OA19653A - BCMA binding molecules and methods of use thereof. - Google Patents

Abstract

The invention provides antibodies, antigen binding fragments thereof, chimeric antigen receptors (CARs), and engineered T cell receptors, polynucleotides encoding the same, and in vitro cells comprising the same. The polynucleotides, polypeptides, and in vitro cells described herein can be used in an engineered CAR T cell therapy for the treatment of a patient suffering from a cancer. In one embodiment, the polynucleotides, polypeptides. and in vitro cells described herein can be used for the treatment of multiple myeloma.

Description

BCMA BINDING MOLECULES AND METHODS OF USE THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application daims the benefit of U.S. Provisional Patent Application No. 62/317,334, filed April 1, 2016, which is hereby incorporated by reference in its entirety.

SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on June 11, 2019, is named K-1030_02US_SL.txt and is 396,355 bytes in size.

FIELD OF THE INVENTION

[0003] This invention relates to chimeric antigen receptors (CARs) and engineered T cell receptors (TCRs) comprising an antigen binding molécule which binds to B-cell maturation antigen (BCMA), polynucleotides encoding the same, and methods of treating a cancer or other disease or disorder in a patient using the same.

BACKGROUND OF THE INVENTION

[0004] Human cancers are by their nature comprised of normal cells that hâve undergone a genetic or epigenetic conversion to become abnormal cancer cells. In doing so, cancer cells begin to express proteins and other antigens that are distinct from those expressed by normal cells. These aberrant tumor antigens can be used by the body's innate immune System to specifically target and kill cancer cells. However, cancer cells employ various mechanisms to prevent immune cells, such as T and B lymphocytes, from successfùlly targeting cancer cells.

[0005] Human T cell thérapies rely on enriched or modified human T cells to target and kill cancer cells in a patient. To increase the ability of T cells to target and kill a particular cancer cell, methods hâve been developed to engineer T cells to express constructs which direct T cells to a particular target cancer cell. Chimeric antigen receptors (CARs) and engineered T cell receptors (TCRs), which comprise binding domains capable of mteracting with a particular tumor antigen, allow T cells to target and kill cancer cells that express the particular tumor antigen.

[0006] Current thérapies for hématologie malignancies hâve shown varying levels of effectiveness with undesired side effects. Therefore, a need exists to identify novel and improved thérapies for treating BCMA related diseases and disorders.

SUMMARY OF THE INVENTION

[0007] The présent invention is directed to an isolated polynucleotide encoding a chimeric antigen receptor (CAR) or T cell receptor (TCR) comprising a binding molécule that specifically binds to B-cell maturation antigen (BCMA), wherein the binding molécule comprises: (a) a heavy chain variable région (VH) complementarity determining région (CDR) 1 comprising, consisting of, or consisting essentially of the amino acid sequence GX2X3X4X5X6X7SY (SEQ ID NO: 145) wherein: X₂ is not présent or G, X3 is not présent or S; X4 is F, G, I, or Y; X5 is S or T; Xô is F or S; and X7 is S or T; and/or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X1IX3X4X5X6X7X8X9X10YX12X13X14X15X16X17 (SEQ ID NO: 146), wherein: Xi is A, G, I, S, T, or V; X₃ is I, N, or S; X₄ is G, P, S, or Y; X5 is D, G, I, or S; Xô is F, G, or S; X7 is not présent or G or S; X₈ is N, S, or T; X₉ is A, I, K, or T; X10 is N, S, or Y; X12 is A or N; X13 is D, P, or Q; X14 is K or S; X15 is F, L, or V; Xiô is K or Q; and X17 is G or S; and/or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17DX19 (SEQ ID NO: 147), wherein: Xi is A or V; X2 is K or R; X3 is not présent or D, G, or T; X4 is not présent or A, D, G, P, R, or S; X₅ is not présent or E, F, G, L, Q, or T; Xô is not présent or E, M, Q, W, or Y; X7 is not présent or A, E, L, or S; X₈ is not présent or G, P, S, or T; X₉ is not présent or G, P, or S; X10 is not présent or I, L, P, or Y; Xn is not présent or W; X12 is not présent or H; X13 is not présent or E or Y; X14 is not présent or D, G, H, P, S, W, or Y; X15 is A, G, L, W, or Y; Xiô is not présent or A, G, I, P, or V; X17 is F, L, or M; and X19 is I, L, V, or Y; and/or (d) a light chain variable région (VL) CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2SQX5X6X7X8X9X10X11X12X13X14X15LX17 (SEQ ID NO: 148), wherein Xi is K or R; X2 is A or S; Xs is G or S; Xô is I, L, or V; X7 is L or S; X₈ is not présent or H or Y; X₉ is not présent or S; X10 is not présent or N or S; Xn is not présent or G or N; X12 is not présent or N; X13 is not présent or K or Y; X14 is N, R, or S; X15 is N, W, or Y; and X17 is A or D; (e) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid

-219653 sequence XiX2SX4X5XôX7(SEQ ID NO: 149), wherein Xi is D, G, L, S, or W; X₂ is A or G; X₄ is N, S, or T; X5 is L or R; Χβ is A, E, or Q; and X7 is S or T; and/or (f) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence XiQX₃X₄X5X6PX8T(SEQ ID NO: 150), wherein Xi is M or Q; X₃ is F, G, H, I, R, or Y; X₄ is A, F, H, I, L, or Y; X₅ is A, G, H, S, T, V, or Y; Xe is F, L, T, W, or Y; and Xs is not présent or F, L, P, or W.

[0008] In another embodiment, the invention is directed to an isolated polynucleotide encoding an antibody or an antigen binding molécule thereof that specifically binds to BCMA, wherein the antibody or the antigen binding molécule thereof comprises: (a) a heavy chain variable région (VH) complementarity determining région (CDR) 1 comprising, consisting of, or consisting essentially of the amino acid sequence GX₂X₃X4X5XôX7SY (SEQ ID NO: 145), wherein: X₂ is not présent or G; Xs is not présent or S; X4 is F, G, I, or Y; X5 is S or T; X₆ is F or S; and X7 is S or T; and/or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence XiIX₃X4X₅X6X7X8X9XioYXi2Xi3Xi4Xi₅Xi6Xi7(SEQ ID NO: 146), wherein: Xi is A, G, I, S, T, or V; X₃ is I, N, or S; X₄ is G, P, S, or Y; X5 is D, G, I, or S; X₆ is F, G, or S; X7 is not présent or G or S; Xs is N, S, or T; X9 is A, I, K, or T; X10 is N, S, or Y; X12 is A or N; Xi₃ is D, P, or Q; X14 is K or S; X15 is F, L, or V; Xi6 is K or Q; and X17 is G or S; and/or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence XiX2X3X₄X5X6X7X8X9XioXiiXi2Xi3Xi₄Xi5Xi6Xi7DXi₉(SEQ ID NO: 147), wherein: Xi is A or V; X2 is K or R; X₃ is not présent or D, G, or T; X4 is not présent or A, D, G, P, R, or S; X5 is not présent or E, F, G, L, Q, or T; Xô is not présent or E, M, Q, W, or Y; X₇ is not présent or A, E, L, or S; Xs is not présent or G, P, S, or T; X₉ is not présent or G, P, or S; X10 is not présent or I, L, P, or Y; Xn is not présent or W; X12 is not présent or H; X13 is not présent or E or Y; X14 is not présent or D, G, H, P, S, W, or Y; X15 is A, G, L, W, or Y; Xi6 is not présent or A, G, I, P, or V; X17 is F, L, or M; and X19 is I, L, V, or Y; and/or (d) a light chain variable région (VL) CDRl comprising, consisting of, or consisting essentially of the amino acid sequence X1X2SQX5X6X7X8X9X10X11X12X13X14X15LX17 (SEQ ID NO: 148), wherein Xi is K or R; X₂ is A or S; X5 is G or S; Xô is I, L, or V; X₇ is L or S; Xs is not présent or H or Y; X9 is not présent or S; X10 is not présent or N or S; X11 is not présent or G or N; X12 is not présent or N; X13 is not présent or K or Y; X14 is N, R, or S; X15 is N, W, or Y; and X17 is A or D; (e) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence XiX2SX₄X5X6X7(SEQ ID NO: 149), wherein Xi is D, G, L, S, or W; X₂ is A or G;

-3 19653

X₄ is N, S, or T; X5 is L or R; Xe is A, E, or Q; and X7 is S or T; and/or (f) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence XiQX₃X₄X5X6PX8T(SEQ ID NO: 150), wherein Xi is M or Q; X₃ is F, G, H, I, R, or Y; X₄ is A, F, H, I, L, or Y; X5 is A, G, H, S, T, V, or Y; X₆ is F, L, T, W, or Y; and Xs is not présent or F, L, P, or W.

[0009] In sonie embodiments, the VH CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 9-16. In some embodiments, the VH CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 25-32. In some embodiments, the VL CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 81-88. In some embodiments, the VL CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 97-104. In some embodiments, the VL CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 113-120.

[0010] In some embodiments, the binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 9; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 25; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 41; a VL CDRl région comprising the amino acid sequence of SEQ ID NO: 81; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 97; and a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 113; (b) a VH CDRl région comprising the amino acid sequence of SEQ ID NO: 10; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 26; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 42; a VL CDRl région comprising the amino acid sequence of SEQ ID NO: 82; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 98; and a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 114; (c) a VH CDRl région comprising the amino acid sequence of SEQ ID NO: 11; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 27; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 43; a VL CDRl région comprising the amino acid sequence of SEQ ID NO: 83; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 99; and a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 115; (d) a VH CDRl région comprising the amino acid sequence of SEQ ID NO: 12; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 28; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 44; a VL CDRl région comprising the amino acid sequence of SEQ ID NO: 84; a VL CDR2 région comprising the

-419653 amino acid sequence of SEQ ID NO: 100; and a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 116; (e) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 13; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 29; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 45; a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 85; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 101; and a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 117; (f) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 14; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 30; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 46; a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 86; a VE CDR2 région comprising the amino acid sequence of SEQ ID NO: 102; and a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 118; (g) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 15; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 31 ; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 47; a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 87; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 103; and a VL CDR3 région comprising the amino acid sequence of SEQ ED NO: 119; or (h) a VH CDRI région comprising the amino acid sequence of SEQ ID NO: 16; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 32; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 48; a VL CDRI région comprising the amino acid sequence of SEQ ID NO: 88; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 104, and a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 120.

[0011] In some embodiments, the binding molécule is single chained. In some embodiments, the binding molécule comprises an scFv.

[0012] In some embodiments, the CAR comprises a transmembrane domain. In some embodiments, the transmembrane domain is a transmembrane domain of CD28, 41BB/CD137, CD8 (e.g., CD8 alpha, CD4, CD 19, CD3 epsilon, CD45, CD5, CD9, CD 16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, an alpha chain of a T cell receptor, a beta chain of a T cell receptor, a zêta chain of a T cell receptor, or any combination thereof. In some embodiments, the CAR comprises a hinge région between the transmembrane domain and the binding molécule. In some embodiments, the hinge région is of IgGl, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM, CD28, or CD8 alpha. In some embodiments, the CAR or TCR comprises a costimulatory région. In some embodiments, the costimulatory

- 5 19653 région is a signaling région of CD28, OX-40, 4-1BB/CD137, CD2, CD7, CD27, CD30, CD40, programmed death-1 (PD-1), inducible T cell costimulator (ICOS), lymphocyte function-associated antigen-1 (LFA-1 (CD1 la/CD18), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7-H3), LIGHT (tumor necrosis factor superfamily member 14; TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, Fc gamma receptor, MHC class I molécule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molécules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD 19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 Id, ITGAE, CD 103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 1b, ITGAX, CD1 le, ITGB1, CD29, ITGB2, CD 18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD 162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD 19a, a ligand that specifically binds with CD83, or any combination thereof. In some embodiments, the CAR or TCR comprises an activation domain. In some embodiments, the activation domain is a CD3 zêta domain.

[0013] In other embodiments, the invention is directed to a vector comprising the polynucleotide or a polypeptide encoded by the polynucléotide.

[0014] In certain embodiments, the invention is directed to a cell comprising the polynucleotide, the vector, the polypeptide, or any combination thereof. In other embodiments, the invention is directed to a cell, e.g., an immune cell, e.g., atumor-infiltrating lymphocyte (TIL), autologous T cell, engineered autologous T cell (eACT), an allogeneic T cell, or any combination thereof.

[0015] In other embodiments, the invention is directed to a method of inducing an immunity against a tumor comprising administering to a subject an effective amount of a cell comprising the polynucleotide, the vector, the polypeptide, or any combination thereof. Other aspects of the invention include a method of treating a cancer in a subject in need thereof comprising administering to the subject the polynucleotide, the vector, the polypeptide, the cell, or the composition. The cancer treatable by the method can be a hématologie cancer.

-619653

BRIEF DESCRIPTION OF THE FIGURES

[0016] FIG.1A-1F show CLUTSTAL W (1.83) multiple sequence alignments of eight example anti-BCMA binding molécules disclosed herein. FIG. IA shows a sequence alignment of example anti-BCMA binding molécules comprising a VH domain. Complementarity determining régions (CDRs) and framework régions (FRs) are shown, as determined by Chothia. FIG. IB is a table providing the SEQ ID NO for each VH, CDR, and FR sequence illustrated in FIG. IA. FIG. IC shows a sequence alignment of example antiBCMA binding molécules comprising a VH domain, with alternate CDRs and FRs shown. FIG. ID is a table providing the SEQ ID NO for each VH, CDR, and FR sequence illustrated in FIG. IC. FIG. 1E shows a sequence alignment of example anti-BCMA binding molécules comprising a VL domain. CDRs and FRs are shown, as determined by Chothia. FIG. 1F is a table providing the SEQ ID NO for each VH, CDR, and FR sequence illustrated in FIG. 1E. [0017] FIGs. 2A-2F show BCMA expression in various cells. FIG. 2A shows multiple myeloma cell expression of BCMA, CD 138, CS-1, CD38, and CD 19. Box-plot analysis shows the distribution of gene expression levels in the various multiple myeloma cell lines tested (FIG. 2A). FIGs. 2B-2D show BCMA expression in EoLl (FIG. 2B), MM1S (FIG. 2C), and NCI-H929 (FIG. 2D) cancer cell lines as measured by flow cytométrie analysis of BCMA cell surface expression on the respective cell lines. FIG. 2E shows the expression of BCMA, CS-1, CLL-1, DLL3, CD70, and FLT3 in altematively activated macrophages; CD14-positive, CD16-negative cells; CD38-negative naïve B cells; CD4-positive, alpha-beta T cells; central memory CD4-positive cells; central memory CD8-positve cells; class switched memory B cells; cytotoxic CD56-dim natural killer cell; effector memory CD4positive cells; effector memory CD8-positive cells; inflammatory macrophages; macrophages; mature neutrophils; memory B cells; monocytes; myeloid cells; and regulatory T cells. FIG. 2F shows the expression of BCMA, CD138, CS-1, CD38, and CD19 in the same cell types as in Fig. 2E. Gene expression is shown as fragments per kilobase of exon per million reads mapped (FPKM) (FIG. 2A, FIG. 2E, and FIG. 2F).

[0018] FIG. 3A and FIG. 3B show CAR expression in lentivirus transduced primary human T cells from a first healthy donor (FIG. 3A) and a second healthy donor (FIG. 3B).

[0019] FIGs 4A-4F shows IFNy, TNFa, and IL-2 production by lentivirus transduced CAR T cells from two healthy donors following 16 hours of co-cultured with EoL-1 (Black), NCI-H929 (light grey), or MM1S (grey) target cell lines. FIGs. 4A and 4B show the IFNy (pg/ml; y-axis) production in lentivirus transduced CAR T cells from a first donor (FIG. 4A)

-7 19653 and a second donor (FIG. 4B). FIGs. 4C and 4D show the TNFa (pg/ml; y-axis) production in lentivirus transduced CAR T cells from a first donor (FIG. 4C) and a second donor (FIG. 4D). FIGs. 4E and 4F show the IL-2 production (pg/ml; y-axis) in lentivirus transduced CAR T cells from a first donor (FIG. 4E) and a second donor (FIG. 4F).

[0020] FIGs. 5A-5F show the average cytolytic activity (as a percentage of viable target cells remaining; y-axis) over time from two healthy donors expressing the indicated CARs co-cultured with EoLl (FIGs. 5A and 5B), NCI-H929 (FIGs. 5C and 5D), or MM1S (FIGs. 5E and 5F) target cells for 16 hours, 40 hours, 64 hours, 88 hours, or 112 hours. FIGs. 5A and 5B show the average cytolytic activity of transduced CAR T cells from a first donor (FIG. 5A) and a second donor (FIG. 5B) co-cultured with EoLl target cells for 16 hours, 40 hours, 64 hours, 88 hours, or 112 hours. FIGs. 5C and 5D show the average cytolytic activity of transduced CAR T cells from a first donor (FIG. 5C) and a second donor (FIG. 5D) cocultured with NCI-H929 target cells for 16 hours, 40 hours, 64 hours, 88 hours, or 112 hours. FIGs. 5E and 5F show the average cytolytic activity of transduced CAR T cells from a first donor (FIG. 5E) and a second donor (FIG. 5F) co-cultured with MM1S target cells for 16 hours, 40 hours, 64 hours, 88 hours, or 112 hours.

[0021] FIGs. 6A and 6B show prolifération of CFSE-labeled lentivirus transduced CAR T cells from a first healthy donor (FIG. 6A) and a second healthy donor (FIG. 6B) following 5 days of co-culture with CD3-CD28 beads (top row), EoL-1 (second row), NCIH929 (third row), or MM1S (bottom row) target cell lines.

[0022] In the Figure descriptions below, underlined sequences dénoté CDR régions calculated using Chothia.

[0023] FIG. 7A shows Clone FS-26528 HC DNA sequence (SEQ ID NO: 271)

[0024] FIG. 7B shows Clone FS-26528 HC AA sequence (SEQ ID NO: 272)

[0025] FIG. 7C shows HC CDR sequences for clone FS-26528.

[0026] FIG. 7D shows Clone FS-26528 LC DNA sequence (SEQ ID NO: 276).

[0027] FIG. 7E shows Clone FS-26528 LC AA sequence (SEQ ID NO: 277).

[0028] FIG. 7F shows LC CDR sequences for clone FS-26528.

[0029] FIG. 7G shows Clone FS-26528 CAR DNA HxL sequences (SEQ ID NO: 281)

[0030] FIG. 7H shows Clone FS-26528 CAR HxL AA sequences (SEQ ID NO: 282)

- 8 19653

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039] 295).

[0040] 296)

[0041] 297).

[0042]

[0043]

[0044]

[0045]

[0046] 304).

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

FIG. 71 shows Clone FS-26528 CAR DNA LxH sequences (SEQ ID NO: 283).

FIG. 7J shows Clone FS-26528 CAR LxH sequences (SEQ ID NO: 284).

FIG. 8A shows Clone PC-26534 HC DNA sequence (SEQ ID NO: 285).

FIG. 8B shows Clone PC-26534 HC sequence (SEQ ID NO: 286).

FIG. 8C shows HC CDR sequences for clone FS-26528.

FIG. 8D shows Clone PC-26534 LC DNA sequences (SEQ ID NO: 290).

FIG. 8E shows the Clone PC-26534 LC sequence (SEQ ID NO: 291).

FIG. 8F shows LC CDR sequences for Clone PC-26534.

FIG. 8G shows the Clone PC-26534 CAR DNA HxL sequence (SEQ ID NO:

FIG. 8H shows the Clone PC-26534 CAR HxL AA sequence (SEQ ID NO:

FIG. 81 shows the Clone PC-26534 CAR DNA LxH sequence (SEQ ID NO:

FIG. 8J shows Clone PC-26534 CAR LxH sequence (SEQ ID NO: 298).

FIG. 9A shows Clone AJ-26545 HC DNA sequence (SEQ ID NO: 299).

FIG. 9B shows Clone AJ-26545 variable HC sequence (SEQ ID NO: 300).

FIG. 9C shows HC CDR sequences for Clone AJ-26545.

FIG. 9D shows Clone AJ-26545 variable LC DNA sequence (SEQ ID NO:

FIG. 9E shows Clone AJ-26545 variable LC AA sequence (SEQ ID NO: 305)

FIG. 9F shows Clone AJ-26545 LC CDR sequences.

FIG. 9G shows Clone AJ-26545 CAR DNAHxL sequence (SEQ ID NO: 309).

FIG. 9H shows Clone AJ-26545 CAR HxL AA sequence (SEQ ID NO: 310)

FIG. 91 shows Clone AJ-26545 CAR DNA LxH sequence (SEQ ID NO: 311)

FIG. 9J shows Clone AJ-26545 CAR LxH sequence (SEQ ID NO: 312).

FIG. 10A shows Clone AJ-26554 HC DNA sequence (SEQ ID NO: 313)

-919653

[0054]	FIG. 10B shows Clone AJ-26554 HC AA sequence (SEQ ID NO: 314).
[0055]	FIG. 10C shows Clone AJ-26554 HC CDR sequences
[0056]	FIG. 10D shows Clone AJ-26554 LC DNA sequence (SEQ ID NO: 318).
[0057]	FIG. 10E shows Clone AJ-26554 LC AA sequence (SEQ ID NO: 319).
[0058]	FIG. 10F shows Clone AJ-26554 LC CDR sequences.
[0059] NO 323).	FIG. 10G shows Clone AJ-26554 CAR DNA HxL chain sequences (SEQ ID
[0060] NO: 324).	FIG. 10H shows Clone AJ-26554 CAR HxL chain AA sequences (SEQ ID
[0061] NO: 325).	FIG. 101 shows Clone AJ-26554 CAR DNA LxH chain sequences (SEQ ID
[0062]	FIG. 10J shows Clone AJ-26554 CAR LxH AA sequences (SEQ ID NO: 326).
[0063]	FIG. 11A shows Clone NM-26562 HC DNA sequence (SEQ ID NO: 327).
[0064]	FIG. 1 IB shows Clone NM-26562 HC AA sequence (SEQ ID NO: 328).
[0065]	FIG. 11C shows Clone NM-26562 HC CDR sequences.
[0066]	FIG. 1 ID shows Clone NM-26562 LC DNA sequence (SEQ ID NO: 332).
[0067]	FIG. 11E shows Clone NM-26562 LC AA sequence (SEQ ID NO: 333).
[0068]	FIG. 11F shows the Clone NM-26562 LC CDR sequences.
[0069] NO: 337)	FIG. 11G shows the Clone NM-26562 CAR DNA HxL sequences (SEQ ID
[0070] 338).	Figure 11H shows Clone NM-26562 CAR HxL AA sequences (SEQ ID NO:
[0071] 339).	FIG. 111 shows Clone NM-26562 CAR DNA LxH sequences (SEQ ID NO:
[0072] 340).	FIG. 11J shows Clone NM-26562 CAR LxH AA sequences (SEQ ID NO:
[0073]	FIG. 12A shows Clone TS-26564 HC DNA sequence (SEQ ID NO: 341).

- 1019653

[0074]

[0075]

[0076]

[0077]

[0078]

[0079] NO: 351).

[0080] IDNO: 352).

[0081]

353)

[0082] 354)

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089] NO: 365)

[0090]

366).

[0091] 367).

[0092]

368).

[0093]

FIG. 12B shows Clone TS-26564 HC AA sequence (SEQ ID NO: 342).

FIG. 12C shows the Clone TS-26564 HC CDR sequences.

FIG. 12D shows the Clone TS-26564 LC DNA sequence (SEQ ID NO: 346).

FIG. 12E shows the Clone TS-26564 LC AA sequence (SEQ ID NO: 347).

FIG. 12F shows the Clone TS-26564 LC CDR sequences.

FIG. 12G shows the Clone TS-26564 CAR DNA HxL sequences (SEQ ID

FIG. 12H shows the Clone TS-26564 CAR HxL chain AA sequences (SEQ

FIG. 121 shows the Clone TS-26564 CAR DNA LxH sequences (SEQ ID NO:

FIG. 12J shows the Clone TS-26564 CAR LxH AA sequences (SEQ ID NO:

FIG. 13A shows the Clone RY-26568 HC DNA sequence (SEQ ID NO: 355)

FIG. 13B shows the Clone RY-26568 HC AA sequence (SEQ ID NO: 356).

FIG. 13C shows the Clone RY-26568 HC CDR sequences.

FIG. 13D shows the Clone RY-26568 LC DNA sequence (SEQ ID NO: 360).

FIG. 13E shows the Clone RY-26568 LC AA sequence (SEQ ID NO: 361).

FIG. 13F shows the Clone RY-26568 LC CDR AA sequences.

FIG. 13G shows the Clone RY-26568 CAR DNA HxL sequences (SEQ ID

FIG. 13H shows the Clone RY-26568 CAR HxL AA sequences (SEQ ID NO:

FIG. 131 shows the Clone RY-26568 CAR DNA LxH sequences (SEQ IDNO:

FIG. 13J shows the Clone RY-26568 CAR LxH AA sequences (SEQ ID NO:

FIG. 14A shows the Clone PP-26575 HC DNA sequence (SEQ ID NO: 369).

- 11 19653

[0094] FIG. 14B shows the Clone PP-26575 HC AA sequence (SEQ ID NO: 370).

[0095] FIG. 14C shows the Clone PP-26575 HC CDR AA sequences.

[0096] FIG. 14D shows the Clone PP-26575 LC DNA sequence (SEQ ID NO: 374).

[0097] FIG. 14E shows the Clone PP-26575 LC AA sequence (SEQ ID NO: 375).

[0098] FIG. 14F shows the Clone PP-26575 LC CDR AA sequences.

[0099] FIG. 14G shows the Clone PP-26575 CAR DNA HxL sequences (SEQ ID NO: 379).

[0100] FIG. 14H shows Clone PP-26575 CAR HxL AA sequences (SEQ ID NO: 380).

[0101] FIG. 141 shows Clone PP-26575 CAR DNA LxH sequence (SEQ ID NO: 381).

[0102] FIG. 14J shows the Clone PP-26575 CAR LxH AA sequence (SEQ ID NO: 382).

[0103] FIG. 15A shows the Clone RD-26576 HC DNA sequence (SEQ ID NO: 383)

[0104] FIG. 15B shows Clone RD-26576 HC AA sequence (SEQ ID NO: 384).

[0105] FIG. 15C shows the Clone RD-26576 HC CDR sequences.

[0106] FIG. 15D shows the Clone RD-26576 LC DNA sequence (SEQ ID NO: 388)

[0107] FIG. 15E shows the Clone RD-26576 LC AA sequence (SEQ ID NO: 389).

[0108] FIG. 15F shows the Clone RD-26576 LC CDR sequences.

[0109] FIG. 15G shoes the Clone RD-26576 CAR DNA HxL sequences (SEQ ID NO: 393).

[0110] FIG. 15H shows the Clone RD-26576 CAR HxL chain AA sequences (SEQ ID NO: 394).

[0111] FIG. 151 shows the CloneRD-26576 CARDNALxH sequences (SEQ ID NO: 395).

[0112] FIG. 15J shows the Clone RD-26576 CAR LxH AA sequences (SEQ ID NO: 396).

[0113] FIG. 16A shows the Clone RD-26578 HC DNA sequences (SEQ ID NO: 397).

- 12 19653

[0114] FIG. 16B shows the Clone RD-26578 HC AA sequence (SEQ ID NO: 398).

[0115] FIG. 16C shows the Clone RD-26578 HC CDR AA sequences.

[0116] FIG. 16D shows the Clone RD-26578 LC DNA sequence (SEQ ID NO: 402).

[0117] FIG. 16E shows the Clone RD-26578 LC AA sequence (SEQ ID NO: 403)

[0118] FIG. 16F shows the Clone RD-26578 LC CDR sequences.

[0119] FIG. 16G shows the Clone RD-26578 CAR DNA HxL chain sequence (SEQ IDNO: 407).

[0120] FIG. 16H shows the Clone RD-26578 CAR HxL AA sequence (SEQ ID NO: 408).

[0121] FIG. 161 shows the Clone RD-26578 CAR DNA LxH sequences (SEQ IDNO: 409).

[0122] FIG. 16J shows the Clone RD-26578 CAR LxH AA sequence (SEQ ID NO: 410).

[0123] FIG. 17 shows the outcome of an in vivo study examining the efficacy of clone

RD-21530 in a subcutaneous RPMI-8226 mouse model. Cohorts of 10 mice each were tested for the CAR (dashed lines) and mock transduced (bolded Unes) T cells.

[0124] FIG. 18A and FIG. 18B show the outcome of an in vitro cytotoxicity assay using the optimized BCMA scFv variants cocultured with NCI-H929 and MM.1S cells, respectively. CAR T cells using these optimized scFvs were incubated overnight with luciferase labeled target cells in 3:1 and 1:1 effector to target cell ratios.

DETAILED DESCRIPTION OF THE INVENTION

[0125] The présent invention relates to antibodies, antigen binding molécules thereof, chimeric antigen receptors (CARs), and engineered T cell receptors, which bind BCMA, polynucleotides encoding the same, and in vitro cells comprising the same. The polynucleotides, polypeptides, and in vitro cells described herein can be used in an engineered CAR T cell therapy, e.g., an autologous cell therapy (eACT™), for the treatment of a patient suffering from a cancer. In particular, the polynucleotides, polypeptides, and in vitro cells described herein can be used for the treatment of multiple myeloma.

- 13 19653

Définitions

[0126] In order that the présent disclosure may be more readily understood, certain ternis are first defined. As used in this application, except as otherwise expressly provided herein, each of the following terms shall hâve the meaning set forth below. Additional définitions are set forth throughout the application.

[0127] The term and/or where used herein is to be taken as spécifie disclosure of each of the two specified features or components with or without the other. Thus, the term and/or as used in a phrase such as A and/or B herein is intended to include A and B, A or B, A (alone), and B (alone). Likewise, the term and/or as used in a phrase such as A, B, and/or C is intended to encompass each of the following aspects: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone). [0128] It is understood that wherever aspects are described herein with the language comprising, otherwise analogous aspects described in terms of consisting of' and/or consisting essentially of' are also provided.

[0129] Unless defmed otherwise, ail technical and scientific terms used herein hâve the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academie Press; and the Oxford Dictionary Of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

[0130] Units, préfixés, and symbols are denoted in their Système International de Unités (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range. The headings provided herein are not limitations of the various aspects of the disclosure, which can be had by reference to the spécification as a whole. Accordingly, the terms defmed immediately below are more fully defmed by reference to the spécification in its entirety.

[0131] Administering refers to the physical introduction of an agent to a subject, using any of the various methods and delivery Systems known to those skilled in the art. Exemplary routes of administration for the formulations disclosed herein include intravenous, intramuscular, subeutaneous, intraperitoneal, spinal or other parentéral routes of administration, for example by injection or infusion. The phrase parentéral administration as used herein means modes of administration other than enterai and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular,

- 1419653 intraarterial, intrathecal, intralymphatic, intralesional, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, épidural and intrastemal injection and infusion, as well as in vivo electroporation. In some embodiments, the formulation is administered via a non-parenteral route, e.g., orally. Other non-parenteral routes include a topical, epidermal or mucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods.

[0132] The term antibody (Ab) includes, without limitation, a glycoprotein immunoglobulin which binds specifically to an antigen. In general, and antibody can comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen binding molécule thereof. Each H chain comprises a heavy chain variable région (abbreviated herein as VH) and a heavy chain constant région. The heavy chain constant région comprises three constant domains, CH1, CH2 and CH3. Each light chain comprises a light chain variable région (abbreviated herein as VL) and a light chain constant région. The light chain constant région is comprises one constant domain, CL. The VH and VL régions can be further subdivided into régions of hypervariability, termed complementarity determining régions (CDRs), interspersed with régions that are more conserved, termed framework régions (FR). Each VH and VL comprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FRI, CDRl, FR2, CDR2, FR3, CDR3, FR4. The variable régions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant régions of the Abs may médiate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune System (e.g., effector cells) and the first component (Clq) of the classical complément System.

[0133] Antibodies can include, for example, 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 molécules, an antibody light chain monomer, an antibody heavy chain monomer, an antibody light chain dimer, an antibody heavy chain dimer, an antibody light chain- antibody heavy chain pair, intrabodies, antibody fusions (sometimes referred to herein as antibody conjugates), heteroconjugate antibodies, single domain antibodies, monovalent antibodies,

- 15 19653 single chain antibodies or single-chain Fvs (scFv), camelized antibodies, affybodies, Fab fragments, F(ab’)₂ fragments, disulfide-linked Fvs (sdFv), anti-idiotypie (anti-Id) antibodies (including, e.g., anti-anti-Id antibodies), minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as antibody mimetics), and antigen-binding fragments of any of the above. In certain embodiments, antibodies described herein refer to polyclonal antibody populations.

[0134] An immunoglobulin may dérivé from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3 and IgG4. Isotype refers to the Ab class or subclass (e.g., IgM or IgGl) that is encoded by the heavy chain constant région genes. The term antibody includes, by way of example, both naturally occurring and non-naturally occurring Abs; monoclonal and polyclonal Abs; chimeric and humanized Abs; human or nonhuman Abs; wholly synthetic Abs; and single chain Abs. A nonhuman Ab may be humanized by recombinant methods to reduce its immunogenicity in man. Where not expressly stated, and unless the context indicates otherwise, the term antibody also includes an antigen-binding fragment or an antigen binding molécule of any of the aforementioned immunoglobulins, and includes a monovalent and a divalent fragment or portion, and a single chain Ab.

[0135] An antigen binding molécule, antigen binding portion, or antibody fragment refers to any molécule that comprises the antigen binding parts (e.g., CDRs) of the antibody from which the molécule is derived. An antigen binding molécule can include the antigenic complementarity determining régions (CDRs). Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, dAb, linear antibodies, scFv antibodies, and multispecific antibodies formed from antigen binding molécules. Peptibodies (i.e., Fc fusion molécules comprising peptide binding domains) are another example of suitable antigen binding molécules. In some embodiments, the antigen binding molécule binds to an antigen on a tumor cell. In some embodiments, the antigen binding molécule binds to an antigen on a cell involved in a hyperproliferative disease or to a viral or bacterial antigen. In certain embodiments, the antigen binding molécule binds to BCMA. In further embodiments, the antigen binding molécule is an antibody of fragment thereof, including one or more of the complementarity determining régions (CDRs) thereof. In fùrther embodiments, the antigen binding molécule is a single chain variable fragment (scFv). In some embodiments, the antigen binding molécule comprises or consists of avimers.

- 1619653

[0136] As used herein, the terms “variable région” or “variable domain” are used interchangeably and are common in the art. The variable région typically refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the aminoterminal 110 to 120 amino acids in the mature heavy chain and about 90 to 115 amino acids in the mature light chain, which differ extensively in sequence among antibodies and are used in the binding and specificity of a particular antibody for its particular antigen. The variability in sequence is concentrated in those régions called complementarity determining régions (CDRs) while the more highly conserved régions in the variable domain are called framework régions (FR). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with antigen. In certain embodiments, the variable région is a human variable région. In certain embodiments, the variable région comprises rodent or murine CDRs and human framework régions (FRs). In particular embodiments, the variable région is a primate (e.g., non-human primate) variable région. In certain embodiments, the variable région comprises rodent or murine CDRs and primate (e.g., nonhuman primate) framework régions (FRs).

[0137] The terms “VL” and “VL domain” are used interchangeably to refer to the light chain variable région of an antibody or an antigen-binding fragment thereof.

[0138] The terms “VH” and “VH domain” are used interchangeably to refer to the heavy chain variable région of an antibody or an antigen-binding fragment thereof.

[0139] A number of définitions of the CDRs are commonly in use: Kabat numbering, Chothia numbering, AbM numbering, or contact numbering. The AbM définition is a compromise between the two used by Oxford Molecular's AbM antibody modelling software. The contact définition is based on an analysis of the available complex crystal structures.

Table 1. CDR Numbering

Loop	Kabat	AbM	Chothia	Contact
L1	L24-L34	L24-L34	L24-L34	L30-L36
L2	L50-L56	L50-L56	L50-L56	L46-L55
L3	L89-L97	L89-L97	L89-L97	L89-L96

- 1719653

H1	H31-H35B (Kabat Numbering)	H26-H35B	H26-H32..34	H30-H35B
H1	H31-H35 (Chothia Numbering)	H26-H35	H26-H32	H3O-H35
H2	H50-H65	H50-H58	H52-H56	H47--H58
H3	H95-H102	H95-H102	H95-H102	H93-H101

[0140] The term “Kabat numbering” and like terms are recognized in the art and refer to a system of numbering amino acid residues in the heavy and light chain variable régions of an antibody, or an antigen binding molécule thereof. In certain aspects, the CDRs of an antibody can be determined according to the Kabat numbering system (see, e.g., Kabat EA & Wu TT (1971) Ann NY Acad Sci 190: 382-391 and Kabat EA et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242). Using the Kabat numbering system, CDRs within an antibody heavy chain molécule are typically présent at amino acid positions 31 to 35, which optionally can include one or two additional amino acids, following 35 (referred to in the Kabat numbering scheme as 35A and 35B) (CDR1), amino acid positions 50 to 65 (CDR2), and amino acid positions 95 to 102 (CDR3). Using the Kabat numbering system, CDRs within an antibody light chain molécule are typically présent at amino acid positions 24 to 34 (CDR1), amino acid positions 50 to 56 (CDR2), and amino acid positions 89 to 97 (CDR3). In a spécifie embodiment, the CDRs of the antibodies described herein hâve been determined according to the Kabat numbering scheme.

[0141] In certain aspects, the CDRs of an antibody can be determined according to the Chothia numbering scheme, which refers to the location of immunoglobulin structural loops (see, e.g., Chothia C & Lesk AM, (1987), J Mol Biol 196: 901-917; Al-Lazikani B et al., (1997) J Mol Biol 273: 927-948; Chothia C et al., (1992) J Mol Biol 227: 799-817; Tramontano A et al., (1990) J Mol Biol 215(1): 175-82; and U.S. Patent No. 7,709,226). Typically, when using the Kabat numbering convention, the Chothia CDR-H1 loop is présent at heavy chain amino acids 26 to 32, 33, or 34, the Chothia CDR-H2 loop is présent at heavy chain amino acids 52 to 56, and the Chothia CDR-H3 loop is présent at heavy chain amino acids 95 to 102, while the Chothia CDR-L1 loop is présent at light chain amino acids 24 to

- 1819653

34, the Chothia CDR-L2 loop is présent at light chain amino acids 50 to 56, and the Chothia CDR-L3 loop is présent at light chain amino acids 89 to 97. The end of the Chothia CDR-HI loop when numbered using the Kabat numbering convention varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at H35A and H35B; if neither 35A nor 35B is présent, the loop ends at 32; if only 35A is présent, the loop ends at 33; if both 35A and 35B are présent, the loop ends at 34). In a spécifie embodiment, the CDRs of the antibodies described herein hâve been determined according to the Chothia numbering scheme.

[0142] As used herein, the terms “constant région” and “constant domain” are interchangeable and hâve a meaning common in the art. The constant région is an antibody portion, e.g., a carboxyl terminal portion of a light and/or heavy chain which is not directly involved in binding of an antibody to antigen but which can exhibit various effector fùnctions, such as interaction with the Fc receptor. The constant région of an immunoglobulin molécule generally has a more conserved amino acid sequence relative to an immunoglobulin variable domain.

[0143] As used herein, the term “heavy chain” when used in référencé to an antibody can refer to any distinct type, e.g., alpha (a), delta (δ), epsilon (ε), gamma (γ) and mu (μ), based on the amino acid sequence of the constant domain, which give rise to IgA, IgD, IgE, IgG and IgM classes of antibodies, respectively, including subclasses of IgG, e.g, IgGi, IgG₂, IgG₃ and IgG₄.

[0144] As used herein, the term “light chain” when used in référencé to an antibody can refer to any distinct type, e.g., kappa (k) or lambda (λ) based on the amino acid sequence of the constant domains. Light chain amino acid sequences are well known in the art. In spécifie embodiments, the light chain is a human light chain.

[0145] “Binding affinity” generally refers to the strength of the sum total of noncovalent interactions between a single binding site of a molécule (e.g., an antibody) and its binding partner (e.g., an antigen). Unless indicated otherwise, as used herein, “binding affinity” refers to intrinsic binding affinity which reflects a 1:1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molécule X for its partner Y can generally be represented by the dissociation constant (Kd). Affinity can be measured and/or expressed in a number of ways known in the art, including, but not limited to, equilibrium dissociation constant (Kd), and equilibrium association constant (Ka). The Kd is calculaied from the quotient of k_Off/k_On, whereas Ka is calculated from the quotient of k_on/k_off.

- 1919653 kon refers to the association rate constant of, e.g., an antibody to an antigen, and k_off refers to the dissociation of, e.g., an antibody to an antigen. The k_on and k_Ofr can be determined by techniques known to one of ordinary skill in the art, such as BIAcore® or KinExA.

[0146] As used herein, a “conservative amino acid substitution” is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having side chains hâve been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, méthionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). In certain embodiments, one or more amino acid residues within a CDR(s) or within a framework region(s) of an antibody or antigen-binding fragment thereof can be replaced with an amino acid residue with a similar side chain.

[0147] As used herein, an “epitope” is a term in the art and refers to a localized région of an antigen to which an antibody can specifically bind. An epitope can be, for example, contiguous amino acids of a polypeptide (linear or contiguous epitope) or an epitope can, for example, corne together from two or more non-contiguous régions of a polypeptide or polypeptides (conformational, non-linear, discontinuous, or non-contiguous epitope). In certain embodiments, the epitope to which an antibody binds can be determined by, e.g., NMR spectroscopy, X-ray diffraction crystallography studies, ELISA assays, hydrogen/deuterium exchange coupled with mass spectrometry (e.g., liquid chromatography electrospray mass spectrometry), array-based oligo-peptide scanning assays, and/or mutagenesis mapping (e.g., site-directed mutagenesis mapping). For X-ray crystallography, crystallization may be accomplished using any of the known methods in the art (e.g., Giegé R et al., (1994) Acta Crystallogr D Biol Crystallogr 50(Pt 4): 339-350; McPherson A (1990) Eur J Biochem 189: 1-23; ChayenNE (1997) Structure 5: 1269-1274; McPherson A (1976) J Biol Chem 251: 6300-6303). Antibody:antigen crystals may be studied using well known X-ray diffraction techniques and may be 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.,·, U.S. 2004/0014194), 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

-2019653

Biol Crystallogr 56(Pt 10): 1316-1323). Mutagenesis mapping studies may be accomplished using any method known to one of skill in the art. See, e.g., Champe M et al., (1995) J Biol Chem 270: 1388-1394 and Cunningham BC & Wells JA (1989) Science 244: 1081-1085 for a description of mutagenesis techniques, including alanine scanning mutagenesis techniques. [0148] As used herein, an antigen binding molécule, an antibody, or an antigen binding molécule thereof cross competes with a reference antibody or an antigen binding molécule thereof if the interaction between an antigen and the first binding molécule, an antibody, or an antigen binding molécule thereof blocks, limits, inhibits, or otherwise reduces the ability of the reference binding molécule, reference antibody, or an antigen binding molécule thereof to interact with the antigen. Cross compétition can be complété, e.g., binding of the binding molécule to the antigen completely blocks the ability of the reference binding molécule to bind the antigen, or it can be partial, e.g., binding of the binding molécule to the antigen reduces the ability of the reference binding molécule to bind the antigen. In certain embodiments, an antigen binding molécule that cross competes with a reference antigen binding molécule binds the same or an overlapping epitope as the reference antigen binding molécule. In other embodiments, the antigen binding molécule that cross competes with a reference antigen binding molécule binds a different epitope as the reference antigen binding molécule. Numerous types of compétitive binding assays can be used to détermine if one antigen binding molécule competes with another, for example: solid phase direct or indirect radioimmunoassay (RIA); solid phase direct or indirect enzyme immunoassay (EIA); sandwich compétition assay (Stahli et al., 1983, Methods in Enzymology 9:242-253); solid phase direct biotin-avidin EIA (Kirkland et al., 1986, J. Immunol. 137:3614-3619); solid phase direct labeled assay, solid phase direct labeled sandwich assay (Harlow and Lane, 1988, Antibodies, A Laboratory Manual, Cold Spring Harbor Press); solid phase direct label RIA using 1-125 label (Morel et al., 1988, Molec. Immunol. 25:7-15); solid phase direct biotinavidin EIA (Cheung, et al., 1990, Virology 176:546-552); and direct labeled RIA (Moldenhauer étal., 1990, Scand. J. Immunol. 32:77-82).

[0149] As used herein, the terms “immunospecifically binds,” “immunospecifically recognizes,” “specifically binds,” and “specifically recognizes” are analogous terms in the context of antibodies and refer to molécules that bind to an antigen (e.g., epitope or immune complex) as such binding is understood by one skilled in the art. For example, a molécule that specifically binds to an antigen may bind to other peptides or polypeptides, generally with lower affmity as determined by, e.g., immunoassays, BIAcore®, KinExA 3000

-21 19653 instrument (Sapidyne Instruments, Boise, ID), or other assays known in the art. In a spécifie embodiment, molécules that specifically bind to an antigen bind to the antigen with a Ka that is at least 2 logs, 2.5 logs, 3 logs, 4 logs or greater than the Ka when the molécules bind to another antigen.

[0150] In another embodiment, spécifie embodiment, molécules that specifically bind to an antigen bind with a dissociation constant (Ka) of about 1 x 10'⁷ M. In some embodiments, the antigen binding molécule specifically binds an antigen with “high affinity” when the Ka is about 1 x ΙΟ’⁹ M to about 5 x ΙΟ'⁹ M. In some embodiments, the antigen binding molécule specifically binds an antigen with “very high affinity” when the Ka is 1 x 10'¹⁰ M to about 5 x 10'¹⁰ M. In one embodiment, the antigen binding molécule has a Ka of 10‘⁹ M. In one embodiment, the off-rate is less than about 1 x 10’⁵. In other embodiments, the antigen binding molécule binds human BCMA with a Ka of between about 1 x ΙΟ'⁷ M and about 1 x ΙΟ'¹³ M. In yet another embodiment, the antigen binding molécule binds human BCMA with a Ka of about 1 x 10'¹⁰ M to about 5 x 10‘¹⁰ M.

