "antitumor effective amount," "tumor-inhibiting effective amount," or "therapeutic amount" is indicated, the exact amount of the composition of the present invention to be administered can be determined by a physician taking into account individual differences in age, weight, tumor size, degree of infection or metastasis, and condition of the patient (subject). Cells can be administered by using injection techniques commonly known in immunotherapy (e.g., Rosenberg et al., New Eng. J. of Med. 319:1676, 1988). The optimal dosage and treatment regimen for a particular patient can be readily determined by one skilled in the medical field by monitoring the patient for signs of disease and adjusting treatment accordingly.

[0348] Administration of the compositions to a subject may be carried out by any convenient method, including aerosol inhalation, injection, ingestion, transfusion, transfer, or transplantat...

Claims

1. Invariant natural killer T (iNKT) cells engineered to express a chimeric antigen receptor containing a B cell maturation antigen (BCMA) binding site and IL-15.

2. The iNKT cell of claim 1, wherein the IL-15 is soluble IL-15.

3. The iNKT cell according to claim 1 or 2, wherein the IL-15 is human IL-15.

4. The iNKT cell according to any one of claims 1 to 3, wherein the iNKT cell kills BCMA-expressing cells.

5. The iNKT cell of claim 4, wherein the iNKT cell directly kills BCMA-expressing cells.

6. The iNKT cell of claim 4 , wherein the iNKT cell indirectly kills BCMA-expressing cells.

7. The iNKT cell according to any one of claims 1 to 6, wherein the iNKT cell maintains response to CD1d and / or NK receptor ligands.

8. The iNKT cell of any one of claims 1 to 7, wherein the iNKT cell comprises a CAR comprising any one of the anti-BCMA antibodies shown in Table 3.

9. The iNKT cell according to any one of claims 1 to 8, wherein the iNKT cell comprises a CAR comprising any one of the CARs shown in Table 4.

10. A method for killing a cell, said method comprising contacting said cell with an iNKT cell according to any one of claims 1 to 9.

11. 10. A method for treating a tumor in a subject, said method comprising administering to a subject suffering from or suspected of suffering from cancer an iNKT cell according to any one of claims 1 to 9.

12. 10. A method for reducing tumor growth, said method comprising contacting a tumor in a subject with an iNKT cell according to any one of claims 1 to 9.

13. The method of claim 11 or 12, wherein the tumor cells express BCMA.

14. The method of any one of claims 11 to 13, wherein said administration of said iNKT cells causes a reduction in tumor burden relative to the tumor burden in said subject prior to said administration.

15. 15. The method of any one of claims 11 to 14, wherein said administration of said iNKT cells results in resistance to T cell exhaustion, enhanced tissue homing of anti-BCMA iNKT cells, selective cytotoxicity against M2 macrophages, and / or stimulation of dendritic cell maturation.

16. The method of any one of claims 11 to 15, wherein the subject does not undergo lymphodepletion prior to administration of the iNKT cells.

17. An antibody or antigen-binding fragment that specifically binds to an amino acid sequence having at least 85% identity to SEQ ID NOs: 38-48.

18. The antibody or antigen-binding fragment of claim 17, wherein the antibody specifically binds to the amino acid sequences set forth in SEQ ID NOs: 38 to 48.

19. An antibody or antigen-binding fragment comprising a heavy chain variable region having the sequence set forth in any one of SEQ ID NOs: 7, 12, 19, or 21.

20. 20. The antibody or antigen-binding fragment of claim 19, wherein the antibody comprises a heavy chain variable region having the sequence set forth in SEQ ID NO: 7, 12, 19, or 21, and a light chain variable region having the sequence set forth in SEQ ID NO: 8, 10, 13, 15, or 22.

21. The antibody (i) a heavy chain variable region having the sequence shown in SEQ ID NO: 7 and a light chain variable region having the sequence shown in SEQ ID NO: 8; (ii) a heavy chain variable region having the sequence shown in SEQ ID NO: 7 and a light chain variable region having the sequence shown in SEQ ID NO: 10; (iii) a heavy chain variable region having the sequence shown in SEQ ID NO: 12 and a light chain variable region having the sequence shown in SEQ ID NO: 13; (iv) a heavy chain variable region having the sequence set forth in SEQ ID NO: 12 and a light chain variable region having the sequence set forth in SEQ ID NO: 15; (v) a heavy chain variable region having the sequence set forth in SEQ ID NO: 7 and a light chain variable region having the sequence set forth in SEQ ID NO: 13; (vi) a heavy chain variable region having the sequence shown in SEQ ID NO: 7 and a light chain variable region having the sequence shown in SEQ ID NO: 15; (vii) a heavy chain variable region having the sequence set forth in SEQ ID NO: 19 and a light chain variable region having the sequence set forth in SEQ ID NO: 10; or (viii) the antibody or antigen-binding fragment of any one of claims 17 to 20, comprising a heavy chain variable region having the sequence set forth in SEQ ID NO: 21 and a light chain variable region having the sequence set forth in SEQ ID NO:

22.