[0151] In another spécifie embodiment, molécules that specifically bind to an antigen do not cross react with other proteins under similar binding conditions. In another spécifie embodiment, molécules that specifically bind to an antigen do not cross react with other nonBCMA proteins. In a spécifie embodiment, provided herein is an antibody or fragment thereof that binds to BCMA with higher affinity than to another unrelated antigen. In certain embodiments, provided herein is an antibody or fragment thereof that binds to BCMA (e.g., human BCMA) with a 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or higher affinity than to another, unrelated antigen as measured by, e.g., a radioimmunoassay, surface plasmon résonance, or kinetic exclusion assay. In a spécifie embodiment, the extent of binding of an anti-BCMA antibody or antigen-binding fragment thereof described herein to an unrelated, non-BCMA protein is less than 10%, 15%, or 20% of the binding of the antibody to BCMA protein as measured by, e.g., a radioimmunoassay.

[0152] In a spécifie embodiment, provided herein is an antibody or fragment thereof that binds to human BCMA with higher affinity than to another species of BCMA. In certain embodiments, provided herein is an antibody or fragment thereof that binds to human BCMA with a 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70% or higher affinity than to another species of BCMA as measured by, e.g., a radioimmunoassay, surface plasmon résonance, or kinetic exclusion assay. In a spécifie embodiment, an antibody or fragment thereof described herein, which binds to human BCMA, will bind to another

-2219653 species of BCMA protein with less than 10%, 15%, or 20% of the binding of the antibody or fragment thereof to the human BCMA protein as measured by, e.g., a radioimmunoassay, surface plasmon résonance, or kinetic exclusion assay.

[0153] An antigen refers to any molécule that provokes an immune response or is capable of being bound by an antibody or an antigen binding molécule. The immune response may involve either antibody production, or the activation of spécifie immunologicallycompetent cells, or both. A person of skill in the art would readily understand that any macromolecule, including virtually ail proteins or peptides, can serve as an antigen. An antigen can be endogenously expressed, Le. expressed by genomic DNA, or can be recombinantly expressed. An antigen can be spécifie to a certain tissue, such as a cancer cell, or it can be broadly expressed. In addition, fragments of larger molécules can act as antigens. In one embodiment, antigens are tumor antigens. In one particular embodiment, the antigen is BCMA.

[0154] The term “neutralizing” refers to an antigen binding molécule, scFv, antibody, or a fragment thereof that binds to a ligand and prevents or reduces the biological effect of that ligand. In some embodiments, the antigen binding molécule, scFv, antibody, or a fragment thereof, directly blocking a binding site on the ligand or otherwise alters the ligand's ability to bind through indirect means (such as structural or energetic alterations in the ligand). In some embodiments, the antigen binding molécule, scFv, antibody, or a fragment thereof prevents the protein to which it is bound from performing a biological function.

[0155] As used herein, the term BCMA refers to B cell maturation antigen, which can include, but is not limited to, native BCMA, an isoform of BCMA, or an interspecies BCMA homolog of BCMA. BCMA (also known as TNFRSF17, CD269, and TNFRSF13A) is a member of the tumor necrosis factor (TNF)-receptor superfamily. BCMA is expressed on the surface of multiple myeloma cells, while highly restricted to plasma cells and a subset of mature B cells in healthy tissue (FIG. 2A and FIG. 2C). The amino acid sequence of human BCMA (hBCMA) is provided in NCBI Accession Q02223.2 (GI:313104029) (SEQ ID NO: 163). As used herein, BCMA includes human BCMA and non-human BCMA homologs, as well as variants, fragments, or post-transnationally modified forms thereof, including, but not limited to, N- and O-linked glycosylated forms of BCMA. BCMA proteins may fùrther include fragments comprising ail or a portion of the extracellular domain of BCMA (e.g., ail or a portion of amino acids 1-54 of hBCMA).

-23 19653

[0156] The term autologous refers to any material derived from the same individual to which it is later to be re-introduced. For example, the engineered autologous cell therapy (eACT™) method described herein involves collection of lymphocytes from a patient, which are then engineered to express, e.g., a CAR construct, and then administered back to the same patient.

[0157] The term allogeneic refers to any material derived from one individual which is then introduced to another individual of the same species, e.g., allogeneic T cell transplantation.

[0158] The terms transduction and transduced refer to the process whereby foreign DNA is introduced into a cell via viral vector (see Jones et al., Genetics: principles and analysis, Boston: Jones & Bartlett Publ. (1998)). In some embodiments, the vector is a retroviral vector, a DNA vector, a RNA vector, an adénoviral vector, a baculoviral vector, an Epstein Barr viral vector, a papovaviral vector, a vaccinia viral vector, a herpes simplex viral vector, an adenovirus associated vector, a lentiviral vector, or any combination thereof.

[0159] A cancer refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and may also metastasize to distant parts of the body through the lymphatic System or bloodstream. A cancer or cancer tissue can include a tumor. Examples of cancers that can be treated by the methods of the présent invention include, but are not limited to, cancers of the immune System including lymphoma, leukemia, myeloma, and other leukocyte malignancies. In some embodiments, the methods of the présent invention can be used to reduce the tumor size of a tumor derived from, for example, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal région, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, multiple myeloma, Hodgkin's Disease, nonHodgkin's lymphoma (NHL), primary médiastinal large B cell lymphoma (PMBC), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), cancer of the esophagus, cancer of the small intestine, cancer of the endocrine System, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pénis, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid

-2419653 leukemia, acute lymphoblastic leukemia (ALL) (including non T cell ALL), chronic lymphocytic leukemia (CLL), solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter, carcinoma of the rénal pelvis, neoplasm of the central nervous System (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, other B cell malignancies, and combinations of said cancers. In one particular embodiment, the cancer is multiple myeloma. The particular cancer can be responsive to chemo- or radiation therapy or the cancer can be refractory. A refractor cancer refers to a cancer that is not amendable to surgical intervention and the cancer is either initially unresponsive to chemo- or radiation therapy or the cancer becomes unresponsive over time. [0160] An anti-tumor effect as used herein, refers to a biological effect that can présent as a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell prolifération, a decrease in the number of métastasés, an increase in overall or progression-free survival, an increase in life expectancy, or amelioration of varions physiological symptoms associated with the tumor. An anti-tumor effect can also refer to the prévention of the occurrence of a tumor, e.g., a vaccine.

[0161] A cytokine, as used herein, refers to a non-antibody protein that is released by one cell in response to contact with a spécifie antigen, wherein the cytokine interacts with a second cell to médiate a response in the second cell. A cytokine can be endogenously expressed by a cell or administered to a subject. Cytokines may be released by immune cells, including macrophages, B cells, T cells, and mast cells to propagate an immune response. Cytokines can induce various responses in the récipient cell. Cytokines can include homeostatic cytokines, chemokines, pro-inflammatory cytokines, effectors, and acute-phase proteins. For example, homeostatic cytokines, including interleukin (IL) 7 and IL-15, promote immune cell survival and prolifération, and pro-inflammatory cytokines can promote an inflammatory response. Examples of homeostatic cytokines include, but are not limited to, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12p40, IL-12p70, IL-15, and interferon (IFN) gamma. Examples of pro-inflammatory cytokines include, but are not limited to, IL-la, IL-lb, IL-6, IL-13, IL-17a, tumor necrosis factor (TNF)-alpha, TNF-beta, fibroblast growth factor (FGF) 2, granulocyte macrophage colony-stimulating factor (GM-CSF), soluble intercellular adhesion molécule 1 (sICAM-1), soluble vascular adhesion molécule 1 (sVCAM-1), vascular endothélial growth factor (VEGF), VEGF-C, VEGF-D, and placental growth factor (PLGF).

-25 19653

Examples of effectors include, but are not limited to, granzyme A, granzyme B, soluble Fas ligand (sFasL), and perforin. Examples of acute phase-proteins include, but are not limited to, C-reactive protein (CRP) and sérum amyloid A (SAA).

[0162] Chemokines are a type of cytokine that médiates cell chemotaxis, or directional movement. Examples of chemokines include, but are not limited to, IL-8, IL-16, eotaxin, eotaxin-3, macrophage-derived chemokine (MDC or CCL22), monocyte chemotactic protein 1 (MCP-1 or CCL2), MCP-4, macrophage inflammatory protein la (MFP-la, ΜΙΡ-la), ΜΙΡ-Ιβ (MIP-lb), gamma-induced protein 10 (IP-10), and thymus and activation regulated chemokine (TARC or CCL17).

[0163] A therapeutically effective amount, effective dose, effective amount, or therapeutically effective dosage of a therapeutic agent, e.g., engineered CAR T cells, is any amount that, when used alone or in combination with another therapeutic agent, protects a subject against the onset of a disease or promotes disease régression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptomfree periods, or a prévention of impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease régression can be evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model Systems prédictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays.

[0164] The term lymphocyte as used herein includes natural killer (NK) cells, T cells, or B cells. NK cells are a type of cytotoxic (cell toxic) lymphocyte that represent a major component of the inhérent immune System. NK cells reject tumors and cells infected by viruses. It works through the process of apoptosis or programmed cell death. They were termed “natural killers” because they do not require activation in order to kill cells. T-cells play a major rôle in cell-mediated-immunity (no antibody involvement). Its T-cell receptors (TCR) differentiate themselves from other lymphocyte types. The thymus, a specialized organ of the immune System, is primarily responsible for the T cell’s maturation. There are six types of T-cells, namely: Helper T-cells (e.g., CD4+ cells), Cytotoxic T-cells (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cells or killer T cell), Memory T-cells ((i) stem memory Tscm cells, like naïve cells, are CD45RO-, CCR7+, CD45RA+, CD62L+ (L-selectin), CD27+, CD28+ and IL-7Ra+, but they also express large amounts of CD95, IL-2R3, CXCR3, and LFA-1, and show numerous functional attributes distinctive of memory cells); (ii) central memory Tcm cells express L-selectin and the CCR7,

-2619653 they secrete IL-2, but not IFNy or IL-4, and (iii) effector memory Tem cells, however, do not express L-selectin or CCR7 but produce effector cytokines like IFNy and IL-4), Regulatory T-cells (Tregs, suppressor T cells, or CD4+CD25+ regulatory T cells), Natural Killer T-cells (NKT) and Gamma Delta T-cells. B-cells, on the other hand, play a principal rôle in humoral immunity (with antibody involvement). It makes antibodies and antigens and performs the rôle of antigen-presenting cells (APCs) and turns into memory B-cells after activation by antigen interaction. In mammals, immature B-cells are formed in the bone marrow, where its name is derived from.

[0165] The term genetically engineered or engineered refers to a method of modifying the genome of a cell, including, but not limited to, deleting a coding or non-coding région or a portion thereof or inserting a coding région or a portion thereof. In some embodiments, the cell that is modified is a lymphocyte, e.g., a T cell, which can either be obtained from a patient or a donor. The cell can be modified to express an exogenous construct, such as, e.g., a chimeric antigen receptor (CAR) or a T cell receptor (TCR), which is incorporated into the cell's genome.

[0166] An immune response refers to the action of a cell of the immune System (for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils) and soluble macromolecules produced by any of these cells or the liver (including Abs, cytokines, and complément) that results in sélective targeting, binding to, damage to, destruction of, and/or élimination from a vertebrate's body of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.

[0167] The term immunotherapy refers to the treatment of a subject afflicted with, or at risk of contracting or suffering a récurrence of, a disease by a method comprising inducing, enhancing, suppressing or otherwise modifying an immune response. Examples of immunotherapy include, but are not limited to, T cell thérapies. T cell therapy can include adoptive T cell therapy, tumor-infiltrating lymphocyte (TIL) immunotherapy, autologous cell therapy, engineered autologous cell therapy (eACT), and allogeneic T cell transplantation. However, one of skill in the art would recognize that the conditioning methods disclosed herein would enhance the effectiveness of any transplanted T cell therapy. Examples of T cell thérapies are described in U.S. Patent Publication Nos. 2014/0154228 and 2002/0006409, U.S. Patent No. 5,728,388, and International Publication No. WO 2008/081035.

-2719653

[0168] The T cells of the immunotherapy can corne from any source known in the art.

For example, T cells can be differentiated in vitro from a hematopoietic stem cell population, or T cells can be obtained from a subject. T cells can be obtained from, e.g., peripheral blood mononuclear cells (PBMCs), bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In addition, the T cells can be derived from one or more T cell lines available in the art. T cells can also be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan, such as FICOLL™ séparation and/or apheresis. Additional methods of isolating T cells for a T cell therapy are disclosed in U.S. Patent Publication No. 2013/0287748, which is herein incorporated by references in its entirety.

[0169] The term engineered Autologous Cell Therapy, which can be abbreviated as eACT™, also known as adoptive cell transfer, is a process by which a patient's own T cells are collected and subsequently genetically altered to recognize and target one or more antigens expressed on the cell surface of one or more spécifie tumor cells or malignancies. T cells can be engineered to express, for example, chimeric antigen receptors (CAR) or T cell receptor (TCR). CAR positive (+) T cells are engineered to express an extracellular single chain variable fragment (scFv) with specificity for a particular tumor antigen linked to an intracellular signaling part comprising at least one costimulatory domain and at least one activating domain. The costimulatory domain can be derived from, e.g., CD28, and the activating domain can be derived from, e.g., CD3-zeta. In certain embodiments, the CAR is designed to hâve two, three, four, or more costimulatory domains. The CAR scFv can be designed to target, for example, CD 19, which is a transmembrane protein expressed by cells in the B cell lineage, including ail normal B cells and B cell malignances, including but not limited to NHL, CLL, and non-T cell ALL. In some embodiments, the CAR is engineered such that the costimulatory domain is expressed as a separate polypeptide chain. Example CAR T cell thérapies and constructs are described in U.S. Patent Publication Nos. 2013/0287748, 2014/0227237, 2014/0099309, and 2014/0050708, and these references are incorporated by reference in their entirety.

[0170] A patient as used herein includes any human who is afflicted with a cancer (e.g., a lymphoma or a leukemia). The terms subject and patient are used interchangeably herein.

[0171] As used herein, the term in vitro cell refers to any cell which is cultured ex vivo. In particular, an in vitro cell can include a T cell.

-28 19653

[0172] The terms peptide, polypeptide, and protein are used interchangeably, and refer to a compound comprised of amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and no limitation is placed on the maximum number of amino acids that can comprise a protein's or peptide's sequence. Polypeptides include any peptide or protein comprising two or more amino acids joined to each other by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types. Polypeptides include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, dérivatives, analogs, fusion proteins, among others. The polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.

[0173] In some aspects, the polypeptides and/or proteins hâve délétions from, additions to, and/or substitutions of one or more amino acid of antigen-binding protein, and in some embodiments preferably no more than 8 amino acid substitutions therein. Useful polypeptide fragments may include immunologically functional fragments of antigen binding molécules, including not limited to one or more CDR régions, variable domains of a heavy and/or light chain, a portion of other portions of an antibody chain, and the like. Additionally, polypeptide fragments of activating and/or costimulatory molécules and the like are within the scope of the invention.

[0174] “Activation” or “Stimulation” as used herein, refers to a primary response induced by binding of an activating molécule with its cognate ligand, wherein the binding médiates a signal transduction event. An “activating molécule” or “stimulating molécule” refers to a molécule on a T cell, e.g., the TCR/CD3 complex that specifically binds with a cognate stimulatory ligand présent on an antigen présent cell. Suitable activating molécules are described herein.

[0175] A stimulatory ligand is a ligand that when présent on an antigen presenting cell (e.g., an aAPC, a dendritic cell, a B-cell, and the like) can specifically bind with a stimulatory molécule on a T cell, thereby mediating a primary response by the T cell, including, but not limited to, activation, initiation of an immune response, prolifération, and the like. Stimulatory ligands include, but are not limited to, an MHC Class I molécule loaded

-2919653 with a peptide, an anti-CD3 antibody, a superagonist anti-CD28 antibody, and a superagonist anti-CD2 antibody.

[0176] A costimulatory signal, as used herein, refers to a signal, which in combination with a primary signal, such as TCR/CD3 ligation, leads to a T cell response, such as, but not limited to, prolifération and/or upregulation or down régulation of key molécules.

[0177] A costimulatory ligand as used herein, includes a molécule on an antigen presenting cell that specifically binds a cognate co-stimulatory molécule on a T cell. Binding of the costimulatory ligand provides a signal that médiates a T cell response, including, but not limited to, prolifération, activation, différentiation, and the like. A costimulatory ligand induces a signal that is in addition to the primary signal provided by a stimulatory molécule, for instance, by binding of a T cell receptor (TCR)/CD3 complex with a major histocompatibility complex (MHC) molécule loaded with peptide. A co-stimulatory ligand can include, but is not limited to, CD7, B7-1 (CD80), B7-2 (CD86), programmed death (PD) Ll, PD-L2, 4-1BB ligand, 0X40 ligand, inducible costimulatory ligand (ICOS-L), intercellular adhesion molécule (ICAM), CD30 ligand, CD40, CD70, CD83, human leukocyte antigen G (HLA-G), MHC class I chain-related protein A (MICA), MHC class I chain-related protein B (MICB), herpes virus entry mediator (HVEM), lymphotoxin beta receptor, 3/TR6, immunoglobulin-like transcript (ILT) 3, ILT4, an agonist or antibody that binds Toll ligand receptor and a ligand that specifïcally binds with B7-H3. A co-stimulatory ligand includes, without limitation, an antibody that specifïcally binds with a co-stimulatory molécule présent on a T cell, such as, but not limited to, CD27, CD28, 4-1BB, 0X40, CD30, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, tumor necrosis factor superfamily member 14 (TNFSF14 or LIGHT), natural killer cell receptor C (NKG2C), B7-H3, and a ligand that specifïcally binds with CD83.

[0178] A costimulatory molécule is a cognate binding partner on a T cell that specifïcally binds with a costimulatory ligand, thereby mediating a costimulatory response by the T cell, such as, but not limited to, prolifération. Costimulatory molécules include, but are not limited to, CD28, CD28T, OX40, 4-1BB/CD137, CD2, CD3 (alpha, beta, delta, epsilon, gamma, zêta), CD4, CD5, CD7, CD9, CD16, CD22, CD27, CD30, CD 33, CD37, CD40, CD 45, CD64, CD80, CD86, CD134, CD137, CD154, PD-1, ICOS, lymphocyte functionassociated antigen-1 (LFA-1 (CD1 la/CD18), CD247, CD276 (B7-H3), LIGHT (tumor necrosis factor superfamily member 14; TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, Fc

-3019653 gamma receptor, MHC class I molécule, TNF, TNFr, integrin, signaling lymphocytic activation molécule, BTLA, Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KFRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD 19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VL Al, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDl-ld, ITGAE, CD 103, ITGAL, CDl-la, LFA-1, ITGAM, CDl-lb, ITGAX, CDl-lc, ITGB1, CD29, ITGB2, CD 18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD 150, IPO-3), BLAME (SLAMF8), SELPLG (CD 162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD 19a, CD83 ligand, or fragments or combinations thereof.

[0179] The terms reducing and decreasing are used interchangeably herein and indicate any change that is less than the original. Reducing and decreasing are relative terms, requiring a comparison between pre- and post- measurements. Reducing and decreasing include complété déplétions.

[0180] Treatment or treating of a subject refers to any type of intervention or process performed on, or the administration of an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowing down or preventing the onset, progression, development, severity or récurrence of a symptom, complication or condition, or biochemical indicia associated with a disease. In one embodiment, treatment or treating includes a partial remission. In another embodiment, treatment or treating includes a complété remission.

[0181] To calculate percent identity, the sequences being compared are typically aligned in a way that gives the largest match between the sequences. One example of a computer program that can be used to détermine percent identity is the GCG program package, which includes GAP (Devereux et al., 1984, Nucl. Acid Res. 12:387; Genetics Computer Group, University of Wisconsin, Madison, Wis.). The computer algorithm GAP is used to align the two polypeptides or polynucleotides for which the percent sequence identity is to be determined. The sequences are aligned for optimal matching of their respective amino acid or nucléotide (the matched span, as determined by the algorithm). In certain embodiments, a standard comparison matrix (see, Dayhoff et al., 1978, Atlas of Protein Sequence and Structure 5:345-352 forthe PAM 250 comparison matrix; Henikoffétal., 1992,

- 31 19653

Proc. Natl. Acad. Sci. U.S.A. 89:10915-10919 for the BLOSUM 62 comparison matrix) is also used by the algorithm.

[0182] The use of the alternative (e.g., or) should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the indefmite articles a or an should be understood to refer to one or more of any recited or enumerated component.

[0183] The terms about or comprising essentially of refer to a value or composition that is within an acceptable error range for the particular value or composition as determined by one of ordinary skill in the art, which will dépend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, about or comprising essentially of can mean within 1 or more than 1 standard déviation per the practice in the art. Alternatively, about or comprising essentially of can mean a range of up to 10% (i.e., ±10%). For example, about 3mg can include any number between 2.7 mg and 3.3 mg (for 10%). Furthermore, particularly with respect to biological Systems or processes, the terms can mean up to an order of magnitude or up to 5fold of a value. When particular values or compositions are provided in the application and claims, unless otherwise stated, the meaning of about or comprising essentially of should be assumed to be within an acceptable error range for that particular value or composition.

[0184] As described herein, any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer), unless otherwise indicated.

[0185] Various aspects of the invention are described in further detail in the following sub sections.

II. Binding Molécules and Polynucleotides Encoding the Same

[0186] The présent invention is directed to a polynucleotide encoding an anti-BCMA antibody or antigen binding molécule thereof which cross competes with one or more antibodies described herein (i.e., one or more described in Figure 1) or an antibody or antigen binding molécule thereof encoded by the polynucleotide. In one embodiment, the invention is directed to a polynucleotide encoding an anti-BCMA antibody or antigen binding molécule thereof which binds to the same epitope as one or more antibodies described in Figure 1 or an antibody or antigen binding molécule thereof encoded by the polynucleotide. In some embodiments, the polynucleotide encodes an antibody or antigen binding molécule thereof

-3219653 that specifically binds to BCMA, wherein the antibody or binding molécule comprises a heavy chain VH comprising: (a) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence GX2X3X4X5X6X7SY (SEQ ID NO: 145), wherein: X2 is not présent or G; X3 is not présent or S; X4 is F, G, I, or Y; X5 is S or T; Xg is F or S; and X7 is S or T; and/or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X1IX3X4X5X6X7X8X9X10YX12X13X14X15X16X17 (SEQ ID NO: 146), wherein: Xi is A, G, I, S, T, or V; X₃ is I, N, or S; X4 is G, P, S, or Y; X5 is D, G, I, or S; Xg is F, G, or S; X7 is not présent or G or S; Xs is N, S, or T; X9 is A, I, K, or T; X10 is N, S, or Y; X12 is A or N; Xi₃ is D, P, or Q; Xi₄ is K or S; X15 is F, L, or V; Xjg is K or Q; and X17 is G or S; and/or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence XiX2X3X₄X5XgX7X8X9XioXiiXi2Xi3Xi₄Xi5Xi6Xi7DXi9(SEQ ID NO: 147), wherein: Xi is A or V; X2 is K or R; X₃ is not présent or D, G, or T; X4 is not présent or A, D, G, P, R, or S; X5 is not présent or E, F, G, L, Q, or T; Xg is not présent or E, M, Q, W, or Y; X7 is not présent or A, E, L, or S; Xs is not présent or G, P, S, or T; X9 is not présent or G, P, or S; X10 is not présent or I, L, P, or Y; Xn is not présent or W; X12 is not présent or H; X13 is not présent or E or Y; X14 is not présent or D, G, H, P, S, W, or Y; X15 is A, G, L, W, or Y; Xi6 is not présent or A, G, I, P, or V; X17 is F, L, or M; and X19 is I, L, V, or Y.

[0187] In one particular embodiment, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises a VH comprising: (a) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2X3X4X5X6SYX9X10X11 (SEQ ID NO: 263), wherein: Xi is not présent or G; X2 is not présent or S X₃ is F, G, I, or Y; X4 is S or T; X5 is F or S; Xg is S or T; X9 is A, G, S, or Y; Xw is I, M, or W; and Xn is G, H, N, or S; and/or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence XiIX₃X4X5XgX7X8X9XioYXi2Xi3Xi₄Xi5Xi6Xi7(SEQ ID NO: 146), wherein: Xi is A, G, I, S, T, or V; X₃ is I, N, or S; X₄ is G, P, S, or Y; X₅ is D, G, I, or S; Xg is F, G, or S; X7 is G or S; Xs is not présent or N, S, or T; X9 is A, I, K, or T; X10 is N, S, or Y; X12 is A or N; X13 is D, P, or Q; X14 is K or S; X15 is F, L, or V; Xi6 is K or Q; and X17 is G or S; and/or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence XiX₂X₃X₄X₅X6X7X8X9XioXiiXi2Xi3Xi₄Xi5Xi6Xi7Xi8Xi9DX2i (SEQ ID NO: 264), wherein: Xi is A or V; X2 is K or R; X₃ is not présent or D, G, or T; X4 is not présent or D, G, or P; X5 is not présent or F, L, or T; Xg is not présent or P, Q, R, W, or Y; X7 is not présent or E, G, L, or S; Xs is not présent or A, G, P, S, or Y; X₉ is not présent or A, E, G, P,

- 33 19653

Q, or S; Xio is not présent or E, L, M, PS, T, or Y; Xn is not présent or D, G, El, P, S or W; X12 is not présent or A, G, I, L, or Y; X13 is not présent or A, G, I, V, or W; X14 is not présent or H; X15 is not présent or Y; Xiô is not présent or Y; X17 is not présent or W or Y; Xi₈ is not présent or P or G; X19 is F, L, or M; and X21 is I, L, V, or Y.

[0188] In another embodiment, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises a VL comprising: (a) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence XiX2SQX5XôX7X₈X9XioXnXi2Xi3Xi4Xi5LXi7(SEQ ID NO: 148), wherein Xi is K or R; X2 is A or S; X5 is G or S; Xô is I, L, or V; X7 is L or S; X₈ is not présent or H or Y; X9 is not présent or S; X10 is not présent or N or S; Xn is not présent or G or N; X12 is not présent or N; X13 is not présent or K or Y; X14 is N, R, or S; X15 is N, W, or Y; and X17 is A or D; and/or (b) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2SX4X5X6X7 (SEQ ID NO: 149), wherein Xi is D, G, L, S, or W; X2 is A or G; X4 is N, S, or T; X5 is L or R; Xô is A, E, or Q; and X7 is S or T; and/or (c) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence X1QX3X4X5X6PX8T (SEQ ID NO: 150), wherein Xi is M or Q; X₃ is F, G, H, I, R, or Y; X₄ is A, F, H, I, L, or Y; X₅ is A, G, H, S, T, V, or Y; X₆ is F, L, T, W, or Y; and X₈ is not présent or F, L, P, or W.

[0189] In one particular embodiment, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises a VH comprising: (a) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence GX2X3X4X5X6X7SY (SEQ ID NO: 145), wherein: X2 is not présent or G; X₃ is not présent or S; X4 is F, G, I, or Y; X5 is S or T; Xô is F or S; and X7 is S or T; and/or (b) a VH CDR2 comprising, consisting of, or consisting essentially ofthe amino acid sequence XiIX3X4X5XôX7X₈X9XioYXi2Xi3Xi4Xi5XiôXi7(SEQ ID NO: 146), wherein: Xi is A, G, I, S, T, or V; X₃ is I, N, or S; X4 is G, P, S, or Y; X5 is D, G, I, or S; Xô is F, G, or S; X7 is not présent or G or S; X₈ is N, S, or T; X9 is A, I, K, or T; X10 is N, S, or Y; X12 is A or N; X13 is D, P, or Q; Xi₄ is K or S; X15 is F, L, or V; Xiô is K or Q; and X17 is G or S; and/or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence

X1X2X3X4X5X6X7X₈X9X10X11X12X13X14X15X16X17DX19(SEQIDNO: 147), wherein: Xi is A or V; X2 is K or R; X₃ is not présent or D, G, or T; X₄ is not présent or A, D, G, P, R, or S; X5 is not présent or E, F, G, L, Q, or T; Xô is not présent or E, M, Q, W, or Y; X7 is not présent

-3419653 or A, E, L, or S; Xs is not présent or G, P, S, or T; X₉ is not présent or G, P, or S; Xio is not présent or I, L, P, or Y; Xn is not présent or W; X12 is not présent or H; X13 is not présent or E or Y; X14 is not présent or D, G, H, P, S, W, or Y; X15 is A, G, L, W, or Y; Xi₆ is not présent or A, G, I, P, or V; X17 is F, L, or M; and X19 is I, L, V, or Y; and/or (d) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence XiX2SQX₅X6X7X8X9XioXiiXi2Xi₃Xi4Xi5LXi7(SEQ ID NO: 148), wherein Xi is K or R; X₂ is A or S; X₅ is G or S; Xe is I, L, or V; X7 is L or S; Xs is not présent or H or Y; X9 is not présent or S; X10 is not présent or N or S; Xn is not présent or G or N; X12 is not présent or N; X13 is not présent or K or Y; X14 is N, R, or S; X15 is N, W, or Y; and X17 is A or D; and/or (e) a VL CDR2 comprising, consisting of, or consisting essentially ofthe amino acid sequence X1X2SX4X5X6X7 (SEQ 1D NO: 149), wherein Xi is D, G, L, S, or W; X₂ is A or G; X₄ is N, S, or T; X5 is L or R; Xô is A, E, or Q; and X7 is S or T; and/or (1) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence X1QX3X4X5X6PX8T (SEQ ID NO: 150), wherein Xi is M or Q; X3 is F, G, H, I, R, or Y; X4 is A, F, H, I, L, or Y; X5 is A, G, H, S, T, V, or Y; Xe is F, L, T, W, or Y; and Xs is not présent or F, L, P, or W.

[0190] In one particular embodiment, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises a VH comprising: (a) a VH CDRl comprising, consisting of, or consisting essentially of the amino acid sequence X1X2X3X4X5X6SYX9X10X11 (SEQ ID NO: 263), wherein: Xi is not présent or G; X₂ is not présent or S X3 is F, G, I, or Y; X4 is S or T; X5 is F or S; Xô is S or T; X₉ is A, G, S, or Y; Xw is I, M, or W; and Xn is G, H, N, or S; and/or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X1IX3X4X5X6X7X8X9X10YX12X13X14X15X16X17 (SEQ ID NO: 146), wherein: Xi is A, G, I, S, T, or V; X₃ is I, N, or S; X₄ is G, P, S, or Y; X₅ is D, G, I, or S; X₆ is F, G, or S; X7 is G or S; Xs is not présent or N, S, or T; X₉ is A, I, K, or T; X10 is N, S, or Y; X12 is A or N; X13 is D, P, or Q; X14 is K or S; X15 is F, L, or V; Χιβ is K or Q; and X17 is G or S; and/or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence XiX₂X3X4X5X6X7X8X9XioXiiXi2Xi3Xi4Xi5Xi6Xi7Xi8Xi₉DX₂i (SEQ ID NO: 264), wherein: Xi is A or V; X₂ is K or R; X3 is not présent or D, G, or T; X4 is not présent or D, G, or P; X5 is not présent or F, L, or T; Xô is not présent or P, Q, R, W, or Y; X7 is not présent or E, G, L, or S; X₈ is not présent or A, G, P, S, or Y; X₉ is not présent or A, E, G, P, Q, or S; X10 is not présent or E, L, M, PS, T, or Y; Xn is not présent or D, G, H, P, S or W; X12 is not présent or A, G, I, L, or Y; X13 is not présent or A, G, I, V, or W; X14 is not présent

-35 19653 or H; Xi5 is not présent or Y; Xie is not présent or Y; X17 is not présent or W or Y; Xis is not présent or P or G; X19 is F, L, or M; and X21 is I, L, V, or Y; and/or (d) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence XiX₂SQX₅X6X7X8X9XioXiiXi2Xi3Xi4Xi5LXi7(SEQ IDNO: 148), wherein Xi is K or R; X₂ is A or S; X5 is G or S; Χβ is I, L, or V; X7 is L or S; Xs is not présent or H or Y; X₉ is not présent or S; X10 is not présent or N or S; Xn is not présent or G or N; X12 is not présent or N; X13 is not présent or K or Y; Xm is N, R, or S; X15 is N, W, or Y; and X17 is A or D; and/or (e) a VL CDR2 comprising, consisting of, or consisting essentially ofthe amino acid sequence X1X2SX4X5X6X7 (SEQ ID NO: 149), wherein Xj is D, G, L, S, or W; X₂ is A or G; X₄ is N, S, or T; X5 is L or R; Xe is A, E, or Q; and X7 is S or T; and/or (f) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence X1QX3X4X5X6PX8T (SEQ ID NO: 150), wherein Xi is M or Q; X3 is F, G, H, I, R, or Y; X4 is A, F, H, I, L, or Y; X5 is A, G, H, S, T, V, or Y; Xe is F, L, T, W, or Y; and Xs is not présent or F, L, P, or W.

[0191] In another embodiment, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises a VH and a VL, wherein: (i) the VH comprises: (a) a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence

GX2X3X4X5X6X7SY (SEQ ID NO: 145), wherein: X2 is not présent or G; X3 is not présent or S; X4 is F, G, I, or Y; X5 is S or T; Xe is F or S; and X7 is S or T; and/or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence

X1IX3X4X5X6X7X8X9X10YX12X13X14X15X16X17 (SEQ ID NO: 146), wherein: Xi is A, G, I,

S, T, or V; X3 is I, N, or S; X4 is G, P, S, or Y; X5 is D, G, I, or S; Xe is F, G, or S; X7 is not présent or G or S; Xs is N, S, or T; X9 is A, I, K, or T; X10 is N, S, or Y; X12 is A or N; X13 is D, P, or Q; Xi₄ is K or S; X15 is F, L, or V; Xië is K or Q; and X17 is G or S; and/or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17DX19 (SEQ ID NO: 147), wherein: Xi is A or V; X₂ is K or R; X3 is not présent or D, G, or T; X4 is not présent or A, D, G, P, R, or S; Xs is not présent or E, F, G, L, Q, or T; Xë is not présent or E, M, Q, W, or Y; X7 is not présent or A, E, L, or S; Xs is not présent or G, P, S, or T; X9 is not présent or G, P, or S; X10 is not présent or I, L, P, or Y; Xn is not présent or W; X12 is not présent or H; X13 is not présent or E or Y; X14 is not présent or D, G, H, P, S, W, or Y; X15 is A, G, L, W, or Y; Xië is not présent or A, G, I, P, or V; X17 is F, L, or M; and X19 is I, L, V, or Y; and (ii) the VL comprises: (a) a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence

- 36 19653

XiX2SQX₃X6X7XsX«XioXhX12X13X14Xi5LXi7(SEQ ID NO: 148), wherein Xi is K or R; X₂ is A or S; X5 is G or S; Xé is I, L, or V; X₇ is L or S; Xs is not présent orHor Y; X9 is not présent or S; X10 is not présent or N or S; Xn is not présent or G or N; X12 is not présent or N; X13 is not présent or K or Y, X14 is N, R, or S; X15 is N, W, or Y; and X17 is A or D; and/or (b) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2SX4X5X6X7 (SEQ ID NO: 149), wherein Xi is D, G, L, S, or W; X₂ is A or G; X₄ is N, S, or T; X5 is L or R; Xô is A, E, or Q; and X₇ is S or T; and/or (c) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence X1QX3X4X5X6PX8T (SEQ ID NO: 150), wherein Xi is M or Q; X₃ is F, G, H, I, R, or Y; X4 is A, F, H, I, L, or Y; X5 is A, G, H, S, T, V, or Y; Xô is F, L, T, W, or Y; and X₈ is not présent or F, L, P, or W.

[0192] In another embodiment, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises a VH and a VL, wherein: (i) the VH comprises: (a) a VH CDRl comprising, consisting of, or consisting essentially of the amino acid sequence X1X2X3X4X5X6SYX9X10X11 (SEQ ID NO: 263), wherein: Xi is not présent or G; X₂ is not présent or S X₃ is F, G, I, or Y; X4 is S or T; X5 is F or S; Xe is S or T; X9 is A, G, S, or Y; X10 is I, M, or W; and Xn is G, H, N, or S, and/or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence XiIX₃X₄X₅X6X7X8X9XioYXi2Xi3Xi4Xi5Xi6Xi7(SEQ IDNO: 146), wherein: Xi is A, G, I, S, T, or V; X₃ is I, N, or S; X₄ is G, P, S, or Y; X₅ is D, G, I, or S; X₆ is F, G, or S; X₇ is G or S; X₈ is not présent or N, S, or T; X9 is A, I, K, or T; X10 is N, S, or Y; X12 is A or N; Xi₃ is D, P, or Q; X14 is K or S; X15 is F, L, or V; Xi6 is K or Q; and X17 is G or S; and/or (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence XiX₂X₃X₄X₅X6X7X8X9XioXi 1X12X13X14X15X16X17X18X19DX21 (SEQ ID NO: 264), wherein: Xi is A or V; X₂ is K or R; X₃ is not présent or D, G, or T; X4 is not présent or D, G, or P; X5 is not présent or F, L, or T; Xe is not présent or P, Q, R, W, or Y; X₇ is not présent or E, G, L, or S; X₈ is not présent or A, G, P, S, or Y; X9 is not présent or A, E, G, P, Q, or S; X10 is not présent or E, L, M, P, S, T, or Y; Xn is not présent or D, G, H, P, S or W; X12 is not présent or A, G, I, L, or Y; Xi₃ is not présent or k, G, I, V, or W; X14 is not présent or H; X15 is not présent or Y; Xi6 is not présent or Y; X17 is not présent or W or Y; Xi₈ is not présent or P or G; X19 is F, L, or M; and X21 is I, L, V, or Y; and (ii) the VL comprises: (a) a VL CDRl comprising, consisting of, or consisting essentially of the amino acid sequence X1X2SQX5X6X7X8X9X10X11X12X13X14X1₅LXi₇ (SEQ ID NO: 148), wherein Xi is K or R; X₂

-3719653 is A or S; X5 is G or S; Χδ is I, L, or V; X7 is L or S; X₈ is not présent or H or Y; X9 is not présent or S; X10 is not présent or N or S; Xu is not présent or G or N; X12 is not présent or N; X13 is not présent or K or Y; X14 is N, R, or S; X15 is N, W, or Y; and X17 is A or D; and/or (b) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2SX4X5X6X7 (SEQ ID NO: 149), wherein Xi is D, G, L, S, or W; X₂ is A or G; X₄ is N, S, or T; X₅ is L or R; X₆ is A, E, or Q; and X7 is S or T; and/or (c) a VL CDR3 comprising, consisting of, or consisting essentially ofthe amino acid sequence X1QX3X4X5X6PX8T (SEQ ID NO: 150), wherein Xi is M or Q; X3 is F, G, H, I, R, or Y; X4 is A, F, H, I, L, or Y; X5 is A, G, H, S, T, V, or Y; Χδ is F, L, T, W, or Y; and X₈ is not présent or F, L, P, or W.

[0193] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g., hBCMA), comprises a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence GX2X3X4X5X6X7SY (SEQ ID NO: 145), wherein: X2 is not présent or G; X3 is not présent or S; X4 is F, G, I, or Y; X5 is S or T, Χδ is F or S; and X7 is S or T.

[0194] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g., hBCMA), comprises a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence GX2TFSSY (SEQ ID NO: 151), wherein: X2 is F or G.

[0195] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g., hBCMA), comprises a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence GX2X3X4X5X6SSY (SEQ ID NO: 152), wherein: X2 is not présent or G; X₃ is not présent or S; X₄ is F, G, or I; X5 is S or T; and Χδ is F or S.

[0196] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g., hBCMA), comprises a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2X3X4X5X6SYX9X10X11 (SEQ ID NO: 263), wherein: Xi is not présent or G; X2 is not présent or S X3 is F, G, I, or Y; X₄ is S or T; X5 is F or S; Χδ is S or T; X₉ is A, G, S, or Y; X10 is I, M, or W; and Xu is G, H, N, or S.

[0197] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g., hBCMA), comprises a VH CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence XiTFX4SYX7X₈X9 (SEQ ID NO.

-3819653

265), wherein: Xi is F, G, or Y; X₄ is S or T; X₇ is A, G, S, or Y; X₈ is I or M; and X9 is H, N, or S.

[0198] In one embodiment, the antibody or antigen binding molécule, which specifîcally binds to BCMA (e.g., hBCMA), comprises a VH CDRI comprising, consisting of, or consisting essentially of the amino acid sequence FTFSSYX7MX9 (SEQ LD NO: 266), wherein: X₇ is A, G, or S; and X9 is H, N, or S.

[0199] In one embodiment, the antibody or antigen binding molécule, which specifîcally binds to BCMA (e.g., hBCMA), comprises a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence XiIX₃X₄X5X6X7X8X9XioYXi₂Xi3Xi4Xi5Xi6Xi7(SEQ ID NO: 146), wherein: Xi is A, G, I, S, T, or V; X₃ is I, N, or S; X₄ is G, P, S, or Y; X₅ is D, G, I, or S; X₆ is F, G, or S; X₇ is G or S; X₈ is not présent or N, S, or T; X9 is A, I, K, or T; X10 is N, S, or Y, X12 is A or N; Xi₃ is D, P, or Q; X14 is K or S; X15 is F, L, or V; Xiô is K or Q; and X17 is G or S.

[0200] In one embodiment, the antibody or antigen binding molécule, which specifîcally binds to BCMA (e.g., hBCMA), comprises a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence XiIX₃X₄X₅X6X7X8X9XioYAXi₃Xi₄Xi5Xi6G(SEQ ID NO: 153), wherein: Xi is A, G, I, T, or V; X₃ is I, N, or S; X₄ is G, P, S, or Y; X5 is D, G, I, or S; Xô is F, G, or S; X₇ is G or S; X₈ is N, S, or T; X9 is A, I, K, or T; Xw is N, S, or Y; Xi₃ is D or Q; Xi₄ is K or S; X15 is F or V; and Xi6 is K or Q.

[0201] In one embodiment, the antibody or antigen binding molécule, which specifîcally binds to BCMA (e.g., hBCMA), comprises a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X1ISX4X5X6X7X8X9YYADSVKG (SEQ ID NO: 154), wherein: Xi is A, T, or V; X₄ is G, S, or Y; X5 is D or S; Xô is G or S; X₇ is G or S; X₈ is N, S, or T; and X9 is I, K, or T.

[0202] In one embodiment, the antibody or antigen binding molécule, which specifîcally binds to BCMA (e.g., hBCMA), comprises a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence XiDGPXsXeGXgXgXioYAQKFQG (SEQ LD NO: 155), wherein: Xi is G or I; X₃ is I or N; X5 is G or I; Xe is F or G; X₈ is S or T; X9 is A or T; and X10 is N or S.

[0203] In one embodiment, the antibody or antigen binding molécule, which specifîcally binds to BCMA (e.g., hBCMA), comprises three VH CDRs and three VL CDRs, wherein the VH CDR3 comprising, consisting of, or consisting essentially of the amino acid

-3919653 sequence X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17DX19 (SEQ ID NO: 147) and wherein: Xi is A or V; X₂ is K or R; X3 is not présent or D, G, or T; X4 is not présent or A, D, G, P, R, or S; X5 is not présent or E, F, G, L, Q, or T; Xe is not présent or E, M, Q, W, or Y; X7 is not présent or A, E, L, or S; X₈ is not présent or G, P, S, or T; X9 is not présent or G, P, or S; X10 is not présent or I, L, P, or Y; Xh is not présent or W; X12 is not présent or H; X13 is not présent or E or Y; X14 is not présent or D, G, H, P, S, W, or Y; X15 is A, G, L, W, or Y; Xi6 is not présent or A, G, I, P, or V; X17 is F, L, or M; and X19 is I, L, V, or Y.

[0204] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g., hBCMA), comprises three VH CDRs and three VL CDRs, wherein the VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence ARX3X4X5X6X7X8X9X10X11X12X13X14X15X16X17DX19 (SEQ ID NO: 156) and wherein: X3 is not présent or D, G, or T; X4 is not présent or A, D, G, P, R, or S; X5 is not présent or E, F, G, Q, or T; Xe is not présent or E, M, W, or Y; X7 is not présent or A, L, or S; X₈ is not présent or G, S, or T; X₉ is not présent or G or S; X10 is not présent or I, L, or P; X11 is not présent or W; X12 is not présent or H; X13 is not présent or E or Y; X14 is not présent or G, H, P, S, W, or Y; X15 is A, G, L, W, or Y; Χιβ is not présent or A, G, I, P, or V; X17 is F, L, or M; and X19 is I, L, V, or Y.

[0205] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g., hBCMA), comprises three VH CDRs and three VL CDRs, wherein the VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19DX21 (SEQ ID NO: 264) and wherein: Xi is A or V; X₂ is K or R; X3 is not présent or D, G, or T; X4 is not présent or D, G, or P; X5 is not présent or F, L, or T; Xô is not présent or P, Q, R, W, or Y; X7 is not présent or E, G, L, or S; X₈ is not présent or A, G, P, S, or Y; X₉ is A, E, G, P, Q, or S; X10 is E, L, M, P, S, T, or Y; X11 is not présent or D, G, H, P, S or W; X12 is not présent or A, G, I, L, or Y; X13 is not présent or A, G, I, V, or W; X14 is not présent or H; X15 is not présent or Y; Xi6 is not présent or Y; X17 is not présent or W or Y; Xis is not présent or P or G; X19 is F, L, or M; and X21 is I, L, V, or Y.

[0206] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g., hBCMA), comprises three VH CDRs and three VL CDRs, wherein the VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence ARX3X4X5X6X7X8X9X10X11X12X13X14X15X16X17X18X19DX21 (SEQ ID NO: 267), wherein: X3 is not présent or D or T; X4 is not présent or D or G; X5 is not présent or F or T;

-4019653

Χό is not présent or P, R, W, or Y; X7 is not présent or E, G, L, or S; Xs is not présent or A, G, S, or Y; X9 is A, E, G, Q, or S; X10 is E, L, M, P, S, or T; Xn is not présent or G, H, P, S or W; X12 is not présent or A, G, I, L, or Y; X13 is not présent or A, I, V, or W; X14 is not présent or H; X15 is not présent or Y; Xi6 is not présent or Y; X17 is not présent or W or Y; Xi₈ is not présent or P or G; X19 is F, L, or M; and X21 is I, L, V, or Y.

[0207] In some embodiments, the polynucleotide encodes an antibody or antigen binding molécule that specifïcally binds to BCMA, wherein the antibody or antigen binding molécule comprises one, two, or ail three of any of the VH CDRs listed above or described in FIG. IA or FIG. IB. In some embodiments, the antibody or antigen binding molécule comprises the VH Framework régions (FRs) described herein. In spécifie embodiments, the antibody or antigen binding molécule comprises the VH FRs of an antibody set forth in FIG. 1A or FIG. IB (e.g., one, two, three, or four of the FRs in one sequence of FIG. 1 A).

[0208] In one embodiment, the antibody or antigen binding molécule, which specifïcally binds to BCMA (e.g., hBCMA), comprises a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence XiX₂SQX5X₆X7X8X9XioXiiXi2Xi3Xi4Xi5LXi7(SEQ ID NO: 148), wherein: Xi is K or R; X₂ is A or S; X5 is G or S; Xô is I, L, or V; X7 is L or S; X₈ is not présent or H or Y; X9 is not présent or S; X10 is not présent or N or S; Xn is not présent or G or N; X12 is not présent or N; X13 is not présent or K or Y; X14 is N, R, or S; X15 is N, W, or Y; and X17 is A or D.

[0209] In one embodiment, the antibody or antigen binding molécule, which specifïcally binds to BCMA (e.g., hBCMA), comprises a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence RASQX5XeSX₈X₉LA (SEQ ID NO: 157), wherein: X5 is G or S; Xô is I or V; Xs is R or S; and X₉ is N, W, or Y.

[0210] In one embodiment, the antibody or antigen binding molécule, which specifïcally binds to BCMA (e.g., hBCMA), comprises a VL CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence XiSSQSX6LX₈SXioXiiXi2Xi3NYLXi7 (SEQ ID NO: 158), wherein: Xi is K or R; X₆ is L or V; X₈ is H or Y; X10 is N or S; Xn is G or N; X12 is not présent or N; X13 is K or Y; and X17 is A or D.

[0211] In one embodiment, the antibody or antigen binding molécule, which specifïcally binds to BCMA (e.g., hBCMA), comprises a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2SX4X5X6X7 (SEQ ID NO: 149),

-41 19653 wherein: Xi is D, G, L, S, or W; X₂ is A or G; X₄ is N, S, or T; X5 is L or R; Xô is A, E, or Q; and X7 is S or T.

[0212] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g, hBCMA), comprises a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence XiASX₄RAT (SEQ ID NO: 159), wherein: Xi is D, G, or S; and X₄ is N or T.

[0213] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g., hBCMA), comprises a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence Xi ASX^sXôX? (SEQ ID NO: 160), wherein: Xi is D, G, or S; X₄ is N, S, or T; X5 is L or R; Xô is A or Q; and X₇ is S or T.

[0214] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g, hBCMA), comprises a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence XiX₂SX₄RXôS (SEQ ID NO: 161), wherein Xi is L or W; X₂ is A or G; X₄ is N or T; and Xô is A or E.

[0215] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g., hBCMA), comprises a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence XiQXsX^sXôPXsT (SEQ ID NO: 150), wherein: Xi is M or Q; X3 is F, G, H, I, R, or Y; X₄ is A, F, H, I, L, or Y; X5 is A, G, H, S, T, V, or Y; Xô is F, L, T, W, or Y; and Xs is not présent or F, L, P, or W.

[0216] In one embodiment, the antibody or antigen binding molécule, which specifically binds to BCMA (e.g., hBCMA), comprises a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence QQXsX^sXôPXsT (SEQ ID NO: 162), wherein: X₃ is H, I, R, or Y; X₄ is A, F, H, I, or Y; X5 is A, S, T, V, or Y; Xô is F, W, or Y; and Xs is not présent or F, L, P, or W.

[0217] In some embodiments, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises one, two, or ail three of any of the VL CDRs listed above or described in FIG. 2. In some embodiments, the antibody or antigen binding molécule comprises the VL Framework régions (FRs) described herein. In spécifie embodiments, the antibody or antigen binding molécule comprises the VL FRs of an antibody set forth in FIG. 4 (e.g., one, two, three, or four of the FRs in one row of FIG. 4).

[0218] In some embodiments, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding

-4219653 molécule comprises a VH CDR1, wherein the VH CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 9-16. In other embodiments, the antibody or antigen binding molécule comprises a VH CDR1, wherein the VH CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 215-222. In some embodiments, the antibody or antigen binding molécule comprises a VH CDR2, wherein the VH CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 25-32. In some embodiments, the antibody or antigen binding molécule comprises a VH CDR2, wherein the VH CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 231-238. In some embodiments, the antibody or antigen binding molécule comprises a VH CDR3, wherein the VH CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO : 41 -48. In some embodiments, the antibody or antigen binding molécule comprises a VH CDR3, wherein the VH CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 247-254.

[0219] In some embodiments, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises a VH CDR1, a VH CDR2, and VH CDR3, wherein the VH CDR1, VH CDR2, and VH CDR3 comprise the amino acid sequence of the VH CDR1, VH CDR2, and VH CDR3 of an antibody in FIG. 1A or FIG. IB, respectively.

[0220] In some embodiments, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises a VL CDR1, wherein the VL CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 81-88. In some embodiments, the antibody or antigen binding molécule comprises a VL CDR2, wherein the VL CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 97-104. In some embodiments, the antibody or antigen binding molécule comprises a λ/D CDR3, wherein the VL CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 113-120.

[0221] In some embodiments, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises a VIL CDR1, a VT CDR2, and VT CDR3, wherein the VT CDR1, VT CDR2, and VT CDR3 comprise the amino acid sequence of the VT CDR1, λΤ CDR2, and λΤ CDR3 of an antibody in FIG. IC, respectively.

-43 19653

[0222] In some embodiments, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises a VH framework région 1 (FRI), wherein the AH FRI comprises an amino acid sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to an amino acid sequence selected from SEQ ID NOs: 1-8 and 207-214. In some embodiments, the antibody or antigen binding molécule comprises a VH FR2, wherein the VH FR2 comprises an amino acid sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to an amino acid sequence selected from SEQ ID NOs: 17-24 and 223-23. In some embodiments, the antibody or antigen binding molécule comprises a VH FR3, wherein the VH FR3 comprises an amino acid sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to an amino acid sequence selected from SEQ ID NOs: 33-40 and 239-246. In some embodiments, the antibody or antigen binding molécule comprises a VH FR4, wherein the VH FR4 comprises an amino acid sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to an amino acid sequence selected from SEQ ID NOs: 49-56 and 255-262.

[0223] In some embodiments, the antibody or antigen binding molécule or a fragment thereof comprises a VL FRI, wherein the VL FRI comprises an amino acid sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to an amino acid sequence selected from SEQ ID NOs: 73-80. In some embodiments, the antibody or antigen binding molécule or a fragment thereof comprises a VL FR2, wherein the VL FR2 comprises an amino acid sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to an amino acid sequence selected from SEQ ID NOs: 89-96. In some embodiments, the antibody or antigen binding molécule or a fragment thereof comprises a VL FR3, wherein the VL FR3 comprises an amino acid sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about

-4419653

99%, or 100% identical to an amino acid sequence selected from SEQ ID NOs: 105-112. In some embodiments, the antibody or antigen binding molécule or a fragment thereof comprises a VL FR4, wherein the VL FR4 comprises an amino acid sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to an amino acid sequence selected from SEQ ID NOs: 121-128.

[0224] In some embodiments, the polynucleotide encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule comprises any one, two, and/or three VH CDR sequences disclosed herein. In certain embodiments, the antibody or antigen binding molécule comprises a VH CDR1, a VH CDR2, and a VH CDR3 having the amino acid sequence of any VH CDR1, VH CDR2, and VH CDR3 disclosed herein, respectively. In some embodiments, the antibody or antigen binding molécule comprises any one, two, and/or three VL CDR sequences disclosed herein. In certain embodiments, the antibody or antigen binding molécule comprises a VL CDR1, a VL CDR2, and a VL CDR3 having the amino acid sequence of any VL CDR1, VL CDR2, and VL CDR3 disclosed herein, respectively.

[0225] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 9; (b) a VH CDR2 région comprising the amino acid sequence of SEQ LD NO: 25; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 41; (d) a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 81; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 97; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 113.

[0226] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 10; (b) a VH CDR2 région comprising the amino acid sequence of SEQ LD NO: 26; (c) a VH CDR3 région comprising the amino acid sequence of SEQ LD NO: 42; (d) a VL CDR1 région comprising the amino acid sequence of SEQ LD NO: 82; (e) a VL CDR2 région comprising the amino acid sequence of SEQ LD NO: 98; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ LD NO: 114.

[0227] Ln one embodiment, the antibody or antigen binding molécule comprises:(a) a VH CDR1 région comprising the amino acid sequence of SEQ LD NO: 11; (b) a VH CDR2 région comprising the amino acid sequence of SEQ LD NO: 27; (c) a VH CDR3 région

-45 19653 comprising the amino acid sequence of SEQ ID NO: 43; (d) a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 83; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 99; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 115.

[0228] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 12; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 28; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 44; (d) a VL CDRl région comprising the amino acid sequence of SEQ ID NO: 84; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 100; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 116.

[0229] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDRl région comprising the amino acid sequence of SEQ ID NO: 13; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 29; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 45; (d) a VL CDRl région comprising the amino acid sequence of SEQ ED NO: 85; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 101; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 117.

[0230] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDRl région comprising the amino acid sequence of SEQ ID NO. 14; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 30; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ED NO: 46; (d) a VL CDRl région comprising the amino acid sequence of SEQ ID NO: 86; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 102; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 118.

[0231] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDRl région comprising the amino acid sequence of SEQ ID NO: 15; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ED NO: 31; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ED NO: 47; (d) a VL CDRl région comprising the amino acid sequence of SEQ ED NO: 87; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ED NO: 103; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ED NO: 119.

-4619653

[0232] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 16; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 32; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 48; (d) a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 88; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 104; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 120.

[0233] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 215; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 231; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 247; (d) a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 81; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 97; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 113.

[0234] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 216; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 232; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 248; (d) a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 82; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 98; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 114.

[0235] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 217; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 233; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 249; (d) a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 83; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 99; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 115.

[0236] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO:218; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 234; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 250; (d) a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 84; (e) a VL CDR2 région comprising the amino

-4719653 acid sequence of SEQ ID NO: 100; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 116.

[0237] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 219; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 235; (c) a VH CDR3 région comprising the amino acid sequence of SEQ LD NO: 251; (d) a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 85; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 101; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 117.

[0238] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 220; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 236; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 252; (d) a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 86; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 102; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 118.

[0239] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 221; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ED NO: 237; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ID NO. 253; (d) a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 87; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 103; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 119.

[0240] In one embodiment, the antibody or antigen binding molécule comprises: (a) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 222; (b) a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 238; (c) a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 254; (d) a VL CDRl région comprising the amino acid sequence of SEQ ID NO: 88; (e) a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 104; and (f) a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 120.

[0241] In some embodiments, the antibody or antigen binding molécule comprises a heavy chain variable région sequence comprising an amino acid sequence of FIG. 1A or FIG. IB. In some embodiments, the antibody or antigen binding molécule comprises a heavy chain

-4819653 variable région sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 65-72. In some embodiments, the antibody or antigen binding molécule comprises a light chain variable région sequence comprising an amino acid sequence selected from FIG. IC. In some embodiments, the antibody or antigen binding molécule comprises a light chain variable région sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-144.

[0242] In some embodiments, the antibody or antigen binding molécule comprises (a) a heavy chain variable région comprising the amino acid sequence of SEQ ID NO: 65; and (b) a light chain variable région comprising the amino acid sequence of SEQ ID NO 137.

[0243] In some embodiments, the antibody or antigen binding molécule comprises (a) a heavy chain variable région comprising the amino acid sequence of SEQ ID NO: 66; and (b) a light chain variable région comprising the amino acid sequence of SEQ ID NO: 138.

[0244] In some embodiments, the antibody or antigen binding molécule comprises (a) a heavy chain variable région comprising the amino acid sequence of SEQ ID NO: 67; and (b) a light chain variable région comprising the amino acid sequence of SEQ ID NO. 139.

[0245] In some embodiments, the antibody or antigen binding molécule comprises (a) a heavy chain variable région comprising the amino acid sequence of SEQ ID NO: 68; and (b) a light chain variable région comprising the amino acid sequence of SEQ ID NO: 140.

[0246] In some embodiments, the antibody or antigen binding molécule comprises (a) a heavy chain variable région comprising the amino acid sequence of SEQ ID NO: 69; and (b) a light chain variable région comprising the amino acid sequence of SEQ ID NO: 141.

[0247] In some embodiments, the antibody or antigen binding molécule comprises (a) a heavy chain variable région comprising the amino acid sequence of SEQ ID NO: 70; and (b) a light chain variable région comprising the amino acid sequence of SEQ ID NO: 142.

[0248] In some embodiments, the antibody or antigen binding molécule comprises (a) a heavy chain variable région comprising the amino acid sequence of SEQ ID NO: 71; and (b) a light chain variable région comprising the amino acid sequence of SEQ ID NO: 143.

[0249] In some embodiments, the antibody or antigen binding molécule comprises (a) a heavy chain variable région comprising the amino acid sequence of SEQ ID NO: 72; and (b) a light chain variable région comprising the amino acid sequence of SEQ ID NO: 144.

[0250] In one particular embodiment, the polynucleotide of the présent invention comprises a nucléotide sequence at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about

-4919653

97%, at least about 98%, at least about 99%, or about 100% identical to a nucléotide sequence selected form the group consisting of SEQ ID NOs: 57-64. In another embodiment, the polynucleotide of the présent invention comprises a nucléotide sequence at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to a nucléotide sequence selected form the group consisting of SEQ ID NOs: 129-136.

[0251] The antibody or antigen binding molécule encoded by the polypeptide of the présent invention can be single chained or double chained. In some embodiments, the antibody or antigen binding molécule comprises is single chained. In certain embodiments, the antigen binding molécule is selected from the group consisting of an scFv, an Fab, an Fab', an Fv, an F(ab')2, a dAb, and any combination thereof. In one particular embodiment, the antibody or antigen binding molécule comprises an scFv.

[0252] In certain embodiments, the antibody or antigen binding molécule comprises a single chain, wherein the heavy chain variable région and the light chain variable région are connected by a linker. In some embodiments, the VH is located at the N terminus of the linker and the VL is located at the C terminus of the linker. In other embodiments, the VL is located at the N terminus of the linker and the VH is located at the C terminus of the linker. In some embodiments, the linker comprises at least about 5, at least about 8, at least about 10, at least about 13, at least about 15, at least about 18, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, or at least about 100 amino acids. In some embodiments, the linker comprises at least about 18 amino acids. In certain embodiments, the linker comprises an amino acid sequence that is at least about 75%, at least about 85%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to the amino acid sequence GSTSGSGKPGSGEGSTKG (SEQ ID NO: 174) or a poly-Gly linker such as the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO: 268). Or

GGGGSGGGGSGGGGSGGGGS (SEQ ID NO: 411). In one embodiment, the linker is a Whitlow linker. In certain embodiments, the antibody or antigen binding molécule comprises a single chain, wherein the heavy chain variable région and the light chain variable région are connected by a linker, wherein the linker comprises the amino acid sequence of SEQ ID NO: 174.

- 5019653

[0253] In some embodiments, the antibody or antigen binding molécules of the présent invention specifically bind BCMA (e.g., hBCMA). In certain embodiments, an antiBCMA antibody or antigen binding molécule of the présent invention binds human BCMA with a Kd of less than 1 x 10'⁶M, less than 1 x 10'⁷M, less than 1 x 1O'^SM, or less than 1 x 10'⁹M. In one particular embodiment, the anti-BCMA antibody or antigen binding molécules binds human BCMA with a Kd of less than 1 x ΙΟ'⁷ M. In another embodiment, the antiBCMA antibody or antigen binding molécules binds human BCMA with a Kd of less than 1 x 10‘⁸M. In some embodiments, the anti-BCMA antibody or antigen binding molécules binds human BCMA with a Koof about 1 x 10'⁷M, about 2 x 10‘⁷M, about 3 x 10⁷M, about 4 x 10‘⁷M, about 5 x 10‘⁷M, about 6 x 10‘⁷M, about 7 x 10‘⁷M, about 8 x 10‘⁷M, about 9 x 10‘⁷ M, about 1 x 10‘⁸M, about 2 x 10'⁸M, about 3 x 10‘⁸M, about 4 x 10'⁸M, about 5 x 10‘⁸M, about 6 x 10'⁸M, about 7 x 10‘⁸M, about 8 x 10'⁸M, about 9 x 10‘⁸M, about 1 x 10’⁹M, about 2 x 10‘⁹M, about 3 x 10‘⁹M, about 4 x 10’⁹M, about 5 x 10‘⁹M, about 6 x 10‘⁹M, about 7 x 10’⁹M, about 8 x 10‘⁹M, about 9 x 10‘⁹M, about 1 x 10’¹⁰M, or about 5 x 10¹⁰ M. In certain embodiments, the Kd is calculated as the quotient of k_off/k_On, and the k_on and k_off are determined using a monovalent antibody, such as a Fab fragment, as measured by, e.g., BIAcore® surface plasmon résonance technology. In other embodiments, the Kd is calculated as the quotient of koff/k_on, and the k_on and koff are determined using a bivalent antibody, such as a Fab fragment, as measured by, e.g., BIAcore® surface plasmon résonance technology.

[0254] In other embodiments, the anti-BCMA antibody or antigen binding molécule binds human BCMA-Fc with a Kd of less than 1 x 10‘⁹M, less than 3 x 10‘⁹M, less than 5 x 10‘⁹ M, less than 1 x 10'¹⁰ M, less than 3 x 10'¹⁰ M, or less than 5 x 10'¹⁰ M. In other embodiments, the anti-BCMA antibody or antigen binding molécules binds cyno BCMA-Fc with a Kd of less than 1 x 10'⁵ M, less than 1 x 10'⁶M, less than 1 x 10'⁷M, less than 1x10’ ⁸M, less than 1 x 10'⁹M, or less than 1 x 10'¹⁰M.

[0255] In some embodiments, the anti-BCMA antibody or antigen binding molécule binds human BCMA with an association rate (k_on) of less than 1 x ΙΟ'⁴ M'¹ s'¹, less than 2 x ΙΟ'⁴ M'¹ s'¹, less than 3 x 10‘⁴ M'¹ s’¹, less than 4 x 10‘⁴ M’¹ s’¹, less than 5 x ΙΟ’⁴ M'¹ s'¹, less than 6 x 10‘⁴ M'¹ s’¹, less than 7 x 10‘⁴ M'¹ s'¹, less than 8 x ΙΟ'⁴ M'¹ s'¹, less than 9 x ΙΟ'⁴ M' ¹ s’¹, less than 1 x ΙΟ’³ M'¹ s’¹, less than 2 x 10⁵ M'¹ s'¹, less than 3 x 10'⁵ M'¹ s'¹, less than 4 x 10'³ M'¹ s’¹, less than 5 x 10‘⁵ M’¹ s’¹, less than 6 x 10’⁵ M'¹ s’¹, less than 7 x 10‘⁵ M’¹ s'¹, less than 8 x 10'⁵ M'¹ s’¹, less than 9 x 10'⁵ M’¹ s¹, less than 1 x ΙΟ’⁶ M'¹ s’¹, less than 2 x 10’ ⁶ M'¹ s'¹, less than 3 x 10'⁶ M'¹ s'¹, less than 4 x ΙΟ'⁶ M'¹ s'¹, less than 5 x ΙΟ'⁶ M'¹ s’¹, less than

- 51 19653 χ ΙΟ’⁶ Μ'¹ s⁴, less than 7 x ΙΟ’⁶ M’¹ s'¹, less than 8 x 10‘⁶ M^-1 s’¹, less than 9 x 10⁶ M'¹ s'¹, or less than 1 x 10‘⁷ M'¹ s’¹. In certain embodiments, the k_on is determined using a monovalent antibody, such as a Fab fragment, as measured by, e.g., BIAcore® surface plasmon résonance technology. In other embodiments, the k_on is determined using a bivalent antibody as measured by, e.g., BIAcore® surface plasmon résonance technology.

[0256] In some embodiments, the anti-BCMA antibody or antigen binding molécule binds human BCMA with an dissociation rate (k_Off) of less than 1 x 10‘² s’¹, less than 2 x 10’² s’¹, less than 3 x 10‘² s'¹, less than 4 x 10‘² s’¹, less than 5 x 10‘² s’¹, less than 6 x 10‘² s’¹, less than 7 x 10'² s’¹, less than 8 x 10'² s'¹, less than 9 x 10’² s'¹, less than 1 x 10'³ s⁴, less than 2 x 10⁴ s’¹, less than 3 x 10'³ s¹, less than 4 x 10'³ s⁴, less than 5 x 10’³ s⁴, less than 6 x 10‘³ s⁴, less than 7 x 10'³ s⁴, less than 8 x 10’³ s⁴, less than 9 x 10‘³ s⁴, less than 1 x 10⁴ s⁴, less than 2 x 10⁴ s⁴, less than 3 x 10⁴ s⁴, less than 4 x 10⁴ s⁴, less than 5 x 10⁴ s⁴, less than 6 x 10⁴ s⁴, less than 7 x 10⁴ s⁴, less than 8 x 10⁴ s⁴, less than 9 x 10⁴ s⁴, less than 1 x 10⁴ s⁴, or less than 5 x 10⁴ s⁴. In certain embodiments, the k_off is determined using a monovalent antibody, such as a Fab fragment, as measured by, e.g., BIAcore® surface plasmon résonance technology. In other embodiments, the k_off is determined using a bivalent antibody as measured by, e.g., BIAcore® surface plasmon résonance technology.

[0257] In some embodiments, the polynucleotide of the présent invention encodes an antibody or antigen binding molécule that specifically binds to BCMA, wherein the antibody or antigen binding molécule cross competes with a reference antibody disclosed herein. In certain embodiments, the antibody or antigen binding molécule cross competes with a reference antibody comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-56, 65-128, and 137-144. In some embodiments, the antibody or antigen binding molécule cross competes with a reference antibody comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 65-72 and 137-144. In certain embodiments, the antibody or antigen binding molécule cross competes with a reference antibody, wherein the reference antibody comprises a VH CDR1 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-16. In certain embodiments, the antibody or antigen binding molécule cross competes with a reference antibody, wherein the reference antibody comprises a VH CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 25-32. In certain embodiments, the antibody or antigen binding molécule cross competes with a reference antibody, wherein the reference antibody comprises a VH CDR3 comprising an amino acid sequence selected from the group

- 5219653 consisting of SEQ ID NOs: 41-48. In some embodiments, the antibody or antigen binding molécule cross competes with a reference antibody, wherein the reference antibody comprises a VL CDRI comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 89-96. In certain embodiments, the antibody or antigen binding molécule cross competes with a reference antibody, wherein the reference antibody comprises a VL CDR2 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 105112. In certain embodiments, the antibody or antigen binding molécule cross competes with a reference antibody, wherein the reference antibody comprises a VL CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 121-128. In one embodiment, the antibody or antigen binding molécule cross competes with a reference antibody, wherein the reference antibody comprises a VH comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 65-72. In another embodiment, the antibody or antigen binding molécule cross competes with a reference antibody, wherein the reference antibody comprises a VL comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-144.

[0258] In some embodiments, the polynucleotide of the présent invention encodes an antibody or antigen binding molécule that specifîcally binds to BCMA, wherein the antibody or antigen binding molécule binds the same or an overlapping epitope as a reference antibody disclosed herein (e.g., Figure 1). In certain embodiments, the antibody or antigen binding molécule binds the same or an overlapping epitope as a reference antibody comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-56, 65-128, and 137-144. In some embodiments, the antibody or antigen binding molécule binds the same or an overlapping epitope as a reference antibody comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 65-72 and 137-144.

III Poly nucléotides Encoding Chimeric Antigen Receptors and T Cell Receptors

[0259] The présent invention is also directed to polynucleotides encoding chimeric antigen receptors (CARs) or T cell receptors (TCRs) comprising an antigen binding molécule that specifîcally binds to BCMA described in Section II, and engineered T cells comprising an antigen binding molécule that specifîcally binds to BCMA described in Section IL In some embodiments, an anti-BCMA CAR or TCR encoded by the polynucleotide of the présent invention comprises an antigen binding molécule that specifîcally binds to BCMA. In some embodiments, the anti-BCMA CAR or TCR encoded by the polynucleotide further comprises

- 53 19653 a costimulatory domain. In some embodiments, the costimulatory domain in the anti-BCMA CAR or TCR encoded by the polynucleotide comprises an extracellular domain (i.e., a hinge région), a transmembrane domain, and/or an intracellular (signaling) domain. In some embodiments, the anti-BCMA CAR or TCR encoded by the polynucleotide further comprises a CD3 zêta activating domain. In one particular embodiment, the anti-BCMA CAR or TCR encoded by the polynucleotide comprises an antigen binding molécule that specifically binds BCMA (e.g., hBCMA), a costimulatory domain comprising an extracellular domain, a transmembrane domain, and an intracellular domain, and a CD3 zêta activating domain.

[0260] In some embodiments, the polynucleotide of the présent invention encodes a TCR, wherein the TCR comprises an antigen binding molécule that specifically binds to BCMA, and wherein the TCR further comprises a fourth complementarity determining région (CDR4). In certain embodiments, the polynucleotide encodes a TCR, wherein the TCR comprises an antigen binding molécule that specifically binds to BCMA, and a constant région. In some embodiments, the constant région is selected from a constant région of IgGl, IgG2, IgG3, IgG4, IgA, IgD, IgE, and IgM.

- 5419653

ΙΠ.Α. Costimulatory Domain

[0261] In some embodiments, the polynucleotide of the présent invention encodes a CAR, wherein the CAR comprises an antigen binding molécule that specifically binds to BCMA (one or more antigen binding molécules in Section II), and wherein the CAR fùrther comprises a costimulatory domain. In some embodiments, the costimulatory domain is positioned between the antigen binding molécule and an activating domain. In certain embodiments, the costimulatory domain can comprise an extracellular domain, a transmembrane domain, and an intracellular signaling domain.

[0262] Extracellular Domain. In one embodiment, the extracellular domain comprises a hinge région (e.g., a spacer région). In another embodiment, the extracellular domain is from or derived from (e.g., comprises) CD28, CD28T, 0X40, 4-1BB/CD137, CD2, CD3 (alpha, beta, delta, epsilon, gamma, zêta), CD4, CD5, CD7, CD8, CD9, CD 16, CD22, CD27, CD30, CD 33, CD37, CD40, CD 45, CD64, CD80, CD86, CD134, CD137, CD154, programmed death-1 (PD-1), ICOS, April, BAFF, lymphocyte ftmction-associated antigen-1 (LFA-1 (CD1 la/CD18), CD247, CD276 (B7-H3), LIGHT (tumor necrosis factor superfamily member 14; TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, Fc gamma receptor, MHC class I molécule, TNFr, integrin, signaling lymphocytic activation molécule, BTLA, Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2R beta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDl-ld, ITGAE, CD103, ITGAL, CDl-la, LFA-1, ITGAM, CDl-lb, ITGAX, CDl-lc, ITGB1, CD29, ITGB2, CD 18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD 150, IPO-3), BLAME (SLAMF8), SELPLG (CD 162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD 19a, CD83 ligand, or fragments or combinations thereof. The extracellular domain can be derived either from a natural or from a synthetic source.

[0263] In some embodiments, the extracellular domain in the costimulatory domain is positioned between the antigen binding molécule and the transmembrane domain. In certain embodiments, the extracellular domain in the costimulatory domain is from or derived from an immunoglobulin. In some embodiments, the extracellular domain in the costimulatory domain is selected from the hinge régions of IgGl, IgG2, IgG3, IgG4, IgA, IgD, IgE, and

- 55 19653

IgM, or a fragment thereof. In other embodiments, the extracellular domain in the costimulatory domain is from or derived from the hinge région of CD8 alpha. In one particular embodiment, the extracellular domain in the costimulatory domain is from or derived from the hinge région of CD28. In certain embodiments, the extracellular domain in the costimulatory domain comprises a fragment of the hinge région of CD8 alpha or a fragment of the hinge région of CD28, wherein the fragment is anything less than the whole hinge région. In some embodiments, the fragment of the CD8 alpha hinge région or the fragment of the CD28 hinge région comprises an amino acid sequence that excludes at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 amino acids at the N-terminus or C-Terminus, or both, of the CD8 alpha hinge région of the CD28 hinge région.

[0264] In certain embodiments, the extracellular domain in the costimulatory domain comprises an amino acid sequence that is at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to the amino acid sequence LDNEKSNGTIIHVKGKHLCPSPLFPGPSKP (SEQ ID NO: 167) or a fragment thereof. In some embodiments, the extracellular domain in the costimulatory domain comprises the amino acid sequence of SEQ ID NO: 167 or a fragment thereof.

[0265] In certain embodiments, the extracellular domain in the costimulatory domain is encoded by a nucléotide sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to the nucléotide sequence CTTGATAATGAAAAGTCAAACGGAACAATCATT

CACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAG CCA (SEQ ID NO: 166) or a fragment thereof. In some embodiments, the extracellular domain in the costimulatory domain is encoded by a nucléotide sequence that comprises the nucléotide sequence of SEQ ID NO: 166 or a fragment thereof.

[0266] In some embodiments, the CD28T domain is derived from a human CD28 hinge région. In other embodiments, the CD28T domain is derived from a rodent, murine, or primate (e.g., non-human primate) CD28 hinge région. In some embodiments, the CD28T domain is derived from a chimeric CD28 hinge région.

- 5619653

[0267] In some embodiments, the extracellular domain comprises some or ail of a member of the immunoglobulin family such as IgGl, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM, or fragment thereof.

[0268] Transmembrane Domain: The costimulatory domain for the CAR or TCR of the invention can further comprise a transmembrane domain. The transmembrane domain can be designed to be fused to the extracellular domain in the costimulatory domain. It can similarly be fùsed to the intracellular domain in the costimulatory domain. In one embodiment, the transmembrane domain that naturally is associated with one of the domains in a CAR is used. In some instances, the transmembrane domain can be selected or modified by amino acid substitution to avoid binding of such domains to the transmembrane domains of the same or different surface membrane proteins to minimize interactions with other members of the receptor complex. The transmembrane domain may be derived either from a natural or from a synthetic source. Where the source is natural, the domain can be derived from any membrane-bound or transmembrane protein. In some embodiments, the transmembrane domain is derived from CD28, OX-40, 4-1BB/CD137, CD2, CD3 (alpha, beta, delta, epsilon, zêta), CD4, CD5, CD7, CD8, CD9, CD16, CD22, CD27, CD30, CD 33, CD37, CD40, CD 45, CD64, CD80, CD86, CD 134, CD 13 7, CD 154, programmed death-1 (PD-1), ICOS, lymphocyte function-associated antigen-1 (LFA-1 (CD1 la/CD18), CD3 gamma, CD247, CD276 (B7-H3), LIGHT (tumor necrosis factor superfamily member 14; TNFSF14), NK.G2C, Ig alpha (CD79a), DAP-10, Fc gamma receptor, MHC class I molécule, TNFr, integrin, signaling lymphocytic activation molécule, BTLA, Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD19, CD4, CD8alpha, CD8beta, IL2Rbeta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CDl-ld, ITGAE, CD 103, ITGAL, CDl-la, LFA-1, ITGAM, CDl-lb, ITGAX, CDl-lc, ITGB1, CD29, ITGB2, CD 18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD 150, IPO-3), BLAME (SLAMF8), SELPLG (CD 162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD 19a, CD83 ligand, or a fragment thereof.

[0269] Optionally, a short oligo or polypeptide linker, preferably between 2 and 10 amino acids in length may form the linkage between the transmembrane domain and the

- 5719653 cytoplasmic signaling domain of the CAR. A glycine-serine doublet provides a particularly suitable linker.

[0270] In one embodiment, the transmembrane domain in the CAR of the invention comprises the CD8 transmembrane domain. In one embodiment, the CD8 transmembrane domain comprises the transmembrane portion of the nucleic acid sequence of GCTGCAGCATTGAGCAACTCAATAATGTATTTTAGTCACTTTGTACCAGTGTTCT TGCCGGCTAAGCCTACTACCACACCCGCTCCACGGCCACCTACCCCAGCTCCTA CCATCGCTTCACAGCCTCTGTCCCTGCGCCCAGAGGCTTGCCGACCGGCCGCAG GGGGCGCTGTTCATACCAGAGGACTGGATTTCGCCTGCGATATCTATATCTGGG CACCCCTGGCCGGAACCTGCGGCGTACTCCTGCTGTCCCTGGTCATCACGCTCT ATTGTAATCACAGGAAC (SEQ ID NO: 269). In one embodiment, the CD8 transmembrane domain comprises the nucleic acid sequence that encodes the transmembrane amino acid sequence contained within

AAALSNSIMYFSHFVPVFLPAKPTTTPAPRPPTPAPTIASQP LSLRPEACRPAAGGAVHTRGEDFACDIYIWAPLAGTCGVLLLSLVÎTEYCNHRN (SEQ ID NO: 270).

[0271] In another embodiment, the transmembrane domain in the costimulating domain is a CD28 transmembrane domain. In some embodiments, the transmembrane domain comprises an amino acid sequence that is at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to the amino acid sequence fwvlwvggvlacysllvtvafiifwv (SEQ ID NO: 169). In some embodiments, the transmembrane domain comprises the amino acid sequence of SEQ ID NO: 169.

[0272] In some embodiments, the transmembrane domain is encoded by a nucléotide sequence at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to the nucléotide sequence TTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCA CCGTGGCTTTTATAATCTTCTGGGTT (SEQ ID NO: 168). In some embodiments, the transmembrane domain is encoded by a nucléotide sequence that comprises the nucléotide sequence of SEQ ID NO: 168.

[0273] Intracellular (signaling) Domain: The intracellular (signaling) domain of the engineered T cells of the invention can provide signaling to an activating domain, which then

- 5819653 activâtes at least one of the normal effector fonctions of the immune cell. Effector fonction of a T cell, for example, can be cytolytic activity or helper activity including the sécrétion of cytokines.

[0274] In certain embodiments, suitable intracellular signaling domain include (i.e., comprise), but are not limited to CD28, CD28T, OX-40, 4-1BB/CD137, CD2, CD7, CD27, CD30, CD40, programmed death-1 (PD-1), inducible T cell costimulator (ICOS), lymphocyte function-associated antigen-1 (LFA-1, CDLla/CD18), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7-H3), LIGHT, (TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, Fc gamma receptor, MHC class 1 molécule, TNF receptor proteins, an Immunoglobulin protein, cytokine receptor, integrins, Signaling Lymphocytic Activation Molécules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD 19, CD4, CD8alpha, CD8beta, IL-2R beta, IL-2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 Id, ITGAE, CD 103, ITGAL, CD1 la, LFA-1, ITGAM, CD1 1b, ITGAX, CD1 le, ITGB1, CD29, ITGB2, CD 18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD 160 (BY55), PSGL1, CD 100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD 150, IPO-3), BLAME (SLAMF8), SELPLG (CD 162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, a ligand that specifically binds with CD83, or any combination thereof.

[0275] An example of a nucléotide sequence encoding the intracellular signaling domain is set forth in SEQ ID NO. 170:

AGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTC CACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACC TAGAGATTTCGCTGCCTATCGGAGC

[0276] In one embodiment, the polynucleotide encoding an intracellular signaling domain within a costimulatory domain comprises a nucléotide sequence at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the nucléotide sequence of SEQ IDNO: 170.

- 5919653

[0277] An example of an intracellular signaling domain is set forth in SEQ ID NO. 171:

RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS.

[0278] In one particular embodiment, the intracellular signaling domain within a costimulatory domain comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ IDNO: 171.

[0279] The intracellular signaling sequences within the CAR of the invention can be linked to each other or to an activating domain in a random or specified order. Optionally, a short oligo- or polypeptide linker, preferably between 2 and 10 amino acids in length may form the linkage. A glycine-serine doublet provides a particularly suitable linker.

[0280] It will further be appreciated that where desired, the costimulatory régions described herein can be expressed in a separate chain from the antigen binding molécule (e.g., scFv) and activating domains, in so-called “trans” configuration.

HL B Activating Domain

[0281] In some embodiments, intracellular domains for use in the engineered T cell of the invention include cytoplasmic sequences of the T cell receptor (TCR) and co-receptors that act in concert to initiate signal transduction following antigen/receptor engagement, as well as any dérivative or variant of these sequences and any synthetic sequence that has the same functional capability. CD3 is an element of the T cell receptor on native T cells, and has been shown to be an important intracellular activating element in CARs. In one embodiment, the activating domain is CD3, e.g., CD3 zêta, the nucléotide sequence of which is set forth in SEQ IDNO. 172:

AGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCC AGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATG ACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACC AAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGA TAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAG AAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACG AAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG.

-6019653

[0282] In some embodiments, the polynucleotide encoding an activating domain comprises a nucléotide sequence at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the nucléotide sequence of SEQ ID NO: 172.

[0283] The corresponding amino acid of intracellular CD3 zêta is set forth in SEQ ID NO. 173:

RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPR RKNPQEGLYNELQK DKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR.

[0284] In some embodiments, the activating domain comprises an amino acid sequence at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of SEQ ID NO: 173.

[0285] Additionally, in certain embodiments the activating domain comprises an amino acid sequence at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence of a CD3 zêta variant as set forth in SEQ ID NO: 412:

RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRR KNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTY DALHMQALPPR

III. C. Leader Peptide

[0286] In some embodiments, the polynucleotide of the présent invention encodes a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molécule that specifically binds to BCMA, and wherein the CAR or the TCR fürther comprises a leader peptide (also referred to herein as a signal peptide). In certain embodiments, the leader peptide comprises an amino acid sequence that is at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to the amino acid sequence MALPVTALLLPLALLLHAARP (SEQ ID NO: 165). In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 165. In some embodiments, the

-61 19653 leader peptide is encoded by a nucléotide sequence at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 164.

[0287] In some embodiments, the polynucleotide of the présent invention encodes a CAR, wherein the CAR comprises a leader peptide (P), an antigen binding molécule (B), a hinge domain (H), a transmembrane domain (T), a costimulatory région (C), and an activation domain (A), wherein the CAR is configured according to the following: P-B-H-T-C-A. In some embodiments, the antigen binding molécule comprises a VH and a VL, wherein the CAR is configured according to the following: P-VH-VL-H-T-C-A or P-VL-VH-H-T-C-A. In some embodiments, the VH and the VL are connected by a linker (L), wherein the antiBCMA CAR is configured according to the following, from N-terminus to C-terminus: PVH-L-VL-H-T-C-A or P-VH-L-VL-H-T-C-A.

[0288] In some embodiments, the polynucleotide of the présent invention encodes a CAR, wherein the CAR comprises an amino acid sequence at least about 75%, at least about 85%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to an amino acid sequence selected from Table 2. In certain embodiments, the polynucleotide of the présent invention encodes a CAR, wherein the CAR comprises an amino acid sequence selected from Table 2.

Table 2. Example CAR Sequences

Anti- BCMA CAR	Nucléotide Sequence	SEQ ID NO:	Amino Acid Sequence	SEQ ID NO:
FS21495CAR HxL	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGGAGGTGCAGCTGTTGGAGTCT GGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCC TGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGC TGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCA GCT ATT AGT GGTAGT GGT GGTAGCACATACT ACGCAGACT C C GTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GCGGTGTACTACTGCGCAAGAGCCGAGATGGGAGCCGTATTC GACATATGGGGTCAGGGTACAATGGTCACCGTCTCCTCAGGG TCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGT ACAAAGGGGGAAATTGTGTTGACACAGTCTCCAGCCACCCTG TCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTAGCAGGTACTTAGCCTGGTACCAACAGAAA CCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAAC AGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCT GGGACAGACTTCACTCTCACCATCA.GCAGCCTAGAGCCTGAA GATTTTGCAGTTTATTACTGTCAGCAGAGAATCTCCTGGCCT	175	MALPVTALLLPLALLLHAA RPEVQLLESGGGLVQPGGS LRLSCAASGFTFSSYAMSW VRQAPGKGLEWVSAIS GS G GSTYYADSVKGRFTISRDN SKNTLYLQMNSLRAEDTAV YYCARAEMGAVFDIWGQGT MVTVSSGSTSGSGKPGSGE GSTKGEIVLTQSPATLSLS PGERATLSCRASQSVSRYL AWYQQKPGQAPRLLIYDAS NRATGIPARFSGSGSGTDF TLTISSLEPEDFAVYYCQQ RISWP FT FGGGT KVEIKRA AALDNEKSNGTIIHVKGKH LCPSPLFPGPSKPFWVLW VGGVLACYSLLVTVAFIIF WVRSKRSRLLHSDYMNMTP	176

- 6219653

	TTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGCC GCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCAC GTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGT CCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTC CTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATC TTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGAT TACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAA CACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTAT CGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCG TATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTG GGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGA CGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCC CAGGAGGGT CT CTATAATGAGCTGCAGAAGGATAAGAT GGCT GAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGG GGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCT ACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCA CCTAGGTAA		RRPGPTRKHYQPYAPPRDF AAYRS RVKFS RSADAPAYQ QGQNQLYNELNLGRREEYD VL D KRRGRD P EMGGK P RRK NPQEGLYNELQKDKMAEAY SEIGMKGERRRGKGHDGLY QGLSTATKDTYDALHMQAL PPR
FS21495CAR LxH	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGGAAATTGTGTTGACACAGTCT CCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTC TCCTGCAGGGCCAGTCAGAGTGTTAGCAGGTACTTAGCCTGG TACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT GATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGT GGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGC CTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGAGA ATCTCCTGGCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAG ATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGT GGCGAAGGTAGTACAAAGGGGGAGGTGCAGCTGTTGGAGTCT GGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCC TGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGC TGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCA GCTAT TAGT GGTAGT GGT GGT AGCACATACTACGCAGACT CC GTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GCGGTGTACTACTGCGCAAGAGCCGAGATGGGAGCCGTATTC GACATAT GGGGT CAGGGTACAAT GGT CAC C GT CT C CT CAGC C GCT GCCCTT GATAAT GAAAAGT CAAACGGAACAATCATTCAC GTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGT CCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTC CTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATC TTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGAT TACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAA CACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTAT CGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCG TATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTG GGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGA CGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCC CAGGAGGGT CT CT AT AAT GAGCT GCAGAAGGAT AAGAT GGCT GAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGG GGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCT ACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCA CCTAGGTAA	177	MALPVTALLLPLALLLHAA RPEIVLTQSPATLSLSPGE RATLSCRASQSVSRYLAWY QQKPGQAPRLLIYDASNRA TGIPARFSGSGSGTDFTLT ISS LEPEDFAVYYCQQRIS WPFTFGGGTKVEIKRGSTS GSGKPGSGEGSTKGEVQLL ESGGGLVQPGGSLRLSCAA SGFTFSSYAMSWVRQAPGK GLEWVSAIS GS GGSTYYAD SVKGRFTISRDN S KNTLYL QMNSLRAEDTAVYYCARAE MGAVFDIWGQGTMVTVSSA AALDNEKSNGTIIHVKGKH LCPSPLFPGPSKPFWVLW VGGVLACYSLLVTVAFIIF WVRSKRSRLLHSDYMNMTP RRPGPTRKHYQPYAPPRDF AAYRSRVKFSRSADAPAYQ QGQNQLYNELNLGRREEYD VLDKRRGRDPEMGGKPRRK NPQEGLYNELQKDKMAEAY SEIGMKGERRRGKGHDGLY QGLSTATKDTYDALHMQAL PPR	178
PC21497CAR HxL	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGCAGGTGCAGCTGGTGGAGTCT GGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCC TGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCAC TGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCA GTTATATCGTATGATGGAAGTAATAAATACTATGCAGACTCC	179	MALPVTALLLPLALLLHAA RPQVQLVESGGGWQPGRS LRLSCAASGFTFSSYGMHW VRQAPGKGLEWVAVISYDG SNKYYADSVKGRFTIS RDN SKNTLYLQMNSLRAEDTAV	180

-6319653

GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GCGGTGTACTACTGCGCCAGAGACGGTACTTATCTAGGTGGT CTCTGGTACTTCGACTTATGGGGGAGAGGTACCTTGGTCACC GTCTCCTCAGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGT GGCGAAGGT AGTACAAAGGGGGATATT GT GAT GACT CAGT CT CCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATC TCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGATAC AACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCA CAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTC CCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACA CTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTAT TACTGCATGCAGGGACTCGGCCTCCCTCTCACTTTTGGCGGA GGGACCAAGGTTGAGATCAAACGGGCCGCTGCCCTTGATAAT GAAAAGT CAAACGGAACAAT GATT CAC GT GAAGGGCAAGCAC CTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTC TGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCT CTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCC AAAAGAAGC C GCCT GCT CCAT AGC GAT T ACAT GAAT AT GACT CCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTAC GCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAG TTT T C CAGAT CT GCAGAT GCAC CAGC GTAT CAGCAGGGC CAG AACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAG TATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATG GGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTAT AAT GAGCT GCAGAAGGATAAGAT GGCT GAAGCCTATT CTGAA ATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGAC GGT TT GTAC CAGGGACT CAGCACT GCTACGAAGGATACTTAT GACGCTCTCCACATGCAAGCCCTGCCACCTAGGTAA

PC21497CAR HxL

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGGATATTGTGATGACTCAGTCT CCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATC TCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGATAC AACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCA CAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTC CCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACA CTGAAAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTAT TACTGCATGCAGGGACTCGGCCTCCCTCTCACTTTTGGCGGA GGGACCAAGGTTGAGATCAAACGGGGGTCTACATCCGGCTCC GGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCAGGTG CAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGG TCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGT AGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGG CT GGAGT GGGT GGCAGTTAT AT CGTAT GAT GGAAGTAATAAA TACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGA GACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTG AGAGCCGAGGACACGGCGGTGTACTACTGCGCCAGAGACGGT ACTTATCTAGGTGGTCTCTGGTACTTCGACTTATGGGGGAGA GGTACCTTGGTCACCGTCTCCTCAGCCGCTGCCCTTGATAAT GAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCAC CTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTC TGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCT CTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCC AAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACT CCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTAC GCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAG TTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAG AACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAG TATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATG

181

YYCARDGTYLGGLWYFDLW GRGTLVTVS3GSTSGSGKP GSGEGSTKGDIVMTQSPLS LPVTPGEPASISCRSSQSL LHSNGYNYLDWYLQKPGQS PQLLIYLGSNRASGVPDRF SGSGSGTDFTLKISRVEAE DVGVYYCMQGLGLPLTFGG GTKVEIKRAAALDNEKSNG TIIHVKGKHLCPSPLFPGP S KP FWVL VWGGVLAC YS L LVTVAFIIFWVRS KRS RLL HSDYMNMTPRRPGPTRKHY QPYAPPRDFAAYRSRVKFS RSADAPAYQQGQNQLYNEL NLGRREEYDVLDKRRGRDP EMGGKPRRKNPQEGLYNEL QKDKMAEAYSEIGMKGERR RGKGHDGLYQGLSTATKDT YDALHMQALPPR

MALPVTALLLPLALLLHAA RPDIVMTQSPLSLPVTPGE PASISCRSSQSLLHSNGYN YLDWYLQKPGQSPQLLIYL GSNRASGVPDRFSGSGSGT DFTLKISRVEAEDVGVYYC MQGLGLPLTFGGGTKVEIK RGSTSGSGKPGSGEGSTKG QVQLVES GGGWQPGRS LR LSCAASGFTFSSYGMHWVR QAPGKGLEWVAVISYDGSN KYYAD SVKGRFTISRDNSK NTLYLQMNSLRAEDTAVYY CARDGTYLGGLWYFDLWGR GTLVTVSSAAALDNEKSNG TIIHVKGKHLCPSPLFPGP S KP FWVLVVVGGVLACYS L LVTVAFIIFWVRSKRS RLL HSDYMNMTPRRPGPTRKHY QPYAPPRDFAAYRSRVKFS RSADAPAYQQGQNQLYNEL NLGRREEYDVLDKRRGRDP EMGGKPRRKNPQEGLYNEL QKDKMAEAYSEIGMKGERR RGKGHDGLYQGLSTATKDT YDALHMQALPPR

182

-6419653

	GGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTAT AATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAA ATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGAC GGTT T GTAC CAGGGACT CAGCACT GCT AC GAAGGATACTTAT GACGCTCTCCACATGCAAGCCCTGCCACCTAGGTAA
AJ21508CAR HxL	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGCAGGTGCAGCTGGTGCAGTCT GGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCC T GCAAGGCAT CT GGATACACCTT CACCAGCTACTAT AT GCAC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGA ATAATCAACCCTGGTGGTGGTAGCACAAGCTACGCACAGAAG TTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGC ACAGTCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACG GCGGT GTACTACT GC GCCAGAGAGAGT T GGC CAAT GGAC GTA TGGGGCCAGGGAACAACTGTCACCGTCTCCTCAGGGTCTACA TCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAG GGGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTG TCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAG AGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGC CAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCC ACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACA GAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTT GCAGTTTATTACTGTCAGCAGTACGCCGCCTACCCTACTTTT GGCGGAGGGACCAAGGTTGAGATCAAACGGGCCGCTGCCCTT GATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGC AAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAG CCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGT TACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTT AGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAAT ATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAG CCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGG GTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAG GGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGG GAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCT GAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGT CTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTAT T CT GAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGG CACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGAT ACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGGTAA	183	MALPVTALLLPLALLLHAA RPQVQLVQSGAEVKKPGAS VKVSCKASGYTFTSYYMHW VRQAPGQGLEWMGIINPGG GSTSYAQKFQGRVTMTRDT STSTVYMELSSLRSEDTAV YYCARESWPMDVWGQGTTV TVSSGSTSGSGKPGSGEGS TKGEIVMTQSPATLSVSPG ERATLSCRASQSVSSNLAW YQQKPGQAPRLLIYGASTR ATGIPARFSGSGSGTEFTL TISSLQSEDFAVYYCQQYA AYPTFGGGTKVEIKRAAAL DNEKSNGTIIHVKGKHLCP SPLFPGPSKPFWVLVWGG VLACYSLLVTVAFIIFWVR S KRS RLLH S DYMNMT P RRP GPTRKHYQPYAPPRDFAAY RS RVK F S RSADAPAYQ Q GQ NQLYNELNLGRREEYDVLD KRRGRDPEMGGKPRRKNPQ EGLYNELQKDKMAEAYSEI GMKGERRRGKGHDGLYQGL STATKDTYDALHMQALPPR	184
AJ21508CAR LxH	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGGAAATAGTGATGACGCAGTCT CCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTC TCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT GGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGT GGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGC CTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTAC GCCGCCTACCCTACTTTTGGCGGAGGGACCAAGGTTGAGATC AAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGC GAAGGTAGTACAAAGGGGCAGGTGCAGCTGGTGCAGTCTGGG GCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTTCCTGC AAGGCAT CT GGATACAC CTT CACCAGCTACTAT AT GCACT GG GTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAATA ATCAACCCTGGTGGTGGTAGCACAAGCTACGCACAGAAGTTC CAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCACA GT CTACAT GGAGCT GAGCAGC CT GAGAT CT GAGGACAC GGCG GTGTACTACTGCGCCAGAGAGAGTTGGCCAATGGACGTATGG GGCCAGGGAACAACTGTCACCGTCTCCTCAGCCGCTGCCCTT	185	MALPVTALLLPLALLLHAA RPEIVMTQSPATLSVSPGE RATLSCRASQSVSSNLAWY QQKPGQAPRLLIYGASTRA TGIPARFSGSGSGTEFTLT ISSLQSEDFAVYYCQQYAA YPTFGGGTKVEIKRGSTSG SGKPGSGEGSTKGQVQLVQ SGAEVKKPGASVKVSCKAS GYT FT S YYMHWVRQAP GQ G LEWMGIINPGGGSTSYAQK FQGRVTMTRDTSTSTVYME L S S LRS EDTAVYYCARESW PMDVWGQGTTVTVS SAAAL DNEKSNGTIIHVKGKHLCP SPLFPGPSKPFWVLVWGG VLACYSLLVTVAFIIFWVR SKRSRLLHSDYMNMTPRRP GPTRKHYQPYAPPRDFAAY	186

- 65 19653

	GATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGC AAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAG CCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGT TACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTT AGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAAT ATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAG CCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGG GTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAG GGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGG GAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCT GAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGT CTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTAT TCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGG CACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGAT ACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGGTAA		RSRVKFSRSADAPAYQQGQ NQLYNELNLGRREEYDVLD KRRGRDPEMGGKPRRKNPQ EGLYNELQKDKMAEAYSEI GMKGERRRGKGHDGLYQGL STATKDTYDALHMQAAPPR
NM21517CAR HxL	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGCAGCTGCAGCTGCAGGAGTCG GGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACC T GCACT GT CT CT GGT GGCT C CAT CAGCAGTAGTAGTTACTAC TGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG ATTGGGAGTATCTCCTATAGTGGGAGCACCTACTACAACCCG T C C C T CAAGAGTCGAGTCACGATATCCGTAGACACGT CCAAG AACCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCAGAC ACGGCGGTGTACTACTGCGCCAGAGGCAGGGGATATGCAACC AGCTTAGCCTTCGATATCTGGGGTCAGGGTACAATGGTCACC GTCTCCTCAGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGT GGC GAAGGTAGTACAAAGGGGGAAATT GT GTT GACACAGT CT CCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTC TCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGG TACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT GATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGT GGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGC CTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGAGA CACGTCTGGCCTCCTACTTTTGGCGGAGGGACCAAGGTTGAG ATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGA ACLAACATTCACGTGAAGGGCAA.GCACCTCTGTCCGTCACCC TTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTA GTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTG GCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTG CTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGC CCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGAT TTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCA GATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAAC GAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGAC AAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGA CGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAG GATAAGAT GGCT GAAGC CTATT CT GAAATAGGCAT GAAAGGA GAGCGGAGAAGGGGAAA7ÆGGCACGACGGTTTGTACCAGGGA CT CAGCACT GCTAC GAAGGATACTT AT GACGCT CT CCACAT G CAAGCCCTGCCACCTAGGTAA	187	MALPVTALLLPLALLLHAA RPQLQLQESGPGLVKPSET LSLTCTVSGGSISSSSYYW GWIRQPPGKGLEWIGSISY SGSTYYNPSLKSRVTISVD TSKNQFSLKLSSVTAADTA VYYCARGRGYAT S LAFDIW GQGTMVTVSSGSTSGSGKP GSGEGSTKGEIVLTQSPAT LSLSPGERATLSCRASQSV SSYLAWYQQKPGQAPRLLI YDASNRATGIPARFSGSGS GTDFTLTISSLEPEDFAVY YCQQRHWPPTFGGGTKVE IKRAAALDNEKSNGTIIHV KGKHLCPSPLFPGPSKPFW VLVVVGGVLACYSLLVTVA FIIFWVRSKRSRLLHSDYM NMT P RRP G P T RKHYQP YAP P RD FAAYRS RVKF S RSADA PAYQQGQNQLYNELNLGRR EEYDVLDKRRGRDPEMGGK PRRKNPQEGLYNELQKDKM AEAYSEIGMKGERRRGKGH DGLYQGLSTATKDTYDALH MQALPPR	188
NM21517CAR LxH	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGGAAATTGTGTTGACACAGTCT CCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTC TCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGG TACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT GATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGT GGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGC CTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGAGA	189	MALPVTALLLPLALLLHAA RPEIVLTQSPATLSLSPGE RAT L S CRAS Q SVS SYLAWY QQKPGQAPRLLIYDASNRA TGIPARFSGSGSGTDFTLT IS SLEPEDFAVYYCQQRHV WPPTFGGGTKVEIKRGSTS GSGKPGSGEGSTKGQLQLQ	190

-6619653

CACGTCTGGCCTCCTACTTTTGGCGGAGGGACCAAGGTTGAG ATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGT GGCGAAGGTAGTACAAAGGGGCAGCTGCAGCTGCAGGAGTCG GGCCCAGGACTGGTGAAGCCTTCGGAGACCCTGTCCCTCACC TGCACTGTCTCTGGTGGCTCCATCAGCAGTAGTAGTTACTAC TGGGGCTGGATCCGCCAGCCCCCAGGGAAGGGGCTGGAGTGG ATTGGGAGTATCTCCTATAGTGGGAGCACCTACTACAACCCG TCCCTCAAGAGTCGAGTCACCATATCCGTAGACACGTCCAAG AACCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCAGAC ACGGCGGTGTACTACTGCGCCAGAGGCAGGGGATATGCAACC AGCTTAGCCTTCGATATCTGGGGTCAGGGTACAATGGTCACC GTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGA AC7\AT GATT CACGT GAAGGGCAAGCACCT CT GTCCGTCACCC TTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTA GTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTG GCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTG CTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGC CCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGAT TTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCA GATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAAC GAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGAC AAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGA CGAAAAAAC C C C CAGGAGGGT CT CT AT AAT GAGCT GCAGAAG GATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGA GAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGA CTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATG CAAGCCCTGCCACCTAGGTAA

TS21522CAR HxL

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGGAGGTGCAGCTGGTGGAGTCT GGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCC TGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAAC TGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCA ACCATTAGTAGTAGTAGTAGTACCATATACTACGCAGACTCT GTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAAC TCACT GTAT CT GCAAATGAACAGCCTGAGAGCT GAGGACACG GCGGTGTACTACTGCGCCAGAGGTTCTCAGGAGCACCTGATT TTCGATTATTGGGGACAGGGTACATTGGTCACCGTCTCCTCA GGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGT AGT ACAAAGGGGGAAATT GT GT T GACACAGT CT CCAGC CAC C CTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG GCCAGTCAGAGTGTTAGCAGGTACTTAGCCTGGTACCAACAG AAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCC AACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGG TCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCT GAAGAT TTT GCAGTT T ATTACT GT CAGCAGAGAT T CTACTAC CCTTGGACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGG GCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATT CACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCT GGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGA GTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATA ATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGC GATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGG AAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCC TATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCA GC GTAT CAGCAGGGCCAGAAC CAACT GTAT AAC GAGCT CAAC CTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGA GGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAAC CCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATG GCT GAAGCCTAT T CT GAAATAGGCAT GAAAGGAGAGC GGAGA

191

ESGPGLVKPSETLSLTCTV SGGSISSSSYYWGWIRQPP GKGLEWIGSISYSGSTYYN PSLKSRVTISVDTSKNQFS LKLS SVTAADTAVYYCARG RGYAT S LAFDIWGQGTMVT VSSAAALDNEKSNGTIIHV KGKHLCPSPLFPGPSKPFW VLVWGGVLACYS LLVTVA FIT FWVRS KRS RLLHS DYM NMT P RRP GP T RKHYQ P YAP P RD FAAYRS RVKF S RS ADA PAYQQGQNQLYNELNLGRR EEYDVLDKRRGRDPEMGGK PRRKNPQEGLYNELQKDKM AEAYSEIGMKGERRRGKGH DGLYQGLSTATKDTYDALH MQALPPR

192

RPEVQLVESGGGLVQPGGS LRLSCAASGFTFSSYSMNW VRQAPGKGLEWVSTISS S S STIYYADSVKGRFTIS RDN AKNSLYLQMNSLRAEDTAV YYCARGSQEHLIFDYWGQG TLVTVSSGSTSGSGKPGSG EGSTKGEIVLTQSPATLSL SPGERATLSCRASQSVSRY LAWYQQKPGQAPRLLIYDA SNRATGIPARFSGSGSGTD FTLTISSLEPEDFAVYYCQ QRFYYPWTFGGGTKVEIKR AAALDNEKSNGTIIHVKGK HLCPSPLFPGPSKPFWVLV VVGGVLACYSLLVTVAFII FWVRSKRSRLLHSDYMNMT PRRPGPTRKHYQPYAPPRD FAAYRS RVKFS RSADAPAY QQGQNQLYNELNLGRREEY DVLDKRRGRDPEMGGKPRR KNPQEGLYNELQKDKMAEA YSEIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQA LPPR

- 6719653

	AGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTG CCACCTAGGTAA
TS21522CAR LxH	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGGAAATTGTGTTGACACAGTCT CCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTC TCCTGCAGGGCCAGTCAGAGTGTTAGCAGGTACTTAGCCTGG TACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT GATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGT GGCAGT GGGTCT GGGACAGACTT CACTCT CACCATCAGCAGC CTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGAGA TTCTACTACCCTTGGACTTTTGGCGGAGGGACCAAGGTTGAG ATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGT GGCGAAGGTAGTACAAAGGGGGAGGT GCAGCT GGT GGAGT CT GGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCC TGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAAC TGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCA ACCATTAGTAGTAGTAGTAGTACCATATACTACGCAGACTCT GTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAAC T CACT GTAT CT GCAAAT GAACAGC CT GAGAGCT GAGGACAC G GCGGTGTACTACTGCGCCAGAGGTTCTCAGGAGCACCTGATT TTCGATTATTGGGGACAGGGTACATTGGTCACCGTCTCCTCA GCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATT CACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCT GGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGA GTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATA ATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGC GATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGG AAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCC TATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCA GCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAAC CTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGA GGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAAC CCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATG GCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGA AGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTG CCACCTAGGTAA	193	MALPVTALLLPLALLLHAA RPEIVLTQSPATLSLSPGE RAT L S C RAS Q S VS RYLAW Y QQKPGQAPRLLIYDASNRA TGIPARFSGSGSGTDFTLT ISSLEPEDFAVYYCQQRFY YPWTFGGGTKVEIKRGSTS GSGKPGSGEGSTKGEVQLV ESGGGLVQPGGSLRLSCAA SGFTFSSYSMNWVRQAPGK GLEWVSTISSSSSTIYYAD SVKGRFTIS RDNAKN S LYL QMNSLRAEDTAVYYCARGS QEHLIFDYWGQGTLVTVSS AAALDNEKSNGTIIHVKGK HLCPSPLFPGPSKPFWVLV WGGVLACYS LLVTVAFII FWVRS KRS RLLHS DYMNMT P RRP G PT RKHYQ P YAP P RD FAAYRS RVKFS RSADAPAY QQGQNQLYNELNLGRREEY DVLDKRRGRDPEMGGKPRR KNPQEGLYNELQKDKMAEA YS EIGMKGERRRGKGHDGL YQGLSTATKDTYDALHMQA LPPR	194
RY21527CAR HxL	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGCAGGTGCAGCTGGTGGAGTCT GGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCC TGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCAC TGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCA GT TATAT C GTAT GAT GGAAGTAAT AAATACTAT GCAGACT C C GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GCGGTGTACTACTGCGCCAGAACTGACTTCTGGAGCGGATCC CCTCCAGGCTTAGATTACTGGGGACAGGGTACATTGGTCACC GTCTCCTCAGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGT GGCGAAGGTAGTACAAAGGGGGACATCCAGTTGACCCAGTCT C CAT CT T C C GT GT CT GCAT CT GTAGGAGACAGAGT CAC CAT C ACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGG TATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTAT GGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGC GGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGC CTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGATA TACACCTTCCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAG ATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGA	195	MALPVTALLLPLALLLHAA RPQVQLVESGGGWQPGRS LRLSCAASGFTFSSYGMHW VRQAP GKGL EWVAVIS YD G SNKYYAD SVKGRFTIS RDN SKNTLYLQMNSLRAEDTAV YYCARTDFWSGSPPGLDYW GQGTLVTVSSGSTSGSGKP GSGEGSTKGDIQLTQSPSS VSASVGDRVTITCRASQGI SSWLAWYQQKPGKAPKLLI YGASSLQSGVPSRFSGSGS GTDFTLTISSLQPEDFATY YCQQIYT FP FT FGGGT KVE IKRAAALDNEKSNGTIIHV KGKHLCPSPLFPGPSKPFW VLVWGGVLACYSLLVTVA FIIFWVRSKRS RLLHS DYM NMTPRRPGPTRKHYQPYAP PRDF7XAYRSRVKFSRSADA	196

- 68 19653

	ACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCC TTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTA GTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTG GCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTG CTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGC CCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGAT TTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCA GATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAAC GAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGAC AAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGA CGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAG GATAAGATGGCTGYAGCCTATTCTGAAATAGGCATGAAAGGA GAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGA CTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATG CAAGCCCTGCCACCTAGGTAA		PAYQQGQNQLYNELNLGRR EEYDVLDKRRGRDPEMGGK PRRKNPQEGLYNELQKDKM AEAYS EIGMKGERRRGKGH DGLYQGLSTATKDTYDALH MQALPPR
RY21527CAR LxH	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGGACATCCAGTTGACCCAGTCT CCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATC ACTTGTCGGGCGAGTCAGGGTATTAGCAGCTGGTTAGCCTGG TAT CAGCAGAAACCAGGGAAAGCCCCT AAGCT CCT GAT CTAT GGT GCATCCAGTTT GCAAAGTGGGGTCCCAT CAAGGTT CAGC GGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGC CTGCAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGATA TACACCTTCCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAG ATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGT GGCGAAGGTAGTACAAAGGGGCAGGTGCAGCTGGTGGAGTCT GGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCC TGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCAC TGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCA GT TATAT C GTAT GAT GGAAGTAAT AAATACT AT GCAGACT C C GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GCGGTGTACTACTGCGCCAGAACTGACTTCTGGAGCGGATCC CCTCCAGGCTTAGATTACTGGGGACAGGGTACATTGGTCACC GTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGA ACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCC TTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTA GTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTG GCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTG CTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGC CCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGAT TTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCA GATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAAC GAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGAC AAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGA CGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAG GATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGA GAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGA CTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATG CAAGCCCTGCCACCTAGGTAA	197	MALPVTALLLPLALLLHAA RPDIQLTQSPSSVSASVGD RVTITCRASQGISSWLAWY QQKPGKAPKLLIYGASSLQ SGVPSRFSGSGSGTDFTLT ISSLQPEDFATYYCQQIYT FPFTFGGGTKVEIKRGSTS GSGKPGSGEGSTKGQVQLV ESGGGWQPGRSLRLSCAA SGFTFSSYGMHWVRQAPGK GLEWVAVISYDGSNKYYAD SVKGRFTISRDNSKNTLYL QMNSLRAEDTAVYYCARTD FWSGSPPGLDYWGQGTLVT VSSAAALDNEKSNGTIIHV KGKHLCPSPLFPGPSKPFW VLVWGGVLACYSLLVTVA FI I FWVRS krs rllhs dym NMTPRRPGPTRKHYQPYAP PRDFAAYRSRVKFSRSADA PAYQQGQNQLYNELNLGRR EEYDVLDKRRGRDPEMGGK PRRKNPQEGLYNELQKDKM AEAYSEIGMKGERRRGKGH DGLYQGLSTATKDTYDALH MQALPPR	198
PP21528CAR HxL	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGCAGGTGCAGCTGGTGCAGTCT GGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCC TGCAAGGCTTCTGGAGGCACCTTCAGCAGCTATGCTATCAGC TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGA GGGATCATCCCTATCTTTGGTACAGCAAACTACGCACAGAAG TTCCAGGGCAGAGTCACGATTACCGCGGACGAATCCACGAGC ACAGCCTACAT GGAGCT GAGCAGCCT GAGAT CT GAGGACACG	199	MALPVTALLLPLALLLHAA RP QVQLVQ S GAEVKK P GS S VKVS CKAS GGT FS S YAISW VRQAPGQGLEWMGGIIPIF GTANYAQKFQGRVTITADE STSTAYMELSSLRSEDTAV YYCARTPEYSSSIWHYYYG MDVWGQGTTVTVS S GST S G	200

- 6919653

GCGGTGTACTACTGCGCCAGAACTCCTGAATACTCCTCCAGC ATATGGCACTATTACTACGGCATGGACGTATGGGGCCAGGGA ACAACTGTCACCGTCTCCTCAGGGTCTACATCCGGCTCCGGG AAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGACATCGTG ATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAG AGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATAC AGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAA CCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACC CGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCT GGGACAGAT T T CACT CT CAC CAT CAGCAGCCT GCAGGCT GAA GATGTGGCAGTTTATTACTGTCAGCAGTTCGCCCACACTCCT TTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGCC GCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCAC GTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGT CCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTC CTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATC TTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGAT TACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAA CACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTAT CGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCG TAT CAGCAGGGCCAGAACCAACT GTATAACGAGCTCAACCT G GGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGA C GGGAC CCT GAGAT GGGT GGCAAACCAAGACGAAAAAACC CC CAGGAGGGT CT CTAT AAT GAGCT GCAGAAGGATAAGAT GGCT GAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGG GGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCT ACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCA CCTAGGTAA pp_ 21528CAR LxH

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGGACATCGTGATGACCCAGTCT CCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCATC AACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAAT AAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCT CCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGG GTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTC ACT CT CACCAT CAGCAGCCT GCAGGCT GAAGAT GT GGCAGTT TATTACTGTCAGCAGTTCGCCCACACTCCTTTCACTTTTGGC GGAGGGACCAAGGTTGAGATCAAACGGGGGTCTACATCCGGC TCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCAG GTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGG TCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCTTC AGCAGCTATGCTATCAGCTGGGTGCGACAGGCCCCTGGACAA GGGCTTGAGTGGATGGGAGGGATCATCCCTATCTTTGGTACA GCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTACC GCGGACGAATCCACGAGCACAGCCTACATGGAGCTGAGCAGC CTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAACT CCTGAATACTCCTCCAGCATATGGCACTATTACTACGGCATG GACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCAGCC GCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCAC GTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGT CCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTC CTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATC TTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGAT TACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAA CACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTAT CGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCG TATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTG GGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGA CGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCC

201

SGKPGSGEGSTKGDIVMTQ SPDSLAVSLGERATINCKS SQSVLYSSNNKNYLAWYQQ KPGQPPKLLIYWASTRESG VPDRFSGSGSGTDFTLTIS S LQAEDVAVYYCQQFAHTP FTFGGGTKVEIKRAAALDN EKSNGTIIHVKGKHLCPSP LFPGPSKPFWVLVWGGVL ACYS LLVTVAFIIFWVRS K RSRLLHSDYMNMTPRRPGP TRKHYQPYAPPRDFAAYRS RVKFSRSADAPAYQQGQNQ LYNELNLGRREEYDVLDKR RGRDPEMGGKPRRKNPQEG LYNELQKDKMAEAYSEIGM KGERRRGKGHDGLYQGLST ATKDTYDALHMQALPPR

MALPVTALLLPLALLLHAA RPDIVMTQSPDSLAVSLGE RATINCKSSQSVLYSSNNK NYLAWYQQKPGQPPKLLIY WASTRESGVPDRFSGSGSG TDFTLTISSLQAEDVAVYY CQQFAHTP FT FGGGTKVEI KRGSTSGSGKPGSGEGSTK GQVQLVQSGAEVKKPGSSV KVS CKAS GGT FS SYAIS WV RQAPGQGLEWMGGIIPIFG TANYAQKFQGRAZTITADES TSTAYMELSSLRSEDTAVY YCART P EYS S SIWHYYYGM DVWGQGTTVTVSSAAALDN EKSNGTIIHVKGKHLCPSP LFPGPSKPFWVLVWGGVL ACYSLLVTVAFIIFWVRSK RSRLLHSDYMNMTPRRPGP T RKHYQ PYAP P RD FAAYRS RVKFSRSADAPAYQQGQNQ LYNELNLGRREEYDVLDKR RGRDPEMGGKPRRKNPQEG LYNELQKDKMAEAYSEIGM KGERRRGKGHDGLYQGLST ATKDTYDALHMQALPPR

202

- 7019653

	CAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCT GAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGG GGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCT AC GAAGGATACTTAT GACGCT CT C CACAT GCAAGC C CT GC CA CCTAGGTAA
RD21530CAR HxL	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGCAGGTGCAGCTGGTGGAGTCT GGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCC TGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCAC T GGGT CCGCCAGGCT C CAGGCAAGGGGCT GGAGT GGGT GGCA GTTATATCGTATGATGGAAGTAATAAATACTATGCAGACTCC GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACG GCGGTGTACTACTGCGTCAAGGGGCCGTTGCAGGAGCCGCCA TACGATTATGGAATGGACGTATGGGGCCAGGGAACAACTGTC ACCGTCTCCTCAGGGTCTACATCCGGCTCCGGGAAGCCCGGA AGT GGCGAAGGTAGTACAAAGGGGGAAATAGT GAT GACGCAG TCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACC CT CT CCT GCAGGGCCAGT CAGAGT GTTAGCAGCAACTTAGC C TGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATC TATAGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTC AGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGC AGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAG CACCACGTCTGGCCTCTCACTTTTGGCGGAGGGACCAAGGTT GAGAT CAAACGGGCCGCT GC C CT T GATAAT GAAAAGT CAAAC GGAACAAT CATT CACGT GAAGGGCAAGCAC CT CT GT C CGT CA CCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTC GTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACC GTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGC CTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCT GGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGA GATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCT GCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTAT AACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTG GACAAGCGCAGAGGACGGGACCCT GAGATGGGTGGCAAACCA AGACGAAAAAACCCCCAGGAGGGT CT CTATAATGAGCT GCAG AAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCAT GAAA GGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAG GGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCAC ATGCAAGCCCTGCCACCTAGGTAA	203	MALPVTALLLPLALLLHAA RPQVQLVE S GGGWQP GRS LRLSCAASGFTFSSYGMHW VRQAPGKGLEWVAVI S YDG SNKYYADSVKGRFTIS RDN SKNTLYLQMNSLRAEDTAV YYCVKGPLQEPPYDYGMDV WGQGTTVTVSSGSTSGSGK PGSGEGSTKGEIVMTQSPA TLSVSPGERATLSCRASQS VSSNLAWYQQKPGQAPRLL IYSASTRATGIPARFSGSG SGTEFTLTISSLQSEDFAV YYCQQHHVWPLTFGGGTKV EIKRAAALDNEKSNGTIIH VKGKHLCPSPLFPGPSKPF WVLVWGGVLAC YS L LVT V AFIIFWVRSKRSRLLHSDY MNMTPRRPGPTRKHYQPYA PPRDFAAYRSRVKFSRSAD APAYQQGQNQLYNELNLGR REEYDVLDKRRGRDPEMGG KPRRKNPQEGLYNELQKDK MAEAYSElGMKGERRRGKG HDGLYQGLSTATKDTYDAL HMQALPPR	204
RD21530CAR LxH	ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTG CTCCTGCACGCCGCACGCCCGGAAATAGTGATGACGCAGTCT CCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTC TCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGG TACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT AGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGT GGCAGTGGGT CT GGGACAGAGTTCACTCT CACCAT CAGCAGC CTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCAC CACGTCTGGCCTCTCACTTTTGGCGGAGGGACCAAGGTTGAG ATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGT GGCGAAGGTAGTACAAAGGGGCAGGTGCAGCTGGTGGAGTCT GGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCTCC TGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATGCAC TGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCA GTT ATATCGTAT GAT GGAAGT AATAAATACTAT GCAGACT CC GTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAAC ACGCT GTAT CT GCAAAT GAACAGC CT GAGAGCCGAGGACAC G GCGGTGTACTACTGCGTCAAGGGGCCGTTGCAGGAGCCGCCA	205	MALPVTALLLPLALLLHAA. RPEIVMTQSPATLSVSPGE RATLSCRASQSVSSNLAWY QQKPGQAPRLLIYSASTRA TGIPARFSGSGSGTEFTLT ISSLQSEDFAVYYCQQHHV WPLTFGGGTKVEIKRGSTS GSGKPGSGEGSTKGQVQLV ESGGGWQPGRSLRLSCAA SGFTFSSYGMHWVRQAPGK GLEWVAVISYDGSNKYYAD SVKGRFTIS RDNS KNTLYL QMNSLRAEDTAVYYCVKGP LQEPPYDYGMDVWGQGTTV TVSSAAALDNEKSNGTIIH VKGKHLCPSPLFPGPSKPF WVLVWGGVLAC YS L LVT V AFIIFWVRSKRSRLLHSDY	206

- 71 19653

TAC GATTAT GGAAT GGAC GTAT GGGGCCAGGGAACAACTGTC ACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAAC GGAACAAT CATT CACGT GAAGGGCAAGCACCT CT GT C C GT CA CCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTC GTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACC GTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGC CTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCT GGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGA GATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCT GCAGAT GCAC CAGC GT AT CAGCAGGGC CAGAAC CAACT GTAT AACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTG GACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCA AGACG^AAAAA C C C C CAGGAGGGT CT CT AT AAT GAGCT GCAG AAGGATAAGAT GGCT GAAGCCTATT CTGAAATAGGCATGAAA GGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAG GGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCAC ATGCAAGCCCTGCCACCTAGGTAA

MNMTPRRPGPTRKHYQPYA P P RD FAAYRS RVK F S RS AD APAYQQGQNQLYNELNLGR REEYDVLDKRRGRDPEMGG KPRRKNPQEGLYNELQKDK HDGLYQGLSTATKDTYDAL HMQALPPR

[0289] In some embodiments, the polynucleotide of the présent invention encodes a CAR, wherein the CAR comprises an amino acid sequence at least about 75%, at least about 85%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, and 206. In certain embodiments, the CAR comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, and 206. In one embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 176. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 178. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 180. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 182. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 184. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 186. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 188. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 190. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 192. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 194. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 196. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 198. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 200. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 202. In another

-7219653 embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 204. In another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 206.

[0290] In some embodiments, the polynucleotide of the présent invention comprises an nucléotide sequence at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 85%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, and 205. In certain embodiments, the polynucleotide comprises a nucléotide sequence selected from the group consisting of SEQ ID NOs: 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, and 205. In one embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 175. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 177. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 179. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 181. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 183. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 185. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 187. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 189. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 191. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 193. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 195. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 197. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 199. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 201. In another embodiment, the polynucleotide comprises the nucléotide sequence of SEQ ID NO: 203. In another embodiment, the polynucleotide comprises the nucléotide sequence ofSEQIDNO: 205.

[0291] In further embodiments, the invention relates to Clone FS-26528 HC DNA (SEQ ID NO: 271) as follows:

GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGACGACTATGCC

- 73 19653

ATGGCATGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAG CTATTAGTGATGCAGGTGACAGAACATACTACGCAGACTCCGTGAGGGG CCGGTTCACCATCTCCAGAGACAATTCCAAGAACACACTGTATCTGCAA ATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCAAGA GCCGAGATGGGAGCCGTATTCGACATATGGGGTCAGGGTACAATGGTCA CCGTCTCCTCA

[0292] In further embodiments, the invention relates to the Clone FS-26528 HC amino acid sequence (SEQ ID NO: 272):

EVQLLESGGG LVQPGGSLRL SCAASGFTFD DYAMAWVRQA PGKGLEWVSAISDAGDRTYY ADSVRGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARAE MGAVFDIWGQ GTMVTVSS

[0293] In fùrther embodiments, the invention relates to HC CDRI thereof: SCAASGFTFDDYAMA (SEQ ID NO: 273). In further embodiments, the invention relates to HC CDR2 thereof: AISDAGDRTYYADSVRG (SEQ ID NO: 274). In further embodiments, the invention relates to HC CDR3 thereof: ARAEMGAVFDI (SEQ ID NO: 275) [HC CDR3]

[0294] In further embodiments, the invention relates to Clone FS-26528 LC DNA (SEQ ID NO: 276):

GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGGTACTTA GCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATG ATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAGCAGAGAATCTCCTGGCCTTTCACTTTTGGC GGAGGGACCAAGGTTGAGATCAAACGG

[0295] In further embodiments, the invention relates to Clone FS-26528 LC AA sequence (SEQ ID NO: 277):

EIVLTQSPAT LSLSPGERAT LSCRASQSVS RYLAWYOQKP GQAPRLLIYD ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RISWPFTFGG GTKVEIKR.

[0296] In fùrther embodiments, the invention relates to LC CDRI thereof: RASQSVSRYLA (SEQ ID NO: 278). In further embodiments, the invention relates to LC

-7419653

CDR2 thereof: DASNRAT (SEQ ID NO: 279). In further embodiments, the invention relates to the LC CDR3 thereof: QQRISWPFT (SEQ ID NO: 280).

[0297] In further embodiments, the invention relates to Clone FS-26528 CAR DNA HxL (SEQ ID NO: 281):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTA CAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTT TGACGACTATGCCATGGCATGGGTCCGCCAGGCTCCAGGGAAGGGGCTG GAGTGGGTCTCAGCTATTAGTGATGCAGGTGACAGAACATACTACGCAG ACTCCGTGAGGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACAC ACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTAC TACTGCGCAAGAGCCGAGATGGGAGCCGTATTCGACATATGGGGTCAGG GTACAATGGTCACCGTCTCCTCAGGGTCTACATCCGGCTCCGGGAAGCCC GGAAGTGGCGAAGGTAGTACAAAGGGGGAAATTGTGTTGACACAGTCTC CAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG GCCAGTCAGAGTGTTAGCAGGTACTTAGCCTGGTACCAACAGAAACCTG GCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGG CATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTC ACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCA GAGAATCTCCTGGCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAGATC AAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTC ACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCC AAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTC TCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAA GCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGC CCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTG CCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTA TCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGG GAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATG GGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAG CTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAG GAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCA

-7519653

GCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCC ACCTAGG

[0298] In further embodiments, the invention relates to Clone FS-26528 CAR HxL AA sequence (SEQ ID NO: 282):

MALPVTALLL PLALLLHAAR PEVQLLESGG GLVQPGGSLR LSCAASGFTF DDYAMAWVRQ APGKGLEWVS AISDAGDRTY YADSVRGRFT ISRDNSKNTL YLQMNSLRAE DTAVYYCARA EMGAVFDIWG QGTMVTVSSG STSGSGKPGS GEGSTKGEIV LTQSPATLSL SPGERATLSC RASQSVSRYL AWYQQKPGQA PRLLIYDASN RATGIPARFS GSGSGTDFTL TISSLEPEDF AVYYCQQRIS WPFTFGGGTK VEIKRAAALD NEKSNGTIIH VKGKHLCPSP LFPGPSKPFW VLVVVGGVLA CYSLLVTVAF IIFWVRSKRS RLLHSDYMNM TPRRPGPTRK HYQPYAPPRD FAAYRSRVKF

SRSADAPAYQ QGQNQLYNEL NLGRREEYDV LDKRRGRDPE

MGGKPRRKNP QEGLYNELQK DKMAEAYSEI GMKGERRRGK

GHDGLYQGLS TATKDTYDAL HMQALPPR

[0299] In fùrther embodiments, the invention relates to Clone FS-26528 CAR DNA LxH (SEQ ID NO: 283):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTT TGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT TAGCAGGTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGG CTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTA GAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGAGAATCTCCTGGCC TTTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTACA TCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAG GTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCC TGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGACGACTATGCCATG GCATGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTA TTAGTGATGCAGGTGACAGAACATACTACGCAGACTCCGTGAGGGGCCG GTTCACCATCTCCAGAGACAATTCCAAGAACACACTGTATCTGCAAATG AACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCAAGAGCC GAGATGGGAGCCGTATTCGACATATGGGGTCAGGGTACAATGGTCACCG

-7619653

TCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATT CACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATC CAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACT CTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGA AGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGG CCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCT GCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGT ATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAG GGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGAT GGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGA GCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAA GGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTC AGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGC CACCTAGG

[0300] In further embodiments, the invention relates to the Clone FS-26528 CAR LxH AA sequence (SEQ ID NO: 284):

MALPVTALLL PLALLLHAAR PEIVLTQSPA TLSLSPGERA TLSCRASQSV SRYLAWYQQK PGQAPRLLIY DASNRATGIP ARFSGSGSGT DFTLTISSLE PEDFAVYYCQ QRISWPFTFG GGTKVEIKRG STSGSGKPGS GEGSTKGEVQ LLESGGGLVQ PGGSLRLSCA ASGFTFDDYA MAWVRQAPGK GLEWVSAISD AGDRTYYADS VRGRFTISRD NSKNTLYLQM NSLRAEDTAV YYCARAEMGA VFDIWGQGTM VTVSSAAALD NEKSNGTIIH VKGKHLCPSP LFPGPSKPFW VLVWGGVLA CYSLLVTVAF IIFWVRSKRS RLLHSDYMNM TPRRPGPTRK HYQPYAPPRD FAAYRSRVKF

SRSADAPAYQ QGQNQLYNEL NLGRREEYDV LDKRRGRDPE

MGGKPRRKNP QEGLYNELQK DKMAEAYSEI GMKGERRRGK

GHDGLYQGLS TATKDTYDAL HMQALPPR

[0301] In further embodiments, the invention relates to Clone PC-26534 HC DNA (SEQ ID NO: 285) as follows:

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTGAGCATGGC ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAG CTATATCTTATGATGGAAGGAATAAACACTATGCAGACTCCGTGAAGGG

- 7719653

CCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAA ATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCCAGAG ACGGTACTTATCTAGGTGGTCTCTGGTACTTCGACTTATGGGGGAGAGGT ACCTTGGTCACCGTCTCCTCA

[0302] In further embodiments, the invention relates to Clone PC-26534 HC (SEQ ID

NO: 286):

QVQLVESGGG WQPGRSLRL SCAASGFTFS - EHGMHWVRQA

PGKGLEWVAA ISYDGRNKHY AD S VKGRFT I SRDNSKNTLY

LQMNSLRAED TAVYYCARDG TYLGGLWYFD LWGRGTLVTV SS.

[0303] In further embodiments, the invention relates to HC CDRI thereof: FTFSEHGMH (SEQ ID NO: 287). In fùrther embodiments, the invention relates to HC CDR2 thereof: AISYDGRNKHYADSVKG (SEQ ID NO: 288). In fùrther embodiments, the invention relates to HC CDR3 thereof: ARDGTYLGGLWYFDL (SEQ ID NO: 289).

[0304] In fùrther embodiments, the invention relates to Clone PC-26534 LC DNA (SEQ ID NO: 290) as follows:

GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGA GCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATG GATACAACTATTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACA GCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGT TCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGT GGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAGGGACTCGGCCTC CCTCTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGG

[0305] In fùrther embodiments, the invention relates to Clone PC-26534 LC AA sequence (SEQ ID NO: 291):

DIVMTQSPLS LPVTPGEPAS ISCRSSOSLL HSNGYNYLDW YLQKPGQSPQ LLIYLGSNRA SGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCMQGLGLP LTFGGGTKVE 1KR.

[0306] In fùrther embodiments, the invention relates to LC CDRI AA sequence thereof: RSSQSLLHSNGYNYLD (SEQ ID NO: 292). In fùrther embodiments, the invention relates to LC CDR2 thereof: LGSNRAS (SEQ ID NO: 293). In fùrther embodiments, the invention relates to LC CDR3 thereof: MQGLGLPLT (SEQ ID NO: 294).

[0307] In fùrther embodiments, the invention relates to Clone PC-26534 CAR DNA HxL (SEQ ID NO: 295) as follows:

- 78 19653

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTC CAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT CAGTGAGCATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTG GAGTGGGTGGCAGCTATATCTTATGATGGAAGGAATAAACACTATGCAG ACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACAC GCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTAC TACTGCGCCAGAGACGGTACTTATCTAGGTGGTCTCTGGTACTTCGACTT ATGGGGGAGAGGTACCTTGGTCACCGTCTCCTCAGGGTCTACATCCGGCT CCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGATATTGTGA TGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCC ATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGATACAACTA TTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCT ATTTGGGTTCTAATCGGGCCTCCGGGGTCCCTGACAGGTTCAGTGGCAGT GGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGG ATGTTGGGGTTTATTACTGCATGCAGGGACTCGGCCTCCCTCTCACTTTT GGCGGAGGGACCAAGGTTGAGATCAAACGGGCCGCTGCCCTTGATAATG AAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCC GTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAG TGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAA TCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATG AATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTT ACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCC AGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATA ACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCG CAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCC CCAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCC TATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCAC GACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACG CTCTCCACATGCAAGCCCTGCCACCTAGG

[0308] In further embodiments, the invention relates to Clone PC-26534 CAR HxL AA sequence (SEQ ED NO: 296):

- 7919653

MALPVTALLL PLALLLHAAR PQVQLVESGG GWQPGRSLR LSCAASGFTF SEHGMHWVRQ APGKGLEWVA AISYDGRNKH YADSVKGRFT ISRDNSKNTL YLQMNSLRAE DTAVYYCARD GTYLGGLWYF DLWGRGTLVT VSSGSTSGSG KPGSGEGSTK GDIVMTQSPL SLPVTPGEPA SISCRSSQSL LHSNGYNYLD WYLQKPGQSP QLLIYLGSNR ASGVPDRFSG SGSGTDFTLK ISRVEAEDVG VYYCMQGLGL PLTFGGGTKV EIKRAAALDN EKSNGTIIHV KGKHLCPSPL FPGPSKPFWV LVVVGGVLAC YSLLVTVAFI IFWVRSKRSR LLHSDYMNMT PRRPGPTRKH YQPYAPPRDF AAYRSRVKFS RSADAPAYQQ GQNQLYNELN LGRREEYDVL DKRRGRDPEM GGKPRRKNPQ EGLYNELQKD KMAEAYSEIG MKGERRRGKG HDGLYQGLST ATKDTYDALH MQALPPR

[0309] In fiirther embodiments, the invention relates to Clone PC-26534 CAR DNA

LxH (SEQ ID NO: 297):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCG TCACCCCTGGAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTC CTGCATAGTAATGGATACAACTATTTGGATTGGTACCTGCAGAAGCCAG GGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGG GTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGA AAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCA GGGACTCGGCCTCCCTCTCACTTTTGGCGGAGGGACCAAGGTTGAGATC AAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGT AGTACAAAGGGGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTC CAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT CAGTGAGCATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTG GAGTGGGTGGCAGCTATATCTTATGATGGAAGGAATAAACACTATGCAG ACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACAC GCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTAC TACTGCGCCAGAGACGGTACTTATCTAGGTGGTCTCTGGTACTTCGACTT ATGGGGGAGAGGTACCTTGGTCACCGTCTCCTCAGCCGCTGCCCTTGATA ATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTG TCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGT AGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTAT

-8019653

AATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTAC ATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGC CTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTT TCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGT ATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAA GCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAA CCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAA

GCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGG

CACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATG

ACGCTCTCCACATGCAAGCCCTGCCACCTAGG

[0310] In fùrther embodiments, the invention relates to Clone PC-26534 CAR LxH chain sequences (SEQ ID NO: 298):

MALPVTALLL PLALLLHAAR PDIVMTQSPL SLPVTPGEPA SISCRSSQSL LHSNGYNYLD WYLQKPGQSP QLLIYLGSNR ASGVPDRFSG SGSGTDFTLK ISRVEAEDVG VYYCMQGLGL PLTFGGGTKV EIKRGSTSGS GKPGSGEGST

KGQVQLVESG QAPGKGLEWV LYLQMNSLRA

GGVVQPGRSL

AAISYDGRNK

EDTAVYYCAR

RLSCAASGFT

HYADSVKGRF

DGTYLGGLWY

FSEHGMHWVR

TISRDNSKNT

FDLWGRGTLV

TVSSAAALDN EKSNGTIIHV KGKHLCPSPL FPGPSKPFWV LVVVGGVLAC

YSLLVTVAFI IFWVRSKRSR LLHSDYMNMT PRRPGPTRKH YQPYAPPRDF AAYRSRVKFS RSADAPAYQQ GQNQLYNELN LGRREEYDVL DKRRGRDPEM GGKPRRKNPQ EGLYNELQKD KMAEAYSEIG MKGERRRGKG HDGLYQGLST ATKDTYDALH MQALPPR

[0311] In further embodiments, the invention relates to Clone AJ-26545 HC DNA (SEQ ID NO: 299):

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCT CAGTGAAGGTTTCCTGCAGGGCATCTGGATACACCTTCATGGAGCACTAT

ATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAG TAATCGGGCCTAGTGGTGGTAAGACAAGCTACGCACAGAAGTTCCAGGG CAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACATGGAG CTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAG AGAATTGGCCAATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTC CTCA

- 81 19653

[0312] In further embodiments, the invention relates to Clone AJ-26545 HC AA sequence (SEQ ID NO: 300):

QVQLVQSGAE VKKPGASVKV SCRASGYTFM EHYMHWVRQA PGQGLEWMGV IGPSGGKTSY AQKFQGRVTM TRDTSTSTVY MELSSLRSED TAVYYCARES WPMDVWGOGT TVTVSS.