22. An antibody or antigen-binding fragment comprising a variable heavy chain region comprising a complementarity determining region 3 (CDRH3) having the sequence set forth in SEQ ID NO: 3 or 33.

23. 23. The antibody or antigen-binding fragment of claim 22, further comprising a variable light chain region having a complementarity determining region 3 (CDRL3) having the sequence set forth in any one of SEQ ID NOs: 6, 29, 30, or 36.

24. 1. An antibody or antigen-binding fragment comprising six complementarity determining regions (CDRs): CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3; (i) CDRH1 comprises the sequence set forth in SEQ ID NO: 1, CDRH2 comprises the sequence set forth in SEQ ID NO: 2, CDRH3 comprises the sequence set forth in SEQ ID NO: 3, CDRL1 comprises the sequence set forth in SEQ ID NO: 4, CDRL2 comprises the sequence set forth in SEQ ID NO: 5, and CDRL3 comprises the sequence set forth in SEQ ID NO: 6; (ii) CDRH1 comprises the sequence set forth in SEQ ID NO: 1, CDRH2 comprises the sequence set forth in SEQ ID NO: 2, CDRH3 comprises the sequence set forth in SEQ ID NO: 3, CDRL1 comprises the sequence set forth in SEQ ID NO: 4, CDRL2 comprises the sequence set forth in SEQ ID NO: 5, and CDRL3 comprises the sequence set forth in SEQ ID NO: 6; (iii) CDRH1 comprises the sequence set forth in SEQ ID NO:25, CDRH2 comprises the sequence set forth in SEQ ID NO:27, CDRH3 comprises the sequence set forth in SEQ ID NO:3, CDRL1 comprises the sequence set forth in SEQ ID NO:4, CDRL2 comprises the sequence set forth in SEQ ID NO:24, and CDRL3 comprises the sequence set forth in SEQ ID NO:30; (iv) CDRH1 comprises the sequence set forth in SEQ ID NO:25, CDRH2 comprises the sequence set forth in SEQ ID NO:27, CDRH3 comprises the sequence set forth in SEQ ID NO:3, CDRL1 comprises the sequence set forth in SEQ ID NO:4, CDRL2 comprises the sequence set forth in SEQ ID NO:24, and CDRL3 comprises the sequence set forth in SEQ ID NO:29; (v) CDRH1 comprises the sequence set forth in SEQ ID NO: 1, CDRH2 comprises the sequence set forth in SEQ ID NO: 2, CDRH3 comprises the sequence set forth in SEQ ID NO: 3, CDRL1 comprises the sequence set forth in SEQ ID NO: 4, CDRL2 comprises the sequence set forth in SEQ ID NO: 24, and CDRL3 comprises the sequence set forth in SEQ ID NO: 30; (vi) CDRH1 comprises the sequence set forth in SEQ ID NO: 1, CDRH2 comprises the sequence set forth in SEQ ID NO: 2, CDRH3 comprises the sequence set forth in SEQ ID NO: 3, CDRL1 comprises the sequence set forth in SEQ ID NO: 4, CDRL2 comprises the sequence set forth in SEQ ID NO: 24, and CDRL3 comprises the sequence set forth in SEQ ID NO: 29; (vii) CDRH1 comprises the sequence set forth in SEQ ID NO:26, CDRH2 comprises the sequence set forth in SEQ ID NO:28, CDRH3 comprises the sequence set forth in SEQ ID NO:3, CDRL1 comprises the sequence set forth in SEQ ID NO:4, CDRL2 comprises the sequence set forth in SEQ ID NO:24, and CDRL3 comprises the sequence set forth in SEQ ID NO:6; or (viii) An antibody or antigen-binding fragment, wherein CDRH1 comprises the sequence set forth in SEQ ID NO: 31, CDRH2 comprises the sequence set forth in SEQ ID NO: 32, CDRH3 comprises the sequence set forth in SEQ ID NO: 33, CDRL1 comprises the sequence set forth in SEQ ID NO: 34, CDRL2 comprises the sequence set forth in SEQ ID NO: 35, and CDRL3 comprises the sequence set forth in SEQ ID NO:

36.

25. The antibody or antigen-binding fragment of any one of claims 17 to 24, wherein the antibody or antigen-binding fragment is chimeric.

26. The antibody or antigen-binding fragment of any one of claims 17 to 25, wherein the antibody or antigen-binding fragment is humanized.

27. The antibody or antigen-binding fragment of any one of claims 17 to 26, wherein the antibody or antigen-binding fragment is a single-chain variable fragment (scFv).