[0313] In further embodiments, the invention relates to HC CDR1 thereof: YTFMEHYMH (SEQ ID NO: 301). In further embodiments, the invention relates to HC CDR2 thereof: VIGPSGGKTSYAQKFQG (SEQ ID NO: 302). In further embodiments, the invention relates to HC CDR3 thereof: ARESWPMDV (SEQ ID NO: 303).

[0314] In further embodiments, the invention relates to Clone AJ-26545 LC DNA (SEQ ID NO: 304):

GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGG AAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTT AGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT GGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTG GGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGA TTTTGCAGTTTATTACTGTCAGCAGTACGCCGCCTACCCTACTTTTGGCG GAGGGACCAAGGTTGAGATCAAACGG

[0315] In further embodiments, the invention relates to Clone AJ-26545 LC AA sequence (SEQ ID NO: 305):

EIVMTQSPAT LSVSPGERAT LSCRASOSVS SNLAWYQQKP GQAPRLLIYG ASTRATGIPA RFSGSGSGTE FTLTISSLQS EDFAVYYCQQ YAAYPTFGGG TKVEIKR.

[0316] In further embodiments, the invention relates to LC CDR1 thereof: RASQSVSSNLA (SEQ ID NO: 306). In further embodiments, the invention relates to LC CDR2 thereof: GASTRAT (SEQ ID NO: 307). In further embodiments, the invention relates to the LC CDR3 thereof: QQYAAYPT (SEQ ID NO: 308).

[0317] In further embodiments, the invention relates to Clone AJ-26545 CAR DNA HxL (SEQ ID NO: 309):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAG AAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAGGGCATCTGGATACACCT TCATGGAGCACTATATGCACTGGGTGCGACAGGCCCCTGGACAAGGGCT

- 8219653

TGAGTGGATGGGAGTAATCGGGCCTAGTGGTGGTAAGACAAGCTACGCA CAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCA CAGTCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTA CTACTGCGCCAGAGAGAATTGGCCAATGGACGTATGGGGCCAGGGAACA ACTGTCACCGTCTCCTCAGGGTCTACATCCGGCTCCGGGAAGCCCGGAA GTGGCGAAGGTAGTACAAAGGGGGAAATAGTGATGACGCAGTCTCCAG CCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCC AGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATC CCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCA TCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTAC GCCGCCTACCCTACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGG CCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAA GGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCAT TCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTC GTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCT GCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACA AGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATC GGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCA

GGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGA GTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGC AAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAG AAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAG CGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTA

GG

[0318] In further embodiments, the invention relates to Clone AJ-26545 CAR HxL

AA sequence (SEQ ID NO: 310):

MALPVTALLL PLALLLHAAR

VSCRASGYTF

YAQKFQGRVT

MEHYMHWVRQ

MTRDTSTSTV

PQVQLVQSGA EVKKPGASVK

APGQGLEWMG VIGPSGGKTS

YMELSSLRSE DTAVYYCARE

SWPMDVWGQG TTVTVSSGST SGSGKPGSGE GSTKGEIVMT QSPATLSVSP GERATLSCRA SQSVSSNLAW YQQKPGQAPR LLIYGASTRA TGIPARFSGS

- 83 19653

GSGTEFTLTI SSLQSEDFAV YYCQQYAAYP TFGGGTKVEI KRAAALDNEK SNGTIIHVKG KHLCPSPLFP GPSKPFWVLV VVGGVLACYS LLVTVAFIIF WVRSKRSRLL HSDYMNMTPR RPGPTRKHYQ PYAPPRDFAA

YRSRVKFSRS ADAPAYQQGQ NQLYNELNLG RREEYDVLDK

RRGRDPEMGG KPRRKNPQEG LYNELQKDKM AEAYSEIGMK

GERRRGKGHD GLYQGLSTAT KDTYDALHMQ ALPPR

[0319] In further embodiments, the invention relates to Clone AJ-26545 CAR DNA LxH (SEQ IDNO: 311):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTG TTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAG GCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGT TCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCT GCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTACGCCGCCTACC CTACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTACATC CGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCAGGT GCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTG AAGGTTTCCTGCAGGGCATCTGGATACACCTTCATGGAGCACTATATGCA CTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGTAATC GGGCCTAGTGGTGGTAAGACAAGCTACGCACAGAAGTTCCAGGGCAGA GTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACATGGAGCTGA GCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAGAGAA TTGGCCAATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCA GCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGA AGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCA TTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTC GTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCT GCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACA AGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATC GGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCA GGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGA GTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGC

- 8419653

AAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAG AAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAG CGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTA GG

[0320] In further embodiments, the invention relates to Clone AJ-26545 CAR LxH AA sequence (SEQ ID NO: 312):

MALPVTALLL PLALLLHAAR PEIVMTQSPA TLSVSPGERA TLSCRASQSV SSNLAWYQQK PGQAPRLLIY GASTRATGIP ARFSGSGSGT EFTLTISSLQ SEDFAVYYCQ QYAAYPTFGG GTKVEIKRGS TSGSGKPGSG EGSTKGQVQL VQSGAEVKKP GASVKVSCRA SGYTFMEHYM HWVRQAPGQG

LEWMGVIGPS GGKTSYAQKF QGRVTMTRDT STSTVYMELS

SLRSEDTAVY YCARESWPMD VWGQGTTVTV SSAAALDNEK

SNGTIIHVKG KHLCPSPLFP GPSKPFWVLV VVGGVLACYS LLVTVAFIIF WVRSKRSRLL HSDYMNMTPR RPGPTRKHYQ PYAPPRDFAA

YRSRVKFSRS ADAPAYQQGQ NQLYNELNLG RREEYDVLDK

RRGRDPEMGG KPRRKNPQEG LYNELQKDKM AEAYSEIGMK GERRRGKGHD GLYQGLSTAT KDTYDALHMQ ALPPR

[0321] In further embodiments, the invention relates to Clone AJ-26554 HC DNA (SEQIDNO: 313):

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCT CAGTGAAGGTTTCCTGCAAGGCATCTGGATACACCTTCACGGAGCACTA TATGCACTGGGTGCGACAGGCCCCTGGACAAAGGCTTGAGTGGATGGGA GTAATCGGGCCTAGTGGTGGTAAGACAAGCTACGCACAGAAGTTCCAGG GCAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACATGGA GCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGA GAGAGTTGGCCAATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCT CCTCA

[0322] In further embodiments, the invention relates to Clone AJ-26554 HC (SEQ ED

NO. 314): QVQLVQSGAE VKKPGASVKV SCKASGYTFT EHYMHWVRQA PGQRLEWMGV IGPSGGKTSY AQKFQGRVTM TRDTSTSTVY MELSSLRSED TAVYYCARES WPMDVWGOGT T VT VS S

- 85 19653

[0323] In further embodiments, the invention relates to HC CDRI thereof: YTFTEHYMH (SEQ ID NO: 315). In further embodiments, the invention relates to HC CDR2 thereof: VIGPSGGKTSYAQKFQG (SEQ ID NO: 316). In further embodiments, the invention relates to HC CDR3 thereof: ARESWPMDV (SEQ ID NO: 317).

[0324] In further embodiments, the invention relates to Clone AJ-26554 LC DNA (SEQ ID NO: 318):

GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGG AAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTT AGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT GGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTG GGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGA TTTTGCAGTTTATTACTGTCAGCAGTACGCCGCCTACCCTACTTTTGGCG GAGGGACCAAGGTTGAGATCAAACGG

[0325] In fùrther embodiments, the invention relates to Clone AJ-26554 LC AA sequence (SEQ ID NO: 319): EIVMTQSPAT LSVSPGERAT LSCRASQSVS SNLAWYOQKP GQAPRLLIYG ASTRATGIPA RFSGSGSGTE FTLTISSLQS EDFAVYYCQQ YAAYPTFGGG TKVEIKR.

[0326] In fùrther embodiments, the invention relates to the LC CDRI thereof: RASQSVSSNLA (SEQ ID NO: 320). In fùrther embodiments, the invention relates to the LC CDR2 thereof: GASTRAT (SEQ ID NO: 321). In fùrther embodiments, the invention relates to LC CDR3 thereof: QQYAAYPT (SEQ ID NO: 322).

[0327] In fùrther embodiments, the invention relates to Clone AJ-26554 CAR DNA HxL (SEQ ID NO: 323):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAG AAGCCTGGGGCCTCAGTGAAGGTTTCCTGCAAGGCATCTGGATACACCT TCACGGAGCACTATATGCACTGGGTGCGACAGGCCCCTGGACAAAGGCT TGAGTGGATGGGAGTAATCGGGCCTAGTGGTGGTAAGACAAGCTACGCA CAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCA CAGTCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTA CTACTGCGCCAGAGAGAGTTGGCCAATGGACGTATGGGGCCAGGGAACA ACTGTCACCGTCTCCTCAGGGTCTACATCCGGCTCCGGGAAGCCCGGAA GTGGCGAAGGTAGTACAAAGGGGGAAATAGTGATGACGCAGTCTCCAG

- 8619653

CCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC

AGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCC

AGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATC

CCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCA

TCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTAC

GCCGCCTACCCTACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGG

CCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAA

GGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCAT

TCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTC

GTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCT

GCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACA

AGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATC

GGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCA

GGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGA

GTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGC

AAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAG

AAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAG CGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTA

[0328] In fùrther embodiments, the invention relates to Clone AJ-26554 CAR HxL

AA sequence (SEQ ID NO: 324):

MALPVTALLL

VSCKASGYTF

YAQKFQGRVT

PLALLLHAAR

TEHYMHWVRQ

MTRDTSTSTV

PQVQLVQSGA APGQRLEWMG YMELSSLRSE

EVKKPGASVK

VIGPSGGKTS

DTAVYYCARE

SWPMDVWGQG TTVTVSSGST SGSGKPGSGE GSTKGEIVMT QSPATLSVSP

GERATLSCRA SQSVSSNLAW YQQKPGQAPR LLIYGASTRA TGIPARFSGS GSGTEFTLTI SSLQSEDFAV YYCQQYAAYP TFGGGTKVEI KRAAALDNEK SNGTIIHVKG KHLCPSPLFP GPSKPFWVLV WGGVLACYS LLVTVAFIIF

WVRSKRSRLL HSDYMNMTPR RPGPTRKHYQ PYAPPRDFAA

YRSRVKFSRS ADAPAYQQGQ NQLYNELNLG RREEYDVLDK

RRGRDPEMGG KPRRKNPQEG LYNELQKDKM AEAYSEIGMK

GERRRGKGHD GLYQGLSTAT KDTYDALHMQ ALPPR.

- 8719653

[0329] In further embodiments, the invention relates to Clone AJ-26554 CAR DNA

LxH (SEQ ID NO: 325):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTG TTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAG GCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGT TCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCT GCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTACGCCGCCTACC CTACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTACATC CGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCAGGT GCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTG AAGGTTTCCTGCAAGGCATCTGGATACACCTTCACGGAGCACTATATGC ACTGGGTGCGACAGGCCCCTGGACAAAGGCTTGAGTGGATGGGAGTAAT CGGGCCTAGTGGTGGTAAGACAAGCTACGCACAGAAGTTCCAGGGCAGA GTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACATGGAGCTGA GCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAGAGAG TTGGCCAATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCA GCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGA AGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCA TTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTC GTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCT GCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACA AGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATC GGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCA GGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGA GTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGC AAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAG AAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAG CGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTA GG

- 88 19653

[0331] In further embodiments, the invention relates to Clone AJ-26554 CAR LxH AA sequence (SEQ ID NO: 326):

MALPVTALLL PLALLLHAAR PEIVMTQSPA TLSVSPGERA TLSCRASQSV

SSNLAWYQQK PGQAPRLLIY GASTRATGIP ARFSGSGSGT EFTLTISSLQ

SEDFAVYYCQ QYAAYPTFGG GTKVEIKRGS TSGSGKPGSG EGSTKGQVQL

VQSGAEVKKP

LEWMGVIGPS

SLRSEDTAVY

GASVKVSCKA

GGKTSYAQKF

YCARESWPMD

SGYTFTEHYM

QGRVTMTRDT

VWGQGTTVTV

HWVRQAPGQR

STSTVYMELS

SSAAALDNEK

SNGTIIHVKG KHLCPSPLFP GPSKPFWVLV WGGVLACYS LLVTVAFIIF

WVRSKRSRLL HSDYMNMTPR RPGPTRKHYQ PYAPPRDFAA

YRSRVKFSRS ADAPAYQQGQ NQLYNELNLG RREEYDVLDK

RRGRDPEMGG KPRRKNPQEG LYNELQKDKM AEAYSEIGMK

GERRRGKGHD GLYQGLSTAT KDTYDALHMQ ALPPR

[0332] In fürther embodiments, the invention relates to Clone NM-26562 HC DNA (SEQ ID NO: 327):

CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGA CCCTGTCCCTCACCTGTACTGTCTCTGGTGGCTCCATCGGGAGTGGTGGT

AGTTACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGA TTGGGTTGATCTATTACGATGGGAGCACCTACTACAACCCGTCCCTCAAG AGTCGAGTTACCATATCAGTAGACACGTCTAAGAACCAGTTCTCCCTGA AGCTGAGTTCTGTGACCGCCGCAGACACGGCGGTGTACTACTGCGCCAG AGGCAGGGGATATGAGACTTCTTTAGCCTTCGATATCTGGGGTCAGGGT

ACAATGGTCACCGTCTCCTCA

[0333] In further embodiments, the invention relates to Clone NM-26562 HC AA sequence (SEQ ID NO: 328): QVQLQESGPG LVKPSQTLSL TCTVSGGSIG SGGSYWSWIR QHPGKGLEWI GLIYYDGSTY YNPSLKSRVT ISVDTSKNQF SLKLSSVTAA DTAVYYCARG RGYETSLAFD IWGQGTMVTV SS.

[0334] In further embodiments, the invention relates to HC CDR1 thereof: GSIGSGGSYWS (SEQ ID NO: 329). In further embodiments, the invention relates to HC CDR2 thereof: LIYYDGSTYYNPSLKS (SEQ ID NO: 330). In further embodiments, the invention relates to HC CDR3 thereof: ARGRGYETSLAFDI (SEQ ID NO: 331).

[0335] In further embodiments, the invention relates to Clone NM-26562 LC DNA (SEQ ID NO: 332):

- 8919653

GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTA GCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATG ATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAGCAGAGACACGTCTGGCCTCCTACTTTTGG CGGAGGGACCAAGGTTGAGATCAAACGG

[0336] In fùrther embodiments, the invention relates to Clone NM-26562 LC AA sequence (SEQ ID NO: 333):

EIVLTQSPAT LSLSPGERAT LSCRASOSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQO RHVWPPTFGG GTKVEIKR

[0337] In further embodiments, the invention relates to LC CDR1 AA sequence thereof: RASQSVSSYLA (SEQ ID NO: 334) In fùrther embodiments, the invention relates to LC CDR2 AA sequence thereof: DASNRAT (SEQ ID NO: 335). In fùrther embodiments, the invention relates to LC CDR3 AA sequence thereof: QQRHVWPPT (SEQ ID NO: 336) (LC CDR3).

[0338] In fùrther embodiments, the invention relates to Clone NM-26562 CAR DNA

HxL (SEQ ID NO: 337):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTG AAGCCTTCACAGACCCTGTCCCTCACCTGTACTGTCTCTGGTGGCTCCAT CGGGAGTGGTGGTAGTTACTGGAGCTGGATCCGCCAGCACCCAGGGAAG GGCCTGGAGTGGATTGGGTTGATCTATTACGATGGGAGCACCTACTACA ACCCGTCCCTCAAGAGTCGAGTTACCATATCAGTAGACACGTCTAAGAA CCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCAGACACGGCGGTGT ACTACTGCGCCAGAGGCAGGGGATATGAGACTTCTTTAGCCTTCGATATC TGGGGTCAGGGTACAATGGTCACCGTCTCCTCAGGGTCTACATCCGGCTC CGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAAATTGTGTT GACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCA ACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAAC AGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAG

-9019653

ACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTAT TACTGTCAGCAGAGACACGTCTGGCCTCCTACTTTTGGCGGAGGGACCA AGGTTGAGATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGG AACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCC CTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTC GCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGA TCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCAC GCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAG AGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATG CACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCT GGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGA CCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCT CTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATA GGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTAC CAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGC AAGCCCTGCCACCTAGG.

[0339] In further embodiments, the invention relates to Clone NM-26562 CAR HxL (SEQIDNO: 338):

MALPVTALLL PLALLLHAAR PQVQLQESGP GLVKPSQTLS LTCTVSGGSI GSGGSYWSWI RQHPGKGLEW IGLIYYDGST YYNPSLKSRV TISVDTSKNQ FSLKLSSVTA ADTAVYYCAR GRGYETSLAF DIWGQGTMVT VSSGSTSGSG KPGSGEGSTK GEIVLTQSPA TLSLSPGERA TLSCRASQSV SSYLAWYQQK PGQAPRLLIY DASNRATGIP ARFSGSGSGT DFTLTISSLE PEDFAVYYCQ QRHVWPPTFG GGTKVEIKRA AALDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLVWG GVLACYSLLV TVAFIIFWVR SKRSRLLHSD YMNMTPRRPG PTRKHYQPYA PPRDFAAYRS RVKFSRSADA PAYQQGQNQL

YNELNLGRRE EYDVLDKRRG RDPEMGGKPR RKNPQEGLYN

ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT

YDALHMQ ALP PR.

[0340]

[0341] In further embodiments, the invention relates to Clone NM-26562 CAR DNA

LxH (SEQ ID NO: 339):

- 91 19653

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTT TGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT TAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGG CTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTA GAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGAGACACGTCTGGCC TCCTACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTACA TCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCAG GTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCC TGTCCCTCACCTGTACTGTCTCTGGTGGCTCCATCGGGAGTGGTGGTAGT TACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTG GGTTGATCTATTACGATGGGAGCACCTACTACAACCCGTCCCTCAAGAGT CGAGTTACCATATCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAAGCT GAGTTCTGTGACCGCCGCAGACACGGCGGTGTACTACTGCGCCAGAGGC AGGGGATATGAGACTTCTTTAGCCTTCGATATCTGGGGTCAGGGTACAAT GGTCACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGA ACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCC TGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCG CTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGAT CCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACG CCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGA GATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGC ACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTG GGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGAC CCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCT ATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGG CATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCA GGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAA GCCCTGCCACCTAGG

[0342] In further embodiments, the invention relates to Clone NM-26562 CAR LxH (SEQ ID NO: 340):

-9219653

MALPVTALLL PLALLLHAAR PEIVLTQSPA TLSLSPGERA TLSCRASQSV SSYLAWYQQK PGQAPRLLIY DASNRATGIP ARFSGSGSGT DFTLTISSLE PEDFAVYYCQ QRHVWPPTFG GGTKVE1KRG STSGSGKPGS GEGSTKGQVQ LQESGPGLVK PSQTLSLTCT VSGGSIGSGG SYWSWIRQHP GKGLEWIGLI YYDGSTYYNP SLKSRVTISV DTSKNQFSLK LSSVTAADTA VYYCARGRGY ETSLAFDIWG QGTMVTVSSA AALDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLVWG GVLACYSLLV TVAFIIFWVR SKRSRLLHSD YMNMTPRRPG

PTRKHYQPYA PPRDFAAYRS

YNELNLGRRE EYDVLDKRRG

ELQKDKMAEA YSEIGMKGER

YDALHMQALP PR

RVKFSRSADA PAYQQGQNQL

RDPEMGGKPR RKNPQEGLYN

RRGKGHDGLY QGLSTATKDT

[0343] In further embodiments, the invention relates to Clone TS-26564 HC DNA sequence (SEQ ID NO: 341):

GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGT

CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGC

ATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCAA

CCATTAGTAGTAGTAGTAGTATCATATACTACGCAGACTCTGTGAAGGG

CCGATTCACCATCTCCAGAGACAATGCCAAGAACTCACTGTATCTGCAA

ATGAACAGCCTGAGAGCTGAGGACACGGCGGTGTACTACTGCGCCAGAG

GTTCTCAGGAGCACCTGATTTTCGATTATTGGGGACAGGGTACATTGGTC

ACCGTCTCCTCA

[0344] In further embodiments, the invention relates to Clone TS-26564 HC AA sequence (SEQ ID NO: 342): EVQLVESGGG LVQPGGSLRL SCAASGFTFS SYSMNWVROA PGKGLEWVST ISSSSSÜYY ADSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARGS QEHLIFDYWG QGTLVTVSS

[0345] In further embodiments, the invention relates to HC CDRl AA sequence thereof: FTFSSYSMN (SEQ ED NO: 343). In fùrther embodiments, the invention relates to HC CDR2 AA sequence thereof: TISSSSSIIYYADSVKG (SEQ ID NO: 344). In further embodiments, the invention relates to HC CDR3 AA sequence thereof: ARGSQEHLEFDY (SEQ ID NO: 345).

[0346] In fùrther embodiments, the invention relates to Clone TS-26564 LC DNA (SEQ ID NO: 346):

- 93 19653

GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGGTACTTA GCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATG ATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAGCAGAGATTCTACTACCCTTGGACTTTTGGC GGAGGGACCAAGGTTGAGATCAAACGG

[0347] In further embodiments, the invention relates to Clone TS-26564 LC AA sequence (SEQ ID NO: 347):

EIVLTQSPAT LSLSPGERAT LSCRASQSVS RYLAWYQQKP GQAPRLLIYD ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ RFYYPWTFGG GTKVEIKR.

[0348] In further embodiments, the invention relates to LC CDR1 AA sequence thereof: RASQSVSRYLA(SEQ IDNO: 348). In further embodiments, the invention relates to LC CDR2 AA sequence thereof: DASNRAT (SEQ ID NO: 349). In fùrther embodiments, the invention relates to LC CDR3 AA sequence thereof: QQRFYYPWT (SEQ ID NO: 350). [0349] In further embodiments, the invention relates to Clone TS-26564 CAR DNA HxL (SEQ IDNO: 351):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTA CAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTT CAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTG GAGTGGGTTTCAACCATTAGTAGTAGTAGTAGTATCATATACTACGCAG ACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACTC ACTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCGGTGTAC TACTGCGCCAGAGGTTCTCAGGAGCACCTGATTTTCGATTATTGGGGACA GGGTACATTGGTCACCGTCTCCTCAGGGTCTACATCCGGCTCCGGGAAGC CCGGAAGTGGCGAAGGTAGTACAAAGGGGGAAATTGTGTTGACACAGTC TCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCA GGGCCAGTCAGAGTGTTAGCAGGTACTTAGCCTGGTACCAACAGAAACC TGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTG GCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCT CACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGC

- 9419653

AGAGATTCTACTACCCTTGGACTTTTGGCGGAGGGACCAAGGTTGAGAT CAAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATT CACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATC CAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACT CTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGA AGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGG CCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCT GCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGT ATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAG GGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGAT GGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGA GCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAA GGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTC AGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGC CACCTAGG

[0350] In further embodiments, the invention relates to Clone TS-26564 CAR HxL AA sequence (SEQ ID NO: 352):

MALPVTALLL PLALLLHAAR PEVQLVESGG GLVQPGGSLR LSCAASGFTF SSYSMNWVRQ APGKGLEWVS TISSSSSIIY YADSVKGRFT ISRDNAKNSL YLQMNSLRAE DTAVYYCARG SQEHLIFDYW GQGTLVTVSS GSTSGSGKPG SGEGSTKGEI VLTQSPATLS LSPGERATLS CRASQSVSRY LAWYQQKPGQ APRLLIYDAS NRATGIPARF SGSGSGTDFT LTISSLEPED FAVYYCQQRF YYPWTFGGGT KVEIKRAAAL DNEKSNGTII HVKGKHLCPS PLFPGPSKPF WVLVWGGVL ACYSLLVTVA FIIFWVRSKR SRLLHSDYMN MTPRRPGPTR KHYQPYAPPR DFAAYRSRVK FSRSADAPAY

QQGQNQLYNE LNLGRREEYD VLDKRRGRDP EMGGKPRRKN

PQEGLYNELQ KDKMAEAYSE IGMKGERRRG KGHDGLYQGL

STATKDTYDA LHMQALPPR

[0351] In further embodiments, the invention relates to Clone TS-26564 CAR DNA LxH (SEQ ID NO: 353):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTT TGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT

-95 19653

TAGCAGGTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGG CTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTA GAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGAGATTCTACTACCC TTGGACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTACA TCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAG GTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCC TGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGCATG AACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCAACCA TTAGTAGTAGTAGTAGTATCATATACTACGCAGACTCTGTGAAGGGCCG ATTCACCATCTCCAGAGACAATGCCAAGAACTCACTGTATCTGCAAATG AACAGCCTGAGAGCTGAGGACACGGCGGTGTACTACTGCGCCAGAGGTT CTCAGGAGCACCTGATTTTCGATTATTGGGGACAGGGTACATTGGTCACC GTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCA TTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCA TCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTA CTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAA GAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCT GGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCG CTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGC GTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGC AGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAG ATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATG AGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAA AGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACT CAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTG CCACCTAGG

[0352] In further embodiments, the invention relates to Clone TS-26564 CAR LxH AA sequence (SEQ ID NO: 354):

MALPVTALLL PLALLLHAAR PEIVLTQSPA TLSLSPGERA TLSCRASQSV SRYLAWYQQK PGQAPRLLIY DASNRATGIP ARFSGSGSGT DFTLTISSLE PEDFAVYYCQ QRFYYPWTFG GGTKVEIKRG STSGSGKPGS GEGSTKGEVQ LVESGGGLVQ PGGSLRLSCA ASGFTFSSYS MNWVRQAPGK GLEWVSTISS

-9619653

SSSIIYYADS VKGRFTISRD NAKNSLYLQM NSLRAEDTAV YYCARGSQEH LIFDYWGQGT LVTVSSAAAL DNEKSNGTII HVKGKHLCPS PLFPGPSKPF WVLWVGGVL ACYSLLVTVA FIIFWVRSKR SRLLHSDYMN MTPRRPGPTR KHYQPYAPPR DFAAYRSRVK FSRSADAPAY QQGQNQLYNE

LNLGRREEYD VLDKRRGRDP EMGGKPRRKN PQEGLYNELQ

KDKMAEAYSE IGMKGERRRG KGHDGLYQGL STATKDTYDA

LHMQALPPR

[0353] In further embodiments, the invention relates to Clone RY-26568 HC DNA (SEQIDNO: 355):

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCGGGAGCTATGGC ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAG TTATACATTATGATGGAAGTGTTGAATACTATGCAGACTCCGTGAAGGG CCGATTCACCATCTCCAGAGACAATTCCAAGGACACGCTGTATCTGCAA ATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCCAGAA CTGACTTCTGGAGCGGATCCCCTCCAAGCTTAGATTACTGGGGACAGGG TACATTGGTCACCGTCTCCTCA

[0354] In fùrther embodiments, the invention relates to Clone RY-26568 HC AA sequence (SEQ ID NO: 356): QVQLVESGGG VVQPGRSLRL SCAASGFTFG SYGMHWVROA PGKGLEWVAV IHYDGSVEYY ADSVKGRFTI SRDNSKDTLY LQMNSLRAED TAVYYCARTD FWSGSPPSLD YWGQGTLVTV SS

[0355] In further embodiments, the invention relates to HC CDR1 thereof: FTFGSYGMH (SEQ ID NO: 357). In fùrther embodiments, the invention relates to HC CDR2 thereof: VIHYDGSVEYYADSVKG (SEQ ID NO: 358). In fùrther embodiments, the invention relates to HC CDR3 thereof: ARTDFWSGSPPSLDY (SEQ ID NO: 359).

[0356] In fùrther embodiments, the invention relates to Clone RY-26568 LC DNA (SEQ ID NO: 360):

GACATCCAGTTGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGTCGGGCGAGTCGGGGTATTAGCAGCTGGTTA GCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATG GTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGG ATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATT

-9719653

TTGCAACTTATTACTGTCAGCAGATATACACCTTCCCTTTCACTTTTGGCG GAGGGACCAAGGTTGAGATCAAACGG

[0357] In further embodiments, the invention relates to Clone RY-26568 LC AA sequence (SEQ ID NO: 361):

DIQLTQSPSS VSASVGDRVT ITCRASRGIS SWLAWYQQKP GKAPKLLIYG ASSLOSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ IYTFPFTFGG GTKVEIKR.

[0358] In fùrther embodiments, the invention relates to LC CDRl AA sequence thereof: RASRGISSWLA (SEQ ID NO: 362). In further embodiments, the invention relates to LC CDR2 AA sequence thereof: GASSLQS (SEQ ID NO: 363). In further embodiments, the invention relates to LC CDR3 AA sequence thereof: QQIYTFPFT (SEQ ID NO: 364) (LC CDR3).

[0359] In further embodiments, the invention relates to Clone RY-26568 CAR DNA

HxL (SEQ ID NO: 365):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTC CAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT CGGGAGCTATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTG GAGTGGGTGGCAGTTATACATTATGATGGAAGTGTTGAATACTATGCAG ACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGGACAC GCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTAC TACTGCGCCAGAACTGACTTCTGGAGCGGATCCCCTCCAAGCTTAGATTA CTGGGGACAGGGTACATTGGTCACCGTCTCCTCAGGGTCTACATCCGGCT CCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGACATCCAGT TGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACC ATCACTTGTCGGGCGAGTCGGGGTATTAGCAGCTGGTTAGCCTGGTATCA GCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGGTGCATCCAGT TTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAG ATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTAT TACTGTCAGCAGATATACACCTTCCCTTTCACTTTTGGCGGAGGGACCAA GGTTGAGATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGA ACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCC TGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCG

- 98 19653

CTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGAT CCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACG CCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGA GATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGC ACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTG GGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGAC CCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCT ATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGG CATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCA GGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAA GCCCTGCCACCTAGG

[0360] In further embodiments, the invention relates to Clone RY-26568 CAR HxL AA sequence (SEQ ID NO: 366):

MALPVTALLL PLALLLHAAR PQVQLVESGG GWQPGRSLR LSCAASGFTF GSYGMHWVRQ APGKGLEWVA VIHYDGSVEY YADSVKGRFT ISRDNSKDTL YLQMNSLRAE DTAVYYCART DFWSGSPPSL DYWGQGTLVT VSSGSTSGSG KPGSGEGSTK GDIQLTQSPS SVSASVGDRV TITCRASRGI SSWLAWYQQK PGKAPKLLIY GASSLQSGVP SRFSGSGSGT DFTLTISSLQ PEDFATYYCQ QIYTFPFTFG GGTKVEIKRA AALDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLVVVG GVLACYSLLV TVAFIIFWVR SKRSRLLHSD YMNMTPRRPG PTRKHYQPYA PPRDFAAYRS RVKFSRSADA PAYQQGQNQL YNELNLGRRE EYDVLDKRRG RDPEMGGKPR RKNPQEGLYN ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT YDALHMQALP PR

[0361] In fürther embodiments, the invention relates to Clone RY-26568 CAR DNA

LxH (SEQ ID NO: 367):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGACATCCAGTTGACCCAGTCTCCATCTTCCGTGTCTG CATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCGGGGTAT TAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAG CTCCTGATCTATGGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTT CAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTG CAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGATATACACCTTCCC

-9919653

TTTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTACA TCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCAG GTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCC TGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCGGGAGCTATGGCATG CACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTA TACATTATGATGGAAGTGTTGAATACTATGCAGACTCCGTGAAGGGCCG ATTCACCATCTCCAGAGACAATTCCAAGGACACGCTGTATCTGCAAATG AACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCCAGAACTG ACTTCTGGAGCGGATCCCCTCCAAGCTTAGATTACTGGGGACAGGGTAC ATTGGTCACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACG GAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTC CCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCT CGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAG ATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCA CGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTA GAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGAT GCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACC TGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGG ACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTC

TCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAAT AGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTA CCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATG CAAGCCCTGCCACCTAGG

[0362] In further embodiments, the invention relates to Clone RY-26568 CAR LxH AA sequence (SEQ ID NO: 368):

MALPVTALLL PLALLLHAAR PDIQLTQSPS SVSASVGDRV TITCRASRGI SSWLAWYQQK PGKAPKLLIY GASSLQSGVP SRFSGSGSGT DFTLTISSLQ PEDFATYYCQ QIYTFPFTFG GGTKVEIKRG STSGSGKPGS GEGSTKGQVQ LVESGGGWQ PGRSLRLSCA ASGFTFGSYG MHWVRQAPGK

GLEWVAVIHY DGSVEYYADS VKGRFTISRD NSKDTLYLQM

NSLRAEDTAV YYCARTDFWS GSPPSLDYWG QGTLVTVSSA

AALDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLVVVG GVLACYSLLV TVAFIIFWVR SKRSRLLHSD YMNMTPRRPG PTRKHYQPYA PPRDFAAYRS

- 10019653

RVKFSRSADA PAYQQGQNQL YNELNLGRRE EYDVLDKRRG RDPEMGGKPR RKNPQEGLYN ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT YDALHMQALP PR

[0363] In further embodiments, the invention relates to Clone PP-26575 HC DNA (SEQ ID NO: 369):

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCCTCAGCAGCCTGGC TATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGA GGGGTCATCCCTATCTTGGGTCGGGCAAACTACGCACAGAAGTTCCAGG GCAGAGTCACGATTACCGCGGACGAGTCCACGAGCACAGCCTACATGGA GCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGA ACTCCTGAATACTCCTCCAGCATATGGCACTATTACTACGGCATGGACGT ATGGGGCCAGGGAACAACTGTCACCGTCTCCTCA

[0364] In further embodiments, the invention relates to Clone PP-26575 HC AA sequence (SEQ ID NO: 370):

QVQLVQSGAE VKKPGSSVKV SCKASGGTLS SLAISWVRQA PGQGLEWMGG VIPILGRANY AQKFQGRVTI TADESTSTAY MELSSLRSED TAVYYCARTP EYSSSIWHYY YGMDVWGQGT TVTVSS.

[0365] In further embodiments, the invention relates to HC CDR1 AA sequence thereof: GTLSSLAIS (SEQ ID NO: 371). In further embodiments, the invention relates to HC CDR2 AA sequence thereof: GVIPILGRANYAQKFQG (SEQ ID NO: 372). In fùrther embodiments, the invention relates to HC CDR3 thereof: ARTPEYSSSIWHYYYGMDV (SEQIDNO: 373).

[0366] In fùrther embodiments, the invention relates to Clone PP-26575 LC DNA (SEQIDNO: 374):

GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGA GAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCC AACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTC CTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGAC CGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCAGCA GCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAGTTCGCCCAC ACTCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGG

- 101 19653

[0367] In fùrther embodiments, the invention relates to Clone PP-26575 LC AA sequence (SEQ ID NO: 375):

DIVMTQSPDS LAVSLGERAT INCKSSQSVL YSSNNKNYLA WYQQKPGQPP KLLIYWASTR ESGVPDRFSG SGSGTDFTLT ISSLQAEDVA VYYCQQFAHT PFTFGGGTKV EIKR.

[0368] In further embodiments, the invention relates to LC CDR 1 AA sequence thereof: KSSQSVLYSSNNKNYLA (SEQ ID NO: 376). In further embodiments, the invention relates to LC CDR2 AA sequence thereof: WASTRES (SEQ ID NO: 377). In further embodiments, the invention relates to LC CDR3 AA sequence thereof: QQFAHTPFT (SEQ ID NO: 378).

[0369] In further embodiments, the invention relates to Clone PP-26575 CAR DNA HxL (SEQ ID NO: 379):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAG AAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCC TCAGCAGCCTGGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCT TGAGTGGATGGGAGGGGTCATCCCTATCTTGGGTCGGGCAAACTACGCA CAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAGTCCACGAGCA CAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTA CTACTGCGCCAGAACTCCTGAATACTCCTCCAGCATATGGCACTATTACT ACGGCATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCAGG GTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAG GGGGACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGG CGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGC TCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGC CTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCT GACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCA GCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAGTTCGCC CACACTCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGG CCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAA GGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCAT TCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTC GTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCT

- 10219653

GCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACA AGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATC GGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCA GGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGA GTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGC AAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAG AAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAG CGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTA GG

[0370] In further embodiments, the invention relates to Clone PP-26575 CAR HxL AA sequence (SEQ ID NO: 380):

MALPVT ALLL PLALLLHAAR PQVQLVQSGA EVKKPGSSVK VSCKASGGTL SSLAISWVRQ APGQGLEWMG GVIPILGRAN YAQKFQGRVT ITADESTSTA YMELSSLRSE DTAVYYCART PEYSSSIWHY YYGMDVWGQG TTVTVSSGST SGSGKPGSGE GSTKGDIVMT QSPDSLAVSL GERATINCKS SQSVLYSSNN KNYLAWYQQK PGQPPKLLIY WASTRESGVP DRFSGSGSGT DFTLTISSLQ AEDVAVYYCQ QFAHTPFTFG GGTKVEIKRA AALDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLWVG GVLACYSLLV TVAFIIFWVR SKRSRLLHSD YMNMTPRRPG PTRKHYQPYA PPRDFAAYRS RVKFSRSADA PAYQQGQNQL YNELNLGRRE EYDVLDKRRG RDPEMGGKPR RKNPQEGLYN ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT YDALHMQ ALP PR

[0371] In further embodiments, the invention relates to Clone PP-26575 CAR DNA LxH (SEQ IDNO: 381):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGACATCGTGATGACCCAGTCTCCAGACTCCCTGGCT GTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTG TTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAA ACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAAT CCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCAC TCTCACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTC AGCAGTTCGCCCACACTCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAG

- 103 19653

ATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAG GTAGTACAAAGGGGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAA GAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACC CTCAGCAGCCTGGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGC TTGAGTGGATGGGAGGGGTCATCCCTATCTTGGGTCGGGCAAACTACGC ACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAGTCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGT ACTACTGCGCCAGAACTCCTGAATACTCCTCCAGCATATGGCACTATTAC TACGGCATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCAG CCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAA GGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCAT TCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTC GTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCT GCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACA AGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATC GGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCA GGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGA GTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGC AAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAG AAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAG CGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTA GG

[0372] In further embodiments, the invention relates to Clone PP-26575 CAR LxH AA sequence (SEQ ID NO: 382):

MALPVTALLL PLALLLHAAR PDIVMTQSPD SLAVSLGERA TINCKSSQSV LYSSNNKNYL AWYQQKPGQP PKLLIYWAST RESGVPDRFS GSGSGTDFTL TISSLQAEDV AVYYCQQFAH TPFTFGGGTK VEIKRGSTSG SGKPGSGEGS TKGQVQLVQS GAEVKKPGSS VKVSCKASGG TLSSLAISWV RQAPGQGLEW MGGVIPILGR ANYAQKFQGR VTITADESTS TAYMELSSLR SEDTAVYYCA RTPEYSSSIW HYYYGMDVWG QGTTVTVSSA AALDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLVVVG GVLACYSLLV TVAFIIFWVR SKRSRLLHSD YMNMTPRRPG PTRKHYQPYA PPRDFAAYRS

- 10419653

RVKFSRSADA PAYQQGQNQL YNELNLGRRE EYDVLDKRRG RDPEMGGKPR RKNPQEGLYN ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT YDALHMQALP PR

[0373] In fùrther embodiments, the invention relates to Clone RD-26576 HC DNA (SEQIDNO: 383):

CAGGTGCGGCTGGTGGAGTCTGGGGGGGGCGTGGTCCAGCCTGGGAGGT CCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGC ATACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAG TTATAGGGTATGATGGACAGGAGAAATACTATGCAGACTCCGTGAAGGG CCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAA ATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGTCAAGG GGCCGTTGCAGGAGCCGCCATACGCTTTTGGGATGGACGTATGGGGCCA GGGAACAACTGTCACCGTCTCCTCA

[0374] In fùrther embodiments, the invention relates to Clone RD-26576 HC AA sequence (SEQ ID NO: 384):

QVRLVESGGG WQPGRSLRL SCAASGFTFS SYGIHWVRQA

PGKGLEWVAV IGYDGQEKYY ADSVKGRFTI SRDNSKNTLY

LQMNSLRAED TAVYYCVKGP LQEPPYAFGM DVWGQGTTVT VSS.

[0375] In further embodiments, the invention relates to HC CDRl AA sequence thereof: FTFSSYGIH (SEQ ID NO: 385). In further embodiments, the invention relates to HC CDR2 AA sequence thereof: VIGYDGQEKYYADSVKG (SEQ ID NO: 386). In further embodiments, the invention relates to the HC CDR3 AA sequence thereof: VKGPLQEPPYAFGMDV (SEQ ID NO: 387).

[0376] In further embodiments, the invention relates to Clone RD-26576 LC DNA (SEQIDNO: 388):

GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGG AAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTT AGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT AGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTG GGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGA TTTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGG CGGAGGGACCAAGGTTGAGATCAAACGG

- 105 19653

[0377] In fùrther embodiments, the invention relates to Clone RD-26576 LC AA sequence (SEQ ID NO: 389):

EIVMTQSPAT LSVSPGERAT LSCRASQSVS SNLAWYQQKP GQAPRLLIYS ASTRATGIPA RFSGSGSGTE FTLTISSLQS EDFAVYYCQQ HHVWPLTFGG GTKVEIKR.

[0378] In further embodiments, the invention relates to LC CDRl AA sequence thereof: RASQSVSSNLA (SEQ ID NO: 390). In further embodiments, the invention relates to LC CDR2 AA sequence thereof: SASTRAT (SEQ ID NO: 391). In further embodiments, the invention relates to LC CDR3 AA sequence thereof: QQHHVWPLT (SEQ ID NO: 392). [0379] In further embodiments, the invention relates to Clone RD-26576 CAR DNA HxL (SEQ ID NO: 393):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGCAGGTGCGGCTGGTGGAGTCTGGGGGGGGCGTGGTC CAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT CAGTAGCTATGGCATACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTG GAGTGGGTGGCAGTTATAGGGTATGATGGACAGGAGAAATACTATGCAG ACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACAC GCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTAC TACTGCGTCAAGGGGCCGTTGCAGGAGCCGCCATACGCTTTTGGGATGG ACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCAGGGTCTACATC CGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAAAT AGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGA GCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCT GGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAGCGC ATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCT

GGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC AGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGGCGGAG GGACCAAGGTTGAGATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTC AAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCC TTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGG AGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTG GGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATG ACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCAC

- 10619653

CACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCT GCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGC TCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGG ACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGA GGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCT GAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGG TTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCC ACATGCAAGCCCTGCCACCTAGG

[0380] In further embodiments, the invention relates to Clone RD-26576 CAR HxL AA sequence (SEQ ID NO: 394);

MALPVTALLL PLALLLHAAR PQVRLVESGG GVVQPGRSLR LSCAASGFTF SSYGIHWVRQ APGKGLEWVA VIGYDGQEKY YADSVKGRFT ISRDNSKNTL YLQMNSLRAE DTAVYYCVKG PLQEPPYAFG MDVWGQGTTV TVSSGSTSGS GKPGSGEGST KGEIVMTQSP ATLSVSPGER ATLSCRASQS VSSNLAWYQQ KPGQAPRLLI YSASTRATGI PARFSGSGSG TEFTLTISSL QSEDFAVYYC QQHHVWPLTF GGGTKVEIKR AAALDNEKSN GTIIHVKGKH LCPSPLFPGP SKPFWVLVW GGVLACYSLL VTVAFIIFWV RSKRSRLLHS DYMNMTPRRP GPTRKHYQPY APPRDFAAYR SRVKFSRSAD APAYQQGQNQ LYNELNLGRR EEYDVLDKRR GRDPEMGGKP RRKNPQEGLY NELQKDKMAE AYSEIGMKGE RRRGKGHDGL YQGLSTATKD TYDALHMQAL PPR.

[0381] In further embodiments, the invention relates to Clone RD-26576 CAR DNA LxH (SEQ ID NO: 395):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTG TTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAG GCTCCTCATCTATAGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGT TCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCT GCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGC CTCTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTAC ATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCA GGTGCGGCTGGTGGAGTCTGGGGGGGGCGTGGTCCAGCCTGGGAGGTCC

- 10719653

CTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCAT ACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTT ATAGGGTATGATGGACAGGAGAAATACTATGCAGACTCCGTGAAGGGCC GATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAAT GAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGTCAAGGG GCCGTTGCAGGAGCCGCCATACGCTTTTGGGATGGACGTATGGGGCCAG GGAACAACTGTCACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTC AAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCC TTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGG AGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTG GGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATG ACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCAC CACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCT GCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGC TCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGG ACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGA GGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCT GAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGG TTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCC ACATGCAAGCCCTGCCACCTAGG

[0382] In fùrther embodiments, the invention relates to Clone RD-26576 CAR LxH AA sequence (SEQ ID NO: 396):

MALPVTALLL PLALLLHAAR PEIVMTQSPA TLSVSPGERA TLSCRASQSV SSNLAWYQQK PGQAPRLLIY SASTRATGIP ARFSGSGSGT EFTLTISSLQ SEDFAVYYCQ QHHVWPLTFG GGTKVEIKRG STSGSGKPGS GEGSTKGQVR LVESGGGVVQ PGRSLRLSCA ASGFTFSSYGIHWVRQAPGK GLEWVAVIGY DGQEKYYADS VKGRFTISRD NSKNTLYLQM NSLRAEDTAV YYCVKGPLQE PPYAFGMDVW GQGTTVTVSS AAALDNEKSN GTIIHVKGKH LCPSPLFPGP SKPFWVLVW GGVLACYSLL VTVAFIIFWV RSKRSRLLHS DYMNMTPRRP GPTRKHYQPY APPRDFAAYR SRVKFSRSAD APAYQQGQNQ LYNELNLGRR EEYDVLDKRR GRDPEMGGKP RRKNPQEGLY NELQKDKMAE AYSEIGMKGE RRRGKGHDGL YQGLSTATKD TYDALHMQAL PPR.

- 10819653

[0383] In further embodiments, the invention relates to Clone RD-26578 HC DNA (SEQ ID NO: 397):

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGT CCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCCGTGGC ATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAG TTATAGGGTATGATGGACAGGAGAAATACTATGCAGACTCCGTGAAGGG CCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAA ATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGTCAAGG GGCCGTTGCAGGAGCCGCCATACGATTATGGAATGGACGTATGGGGCCA GGGAACAACTGTCACCGTCTCCTCA

[0384] In further embodiments, the invention relates to Clone RD-26578 HC AA sequence (SEQ ID NO: 398):

QVQLVESGGG WQPGRSLRL SCAASGFTFS SRGMHWVRQA PGKGLEWVAV IGYDGQEKYY ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCVKGP LQEPPYDYGM DVWGOGTTVT VSS.

[0385] In further embodiments, the invention relates to HC CDR1 AA sequence thereof: FTFSSRGMH (SEQ ID NO: 399). In further embodiments, the invention relates to HC CDR2 AA sequence thereof: VIGYDGQEKYYADSVKG (SEQ ID NO: 400). In further embodiments, the invention relates to HC CDR3 thereof: VKGPLQEPPYDYGMDV (SEQ ID NO: 401).

[0386] In fùrther embodiments, the invention relates to Clone RD-26578 LC DNA (SEQ ID NO: 402):

GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGG AAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTT AGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT AGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTG GGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGA TTTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGG CGGAGGGACCAAGGTTGAGATCAAACGG

[0387] In fùrther embodiments, the invention relates to Clone RD-26578 LC AA sequence (SEQ ID NO: 403):

- 10919653

EIVMTQSPAT LSVSPGERAT LSCRASQSVS SNLAWYQQKP GQAPRLLIYS ASTRATGIPA RFSGSGSGTE FTLTISSLQS EDFAVYYCQQ HHVWPLTFGG GTKVEIKR.

[0388] In further embodiments, the invention relates to LC CDR1 AA sequence: RASQSVSSNLA (SEQ ID NO: 404). In further embodiments, the invention relates to LC CDR2 AA sequence thereof: SASTRAT (SEQ ID NO: 405). In fùrther embodiments, the invention relates to LC CDR3 AA sequence thereof: QQHHVWPLT (SEQ ID NO: 406).

[0389] In fùrther embodiments, the invention relates to Clone RD-26578 CAR DNA

HxL (SEQ ID NO: 407):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTC CAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT CAGTAGCCGTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTG GAGTGGGTGGCAGTTATAGGGTATGATGGACAGGAGAAATACTATGCAG ACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACAC GCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTAC TACTGCGTCAAGGGGCCGTTGCAGGAGCCGCCATACGATTATGGAATGG ACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCAGGGTCTACATC CGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAAAT AGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGA GCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCT GGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAGCGC ATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCT GGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC AGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGGCGGAG GGACCAAGGTTGAGATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTC AAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCC TTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGG AGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTG GGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATG ACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCAC CACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCT GCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGC

- 11019653

TCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGG ACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGA GGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCT GAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGG TTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCC ACATGCAAGCCCTGCCACCTAGG

[0390] In further embodiments, the invention relates to Clone RD-26578 CAR HxL AA sequence (SEQ ID NO: 408):

MALPVTALLL PLALLLHAAR PQVQLVESGG GWQPGRSLR LSCAASGFTF SSRGMHWVRQ APGKGLEWVA VIGYDGQEKY YADSVKGRFT ISRDNSKNTL YLQMNSLRAE DTAVYYCVKG PLQEPPYDYG MDVWGQGTTV TVSSGSTSGS GKPGSGEGST KGEIVMTQSP ATLSVSPGER ATLSCRASQS VSSNLAWYQQ KPGQAPRLLI YSASTRATGI PARFSGSGSG TEFTLTISSL QSEDFAVYYC QQHHVWPLTF GGGTKVEIKR AAALDNEKSN GTIIHVKGKH LCPSPLFPGP SKPFWVLVW GGVLACYSLL VTVAFIIFWV RSKRSRLLHS DYMNMTPRRP GPTRKHYQPY APPRDFAAYR SRVKFSRSAD APAYQQGQNQ LYNELNLGRR EEYDVLDKRR GRDPEMGGKP RRKNPQEGLY NELQKDKMAE AYSEIGMKGE RRRGKGHDGL YQGLSTATKD TYDALHMQAL PPR

[0391] In further embodiments, the invention relates to Clone RD-26578 CAR DNA LxH (SEQ ID NO: 409):

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTG TTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAG GCTCCTCATCTATAGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGT TCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCT GCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGC CTCTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTAC ATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCA GGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCC CTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCCGTGGCAT GCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTT

- 111 19653

ATAGGGTATGATGGACAGGAGAAATACTATGCAGACTCCGTGAAGGGCC GATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAAT GAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGTCAAGGG GCCGTTGCAGGAGCCGCCATACGATTATGGAATGGACGTATGGGGCCAG GGAACAACTGTCACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTC AAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCC TTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGG AGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTG GGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATG ACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCAC CACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCT GCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGC TCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGG ACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGA GGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCT GAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGG TTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCC

ACATGCAAGCCCTGCCACCTAGG

[0392] In further embodiments, the invention relates to Clone RD-26578 CAR LxH

AA sequence (SEQ ID NO: 410):

MALPVTALLL PLALLLHAAR PEIVMTQSPA TLSVSPGERA TLSCRASQSV

SSNLAWYQQK PGQAPRLLIY SASTRATGIP ARFSGSGSGT EFTLTISSLQ

SEDFAVYYCQ GEGSTKGQVQ MHWVRQAPGK NSKNTLYLQM

QHHVWPLTFG

LVESGGGVVQ GLEWVAVIGY

NSLRAEDTAV

GGTKVEIKRG

PGRSLRLSCA

DGQEKYYADS

YYCVKGPLQE

STSGSGKPGS

ASGFTFSSRG

VKGRFTISRD

PPYDYGMDVW

GQGTTVTVSS AAALDNEKSN GTIIHVKGKH LCPSPLFPGP SKPFWVLVVV

GGVLACYSLL VTVAFIIFWV RSKRSRLLHS DYMNMTPRRP GPTRKHYQPY

APPRDFAAYR SRVKFSRSAD APAYQQGQNQ LYNELNLGRR

EEYDVLDKRR GRDPEMGGKP RRKNPQEGLY NELQKDKMAE AYSEIGMKGE RRRGKGHDGL YQGLSTATKD TYDALHMQAL PPR.

[0393] It will be appreciated that the sequences recited herein can be useful by themselves, in combination with one or more sequences recited herein, and/or incorporated

- 11219653 into cells (such as CAR or TCR- based T cells) for use in immune- or other thérapies. It will be further appreciated that these sequences can be used in accordance with the invention incorporated in vectors for transduction, transfection, and the like, into cells.

[0394] It will be appreciated that adverse events may be minimized by transducing the immune cells (containing one or more CARs or TCRs) with a suicide gene. It may also be desired to incorporate an inducible “on” or “accelerator” switch into the immune cells. Suitable techniques include use of inducible caspase-9 (U.S. Appl. 2011/0286980) or a thymidine kinase, before, after or at the same time, as the cells are transduced with the CAR construct of the présent invention. Additional methods for introducing suicide genes and/or “on” switches include TALENS, zinc fingers, RNAi, siRNA, shRNA, antisense technology, and other techniques known in the art.

[0395] In accordance with the invention, additional on-off or other types of control switch techniques may be incorporated herein. These techniques may employ the use of dimerization domains and optional activators of such domain dimerization. These techniques include, e.g., those described by Wu et al., Science 2014 350 (6258) utilizing FKBP/Rapalog dimerization Systems in certain cells, the contents of which are incorporated by reference herein in their entirety. Additional dimerization technology is described in, e.g., Fegan et al. Chem. Rev. 2010, 110, 3315-3336 as well as U.S. Patent Nos. 5,830,462; 5,834,266; 5,869,337; and 6,165,787, the contents of which are also incorporated by reference herein in their entirety. Additional dimerization pairs may include cyclosporine-A/cyclophilin, receptor, estrogen/estrogen receptor (optionally using tamoxifen), glucocorticoids/glucocorticoid receptor, tetracycline/tetracycline receptor, vitamin D/vitamin D receptor. Further examples of dimerization technology can be found in e.g., WO2014/127261, WO2015/090229, US2014/0286987, US2015/0266973,

US2016/0046700, U.S. Patent No. 8,486,693, US2014/0171649, and US2012/0130076, the contents of which are further incorporated by reference herein in their entirety.

IV. Vectors, Cells, and Pharmaceutical Compositions

[0396] In certain aspects, provided herein are vectors comprising a polynucleotide of the présent invention. In some embodiments, the présent invention is directed to a vector or a set of vectors comprising a polynucleotide encoding a CAR or a TCR, as described herein. In other embodiments, the présent invention is directed to a vector or a set of vectors comprising

- 113 19653 a polynucleotide encoding an antibody or an antigen binding molécule thereof that specifically binds to BCMA, as disclosed herein.

[0397] Any vector known in the art can be suitable for the présent invention. In some embodiments, the vector is a viral vector. In some embodiments, the vector is a retroviral vector (such as pMSVGl), a DNA vector, a murine leukemia virus vector, an SFG vector, a plasmid, a RNA vector, an adénoviral vector, a baculoviral vector, an Epstein Barr viral vector, a papovaviral vector, a vaccinia viral vector, a herpes simplex viral vector, an adenovirus associated vector (AAV), a lentiviral vector (such as pGAR), or any combination thereof.

[0398] The pGAR sequence is as follows:

[0399] CTGACGCGCCCTGTAGCGGCGCATTAAGCGCGGCGGGTGTGGTGG

TTACGCGCAGCGTGACCGCTACACTTGCCAGCGCCCTAGCGCCCGCTCCTT TCGCTTTCTTCCCTTCCTTTCTCGCCACGTTCGCCGGCTTTCCCCGTCAAGC TCTAAATCGGGGGCTCCCTTTAGGGTTCCGATTTAGTGCTTTACGGCACCT CGACCCCAAAAAACTTGATTAGGGTGATGGTTCACGTAGTGGGCCATCGC CCTGATAGACGGTTTTTCGCCCTTTGACGTTGGAGTCCACGTTCTTTAATA GTGGACTCTTGTTCCAAACTGGAACAACACTCAACCCTATCTCGGTCTATT CTTTTGATTTATAAGGGATTTTGCCGATTTCGGCCTATTGGTTAAAAAATG AGCTGATTTAACAAAAATTTAACGCGAATTTTAACAAAATATTAACGCTTA CAATTTGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCG GTGCGGGCCTCTTCGCTATTACGCCAGCTGGCGAAAGGGGGATGTGCTGC AAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTA AAACGACGGCCAGTGAATTGTAATACGACTCACTATAGGGCGACCCGGGG ATGGCGCGCCAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATG GAGTTCCGCGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCC

AACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACG CCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACT GCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATT GACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGAC CTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATT ACCATGCTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTT GACTCACGGGGATTTCCAAGTCTCCACCCCATTGACGTCAATGGGAGTTTG TTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCC

-11419653

CCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAG CAGAGCTGGTTTAGTGAACCGGGGTCTCTCTGGTTAGACCAGATCTGAGCC TGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAG CTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGT AACTAGAGATCCCTCAGACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGT GGCGCCCGAACAGGGACTTGAAAGCGAAAGGGAAACCAGAGGAGCTCTC TCGACGCAGGACTCGGCTTGCTGAAGCGCGCACGGCAAGAGGCGAGGGG CGGCGACTGGTGAGTACGCCAAAAATTTTGACTAGCGGAGGCTAGAAGGA GAGAGATGGGTGCGAGAGCGTCAGTATTAAGCGGGGGAGAATTAGATCG CGATGGGAAAAAATTCGGTTAAGGCCAGGGGGAAAGAAAAAATATAAAT TAAAACATATAGTATGGGCAAGCAGGGAGCTAGAACGATTCGCAGTTAAT CCTGGCCTGTTAGAAACATCAGAAGGCTGTAGACAAATACTGGGACAGCT ACAACCATCCCTTCAGACAGGATCAGAAGAACTTAGATCATTATATAATA CAGTAGCAACCCTCTATTGTGTGCATCAAAGGATAGAGATAAAAGACACC AAGGAAGCTTTAGACAAGATAGAGGAAGAGCAAAACAAAAGTAAGACCA CCGCACAGCAAGCCGCCGCTGATCTTCAGACCTGGAGGAGGAGATATGAG GGACAATTGGAGAAGTGAATTATATAAATATAAAGTAGTAAAAATTGAAC CATTAGGAGTAGCACCCACCAAGGCAAAGAGAAGAGTGGTGCAGAGAGA AAAAAGAGCAGTGGGAATAGGAGCTTTGTTCCTTGGGTTCTTGGGAGCAG CAGGAAGCACTATGGGCGCAGCGTCAATGACGCTGACGGTACAGGCCAGA CAATTATTGTCTGGTATAGTGCAGCAGCAGAACAATTTGCTGAGGGCTATT GAGGCGCAACAGCATCTGTTGCAACTCACAGTCTGGGGCATCAAGCAGCT CCAGGCAAGAATCCTGGCTGTGGAAAGATACCTAAAGGATCAACAGCTCC TGGGGATTTGGGGTTGCTCTGGAAAACTCATTTGCACCACTGCTGTGCCTT GGAATGCTAGTTGGAGTAATAAATCTCTGGAACAGATTTGGAATCACACG ACCTGGATGGAGTGGGACAGAGAAATTAACAATTACACAAGCTTAATACA CTCCTTAATTGAAGAATCGCAAAACCAGCAAGAAAAGAATGAACAAGAAT TATTGGAATTAGATAAATGGGCAAGTTTGTGGAATTGGTTTAACATAACA AATTGGCTGTGGTATATAAAATTATTCATAATGATAGTAGGAGGCTTGGTA GGTTTAAGAATAGTTTTTGCTGTACTTTCTATAGTGAATAGAGTTAGGCAG GGATATTCACCATTATCGTTTCAGACCCACCTCCCAACCCCGAGGGGACCC GACAGGCCCGAAGGAATAGAAGAAGAAGGTGGAGAGAGAGACAGAGAC AGATCCATTCGATTAGTGAACGGATCTCGACGGTATCGGTTAACTTTTAAA

- 115 19653

AGAAAAGGGGGGATTGGGGGGTACAGTGCAGGGGAAAGAATAGTAGACA TAATAGCAACAGACATACAAACTAAAGAATTACAAAAACAAATTACAAA ATTCAAAATTTTATCGCGATCGCGGAATGAAAGACCCCACCTGTAGGTTTG GCAAGCTAGCTTAAGTAACGCCATTTTGCAAGGCATGGAAAATACATAAC TGAGAATAGAGAAGTTCAGATCAAGGTTAGGAACAGAGAGACAGCAGAA TATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGG GCCAAGAACAGATGGTCCCCAGATGCGGTCCCGCCCTCAGCAGTTTCTAG AGAACCATCAGATGTTTCCAGGGTGCCCCAAGGACCTGAAAATGACCCTG TGCCTTATTTGAACTAACCAATCAGTTCGCTTCTCGCTTCTGTTCGCGCGCT TCTGCTCCCCGAGCTCAATAAAAGAGCCCACAACCCCTCACTCGGCGCGC CAGTCCTTCGAAGTAGATCTTTGTCGATCCTACCATCCACTCGACACACCC GCCAGCGGCCGCTGCCAAGCTTCCGAGCTCTCGAATTAATTCACGGTACCC ACCATGGCCTAGGGAGACTAGTCGAATCGATATCAACCTCTGGATTACAA AATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTGCTCCTTTTACGCTA TGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGG CTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTTTATGAGGA GTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGA CGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGTCAGCTCCTTTCCGG GACTTTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTG CCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGT GGTGTTGTCGGGGAAGCTGACGTCCTTTTCATGGCTGCTCGCCTGTGTTGC CACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAA TCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCCGGCTCTGCGGCCTCTTCC GCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTC CCCGCCTGGTTAATTAAAGTACCTTTAAGACCAATGACTTACAAGGCAGCT GTAGATCTTAGCCACTTTTTAAAAGAAAAGGGGGGACTGGAAGGGCGAAT TCACTCCCAACGAAGACAAGATCTGCTTTTTGCTTGTACTGGGTCTCTCTG GTTAGACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCAC TGCTTAAGCCTCAATAAAGCTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCC GTCTGTTGTGTGACTCTGGTAACTAGAGATCCCTCAGACCCTTTTAGTCAG TGTGGAAAATCTCTAGCAGGCATGCCAGACATGATAAGATACATTGATGA GTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTGTG AAATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAAC

- 11619653

AAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGG TGTGGGAGGTTTTTTGGCGCGCCATCGTCGAGGTTCCCTTTAGTGAGGGTT AATTGCGAGCTTGGCGTAATCATGGTCATAGCTGTTTCCTGTGTGAAATTG TTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTA AAGCCTGGGGTGCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCT CACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAA TCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTT CCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTAT CAGCTCACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAAC GCAGGAAAGAACATGTGAGCAAAAGGCCAGCAAAAGGCCAGGAACCGTA AAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGC ATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTA TAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTT CCGACCCTGCCGCTTACCGGATACCTGTCCGCCTTTCTCCCTTCGGGAAGC GTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTC GTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGC TGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGAC TTATCGCCACTGGCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTA TGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACA CTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCG GAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGC GGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATC TCAAGAAGATCCTTTGATCTTTTCTACGGGGTCTGACGCTCAGTGGAACGA AAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCAC CTAGATCCTTTTAAATTAAAAATGAAGTTTTAAATCAATCTAAAGTATATA TGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTAT CTCAGCGATCTGTCTATTTCGTTCATCCATAGTTGCCTGACTCCCCGTCGTG TAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAAT GATACCGCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACC AGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCGCC TCCATCCAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCA GTTAATAGTTTGCGCAACGTTGTTGCCATTGCTACAGGCATCGTGGTGTCA CGCTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGG

- 11719653

CGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCCTCC GATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGGCAGCAC TGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGACTGGTGAGT ACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGTTGCTCTTGCCCG GCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTTAAAAGTGCTCATCA TTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCTTACCGCTGTTGAGATCC AGTTCGATGTAACCCACTCGTGCACCCAACTGATCTTCAGCATCTTTTACTTTCACC AGCGTTTCTGGGTGAGCAAAAACAGGAAGGCAAAATGCCGCAAAAAAGGGAATA AGGGCGACACGGAAATGTTGAATACTCATACTCTTCCTTTTTCAATATTATTGAAG CATTTATCAGGGTTATTGTCTCATGAGCGGATACATATTTGAATGTATTTAGAAAA ATAAACAAATAGGGGTTCCGCGCACATTTCCCCGAAAAGTGCCAC (SEQ ID NO:

413)

[0400] The pGAR vector map is set forth below:

[0401] Suitable additional exemplary vectors include e.g., pBABE-puro, pBABE-neo largeTcDNA, pBABE-hygro-hTERT, pMKO.l GFP, MSCV-1RES-GFP, pMSCV PIG (Puro IRES GFP empty plasmid), pMSCV-loxp-dsRed-loxp-eGFP-Puro-WPRE, MSCV IRES Luciferase, pMIG, MDH1-PGK-GFP_2.O, TtRMPVIR, pMSCV-IRES-mCherry FP, pRetroX GFP T2A Cre, pRXTN, pLncEXP, and pLXIN-Luc.

- 11819653

[0402] In other aspects, provided herein are cells comprising a polynucleotide or a vector of the présent invention. In some embodiments, the présent invention is directed to cells, in vitro cells, comprising a polynucleotide encoding a CAR or a TCR, as described herein. In some embodiments, the présent invention is directed to cells, e.g., in vitro cells, comprising a polynucleotide encoding an antibody or an antigen binding molécule thereof that specifically binds to BCMA, as disclosed herein. In other embodiments, the présent invention is directed to in vitro cells comprising a polypeptide encoded by a polynucleotide encoding a CAR or a TCR, as disclosed herein. In other embodiments, the présent invention is directed to cells, in vitro cells, comprising a polypeptide encoded by a polynucleotide encoding an antibody or an antigen binding molécule thereof that specifically binds to BCMA, as disclosed herein.

[0403] Any cell may be used as a host cell for the polynucleotides, the vectors, or the polypeptides of the présent invention. In some embodiments, the cell can be a prokaryotic cell, fùngal cell, yeast cell, or higher eukaryotic cells such as a mammalian cell.. Suitable prokaryotic cells include, without limitation, eubacteria, such as Gram-negative or Grampositive organisms, for example, Enterobactehaceae such as Escherichia, e.g., E. colr, Enterobacter, Erwinia, Klebsiella, Proteus', Salmonella, e.g., Salmonella typhimurium', Serratia, e.g., Serratia marcescans, and Shigella, Bacilli such as B. subtilis and B. licheniformis-, Pseudomonas such as P. aeruginosa-, and Streptomyces. In some embodiments, the cell is a human cell. In some embodiments, the cell is an immune cell. In some embodiments, the immune cell is selected from the group consisting of a T cell, a B cell, a tumor infiltrating lymphocyte (TIL), a TCR expressing cell, a natural killer (NK) cell, a dendritic cell, a granulocyte, an innate lymphoid cell, a megakaryocyte, a monocyte, a macrophage, a platelet, a thymocyte, and a myeloid cell. In one embodiment, the immune cell is a T cell. In another embodiment, the immune cell is an NK cell. In certain embodiments, the T cell is a tumor-infiltrating lymphocyte (TIL), autologous T cell, engineered autologous T cell (eACT™), an allogeneic T cell, a heterologous T cell, or any combination thereof.

[0404] The cell of the présent invention can be obtained through any source known in the art. For example, T cells can be differentiated in vitro from a hematopoietic stem cell population, or T cells can be obtained from a subject. T cells can be obtained from, e.g., peripheral blood mononuclear cells, bone marrow, lymph node tissue, cord blood, thymus tissue, tissue from a site of infection, ascites, pleural effusion, spleen tissue, and tumors. In addition, the T cells can be derived from one or more T cell lines available in the art. T cells

- 11919653 can also be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled artisan, such as FICOLL™ séparation and/or apheresis. In certain embodiments, the cells collected by apheresis are washed to remove the plasma fraction, and placed in an appropriate buffer or media for subséquent processing. In some embodiments, the cells are washed with PBS. As will be appreciated, a washing step can be used, such as by using a semiautomated flowthrough centrifuge, e.g., the COBE™ 2991 cell processor, the Baxter CYTOMATE™, or the like. In some embodiments, the washed cells are resuspended in one or more biocompatible buffers, or other saline solution with or without buffer. In certain embodiments, the undesired components of the apheresis sample are removed. Additional methods of isolating T cells for a T cell therapy are disclosed in U.S. Patent Publication No. 2013/0287748, which is herein incorporated by references in its entirety.

[0405] In certain embodiments, T cells are isolated from PBMCs by lysing the red blood cells and depleting the monocytes, e.g., by using centrifugation through a PERCOLL™ gradient. In some embodiments, a spécifie subpopulation of T cells, such as CD28⁺, CD4⁺, CD8⁺, CD45RA7, and CD45RO⁺ T cells is further isolated by positive or négative sélection techniques known in the art. For example, enrichment of a T cell population by négative sélection can be accomplished with a combination of antibodies directed to surface markers unique to the negatively selected cells. In some embodiments, cell sorting and/or sélection via négative magnetic immunoadherence or flow cytometry that uses a cocktail of monoclonal antibodies directed to cell surface markers présent on the cells negatively selected can be used. For example, to enrich for CD4⁺ cells by négative sélection, a monoclonal antibody cocktail typically includes antibodies to CD14, CD20, CD11b, CD16, HLA-DR, and CD8. In certain embodiments, flow cytometry and cell sorting are used to isolate cell populations of interest for use in the présent invention.

[0406] In some embodiments, PBMCs are used directly for genetic modification with the immune cells (such as CARs or TCRs) using methods as described herein. In certain embodiments, after isolating the PBMCs, T lymphocytes are further isolated, and both cytotoxic and helper T lymphocytes are sorted into naïve, memory, and effector T cell subpopulations either before or after genetic modification and/or expansion.

[0407] In some embodiments, CD8⁺ cells are further sorted into naïve, central memory, and effector cells by identifying cell surface antigens that are associated with each of these types of CD8 cells. In some embodiments, the expression of phenotypic markers of

- 12019653 central memory T cells includes CD45RO, CD62L, CCR7, CD28, CD3, and CD127 and are négative for granzyme B. In some embodiments, central memory T cells are CD45RO⁺, CD62L⁺, CD8⁺ T cells. In some embodiments, effector T cells are négative for CD62L, CCR7, CD28, and CD 127 and positive for granzyme B and perforin. In certain embodiments, CD4⁺ T cells are further sorted into subpopulations. For example, CD4⁺ T helper cells can be sorted into naïve, central memory, and effector cells by identifying cell populations that hâve cell surface antigens.

[0408] In some embodiments, the immune cells, e.g., T cells, are genetically modified following isolation using known methods, or the immune cells are activated and expanded (or differentiated in the case of progenitors) in vitro prior to being genetically modified. In another embodiment, the immune cells, e.g., T cells, are genetically modified with the chimeric antigen receptors described herein (e.g., transduced with a viral vector comprising one or more nucléotide sequences encoding a CAR) and then are activated and/or expanded in vitro. Methods for activating and expanding T cells are known in the art and are described, e.g., in U.S. Patent Nos. 6,905,874; 6,867,041; and 6,797,514; and PCT Publication No. WO 2012/079000, the contents of which are hereby incorporated by référencé in their entirety. Generally, such methods include contacting PBMC or isolated T cells with a stimulatory agent and costimulatory agent, such as anti-CD3 and anti-CD28 antibodies, generally attached to a bead or other surface, in a culture medium with appropriate cytokines, such as IL-2. Anti-CD3 and anti-CD28 antibodies attached to the same bead serve as a “surrogate” antigen presenting cell (APC). One example is The Dynabeads® System, a CD3/CD28 activator/stimulator System for physiological activation of human T cells. In other embodiments, the T cells are activated and stimulated to proliferate with feeder cells and appropriate antibodies and cytokines using methods such as those described in U.S. Patent Nos. 6,040,177 and 5,827,642 and PCT Publication No. WO 2012/129514, the contents of which are hereby incorporated by reference in their entirety.

[0409] In certain embodiments, the T cells are obtained from a donor subject. In some embodiments, the donor subject is human patient afflicted with a cancer or a tumor. In other embodiments, the donor subject is a human patient not afflicted with a cancer or a tumor.

[0410] Other aspects of the présent invention are directed to compositions comprising a polynucleotide described herein, a vector described herein, a polypeptide described herein, or an in vitro cell described herein. In some embodiments, the composition comprises a pharmaceutically acceptable carrier, diluent, solubilizer, emulsifier, preservative and/or

- 121 19653 adjuvant. In some embodiments, the composition comprises an excipient. In one embodiment, the composition comprises a polynucleotide encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molécule that specifîcally binds to BCMA. In another embodiment, the composition comprises a CAR or a TCR encoded by a polynucleotide of the présent invention, wherein the CAR or the TCR comprises an antigen binding molécule that specifîcally binds to BCMA. In another embodiment, the composition comprises a T cell comprising a polynucleotide encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molécule that specifîcally binds to BCMA. In another embodiment, the composition comprises an antibody or an antigen binding molécule thereof encoded by a polynucleotide of the présent invention. In another embodiment, the composition comprises an in vitro cell comprising a polynucleotide encoding an antibody or an antigen binding molécule thereof encoded by a polynucleotide of the présent invention.

[0411] In some embodiments, the composition includes more than one different antigen binding molécule to BMCA. In some embodiments, the composition included more than one antigen binding molécule to BCMA, wherein the antigen binding molécules to BCMA bind more than one epitope. In some embodiments, the antigen binding molécules will not compete with one another for binding to BCMA. In some embodiments, any of the antigen binding molécules provided herein are combined together in a pharmaceutical composition.

[0412] In other embodiments, the composition is selected for parentéral delivery, for inhalation, or for delivery through the digestive tract, such as orally. The préparation of such pharmaceutically acceptable compositions is within the ability of one skilled in the art. In certain embodiments, buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8. In certain embodiments, when parentéral administration is contemplated, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution comprising a desired antigen binding molécule to BCMA, with or without additional therapeutic agents, in a pharmaceutically acceptable vehicle. In certain embodiments, the vehicle for parentéral injection is stérile distilled water in which an antigen binding molécule to BCMA, with or without at least one additional therapeutic agent, is formulated as a stérile, isotonie solution, properly preserved. In certain embodiments, the préparation involves the formulation of the desired molécule with polymeric compounds (such as polylactic acid or polyglycolic acid), beads or liposomes, that provide for the controlled or sustained release of the product, which

- 12219653 are then be delivered via a depot injection. In certain embodiments, implantable drug delivery devices are used to introduce the desired molécule.

V. Methods of the Invention

[0413] Another aspect of the invention is directed to a method of making a cell expressing a CAR or a TCR comprising transducing a cell with a polynucleotide disclosed herein under suitable conditions. In some embodiments, the method comprises transducing a cell with a polynucleotide encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molécule that specifically binds to BCMA, as disclosed herein. In some embodiments, the method comprises transducing a cell with a vector comprising the polynucleotide encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molécule that specifically binds to BCMA. In other embodiments, the method comprises transducing a cell with a polynucleotide encoding an antibody or an antigen binding molécule thereof that specifically binds to BCMA, as disclosed herein. In some embodiments, the method comprises transducing a cell with a vector comprising the polynucleotide encoding an antibody or an antigen binding molécule thereof that specifically binds to BCMA, as described herein. In some embodiments, the method further comprises isolating the cell.

[0414] Another aspect of the présent invention is directed to a method of inducing an immunity against a tumor comprising administering to a subject an effective amount of a cell comprising a polynucleotide described herein, a vector described herein, or a CAR or a TCR described herein. In one embodiment, the method comprises administering to a subject an effective amount of a cell comprising a polynucleotide encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molécule that specifically binds to BCMA, as disclosed herein. In another embodiment, the method comprises administering to a subject an effective amount of a cell comprising a vector comprising a polynucleotide encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molécule that specifically binds to BCMA, as disclosed herein. In another embodiment, the method comprises administering to a subject an effective amount of a cell comprising a CAR or a TCR encoded by a polynucleotide disclosed herein, wherein the CAR or the TCR comprises an antigen binding molécule that specifically binds to BCMA. In other embodiments, the method comprises administering to a subject an effective amount of a cell comprising a polynucleotide encoding an antibody or an antigen binding molécule thereof that specifically

- 123 19653 binds to BCMA, as disclosed herein. In another embodiment, the method comprises administering to a subject an effective amount of a cell comprising a vector comprising a polynucleotide encoding an antibody or an antigen binding molécule thereof that specifically binds to BCMA, as disclosed herein. In another embodiment, the method comprises administering to a subject an effective amount of a cell comprising an antibody or antigen binding molécule thereof encoded by a polynucleotide disclosed herein, wherein the antibody or antigen binding molécule thereof specifically binds to BCMA.

[0415] Another aspect of the présent invention is directed to a method of inducing an immune response in a subject comprising administering an effective amount of the engineered immune cells of the présent application. In some embodiments, the immune response is a T cell-mediated immune response. In some embodiments, the T cell-mediated immune response is directed against one or more target cells. In some embodiments, the engineered immune cell comprises a CAR or a TCR. In some embodiments, the target cell is a tumor cell.

[0416] Another aspect of the présent invention is directed to a method for treating or preventing a malignancy, said method comprising administering to a subject in need thereof an effective amount of at least one isolated antigen binding molécule described herein or at least one immune cell, wherein the immune cell comprises at least one CAR, TCR, and/or an isolated antigen binding molécule as described herein.

[0417] Another aspect of the présent invention is directed to a method of treating a hyperproliferative disorder or an inflammatory disease in a subject in need thereof comprising administering to the subject a polynucleotide disclosed herein, a vector disclosed herein, a CAR or a TCR disclosed herein, a cell disclosed herein, or a composition disclosed herein. In some embodiments, the inflammatory disease is selected from the group consisting of rheumatoid arthritis, psoriasis, allergies, asthma, autoimmune diseases such as Crohn’s, IBD, fibromyalga, mastocytosis, Celiac disease, and any combination thereof. Additionally, the présent invention may be useful to treat diabètes, particularly Type 1 diabètes.

[0418] Another aspect of the présent invention is directed to a method of treating a cancer in a subject in need thereof comprising administering to the subject a polynucleotide disclosed herein, a vector disclosed herein, a CAR or a TCR disclosed herein, a cell disclosed herein, or a composition disclosed herein. In one embodiment, the method comprises administering a polynucleotide encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molécule that specifically binds to BCMA, as disclosed herein. In another embodiment, the method comprises administering a vector comprising a

- 12419653 polynucleotide encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molécule that specifically binds to BCMA, as disclosed herein. In another embodiment, the method comprises administering a CAR or a TCR encoded by a polynucleotide disclosed herein, wherein the CAR or the TCR comprises an antigen binding molécule that specifically binds to BCMA. In another embodiment, the method comprises administering a cell comprising the polynucleotide, or a vector comprising the polynucleotide, encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molécule that specifically binds to BCMA, as disclosed herein. In other embodiments, the method comprises administering a polynucleotide encoding an antibody or an antigen binding molécule thereof that specifically binds to BCMA, as disclosed herein. In another embodiment, the method comprises administering a vector comprising a polynucleotide encoding an antibody or an antigen binding molécule thereof that specifically binds to BCMA, as disclosed herein. In another embodiment, the method comprises administering an antibody or an antigen binding molécule thereof encoded by a polynucleotide disclosed herein, wherein the antibody or the antigen binding molécule thereof specifically binds to BCMA. In another embodiment, the method comprises administering a cell comprising the polynucleotide, or a vector comprising the polynucleotide, encoding an antibody or an antigen binding molécule thereof that specifically binds to BCMA, as disclosed herein.

[0419] In some embodiments, an antigen binding molécule to BCMA is administered alone. In certain embodiments, an antigen binding molécule to BCMA is administered as part of a CAR, TCR, or other immune cell. In such immune cells, the antigen binding molécule to BCMA can be under the control of the same promoter région, or a separate promoter. In certain embodiments, the genes encoding protein agents and/or an antigen binding molécule to BCMA can be in separate vectors.

[0420] In some embodiments, the methods of treating a cancer in a subject in need thereof comprise a T cell therapy. In one embodiment, the T cell therapy of the présent invention is engineered Autologous Cell Therapy (eACT™). According to this embodiment, the method can include collecting blood cells from the patient. The isolated blood cells (e.g., T cells) can then be engineered to express an anti-BCMA CAR ofthe présent invention (antiBCMA CAR T cells). In a particular embodiment, the anti-BCMA CAR T cells are administered to the patient. In some embodiments, the anti-BCMA CAR T cells treat a tumor

- 125 19653 or a cancer in the patient. In one embodiment the anti-BCMA CAR T cells reduce the size of a tumor or a cancer.

[0421] In some embodiments, the donor T cells for use in the T cell therapy are obtained from the patient (e.g., for an autologous T cell therapy). In other embodiments, the donor T cells for use in the T cell therapy are obtained from a subject that is not the patient.

[0422] The T cells can be administered at a therapeutically effective amount. For example, a therapeutically effective amount of the T cells can be at least about 10⁴ cells, at least about 10⁵ cells, at least about 10⁶ cells, at least about 10⁷ cells, at least about 10⁸ cells, at least about 10⁹ cells, at least about 10¹⁰ cells, or at least about 10¹¹ cells. In another embodiment, the therapeutically effective amount of the T cells is about 10⁴ cells, about 10⁵ cells, about 10⁶ cells, about 10⁷ cells, or about 10⁸ cells. In one particular embodiment, the therapeutically effective amount of the anti-BCMA CAR T cells is about 2 X 10⁶ cells/kg, about 3 X 10⁶ cells/kg, about 4 X 10⁶ cells/kg, about 5 X 10⁶ cells/kg, about 6 X 10⁶ cells/kg, about 7 X 10⁶ cells/kg, about 8 X 10⁶ cells/kg, about 9 X 10⁶ cells/kg, about 1 X 10⁷ cells/kg, about 2 X 10⁷ cells/kg, about 3 X 10⁷ cells/kg, about 4 X 10⁷ cells/kg, about 5 X 10⁷ cells/kg, about 6 X 10⁷ cells/kg, about 7 X 10⁷ cells/kg, about 8 X 10⁷ cells/kg, or about 9 X 10⁷ cells/kg.

[0423] Another aspect of the présent invention is directed to methods of diagnosis, détection, or validation. In some embodiments, the antigen binding molécule is used as a diagnostic or validation tool. In certain embodiments, the antigen binding molécules disclosed herein are used to assay the amount of BCMA présent in a sample and/or subject. In some embodiments, the diagnostic antigen binding molécule is not neutralizing. In some embodiments, the antigen binding molécules disclosed herein are used or provided in an assay kit and/or method for the détection of BCMA in mammalian tissues or cells in order to screen/diagnose for a disease or disorder associated with changes in levels of BCMA. In some embodiments, the kit comprises an antigen binding molécule that binds BCMA, along with means for indicating the binding of the antigen binding molécule with BCMA, if présent, and optionally BCMA protein levels. Various means for indicating the presence of an antigen binding molécule can be used. For example, fluorophores, other molecular probes, or enzymes can be linked to the antigen binding molécule and the presence of the antigen binding molécule can be observed in a variety of ways. As will be appreciated by one of skill in the art, the degree of antigen binding molécule binding can be used to détermine how much BCMA is in a sample.

- 12619653

V.A. Cancer Treatment

[0424] The methods of the invention can be used to treat a cancer in a subject, reduce the size of a tumor, kill tumor cells, prevent tumor cell prolifération, prevent growth of a tumor, eliminate a tumor from a patient, prevent relapse of a tumor, prevent tumor metastasis, induce remission in a patient, or any combination thereof. In certain embodiments, the methods induce a complété response. In other embodiments, the methods induce a partial response.

[0425] Cancers that may be treated include tumors that are not vascularized, not yet substantially vascularized, or vascularized. The cancer may also include solid or non-solid tumors. In some embodiments, the cancer is a hématologie cancer. In some embodiments, the cancer is of the white blood cells. In other embodiments, the cancer is of the plasma cells. In some embodiments, the cancer is leukemia, lymphoma, or myeloma. In certain embodiments, the cancer is multiple myeloma, Hodgkin's Disease, non-Hodgkin's lymphoma (NHL), primary médiastinal large B cell lymphoma (PMBC), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), chronic or acute leukemia, myeloid diseases including but not limited to acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL) (including non T cell ALL), chronic lymphocytic leukemia (CLL), T-cell lymphoma, one or more of B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliférative conditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, myelodysplasia and myelodysplastic syndrome (MDS), hemophagocytic syndrome (Macrophage Activating Syndrome (MAS), and hemophagocytic lymphohistocytosis (HLH)), chronic or acute granulomatous disease, large cell granuloma, leukocyte adhesion defîciency, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, plasma cell proliférative disorders (e.g., asymptomatic myeloma (smoldering multiple myeloma or indolent myeloma), monoclonal gammapathy of undetermined significance (MGUS), plasmacytomas (e.g., plasma cell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullary plasmacytoma, and multiple plasmacytoma), systemic amyloid light chain amyloidosis, POEMS syndrome (Crow-Fukase

- 12719653 syndrome, Takatsuki disease, PEP syndrome), or combinations thereof. In one embodiment, the cancer is a myeloma. In one particular embodiment, the cancer is multiple myeloma.

[0426] In some embodiments, the methods further comprise administering a chemotherapeutic. In certain embodiments, the chemotherapeutic selected is a lymphodepleting (preconditioning) chemotherapeutic. Bénéficiai preconditioning treatment regimens, along with corrélative bénéficiai biomarkers are described in U.S. Provisional Patent Applications 62/262,143 and 62/167,750 which are hereby incorporated by reference in their entirety herein. These describe, e.g., methods of conditioning a patient in need of a T cell therapy comprising administering to the patient specified bénéficiai doses of cyclophosphamide (between 200 mg/m²/day and 2000 mg/m²/day) and specified doses of fludarabine (between 20 mg/m²/day and 900 mg/m²/day). A preferred dose regimen involves treating a patient comprising administering daily to the patient about 500 mg/m²/day of cyclophosphamide and about 60 mg/m²/day of fludarabine for three days prior to administration of a therapeutically effective amount of engineered T cells to the patient.

[0427] In other embodiments, the antigen binding molécule, transduced (or otherwise engineered) cells (such as CARs or TCRs), and the chemotherapeutic agent are administered each in an amount effective to treat the disease or condition in the subject.

[0428] In certain embodiments, compositions comprising CAR- and/or TCRexpressing immune effector cells disclosed herein may be administered in conjunction with any number of chemotherapeutic agents. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN™); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethyl enemel amine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamine résumé; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin,

- 12819653 rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folie acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofùr, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, 5-FU; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals such as aminoglutéthimide, mitotane, trilostane; folie acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2, 2',2-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxoids, e.g. paclitaxel (TAXOL™, Bristol-Myers Squibb) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer); chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS2000; difluoromethylomithine (DMFO); retinoic acid dérivatives such as Targretin™ (bexarotene), Panretin™, (alitretinoin); ONTAK™ (denileukin diftitox); esperamicins; capecitabine; and pharmaceutically acceptable salts, acids or dérivatives of any of the above. In some embodiments, compositions comprising CAR- and/or TCR-expressing immune effector cells disclosed herein may be administered in conjunction with an anti-hormonal agent that acts to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or dérivatives of any of the above. Combinations of chemotherapeutic agents are also administered where appropriate, including, but not limited to CHOP, i.e.. Cyclophosphamide (Cytoxan®), Doxorubicin (hydroxydoxorubicin), Vincristine (Oncovin®), and Prednisone.

- 12919653

[0429] In some embodiments, the chemotherapeutic agent is administered at the same time or within one week after the administration of the engineered cell or nucleic acid. In other embodiments, the chemotherapeutic agent is administered from 1 to 4 weeks or from 1 week to 1 month, 1 week to 2 months, 1 week to 3 months, 1 week to 6 months, 1 week to 9 months, or 1 week to 12 months after the administration of the engineered cell or nucleic acid. In some embodiments, the chemotherapeutic agent is administered at least 1 month before administering the cell or nucleic acid. In some embodiments, the methods further comprise administering two or more chemotherapeutic agents.

[0430] A variety of additional therapeutic agents may be used in conjunction with the compositions described herein. For example, potentially useful additional therapeutic agents include PD-1 inhibitors such as nivolumab (Opdivo®), pembrolizumab (Keytruda®), pembrolizumab, pidilizumab (CureTech), and atezolizumab (Roche).

[0431] Additional therapeutic agents suitable for use in combination with the invention include, but are not limited to, ibrutinib (Imbruvica®), ofatumumab (Arzerra®), rituximab (Rituxan®), bevacizumab (Avastin®), trastuzumab (Herceptin®), trastuzumab emtansine (KADCYLA®), imatinib (Gleevec®), cetuximab (Erbitux®), panitumumab (Vectibix®), catumaxomab, ibritumomab, ofatumumab, tositumomab, brentuximab, alemtuzumab, gemtuzumab, erlotinib, gefitinib, vandetanib, afatinib, lapatinib, neratinib, axitinib, masitinib, pazopanib, sunitinib, sorafenib, toceranib, lestaurtinib, axitinib, cediranib, lenvatinib, nintedanib, pazopanib, regorafenib, semaxanib, sorafenib, sunitinib, tivozanib, toceranib, vandetanib, entrectinib, cabozantinib, imatinib, dasatinib, nilotinib, ponatinib, radotinib, bosutinib, lestaurtinib, ruxolitinib, pacritinib, cobimetinib, selumetinib, trametinib, binimetinib, alectinib, ceritinib, crizotinib, aflibercept,adipotide, denileukin diftitox, mTOR inhibitors such as Everolimus and Temsirolimus, hedgehog inhibitors such as sonidegib and vismodegib, CDK inhibitors such as CDK inhibitor (palbociclib).

[0432] In additional embodiments, the composition comprising CAR- and/or TCRcontaining immune are administered with an anti-inflammatory agent. Anti-inflammatory agents or drugs can include, but are not limited to, steroids and glucocorticoids (including betamethasone, budesonide, dexamethasone, hydrocortisone acetate, hydrocortisone, hydrocortisone, méthylprednisolone, prednisolone, prednisone, triamcinolone), nonsteroidal anti-inflammatory drugs (NS AID S) including aspirin, ibuprofen, naproxen, méthotrexate, sulfasalazine, leflunomide, anti-TNF médications, cyclophosphamide and mycophenolate. Exemplary NSAIDs include ibuprofen, naproxen, naproxen sodium, Cox-2

- 13019653 inhibitors, and sialylates. Exemplary analgésies include acetaminophen, oxycodone, tramadol of proporxyphene hydrochloride. Exemplary glucocorticoids include cortisone, dexamethasone, hydrocortisone, méthylprednisolone, prednisolone, or prednisone. Exemplary biological response modifiers include molécules directed against cell surface markers (e.g., CD4, CD5, etc.), cytokine inhibitors, such as the TNE antagonists, (e.g., etanercept (ENBREL®), adalimumab (HUMIRA®) and infliximab (REMICADE®), chemokine inhibitors and adhesion molécule inhibitors. The biological response modifiers include monoclonal antibodies as well as recombinant forms of molécules. Exemplary DMARDs include azathioprine, cyclophosphamide, cyclosporine, methotrexate, penicillamine, leflunomide, sulfasalazine, hydroxychloroquine, Gold (oral (auranofm) and intramuscular), and minocycline.