28. 28. The antibody or antigen-binding fragment of claim 27, wherein the scFv comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9, 11, 14, 16, 17, 18, 20, or 23.

29. An isolated nucleic acid encoding the antibody or antigen-binding fragment of any one of claims 17 to 28.

30. 30. The isolated nucleic acid of claim 29, comprising a sequence set forth in any one of SEQ ID NOs: 49 to 64.

31. 30. The isolated nucleic acid of claim 29, comprising a sequence set forth in any one of SEQ ID NOs: 65 to 72.

32. A vector comprising the isolated nucleic acid of any one of claims 29 to 31.

33. The vector of claim 32 , wherein the vector is a viral vector.

34. 34. The vector of claim 33, wherein the viral vector is a lentiviral vector.

35. The vector of claim 34, wherein the lentiviral vector comprises a sequence shown in any one of SEQ ID NOs: 73 to 80.

36. A host cell comprising the antibody or antigen-binding fragment of any one of claims 17 to 28, or the isolated nucleic acid of any one of claims 29 to 31, or the vector of any one of claims 32 to 35.

37. 37. The host cell of claim 36, wherein the cell is a mammalian cell, a bacterial cell, a yeast cell, or an insect cell.

38. The cell of claim 36 or 37, wherein the cell is a hybridoma cell.

39. A chimeric antigen receptor (CAR) comprising the antigen-binding fragment of any one of claims 17 to 28.

40. The CAR of claim 39, further comprising a hinge region.

41. The CAR of claim 40, wherein the hinge region comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:

82.

42. The CAR according to any one of claims 39 to 41, further comprising a transmembrane domain.

43. 41. The CAR of claim 39 or 40, wherein the transmembrane domain comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:

83.

44. The CAR according to any one of claims 39 to 43, further comprising a cytoplasmic domain.

45. The CAR of claim 44, wherein the cytoplasmic domain comprises an amino acid sequence at least 80% identical to SEQ ID NO:

84.

46. The CAR of any one of claims 39 to 45, further comprising a costimulatory domain.

47. 47. The CAR of claim 46, wherein the costimulatory domain comprises an amino acid sequence at least 80% identical to SEQ ID NO:

85.

48. The CAR according to claim 47, wherein the CAR comprises an amino acid sequence shown in any one of SEQ ID NOs: 86 to 93.

49. An immune cell comprising the CAR according to any one of claims 39 to 48.

50. 50. The immune cell of claim 49, wherein the immune cell is a natural killer (NK) cell or a T cell.

51. 51. The immune cell of claim 50, wherein the immune cell is an invariant natural killer T (iNKT) cell.

52. 52. The immune cell of any one of claims 49 to 51, wherein the immune cell is engineered to express one or more immunomodulatory gene products.

53. 53. The immune cell of claim 52, wherein the one or more immunomodulatory gene products comprise IL-15, IL-12, CD40L, or 4-1BB.

54. A pharmaceutical composition comprising an antibody or antigen-binding fragment of any one of claims 17 to 28 or an immune cell of any one of claims 49 to 53, and a pharmaceutically acceptable excipient.

55. 54. A method for killing a cell, said method comprising contacting said cell with an antibody or antigen-binding fragment of any one of claims 17 to 28, an immune cell of any one of claims 49 to 53, or a pharmaceutical composition of claim 54.

56. 56. The method of claim 55, wherein the cell is a mammalian cell.

57. 57. The method of claim 55 or 56, wherein the cell is a human cell.

58. 58. The method of any one of claims 55 to 57, wherein the cells are cancer cells.

59. 59. The method of claim 58, wherein the cancer is a hematological cancer.

60. 60. The method of claim 59, wherein the hematological cancer is leukemia or lymphoma.

61. 61. The method of any one of claims 55 to 60, wherein the cancer is multiple myeloma.

62. 55. A method for treating cancer in a subject, said method comprising administering to a subject suffering from or suspected of suffering from cancer an immune cell according to any one of claims 49 to 53 or a pharmaceutical composition according to claim 54.

63. 55. A method for reducing tumor growth, the method comprising contacting a tumor in a subject with the antibody or antigen-binding fragment of any one of claims 17 to 28, the immune cell of any one of claims 49 to 53, or the pharmaceutical composition of claim 54.

64. 64. The method of claim 62 or 63, wherein the subject is a human.

65. 65. The method of any one of claims 62 to 64, wherein the cancer is a blood cancer.

66. 66. The method of claim 65, wherein the cancer is leukemia or lymphoma.

67. 67. The method of any one of claims 62 to 66, wherein the cancer is multiple myeloma.

68. 68. The method of any one of claims 62 to 67, wherein the administration is via injection.

69. 69. The method of any one of claims 62 to 68, wherein the subject does not undergo lymphodepletion prior to administration of the iNKT cells.

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