[0433] In certain embodiments, the compositions described herein are administered in conjunction with a cytokine. “Cytokine” as used herein is meant to refer to proteins released by one cell population that act on another cell as intercellular mediators. Examples of cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are growth hormones such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor (HGF); fibroblast growth factor (FGF); prolactin; placental lactogen; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothélial growth factor; integrin; thrombopoietin (TPO); nerve growth factors (NGFs) such as NGF-beta; platelet-growth factor; transforming growth factors (TGFs) such as TGF-alpha and TGF-beta; insulin-like growth factor-I and -II; erythropoietin (EPO); osteoinductive factors; interferons such as interferon-alpha, beta, and -gamma; colony stimulating factors (CSFs) such as macrophage-CSF (M-CSF); granulocyte-macrophageCSF (GM-CSF); and granulocyte-CSF (G-CSF); interleukins (ILs) such as IL-1, IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12; IL-15, a tumor necrosis factor such as TNF-alpha or TNF-beta; and other polypeptide factors including LIF and kit ligand (KL). As used herein, the term cytokine includes proteins from natural sources or from recombinant cell culture, and biologically active équivalents of the native sequence cytokines.

- 131 19653

[0434] Ail publications, patents, and patent applications mentioned in this spécification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. However, the citation of a reference herein should not be construed as an acknowledgement that such reference is prior art to the présent invention. To the extent that any of the définitions or terms provided in the references incorporated by reference differ from the terms and discussion provided herein, the présent terms and définitions control.

[0435] The présent invention is further illustrated by the following examples which should not be construed as further limiting. The contents of ail references cited throughout this application are expressly incorporated herein by reference.

EXAMPLES

EXAMPLE 1

[0436] BCMA expression was measured in various cell fines. BCMA was found to be expressed, with a fragments/kilobase of exon/million reads mapped (FPKM) greater than 35, in 99% of multiple myeloma tumor cell fines tested (FIG. 2A). BCMA expression was greater than that of CD70, CS-1, CLL-1, DLL-1 and FLT3 (FIG. 2A). To further characterize the expression of BCMA, EoL-1 (Sigma), NCI-H929 (Molecular Imaging), and MM1S (Molecular Imaging) cells were stained with an anti-BCMA antibody conjugated to PE (Biolegend, San Diego, CA) in stain buffer (BD Pharmingen, San José, CA) for 30 minutes at 4°C. Cells were then washed and resuspended in stain buffer with propidium iodide (BD Pharmingen) prior to data acquisition. Samples were then acquired by flow cytometry and data analyzed (FIGs. 2B-2C). BCMA expression was observed in the myeloma cell fines MM1S (FIG. 2C) and NCI-H929 (FIG. 2D), but not in the human eosinophil cell line EoL-1 (FIG. 2B). In addition, little to no BCMA expression was observed in normal immune cells (FIG. 2E).

EXAMPLE 2

[0437] A third génération lentiviral transfer vector containing the BCMA CAR constructs was used along with the ViraPower™ Lentiviral Packaging Mix (Life Technologies, FIX™) to generate the lentiviral supernatants. Briefly, a transfection mix was generated by mixing 15pg of DNA and 22.5μ1 of polyethileneimine (Polysciences,

- 13219653 lmg/ml) in 600μ1 of OptiMEM media. The transfection mix was incubated for 5 minutes at room température. Simultaneously, 293T cells (ATCC) were trypsinized and counted. A total of 10 x 10⁶ total 293T cells were then plated in a T75 flask with the transfection mix. Following culture for three days, supematants were collected and filtered through a 0.45pm filter and stored at -80°C.

[043 8] Peripheral blood mononuclear cells (PBMCs) were isolated from two different healthy donor leukopaks (Hemacare) using ficoll-paque density centrifügation according to the manufacturer’s instructions. PBMCs were stimulated using OKT3 (Muromonab-CD3, 50ng/ml, Miltenyi Biotec) in RIO media supplemented with IL-2 (300IU/ml, Proleukin®, Prometheus® Therapeutics and Diagnostics). Forty-eight hours post-stimulation, cells were transduced using lentivirus containing the different BCMA CAR constructs at a multiplicity of infection (MOI) of 10. Cells were maintained at 0.5 x 10⁶ - 2.0 x 10⁶ cells/ml prior to use in activity assays.

[0439] At day 12 post-stimulation, transduced T cells were stained with recombinant BCMA-Fc (R&D Systems) in stain buffer (BD Pharmingen) for 30 minutes at 4°C. Cells were then washed and stained with goat anti-human IgG Fc PE (Jackson ImmunoResearch, West Grove, PA) in stain buffer for 30 minutes at 4°C. Cells were then washed and resuspended in stain buffer with propidium iodide (BD Pharmingen) prior to data acquisition. Ail experiments were performed in two different donors. BCMA CAR expression was observed for each of the constructs in both Donor 1 (FIG. 3 A) and Donor 2 (FIG. 3B) transduced cells.

[0440] Effector cells, e.g., anti-BCMA CAR T cells, were cultured with target cells at a 1:1 effector cell to target cell (E:T) ratio in RIO media 12 days after T cell stimulation. Cell lines tested included EoL-1, NCI-H929 and MM1S. Sixteen hours post-co-culture, supematants were analyzed by Luminex (EMD Millipore), according to the manufacturées instructions, for production of the cytokines IFNy (FIGs. 4A-4B), TNFa (FIG. 4C-4D), and IL-2 (FIG. 4E-4F). IFNy (FIGs. 4A-4B), TNFa (FIG. 4C-4D), and IL-2 (FIG. 4E-4F) were observed in the supernatant of NCI-H929 and MM1S target cell co-cultures for each antiBCMA CAR T cell tested in both donors (FIGs. 4A-4B); however, IFNy (FIGs. 4A-4B), TNFa (FIG. 4C-4D), and IL-2 (FIG. 4E-4F) were only observed in the supernatant of EoL1 target cell co-cultures above background for the IR négative control T cells (FIG. 4A).

[0441] Target cell viability was assessed by flow cytométrie analysis of propidium iodide (PI) uptake of CD3 négative cells. The anti-BCMA CAR T cells were co-cultured

- 133 19653 withEoLl (FIGs. 5A-5B), NCI-H929 (FIGs. 5C-5D), orMM!S(FIGs. 5E-5F) target cells for 16 hours, 40 hours, 64 hours, 88 hours, or 112 hours. Little cytolytic activity was observed in the EoL-1 co-cultures at any time period for the anti-BCMA CAR T cells (FIG. 5A-5B). However, co-culture of the anti-BCMA CAR T cells and the NCI-H929 or MM1S target cells resulted in a decrease in the percentage of viable target cells at each time point measured for each of the anti-BCMA CAR T cells.

[0442] To examine prolifération, anti-BCMA CAR T cells were labeled with carboxyfluorescein succinimidyl ester (CFSE) prior to co-culture with EoL-1, NCI-H929, or MM1S target cells at a 1:1 E:T ratio in RIO media. Five days later, T cell prolifération was assessed by flow cytométrie analysis of CFSE dilution. Data was analyzed and plotted as histogram using FlowJo™ (FIGs. 6A-6B). AU experiments were performed in two different donors.

EXAMPLE 3

[0443] Antigens were biotinylated using the EZ-Link Sulfo-NHS-Biotinylation Kit from Pierce/ThermoFisher (Waltham, MA). Goat anti-human F(ab’)2 kappa-FITC (LCFITC), Extravidin-PE (EA-PE) and streptavidin-633 (SA-633) were obtained from Southern Biotech (Birmingham, AL), Sigma (St. Louis, MO) and Molecular Probes/Invitrogen (Waltham, MA), respectively. Streptavidin MicroBeads and MACS LC séparation columns were purchased from Miltenyi Biotec (Gladbachn, Germany).

Naïve Discovery

[0444] Eight naïve human synthetic yeast libraries each of -109 diversity were propagated as described herein (see WO2009036379, WO2010105256, and WO2012009568 to Xu et ai). For the first two rounds of sélection, a magnetic bead sorting technique utilizing the Miltenyi MACs system was performed, as described (Siegel et al., 2004). Briefly, yeast cells (—1010 cells/library) were incubated with 3 ml of 100 nM biotinylated monomeric antigen or 10 nM biotinylated Fc fusion antigen for 15 minutes at room température in FACS wash buffer (phosphate-buffered saline (PBS)/0.1% bovine sérum albumin (BSA)). After washing once with 50 ml ice-cold wash buffer, the cell pellet was resuspended in 40 mL wash buffer, and Streptavidin MicroBeads (500 μ!) were added to the yeast and incubated for 15 minutes at 4°C. Next, the yeast were pelleted, resuspended in 5 mL wash buffer, and loaded onto a Miltenyi LS column. After the 5 mL was loaded, the column was washed 3 times with 3 ml FACS wash buffer. The column was then removed from the magnetic field, and the yeast were eluted with 5 mL of growth media and

- 13419653 then grown overnight. The following rounds of sorting were performed using flow cytometry. Approximately 1^108 yeast were pelleted, washed three times with wash buffer, and incubated with decreasing concentrations of biotinylated monomeric or Fc fusion antigen (100 to 1 nM) under equilibrium conditions at room température. Yeast were then washed twice and stained with LC-FITC (diluted 1:100) and either SA-633 (diluted 1:500) or EA-PE (diluted 1:50) secondary reagents for 15 minutes at 4°C. After washing twice with ice-cold wash buffer, the cell pellets were resuspended in 0.4 mL wash buffer and transferred to strainer-capped sort tubes. Sorting was performed using a FAC S ARIA sorter (BD Biosciences, San José, CA) and sort gates were assigned to select for spécifie binders relative to a background control. Subséquent rounds of sélection were focused on réduction of non-specific reagent binders (utilizing soluble membrane proteins from CHO cell), as well as pressuring for affmity to BCMA. After the final round of sorting, yeast were plated and individual colonies were picked for characterization.

[0445] Affmity Maturation

[0446] Binding optimization of naïve clones was carried out using three maturation strategies: light chain diversification, diversification of VH CDRH1/CDRH2, and performing VHmut/VKmut sélections.

[0447] Light Chain Diversification: Heavy chain plasmids were extracted and transformed into a light chain library with a diversity of 1 x 10⁶. Sélections were performed as described above with one round of MACS sorting and two rounds of FACS sorting using 10 nM or 1 nM biotinylated antigen for respective rounds.

[0448] CDRH1 and CDRH2 Sélection: A selected donor CDRH3 was recombined into a premade library with CDRH1 and CDRH2 variants of a diversity of 1 x 10⁸ and sélections were performed as described above. Affmity pressures were applied by incubating the biotinylated antigen-antibody yeast complex with unbiotinylated antigen for varying amounts of time to select for the highest affmity antibodies.

[0449] VHmut/VKmut Sélection: This round of affmity maturation included error prone PCR-based mutagenesis of the heavy chain and/or light chain. Sélections were performed similar to previous cycles, but employing FACS sorting for ail sélection rounds. Antigen concentration was reduced and cold antigen compétition times were increased to pressure further for optimal affmity.

- 135 19653

Antibody Production and Purification

[0450] Yeast clones were grown to saturation and then induced for 48 h at 30°C with shaking. After induction, yeast cells were pelleted and the supematants were harvested for purification. IgGs were purified using a Protein A column and eluted with acetic acid, pH 2.0. Fab fragments were generated by papain digestion and purified over KappaSelect™ (GE Healthcare LifeSciences, Pittsburg, PA).

ForteBio KD Measurements

[0451] ForteBio affmity measurements were performed generally as previously described (Estep et al., 2013). Briefly, ForteBio affmity measurements were performed by loading IgGs on-line onto AHQ sensors. Sensors were equilibrated off-line in assay buffer for 30 minutes and then monitored on-line for 60 seconds for baseline establishment. Sensors with loaded IgGs were exposed to 100 nM antigen for 5 minutes, afterwards they were transferred to assay buffer for 5 minutes for off-rate measurement. Kinetics were analyzed using the 1:1 binding model.

MSD-SET KD Measurements

[0452] Equilibrium affmity measurements performed generally as previously described (Estep et al., 2013). Briefly, solution equilibrium titrations (SET) were performed in PBS + 0.1% IgG-Free BSA (PBSF) with antigen (BCMA monomer) held constant at 10-100 pM and incubated with 3-to 5-fold serial dilutions of Fab or mAbs starting at ΙΟρΜ-ΙΟηΜ (experimental condition is sample dépendent). Antibodies (20 nM in PBS) were coated onto standard bind MSD-ECL plates overnight at 4°C or at room température for 30 minutes. Plates were then blocked by BSA for 30 minutes with shaking at 700 rpm, followed by three washes with wash buffer (PBSF + 0.05% Tween 20). SET samples were applied and incubated on the plates for 150 seconds with shaking at 700 rpm followed by one wash. Antigen captured on a plate was detected with 250ng/mL sulfotag™-labeled streptavidin in PBSF by incubation on the plate for 3 minutes. The plates were washed three times with wash buffer and then read on the MSD Sector Imager 2400™ instrument using Ix Read Buffer T with surfactant. The percent free antigen was plotted as a function of titrated antibody in Prism™ and fit to a quadratic équation to extract the KD. To improve throughput, liquid handling robots were used throughout MSD-SET experiments, including SET sample préparation.

- 13619653

Octet Red384 Epitope Binning/ligand blocking

[0453] Epitope binning/ligand blocking was performed using a standard sandwich format cross-blocking assay. Control anti-target IgG was loaded onto AHQ sensors and unoccupied Fc-binding sites on the sensor were blocked with an irrelevant human IgGl antibody. The sensors were then exposed to 100 nM target antigen followed by a second anti-target antibody or ligand. Data was processed using ForteBio’s Data Analysis Software 7.0. Additional binding by the second antibody or ligand after antigen association indicates an unoccupied epitope (non-competitor), while no binding indicates epitope blocking (competitor or ligand blocking).

Size Exclusion Chromatography

[0454] A TSKgel SuperSW mAb HTP column (22855) was used for fast SEC analysis of yeast produced mAbs at 0.4 mL/minute with a cycle time of 6 minutes/run. 200 mM Sodium Phosphate and 250 mM Sodium Chloride was used as the mobile phase.

Dynamic Scanning Fluorimetry

[0455] 10 uL of 20x Sypro Orange™ is added to 20 uL of 0.2-1 mg/mL mAb or Fab solution. A RT-PCR instrument (BioRad CFX96 RT PCR) is used to ramp the sample plate température from 40° to 95° C at 0.5C incrément, with 2 minutes to equilibrate at each température. The négative of first dérivative for the raw data is used to extract Tm.

- 13719653

Clone FS-26528 HC DNA (SEQ ID NO: 271)

GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCT CCTGTGCAGCCTCTGGATTCACCTTTGACGACTATGCCATGGCATGGGTCCGCCAGGCTCC AGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGATGCAGGTGACAGAACATACTACGCA GACTCCGTGAGGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACACTGTATCTGC AAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCAAGAGCCGAGATGGG AGCCGTATTCGACATATGGGGTCAGGGTACAATGGTCACCGTCTCCTCA

Clone FS-26528 HC (SEQ ID NO: 272). CDRs 1, 2, and 3 are underlined.

EVQLLESGGGLVQPGGSLRLSCAASGFTFDDYAMAWVRQAPGKGLEWVSAISDAGDRTYY ADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARAEMGAVFDIWGQGTMVTVSS

SCAASGFTFDDYAMA (SEQ ID NO: 273) [HC CDR1]

AISDAGDRTYYADSVRG (SEQ ID NO: 274) [HC CDR2]

ARAEMGAVFDI (SEQ ID NO: 275) [HC CDR3]

Clone FS-26528 LC DNA (SEQ ID NO: 276)

GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCC TCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGGTACTTAGCCTGGTACCAACAGAAACCTGG CCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGG TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAG ATTTTGCAGTTTATTACTGTCAGCAGAGAATCTCCTGGCCTTTCACTTTTGGCGGAGGGAC CAAGG T T GAGAT CAAACGG

Clone FS-26528 LC (SEQ ID NO: 277). CDRs 1, 2, and 3 are underlined.

EIVLTQSPATLSLSPGERATLSCRASQSySRYLAWYQQKPGQAPRLLIYDASNRATGIPAR FSGSGSGTDFTLTISSLEPEDFAVYYCQQ RISWPFTFGGGTKVEIKR

RASQSVSRYLA (SEQ ID NO: 278) [LC CDR1]

DASNRAT (SEQ ID NO: 279) [LC CDR2]

QQRISWPFT (SEQ ID NO: 280) [LC CDRS]

- 13819653

Clone FS-26528 CAR DNA HxL (SEQ ID NO: 281)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTTGACGACTATGCCATGGCATGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGATGCAGGTGACAGAACATACTACG CAGACTCCGTGAGGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACACTGTATCT GCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCAAGAGCCGAGATG GGAGCCGTATTCGACATATGGGGTCAGGGTACAATGGTCACCGTCTCCTCAGGGTCTACAT CCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAAATTGTGTTGACACA GTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGT CAGAGTGTTAGCAGGTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGCTCC TCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTC TGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTAC TGTCAGCAGAGAATCTCCTGGCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAAC GGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCA CCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTG GGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTA GATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGG CCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGC AGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGT ATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACG GGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAG CTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAA GGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGA CGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone FS-26528 CAR HxL (SEQ ID NO: 282)

MALPVTALLLPLALLLHAARPEVQLLE S GGGLVQPGGS LRL S CAAS G FT FDDYAMAWVRQA PGKGLEWVSAISDAGDRTYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARAEM GAVFDIWGQGTMVTVSSGSTSGSGKPGSGEGSTKGEIVLTQSPATLSLSPGERATLSCRAS QSVSRYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYY CQQRISWPFTFGGGTKVEIKRAAALDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVW GGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNE LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

- 13919653

Clone FS-26528 CAR DNA LxH (SEQ ID NO: 283)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCAC CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGGTACTTAGCCTGGTACCAACAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCA GGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGA AGATTTTGCAGTTTATTACTGTCAGCAGAGAATCTCCTGGCCTTTCACTTTTGGCGGAGGG ACCAAGGTTGAGATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAG GTAGTACAAAGGGGGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGACGACTATGCCATGGCATGG GTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTATTAGTGATGCAGGTGACA GAACATACTACGCAGACTCCGTGAGGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAA CACACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCA AGAGCCGAGATGGGAGCCGTATTCGACATATGGGGTCAGGGTACAATGGTCACCGTCTCCT CAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCA CCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTG GGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTA GATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGG CCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGC AGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGT ATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACG GGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAG CTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAA GGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGA CGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone FS-26528 CAR LxH (SEQ ID NO: 284)

MALPVTALLLPLALLLHAARPEIVLTQSPATLSLSPGERATLSCRASQSVSRYLAWYQQKP GQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRISWPFTFGGG TKVEIKRGSTSGSGKPGSGEGSTKGEVQLLESGGGLVQPGGSLRLSCAASGFTFDDYAMAW VRQAPGKGLEWVSAISDAGDRTYYADSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA RAEMGAVFDIWGQGTMVTVSSAAALDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVW GGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNE LQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

- 14019653

Clone PC-26534 HC DNA (SEQ ID NO: 285)

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCT CCTGTGCAGCGTCTGGATTCACCTTCAGTGAGCATGGCATGCACTGGGTCCGCCAGGCTCC AGGCAAGGGGCTGGAGTGGGTGGCAGCTATATCTTATGATGGAAGGAATAAACACTATGCA GACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGC AAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCCAGAGACGGTACTTA TCTAGGTGGTCTCTGGTACTTCGACTTATGGGGGAGAGGTACCTTGGTCACCGTCTCCTCA

Clone PC-26534 HC (SEQ ID NO: 286). CDRs 1, 2, and 3 are underlined.

QVQLVE S GGGWQPGRS LRLS CAAS GFTFSEHGMHWVRQAPGKGLEWVAAISYDGRNKHY ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGTYLGGLWYFDLWGRGTLVTVS S

FTFSEHGMH (SEQ ID NO: 287) [HC CDRl]

AISYDGRNKHYADSVKG (SEQ ID NO: 288) [HC CDR2]

ARDGTYLGGLWYFDL (SEQ ID NO: 289) [HC CDR3]

Clone PC-26534 LC DNA (SEQ ID NO: 290)

GATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCA TCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGATACAACTATTTGGATTGGTA CCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCC GGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAGCA GAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAGGGACTCGGCCTCCCTCTCAC TTTTGGCGGAGGGACCAAGGTTGAGATCAAACGG

Clone PC-26534 LC (SEQ ID NO: 291). CDRs 1, 2, and 3 are underlined.

DIVMTQSPLSLPVTPGEPASISCRSSQ5LLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRA SGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGLGLPLTFGGGTKVEIKR

RSSQSLLHSNGYNYLD (SEQ ID NO: 292) [LC CDRl]

LGSNRAS (SEQ ID NO: 293) [LC CDR2]

MQGLGLPLT (SEQ ID NO: 294) [LC CDR3]

Clone PC-26534 CAR DNA HxL (SEQ ID NO: 295)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTGAGCATGGCATGCACTGGGTCCGCCAGGCT CCAGGCAAGGGGCTGGAGTGGGTGGCAGCTATATCTTATGATGGAAGGAATAAACACTATG CAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCT GCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCCAGAGACGGTACT TATCTAGGTGGTCTCTGGTACTTCGACTTATGGGGGAGAGGTACCTTGGTCACCGTCTCCT CAGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGATAT TGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCCATCTCC

- 141 19653

TGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGATACAACTATTTGGATTGGTACCTGC AGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCTCCGGGGT CCCTGACAGGT T CAGTGGCAGT GGAT CAGGCACAGAT T T TACAC TGAAAAT CAGCAGAGT G GAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAGGGACTCGGCCTCCCTCTCACTTTTG GCGGAGGGACCAAGGTTGAGATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGG AACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCC AAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCA CCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTA CATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCA CCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAG CGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTA TGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAA AACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTG AAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACT CAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone PC-26534 CAR HxL (SEQ ID NO: 296)

MALPVTALLLPLALLLHAARPQVQLWSGGGWQPGRSLRLSCAASGFTFSEHGMHWVRQA PGKGLEWVAAISYDGRNKHYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDGT YLGGLWYFDLWGRGTLVTVSSGSTSGSGKPGSGEGSTKGDIVMTQSPLSLPVTPGEPASIS CRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRV EAEDVGVYYCMQGLGLPLTFGGGTKVEIKRAAALDNEKSNGTIIHVKGKHLCPSPLFPGPS KPFWVLVWGGVLACYSLLVTVAFIIFWVRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAP PRDFAAYRSRVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRK NPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

- 14219653

Clone PC-26534 CAR DNA LxH (SEQ ID NO: 297)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTC CATCTCCTGCAGGTCTAGTCAGAGCCTCCTGCATAGTAATGGATACAACTATTTGGATTGG TACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCTATTTGGGTTCTAATCGGGCCT CCGGGGTCCCTGACAGGTTCAGTGGCAGTGGATCAGGCACAGATTTTACACTGAAAATCAG CAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCAGGGACTCGGCCTCCCTCTC ACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTACATCCGGCTCCGGGAAGC CCGGAAGTGGCGAAGGTAGTACAAAGGGGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGT GGTCCAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTGAG CATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGCTATAT CTTATGATGGAAGGAATAAACACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAG AGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCG GTGTACTACTGCGCCAGAGACGGTACTTATCTAGGTGGTCTCTGGTACTTCGACTTATGGG GGAGAGGTACCTTGGTCACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGG AACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCC AAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCA CCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTA CATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCA CCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAG CGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTA TGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAA AACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTG AAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACT CAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone PC-26534 CAR LxH (SEQ ID NO: 298)

MALPVTALLL PLALLLHAAR PDIVMTQSPL SLPVTPGEPA SISCRSSQSL LHSNGYNYLD WYLQKPGQSP QLLIYLGSNR ASGVPDRFSG SGSGTDFTLK ISRVEAEDVG VYYCMQGLGL PLTFGGGTKV EIKRGSTSGS GKPGSGEGST KGQVQLVESG GGWQPGRSL RLSCAASGFT FSEHGMHWVR QAPGKGLEWV AAISYDGRNK HYADSVKGRF TISRDNSKNT LYLQMNSLRA EDTAVYYCAR DGTYLGGLWY FDLWGRGTLV TVSSAAALDN EKSNGTIIHV KGKHLCPSPL FPGPSKPFWV LVWGGVLAC YSLLVTVAFI IFWVRSKRSR LLHSDYMNMT PRRPGPTRKH YQPYAPPRDF AAYRSRVKFS RSADAPAYQQ GQNQLYNELN LGRREEYDVL DKRRGRDPEM GGKPRRKNPQ EGLYNELQKD KMAEAYSEIG MKGERRRGKG HDGLYQGLST ATKDTYDALH MQALPPR

- 143 19653

Clone AJ-26545 HC DNA (SEQ ID NO: 299)

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTT CCTGCAGGGCATCTGGATACACCTTCATGGAGCACTATATGCACTGGGTGCGACAGGCCCC TGGACAAGGGCTTGAGTGGATGGGAGTAATCGGGCCTAGTGGTGGTAAGACAAGCTACGCA CAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACATGG AGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAGAGAATTGGCC AATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCA

Clone AJ-26545 HC (SEQ ID NO: 300). CDRs 1, 2, and 3 are underlined.

QVQLVQSGAEVKKPGASVKVSCRASGYTFMEHYMHWVRQAPGQGLEWMGVIGPSGGKTSY aqkfqgrvtmtrdtststvymelsslrsedtavyycareswpmdwgqgttvtvss

YTFMEHYMH (SEQ ID NO: 301) (HC CDRI)

VIGPSGGKTSYAQKFQG (SEQ ID NO: 302) (HC CDR2)

ARESWPMDV (SEQ ID NO: 303) (HC CDR3)

Clone AJ-26545 LC DNA (SEQ ID NO: 304)

GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCC TCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGG CCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGG TTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAG ATTTTGCAGTTTATTACTGTCAGCAGTACGCCGCCTACCCTACTTTTGGCGGAGGGACCAA GGTTGAGATCAAACGG

Clone AJ-26545 LC (SEQ ID NO: 305). CDRs 1, 2, and 3 are underlined.

EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLL·IYGASTRATGIPAR FSGSGSGTEFTLTISSLQSEDFAVYYCQQYAAYPTFGGGTKVEIKR

RASQSVSSNLA (SEQ ID NO: 306) (LC CDRI)

GASTRAT (SEQ ID NO: 307) (LC CDR2)

QQYAAYPT (SEQ ID NO: 308) (LC CDR3)

- 14419653

Clone AJ-26545 CAR DNA HxL (SEQ ID NO: 309)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT TTCCTGCAGGGCATCTGGATACACCTTCATGGAGCACTATATGCACTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGAGTAATCGGGCCTAGTGGTGGTAAGACAAGCTACG CACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACAT GGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAGAGAATTGG CCAATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCAGGGTCTACATCCGGCT CCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAAATAGTGATGACGCAGTCTCC AGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGT GTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCT ATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGAC AGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAG CAGTACGCCGCCTACCCTACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGCCGCTG C C C T T GATAAT GAAAAGT CAAAC GGAACAAT CAT T CAC GT GAAGGGCAAGCACC T C T G T C C GTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTC CTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAA GAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAG GAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAG TTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGC TCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGA GATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAG GATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAG GGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCA CATGCAAGCCCTGCCACCTAGG

Clone AJ-26545 CAR HxL (SEQ ID NO: 310)

MALPVTALLL PLALLLHAAR PQVQLVQSGA EVKKPGASVK VSCRASGYTF MEHYMHWVRQ APGQGLEWMG VIGPSGGKTS YAQKFQGRVT MTRDTSTSTV YMELSSLRSE DTAVYYCARE SWPMDWGQG TTVTVSSGST SGSGKPGSGE GSTKGEIVMT QSPATLSVSP GERATLSCRA SQSVSSNLAW YQQKPGQAPR LLIYGASTRA TGIPARFSGS GSGTEFTLTI SSLQSEDFAV YYCQQYAAYP TFGGGTKVEI KRAAALDNEK SNGTIIHVKG KHLCPSPLFP GPSKPFWVLV WGGVLACYS LLVTVAFIIF WVRSKRSRLL HSDYMNMTPR RPGPTRKHYQ PYAPPRDFAA YRSRVKFSRS ADAPAYQQGQ NQLYNELNLG RREEYDVLDK RRGRDPEMGG KPRRKNPQEG LYNELQKDKM AEAYSEIGMK GERRRGKGHD GLYQGLSTAT KDTYDALHMQ ALPPR

- 145 19653

Clone AJ-26545 CAR DNA LxH (SEQ ID NO: 311)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCAC CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCA GGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGA AGATTTTGCAGTTTATTACTGTCAGCAGTACGCCGCCTACCCTACTTTTGGCGGAGGGACC AAGGTTGAGATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTA GTACAAAGGGGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTC AGTGAAGGTTTCCTGCAGGGCATCTGGATACACCTTCATGGAGCACTATATGCACTGGGTG CGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGTAATCGGGCCTAGTGGTGGTAAGA CAAGCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCAC AGTCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGA GAGAATTGGCCAATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCAGCCGCTG C CC T T GATAAT GAAAAG T CAAAC GGAACAAT CAT T CAC GT GAAGGGCAAGCAC CTCTGTCC GTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTC CTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAA GAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAG GAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAG TTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGC TCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGA GATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAG GATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAG GGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCA CATGCAAGCCCTGCCACCTAGG

Clone AJ-26545 CAR LxH (SEQ ID NO: 312)

MALPVTALLL PLALLLHAAR PEIVMTQSPA TLSVSPGERA TLSCRASQSV SSNLAWYQQK PGQAPRLLIY GASTRATGIP ARFSGSGSGT EFTLTISSLQ SEDFAVYYCQ QYAAYPTFGG GTKVEIKRGS TSGSGKPGSG EGSTKGQVQL VQSGAEVKKP GASVKVSCRA SGYTFMEHYM HWVRQAPGQG LEWMGVIGPS GGKTSYAQKF QGRVTMTRDT STSTVYMELS SLRSEDTAVY YCARESWPMD VWGQGTTVTV SSAAALDNEK SNGTIIHVKG KHLCPSPLFP GPSKPFWVLV WGGVLACYS LLVTVAFIIF WVRSKRSRLL HSDYMNMTPR RPGPTRKHYQ PYAPPRDFAA YRSRVKFSRS ADAPAYQQGQ NQLYNELNLG RREEYDVLDK RRGRDPEMGG KPRRKNPQEG LYNELQKDKM AEAYSEIGMK GERRRGKGHD GLYQGLSTAT KDTYDALHMQ ALPPR

- 14619653

Clone AJ-26554 HC DNA (SEQ ID NO: 313)

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGTTT CCTGCAAGGCATCTGGATACACCTTCACGGAGCACTATATGCACTGGGTGCGACAGGCCCC TGGACAAAGGCTTGAGTGGATGGGAGTAATCGGGCCTAGTGGTGGTAAGACAAGCTACGCA CAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACATGG AGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAGAGAGTTGGCC AATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCA

Clone AJ-26554 HC (SEQ ID NO: 314). CDRs 1, 2, and 3 are underlined.

QVQLVQSGAE VKKPGASVKV SCKASGYTFT EHYMHWVRQA PGQRLEWMGV IGPSGGKTSY AQKFQGRVTM TRDTSTSTVY MELSSLRSED TAVYYCARES WPMDWGQGT T VT VS S

YTFTEHYMH (SEQ ID NO: 315) (HC CDR1)

VIGPSGGKTSYAQKFQG (SEQ ID NO: 316) (HC CDR2)

ARESWPMDV (SEQ ID NO: 317) (HC CDR3)

Clone AJ-26554 LC DNA (SEQ ID NO: 318)

GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCC TCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGG CCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGG TTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAG ATTTTGCAGTTTATTACTGTCAGCAGTACGCCGCCTACCCTACTTTTGGCGGAGGGACCAA GGTTGAGATCAAACGG

Clone AJ-26554 LC (SEQ ID NO: 319). CDRs 1, 2, and 3 are underlined.

EIVMTQSPATLSVS PGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYGASTRATGIPA RFSGSGSGTEFTLTISSLQSEDFAVYYCQQYAAYPTFGGGTKVEIKR

RASQSVSSNLA (SEQ ID NO: 320) (LC CDR1)

GASTRAT (SEQ ID NO: 321) (LC CDR2)

QQYAAYPT (SEQ ID NO: 322) (LC CDR3)

- 14719653

Clone AJ-26554 CAR DNA HxL (SEQ ID NO: 323)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTCAGTGAAGGT TTCCTGCAAGGCATCTGGATACACCTTCACGGAGCACTATATGCACTGGGTGCGACAGGCC CCTGGACAAAGGCTTGAGTGGATGGGAGTAATCGGGCCTAGTGGTGGTAAGACAAGCTACG CACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACAT GGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAGAGAGTTGG CCAATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCAGGGTCTACATCCGGCT CCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAAATAGTGATGACGCAGTCTCC AGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGT GTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCT ATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGAC AGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAG CAGTACGCCGCCTACCCTACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGCCGCTG C C C T T GAT AAT GAAAAG T CAAAC GGAAC AAT C AT T CAC G T GAAGGGC AAG C AC C T C T G T C C GTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTC CTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAA GAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAG GAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAG TTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGC TCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGA GATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTAT#ATGAGCTGCAGAAG GATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAG GGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCA CATGCAAGCCCTGCCACCTAGG

Clone AJ-26554 CAR HxL (SEQ ID NO: 324)

MALPVTALLL PLALLLHAAR PQVQLVQSGA EVKKPGASVK VSCKASGYTF TEHYMHWVRQ APGQRLEWMG VIGPSGGKTS YAQKFQGRVT MTRDTSTSTV YMELSSLRSE DTAVYYCARE SWPMDWGQG TTVTVSSGST SGSGKPGSGE GSTKGEIVMT QSPATLSVSP GERATLSCRA SQSVSSNLAW YQQKPGQAPR LLIYGASTRA TGIPARFSGS GSGTEFTLTI SSLQSEDFAV YYCQQYAAYP TFGGGTKVEI KRAAALDNEK SNGTIIHVKG KHLCPSPLFP GPSKPFWVLV WGGVLACYS LLVTVAFIIF WVRSKRSRLL HSDYMNMTPR RPGPTRKHYQ PYAPPRDFAA YRSRVKFSRS ADAPAYQQGQ NQLYNELNLG RREEYDVLDK RRGRDPEMGG KPRRKNPQEG LYNELQKDKM AEAYSEIGMK GERRRGKGHD GLYQGLSTAT KDTYDALHMQ ALPPR

- 148 19653

Clone AJ-26554 CAR DNA LxH (SEQ ID NO: 325)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCAC CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCA GGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGA AGATTTTGCAGTTTATTACTGTCAGCAGTACGCCGCCTACCCTACTTTTGGCGGAGGGACC AAGGTTGAGATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTA GTACAAAGGGGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCTC AGTGAAGGTTTCCTGCAAGGCATCTGGATACACCTTCACGGAGCACTATATGCACTGGGTG CGACAGGCCCCTGGACAAAGGCTTGAGTGGATGGGAGTAATCGGGCCTAGTGGTGGTAAGA CAAGCTACGCACAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCAC AGTCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGA GAGAGTTGGCCAATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCAGCCGCTG CCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCC GTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTC CTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAA GAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAG GAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAG T T T T C CAGAT C T GCAGAT GCAC CAGC GTAT CAGCAGGGC CAGAAC CAAC T G TATAAC GAGC TCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGA GATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAG GATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAG GGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCA CATGCAAGCCCTGCCACCTAGG

Clone AJ-26554 CAR LxH (SEQ ID NO: 326)

MALPVTALLL PLALLLHAAR PEIVMTQSPA TLSVSPGERA TLSCRASQSV SSNLAWYQQK PGQAPRLLIY GASTRATGIP ARFSGSGSGT EFTLTISSLQ SEDFAVYYCQ QYAAYPTFGG GTKVEIKRGS TSGSGKPGSG EGSTKGQVQL VQSGAEVKKP GASVKVSCKA SGYTFTEHYM HWVRQAPGQR LEWMGVIGPS GGKTSYAQKF QGRVTMTRDT STSTVYMELS SLRSEDTAVY YCARESWPMD VWGQGTTVTV SSAAALDNEK SNGTIIHVKG KHLCPSPLFP GPSKPFWVLV WGGVLACYS LLVTVAFIIF WVRSKRSRLL HSDYMNMTPR RPGPTRKHYQ PYAPPRDFAA YRSRVKFSRS ADAPAYQQGQ NQLYNELNLG RREEYDVLDK RRGRDPEMGG KPRRKNPQEG LYNELQKDKM AEAYSEIGMK GERRRGKGHD GLYQGLSTAT KDTYDALHMQ ALPPR

- 149 19653

Clone NM-26562 HC DNA (SEQ ID NO: 327)

CAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCTCA CCTGTACTGTCTCTGGTGGCTCCATCGGGAGTGGTGGTAGTTACTGGAGCTGGATCCGCCA GCACCCAGGGAAGGGCCTGGAGTGGATTGGGTTGATCTATTACGATGGGAGCACCTACTAC AACCCGTCCCTCAAGAGTCGAGTTACCATATCAGTAGACACGTCTAAGAACCAGTTCTCCC TGAAGCTGAGTTCTGTGACCGCCGCAGACACGGCGGTGTACTACTGCGCCAGAGGCAGGGG ATATGAGACTTCTTTAGCCTTCGATATCTGGGGTCAGGGTACAATGGTCACCGTCTCCTCA

Clone NM-26562 HC (SEQ ID NO: 328). CDRs 1, 2, and 3 are underlined.

QVQLQESGPGLVKPSQTLSLTCTVSGGSIGSGGSYWSWIRQHPGKGLEWIGLIYYDGSTY YNPSLKSRVTISVDTSKNQFS LKLS SVTAADTAVYYCARGRGYETSLAFDIWGQGTMVTVS S

GSIGSGGSYWS (SEQ ID NO: 329) (HC CDR1)

LIYYDGSTYYNPSLKS (SEQ ID NO: 330) (HC CDR2)

ARGRGYETSLAFDI (SEQ ID NO: 331) (HC CDR3)

Clone NM-26562 LC DNA (SEQ ID NO: 332)

GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCC TCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGG CCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGG TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAG ATTTTGCAGTTTATTACTGTCAGCAGAGACACGTCTGGCCTCCTACTTTTGGCGGAGGGAC CAAGGTTGAGATCAAACGG

Clone NM-26562 LC (SEQ ID NO: 333). CDRs 1, 2, and 3 are underlined.

EIVLTQS PATLS LS PGERATLS CRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRHVWPPTFGGGTKVEIKR

RASQSVSSYLA (SEQ ID NO: 334) (LC CDR1)

DASNRAT (SEQ ID NO: 335) (LC CDR2)

QQRHVWPPT (SEQ ID NO: 336) (LC CDR3)

Clone NM-26562 CAR DNA HxL (SEQ ID NO: 337)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCCTGTCCCT CACCTGTACTGTCTCTGGTGGCTCCATCGGGAGTGGTGGTAGTTACTGGAGCTGGATCCGC CAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTTGATCTATTACGATGGGAGCACCTACT ACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGTAGACACGTCTAAGAACCAGTTCTC CCTGAAGCTGAGTTCTGTGACCGCCGCAGACACGGCGGTGTACTACTGCGCCAGAGGCAGG GGATATGAGACTTCTTTAGCCTTCGATATCTGGGGTCAGGGTACAATGGTCACCGTCTCCT

- 150 19653

CAGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAAAT TGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCC TGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGG CTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAG TGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAGATTTT GCAGTTTATTACTGTCAGCAGAGACACGTCTGGCCTCCTACTTTTGGCGGAGGGACCAAGG TTGAGATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGT GAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTG TTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAA TCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCC ACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCT GCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCC AGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAA GCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGT C T C TATAAT GAGC T GCAGAAGGATAAGAT GGC T GAAGCC TAT T C T GAAATAGGCAT GAAAG GAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAA GGATAC T TAT GACGC T C T C CACAT GCAAGC C C T GG CACC TAGG

Clone NM-26562 CAR HxL (SEQ ID NO: 338)

MALPVTALLL GSGGSYWSWI FSLKLSSVTA KPGSGEGSTK PGQAPRLLIY QRHVWPPTFG KPFWVLVWG PTRKHYQPYA EYDVLDKRRG RRGKGHDGLY

PLALLLHAAR RQHPGKGLEW ADTAVYYCAR GEIVLTQSPA DASNRATGIP GGTKVEIKRA GVLACYSLLV PPRDFAAYRS RDPEMGGKPR QGLSTATKDT

PQVQLQESGP IGLIYYDGST GRGYETSLAF TLSLSPGERA ARFSGSGSGT AALDNEKSNG TVAFIIFWVR RVKFSRSADA RKNPQEGLYN YDALHMQALP

GLVKPSQTLS YYNPSLKSRV DIWGQGTMVT TLSCRASQSV DFTLTISSLE TIIHVKGKHL SKRSRLLHSD PAYQQGQNQL ELQKDKMAEA PR

LTCTVSGGSI TISVDTSKNQ VSSGSTSGSG SSYLAWYQQK PEDFAVYYCQ CPSPLFPGPS YMNMTPRRPG YNELNLGRRE YSEIGMKGER

- 151 19653

Clone NM-26562 CAR DNA LxH (SEQ ID NO: 339)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCAC CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCAACAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCA GGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGA AGATTTTGCAGTTTATTACTGTCAGCAGAGACACGTCTGGCCTCCTACTTTTGGCGGAGGG ACCAAGGTTGAGATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAG GTAGTACAAAGGGGCAGGTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACA GACCCTGTCCCTCACCTGTACTGTCTCTGGTGGCTCCATCGGGAGTGGTGGTAGTTACTGG AGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTGGGTTGATCTATTACGATG GGAGCACCTACTACAACCCGTCCCTCAAGAGTCGAGTTACCATATCAGTAGACACGTCTAA GAACCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCAGACACGGCGGTGTACTACTGC GCCAGAGGCAGGGGATATGAGACTTCTTTAGCCTTCGATATCTGGGGTCAGGGTACAATGG TCACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGT GAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTG TTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAA TCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCC ACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCT GCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCC AGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAA GCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGT CTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAG GAGAGCGGAGAAGGGGAAAAGGGCACGACGGT T TGTACCAGGGAC T CAGCAC TGC TACGAA GGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone NM-26562 CAR LxH (SEQ ID NO: 340)

MALPVTALLL PLALLLHAAR PEIVLTQSPA TLSLSPGERA TLSCRASQSV SSYLAWYQQK PGQAPRLLIY DASNRATGIP ARFSGSGSGT DFTLTISSLE PEDFAVYYCQ QRHVWPPTFG GGTKVEIKRG STSGSGKPGS GEGSTKGQVQ LQESGPGLVK PSQTLSLTCT VSGGSIGSGG SYWSWIRQHP GKGLEWIGLI YYDGSTYYNP SLKSRVTISV DTSKNQFSLK LSSVTAADTA VYYCARGRGY ETSLAFDIWG QGTMVTVSSA AALDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLVWG GVLACYSLLV TVAFIIFWVR SKRSRLLHSD YMNMTPRRPG PTRKHYQPYA PPRDFAAYRS RVKFSRSADA PAYQQGQNQL YNELNLGRRE EYDVLDKRRG RDPEMGGKPR RKNPQEGLYN ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT YDALHMQALP PR

- 15219653

Clone TS-26564 HC DNA (SEQ ID NO: 341)

GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCT CCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCC AGGGAAGGGGCTGGAGTGGGTTTCAACCATTAGTAGTAGTAGTAGTATCATATACTACGCA GACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACTCACTGTATCTGC AAATGAACAGCCTGAGAGCTGAGGACACGGCGGTGTACTACTGCGCCAGAGGTTCTCAGGA GCACCTGATTTTCGATTATTGGGGACAGGGTACATTGGTCACCGTCTCCTCA

Clone TS-26564 HC (SEQ ID NO: 342). CDRs 1, 2, and 3 are underlined.

EVQLVE S GGGLVQPGGS LRLS CAAS GFTFSSYSMNWVRQAPGKGLEWVSTISSSSSIIYY ADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARGSQEHLIFDYWGQGTLVTVSS

FTFSSYSMN (SEQ ID NO: 343) (HC CDR1)

TISSSSSIIYYADSVKG (SEQ ID NO: 344) (HC CDR2)

ARGSQEHLIFDY (SEQ ID NO: 345) (HC CDR3)

Clone TS-26564 LC DNA (SEQ ID NO: 346)

GAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCC TCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGGTACTTAGCCTGGTACCAACAGAAACCTGG CCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGG TTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGAAG ATTTTGCAGTTTATTACTGTCAGCAGAGATTCTACTACCCTTGGACTTTTGGCGGAGGGAC CAAGG T T GAGAT CAAACGG

Clone TS-26564 LC (SEQ ID NO: 347). CDRs 1, 2, and 3 are underlined.

EIVLTQS PATLSLS PGERATLSCRASQSVSRYLAWYQQKPGQAPRLLIYDASNRATGIPA RFSGSGSGTDFTLTISSLEPEDFAVYYCQQRFYYPWTFGGGTKVEIKR

RASQSVSRYLA (SEQ ID NO: 348) (LC CDR1)

DASNRAT (SEQ ID NO: 349) (LC CDR2)

QQRFYYPWT (SEQ ID NO: 350) (LC CDR3)

- 153 19653

Clone TS-26564 CAR DNA HxL (SEQ ID NO: 351)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACT CTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGGGTCCGCCAGGCT CCAGGGAAGGGGCTGGAGTGGGTTTCAACCATTAGTAGTAGTAGTAGTATCATATACTACG CAGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACTCACTGTATCT GCAAATGAACAGCCTGAGAGCTGAGGACACGGCGGTGTACTACTGCGCCAGAGGTTCTCAG GAGCACCTGATTTTCGATTATTGGGGACAGGGTACATTGGTCACCGTCTCCTCAGGGTCTA CATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAAATTGTGTTGAC ACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AGTCAGAGTGTTAGCAGGTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGGC TCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GT C T GGGACAGAC T T CAC T C T CAC CAT CAGCAGCC TAGAGCC T GAAGAT T T T GCAG T T T AT TACTGTCAGCAGAGATTCTACTACCCTTGGACTTTTGGCGGAGGGACCAAGGTTGAGATCA AACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAA GCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTA GTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGG TTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCC TGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGG AGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAAC TGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGG ACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAAT GAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGA GAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTA TGACGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone TS-26564 CAR HxL (SEQ ID NO: 352)

MALPVTALLL PLALLLHAAR PEVQLVESGG GLVQPGGSLR LSCAASGFTF SSYSMNWVRQ APGKGLEWVS TISSSSSIIY YADSVKGRFT ISRDNAKNSL YLQMNSLRAE DTAVYYCARG SQEHLIFDYW GQGTLVTVSS GSTSGSGKPG SGEGSTKGEI VLTQSPATLS LSPGERATLS CRASQSVSRY LAWYQQKPGQ APRLLIYDAS NRATGIPARF SGSGSGTDFT LTISSLEPED FAVYYCQQRF YYPWTFGGGT KVEIKRAAAL DNEKSNGTII HVKGKHLCPS PLFPGPSKPF WVLVWGGVL ACYSLLVTVA FIIFWVRSKR SRLLHSDYMN MTPRRPGPTR KHYQPYAPPR DFAAYRSRVK FSRSADAPAY QQGQNQLYNE LNLGRREEYD VLDKRRGRDP EMGGKPRRKN PQEGLYNELQ KDKMAEAYSE IGMKGERRRG KGHDGLYQGL STATKDTYDA LHMQALPPR

- 15419653

Clone TS-26564 CAR DNA LxH (SEQ ID NO: 353)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCAC CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGGTACTTAGCCTGGTACCAACAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCA GGTTCAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTAGAGCCTGA AGATTTTGCAGTTTATTACTGTCAGCAGAGATTCTACTACCCTTGGACTTTTGGCGGAGGG ACCAAGGTTGAGATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAG GTAGTACAAAGGGGGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGG GTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGCATGAACTGG GTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCAACCATTAGTAGTAGTAGTAGTA TCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAA CTCACTGTATCTGCAAATGAACAGCCTGAGAGCTGAGGACACGGCGGTGTACTACTGCGCC AGAGGTTCTCAGGAGCACCTGATTTTCGATTATTGGGGACAGGGTACATTGGTCACCGTCT CCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAA GCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTA GTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGG T T AGAT C C AAAAGAAGC C GC C T GC T C C AT AG C GAT T AC AT GAAT AT GAG T C CAC GC C G C C C TGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGG AGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAAC TGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGG ACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAAT GAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGA GAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTA TGACGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone TS-26564 CAR LxH (SEQ ID NO: 354)

MALPVTALLL PLALLLHAAR PEIVLTQSPA TLSLSPGERA TLSCRASQSV SRYLAWYQQK PGQAPRLLIY DASNRATGIP ARFSGSGSGT DFTLTISSLE PEDFAVYYCQ QRFYYPWTFG GGTKVEIKRG STSGSGKPGS GEGSTKGEVQ LVESGGGLVQ PGGSLRLSCA ASGFTFSSYS MNWVRQAPGK GLEWVSTISS SSSIIYYADS VKGRFTISRD NAKNSLYLQM NSLRAEDTAV YYCARGSQEH LIFDYWGQGT LVTVSSAAAL DNEKSNGTII HVKGKHLCPS PLFPGPSKPF WVLVWGGVL ACYSLLVTVA FIIFWVRSKR SRLLHSDYMN MTPRRPGPTR KHYQPYAPPR DFAAYRSRVK FSRSADAPAY QQGQNQLYNE LNLGRREEYD VLDKRRGRDP EMGGKPRRKN PQEGLYNELQ KDKMAEAYSE IGMKGERRRG KGHDGLYQGL STATKDTYDA LHMQALPPR

Clone RY-26568 HC DNA (SEQ ID NO: 355)

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCT CCTGTGCAGCGTCTGGATTCACCTTCGGGAGCTATGGCATGCACTGGGTCCGCCAGGCTCC AGGCAAGGGGCTGGAGTGGGTGGCAGTTATACATTATGATGGAAGTGTTGAATACTATGCA GACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGGACACGCTGTATCTGC AAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCCAGAACTGACTTCTG GAGCGGATCCCCTCCAAGCTTAGATTACTGGGGACAGGGTACATTGGTCACCGTCTCCTCA

Clone RY-26568 HC (SEQ ID NO: 356). CDRs 1, 2, and 3 are underlined.

QVQLVESGGG WQPGRSLRL SCAASGFTFG SYGMHWVRQA PGKGLEWVAV IHYDGSVEYY ADSVKGRFTI SRDNSKDTLY LQMNSLRAED TAVYYCARTD FWSG5PPSLD YWGQGTLVTV SS

FTFGSYGMH (SEQ ID NO: 357) (HC CDRl)

VIHYDGSVEYYADSVKG (SEQ ID NO: 358) (HC CDR2)

ARTDFWSGSPPSLDY (SEQ ID NO: 359) (HC CDR3)

Clone RY-26568 LC DNA (SEQ ID NO: 360)

GACATCCAGTTGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCA TCACTTGTCGGGCGAGTCGGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGG GAAAGCCCCTAAGCTCCTGATCTATGGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGG TTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAG ATTTTGCAACTTATTACTGTCAGCAGATATACACCTTCCCTTTCACTTTTGGCGGAGGGAC CAAGGT TGAGAT CAAACGG

Clone RY-26568 LC (SEQ ID NO: 361). CDRs 1, 2, and 3 are underlined.

DIQLTQSPSSVSASVGDRVTITCRASRGISSWLAWYQQKPGKAPKLLIYGASSLQSGVPSR FSGSGSGTDFTLTISSLQPEDFATYYCQQIYTFPFTFGGGTKVEIKR

RASRGISSWLA (SEQ ID NO: 362) (LC CDRl)

GASSLQS (SEQ ID NO: 363) (LC CDR2) QQIYTFPFT (SEQ ID NO: 364) (LC CDR3)

Clone RY-26568 CAR DNA HxL (SEQ ID NO: 365)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCGGGAGCTATGGCATGCACTGGGTCCGCCAGGCT CCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATACATTATGATGGAAGTGTTGAATACTATG CAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGGACACGCTGTATCT GCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCCAGAACTGACTTC TGGAGCGGATCCCCTCCAAGCTTAGATTACTGGGGACAGGGTACATTGGTCACCGTCTCCT CAGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGACAT

- 15619653

CCAGTTGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCACCATCACT TGTCGGGCGAGTCGGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAG CCCCTAAGCTCCTGATCTATGGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAG CGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTT GCAACTTATTACTGTCAGCAGATATACACCTTCCCTTTCACTTTTGGCGGAGGGACCAAGG TTGAGATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGT GAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTG TTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAA TCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCC ACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCT GCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCC AGAACCAACT GTATAACGAGCTCAACCT GGGACGCAGGGAAGAGTATGACGT T T T GGACAA GCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGT CTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAG GAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAA GGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone RY-26568 CAR HxL (SEQ ID NO: 366)

MALPVTALLL PLALLLHAAR PQVQLVESGG GWQPGRSLR LSCAASGFTF GSYGMHWVRQ APGKGLEWVA VIHYDGSVEY YADSVKGRFT ISRDNSKDTL YLQMNSLRAE DTAVYYCART DFWSGSPPSL DYWGQGTLVT VSSGSTSGSG KPGSGEGSTK GDIQLTQSPS SVSASVGDRV TITCRASRGI SSWLAWYQQK PGKAPKLLIY GASSLQSGVP SRFSGSGSGT DFTLTISSLQ PEDFATYYCQ QIYTFPFTFG GGTKVEIKRA AALDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLVWG GVLACYSLLV TVAFIIFWVR SKRSRLLHSD YMNMTPRRPG PTRKHYQPYA PPRDFAAYRS RVKFSRSADA PAYQQGQNQL YNELNLGRRE EYDVLDKRRG RDPEMGGKPR RKNPQEGLYN ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT YDALHMQALP PR

- 15719653

Clone RY-26568 CAR DNA LxH (SEQ ID NO: 367)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGACATCCAGTTGACCCAGTCTCCATCTTCCGTGTCTGCATCTGTAGGAGACAGAGTCAC CATCACTTGTCGGGCGAGTCGGGGTATTAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCA GGGAAAGCCCCTAAGCTCCTGATCTATGGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAA GGTTCAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTGCAGCCTGA AGATTTTGCAACTTATTACTGTCAGCAGATATACACCTTCCCTTTCACTTTTGGCGGAGGG ACCAAGGTTGAGATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAG GTAGTACAAAGGGGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCGGGAGCTATGGCATGCACTGG GTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATACATTATGATGGAAGTG TTGAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGGA CACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCC AGAACTGACTTCTGGAGCGGATCCCCTCCAAGCTTAGATTACTGGGGACAGGGTACATTGG TCACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGT GAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGGGTG TTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAA TCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCC ACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCT GCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCC AGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAA GCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGT C TC TATAAT GAGCT GCAGAAGGATAAGAT GGC T GAAGCCTAT T C TGAAATAGGCAT GAAAG GAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAA GGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone RY-26568 CAR LxH (SEQ ID NO: 368)

MALPVTALLL PLALLLHAAR PDIQLTQSPS SVSASVGDRV TITCRASRGI SSWLAWYQQK PGKAPKLLIY GASSLQSGVP SRFSGSGSGT DFTLTISSLQ PEDFATYYCQ QIYTFPFTFG GGTKVEIKRG STSGSGKPGS GEGSTKGQVQ LVESGGGWQ PGRSLRLSCA ASGFTFGSYG MHWVRQAPGK GLEWVAVIHY DGSVEYYADS VKGRFTISRD NSKDTLYLQM NSLRAEDTAV YYCARTDFWS GSPPSLDYWG QGTLVTVSSA AALDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLVWG GVLACYSLLV TVAFIIFWVR SKRSRLLHSD YMNMTPRRPG PTRKHYQPYA PPRDFAAYRS RVKFSRSADA PAYQQGQNQL YNELNLGRRE EYDVLDKRRG RDPEMGGKPR RKNPQEGLYN ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT YDALHMQALP PR

- 158 19653

Clone PP-26575 HC DNA (SEQ ID NO: 369)

CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCT CCTGCAAGGCTTCTGGAGGCACCCTCAGCAGCCTGGCTATCAGCTGGGTGCGACAGGCCCC TGGACAAGGGCTTGAGTGGATGGGAGGGGTCATCCCTATCTTGGGTCGGGCAAACTACGCA CAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAGTCCACGAGCACAGCCTACATGG AGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAACTCCTGAATA CTCCTCCAGCATATGGCACTATTACTACGGCATGGACGTATGGGGCCAGGGAACAACTGTC ACCGTCTCCTCA

Clone PP-26575 HC (SEQ ID NO: 370). CDRs 1, 2, and 3 are underlined.

QVQLVQS GAEVKKPGS SVKVS CKAS GGTLSSLAISWVRQAPGQGLEWMGGVIPILGRANYA QKFQGRVTITADE STS TAYMELS S LRSEDTAVYYCART PEYS S SIWHYYYGMDVWGQGTTV TVSS

GTLSSLAIS (SEQ ID NO: 371) (HC CDR1)

GVIPILGRANYAQKFQG (SEQ ID NO: 372) (HC CDR2)

ARTPEYSSSIWHYYYGMDV (SEQ ID NO: 373) (HC CDR3)

Clone PP-26575 LC DNA (SEQ ID NO: 374)

GACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCACCA TCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCTTG GTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGGAA TCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCATCA GCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAGTTCGCCCACACTCCTTT CACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGG

Clone PP-26575 LC (SEQ ID NO: 375). CDRs 1, 2, and 3 are underlined.

DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTR ESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQFAHTPFTFGGGTKVEIKR

KSSQSVLYSSNNKNYLA (SEQ ID NO: 376) (LC CDR1)

WASTRES (SEQ ID NO: 377) (LC CDR2) QQFAHTPFT (SEQ ID NO: 378) (LC CDR3)

Clone PP-26575 CAR DNA HxL (SEQ ID NO: 379)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAAGGT CTCCTGCAAGGCTTCTGGAGGCACCCTCAGCAGCCTGGCTATCAGCTGGGTGCGACAGGCC CCTGGACAAGGGCTTGAGTGGATGGGAGGGGTCATCCCTATCTTGGGTCGGGCAAACTACG CACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAGTCCACGAGCACAGCCTACAT GGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAACTCCTGAA TACTCCTCCAGCATATGGCACTATTACTACGGCATGGACGTATGGGGCCAGGGAACAACTG

- 15919653

TCACCGTCTCCTCAGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTAC AAAGGGGGACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGG GCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACT TAGCTTGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTAC CCGGGAATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTC ACCATCAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAGTTCGCCCACA CTCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGCCGCTGCCCTTGATAA TGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTG TTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTT ACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCT GCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTAC CAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGAT CTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGG ACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGC AAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATGG CTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGG TTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCC CTGCCACCTAGG

Clone PP-26575 CAR HxL (SEQ ID NO: 380)

MALPVTALLL SSLAISWVRQ YMELSSLRSE SGSGKPGSGE KNYLAWYQQK AEDVAVYYCQ CPSPLFPGPS YMNMTPRRPG YNELNLGRRE YSEIGMKGER

PLALLLHAAR APGQGLEWMG DTAVYYCART GSTKGDIVMT PGQPPKLLIY QFAHTPFTFG KPFWVLWVG PTRKHYQPYA EYDVLDKRRG RRGKGHDGLY

PQVQLVQSGA GVIPILGRAN PEYSSSIWHY QSPDSLAVSL WASTRESGVP GGTKVEIKRA GVLACYSLLV PPRDFAAYRS RDPEMGGKPR QGLSTATKDT

EVKKPGSSVK YAQKFQGRVT YYGMDVWGQG GERATINCKS DRFSGSGSGT AALDNEKSNG TVAFIIFWVR RVKFSRSADA RKNPQEGLYN YDALHMQALP

VSCKASGGTL ITADESTSTA TTVTVSSGST SQSVLYSSNN DFTLTISSLQ TIIHVKGKHL SKRSRLLHSD PAYQQGQNQL ELQKDKMAEA PR

- 16019653

Clone PP-26575 CAR DNA LxH (SEQ ID NO: 381)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGACATCGTGATGACCCAGTCTCCAGACTCCCTGGCTGTGTCTCTGGGCGAGAGGGCCAC CATCAACTGCAAGTCCAGCCAGAGTGTTTTATACAGCTCCAACAATAAGAACTACTTAGCT TGGTACCAGCAGAAACCAGGACAGCCTCCTAAGCTGCTCATTTACTGGGCATCTACCCGGG AATCCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCACTCTCACCAT CAGCAGCCTGCAGGCTGAAGATGTGGCAGTTTATTACTGTCAGCAGTTCGCCCACACTCCT TTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTACATCCGGCTCCGGGA AGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCAGGTGCAGCTGGTGCAGTCTGGGGCTGA GGTGAAGAAGCCTGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCCTCAGC AGCCTGGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGGGG TCATCCCTATCTTGGGTCGGGCAAACTACGCACAGAAGTTCCAGGGCAGAGTCACGATTAC CGCGGACGAGTCCACGAGCACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACG GC GGT G TAC TAC T GCGCCAGAAC T C C T GAAT AC T C C T C CAGCATAT GGCAC TAT TAC T AC G GCATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCAGCCGCTGCCCTTGATAA TGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTG TTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTT ACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCT GCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTAC CAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGAT CTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGG ACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGC AAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATGG CTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGG TTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCC CTGCCACCTAGG

Clone PP-26575 CAR LxH (SEQ ID NO: 382)

MALPVTALLL PLALLLHAAR PDIVMTQSPD SLAVSLGERA TINCKSSQSV LYSSNNKNYL AWYQQKPGQP PKLLIYWAST RESGVPDRFS GSGSGTDFTL TISSLQAEDV AVYYCQQFAH TPFTFGGGTK VEIKRGSTSG SGKPGSGEGS TKGQVQLVQS GAEVKKPGSS VKVSCKASGG TLSSLAISWV RQAPGQGLEW MGGVIPILGR ANYAQKFQGR VTITADESTS TAYMELSSLR SEDTAVYYCA RTPEYSSSIW HYYYGMDVWG QGTTVTVSSA AALDNEKSNG TIIHVKGKHL CPSPLFPGPS KPFWVLWVG GVLACYSLLV TVAFIIFWVR SKRSRLLHSD YMNMTPRRPG PTRKHYQPYA PPRDFAAYRS RVKFSRSADA PAYQQGQNQL YNELNLGRRE EYDVLDKRRG RDPEMGGKPR RKNPQEGLYN ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT YDALHMQALP PR

- 161 19653

Clone RD-26576 HC DNA (SEQ ID NO: 383)

CAGGTGCGGCTGGTGGAGTCTGGGGGGGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCT CCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATACACTGGGTCCGCCAGGCTCC AGGCAAGGGGCTGGAGTGGGTGGCAGTTATAGGGTATGATGGACAGGAGAAATACTATGCA GACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCÀAGAACACGCTGTATCTGC AAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGTCAAGGGGCCGTTGCA GGAGCCGCCATACGCTTTTGGGATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCC T CA

Clone RD-26576 HC (SEQ ID NO: 384). CDRs 1, 2, and 3 are underlined.

QVRLVESGGGWQPGRSLRLSCAASGFT FS SYGIHWVRQAPGKGLEWVAVIGYDGQEKYYA DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCVKGPLQEPPYAFGMDWGQGTTVTVS S

FTFSSYGIH (SEQ ID NO: 385) (HC CDRI)

VIGYDGQEKYYADSVKG (SEQ ID NO: 386) (HC CDR2)

VKGPLQEPPYAFGMDV (SEQ ID NO: 387) (HC CDR3)

Clone RD-26576 LC DNA (SEQ ID NO: 388)

GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCC TCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGG CCAGGCTCCCAGGCTCCTCATCTATAGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGG TTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAG ATTTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGGCGGAGGGAC CAAGGTTGAGATCAAACGG

Clone RD-26576 LC (SEQ ID NO: 389). CDRs 1, 2, and 3 are underlined.

EIVMT QS PAT LSVS PGERATLS CRASQSVSSNLAWYQQKPGQAPRLLIYSASTRATGIPA RFSGSGSGTEFTLTISSLQSEDFAVYYCQQHHVWPLTFGGGTKVEIKR

RASQSVSSNLA (SEQ ID NO: 390) (LC CDRI)

SASTRAT (SEQ ID NO: 391) (LC CDR2)

QQHHVWPLT (SEQ ID NO: 392) (LC CDR3)

Clone RD-26576 CAR DNA HxL (SEQ ID NO: 393)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGCAGGTGCGGCTGGTGGAGTCTGGGGGGGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATACACTGGGTCCGCCAGGCT CCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATAGGGTATGATGGACAGGAGAAATACTATG CAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCT GCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGTCAAGGGGCCGTTG CAGGAGCCGCCATACGCTTTTGGGATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCT

- 16219653

CCTCAGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGA AATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTC TCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCC AGGCTCCCAGGCTCCTCATCTATAGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGAT TTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGGCGGAGGGACCA AGGTTGAGATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCA CGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGG GTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTA TAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGAC TCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTC GCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGG GCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGA CAAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAG GG T C T C T ATAAT GAGC T GCAGAAGGATAAGAT GGC T GAAGC C TAT T C T GAAATAGGCAT GA AAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTAC GAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone RD-26576 CAR HxL (SEQ ID NO: 394)

MALPVTALLL SSYGIHWVRQ YLQMNSLRAE GKPGSGEGST KPGQAPRLLI QQHHWPLTF SKPFWVLVW GPTRKHYQPY EEYDVLDKRR RRRGKGHDGL

PLALLLHAAR APGKGLEWVA DTAVYYCVKG KGEIVMTQSP YSASTRATGI GGGTKVEIKR GGVLACYSLL APPRDFAAYR GRDPEMGGKP YQGLSTATKD

PQVRLVESGG VIGYDGQEKY PLQEPPYAFG ATLSVSPGER PARFSGSGSG AAALDNEKSN VTVAFIIFWV SRVKFSRSAD RRKNPQEGLY TYDALHMQAL

GWQPGRSLR YADSVKGRFT MDVWGQGTTV ATLSCRASQS TEFTLTISSL GTIIHVKGKH RSKRSRLLHS APAYQQGQNQ NELQKDKMAE PPR

LSCAASGFTF ISRDNSKNTL TVSSGSTSGS VSSNLAWYQQ QSEDFAVYYC LCPSPLFPGP DYMNMTPRRP LYNELNLGRR AYSEIGMKGE

- 163 19653

Clone RD-26576 CAR DNA LxH (SEQ ID NO: 395)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCAC CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATAGCGCATCCACCAGGGCCACTGGTATCCCAGCCA GGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGA AGATTTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGGCGGAGGG ACCAAGGTTGAGATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAG GTAGTACAAAGGGGCAGGTGCGGCTGGTGGAGTCTGGGGGGGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGCATACACTGG GTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATAGGGTATGATGGACAGG AGAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAA CACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGTC AAGGGGCCGTTGCAGGAGCCGCCATACGCTTTTGGGATGGACGTATGGGGCCAGGGAACAA CTGTCACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCA CGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGG GTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTA TAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGAC TCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTC GCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGG GCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGA CAAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAG GGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGA AAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTAC GAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone RD-26576 CAR LxH (SEQ ID NO: 396)

MALPVTALLL PLALLLHAAR PEIVMTQSPA TLSVSPGERA TLSCRASQSV SSNLAWYQQK PGQAPRLLIY SASTRATGIP ARFSGSGSGT EFTLTISSLQ SEDFAVYYCQ QHHVWPLTFG GGTKVEIKRG STSGSGKPGS GEGSTKGQVR LVESGGGWQ PGRSLRLSCA ASGFTFSSYG IHWVRQAPGK GLEWVAVIGY DGQEKYYADS VKGRFTISRD NSKNTLYLQM NSLRAEDTAV YYCVKGPLQE PPYAFGMDVW GQGTTVTVSS AAALDNEKSN GTIIHVKGKH LCPSPLFPGP SKPFWVLVW GGVLACYSLL VTVAFIIFWV RSKRSRLLHS DYMNMTPRRP GPTRKHYQPY APPRDFAAYR SRVKFSRSAD APAYQQGQNQ LYNELNLGRR EEYDVLDKRR GRDPEMGGKP RRKNPQEGLY NELQKDKMAE AYSEIGMKGE RRRGKGHDGL YQGLSTATKD TYDALHMQAL PPR

- 16419653

Clone RD-26578 HC DNA (SEQ ID NO: 397)

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACTCT CCTGTGCAGCGTCTGGATTCACCTTCAGTAGCCGTGGCATGCACTGGGTCCGCCAGGCTCC AGGCAAGGGGCTGGAGTGGGTGGCAGTTATAGGGTATGATGGACAGGAGAAATACTATGCA GACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGC AAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGTCAAGGGGCCGTTGCA GGAGCCGCCATACGATTATGGAATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCC T CA

Clone RD-26578 HC (SEQ ID NO: 398) CDRs 1, 2, and 3 are underlined.

QVQLVE S GGGWQPGRS LRLS CAASGFT FS S RGMHWVRQAPGKGLEWVAVIGYDGQEKYYA DSVKGRFTISRDNSKNTL YLQMNS LRAEDTAWYCVKGPLQEPPYDYGMDWGQGTTVTVS S

FTFSSRGMH (SEQ ID NO: 399) (HC CDR1)

VIGYDGQEKYYADSVKG (SEQ ID NO: 400) (HC CDR2)

VKGPLQEPPYDYGMDV (SEQ ID NO: 401) (HC CDR3)

Clone RD-26578 LC DNA (SEQ ID NO: 402)

GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCC TCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGG CCAGGCTCCCAGGCTCCTCATCTATAGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGG TTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAG ATTTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGGCGGAGGGAC CAAGGTTGAGATCAAACGG

Clone RD-26578 LC (SEQ ID NO: 403). CDRs 1, 2, and 3 are underlined.

EIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQKPGQAPRLLIYS

ASTRATGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQHHVWPLTFGGGTKVEIKR

RASQSVSSNLA (SEQ ID NO: 404) (LC CDR1)

SASTRAT (SEQ ID NO: 405) (LC CDR2) QQHHVWPLT (SEQ ID NO: 406) (LC CDR3)

- 165 19653

Clone RD-26578 CAR DNA HxL (SEQ ID NO: 407)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAGGTCCCTGAGACT CTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCCGTGGCATGCACTGGGTCCGCCAGGCT CCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATAGGGTATGATGGACAGGAGAAATACTATG CAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCT GCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGTCAAGGGGCCGTTG CAGGAGCCGCCATACGATTATGGAATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCT CCTCAGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGA AATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTC TCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCC AGGCTCCCAGGCTCCTCATCTATAGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGAT TTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGGCGGAGGGACCA AGGTTGAGATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCA CGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGG GTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTA TAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGAC TCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTC GCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGG GCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGA CAAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAG GGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGA AAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGT T TGTACCAGGGAC T CAGCAC TGC TAC GAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone RD-26578 CAR HxL (SEQ ID NO: 408)

MALPVTALLL PLALLLHAAR PQVQLVESGG GWQPGRSLR LSCAASGFTF SSRGMHWVRQ APGKGLEWVA VIGYDGQEKY YADSVKGRFT ISRDNSKNTL YLQMNSLRAE DTAVYYCVKG PLQEPPYDYG MDWGQGTTV TVSSGSTSGS GKPGSGEGST KGEIVMTQSP ATLSVSPGER ATLSCRASQS VSSNLAWYQQ KPGQAPRLLI YSASTRATGI PARFSGSGSG TEFTLTISSL QSEDFAVYYC QQHHVWPLTF GGGTKVEIKR AAALDNEKSN GTIIHVKGKH LCPSPLFPGP SKPFWVLVW GGVLACYSLL VTVAFIIFWV RSKRSRLLHS DYMNMTPRRP GPTRKHYQPY APPRDFAAYR SRVKFSRSAD APAYQQGQNQ LYNELNLGRR EEYDVLDKRR GRDPEMGGKP RRKNPQEGLY NELQKDKMAE AYSEIGMKGE RRRGKGHDGL YQGLSTATKD TYDALHMQAL PPR

- 16619653

Clone RD-26578 CAR DNA LxH (SEQ ID NO: 409)

ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCACGCCGCACGCC CGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCAC CCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCT GGCCAGGCTCCCAGGCTCCTCATCTATAGCGCATCCACCAGGGCCACTGGTATCCCAGCCA GGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGA AGATTTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGGCGGAGGG ACCAAGGTTGAGATCAAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAG GTAGTACAAAGGGGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTCCAGCCTGGGAG GTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCCGTGGCATGCACTGG GTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTTATAGGGTATGATGGACAGG AGAAATACTATGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAA CACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGTC AAGGGGCCGTTGCAGGAGCCGCCATACGATTATGGAATGGACGTATGGGGCCAGGGAACAA CTGTCACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCA CGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCATTCTGG GTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTA TAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGAC TCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTC GCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCAGG GCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGA CAAGCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAG GGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGA AAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTAC GAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTAGG

Clone RD-26578 CAR LxH (SEQ ID NO: 410)

MALPVTALLL PLALLLHAAR PEIVMTQSPA TLSVSPGERA TLSCRASQSV SSNLAWYQQK PGQAPRLLIY SASTRATGIP ARFSGSGSGT EFTLTISSLQ SEDFAVYYCQ QHHVWPLTFG GGTKVEIKRG STSGSGKPGS GEGSTKGQVQ LVESGGGWQ PGRSLRLSCA ASGFTFSSRG MHWVRQAPGK GLEWVAVIGY DGQEKYYADS VKGRFTISRD NSKNTLYLQM NSLRAEDTAV YYCVKGPLQE PPYDYGMDVW GQGTTVTVSS AAALDNEKSN GTIIHVKGKH LCPSPLFPGP SKPFWVLWV GGVLACYSLL VTVAFIIFWV RSKRSRLLHS DYMNMTPRRP GPTRKHYQPY APPRDFAAYR SRVKFSRSAD APAYQQGQNQ LYNELNLGRR EEYDVLDKRR GRDPEMGGKP RRKNPQEGLY NELQKDKMAE AYSEIGMKGE RRRGKGHDGL YQGLSTATKD TYDALHMQAL PPR

- 16719653

Claims (71)

1. What is claimed is:

   1. An isolated polynucleotide encoding a chimeric antigen receptor (CAR) or T cell receptor (TCR) comprising an antigen binding molécule that specifically binds to B-cell maturation antigen (BCMA), wherein the antigen binding molécule comprises:

   (a) a heavy chain variable région (VH) complementarity determining région (CDR) 1 comprising, consisting of, or consisting essentially of the amino acid sequence GX2X3X4X5X6X7SY (SEQ ID NO: 145), wherein:

   X₂ is not présent or G;

   X3 is not présent or S;

   X₄ is F, G, I, or Y;

   X₅ is S or T;

   Χβ is F or S; and

   X7 is S or T; and/or (b) a VH CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X1IX3X4X5X6X7X8X9X10YX12X13X14X15X16X17 (SEQ ID NO: 146), wherein:

   Xi is A, G, I, S, T, or V;

   X₃ is I, N, or S;

   X₄ is G, P, S, or Y;

   X₅ is D, G, I, or S;

   X₆ is F, G, or S;

   X7 is not présent or G or S;

   Xs is N, S, or T;

   X₉ is A, I, K, or T;

   X10 is N, S, or Y;

   X12 is A or N;

   X13 is D, P, or Q;

   Xi₄ is K or S;

   X15 is F, L, orV;

   X16 is K or Q; and

   X17 is G or S; and/or

   -16819653 (c) a VH CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2X3X4X5X6X7X8X9X10X11X12X13X14X15X16X17DX19 (SEQ ID NO: 147), wherein:

   Xi is AorV;

   X2 is K or R;

   X3 is not présent or D, G, or T;

   X₄ is not présent or A, D, G, P, R, or S;

   X5 is not présent or E, F, G, L, Q, or T;

   Χδ is not présent or E, M, Q, W, or Y;

   X₇ is not présent or A, E, L, or S;

   Xs is not présent or G, P, S, or T;

   X9 is not présent or G, P, or S;

   X10 is not présent or I, L, P, or Y;

   Xn is not présent or W;

   X12 is not présent or H;

   X13 is not présent or E or Y;

   X14 is not présent or D, G, H, P, S, W, or Y;

   X15 is A, G, L, W, or Y;

   X16 is not présent or A, G, I, P, or V;

   X17 is F, L, or M; and

   X19 is I, L, V, or Y; and/or (d) a light chain variable région (VL) CDR1 comprising, consisting of, or consisting essentially of the amino acid sequence XiX₂SQX₅X6X₇X8X9XioXiiXi2Xi₃Xi4Xi5LXi₇(SEQ ID NO: 148), wherein

   Xi is K or R;

   X2 is A or S;

   Xs is G or S;

   Χδ is I, L, or V;

   X₇ is L or S;

   Xs is not présent or H or Y;

   X9 is not présent or S;

   X10 is not présent or N or S;

   Xn is not présent or G or N;

   -16919653

   Xi2 is not présent or N;

   X13 is not présent or K or Y;

   X14 is N, R, or S;

   X15 is N, W, or Y; and

   X17 is A or D;

   (e) a VL CDR2 comprising, consisting of, or consisting essentially of the amino acid sequence X1X2SX4X5X6X7(SEQ ID NO: 149), wherein

   Xi isD,G,L, S, orW;

   X₂ is A or G;

   X₄ is N, S, or T;

   X5 is L or R;

   Xô is A, E, or Q; and

   X7 is S or T; and/or (f) a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence XiQXsX^sXôPXsT (SEQ ID NO: 150), wherein

   Xi is M or Q;

   X₃ is F, G, H, I, R, or Y;

   X₄ is A, F, H, I, L, or Y;

   X₅ is A, G, H, S, T, V, or Y;

   X₆ is F, L, T, W, or Y; and

   X₈ is not présent or F, L, P, or W.
2. 2. The polynucleotide of claim 1, wherein the VH CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 41-48.
3. 3. An isolated polynucleotide encoding a chimeric antigen receptor (CAR) or T cell receptor (TCR) comprising an antigen binding molécule that specifïcally binds to B-cell maturation antigen (BCMA), wherein the antigen binding molécule comprises a VH CDR3 comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 41-48.
4. 4. The polynucleotide of any one of daims 1 to 3, wherein the VH CDR1 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 9-16.

   -17019653
5. 5. The polynucleotide of any one of claims 1 to 4, wherein the VH CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 25-32.
6. 6. The polynucleotide of any one of claims 1 to 5, wherein the VL CDRl comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 81-88.
7. 7. The polynucleotide of any one of claims 1 to 6, wherein the VL CDR2 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 97-104.
8. 8. The polynucleotide of any one of claims 1 to 7, wherein the VL CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 113-120.
9. 9. The polynucleotide of any one of claims 1, 2, and 4 to 8, wherein the VH CDRl, VH CDR2, and VH CDR3 each comprise the amino acid sequence of the VH CDRl, VH CDR2, and VH CDR3 of an antibody in FIG. 1A or FIG. IB.
10. 10. The polynucleotide of any one of claims 1,2, and 4 to 9, wherein the VL CDRl, VL CDR2, and VL CDR3 each comprise the amino acid sequence of the VL CDRl, VL CDR2, and VL CDR3 of an antibody in FIG. IC.
11. 11. The polynucleotide of any one of claims 1 to 10, wherein the antigen binding molécule comprises a heavy chain variable région sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 65-72.
12. 12. The polynucleotide of any one of claims 1 to 11, wherein the antigen binding molécule comprises a light chain variable région sequence comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 137-144.
13. 13. The polynucleotide of any one of claims 1 to 12, wherein the antigen binding molécule comprises:

    (a) a VH CDRl région comprising the amino acid sequence of SEQ ID NO: 9; a VH CDR2 région comprising the amino acid sequence of SEQ ED NO: 25; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 41; a VL CDRl région comprising the amino acid sequence of SEQ ID NO: 81 ; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 97; and a VL CDR3 région comprising the amino acid sequence ofSEQBDNO: 113;

    -17119653 (b) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 10; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 26; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 42; a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 82; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 98; and a VL CDR3 région comprising the amino acid sequence ofSEQIDNO: 114;

    (c) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 11 ; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 27; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 43; a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 83; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 99; and a VL CDR3 région comprising the amino acid sequence ofSEQIDNO: 115;

    (d) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 12; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 28; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 44; a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 84; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 100; and a VL CDR3 région comprising the amino acid sequence ofSEQIDNO: 116;

    (e) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 13; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 29; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 45; a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 85; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 101 ; and a VL CDR3 région comprising the amino acid sequence ofSEQIDNO: 117;

    (f) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 14; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 30; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 46; a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 86; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 102; and a VL CDR3 région comprising the amino acid sequence ofSEQIDNO: 118;

    (g) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 15; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 31 ; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 47; a VL CDR1

    -17219653 région comprising the amino acid sequence of SEQ JD NO: 87; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 103; and a VL CDR3 région comprising the amino acid sequence of SEQ ID NO: 119; or (h) a VH CDR1 région comprising the amino acid sequence of SEQ ID NO: 16; a VH CDR2 région comprising the amino acid sequence of SEQ ID NO: 32; a VH CDR3 région comprising the amino acid sequence of SEQ ID NO: 48; a VL CDR1 région comprising the amino acid sequence of SEQ ID NO: 88; a VL CDR2 région comprising the amino acid sequence of SEQ ID NO: 104; and a VL CDR3 région comprising the amino acid sequence ofSEQIDNO: 120.
14. 14. The polynucleotide of any one of daims 1 to 13, wherein the antigen binding molécule comprises:

    (a) a VH comprising the amino acid sequence of SEQ ID NO: 65; and a VL comprising the amino acid sequence of SEQ ID NO: 137;

    (b) a VH comprising the amino acid sequence of SEQ ID NO: 66; and a VL comprising the amino acid sequence of SEQ ID NO: 138;

    (c) a VH comprising the amino acid sequence of SEQ ID NO : 67; and a VL comprising the amino acid sequence of SEQ ID NO: 139;

    (d) a VH comprising the amino acid sequence of SEQ ID NO: 68; and a VL comprising the amino acid sequence of SEQ ID NO: 140;

    (e) a VH comprising the amino acid sequence of SEQ ID NO: 69; and a VL comprising the amino acid sequence of SEQ ID NO: 141;

    (f) a VH comprising the amino acid sequence of SEQ ID NO: 70; and a VL comprising the amino acid sequence of SEQ ID NO: 142;

    (g) a VH comprising the amino acid sequence of SEQ ID NO: 71 ; and a VL comprising the amino acid sequence of SEQ ID NO: 143; or (h) a VH comprising the amino acid sequence of SEQ ID NO: 72; and a VL comprising the amino acid sequence of SEQ ID NO: 144.
15. 15. The polynucleotide of claim 14, which comprises a nucléotide sequence at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to a nucléotide sequence selected form the group consisting of SEQ ID NOs: 57-64.

    -17319653
16. 16. The polynucleotide of claim 14 or 15, which comprises a nucléotide sequence at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to a nucléotide sequence selected form the group consisting of SEQ ID NOs: 129136.
17. 17. The polynucleotide of any one of claims 1 to 16, wherein the antigen binding molécule is single chained.
18. 18. The polynucleotide of any one of claims 1 to 17, wherein the antigen binding molécule is selected from the group consisting of scFv, Fab, Fab', Fv, F(ab')2, dAb, and any combination thereof
19. 19. The polynucleotide of any one of claims 1 to 18, wherein the antigen binding molécule comprises an scFv.
20. 20. The polynucleotide of any one of claims 1 to 19, wherein the VH and the VL are connected by a linker.
21. 21. The polynucleotide of claim 20, wherein the VH is located at the N terminus of the linker and the VL is located at the C terminus of the linker.
22. 22. The polynucleotide of claim 20, wherein the VL is located at the N terminus of the linker and the VH is located at the N terminus of the linker.
23. 23. The polynucleotide of any one of claims 20 to 22, wherein the linker comprises at least about 5, at least about 8, at least about 10, at least about 13, at least about 15, at least about 18, at least about 20, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, or at least about 100 amino acids.
24. 24. The polynucleotide of any one of claims 20 to 23, wherein the linker comprises an amino acid sequence at least 75%, at least 85%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 174.

    -17419653
25. 25. The polynucleotide of any one of claims 1 to 24, wherein the antigen binding molécule binds to BCMA with a Kd of less than about 1x10'⁶M, less than about 1 x 10'⁷M, less than about 1 x 10'⁸M, or less than about 1 x ΙΟ’⁹M.
26. 26. The polynucleotide of any one of claims 1 to 25, wherein the TCR further comprises a CDR4.
27. 27. The polynucleotide of any one of claims 1 to 26, wherein the TCR further comprises a constant région.
28. 28. The polynucleotide of any one of claims 1 to 25, wherein the CAR comprises a transmembrane domain.
29. 29. The polynucleotide of claim 28, wherein the transmembrane domain is a transmembrane domain ofCD28,4-1BB/CD137, CD8 alpha, CD4, CD19, CD3 epsilon, CD45, CD5, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, an alpha chain of a T cell receptor, a beta chain of a T cell receptor, a zêta chain of a T cell receptor, or any combination thereof.
30. 30. The polynucleotide of claim 28 or 29, wherein the transmembrane domain is a CD28 transmembrane domain.
31. 31. The polynucleotide of claim 30, wherein the CD28 transmembrane domain comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 169.
32. 32. The polynucleotide of claim 31, wherein the CD28 transmembrane domain is encoded by a nucléotide sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 168.
33. 33. The polynucleotide of any one of claims 28 to 32, wherein the CAR comprises a hinge région between the transmembrane domain and the antigen binding molécule.
34. 34. The polynucleotide of claim 33, wherein the hinge région is of IgGl, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM, CD28, or CD8 alpha.

    -17519653
35. 35. The polynucleotide of claim 33 or 34, wherein the hinge région is of CD28.
36. 36. The polynucleotide of claim 35, wherein the hinge région comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQIDNO: 167.
37. 37. The polynucleotide of claim 35 or 36, wherein the hinge région is encoded by a nucléotide sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQIDNO: 166.
38. 38. The polynucleotide of any one of daims 1 to 37, wherein the CAR or TCR comprises a costimulatory région.
39. 39. The polynucleotide of claim 38, wherein the costimulatory région is a signaling région of CD28, OX-40, 4-1BB/CD137, CD2, CD7, CD27, CD30, CD40, programmed death-1 (PD-1), inducible T cell costimulator (ICOS), lymphocyte function-associated antigen-1 (LFA-1 (CD1 la/CD18), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7-H3), LIGHT (tumor necrosis factor superfamily member 14; TNFSF14), NKG2C, Ig alpha (CD79a), DAP-10, Fc gamma receptor, MHC class I molécule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic activation molécules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, ICAM-1, B7-H3, CDS, ICAM-1, GITR, BAFFR, LIGHT, HVEM (LIGHTR), KIRDS2, SLAMF7, NKp80 (KLRF1), NKp44, NKp30, NKp46, CD 19, CD4, CD8alpha, CD8beta, IL2Rbeta, IL2R gamma, IL7R alpha, ITGA4, VLA1, CD49a, ITGA4, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD1 Id, ITGAE, CD103, ITGAL, CD1 la, LFA-1, ITGAM, CD11b, ITGAX, CD1 le, ITGB1, CD29, ITGB2, CD18, LFA-1, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRT AM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 (NTB-A, Lyl08), SLAM (SLAMF1, CD150, IPO-3), BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, a ligand that specifically binds with CD83, or any combination thereof.

    -17619653
40. 40. The polynucleotide of claim 38 or 39, wherein the costimulatory région is a CD28 costimulatory région.
41. 41. The polynucleotide of claim 38 or 39, wherein the costimulatory région is a 4-1BB/CD137 costimulatory région.
42. 42. The polynucleotide of any one of daims 38 to 40, wherein the costimulatory région comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 171.
43. 43. The polynucleotide of claim 42, wherein the costimulatory région is encoded by a nucléotide sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 170.
44. 44. The polynucleotide of any one of daims 1 to 43, wherein the CAR or TCR comprises an activation domain.
45. 45. The polynucleotide of claim 44, wherein the activation domain is a CD3 zêta domain.
46. 46. The polynucleotide of claim 44 or 45, wherein the activation domain comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ IDNO: 173.
47. 47. The polynucleotide of claim 45 or 46, wherein the activation domain is encoded by a nucléotide sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: 172.
48. 48. The polynucleotide of any one of daims 1 to 47, wherein the CAR or TCR further comprises a leader peptide.
49. 49. The polynucleotide of claim 48, wherein the leader peptide comprises an amino acid sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at

    -17719653 least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQIDNO: 165.
50. 50. The polynucleotide of claim 48 or 49, wherein the leader peptide is encoded by a nucléotide sequence at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQIDNO: 164.
51. 51. A vector comprising the polynucleotide of any one of daims 1 to 50.
52. 52. The vector of claim 51, which is a rétro viral vector, a DNA vector, a plasmid, a RNA vector, an adénoviral vector, an adenovirus associated vector, a lentiviral vector, or any combination thereof
53. 53. A CAR or TCR encoded by the polynucleotide of any one of daims 1 to 50 or the vector of claim 51 or 52.
54. 54. A cell comprising the polynucleotide of any one of daims 1 to 50, the vector of claim 51 or 52, the CAR or TCR of claim 53, or any combination thereof.
55. 55. The cell of claim 54, wherein the cell comprises an immune cell.
56. 56. The cell of claim 55, wherein the cell is a T cell.
57. 57. The cell of claim 56, wherein the T cell is a tumor-infiltrating lymphocyte (TIL), autologous T cell, engineered autologous T cell (eACT), an allogeneic T cell, or any combination thereof.
58. 58. The cell of any one of daims 54 to 57, wherein the cell is an in vitro cell.
59. 59. A composition comprising the polynucleotide of any one of daims 1 to 50, the vector of claim 51 or 52, the CAR or TCR of claim 53, or the cell of any one of daims 54 to 58.
60. 60. The composition of claim 59, which is formulated to be delivered to a subject.
61. 61. A method of making a cell expressing a CAR or TCR comprising transducing a cell with the polynucleotide of any one of daims 1 to 50 under suitable conditions.
62. 62. The method of claim 61, further comprising isolating the cell.

    -17819653
63. 63. Use of the cell of claim 54 in the manufacture of a médicament for inducing an immunity against a tumor.
64. 64. Use of the polynucleotide of any one of claims 1 to 50, the vector of claim 51 or 52, the CAR or TCR of claim 53, the cell of any one of claims 54 to 58, or the composition of claim 59 or 60, in the manufacture of a médicament for treating a cancer in a subject in need thereof.
65. 65. The use of claim 64, wherein the cancer is a hématologie cancer.
66. 66. The use of claim 64, wherein the cancer is of the white blood cells.
67. 67. The use of claims 64, wherein the cancer is of the plasma cells.
68. 68. The use of any one of claims 64 to 67, wherein the cancer is leukemia, lymphoma, or myeloma.
69. 69. The use of anyone of claims 64 to 67, wherein the cancer is multiple myeloma, Hodgkin's Disease, non-Hodgkin's lymphoma (NHL), primary médiastinal large B cell lymphoma (PMBC), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia (ALL) (including non T cell ALL), chronic lymphocytic leukemia (CLL), T-cell lymphoma, one or more of B-cell acute lymphoid leukemia (BALL), T-cell acute lymphoid leukemia (TALL), acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, malignant lymphoproliférative conditions, MALT lymphoma, mande cell lymphoma, Marginal zone lymphoma, myelodysplasia and myelodysplastic syndrome, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, a plasma cell proliférative disorder (e.g., asymptomatic myeloma (smoldering multiple myeloma or indolent myeloma), monoclonal gammapathy of undetermined significance (MGUS), plasmacytomas (e.g., plasma cell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullary plasmacytoma, and multiple plasmacytoma), systemic amyloid light chain amyloidosis, POEMS syndrome (also known as Crow-Fukase syndrome, Takatsuki disease, and PEP syndrome), or a combination thereof.

    -17919653
70. 70. The use of any one of claims 64 to 69, wherein the cancer is multiple myeloma.
71. 71. An isolated polynucleotide encoding an antibody or an antigen binding molécule thereof that specifically binds to BCMA, wherein the antibody or the antigen binding molécule thereof comprises:

    (a) a heavy chain variable région (VH) complementarity determining région (CDR) 1 comprising, consisting of, or consisting essentially of the amino acid sequence GX2X3X4X5X6X7SY (SEQ ID NO: 145), wherein: