NZ786715A - 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 This application is a divisional of NZ 746700 and claims the benefit of U.S.

Provisional Patent Application No. 62/317,334, filed April 1, 2016, the entire contents of which are hereby incorporated herein by nce in their ty.

SEQUENCE LISTING The instant application contains a Sequence Listing which has been ted electronically in ASCII format and is hereby orated 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 This invention relates to chimeric antigen receptors (CARs) and ered T cell ors (TCRs) sing an antigen binding molecule which binds to B-cell maturation n (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 Human cancers are by their nature comprised of normal cells that have one 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 successfully targeting cancer cells.

Human T cell therapies 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 have 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 e of interacting with a particular tumor antigen, allow '1' cells to target and kill cancer cells that express the particular tumor antigen [0006} Current therapies for hematologic malignancies have shown varying levels of effectiveness with red side effects. ore, a need exists to identity novel and improved ies for treating BCMA related diseases and disorders.

SLlivlh/lARY Gli' THE lNVENTl'lON The present invention is directed to an isolated polynncleotide encoding a chimeric antigen receptor (CAR) or T cell receptor (TCR) corn prising a binding molecule that specifically binds to B-ceil maturation antigen (BCMA), wherein the g molecule comprises: (a) a heavy chain variable region (VH) complementarity determining region (CDR) l comprising, consisting of, or consisting essentially of the amino acid sequence 4X5X6X7S‘Y (SEQ ll) NO: lAlS) wherein: X; is not present or G; X3 is net present or S; X4 is F, G, l, or ‘1’, X5 is S or ’l‘; X, is l? or S, and X7 is S or "l"; and/or (h) a Vl-l : comprising, consisting of, or consisting essentially of the amino acid sequence XilX3X4X5X6X7XgX9XmYXizxisx14X}5X1¢3Xi7(SEQ ll) NO: l46), wherein: X} is A, G, l, S, 'l‘, or V; X3 is l, N or S, X4. is G, P, S, or Y, X5 is D, G, l, or S, X6 is F, G, or S; X7 is not presenter G or S; X3, is N, S, or T; X) is A, l, K, or T; Xin is N S, or Y; X12, is A or N; X13, is D, P, or Q; X14 is X or S, X5 is F, L, or V, X15, is K or Q, and X17 is G or S; and/er (c) a VB CDR3 comprising, consisting of, or consisting essentially of the amino acid sequence .XthX3X4X5X6X7X8X9XJOX}‘jXlzx1:1.X14X15X16X1'71)XJ9(SEQ ll) N0; 147), wherein: X1 is A or V, X2 is X or R; X3 is not present or L), G, or T; X4. is not present or A, D, G, P, R, or S; X5 is not present or l3, F, G, L, Q, or T; X6 is not present or ii, M, Q, W, or Y; X; is not present or A, E, L, or S; X3 is net present or G, P, S, or T, X9 is net present or G, P, or S; X10 is not present or l, L, P, or Y, Xu is not present or W; X12, is not present or H, X13 is not t or E or Y, X14 is not present or D, G, H, P, S, W, or Y; X15 is A, G, L, W, er Y, X15 is not t or A, G, l, P, or V; X17 is F, L, or M; and X19 is l, L, V, or Y; and/or (d) a light chain variable region (VL‘) CDRl comprising, ting of, or consisting essentially of the amino acid ce X1X2SQX5X6X7X3X9X10X11X12X13X14X1,5l_,X17 (SEQ ID NO: l48); Whfii‘eii": X1 is X or R; X; is A or S, X5 is G or S, X; is l, L, or V, X7 is L or S, X8 is not present or H or Y, X9 is not present or S; X10 is not present or N or S; X11 is not present or G or N; X12 is not present or N, X13 is not present or X or Y, X14 is N, R, or S, X15 is N, W, or Y; and X17 is A or D; (e) a VL CDRZ comprising, consisting of, or consisting essentially oftlie amino acid [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley sequence XinSX4X5X5X7 (SEQ ED NO: 149), wherein X1 is D, G, L, S, or W, X; 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 (if) a VL C1333 comprising, consisting of, or consisting essentiaiiy or" the arnino acid sequence X1QX3X4X5X5PX8T (SEQ ID NO: 150), wherein X1 is M or Q; X5 is E, G, H, I, R, or Y, X4. is A, E, H, i, L, or ‘1’, X5 is A, G, H, S 'i‘, V, or Y, X6 is E, L, 'i‘, W, or Y, and X3 is not present or E, L, P, or W. {0008] in another ment, the invention is directed to an isolated poiynncieotide encoding an antibody or an antigen binding moiecnie thereof that specificaiiy binds to BCMA, n the antibody or the antigen g rnoiecnie thereof comprises: (a) a. heavy chain ie region (VH) cenipiernentarity determining region (CDR) 1 comprising, consisting of, or consisting essentiaiiy ot‘the amino acid sequence GX2X3 X4X5X6X7SY (SEQ 11) NO: 145), wherein: X; is not present or G, X3 is not t or S; X4 is E, G, i, or Y, X5 is S or T, X; is F or S, and X7 is S or T, and/or (is) a VH CDRZ comprising, ting of, or con si sting essenti aiiy of the srnino acid sequence Xi1X3X4X5X6X7X8X9X10YX12X13X14X15X16X17 (SEQ ID NO: 146), wherein: X} 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, X5, is F, G, or S, X7 is not presenter G or S; X8 is N, S, or '1‘; X9 is A, i, K, or T; Xm is N, S, or Y, X; is A or N; X3, is D, P, or Q, X14 is K or S; X5 is F, L, or V, X16 is K or Q; and X17 is G or S, and/or (c) a VH CDR3 comprising, consisting of, or consisting iaiiy of the amino acid sequence X1X2X3X4X5X6X7X§5X9X10X11X12X13X14X15X16X17DX19 (SEQ ID NO: i475, wherein: X1 is A or V, X2 is K or R, X5 is not present or D, G, or T, X4 is not present or A, D, G, 1), K, or S; X5 is not present or E, E, G, L, Q, or T, X6 is not present or E M, Q, W, or Y, X7 is not t or A, E, L, or S; X8 is not present or G, P, S or Ti‘, X9 is not present or G, P, or S, Xio is not present or i, L, E, or Y, Xu is not present or W, X12 is not present or H, X13 is not present or E or Y, X14 is not present or I), G, H, P, S, W, or ‘r’, X15 is A, G, L, W, or Y, X16 is not present or A, G, i, P, or V; X17 is F, L, or M, and X19 is i, L, V, or Y, anti/011d) a light chain variahie region (VL) CDR1 comprising, consisting of, or consisting essentiaiiy of the amino acid sequence X1X2SQX5X6X7X8X9X10X11X12X13X14X15LX17 (SEQ ID NO: i48), wherein X} is K or R; X2 is A or S, X5 is G or S, X6 is I, L, or V, X7 is L or S, X3 is not present or H or Y, X9 is not t or S; X10 is not present or N or S, X1; is not present or G or N, X12 is not present or N; XL; is not present or K or Y, Xit is N, R, or S; X5 is N, W, or Y, and X17 is A or D, (e) a VL CDR2 comprising, ting of, or consisting essentiaiiy of the amino acid serp > X1X28X4X5X5X7(SEQ ED NO: 149), wherein X1 is D, G, L, S, or W, X3 is A or G, [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley X4. is N, S, or '1"; X5 is L or R, X5 is A, E, or Q, and X7 is S or T, and/or (f) a VL CDR3 cornpri sing, consisting of, or consisting essentially of the amino acid sequence xioxixixixsrxgr (sno in NO: 150), wherein xi is M or o; as, is r, o, it, i, n, or r, 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 present or E, L, 13’, or W. {0009} in some embodiments, the VB CDRi comprises an amino acid sequence selected from the group consisting of SEQ TD NO: 9—16, in some embodiments, the Vii CDRZ ses an amino acid sequence seiected from the group consisting of SEQ ii) NQ: 25—32. in some embodiments, the Vii CDRJ comprises an amino acid sequence ed from the group consisting of SEQ 1D NQ: 81—88. in some embodiments, the VL CDRZ comprises an amino acid sequence selected from the group ting of SEQ 1T.) NO: 97~iO4 in some embodiments, the VL CDR3 comprises an amino acid sequence seiected from the group consisting of SEQ [D NO: 113~120 in some embodiments, the binding moiecuie comprises: (a) a Vii (DDR1 region comprising the amino acid sequence of SEQ 11) NO: 9; a VB CDRZ region comprising the amino acid sequence of SEQ it) NQ: 25; a Vi—E CDR3 region comprising the amino acid ce of SEQ 11) N0: 41, a VL CDRT region comprising the amino acid sequence of SEQ [D 'NQ: 81, a We CDRZ region comprising the amino acid sequence of SEQ [D N0: 97; and a VL CDRB region comprising the amino acid sequence of SEQ TD NO: 113; (h) a Vii CDRi region comprising the amino acid ce of SEQ TD NO: 10, a Vii CDRZ region comprising the amino acid sequence of SEQ 11) NO: 26, a Vii CDR3 region comprising the amino acid sequence of SEQ ED NC): 42; a Vii CDR1 region comprising the amino acid ce of SEQ [D NO: 82, a Vi... (31)sz region comprising the amino acid sequence of SEQ ID NO: 98, and a VL CDR3 region comprising the amino acid, sequence of SEQ TD NO: 114, (c) a Vii EDR1 region comprising the amino acid sequence of SEQ [D NC: 1 1, a Viii CDRZ region comprising the amino acid sequence of SEQ 1]) ND: 27, a ‘x/H CDRS region comprising the amino acid sequence of SEQ ii) NO: 43, a We CERT region comprising the amino acid sequence of SEQ 11) N0: 83; a VL CDRZ region comprising the amino acid sequence of SEQ TD NO: 99, and a VL CDR3 region comprising the amino acid sequence of SEQ ii) NO: 115; (d) a Vii CADRE region comprising the amino acid sequence of SEQ i1) NO: 12, a Vii CDRZ region comprising the amino acid sequence of SEQ [D NO: 28; a VB CDR3 region comprising the amino acid sequence of SEQ i1) NO: 44, a VL CDRi region com ‘ng the amino acid sequence of SEQ [D NO: 84, a VL CDRZ region comprising the [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley amino acid ce of SEQ 11) NQ: 100; and a VL CD113 region comprising the amino acid sequence of SEQ 11.1 N1): 116; (e) a V11 CD111 region comprising the amino acid sequence of SEQ 11) NO: 13; a \I1:1 C1) 112 region comprising the amino acid ce of SE 1111 N0: .29; a V11 C3113 region sing the amino acid sequence of SEQ ED NO: 415; a 1.1 C3111 region comprising the amino acid sequence oi SEQ 111 N11: 85; a VL C11112 region comprising the amino acid ce of SEQ 111 N0: 1111; and a V1 CD113 region comprising the amino acid sequence of SEQ 11) NO: 1 17; (1") a. V11 CD111 region comprising the amino acid sequence of SEQ 11) NO: 14; a V11 CD112 region comprising the amino acid sequence of SEQ 11) NO: 30; a V11 CD113 region comprising the amino acid ce of SEQ 11) NQ: 46; a VL 1 region comprising the amino acid sequence of SEQ 11) NO: 86; a VL CD112 region comprising the amino acid sequence of SEQ 11) NQ: 102; and a V1... CD113 region comprising the amino acid sequence of SEQ 11) NO: 118; (g) a V11 {313111 region comprising the amino acid sequence of SEQ 111 ND: 15; a 1v11 CD112 region comprising the amino acid sequence ot S1:3Q111 NO: 31; a V11. C1311 3i'egion comprising the amino acid sequence of SEQ 11) NO: 47; a V1. CD111 region comprising the amino acid sequence of SEQ 111 NO: 87; a VL (1131112 region comprising the amino acid sequence of SEQ111 NQ:103; and a V1 (11113 region comprising the amino acid sequence of SEQ 11) NO: 119; or (h) a V11 C11111 region comprisingthe amino acid sequence of S1:3Q11) N11: 16; a V11 C1)112 region comprising the amino acid sequence of SEQ 111 N11: a V11 CD113 region sing the amino acid sequence. of SEQ 11) N1): 48; a V1. CD111 region comprising the amino acid sequence of SEQ 111 N11: 88; a VL CD112, region comprising the amino acid sequence of SEQ 111 NO: 104; and a V1, CDRS region comprising the amino acid sequence of SEQ 11) NO: 120. 11101 1] 1n some embodiments; the binding moiecuie is singie chained. in some embodiments; the binding moiecuie comprises an scEV. [00121 1n some embodiments; the C A11 comprises a transmemhrane domain. in some embodiments; the transmemhrane domain is a transmemhrane domain of CD28; dim 1111137; (3118 (eg; C118 aipha, C1314; C1119, C113 epsiion, CD45; C115; C119; C1116; CD22; CD33; CD37; CD64, C1180; C1186; C3134, C3137; CD154; an aipha chain ofa T ceii receptor; a beta chain of a T ceii receptor; a zeta chain oi‘a T ceii receptor; or any combination thereof. in some embodiments; the CAR comprises a hinge region between the transmenrhrane domain and the binding molecule. 1n some embodiments; the hinge region is of 1g1.r1 1gGZ 1gG3;1gG4 1s:A 1g1);1gE;1gM C1328 or CD8 aipha 1n some embodiments; theh or TCR comprises a costimu1atory region. 1n some embodiments; the costimuiatory [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley region is a signaling region of CD28, OX~40, 4—lBB/CDl37, CD2, C 7, CD27, CD30, CD40, mmed death~l (PDvl), ble T cell costii'nulator , cyte functioneassociated antigen—l (Lli‘A—l (CDl la/CDlEl), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 (B7—H3), LTGHT (tumor necrosis factor sopertamily member l4; TNT SF l4), NKGZC, lg alpha ((3)7921), {BAP—l0, Fc gamma receptor, Mil-TC class i molecule, 'lNll receptor proteins, lrnmunoglobulin—lilre proteins, cytokine receptors, integrins, ing lymphocytic activation molecules (SlAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, lCAl‘vlw‘l, B7—H3, cos, leaner, one, BAFFR, LIGHT, HVEM (LTGHTR), KTRDSZ, SLAMF’Y, NKpSO (lilRFl), NKpdd, NKp30, Nltipélo, CD19, CD4, CDSalpha, CDSheta, lL2R beta, TL2R gamma, TL7R alpha, lTGAél, VLAl, CDdga, lTGrAll, 1A4, CD491), lTGAfi, VLA-é, co4si‘, Hear), CD}, 1d, lTGAE, Clitl03, lTGAL, CDl la, LFAul, lTGAM, CDl lb, l'i'GAX, CDl lc, l'l‘GBl, CD29, lTGBZ, CDlS, LFAul, T'l'GB'Z’, NKGZD, TNFR2, TRANCE/RANKL, DNAMi (CD226), l (CD244, 234), CD84, (1)96 (Tactile), CEACAl‘s/ll, CRT ANT, Ly? {Cl 2.29), CDloO , PSGCLl, CD100 (SEMA/lD), CD69, SLAMra , Lylt’lg), SLAM (SLAMFl, coiso, ll’O—3), BLAd‘le (Sla—XMFS), SELPTXE (CDléZ), lJl‘BR, LAT, (TADS, SLP-76, PAG/Chp, CDlQa, a ligand that specifically binds with CD83, or any combination thereof. in some embodiments, the CAR or TCR comprises an activation dom ain, lin some embodiments, the activation domain is a CD3 zeta domain.

{OOH} in other embodiments, the invention is directed to a vector comprising the polynncleotide or a polypeptide encoded by the cleotide. {00M} In certain ei'nhodiinents, the el’lthl’l is ed to a cell comprising the polymicleotide, the vector, the polypeptide, or any combination thereof. in other embodiments, the ion is directed to a cell, eg, an immune cell, e.g., a tomormintiltrating lymphocyte (TlL), antologous T cell, engineered antologons T cell (eACT), an allogeneic T cell, or any combination thereof. {thl 5] in other embodiments, the invention is directed to a method of inducing an immunity t a tumor comprising administering to a subject an effective amount of a cell comprising the polyn ucleotide, the , 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 hematologic cancer.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley T DESCRlPTlON OF THE FlGURES {OOlé} FlG, l A," l 3? show Cl...UTSTAl_.. W (183) multiple sequence aligrnnents of eight example anti~BClle hinding les disclosed herein. Flt}. lA shows a sequence alignment of example anti—BCMA binding molecules comprising a ‘vH .

Complementarity determining regions (CDRs) and framework regions (Fits) are shown, as determined by Chothia. FIG. l8 is a table providing the SEQ lD NO for each VH, CDR, and PR, sequence rated in HQ, lA. FlG. lC shows a ce alignment of example anti— BCMA binding molecules comprising a VB domain, with alternate CDRs and FRs shown.

FlG. ll) is a table providing the SEQ ll.) NO for each VH, CDR, and FR ce illustrated in FlG. l C. FlGr. lE shows a sequence alignment of example anti—BCMA binding molecules comprising a. VL . CDRs and FRS are shown, as determined by Chothia, HG. lF is a table providing the SEQ 11) NO for each VH, CDR, and FR sequence illustrated in FlG. lE. {00 l 7] Fle, ZA—ZF show BCMA expression in various cells. FlG. 2A shows multiple niyeloma cell sion of BCMA, CDlZlS, CS—l, CD38, and CDl‘). Box-plot analysis shows the distribution of gene expression levels in the various multiple myeloma cell lines tested (). 9‘le ZED-2D show BCMA expression in EoLl (FlG. ZB), MlvllS (HG: 2C), and NCl—HQZQ {Flt}. 2D) cancer cell lines as measured by flow tric analysis of BCMA cell surface expression on the respective cell lines, li'lG. 2E shows the expression of BCMA, CSml, CLL—l, DLLS, CD70, and FLTS. in alternatively activated macrophages; CD ill—positive, CDlo—negative cells; CD38—negative naive B cells; CD4-positive, alpha—beta T cells; central memory CD4—positiye cells, central memory CDSupositve cells; class ed memory B cells; cytotoxic cosearm natural ltiller cell; effector memory (3de positive cells, effector memory CDS—positiye cells, inflammatory macrophages; macrophages; mature neutrophils; memory B cells; monocytes; rnyeloid cells; and tory T cells. li'lG. 2F shows the expression of BClt/lA, CDl 38, CS—l, CD38, and CDl9 in the same cell types as in Fig. 2E. Gene expression is shown as fragments per kilohase of exon per million reads mapped (FP’KM) (lilG. A, FlG. 2E, and Flt}. 2F). él FlG. 3A and show CAR expression in lentivirus transduced y human 'l‘ cells from a first healthy donor () and a. second healthy donor (Fifi 38). [00"] Fle 4Au4F shows lFNy, 'l'NFct, and lL—Z production by lentivirus transduced CAR T cells from two healthy donors following 16 hours of tured with EoL—l (Black), NClD29 (light grey), or Mil/HS (grey) target cell lines. Fle. 4A and 4B show the lFNy (pg/ml; y—axis) production in lentivirus transduced CAR T cells from a first donor (FlG. 4A) "I...

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley and a second donor (FIG. AB). FlGrs. 4C and 41) show the 'l‘NFu (pg/ml; y—axis‘) production in lentivirus transduced CAR, T cells horn a first, donor () and a. second donor ()). Fle, 4}}; and 4F show the lL—Z production (pg/mi; y—axis) in ientivirus tran sduced CAR T cells from a first donor () and a second donor (). lile, 5A~5F show the average tic activity (as a percentage of viable target cells remaining; y—exis) over tinre front two healthy donors expressing the indicated CARs tured with Eolsl (FIGS. 5A and SB), NClml-i929 @7le 5C and 5D), or MMlS (Fle, iii and SF) target cells for 16 hours, 40 hours, 64 hours, 88 hours, or ll2 hours. Fle. 5A and SB show the average cytolytic activity of transduced CAR T cells front a first, donor () and a second donor (FlG. SB) cowcultured with EoLl target cells for l6 hours, 40 hours, 64 hours, 88 hours, or l l2 hours. Fle, 5C and 5B show the average cytolytic activity of transduced CAR '1" cells from a first donor () and a second donor (FlG. 5D) co~ cultured with NCLHQZQ target cells for l6 hours, 40 hours, 64 hours, 88 hours, or iii: hours. lile. SE and 59‘ show the average tlc activity of transduced CAR T cells from a first donor () and a second donor () co—cultured with MlvllS target cells for l6 hours, 40 hours, 64 hours, 88 hours, or l 12 hours.

[GOT/ll] FlGrs. 6A and 68 show proliferation of CFSEulaheled lentivirus transduced CAR T cells from a first healthy donor (EEG. 6A) and a second healthy donor (lilG; (SB) following 5 days of co—culture with CD3—CD28 heads (top row), EoL—l (second row), NCl— H929 (third row), or Mix/ll S m row) target cell lines. [0022} in the Figure descriptions helow, underlined ces denote CDR regions calculated using Chothia. [0023} HG. 7A shows Clone FSn26528 HC DNA sequence (SEQ [D NO: 27l) {0024} FlG. 7B shows Clone FS~26528 liC AA sequence (SEQ ll) NO: 272) PEG. 7C shows l-liC CDR sequences for clone li‘S—26528, {0026] ) shows Clone FSuZZoSfZS LC DNA ce {SEQ ll) N0: 276). {0027} FlG. 7E shows Clone film/"26528 LC AA sequence (SEQ ID NO: 277). {0028] FlG, 7F shows LC CDR sequences for clone FSQéSZS, {0029] FlG, 7G shows Clone FS~26528 CAR DNA HXL sequences (SEQ ll) NO: [0030} HG. 7H shows Clone FSn26528 CAR HXL AA sequences (SEQ ID NO: 282) [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley {00’I." a] shews CIene FS~26528 CAR DNA LXII sequences (SEQ ID NO: 283). {0032} FIG. "II shows Clone FS—26528 CAR LXI‘I sequences (SEQ ID ND: 28-4). {0033} shows CIcne 34 IIC DNA sequence {SEQ ID NO: 285). {0034} FIG) 833 shows CIene PIS—26534 I-IC sequence (SEQ ID NO: 286). {0035} FIG. III) shows I-IC CDR sequences for cIene FS~26523 {0030} shews Clene P026534 LC DNA sequences (SEQ ID NO: 290). {0037} FIG. SE shews the CIene 13026534 LC sequence (SEQ ID NO: 29I). {0038} shews LC CDR ces for CIene PC~26534 {0039} shews the CIcne PC—26534 CAR DNA I-IXI, sequeme (SEQ ID ND: {0040} shews the Gene PIE—26534 CAR IIXL AA sequence (SEQ ID ND: {0041} FIG. BI shows the (lime PC~26534 CAR DNA LXI-I sequence (SEQ ID ND: {0042} . SI shews Clone PCm26534 CAR. LXI-I sequence (SEQ ID NO: 298). {0043} ‘. 9A shows Cinne AI~26545 I-IC DNA ce (SEQ ID NO: 299). {0044} . QB shews CIene AIu26545 variabIe IIC sequence (SEQ ID ND: 300). {0045} L 9C shews IIC CDR sequences fer CIcne AI426545. {0040} shews CIene AI—26545 variable LC DNA sequence (SEQ ID ND: {0047} shews CIene (AI—26545 venebIe LC AA sequence (SEQ ID NO: 305) {0040} shows CIene Ain26545 LC CDR sequences. {0049} shows Clone AI-26545 CAR DNA I-IxL ce (SEQ ID NO: 309). {0050} shows Cinne AIw26545 CAR I-IXL AA sequence (SEQ ID NO: 310) {005}} shows Clene ASE—26545 CAR DNA LXI-I sequence (SEQ ID ND: 3 I I) {0052:{000 shews CIene 545 CAR LXII ce (SEQ ID NO: 3 I 2). :s_ FIG. IOA shows Chane AIn26554 HC DNA sequence (SEQ ID NO: 313) [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley {0054} FIG. I 08 shcws CIone [AI—26554 FIC AA sequence {SEQ ID N0: 314). {0055} FIG. ICC shcws CIone 54 IIC CDR sequences {0056} FIG. IOD shows CInne AIm26554 LC DNA sequence (SEQ ID N0: 3 I8). {0057} FIG. IOIE shnws Clone [AI—26554 LC AA sequence (SEQ ID NO: 319). [005s} FIG. IOF shnws CInne ALI—26554 LC CDR sequences. {0059} G shcws CInne 554 CAR DNA IIXL chain sequences (SEQ II) N0: 323). {0060] FIG. IOI—I shows CIone ADI—26554 CAR I-IXL chain AA sequences (SEQ ID ns3:324) {006I} FIG. IGI shows CIone AI—"IIISSAI CAR DNA LXII chain sequences (SEQ ID NI):325) {0052} FIG. IOI shews CIone ALI—26554 CAR LXII AA ces (SEQ ID NO: 326). {0053} FIG. IIA shnws CIene TIM—26562 FIC DNA sequence (SEQ ID NO: 327). {0064) FIG. I18 shows CIene hfiIQéSéZ IIC AA sequence (SEQ ID NO: 328). {0065} FIG. I IC shows CIune NM—26562 I-IC CDR sequences {0066) ‘. I II) shuws CIone DIM-26562 LC DNA sequence (SEQ ID NO: 332). {0067] FIG. I IE. shows CIcne NBA—26562 LC AA sequence {SEQ ID NO: 333). {006s} FIG. I IF shows the CIcne hfiI—Zefiéz LC CDR sequences. {0069} FIG. IIG shows the CInne INVIVInZISSéZ CAR DNA HXL sequences (SEQ ID N(>:337) {0070} Figure IIII shnws CIene NMuZéSéf/Z CAR FIXL AA sequences (SEQ ID NO: {0071} FIG. III shows CIone DIM-26562 CAR DNA LXI-I ces (SEQ ID NI): {0072} FIG. III shnws CIcne NMMLZIISQ CAR LXII AA sequences (SEQ ID N0: {007::: FIG. I2A shnws CIene 'IISuZZo’SéL’I IIC DNA sequence (SEQ II) NO: 344).

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] eadley None set by Anne.Headley [Annotation] eadley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley {0074} F113. '1 28 skews C1one TS~26564 HC AA sequence (SEQ 11) NO: 342). {0075} BIG. 131C skews the C1ene TS—"6564 HC CDR sequences. {0070} BIG. 12D shows the C1cne 64 LC DNA sequence (SEQ 1D NO: 3416). {0077} 17103. 12E shews the Clone 13-26564 LC AA sequence (SEQ ID NO: 347), {0070} 1311:}. 1217 shows the C1000 "178426564 LC CDR ces. [0079} F10}. 12G skews the Clcne 18—26564 CAR DNA HXL sequences (SEQ 1139 N0: 351). {0000} 171G. 121-1 shews the Ciene 18—26564 CAR 1-1341; chain AA sequences (SEQ n) 003:3 2) {0001} HG. 1121 shows the C1ene 1&26564 CAR DNA L011 sequences (SEQ 1D ND: {0002} F10}. 121 skews the C1ene 1‘S—26564 CAR L011 AA sequences (SEQ 1D NO: {0003} . 13A shews the C1ene 26568 1-1C DNA sequence (SEQ 11) NO: 355) {0004} ‘. 1313 skews the C10ne RY—26568 131C AA sequence (SEQ 11) ND: 356), {0005} F113. '13C skews the C1ene 131117426568 HC CDR sequences. {0000} HG. 13D shows the C1ene ELY—26568 LC DNA sequence (SEQ 1D NO: 360). {0007} 17103. 13E shews the Clone RY—26568 LC AA seqnenee (SEQ 11) NO: 361). {0000} 17103. 131:7 shows the C1ene RY~26568 LC CDR AA sequences, {0009} 1311:}. 13G shews the Cinne R ’-26568 CAR DNA 1-1010 sequences (SEQ 11) N0: 305) {0090} 1711}. 131-1 shows the C1ene RY~26568 CAR 1101., AA sequences (SEQ 11) ND: {0091} BIG. 131 shows the Clone RY~26568 CAR DNA LXH sequences (SEQ 1]) ND: {0002} 1311:}. 133 shews the (310110 RY—26568 CAR1ex1-1 AA sequences (SEQ ID NO: {0093} 17113. 14A shows the C1ene 1313—26575 1-1C DNA sequeme (SEQ ID NO: 369).

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by eadley {0094} FlG. 148 shows the Clone PPu26575 HC AA sequence (SEQ ID NO: 370). {0095} C shows the Clone PP~26575 HC CDR AA sequences. {0090} D shows the Clone PR26575 LC DNA sequence (SEQ lD NO: 374). {0097} F103. 1413 shows the Clone PP—26575 LC AA sequence (SEQ ID NO: 3'75). {009s} 111G. 1417 shows the Clone RP—26575 LC CDR AA sequences. {0099} F161. MG shows the Clone l’R~26575 CAR DNA HXL sequences (SEQ 11) No: 379). {0100} PEG. 141-1 shows Clone PP—26575 CAR .. AA sequences (SEQ 11) ND: {0101} -1 shows Clone 13326575 CAR DNA LXH sequence (SEQ [D ND: {0102} F161. 14] shows the Clone Pl’u26575 CAR LXH AA sequence (SEQ ID NO: {0103} . 15A shows the Clone RD—26576 HC DNA sequence (SEQ 11‘) NO: 383) {0104} ‘. 1513 shows Clone 1113—26576 E-lC AA sequence (SEQ ED ND: 384). {0105} FlG. 15C shows the Clone RD—26576 HC CDR sequences. {0100} D shows the Clone 76; LC DNA sequence (SEQ ID ND: 388) {0107} F103. 1513 shows the Clone RD—26576 LC AA sequence (SEQ ID NO: 389). {010s} F103. 151:7 shows the Clone RD~26576 LC CDR sequences. {0109} 111G. lSG shoes the Clone RD-26576 CAR DNA 1-1le sequences (SEQ {D N0: 393). {0110} 171G. 1511 shows the Clone RD~26576 CAR HXL 01min AA sequences (SEQ 111 N0; 394). {0111} 1 shows the Clone RD~26576 CAR DNA LXH sequences (SEQ lD ND: {0112} 111G. 153 shows the Clone BAD—26576 CAR luxl-li AA ces (SEQ ID NO: {Cl 13] 171G. 16A, shows the Clone RD1C DNA sequences (SEQ ID NO: 397).

[Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley ation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley {01M} FlG. l 68 shows the Clone RD—26578 HC AA sequence (SEQ 1]) N0: 398). {0115} F18 16C shows the Clone BED—26578 HC CDR AA sequences. {0116} F18 169 shows the Clone 6578 LC DNA sequence (SEQ lD NO: 402). {0117} FR}, 1613 shows the Clone RD—26578 LC AA sequence (SEQ ll) NO: 403) [Cl l8} li'lG. loll shows the Clone EKG—26578 LC CDR sequences. [0119} FIG. ldG shows the Clone 78 CAR DNA HXL chain sequence (SEQ [D NO: 407). [0120} PEG. loll shows the Clone RD-26578 CAR l-lxl, AA sequence (SEQ ll) Nil: 408). {0121} F18 161 shows the Clone RD~26578 CAR DNA LXH sequences (SEQ lD ND: 409). [0122} } shows the Clone RDu26578 CAR LXH AA sequence (SEQ ll) NO: 4-10). {0123} FlG. 17 shows the e of an in vivo study examining the efficacy of clone l®~2l530 in a subcutaneous RPML8226 mouse model. Cohorts of lt‘i mice each were tested for the CAR d lines) and much tran sduced (holded lines) T cells.

[Ol24} li'lG. 18A and PEG. lBB show the outcome of an in Vitro cytotoxicity assay using the optimized BCMA scFV variants cocultured with NEE—H.929 and MMlS cells, respectively. CAR T cells using these optimized scFvs were incubated overnight with luciferase labeled target cells in 3 : l and l2l effector to target cell .

DETAlLEQ DESCRlPTlQN QF THE lNVENllQN {0125} The present invention relates to antibodies, antigen binding molecules thereof, chimeric antigen receptors (CARs), and engineered T cell receptors, which hind BCMA, polynucleotides encoding the same, and in Vitro cells comprising the same. The polynucleotides, polypeptides, and in Vitro cells described herein can he used in an engineered C AR '1" cell therapy, 9.3., an eutologous cell therapy (eAC'l‘TM), for the treatment of a patient suffering from at cancer. ln particular; the polynucleotidesg polypeptides, and in Vitro cells desc ' d herein can he used for the treatment of multiple niyeloina.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Definitions [OK/lo] ln order that the present sure may be more readily understood, certain terms are first . As used in this application, except as otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout the application.

[Ol27l The term "and/or" where used herein is to be taken as ic 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 or" 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).

{OlZSl it is understood that wherever aspects are bed herein with the language ising, H ise analogous aspects described in terms of "consisting of" and/or "consi sting essentially of" are also provided.

[OK/39] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Tuo, Pei—Show, 2nd ed, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed, l999, Academic Press; and the ()xi‘ord nary Of Biochemistry And Molecular Biology, Revised, 2000, Qxford University Press, provide one of skill with a general nary of many of the terms used in this disclosure, {0130] Units, prefixes, and s are denoted in their ne lnternational de Unites (Si) accepted form. Numeric ranges are inclusive of the numbers defining the range, The headings provided herein are not limitations of the s aspects of the disclosure, Wl’llCl‘l can he had by reference to the specification as a whole, Accordingly, the terms delined immediately below are more tul ly deli ned by reference to the specification in its entirety.

{Olfil} "Adniinistering" refers to the physical introduction of an agent to a subject, using any of the various methods and ry s known to those skilled in the art.

Exemplary routes of administration for the formulations disclosed herein include intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as u '1 ,ierein means modes of administration other than l and topical administration, usua and includes, without limitation, intravenous, intramuscular, , by injection, [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley intraarterial, intrathecal, intralymphatic, esional, intracapsular, intraorbital, intracardi ac, ern'ial, intraneritoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinai, epidural and intrasternal injection and infusion, as well as in viva electroporation. in some embodiments, the fonnulation is administered via a nonwparenteral route, e.g, orally, (Either non—parenteral routes include a topical, epidermal or inucosal route of administration, for example, intranasally, vaginally, rectally, sublingually or topically, Administering can also be med, for e, once, a plurality of times, and/or over one or more ed periods.

{W32} The term "antibody" (Ab) includes, t lirnitation, a glycoprotein globulin which binds specifically to an antigen. in general, and antibody can cornpri se at least two heavy (H) chains and two light (L) chains interconnected by disultide bonds, or an antigen binding molecule thereof. Each H chain comprises a heavy chain variable region (abbreviated herein as ‘x/H) and a heavy chain constant . The heavy chain constant region comprises three constant domains, (Ii-ll, (ll-l2 and CH3. Each light chain comprises a light chain variable region viated herein as VL) and a light chain constant region. The light chain nt region is comprises one constant domain, (IL, The Vi-l and VL regions can be further subdivided into regions of hypervariability, termed mentarity determining regions {CDRs}, interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL comprises three CDRs and four PRs, arranged from amino~tenninus to carboxy~terrninus in the following order: PRl, CDRl, FRZ, CDRZ, FR3, CDRB, FEM. The le regions of the heavy and light chains contain a binding domain that cts with an antigen. The constant regions of the Abs may mediate the binding or" the irnnninoglobulin to host tissues or factors, ing various cells of the immune system {c.g effector cells) and the first component (Clq) of the classical complement system.

[Ol33l Antibodies can include, for example, onal antibodies, recombinantly produced antibodies, monospecific antibodies, multi specific antibodies (including bispecific dies), human antibodies, humanized antibodies, chimeric antibodies, inimunoglobulins, synthetic antibodies, tetrarneric antibodies comprising two heavy chain and two light chain molecules, an antibody light chain monomer, an antibody heavy chain r, 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 conjges"), heteroconiugate antibodies, single domain dies, monovalent antibodies, ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by eadley [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley single chain antibodies or —chain Fvs (schv), cameiized antibodies, affybodies, Fab fragments, 2 fragments, ’ide—linlred Fys (sdliy), anti—idiotypic (antidd) antibodies (including, eg, anti-anti—ld antibodies), minibodies, domain antibodies, synthetic antibodies (sometimes referred to herein as "antibody mimetics"), and antigennbinding fragments of any ofthe above. ln certain embodiments, anti bodies described herein refer to polyclonal antibody populations. {0134] An immunoglobulin may derive from any of the commonly known isotypes, ing but not limited to lgA, secretory lgA, lgGr and lgl‘vl. lgG subclasses are also well known to those in the art and e but are not limited to human lgGl, lgGZ, lgG3 and lgGll. "lsotype" refers to the Ab class or subclass (erg, lgiVl or lgGl) that is d by the l'ieayy chain constant region genes. The term "antibody" includes, by way of example, both naturally occurring and nonunaturally occurring Abs; monoclonal and polycional 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 n binding molecule of any of the aforementioned immunoglobulins, and includes a monoyalent and a divalent fragment or portion, and a single chain Ab, {OBS} An "antigen binding molecule," "antigen g portion," or ody fragment" refers to any molecule that comprises the antigen binding parts (eg, CDRS) of the antibody from which the molecule is derived. An antigen binding molecule can include the antigenic complementarity determining regions (CDRS). Examples of antibody fragm ents e, but are not limited to, Fab, li‘ab‘, ili'(ab‘)2, and ili'y nts, dAb, linear antibodies, scFV antibodies, and multispecific antibodies formed from antigen binding molecules.

Peptibodies (i.e., Fc fusion molecules comprising peptide binding domains) are another example of suitable antigen binding molecules. in some embodiments, the antigen binding molecule binds to an antigen on a tumor cell. in some embodiments, the antigen binding molecule binds to an antigen on a cell involved in a hyperproliteratiye disease or to a Viral or bacterial antigen. In certain embodiments, the antigen binding molecule binds to BCMA. in r embodiments, the antigen binding molecule is an antibody of fragment thereof, ing one or more of the complementarity ining regions (CDRs) thereof. in thither embodiments, the antigen binding molecule is a single chain variable fragment (scFV). ln somnibodinients, the antigen binding molecule comprises or consists of ayimers.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley {086] As used herein, the terms "variable region" or "variable domain" are used interchai'igeably and are common in the art. The variable region typically refers to a portion of an antibody, generally, a portion of a light or heavy chain, typically about the amino- terminal llQ to lZO amino acids in the mature heavy chain and about 90 to llS amino acids in the mature light chain, which differ extensively in sequence arnong antibodies and are used in the binding and specificity of a particular antibody for its particular antigen. The ility in sequence is concentrated in those s called complementarity ining s (CDRs) while the more highly conserved regions in the variable domain are called framework regions (FR). t 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 dy with antigen. in certain embodiments, the variable region is a human variable region. in certain embodiments the variable region comprises rodent or murine CDRs and human framework regions (Fits). in particular embodiments, the variable region is a primate (cg, non-human primate) variable region. in n embodiments, the variable region comprises rodent or murine CDRs and e (cg non— human primate) framework s (Elks).

The terms "VL" and ""v’L domain" are used hangeably to refer to the light chain variable region of an antibody or an antigen~binding fragment thereof.

{OBS} The terms "VH" and "VB domain" are used interchangeably to refer to the heavy chain variable region of an antibody or an antigen—binding fragment thereof.

A number of definitions of the CDRs are commonly in use: Kabat numbering Chothia numbering Ablvl ing, or contact numbering The AbM deli nition is a compromise between the two used by Oxford Molecular’s Ablvl antibody modelling software The t definition is based on an analysis of the ble complex crystal structures.

Table l. CDR Numbering Loop Rabat Abllvl Chothia Contact Ll gamma ..34 L24--l_..34 tan—4,36 L2 L50~~L56 Lao—L56 LSOuLfio Lilo—"L55 LSQn—LQ’i L8§L—L97 L89nnL96 [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley .................................................................................................................................................................................

Hi iH3l—uH3SB iHZSwHZ’iSB H26wH32..34 H30——H35B (Rabat Numbering) l in it-ti3l—~i€i35 535 l-{Zewt-BZ incur-r35 (Chethia Numbering) H2 l-iSO—wi-lnfi HSOWHSS i-i47ui-i58 i-l3 ii-iigfi—wi-HOZ i95wi-l102 i-igfiwl-ilOZ i—i93ui-il0l {M40} The term "Rabat numbering" and like terms are recognized in the art and refer te a. system of ing amine acid residues in the heavy and light chain yariahie regions of an antihedy, er an n binding melecule t‘. in certain aspects, the CDRs ct an antihcdy can be determined ing t0 the Kabat numbering system (see, eg, Kabat EA & Wu TT (l97l) Ann NY Acad Sci l90: 382-391 and Kabat EA el‘ al, (19%) Sequences ct" Preteins cf lmmuneiegical interest, Fifth Edition, US. Department cf Health and Human Services, Nil-i Pubiicatien Nu, 2). Using the Kabat ing system, CDRs within an antibedy heavy chain mnlecule are typically t at amine acid cns 3l to 35, which npticnaliy can include ene er twc additional amino acids, feliewing 35 (referred to in the Rabat numbering scheme as 35A and 358) , amine acid pesitiens SO te 65 (CDRZ), and amino acid pusitiens 95 to 102 (CDR3) Using the Kabat numbering system, CDRs within an antibody light chain meiecule are typically t at amine acid pesiticns 24 to 3-4 (CDRl), amino acid pcsitiens 50 to 56 (CDRZ), and amine acid pesitiens 89 to 97 (CDR3). in a specific embodiment, the 03le cf the antibodies described herein have been determined acccrding t0 the Rabat numbering scheme. [0141} in certain s, the CDRs ct an antibedy can be determined according to the Chethia numbering scheme, which refers t0 the location cf irninuncglchuiin structural lccps (see, 43.33., Chethia C & Lesk Alt/ii, 0987), Li Mel Biol lgn: 90l—917, Al—E.azil Typically, when using the Kabat numbering conventien, the Chnthia CDR~Hl leep is present at heavy chain amine acids 26 to 32, 33, or 34, the Chethia CDRri-i2 icep is t at heavy chaiacidsgiinn acids 52 t0 56, and the Chcthia CDR~H3 icep is present at heavy chain amine to lOZ, while the Chcthia CDR—Ll loop is present at light chain amine acids 24 te ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley 34, the Chothia CUR—L2 loop is present at light chain amino acids 50 to 56, and the Chothia CDR—LS loop is present at light chain amino acids 89 to 97 , The end of the Chothia CDRQl—ll loop when nurnbered using the Kabat numbering tion varies between H32 and H34 depending on the length of the loop (this is because the Kabat numbering scheme places the insertions at l-l35A and H358, if neither 35A nor 358 is present, the loop ends at 32, if only 35A is t, the loop ends at 33; if both 35A and 353 are present, the loop ends at 34). hi a specific embodiment, the CDRs of the antibodies described herein have been determined according to the Chothia numbering scheme {DMZ} As used herein, the terms "constant region" and "constant domain" are interchangeable and have a meaning common in the art. The constant region is an antibody portion, cg, a carboxyl terminal portion of a light and/or heavy chain which is not directly ed in g of an antibody to antigen but which can exhibit various effector functions, such as interaction with the Fc receptor. The constant region of an imniunoglobulin molecule generally has a more conserved amino acid sequence relative to an oglobulin variable domain.

[Oldill As used herein, the term "heavy chain" when used in reference to an antibody can refer to any distinct type, cg, alpha (a), delta (6), n (a), gamma (7) and mu (u), based on the amino acid ce of the constant domain, which give rise to lgA, lgl), lgli, lgG and lglvl s of antibodies, tively, ing subclasses of lgG, cg, lgGri, lng, lgGg and lgGi.

[M44] As used herein, the term "light chain" when used in reference to an antibody can refer to any distinct type, eg kappa (K) or lambda (it) based on the amino acid sequence of the constant domains. Light chain amino acid ces are well known in the art. in specific embodiments, the light chain is a human light chain.

{OMS} "Binding affinity" lly refers to the strength of the sum total of non- covalent interactions between a single binding site of a molecule (egg, an antibody) and its binding partner (ag, an antigen). Unless indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a l:l interaction between s of a binding pair (635551, antibody and antigen) The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (Kn). Affinity can be measured and/or expressed in a number of ways known in the art, including, but not limited to, equilibrium dissociation constant (KB), and equilibrium association constant (RA). The K9 is calcud from the quotient Ofkgff/kgfi, whereas RA is calculated from the quotient of legit/hair.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by eadley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley lam refers to the ation rate constant of, eg, an antibody to an n, and has refers to the dissociation, of, eg, an antibody to an antigen. The iron and hon can he determined by techniques itnown to one of ry skill in the art, such as lit lAcore® or A.

[Old-6:} As used herein, a "conservative amino acid tution" is one in which the amino acid residue is ed with an amino acid residue having a similar side chain, Families of amino acid residues haying side chains have been defined in the art. These families include amino acids with basic side chains (rag, lysine, arginine, histidine), acidic side chains (cg, aspartic acid, giutarnic acid), uncharged polar side chains (cg glycine, asparagine, glutaniine, serine, threonine, ne, cysteine, tryptophan), nonpolar side chains (9.3., alanine, vaiine, leucine, isoieucine, proline, phenylalanine, methionine), beta—branched nde chmns nag; dneonnn; yahne,i&fieuchnfi and annnanc nde chmns hag" neonne, phenylalanine, tryptophan, histidine). in n ments, one or more amino acid residues within a CDR(s) or within a framework regionts) of an antibody or antigenmhinding fimmmnmmadmnmanmdwflnmmmmmmdeMemmanmmunficmm, {0147} issusedhennn,an"ephope"isatennintheartandrefinstnaiocahzedregnni of an antigen to which an antihody can specifically bind. An epitope can he, for example, condguousannnozundsofarnnypepdde(hnearorcondguousephope)oranephcpecan,for example, come together from two or more non—contiguous regions of a polypeptide or innypepddes (ccnfinrnadonah ean rhscondnuous, or noneeonnguous epncpe) in certain ments, the epitope to which an antibody binds can be determined by, eg, NMR spectroscopy, Xuray diffraction crystallography studies, ELiSA assays, hydrogen/deuterium exchange coup} ed with mass spectrometry (eg, liquid chrorn atography eiectrospray mass spectrometry), array~hased oligo~peptide scanning assays, and/or mutagenesis mapping (cg, sitendirected mutagenesis mapping). For X—ray crystallography, crystallization may he accomplished using any of the known methods in the art (eg, (liege R e! 525., (i994) Acta Crystallogr D Biol Crystallogr 50(Pt 4): 339—350; McPherson A 0990) ZEurifBiochenil89:l*23,(3hayenlflii(l997)Eurucnne 5:i269—l274,hdc?herson,A.(l976) J Biol Chem 251i: 6300—6303). Antibodyzantigen crystals may he studied using well known X~ray dittraction techniques and may he refined using computer software such as X—PLOR (Yale University, l992, distributed by Molecular Simulations, lnc; see eg Meth Enzymol (1985)vohnnesli4 &;ll§,eds¥Vyckofl"HfiV stain LlS.2004flKH4le),and BLHYFER.

(Bneogne(3(l993)AcnaCkymahogrl)incl{kyMahogr49flh'Dt37L60j8ncogne(}(l997) Metnizyinnl 276A: 36in423, ed Carter CW; Roversi P cr 525., {2000) Acta Crystallogr D [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley Biol Crystallogr 56(Pt 10): 1316:1323). Mutagenesis mapping studies may be accomplished using any method ltnown to one of skill in the art, See, eng, Champe M at 1117., (l 995) J Biol Chem 270: l388—l394 and Cunningham BC & Wells 3A (3939) Science 244: ltlbl—lOSS for a description of nesis techniques, ing alanine scanning inutagenesis techniques.

[OMS] As used herein, an antigen binding molecule, an antibody, or an antigen binding molecule thereof "cross competes" with a reference antibody or an antigen binding rnolecule f if the interaction between an antigen and the first binding molecule, an antibody, or an antigen binding le thereof blocks, limits, inhibits, or otherwise reduces the ability of the reference binding molecule, nce antibody, or an antigen binding molecule thereofto interact with the antigen. Cross competition can be complete, cg, binding of the binding molecule to the antigen completely blocks the ability of the reference binding molecule to bind the antigen, or it can be partial, cg, binding of the binding molecule to the antigen reduces the ability of the reference binding molecule to bind the antigen. in certain embodiments, an antigen binding molecule that cross es with a reference antigen binding molecule binds the same or an overlapping epitope as the reference antigen binding molecule. in other embodiments, the antigen binding molecule that cross competes with a nce antigen binding le binds a different epitope as the reference antigen binding molecule Numerous types of competitive binding assays can he used to determine if one antigen binding le competes with another, for example: solid phase direct or indirect r‘adioimn1unoassay (RM), solid phase direct or indirect enzyme immunoassay (BIA); sandwich competition assay (Stabli er of, l983, Methods in Enzymology 92424253); solid phase direct biotinayidin ElA (Kirkland er of, l936, .l lmmunol l37136l436l9); soli phase direct d assay, solid phase direct labeled ch assay rlow and Lane, l988, Antibodies, A Laboratory Manual, Cold, Spring Harbor Press), solid phase direct label RIA using l—l25 label (Morel at at, l988, Molec. lrnrnunol. 25:7—l5); solid phase direct - ayidin BIA (Cheung, er oi, l990, Virology Haw-66:32), and direct d REA (Moldenhauer er a2, l990 Scandl lmmunol 32:7782) {tilt-lit} As used herein, the terms "iinmunospecifically binds," "ininiunospecifically izes," "specifically binds," and "specifically recognizes" are analogous terms in the context of antibodies and refer to les that bind to an antigen (9.3., epitope or immune complex) as such binding is understood by one skilled in the art. For example, a molecule that specifically binds to an antigen may bind to other peptides or polypeptides, generally Witl yer affinity as ined by, eg, immunoassays, BlAcore®, KinEXA 3000 [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley ment (Sapidyne Instruments, Boise, ID), or other assays known in the art. In a specific embodiment, molecules that ically bind to an anti gen bind to the antigen with a. Kit that is at least 2 logs, 2,5 legs, 3 logs, 4 logs or greater than the KA when the molecules bind to another antigen.

{Ol 50] In another embodiment, specific embodiment, molecules that specifically bind to an antigen bind with a dissociation constant (Kd) of about I x IO"7 M. In some ments, the antigen binding molecule specifically binds an, antigen with "high affinity" when the K5, is about I X 10"9 M to about 5 X IO"j M. In some embodiments, the antigen g molecule specifically binds an antigen with "very high affinity" wliei'i the K; is l x lO'IO M to about 5 x l 0-10 M. In one embodiment, the antigen binding molecule has a K; of l0"9 M. In one ment, the off—rate is less than about I it iii"? In other embodiments, the antigen binding le binds human BCI‘VIA with a K; of between about i X 10"" M and about i X l 0‘13 M.

In yet another embodiment, the antigen binding molecule binds human BCMA with a Kd of aboutl a it)"10 M to about 5 x IO"m M~ {m5 ll In another specific embodiment, molecules that specifically bind to an antigen do not cross react with other ns under similar binding conditions, In another specific embodiment, molecules that specifically bind to an antigen do not cross react with other nonw BCMA proteins, In a specific 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 (sag human BCMA) with a 20%, 25%, see/s, 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.g1, a rnnninoassay, surface plasmon resonance, or c exclusion assay. In a specific embodiment, the extent of binding of an antinBCMA dy or antigennbinding fragment thereof described herein to an unrelated, MA protein is less than 10%, l5%, or 20% of the binding of the antibody to BCMA n as measured by, tag, a radioimmunoassay.

{Ol 52] In a specific embodiment, provided herein is an antibody or nt thereof that binds to human BCh/IA with higher affinity than to another species ofBCMA. In certain embodiments, provided herein is an antibody or fragment thereof that binds to human BCMA with a 5%, 10%, i L1: %, 20%, 25%, 30%, 35%, 4 st, 45%, 50%, 55%, 60%, 65%, 7n% or higher affinity than to another species ot‘BCMA, as measured by, tag, a radioirnn'iunoassay, surface plasmon resonance, or kinetic exclusion assay. In a specific embodiment, an antibody or fluent thereof described herein, which binds to human BCMA, will bind to another ’77") [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley species of BCMA protein with less than l 0%, l5%, or 20% of the binding of the antibody or fragment thereof to the human BCMA protein as measured by, eg, a radioiinmunoassay, surface plasrnon resonance, or kinetic exclusion assay [Ol53l An "antigen" refers to any molecule that provokes an immune se or is capable ofheing bound by an antibody or an antigen binding molecule, The immune response may involve either antibody production, or the activation of ic immunologically— cornpetent cells, or both. A person of skill in the art would readily understand that any rnacromolecule, including lly all proteins or peptides, can serve as an n. An antigen can be endogenously expressed, is. expressed by genomic DNA, or can be inantly expressed. An antigen can be specific to a certain tissue, such as a cancer cell, or it can be broadly expressed, in addition, fragments of larger molecules can act as antigens. in one embodiment, ns are tumor antigens. in one particular embodiment, the antigen is BCh/lA.

{Ol 54] The term "neutralizing" refers to an antigen binding molecule, scli‘y, antibody, or a nt thereof that binds to a ligand and prevents or reduces the biological effect of that ligand. in some ments, the antigen binding molecule, scli'y, antibody, or a fragment thereof, directly blocking a binding site on the ligand or otherwise alters the s ability to bind through indirect means (such as structural or energetic alterations in the ligand), ln some embodiments, the antigen binding molecule, , antibody, or a fragment thereof prevents the protein to Wl’llCl‘l it is hound from ming a. ical function.

[Ol55] As used , the term "BCMA" refers to B cell maturation antigen, which can include, but is not d to, native BCMA, an isoform of BCMA, or an pecies BCMA homolog of Billy/EA. BCMA (also lrnown as TNFRSFW, (3)269, and 'l'NFRSFlSA) is a member of the tumor necrosis factor (Tl‘ihiyreceptor superfamily. BCMA is expressed, on the surface of multiple rnyelonia cells, while highly restricted to plasma cells and a subset of mature B cells in healthy tissue ( and ). The amino acid, sequence of human BCMA (secs/rs) is provided in NCBI Accession oczzzaz ((let3l3104029) (SEQ to no; l63). As used herein, BCMA includes human BCMA and non—human BCMA homologs, as well as variants, fragments, or post~transnationally modifi ed forrns thereof, including, but not limited to, Na and Q—linhed glycosylated forms of BCMA. BCMA proteins may further include fragments cornpri sing all or a portion of the extracellular domain ot‘BCMA (eg, all or a portion of amino acids l—Sd of hBCMA).

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley {0156] The term "autologous" refers to any material derived from the same individual to which it is later to he re—introduced, For example, the engineered autologous cell therapy (eACTl‘m) method described herein involves collection of lymphocytes from a, patient, which are then engineered to express, eg, a CAR construct, and then administered hack to the same patient. {0l57l The term "allogeneic" refers to any material derived from one individual which is then introduced to another individual of the same species, eg, allogeneic T cell transplantation.

{OlSSl The terms "transduction" and "transduced" refer to the process y foreign DNA is introduced into a cell via viral vector (see lones at of, "Genetics: principles and analysis," Boston: lones & Bartlett Pub}. 6998)). ln some embodiments, the vector is a retroviral vector, a DNA vector, a RNA vector, an adenoviral vector, a haculoviral vector, an Epstein Barr viral vector, a papovaviral vector, a vaccinia viral vector, a herpes simplex viral vector, an adenovirus associated vector, a iral vector, or any combination thereof.

{Qlfllll A "cancer" refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the hody. Unregulated cell division and growth results in the formation of malignant tumors that invade neighboring tissues and may also asize to distant parts of the body through the tic system or bloodstream, A r" or "cancer tissue" can include a tumor. Examples of s that can he treated hy the methods of the present invention e, but are not d to, cancers of the immune system including lymphoma, leukemia, myeloma, and other leukocyte malignancies. ln some embodiments, the methods of the present invention can he used to reduce the tumor size of a tumor derived from, for example, hone cancer, pancreatic , skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the ian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, multiple myeloma, l-liodgkin‘s Disease, non— Hodgkin‘s lymphoma (NHL), primary mediastinal large B cell lymphoma (PMBC), e large B cell lymphoma ), 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 yroid gland, cancer of the adrenal gland, sarcoma of soft , cancer of the a, cancflf the penis, chronic or acute leukemia, acute myeloid leukemia, chronic myeloid [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley ation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley leulremia, acute lymphohlastic 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 renal 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, Tmcell lymphoma, environmentally induced cancers including those induced by asbestos, other B cell malignancies, and ations of said cancers. In one particular embodiment, the cancer is multiple rnyeloma. The particular cancer can be responsive to chemo— or radiation y or the cancer can be refractory. A refractor cancer refers to a cancer that is not amendahle to surgical intervention and the cancer is either initially unresponsive to chemo~ or radiation therapy or the cancer becomes unresponsive over time, [elect An "anti—tumor " as used herein, refers to a biological effect that can t as a decrease in tumor volume, a decrease in the number of tumor cells, a decrease in tumor cell proliferation, a decrease in the number of metastases, an increase in l or progressionnfree survival, an increase in life expectancy, or amelioration of various physiological symptoms ated with the tumor An antiwtum or effect can also refer to the prevention of the occurrence of a tumor, cg, a vaccine.

[Clot] A "cytolrine," as used herein, refers to a non-antibody protein that is released by one cell in response to contact with a specific antigen, wherein the cytolrine interacts with a second cell to mediate a response in the second cell, A, cytolrine can be endogenously expressed by a cell or administered to a subject. Cytolrines may be released lay immune cells, ing macrophages, l3 cells, T cells, and mast cells to propagate an immune response, Cytolrines can induce s responses in the recipient cell. Cytokines can include homeostatic cytolrines, chemolrines, prominflammatory cytokines, ors, and acutenpliase ns. For e, tatic cytolrines, including interleukin (1L) 7 and lilo-l5, promote immune cell al and proliferation, and promint’lammatory cytolrines can promote an inflammatory response, Examples of homeostatic cytokines include, but are not limited to, lL—Z, lL—r-‘l, lL—S, lL—7, lL—lt’l, lL~l2p4Q, lL—lllp’it), lL—lS, and interferon (EN) gamma.

Examples of pro—inflammatory cytolrines e, but are not limited to, llfla, lL—lb, TEL-6, lL—l3, lL—l?a, tumor necrosis factor ('l‘NF)—alpha, 'l'NF—beta, fibroblast growth factor (ESP) 2, granulocyte macrophage colony—stimulating factor (GMmCSF), soluble intercellular adhesion molecule l (leAh/lul), soluhle vascular adhesion molecule l /l—l), ar endtDial growth factor (VEGF), VEGFnC, VEGF—D, and placental growth factor (PLGF).

[Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley ed set by Anne.Headley Examples of effectors include, but are not limited to, granzyme A, granzyme B, soluble Fas ligand ), and perform. Examples of acute phase—proteins include, but are not d to, C-reactive protein (CRP) and serum d A (3AA).

[Ol62l "Chemokines" are a type of ne that es cell chemotaxis, or directional movement, Zliixarnples of chemokines include, but are not limited to, [ls—8, ill—lo, eotaxin, eotaxinn3, macrophage—derived chemokine {M3363 or CCL22), monocyte chemotactic protein l (h/lCP-l or CCLZ}, MCP—4, n'iacrophage inflammatory protein lo (Mllhlu, h/llP—la), Mllhlfi (iMlP—lh), gamma~induced n l0 (lP—lO), and thymus and activation regulated chemokine (TARC or CCLlV} {OMB} A "therapeutically effective amount, H H effective dose, H H effective ," or "therapeutically effective. dosage" ofa tl’ierapeutic agent, ag, ered 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 regression evidenced by a decrease in severity of disease symptoms, an increase in frequency and duration of disease symptom— free periods, or a prevention of impairment or disability due to the disease affliction. The ability of a therapeutic agent to promote disease regression can he evaluated using a variety of methods known to the skilled practitioner, such as in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or by assaying the activity of the agent in in vitro assays. {0164] The term "lyn'iphocyte" as used herein includes natural killer (NK) cells, T cells, or B cells. NK cells are a type of xic (cell toxic) lymphocyte that represent a maj or con'iponent of the inherent 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 role in cell-niediated—immunity the antibody involvement). its T—cell receptors (TCR) differentiate themselves from other lymphocyte types. The thymus, a specialized organ ofthe immune system, is primarily responsible for the T cells tion. There are six types of T—cells, namely: Helper T—cells (cg CD4+ cells), xic Tmcells (also known as TC, cytotoxic T lymphocyte, CTL, T—killer cell, cytolytic T cell, (338+ T-cells or killer T cell), Memory Tucells (ti) stem memory TSCM cells, like naive cells, are CD45RQ—, CClUwL, CD45RA-l-, CD62L—l- (Laselectin), , (3928+ and lL~7Rd+-, but they also express large amounts of CD95, , CXCR3, and LEA—l, and show us functional utes distinve ofmemory cells); (ii) central memory TQM cells express L—selectin and the CCR7, [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley they secrete {Luz but not lFNy or le4, and (iii) effector memory TEM cells, r, do not s L~selectin or CCRV hut e or cytoltines like TFNy and llimél), Regulatory 'l'ecells (Tregs, suppressor T cells, or (illitzl-t-CilflS-t regulatory T cells), Natural Killer s (hfléT)and<3annnal}ehalficefls.B—cehs,onthernherhand,churaprhnnpalnfleinlnnnorm immunity (with antibody involvement) lt maltes antibodies and antigens and performs the role of antigennpresenting cells (APCs) and turns into memory Emcells after activation by antigen interaction. in mammals, immature B~cells are formed in the bone marrow, wl'iere its nmneisdenvmlfionr {Olefil The term "genetically engineered" or eered" refers to a method of modifying the genome of a cell, including, but not d to, deleting a coding or nonucoding reghni or a pornon.thereof orinsening a coding reghua or a porhon thereof ln sonae embodiments, the cell that is modified is a lymphocyte, eg a T cell, which can either he channed firnn a panent or a donor.’The ceh can he naodnied to express an exogenous cmmmmeumhmgupacMmmmamgmmmmmthAR)malemlmammrflCqummh is incorporated into the cell's genome. {cine} [tn’Hnnnuneresponse"refinstotheachrnrofaceh(naheinnnunesymeni(for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils) and soluble macromolecules ed lay any of these cells or the liver (including Ahs, cytokines, and ment) that results in selective tmgmng,bmdmgtd(Mnmgenrdefinmnonofi2mdkaehmnmnmifimnaveflflnmesmxw of invading pathogens, cells or tissues ed with ens, cancerous or other abnormal cefls, or,in cases of rnrnnty or pathologicalirndananunion, nornialllunaan cefls or ussues {0l67l Thetenn'innnunodnnapy"refinstothetmmnnentofasuhpmtafflhnedivnh, (a m;nsk ofconUacnng orsuflefing arecunence ofi aihseamshy ainedunlconnnimng inducing, enhancing, suppressing or otherwise modifying an immune response. es of irnnninotherapy include,ln1tare notlinnned.to,'l ceh therapies 'f ceh therapy can hichrde mhmnveTcdldmumyaumonhdhnmnglwnmnmym(Tfljimnumodmnmy,mnmcgmmceh therapy, engineered autologous cell therapy (eACT), and allegeheic 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 tl’ierapy, Examples of T cell therapies are described in US. Patent Publication Nos. 29141054228 and 2002/0006409, USDent No. 5,728,388, and international ation No.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] eadley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley {0168] The T cells of the immunotherapy can come 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, cg, 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 ed from a unit of blood collected from a subject using any number of techniques known to the skilled artisan, such as FTCQLLTM tion and/or apheresis. Additional methods lating T cells for a T cell therapy are disclosed in US. Patent Publication No.

ZOE/0287748, which is herein incorporated by references in its entirety. {0169} The term "engineered Autologous Cell Therapy,1 ’ which can be iated as "eACTTM," also known as adoptive cell transfer, is a s 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 specific tumor cells or malignancies. T cells can be ered to express, for example, chimeric antigen receptors (CAR) or T cell receptor (TCR). CAR positive (+33 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 costinnilatory domain and at least one ting domain. The costiinulatoiy domain can be derived from, ewg CD28, and the activating domain can be derived from, ag, (IDS—zeta. ln certain embodiments, the CAR is designed to have two, three, four, or more costinrulatory domains. The CAR scFy can be designed to target, for example, CDlQ, which is a transm enibrane protein expressed by cells in the B cell lineage, including all normal B cells and B cell ances, including but not d to REL, CELL, and nonnT cell ALL. in some embodiments, the CAR is engineered such that the costinnilatory domain is expressed as a separate polypeptide chain. Example CAR T cell therapies and constructs are bed in US. Patent Publication Nos.

ZOE/0287748, 2C>l4,l’022"7237, 099309, and 20l4/0050708, and these references are incorporated by reference in their entirety.

{OF/ll] A "patient" as used herein includes any human who is afflicted with a cancer (eg, a lymphoma or a leukemia). The terms "subj ect" and nt" are used interchangeably herein.

{OF/l] As used herein, the term "in mm cell" refers to any cell which is cultured ex irrivrinparticular, an in vitro cell can include a T cell.

[Annotation] Anne.Headley None set by eadley ation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley {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 lirnitati on is placed on the m number of amino acids that can comprise a protein's or peptide‘s ce.

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 , which generally are referred to in the art as proteins, of which there are many types. "Polypeptides" include, for example, ically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodinters, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others. The polypeptides e natural peptides, recombinant peptides, synthetic peptides, or a combination thereof. [0W3] in some aspects, the polypeptides and/or proteins have deletions from, additions to, and/or substitutions of one or more amino acid of n—binding protein, and in some embodiments ably no more than 8 amino acid substitutions therein. Useful polypeptide fragments may include immunologically functional fragments of antigen binding molecules, including not limited to one or more CDR regions, variahle s of a heavy and/or light chain, a portion of other portions of an antihody chain, and the like. Additionally, polypeptide fragments of activating and/or costirnulatory n'iolecules and the like are within the scope of the invention {Ol74l "Activation" or "Stimulation" as used herein, refers to a primary response induced by binding of an activating molecule with its cognate ligand, wherein the binding mediates a signal transduction event, An "activating molecule" or "stimulating molecule" refers to a le on a "l," cell, eg, the Tillie/{I333 complex that specifically binds with a cognate stimulatory ligand t on an antigen present cell. Suitable activating les are descrihed herein. {0175} A "stimulatory ligand" is a ligand that when present on an antigen presenting cell (eg, an aAPC, a dendritic cell, a B—cell, and the like) can specifically bind with a stimulatory molecule on a T cell, thereby ing a primary se by the T cell, including, but not limited to, activation, initiation of an immune response, proliferation, and the like. Stimulatory ligands include, but are not limited to, an MHC Class l molecule loaded [Annotation] eadley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley with a peptide, an anti—CD3 antibody, a snperagonist anti—CDZZ8 antibody, and a superagcni st anti-CD2 antibody. [0l76l A "costirnnlatory 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, proliferation and/or npregnlation or down regulation of key molecules. {0l77j A "costin'inlatory ligand" as used , includes a eiile on an antigen presenting cell that specifically binds a cognate co—stiinulatory molecule on a T cell. Binding of the eostirnnlatory ligand provides a signal that mediates a T cell response, including, but not limited to, proliferation, activation, differentiation, and the like. A costinnilatory ligand induces a signal that is in addition to the primary signal provided by a stimulatory in olecnle, for instance, by binding of a T cell receptor {'l‘CR)/CD3 complex with a rnaj or histocompatibility complex (MHC) molecule loaded with peptide. A comstininlatory ligand can include, but is not d to, CD7, B7~l (CD80), 87-2 (CD86), progrannned death (PD) Ll, PD—LZZ, 4—lBB ligand, 0X40 ligand, inducible costinnrlatory ligand (lCOSnL), intercellnlar on molecule (lib/AM), CD30 ligand, CD40, CD70, CDll3, human leukocyte n G (HLAuG), MHC class l related protein A (MlCA), MHC class l chain~related protein B (MlCB), herpes Virus entry mediator {l—l‘v’lfill‘vl), lymphotoxin beta receptor, 3/"l‘R6, noglobnlinulike transcript (TLT) 3, lLTd, an agonist or antibody that binds Toll ligand receptor and a ligand that specifically binds with Ell-l3. A (Jo—stimulatory ligand includes, without limitation, an antibody that specifically binds with a ctr—stimulatory molecule present on a T cell, such as, but not, limited to, CD27, CD28, 4—lBB, 0X40, CD30, CD40, PD~l, lCOS, lymphocyte ionwassociated antigen~l {LllA-l), CD2, CD7, turner necrosis factor superfarnily inernber l4 (TNFSFll-l or LIGHT), natural killer cell receptor C ), B7—l—l3, and a ligand that specifically binds with CD83 [0l’78l A nnilatory rnolecule" is a cognate binding partner on a T cell that specifically binds with a nulatory ligand, thereby mediating a inlatory response by the T cell, such as, but not limited to, eration. Costirnulatory molecules include, but are not lirnited to, CD28, CD28T, 0X40, 4—lBB/CDl37, CD2, CD3 (alpha, beta, delta, n, gamma, zeta), CD4, CD5, CD7, CD9, CDld, CD22, CD27, CD30, CD 33, CD37, CD40, CD 45, CD64, CD80, CD86, CDlSd, CDl37, CDl 54, PD—l, lCDS, lymphocyte function» associated antigen—l (Lli‘Aml (CDl la/CDl8), CD247, CD276 (B7438), LlGH’l‘ (turner nech factor aniily niernber l4; TNPSFlZl), REGZC, lg alpha {CD79a}, DAPle, Pc [Annotation] eadley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley ation] eadley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley gamma receptcr, MHC class I rnclecule, 'l'NF, 'l'NFr, integrin, signaling lymphncytic activation molecule, BTLA, Toll ligand receptor, lCAM~L Ell-B, CD8, lCAM—l, GITR, BAFFR, LlGCl-l'l', l-liVlih/l: (LlGl—l’l‘R), KlRDSZ, SLAMFZ NKpilO (:liLRFl), Niliipllfl, NKpEO, NKp46, CDlQ, CD4, CDSalpha, CDSheta, lLZR beta, lLlZR garnma, lL7R alpha, l'l‘GAfl, VLAl, CD49a, lil‘GAJl, liAél, CD491), lTGAé, Vl_,A~6, (31349f, lTGAD, CDl-ld, lTGAE, epics, irGAL, CDlmla, LEA—l, lTGAl‘t/l, CDl—lh, lTGAX, CD149, truer, c329, ITGBZ, CDlS, LEA—l, lTGB7, NEG-e23, TNFRZ, TRANCE/RANKI_., DNAhll (CD226), start/m4 @3244, 2:84), cnsa, erase (Tactile), n/n, car AM, Lye (CD229), CDléO (BYSS), PSGLl, CDlOO (SEMAfllD), CD69, SLAlvlFfi (NTB—A, Lleil), SLAM (SLAl‘t/lFl, CDlSO, lPOuii‘), BLAME. (SLAMFS), SELPLG (CDl62), LTBR, LAT, GADS, SUP—76, FAG/Clip, CDlQa, C983 ligand, er tragrnents or cnrnhinatinns tlierecf.

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 ccmparisnn n pre- and pest— measurements "Reducing" and "decreasing" include cumplete depletiens. [0180} "Treatment" or "treating‘ 9 ct‘ a subject refers to any type of intervention or process perfcrnied en, er the administratinn cf an active agent to, the subject with the chi ective of reversing, alleviating, amelicrating, inhibiting, g dcwn er preventing the unset, prngressicn, develcpntent, severity er recurrence cf a synrptcrn, ceniplicaticn er ccndition, nr mical indicia associated with a disease, In one irnent, "treatment" or "treating" es a partial reniissicn. in ancther emhcdiment, "treatment" or "treating" es a complete remissicn [OlSl] To calculate percent identity, the sequences heing ccrnpared are typically aligned in a way that gives the largest match between the sequences. fine example of a computer ni that can he used to determine percent identity is the GCG program package, which includes GAP eux 8152]., l984, Nucl. Acid Res. l2:387; Genetics Ccmputer (ercup, University cf‘lvlv’iscnnsin, Madiscn, Wis). The ccniputer algnrithrn GAP is used tc align the two pnlypeptides er pnlynucleotides for which the percent sequence ty is to be determined. The sequences are aligned for l matching at their respective amino acid or nuclectide (the "matched span", as determined by the algnrithm). hi certain embodiments, a standard comparison matrix (see, Dayhnff er al, l978, Atlas cf Protein Sequence and ure 5 345—352 for the PAM 2250 ccmpariscn matrix, Henilrnffei (15., 1992, [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Proc. Natl. Acad. Sci. USA. 89:lh‘=915~l09l9 for the BLOSUM 62 comparison matrix) is also used by the algorithm [0182} The use of the alternative (cg, "or") should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the indefinite articles "a" or "an" should be understood to refer to "one or more" of any recited or enumerated {Ol83} 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 ry skill in the art, which will depend in part on how the value or composition is measured or determined, re, the limitations of the measurement .

For example, "about" or "comprising essentially or" can mean within l or more than l rd deviation per the practice in the art. Alternatively, "about" or "comprising ially of" can mean a range of up to 10% (27.6., ilO‘ltt). For example, about 3mg can include any number n 27 mg and 3.3 mg (for ltl%). Furthermore, particularly with t to ical systems or processes, the terms can mean up to an order of magnitude or up to 5— fold of a value. When particular values or compositions are provided in the application and claims, unless ise stated, the meaning of "about" or "compri sing essentially of" should he 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, ons thereof (such as nth and one—hundredth of an integer), unless otherwise indicated. {ill 85] Various aspects of the invention are described in further detail in the following subsections. 11. Binding Malemles and Pniymtclentides Encoding the Same [0186} The present invention is directed to a polynucleotide encoding an anti—BCMA antibody or antigen binding molecule thereof which cross competes with one or more antibodies described herein (ie, one or more described in Figure l) or an antibody or antigen binding molecule thereof encoded by the polynucleotide. In one embodiment, the ion is directed to a cleotide ng an antiuBCMA antibody or antigen g molecule f which binds to the same epitope as one or more antibodies described in Figure l or an antibody or antigen binding molecule thereof encoded by the polynucleotide. In some embnnents, the pnlynucleotide s an antibody or antigen binding molecule thereof 'v) l‘x) [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley that specificaiiy binds to BCMA, n the antibody or binding niciecnie comprises a heavy chain VH cornprising: (a) a. VH CDRi coniprising, ting of, or consisting essentiaiiy of the amino acid sequence GX2X3X4X5X6X'7SY (SEQ iii) NO: 145), wherein: X2 is not present or G; X3 is not present or S, X: is E, G; i, or Y; X5 is S or T; X6 is E or S, and X7 is S or T, and/or (b) a Vii CDRZ comprising consisting of, or consisting essentiaiiy ot‘ the amino acid sequence X1IX3X4X5X5X7X3X3X10YX12X13X14X15X16X17 (SEQ ID NO: 146), wherein: X1 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 E, G, or S; X7 is not t or G or S; X8 is N, S, or '1‘, 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 E, L, or V, X16 is K or Q; and X17 is G or S, and/or (c) a; VH CURE comprising, consisting of, or consisting essentiaiiy of the ernino acid ce X1X2X3X4X5X5X7X3X9X10X11Xiin3X14X15X16XnDX19(SEQ 11) N0: M7), wherein: X1 is A or V , X2 is K or R; X3 is not present or D, G, or T, X is not present or A, D, G, P, R, or S; X3 is not present or E, F, G, L, Q, or T, X; is not present or E, M; Q, W, or Y; X7 is not present or A, E, L, or S, X8 is not present or G, P, S, or T; X9 is not present or G; P, or S, X110 is not present or i, L, P, or Y, X11 is not present or W; X12 is not present or ii; X13 is not present or E or Y; X14 is not present or i), G, H, P, S, W, or Y; X15 is A, G, L, W, or Y, X15 is not presenter A, G, i, P, or V, X17 is F, L, or M, and X19 is i, L, V, or Y. in one particniar embodiment, the poiynncieotide encodes an antibody or antigen g uie that specificsiiy binds to BCMA, wherein the antibody or antigen binding nioiecuie i ses a Vii coinpri sing: (a) a Vii CDRJ comprising, consisting of, or consisting essentialist of the amino acid sequence XiX2X3X4X5XsSYX9X1oX11 (SEQ ID NO: 263), wherein: X1 is not present or G; X2 is not t or S X3 is E, G, i, or Y; X4 is S or T, X; is F or S, X6 is S or '1‘, X9 is A, G, S, or Y; X10 is i, M, or W, and X11 is G, H, N, or S, and/or (‘0) a VB CDRZ comprising, consisting of, or consisting essentisiiy ot‘the amino acid sequence X11X3X4X3X5X7XgX9X10YX12X13X14X15X16X1'7 (SEQ 1D NQ: i463), wherein: X1 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, X5 is P, G; or S; X; is G or S; X8 is not present or N, S, or T; X9 is A, i, K, or 'E‘; X10 is N, S, or Y, .X12 is A or N, X13 is D, P, or Q, X14 is K or S, X15 is E, L, or V; X16 is X or Q, and X17 is G or S; r (c) a VB CDRB comprising, consisting of, or consisting essentiaiiy of the amino acid sequence X3X3X3XiX5X6X7XgX9X1gX11X12X13X14X13X16X17X13X19DX21 (SEQ ED NO: 264), wherein: X1 is A or V; X2 is X or R, X3 is not present or D, G, or T; X4 is not present or D, G, or i), X5 is not present or E, L, or '1", X6 is not present or P, Q, R, W, or Y; X7 is not presun E, G, L, or S; X3 is not present or A, G; P, S, or Y, X9 is not present or A, E, G, P, 'v) 'v) [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Q, or S, X0 is not present or E, L, M, PS, T, or Y, X11 is not t or D, G, H, P, S or W, X12 is not present or A, G, i, L, or Y, X13 is not present or A, G, I, V, or W, X14 is not present or H, X5 is not present or Y, X15, is not present or Y, Xi7 is not present or W or Y, X15; is not present or P or G; X19 is F, L, or M; and, X21 is i, L, V, or Y. in another ment, the poiynircieotide encodes an antibody or antigen binding molecule that speciiieaiiy binds to BCMA, wherein the antibody or antigen binding inoiecnie cornpri ses a VL eornpii sing: (a) a VL CDRJ cornpri sing, consisting of, or ting essentiaiiy of the amino acid sequence X:XZSQX5X6X7XngXioXi-iXigXBXiiXisLX-i 7 (SEQ TD NO: "148), wherein X1 is K or R, X; is A or S; X5 is G or S, X; is i, L, or V, X7 is L or S, X8 is not t or H or Y, X9 is not present or S, X10 is not present or N or S; Xn is not present or G or N; X12, is not present or N, X13 is not present or K or Y, X14 is N, R, or S, X15 is N, W, or Y, and X17 is A or D, and/or (h) a VL CDR2 sing, consisting of, or consisting essentiaiiy of the amino acid sequence XinSX4X5X6X7 (SEQ ID NO: 149), wherein Xi is i), G, L, S or W, X2 is A or G, X4 is N S, or T, X5, is L or R, X; is A, E, or Q, and X7 is S or T; and/or (c) a VL- CDR3 sing, consisting of, or consisting essentiaiiy of the amino acid sequence .X1(}X3X4X5.X6PX8T (SEQ it) NO: 150), wherein X1 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 X3 is not present or F, L, P, or W, {0189] In one particular embodiment, the poiynueieotide encodes an antibody or antigen bil’idil’ig rnoiecuie that specificeiiy binds to BCMA, n the antibody or antigen binding niniecnie comprises a VH comprising: (a) a VH CUR} comprising, consisting of, or consisting iaiiy of the amino acid sequence GX2X3X4X5X6X7SY (SEQ TD NC): 145), wherein: X: is not t or G; X13 is not present 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 CDRE comprising, consisting of, or consisting essentiaiiy ofthe amino acid sequence X11X3X4X5X5X7XgnginYXiquXJ4X15X16XJ'7 (SEQ TD NO: 146), wherein: X1 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 present or G or S; X8 is N, S, or T; X9 is A, i, X, or T, X10 is N, S, or Y; Xu is A or N, X13. is D, P, or Q, X14 is K or S; X5 is F, L, or V, X15 is K or Q, and Xi7 is G or S, and/or (c) a VH CDRB comprising, consisting of, or consisting essentiaiiy of the amino acid sequence X4X5X6X7X3X9thxi1X17}:13X14X15X16X17DX19 (SEQ TU NO i47), wherein: X1 is A or V, X; is is"; or R, X3 is not present or D, G, or T; X4. is not present or A, D, G, P, R, or S, X5 in present or E, F, G, L, Q, or T, X6 is not present or E, M, Q, W, or Y, X7 is not present [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley er A, E, E, er S; X8 is net present er G, P, S, er '1‘, X9 is net present er G, P, er S, Xio is net present or i, L, P, er Y, X i i is net present er W; X12 is net present er H, X13 is net present er E or Y, X14 is net t er I), G, H, P, S W, or Y, X15 is A, G, L, W, or Y; X16 is net present er A, G, T, P, er V, X17 is F, L, er M, and, X19 is T, L, V, or Y, and/or {(3) a VL CERT comprising, consisting ei‘, er ting essentiaiiy er" the antine acid sequence XngSQX5X6X7XgX9X10X11X12X13X14X15LX17(SEQ ID NO: 148), wherein X1 is K er R, X2 is A, or S; X5 is G er Sf, X5 is i, L, or V; X7 is L er S; X3 is net present or H er Y, X9 is net present er S, X10 is net present er N er S, Xii is net t or G er N, X12 is net present or N, X15 is net present er K or Y, X14 is N, R, er S; X15 is N, W, er Y, and X7 is A er D; and/er (e) a; VL CDRZZ comprising, consisting ef, er consisting essentiaiiy eftiie amine acid sequence XinSX4X5X6X7 (SEQ ID NO: 149), wherein X1 is D, G, E, S, er W; X2 is A, or G; X4 is N, S, er T; X5 is E er R, X6 is A, E, er Q, and; X7, is S er '1‘, anti/er (f) a VL CDR3 cernprising, censisting ef, er censisting essentiaiiy cf the amine acid sequence XiQX3X4X5X6PXgT (SEQ [D N0: TSO), wherein X1 is M er Q, X5 is F, G, H, i, R, er Y, X4 is A, F, B, E, L, er Y, X5 is A, G, H, S, T, V, er Y; X6 is F, L, T, W, er Y; and, X8 is net present er F, L, P, er W. [0190} in one particular inient, tiie peiynncieetide encedes an antibody or antigen binding rneiecnie that specificaiiy binds te BCMA, wherein the antihed‘y er antigen hintiing nie comprises a Vii comprising: (a) a Vii CERT cernpri sing, consisting of, er censi sting essentiaiiy of the amine acid sequence X:X2X5X4X5X6S'YX9X10X11 (SEQ TD N0: 263), wherein: X1 is net present er G, X2 is net t or S X5 is F, G, T, er Y; X4 is S er T, X5 is F er S, Xsis S er T; X9 is A, G, S, er Y, X10 is i, M, er W, and; X11 is G, H, N, er S, and/er (h) a Vii CDRZ comprising, consisting ef, er censisting cssentiaiiy ef the ernine acid sequence X iEX5X4X5X6X7X3X9X1n‘t’X i2X15X14X 15X15X17 (SEQ iii) N0: 146), wherein: X; is A, (3,1, S, T, er V, X; is i, N, er S, X: is G, P, S, or Y, X5 is D, G, T, or S; X5 is F, G, er S, X7 is Ger S, X3 is net present er N S, er T, X9 is A, T, K, er T, X10 is N S, er Y, X12 is A or N; X13 is D, P, er Q; X14 is K er S, X15 is F, L, er V, X16 is K er Q, and, X17 is G er S, and/er (c) e VE-i CDR3 cerhprising censisting er", er censisting essentiaiiy ef the antine acid sequence X1X2X5X4X5X5X7X8X9X10X11X12X13X14X15X16X17X13X19DX21 (SEQ TD NO: 264), wherein: X1 is A er V, X2 is K or R, X3 is net t er 1), G, er T; X4 is net present or D, G, or P; X5 is net present or F, L, er '1‘, X6 is net t er P, Q, R, W, er Y, X7 is net present er E, G, L, or S; X3, is net present er A, G, P, S, er Y, X9 is net present er A, E, G, P, Q, er S; Xig is net present er E, L, M, PS, T, er Y, X1} is net present or D, G, H, P, S er W , X12 at present er A, G, T, E, er Y, X3 is net present or A, G, i, V, er W , X14. is net present [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley er H, X15 is net present or Y; X11; is net present er Y, X17 is net present or W er Y; X18 is net present er P or G; X19 is F, L; er M; and X21 is i, E, V, or Y; end/er (d) a VL CDR l, een'ipri sing, consisting of, ‘ er censisting essentialiy et the amine acid sequence X1XZSQX5§QX7X8X9X10X11X12X13X14X15LX17{SEQ [D N0: 148), wherein X1 is K or R; X2 is A or S; X5 is G er S; X; is i, L, or Y; X7 is L or S; X5; is net present or H er Y; X9 is net present er S; X10 is net present or N er S; X11 is net t er G or N; X12 is net present er N; X13 is net present or K er Y; X14 is N R; er S; X15 is N, W, er Y; and X17 is A er D; anti/er (e) a VL CDRZ eenipri sing, eensisting of; or eensisting essentisiiy efthe antine acid sequence X1X2SX4X5X¢3X7 (SEQ ED NO: 149); wherein X1 is D, G, L, S; er W; X2 is A er (3; X4 is N, S, er '1‘; X5 is L or R; X5 is A, E, er Q; and X7 is S or T; and/er (f) a VL CDR3 sing, censisting et‘, er een si sting essentiaiiy ef the amino acid sequence 4X5X6PX8T (SEQ ID NO: 150), wherein X1 is M or Q; X3 is E, G, H, i, R, er Y; X4 is A, E, H I, L, or Y; X5 is A, G, H, S, T, V, er Y; X; is E, L, T, W, or Y; and X8 is net present or E, L, P, or W.

[OlQi] in another embodiment, the cieetide encedes an antibody or antigen binding meleeule that speciiiealiy binds te BCMA, wherein the sntibedy er antigen binding nie ceniprises a VH and s YL, wherein: (it the VH cenipri ses: (a) a, Vii-i CDRi cenipri sing, censisting of, or consisting ially of the amine acid sequenee GX2X3X4X5X6X7SY (SEQ 11) N0: 145), wherein: X2 is net present or G; X3 is net present er S; X4 is F, G, 1, er Y; X5 is S or T; X6 is F er S; and X7 is S or T; and/er (h) a VH CDRZ cernpri sing, censisting er"; er consisting essentially of the amine acid ce X1ngXiX5X6X'7X3X9X1GYX13X13X14X15X15X17 (SEQ 1D N0: l46), wherein: X1 is A, G, i, S, T, er Y; X3 is i, N er S; X4 is G, P, S, er Y; X5 is D, G, 1, er S; X6 is E, G, er S; X7 is net present or G er S; X8 is N S, er '1'; X9 is A, i, K, er '1‘; X111 is N S er Y; X12 is A er N; X1; is D, P, er Q; X14. is K er S; X15 is F, L, er V; X16 is K er Q; and, X17 is G or S; and/er (e) a VH CDE 3 cernprising, censisting ef, er ting essentieiiy ef the amine acid sequence X1X2X3X4X5X5X7X8X9X10X11X12X13X14X15X16X17DX19 (SEQ iD NO: i477), wherein: X1 is A er Y; X; is ii: er R; X3 is net present er D, (3, er T; X4 is net present er A, D, G, P, R, er S; X5 is net present er E, E, G, L, Q, er T; X6 is net present er E, M, Q, W, or Y; X7 is net present er A; E; L, er S; X; is net present er G; P, S, er T; X; is net present er 6, P, or S; X10 is net present er i; L; i), or Y; X11 is net present or W; X1; is net present or H; X13 is net present or E er Y; X14 is net present er D, G, H, P; S, W, er Y; X15 is A, G; L, W, er Y; X16, is net present er A, G, i, P, er V; X17 is E, L, er M, and X19 is i, L, V, or Y; and (ii) the YL cernprises: (a) e YIDDRi comprising, eensisting ef’, er censisting essentialiy ef’ the amine acid, sequence [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley X5X6/7X8X9XtoXuXuXt3X14X,5LX17{SEQ ID NO: 148), wherein X, is K or R, X2 is A or S, X5 is G or S; X5 is I, L, or V, X7 is L or S; X3 is not present or II or Y, X9 is not present or S; Xm is not present or N or S, Xii is not present or G or N, X12 is not present or N, X13 is not present or I: or Y, X", is N, R, or S, X15 is N, W, or Y, and, X17 is A or D, and/or (b) a VL CDRZ comprising consisting of, or consisting essentially of the amino acid sequence X,X2SX4X5X6X7 {SEQ ID NO: 149), wherein X, 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; end/or (c) a VI, (IDES sing, consisting of, or consisting essentiaiiy of the amino acid sequence X,QX3X4X5X6PX8T (SEQ TD NO: "150), wherein X, is M or Q, X3 is F, G, H, I, R, or Y, X4 is A, F TI, T, L, or Y, X5 is A, G, H, S, I V, or Y, X6 is F, L, T, W, or Y, and X3 is not present or F, L, P, or W. {0192] in another embodiment, the poiynucieotide encodes an antibody or antigen binding molecule that specificaiiy binds to BCMA, wherein the dy or antigen binding rnoiecuie comprises a VB and a VL, wherein: (i) the VH ses: (a) e VIE CDRI comprising, consisting ct‘, or consisting essentiaiiy ot‘ the amino acid sequence X,X2X3X4X5XéSYX9X10X,, (SEQ ID NO: 263), wherein: X, is not present or (3; X2 is not present or S XsiS F, G, E, or Y; X4 is S or T; Xsis E3 or S; Xsis S or "I; X9 is A, G, S or Y; Xm is I, M, or W, and X,, is G, H, N, or S, end/or (b) a VH CDRZ comprising, consisting of, or consisting iai iy ot‘ the amino acid sequence X,IX;X4X5X6X7XgX9XmYX,2X13X14X,5X16X17(SEQ II) NO: 146), wherein: X, is A, G, I, S, T, or V, X3 is I, N, or S, X4 is 6,13, S, or Y, X5 is D, G, I, or S; X6 is F, G, or S, X7 is G or S; X8 is not t or N, S, or '1‘, X9 is A, i, K, or T, X10 is N, S, or Y, X12 is A or N, X13 is T), P, or Q, X14 is X or S, X,5 is P, L, or V, X16 is K or Q, and X17 is G or S, and/or (c) a VII (DDR3 comprising, consisting of, or consisting essentiaiiy of the amino acid sequence X1X2X3X4X5X6X7X8X9X10Xi1X12X13X14X1ininerinsDXn (SEQ ID NO: 264), wherein: X is A or V, X2 is K or R, X; is not present or D, G, or T; X; is not present or I), G, or P, X5 is not present or F, L, or T, X6 is not present or P, Q, R, W, or Y, X7 is not present or E, G, L, or S, X; is not present or A, G, I’, S or Y, X9 is not t or A, I3, (3, P, Q, or S; X10 is not present or E, L, M, P, S, I, or Y, X11 is not present or L), (3, II, I’, S or W, X12 is not t or A, G, i, L, or Y, X ,3 is not present or A, G, L V, or W, X14 is not present or H, X5 is not present or Y, Xis is not present or Y, X17 is not present or W or Y; th is not present or P or G, X:,9 is P, L, or M, and X2, is I, L, V, or Y; and (ii) the VL comprises: (a) a. VL CDRi comprising, ting of, or consisting essentially of the amino acid sequence X1XQX5X6X7X3X9X10X11X12X13X14X15LX17 (SEQ 113 NO: 148), wherein X1 is K Of R, X: [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley is A or S; X5 is G 01‘ S; X6 is i, L, or V; X7 is L 01‘ S; X8 is net present or H 01‘ Y; X; is not present at S; X10 is not t or N or S; Xn is net present or G or N; X12 is net present or N; X13 is net present or K or Y; X14 is N, R, or S; X35 is N, W, er Y; and X17 is A or D; end/or (b) a VL CDRZ comprising; ccnsisting of, or cnnsi sting essentiaiiy cfthe amino acid sequence .XinSX4X5X6Xs-x (SEQ ii) NO: 149), n X1 is i), 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, er Q; and X7 is S 01* T; end/er (c) a VL CDR3 comprising; consisting of, 03" consisting essentiaiiy oi" the amino acid sequence XiQX3X4X5X6PXgT (SEQ ii) NO: 150), wherein X; is M or Q; X3 is F; G, H, i, R, 01‘ Y; X4 is A, P; H, i, L, or Y; X5 is A, G, H, S, T, V, or Y; X5, is F, L, T, W, or Y; and X3 is not t or F, is, P, or W, {0193] in one enibedinient, the antibody or antigen binding tnoiecuie, which speciiieeiiy binds to BCMA (eg, hBCMA), ’ises a Vii CDRi conipi‘ising, consisting of; er censisting essentiaiiy of the amino acid sequence GX2X3X4X5X6X7SY (SEQ Ti) NO: 145), wherein: X2 is not present or G; X3 is net presenter S; X is F, G, i, or Y; X5 is S or T; X6 is F or S; and X7 is S or i {0194} in one embndinient; the antihndy er antigen binding nioiecuie; which speciiiceiiy binds tn BCMA (eg, hBCMA), comprises a Vi—i CDRi comprising, ccnsisting of; or censisting essentieiiy nf the amine acid sequence GXz'i‘FSSY (SEQ Ti) NO: 151), wherein: X: is i? or G. {0195] in one enibedinient, the antibody or n binding tnoiecuie, which speciiieeiiy binds to BCMA (eg, hBCMA), ’ises a Vii CDRi conipi‘ising, consisting of; or consisting iaiiy of the amino acid sequence GXngXiXsXsSSY (SEQ ii) NO: 152), wherein: X2 is net present 01' G; X3 is net present 01' S; X4 is F, G, O)" 1; X5 is S or T; and X6 is F or S. {0196} in one embndinient; the antihndy er antigen binding nioiecuie; which speciiiceiiy binds tn BCMA (eg, hBCMA), comprises a Vi—i CDRi comprising, ccnsisting of; or consisting essentiaiiy of the amino acid sequence X1X2X3X4X5XigSYX9XmXu (SEQ [D Ni): 263), wherein: X is not t or G; X2 is not presenter S X3 is F, G, E, Di Y; X4 is S er T; X5 is F er S; X6is S or T; X9 is A, G, S, er Y; X10 is i, M, or W; and X11 is G, H, N; or S, in ene embodiment, the antibody 01‘ antigen binding niniecnie, which speciiicaiiy binds to BCMA (eg, , comprises a Vii CDRi cninprisino{:39 consisting pf, 01‘ censisting essentiaiiy of the amine acid sequence Xi'i‘FXiSYXngXg (SEQ ii) N0: [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley 265), wherein: X1 is F, G, or Y, X4 is S or '1‘, 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 molecule, which icaiiy binds to BCMA (cg, hBCMA), comprises a ‘l/H CD311 comprising, consisting oi’, or consisting ially of the amino acid sequence F'l‘iiiSSYth/ng (SEQ ii) 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 molecule, which specifically binds to BCMA (cg, hBCMA), comprises a VH CDRZ comprising, consisting of, or consisting essentially of the amino acid sequence X11X3X4X5X6X7XgX9XmYX-12X13X14X:sXan (SEQ ID NO: 146), wherein: X: is A, G, i, S, T, or V; X3 is l, N, or S, X4 is G, P, S, or Y, X5 is D, G, l, or S, X6 is F, G, or S, X7 is G or S; X8 is not present or N, S, or '1‘, X9 is A, i, K, or '1', X10 is N, S, or Y, X12 is A or N, X13 is D, P, or Q, X14 is K or S, X5, is F, L, or V, X16 is K or Q, and X17 is G or S.

[OZOO] in one embodiment, the antibody or antigen binding molecule, which specifically binds to BCMA (cg, hBCMA), comprises a VB CDRLZ comprising, consisting of, or consisting essentieiiy of the amino acid sequence XingXiiX5X5X7XgX9XmYAX;3X14X15X16G (SEQ ii) N0: l 53), wherein: X1 is A, G, i, T, or V, X3 is i, N or S, X4 is G, P, S, or Y, X5 is D, G, l, or S; X5 is F, G, or S, X7 is G or S, X; is N, S, or '1", X9 is A, l, K, or T, X10 is N, S, or Y, X13 is D or Q; X14 is K or S, X15 is F or V, and X16 is X or Q. in one embodiment, the antibody or antigen binding le, which specifically binds to BCMA (cg, hBCMA), comprises a Vii CDRZ comprising, ting oi’, or consisting essentiaiiy of the amino acid sequence XiliSXsXs-XerXngYYADSVKG (SEQ ED ND: 154), wherein: X1 is A, T, or V, X4 is G, S, or Y; X5 is D or S, X5 is G or S, X7 is G or S, X; is N, S, or T, and X9 is i, K, or T, [0202} in one embodiment, the antibody or antigen binding molecule, which specificaily binds to BCMA {c.gx, hBCh/liA), comprises a, Vii CDRZ comprising, consisting of, or consisting essentiaiiy of the amino acid sequence XingPXngGXngXioYAQKFQG (SEQ [D NO: 155), wherein: X, is G or 1, X3 is l or N; X5 is G or 1; X6 is F or G, X3 is S or T, X9 is A or T, and X10 is N or S. {0203} In one embodiment, the antibody or antigen binding le, which specifically binds to BCMA (cg, hBCMA), comprises three VH. CDRs and three VL CDRs, when the ‘v’H CDR3 comprising, consisting of, or ting essentially of the arnino acid ation] eadley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley sequence X1X2X5X4X5X5X7X8X9X10Xr1X12X13X14X15X16X117DX19 (SEQ 1D NO: 147) and wherein: X1, is A er V; X2 is K er R, X3 is net present er D, G, er T, X4 is net present er A, i), G, P, R, er S, X5 is net present er E, F, G, L, Q, er T, X6 is net present er E, M, Q, W, or Y, X7 is net present er A, E, L, er S; X3 is net present er G, P, S, er T; X5 is net present er G, P, or S, X10 is net present or i, L, P, er Y, X" is net present er W, X12 is net present or H, X1; is net present or E or Y, X14 is net present er L), G, H, P, S, W, er Y, X15 is A, G, L, W, er Y, X55, is net t er A, G, i, P, er V, X17 is F, L, er M, and X19 is i, L, V, er Y, in ene embodiment, the antibody er antigen binding nieieceie, which speeiticaiiy binds te BCMA (rag, i’iBCMA), comprises three Vii CDRs and three VL CDRs, wherein the 'VH CDRE ceniprising, censisting cf, er consisting iaiiy of the arnine acid sequence ARX3X4X5X6X7X3X9X10Xt13(12thX14X15X16XHDX19 (SEQ LL) NO: i576) and n: X3 is net present or D, G, er T; X is net present er A, D, G, P, R, er S, X5 is net present er E, E, G, Q, or T; X6 is net present er E, M, W, er Y, X7 is net present or A, L, er S, X; is net present er G, S er T; X9 is net presenter G or S, X10 is net present er E, L, er P, X, 1 is net present er W, X12 is net present er H; X13 is net present or E er Y; X14 is net present or G, H, P, S, W, er Y; X 5 is A, G, L, W, er Y; X16 is net present er A, G, i, P, er V; X17 is F, L, er M, and X19 is i, L, V, er Y [OZOS] in one enihedinient, the dy er antigen binding rneiecuie, which specificaiiy binds te BCMA (6.2g, , ceniprises three VH. CDRs and three VL CDRs, n the Vii CDR3 comprising, censi sting of, er cen si sting iaiiy et‘ the amino acid sequence X1X2X5X4X5X6X7XgX9XtoX1iXuXt3X14X15X15X17X18X19L3X21(SEQ ID N0: 2641) and wherein: X1 is A er V, X2 is X er R; X3 is net present er D, G, or T, X4 is net present er D, G, er P, X5 is net present er E, L, or T, X6 is net present or P, Q, R, W, or Y, X7 is net present er E, G, L, or S, X3 is net present er A, G, P, S, er Y, X9 is A, E, G, P, Q, or S, X10 is E, L, M, P, S, T, or Y, X11 is net present er D, G, LE, P, S er W, X12 is net present er A, G, E, L, er Y, X15 is net present er A, G, I, V, er W, X14 is net present er H, X15 is net present er Y, X16 is net present er Y; X17 is net t er W er Y, X15; is net present or P er G, X19 is F, L, er M, and X21 is i, L, V, or Y. {0206] in, ene embodiment, the antibody or anti gen binding molecule, which specit‘iceiiy binds to BCMA (8g, hBCMA), cernprises three VH CDRs and three VL CDRs, wi'ierein the VH CDR3 cemprising, consisting ef, er censisting essentittiiy ef the amino acid sequence ARX3X4X5X6X7X8X9X10X11X12X15X14Xt5X15X17Xt8X19DX21 (SEQ TD N0: 267), when: X3 is net present er D er T; X4 is net present or D er G, X5 is net present er F er T, [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley X6 is not present or P, R, W, or Y; X7 is not present or E, G, L, or S; X8 is not present or A, G, S, or Y; X9 is A, E, G, Q, or S; Xio is E, I..., M, P, S, or T; X11 is not present or G, H, P, S or W, X". is not present or A, G, I, L, or Y; X}; is not present or A, i, V, or W; X34 is not present or H, X15 is not present or Y; X16 is not present or Y, X17 is not present or W or Y, X3 is not present or P or G; X19 is I", L, or M; and X2; is I; L, V , or Y. {0207} In some embodiments, the poiynncieotide encodes an dy or antigen binding moiecnie that speciticaiiy binds to BCMA, wherein the antibody or antigen binding rnoiecuie comprises one, two, or aii three of any of the VB CDRs iisted above or described in FIG. IA or FIG. "EB, In some embodiments, the antibody or antigen binding moiecuie comprises the VII framework regions (I'Rs) described herein. In specific ments, the dy or antigen binding moiecuie comprises the VII FRs of an antibody set forth, in FIG.

Mr or FIG. IB (cg, one, two, three, or four of the IRS in one sequence of FIG. iA). [0208} In one embodiment, the antibody or antigen g molecule, which specificaiiy binds to BCMA , hBCMA), comprises a Vi... CDRI comprising, consisting of, or consisting essentiaiiy of the amino acid sequence X5X5X7X8X9X10XJiXiinngXmLXr-x (SEQ II) NE): 148), wherein: X} is K; or R; X; is A or S; X5 is G or S, X; is I, L, or V; X7 is L or S, X3 is not present or H or Y, X; is not present or S; X10 is not present or N or S; X i is not present or G or N; X12 is not t or N; X13 is not present or K or Y; X14 is N, R, or S, X15 is N, W, or Y, and X17 is A or I). {0209] In one ment, the antibody or antigen binding molecule, which ‘icaiiy binds to BCMA (cg, hBCMA), comprises a VL CDRI comprising, consisting of, or consisting essentiaiiy of the amino acid sequence RASQXin-iSXnghA (SEQ ID NC): 157), wherein: X5 is G or S; X}, is Ior V; X; is R or S; and X9 is N, W, or Y. {mm} In one embodiment, the antibody or antigen binding molecule, which speciiicaiiy binds to BCMA (cg, hflfiCMA), comprises a, VL CDRi comprising, consisting of, or ting essentiaiiy of the amino acid sequence XiSSQSXsLXgSXmXuXJ2X13NY’LX 17 (SEQ II) N0: 158), wherein: X1 is K or R, X6 is L or V; X8 is H or Y; X10 is N or S, X11 is G or N; X12 is not present or N, X13 is K or Y, and X17 is A or I), In one embodiment; the antibody or n binding molecule, which speciticaiiy binds to BCMA (cg, i’iBCIViA), comprises 3 Vi, CDRZ comprising{:37 consisting of, or consisting essentiaiiy of the amino acid sequence X1X28X4X5X6X7 (SEQ ID NO: 149), [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley wherein: X1 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 [OZlZl in one embodiment; the antibody or antigen binding molecule, which specifically binds to BCMA (cg, liBCMA), comprises a VL CDRZ comprising, consisting of, or consisting essentially of the amino acid sequence XiASXiRA'l‘ (SEQ ll) N0: 159), wherein: X1 is D, G, or S, and X4 is N or T. {02%} ln one embodiment, the antibody or antigen g molecule, which specifically binds to BCMA (cg, hBCMA), comprises a VL CDRZ comprising, consisting of, or consisting essentially of the amino acid sequence XiASXiXsXaX7 (SEQ ll) NO: 160), wherein: X; is l), G, or S; X4 is N, S, or T; X5 is L or R, X6 is A or Q; and X7 is S or '1". {02M} ln one embodiment, the dy or antigen binding molecule, which specifically binds to BCMA (cg, hBCMA), comprises a VL CDRZ sing, consisting of, or consisting essentially of the amino acid sequence XinSXaRXsS (SEQ [D NO: lei), wherein X1 is L or W, X2 is A or (3; X4 is N or T; and X6 is A or E. {02%} In one embodiment, the antibody or antigen binding molecule, which specifically binds to BCM A (cg, hBCMA), comprises a VL CDR3 comprising, consisting of, or consisting essentially of the amino acid ce XiQX3X4X5X613Xg'l' (SEQ ll) NO: lSO), wherein: X; is M or Q, X3 is F, G, H; l, R, or Y, X4 is A, ll, H, l, is, or ‘1’, X5 is A, G, H, S, T, V, or Y; X5 is E, L, 'l', W, or Y; and Xg is not present or F, L, P, or W. {02%} ln one embodiment, the dy or antigen binding molecule, which specifically binds to BCMA (cg, hBCMA), comprises a VL CDR3 sing, consisting of, or consisting essentially of the amino acid sequence QQXgXiXsXaPXgT (SEQ ll) NO: res), wherein: X3 is H, l; R, or Y, X4 is A, F, H, l, or Y; X5 is A, S, T, V, or Y, X6 is F, W, or Y; and X8 is not present or F, L, P, or W.

[Of/1W} in some embodiments, the polymicleotide encodes an antibody or n binding molecule that specifically binds to BCMA, wherein the antibody or antigen binding molecule comprises one, two, or all three of any of the Vt, (IDRs listed above or described in in some embodiments, the antibody or n binding molecule comprises the VL framework regions (PRs) described . hi specific embodiments, the antibody or n binding molecule ses the VL ERs of an antibody set forth in (eg, one, two, three, or four of the ERs in one row ot‘FlG, 4).

{OZES} In some embodiments, the polynucleotide encodes an antibody or n bint le that specifically binds to BCMA, wherein the antibody or antigen binding [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley molecule comprises a VB CDRl, wherein the Vii CDRl comprises an amino acid sequence selected from the group consisting of SEQ [D NO: 9—l 6, in other embodiments, the antibody or antigen binding molecule comprises a Vl-l (ii/Dill, wherein the VH CDRl ses an amino acid sequence selected from the group ting of SEQ [D NO: . in some embodiments, the antibody or antigen binding molecule comprises a Vl—l CDRZ, wherein the VH CDRZ comprises an amino acid sequence selected from the group consisting of SEQ lD NC): 25-32. in some ernbodirn ents, the antibody or antigen binding molecule. comprises a VB CDRZ, wherein the VH. CDR2 comprises an amino acid sequence selected from the group ting of SEQ ll) NO: 23 l~233 in some embodiments, the antibody or n binding molecule comprises a VB CDRZi, wherein the Vii CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 4 l 48. in some embodiments, the dy or antigen binding niolecuie comprises a VB CDRB, wherein the VB CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ll) NO: 2474354, [02W] in some embodiments, the polynucleotide encodes an antibody or antigen binding molecule that cally binds to BCMA, wherein the antibody or antigen binding molecule comprises a Vl—l (Bill, a Vii (DDR2, and Vl—l CDR3, wherein the Vii (ii/Dill Vii-l CDRZ, and VH CDR3 comprise the amino acid sequence of the VB CDRl, 7H CDRZ, and Vii CDl 3 of an antibody in Flt}. lA or FIG. iii, respectively. {0220] in some embodiments, the polynucleotide encodes an antibody or antigen binding molecule that specifically binds to BCMA, wherein the antibody or antigen binding molecule comprises a VL CDRl, wherein the VL CDRi ses an antino acid ce selected from the group consi sting of SEQ ll) NC): 8 l~88 in some embodiments, the antibody or antigen binding le comprises a Vii CDRZ, wherein the VL CDl 2 comprises an amino acid sequence selected from the group ting of SEQ [D NO: 97404. in some embodiments, the antibody or antigen binding molecule comprises a Vlu CDRZi, wherein the V1 CDR3 comprises an amino acid sequence selected from the group consisting of SEQ ll) NO: ll3-l2tl. {022i} in some embodiments, the polynucleotide encodes an antibody or antigen binding molecule that specifically binds to BCMA, wherein the dy or antigen binding molecule comprises a VL CDRi, a VL CDRZ, and 'VL CDR3, n the VL CDRi, VL CDRZ, and Vi... CDR3 comprise the amino acid sequence of the Vi, CDRl, VL CDRZ, and 'VL CDR3 of an antibody in FIG. l C, respectively.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley {0222, In some embodiments, the polynucleotide s an antibody or antigen binding molecule that specifically binds to BCMA, wherein the antibody or antigen binding molecule comprises a VB framework region 1 (liRl), wherein the Vl-l li‘Rl 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 l00% identical to an amino acid sequence selected from SEQ [D NOs: l8 and 207-2l4. ln some embodiments, the dy or antigen binding le comprises a VB FRZ, wherein the 'VH FR}: 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: l7~24 and 223—23, ln some embodiments, the antibody or antigen binding le comprises a VH [R3, 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 [D NGs: 3340 and 239—246. in some embodiments, the antibody or antigen binding le comprises a Vl-l Flint, 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 ce ed from SEQ ll) NOs: 4956 and 255262. [n some embodiments, the antibody or n binding molecule or a fragment thereof comprises a VL FRl, wherein the VL FRl 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 ii) this: 73—80. in some embodiments, the antibody or antigen binding molecule or a fragment thereof comprises a VL FRLZ, wherein the VL FR?) 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 9 %, at least about 9 %, at least about 99%, or 100% identical to an amino acid sequence selected from SEQ [D NDs: 8996. in some embodiments, the antibody or antigen binding molecule or a fragment thereof comprises a VL PR3, wherein the VL FR3 comprises an amino acid sequence at least about 750/8, at least about 80%, at least about 850/8, at least about 90%, at leastDaut 95%, at least about 96%, at least about 97%, at least about 98%, at least about [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley 99%, or 100% identical to an amino acid sequence selected from SEQ ll) NQs: lt‘iS—l l2. in some embodiments, the antibody or antigen binding m olecul e or a tragment thereofcom pri ses a Vi, Ellis wherein the VL E R4 comprises an amino acid sequence at least about 750/25, 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 ltltl% identical to an amino acid ce selected from SEQ 1D NQs: l2l~l28 {0224] in some ments, the polynucleotide s an antibody or antigen binding molecule that specifically binds to BCMA, wherein the antibody or antigen binding molecule comprises any one, two, and/or three Vl-l CDR sequences disclosed herein, in certain embodiments, the antibody or antigen binding molecule comprises a VH. (Bill a VB CDRZ, and a Vii CDR3 haying the amino acid sequence of any Vii CDRl, Vlri CDRZ, and Vii CDR3 disclosed herein, respectively. in some embodiments, the antibody or antigen binding molecule comprises any one, two, and/or three VL CDR sequences disclosed herein. in n embodiments, the antibody or antigen binding le comprises a Vic, CDRl, a Vic CDRZ, and, a VL CDR3 having the amino acid sequence of any VL CDRl, VL CDRLZ, and VL CDR3 disclosed herein? tively. in one embodiment, the antibody or antigen binding molecule comprises: (a) a Vi—l CDRl region comprising the amino acid sequence of SEQ ill) N0: 9; (b) a, Vl-l CDRZ region comprising the amino acid sequence of SEQ ll) NO: 25, (c) a VB CDR3 region cornpri sing the amino acid sequence of SEQ ID NO: 4i; (d) a Vi, €13er region cornpri sing the amino acid ce of SEQ ll) 'NQ: 8i; (e) a VL CDRZ region comprising the amino acid sequence of SEQ ID NO: 97; and (f) a VL CDR3 region comprising the amino acid sequence of SEQ ll) N0: 113. {0226} in one embodiment, the dy or antigen binding molecule comprises: (a) a Vli-l (DDRl region comprising the amino acid ce of SEQ ii) NQ: l0; (b) a VH CDRZ region comprising the amino acid sequence of SEQ 1D NO: 26; (c) a VB CDR3 region comprising the amino acid sequence of SEQ ll) N0: 42; (d) a, Vii CERl region comprising the amino acid sequence of SEQ 1D NO: 82; (e) a VL CDRZ region comprising the amino acid sequence of SEQ 1D NC): 98; and (f) a Vi, CDR3 region comprising the amino acid sequence of SEQ ll) 'NQ: l 14. {0227’ In one embodiment, the antibody or n binding molecule. con'iprisesfa) a VH CDRl region comprising the amino acid sequence of SEQ ll) NO: ll; (b) a VH CDRZ mprising the amino acid sequence of SEQ ID N0: 27; (c) a VB CDR’S region [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley comprising the amino acid sequence of SEQ ID NO: 43; (d) a VL CDRi region comprising the amino acid sequence of SEQ ID NO: 83; (e) a VI, CDRZ region comprising the amino acid sequence of SEQ ID NO: 99; and (f) a We (DDR3 region comprising the amino acid sequence of SEQ ID NO: 115.

In one embodiment, the antibody or antigen binding inolecuie comprises: (a) a VB CDRi region comprising the amino acid sequence of SEQ ID NO: 12; (b) a VII CD32 region comprising the arnino acid ce of SEQ ID N0: 28; (c) a VII CDR3 region comprising the amino acid sequence of SEQ ID NO: 44; (d) a VL CDRI region comprising the amine acid sequence of SEQ ID NO: 84; (e) a. VIJ CDRZ region comprising the amino acid ce of SEQ ID NO: lOI‘i; and (if) a VL CDRZI region comprising the amino acid sequence of SEQ ID NO: 116, In one ment, the antibody or antigen binding melecuie comprises: (a) a VII CDR1 region comprising the amino acid sequence of SEQ ID ND: 13; (b) a VB CDRLZ region comprising the antino acid sequence of SEQ ID NO: 29; (c) a VII EEK?) region comprising the amino acid sequence of SEQ ID NO: 45; (d) a VL CDRI region comprising the amino acid sequence of SEQ ID NQ: 85; (e) a VI... CDRZ region comprising the amino acid sequence of SEQ ID NO: 101; and (f) a VI CDR3 region comprising the amino acid sequence of SEQ 11) ND: 117. {0230] In one embodiment, the antibody or antigen binding melecuie comprises: (a) a VII CDRi region comprising the arnino acid sequence of SEQ ID NO: 14; (b) a VII CDRZ region comprising the amino acid sequence of SEQ ID NO: 30; (c) a VII CDR3 region comprising the amino acid sequence. of SEQ ID NO: 46; (d) a. VL CDRI region sing the amino acid sequence of SEQ ID NO: 86; (e) a, VIJ CDRZ region comprising the amino acid sequence of SEQ ID NO: l02; and (f) a VL CDR3 region comprising the amino acid ce of SEQ ID NQ: i 1 S~ [0231} In one embodiment, the antibody or antigen g molecule ses: (a) a VII CDRi region comprising the amino acid ce of SEQ iii) NO: 15; (h) a Vii CIBRZ region comprising the amino acid sequence of SEQ ID NO: 31; (c) a VB CDR3 region cornpri sing the amino acid sequence of SEQ ID NC): 47; (d) a VI, CDRi region cornpri sing the amino acid sequence of SEQ ID N0: 87; (e) a VI CDRZ region sing the amino acid sequence of SEQ ID NO: KB; and (f) a VI... (IDES region comprising the amino acid sequence of SEQ ID NO: 119.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by eadley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley {0232] In one embodiment, the dy or antigen binding moiecuie comprises: (a) a VB CDRI region comprising the amino acid sequence of SEQ ID NO: 16; (b) a VB CD‘RZ region comprising the amino acid sequence of SEQ ii) NE): 32; (c) a Vii-i CD} 3 region comprising the amino acid sequence of SEQ 1D NS: 48; (d) a VL CDEI region comprising the amino acid sequence of SEQ ii) NO: 88; (e) a, VL CDRZ region comprising the amino acid sequence of SEQ ID NO: 104; and (f) a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 120, In one embodiment, the antibody or antigen binding nioiecuie comprises: (a) a VII CDRJ region comprising the amino acid sequence of SEQ ID NO: 215; (b) a Vii CDR2 region comprising the amino acid sequence of SEQ ID NO: 231; (c) a VII CDR3 region cornpri sing the amino acid sequence of SEQ ID NO: 247; (d) a VL CDRI region sing the amino acid sequence of SEQ ID NO: 81; (e) a VL CDRZ region comprising the amino acid sequence of SEQ 1D N0: 97; and (f) a VL CDR3 region comprising the amino acid sequence of SEQ ii) N0: 113. {0234} In one embodiment; the antibody or antigen binding moiecuie comprises: (a) a Vi-I CDR] region comprising the amino acid sequence of SEQ ii) hit): 216; (h) a Vii CEBU: region comprising the amino acid sequence of SEQ ID N0: 232; (c) a VH CDRE region comprising the amino acid sequence of SEQ ii) N0: 248; (d) 3. Vi... CDRI region comprising the amino acid sequence of SEQ 11') NO: 82; (e) a VL CDRZ region comprising the amino acid sequence of SEQ 1D NC): 98; and (f) a VI, CDR3 region comprising the amino acid sequence of SEQ I1) N0: '1 14. {0235} In one ment, the antibody or antigen binding le comprises: (a) a VI-E CDR1 region comprising the amino acid sequence of SEQ ii) NO: 217; (h) a Vii CDRZ region comprising the amino acid ce of SEQ ID NO: 233; (c) a VB CDR3 region comprising the amino acid sequence of SEQ ii) NO: 249; (d) a VL CDRI region sing the amino acid sequence of SEQ 1D NO: 83; (e) a V1 CDR2 region comprising the amino acid sequence of SEQ ii) N0: 99; and (f) a VL CDE 3 region comprising the amino acid sequence of SEQ iD N0: 115. {0236] In one embodiment; the antibody or antigen binding moiecuie comprises: (a) a Vii CDRI region comprising the amino acid sequence of SEQ ID NOQIS; (b) a VB CDRZ region comprising the amino acid sequence of SEQ ii?) NO: 234; (c) a VI—I CDR3 region sing the amino acid sequence of SEQ 11') N0: 250; (d) a VL CDRI region comprising the no acid sequence of SEQ 1D N0: 84-; (e) a VL CDRZ region comprising the amino [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley acid sequence of SEQ ID NO: 109; and (if) a VL CD16 region comprising the amino acid ce. of SEQ [D NO: 116, [0237} in one embodiment? the antibody or antigen binding moiecuie comprises: (a) a VH CDRI region comprising the amino acid sequence of SEQ ID NO: 219; (b) a VH CDRZ region comprising the amino acid sequence of SEQ [D NO: 235; (c) a Vii (DDR3 region comprising the amino acid sequence of SEQ ID ND: 251; (d) a VL CDRi region comprising the amino acid sequence of SEQ 11) NO: 85; (e) a Vi, CDRZ region comprising the amino acid sequence of SEQ M) NO: 101; and (f) a VL CDR3 region comprising the amino acid sequence of SEQ 11) NO: 117. {0238] In one embodiment, the antibody or n binding ie comprises: (a) a VH CDR], region comprising the amino acid sequence of SEQ ID NO: 220; (b) a Vii CDRZ region comprising the amino acid ce of SEQ 1D NQ: 236; (c) a VH CDRE region comprising the amino acid sequence of SEQ ID NO: 252; (d) a VL CDRi region comprising the amino acid sequence of SEQ it) N0: 86; (e) a VL CDRZ region comprising the amino acid sequence of SEQ [D NO: 102; and (f) a VL CDR3 region comprising the amino acid sequence oi" SEQ 11) N0: 1 18~ 1n one embodiment, the antibody or antigen binding moiecuie ses: (a) a Vii CDR1 region comprising the amino acid sequence of SEQ 11) NO: 221; (b) a Vii CDRZ region comprising the amino acid sequence of SEQ 11) NO: 237; (c) a V131 CDR3 region comprising the amino acid sequence of SEQ 11) N0: 253; (d) a V1.1 CDRi region comprising the amino acid ce of SEQ 11) N0: 87; (e) a VL CDRZ region comprising the amino acid sequence of SEQ ID NO: 103; and (f) a VI... CDR3 region comprising the amino acid sequence of SEQ 11) N0: 119. {0240} In one embodiment, the antibody or antigen g molecule comprises: (a) a Vii CDR] region comprising the amino acid sequence of SEQ it) 'NQ: 22".; (b) a Vii CDRQL region comprising the amino acid ce of SEQ 11:) ND: 238; (c) a VB CDR3 region comprising the amino acid sequence of SEQ it) N0: 254; (d) a V1... (DDR1 region comprising the amino acid, sequence of SEQ ID NO: SS; (e) a VL CDR2 region comprising the amino acid sequence of SEQ ID NC): 104; and (if) a VL CDR3 region comprising the amino acid sequence of SEQ 11) N0: 120. {0241] In some embodiments? the antibody or antigen binding moiecuie comprises a heavy chain variabie region sequence comprising an amino acid sequence of Fifi. 1A or HG. 1B. Esme embodiments, the antibody or antigen binding moiecuie comprises a heavy chain [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley variable region sequence comprising an amino acid ce selected from the group consisting of SEQ [D NQs: 65—72. in some embodiments, the antibody or antigen bii'iding molecule comprises a light chain le region sequence comprising an amino acid sequence selected from HG. lC. in some embodiments, the antibody or antigen binding molecule comprises a light chain variable region sequence sing an amino acid sequence selected from the group consisting of SEQ ID NOs: l37~l£l-4. {0242] in some embodiments, the antibody or anti gen bii'iding molecule comprises (a) a heavy chain variable region comprising the amino acid sequence of SEQ ll) N0: 65; and (b) a light chain variable region comprising the amino acid sequence of SEQ [D NQ l37. {0243] In some embodiments, the antibody or n binding molecule comprises (a) a heavy chain variable region comprising the amino acid sequence of SEQ ll) NO: 66; and (b) alight chain variable region comprising the amino acid sequence of SEQ lD NO: l38. [0244} In some embodiments, the antibody or n binding molecule comprises (a) a heavy chain le region comprising the amino acid ce of SEQ {D NO: 67, and (b) a light chain variable region comprising the amino acid sequence of SEQ [D NO: [39. [0245} in some embodiments, the antibody or anti gen binding le comprises (a) a heavy chain variable region comprising the amino acid sequence of SEQ ll) N0: 68; and (b) a light chain variable region comprising the amino acid sequence of SEQ [D 'NQ: [40~ {0246] In some embodiments, the antibody or antigen binding molecule comprises (a) a heavy chain variable region sing the amino acid sequence of SEQ ll) NO: 69; and (b) alight chain variable region comprising the amino acid sequence of SEQ lD NO: ldl. {0247] In some embodiments, the antibody or antigen binding molecule coi'npri ses (a) a heavy chain le region comprising the amino acid sequence of SEQ {D NO: 70, and (b) a light chain variable region comprising the amino acid ce of SEQ [D NO: l42. [0248} in some embodiments, the antibody or anti gen binding molecule comprises (a) a heavy chain le region comprising the amino acid sequence of SEQ [D NO: 7l; and (b) a light chain variable region comprising the amino acid sequence of SEQ [D 'NQ: [43~ {0249} In some embodiments, the antibody or antigen binding molecule comprises (a) a heavy chain variable region comprising the amino acid sequence of SEQ ll) NO: 72; and (b) alight chain variable region comprising the amino acid sequence of SEQ lD NO: laid. {0250} In one particular embodiment, the polynucleotide of the present invention comprises a nucleotide sequence at least about 70%, at least about 75%, at least about 80%, at leDabout 85%, at least about 909/6, at least about 95%, at least about 96%, at least about [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley 97%, at least about 98%, at least about 99%, or about lOOG/li identical to a nucleotide sequence ed form the group consisting of SEQ ll) NOs: 57~64. In another embodiment, the polynucleotide ot‘ the present invention comprises a tide 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 l00% identical to a nucleotide sequence selected form the group consisting of SEQ ID NOs: l29~l36. [025M The antibody or antigen binding molecule encoded by the polypeptide of the present invention can be single chained or double chained. in some embodiments, the antibody or antigen binding molecule comprises is single chained. in certain embodiments, the antigen g le is selected from the group consisting of an scFv, an Fab, an Fab‘, an FV, an F(ab’)2, a dAb, and any combination f. in one particular embodiment, the dy or antigen binding le ses an scFV. in certain embodiments, the antibody or antigen binding molecule comprises a single chain, wherein the heavy chain variable region and the light chain variable region are connected by a linker. in some ments, the Vl-l is located at the N terminus ot" the linlter and the VL is located at the C terminus of the r. in other ernbodirnents, the VL is d at the N terminus of the linker and the Vl-l 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 l0, at least about l3, at least about 15, at least about l8, at least about 20, at least about 25, at least about , at least about 35, at least about 40, at least about 45, at least about 50, at least about 69, at least about '70, at least about 80, at least about 90, or at least about its) amino acids, in some embodiments, the linker comprises at least about l8 amino acids. lin certain embodiments, the linker ses 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 l00% identical to the amino acid sequence GS'l‘SGSGKP’GSGEGSTFKG (SEQ ill) N0: l74) or a poly~t3ly linker such as the amino acid sequence GGGGSGGGGSGGGGS (SEQ ID NO: 268). Or GGGGSGGGGSGGGGSGGGGS (SEQ ll) NO: ill l) in one ment, the linker is a Whitlow linker. in certain embodiments, the antibody or antigen binding molecule comprises a single chain, wherein the heavy chain variable region and the light chain variable region are connected by a linker, wherein the linker comprises the amino acid sequence of SEQ ll) NO: [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] eadley Unmarked set by Anne.Headley {0253] In some ments, the antibody or antigen binding nioiecuies of the present invention speeiti oaiiy bind BCMA (6.5;, hBCMA), In certain embodiments, an anti— BCMA antibody or antigen binding inoieeuie ot‘ the present, invention binds human BCh/IA with a K13 ofiess than I X It)"6 M, iess than i X it)" M, iess than i X if)"8 M, or iess than i X it)" Its/I. in one particuiar embodiment, the anti—BCMA anti body or antigen binding moiecuies binds huinan BCMA with a KB of iess than i X IO"7 M. In another ment, the anti" BCMA antibody or antigen binding tnoiecuies binds I'iuman BCMA with a K1) of iess than I X IO"8 M. In some embodiments, the anti—BCMA antibody or antigen binding moiecuies binds human BCMA with a bio of about I X it)"7 M, about 2 X IO"7 M, about 3 X 10" M, about 4 X IO" M, about 5 x 't 0‘7 M, about 6 x to" M, about 7 x in"7 M, about a x 10" M, about 9 x t o" M, about 'i X IO"8 M, about 2 X it)"8 M, about 3 X 10'8 M, about 4 X 10'8 M, about 5 X it)"5 M, about a X 10"; M, about 7 X 10" M, about 8 X 10"; M, about 9 X 10"8 M, about I X 10" M, about 2 X I0"9 M, about 3 X 10'9 M, about 4 X 10'9 M, about 5 X I0"9 M, about 6 X 10'9 M, about 7 X it)" M, about 8 X 10") M, about 9 X i0"9 M, about i X IO‘10 M, or about 5 X IO"10 M. In certain embodiments, the K1) is oaicuiated as the quotient of hon/hon, and the km and hair are ined using a monovaient antibody, such as a Fab fragment, as measured by, 9.3:, BIAcore® surface on resonance technology. In other embodiments, the K3 is calculated as the quotient of hog/km, and the has and icon are determined using a bivalent antibody, such as a Fab fragment, as measured by, 6.59:, BIAcoi‘e® surface piasmon resonance technology. {0254] In other embodiments, the MA antibody or antigen binding moieouie binds human BCMAwi‘c with a KB of iess than 'i X 10" M, iess than 3 X it)" M, iess than 5 X '9 M, iess than i, X iO'IO M, iess than 3 X it)" M, or iess than 5 X 10'" M. In other embodiments, the anti~B HI Polynucieotides ng Chimeric Antigen Receptors (tried T Cal! Receptors {0259] The present invention is aiso directed to poiynncieotides encoding chimeric antigen ors (CARs‘) or T ceii ors (TCRs) comprising an n binding nioiecuie that specificaiiy binds to BCMA described in Section E, and engineered T ceiis comprising an antigen binding moiecuie that specificaiiy binds to BCMA described in Section iii. in some embodiments, an antimBCMA CAR or TCR encoded by the poiynucieotide of the present invention comprises an n binding nioiecuie that specificaiiy binds to BCh/SA, in some embnnents, the anti—BCMA CAR or TCR encoded by the poiynucieotide further comprises [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley a costiniuiatory domain. in some embodiments, the costiinulatory domain in the anti—BCMA CAR or TCR encoded by the polynncleotide comprises an extracellular domain (ie, a hinge region), a tran smembrane domain, and/or an intracellular ling) domain. in some embodiments, the anti—BCMA CAR or TCR encoded by the cleotide further comprises a CD3 zeta activating domain, in one particular embodiment, the anti—BCh/EA CAR or Tth encoded by the polynncleotide comprises an antigen binding molecule that specifically binds BCMA (eg hBCMA), a costimula‘tory doinain comprising an, ellular domain, a transmentbtane , and an intracellular domain, and a CD3 zeta activating domain. {0260} In some embodiments, the polynncleotide of the present invention encodes a 'l‘CR, wherein the TCR comprises an antigen binding molecule that specifically binds to BCMA, and wherein the TCR further comptises a fourth complementarity determining region (CDRél). in eeitain embodiments, the cleotide encodes a TCR, wherein the TCR ses an n binding molecule that specifically binds to BCMA, and a constant " in some embodiments, the constant region is selected from a constant region ot‘igGl, lng-l, lgGE, lgGZi, lgA, igD, lgE, and lgM.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley Iii/lo Costimulatmjv [Mamie {026M in some embodiments, the polynucleotide of the present invention encodes a CAR, wherein the CAR comprises an antigen binding le that specifically hinds to BCMA (one or more antigen binding molecules in n ll), and wherein the CAR further ses a costimulatom domain. in some embodiments, the costimulatory domain is positioned between the n binding le and, an activating . In certain embodiments, the costimulatory domain can comprise an extracellular , a emhrane domain, and an ellular signaling domain. {0262} Extraceiluiar Domain: in one embodiment, the extracellular domain comprises a hinge region (eg, a spacer region). in another embodiment, the extracellular domain is from or derived troni (eg, ses) CD28, CD283: (3X40, dimlBB/CDU’Y, CD2, CD3 (alpha, beta, delta, epsilon, gamrna, zeta), CD4, CD5, CD7, CD8, CDQ, CDlo, CD22, CD27, CD30, on 33, CD37, CD40, on 45, CD64, CD80, CD86, cola-4, CDiar, , programmed death—l {PD-l), {(108, April, BAFF, lymphocyte functioneassociated antigen—l (LFAnl (CDl la/CDlS), CD247, CD276 (187$13), LIGHT (tumor necrosis factor superfamily member l4; 'llNiSi" l4), 'NKG2C, lg alpha {CD79a}, BAP—l0, ili'c gamma receptor, Ml—lC class l molecule, "llNFr, integrin, signaling lymphocytic activation molecule, B'l‘LA, 'l'oll ligand receptor, lCAh/l—l, B74313, CD8, lCAl‘s/l—l, Gilli, BAFFR, LlGl-li'l‘, H‘s/EM (LlCifl-l'i'R), KIRDSZ, SLAh/lli‘7, NKpSO {KLRFl}, 'NKpdél, NKpBO, NKpdo, CD19, CD4, CDSalpha, CDdbeta, lLER beta, lLZR gamma, lL7R alpha, ITGAL‘l, VLAl, CDdga, lTGA4, lAd, CD49D, irons, VLA—o, CD49f, l’l'GAD, CDl—ld, rroAE, CD103, rroAL, CDlwla, LFA—l, troAM, CDl—lb, lTGAX, , lTGBl, CD29, iron; core, LEA—l, lTGB7, Nicozo, 'l‘NlFRZ, 'i'RANCH/RANKL, DNAlVll ((311226), SLAl‘Viiizl ((33244, 284), CDS4, (3396 (Tactile), CEACAMl, CRT AM, Lys (CD229), CD160 (arse), PSGL‘l, CDioo (sea/ram), (31169, Sla—XMFD (NIB-A, Lleli), Sl_,Al\/l (SLAMFl, CDl SO, [PG—3), BLAh/lii (SLAB/{Flt}, SELPLG (CD162), LTBR, LAT, GADS, SLP~76, FAG/Clip, coma, CD83 ligand, or fragments or combinations thereof. The extracellular domain can be derived either from a l or from a synthetic source. {0263] in some embodiments, the extracellular domain in the costiinulatory domain is positioned n the antigen binding molecule and the transniembrane domain. In n embodiments, the extracellular domain in the costirnulatory domain is from or derived from an immunoglobulin. ln some embodiments, the extracellular domain in the costimulatory domnis selected from the hinge regions of lgGl, lgGZ, lgGS, lgG4, lgA, lgD, lgE, and [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley lgM, or a fragment thereof. In other embodiments, the extracellular domain in the costi mulatory domain is from or derived from the hinge region ofCD8 alpha. In one particular embodiment, the extracellular domain in the costimulatory domain is from or d from the hinge region of CD28. in certain embodiments, the extracellular domain in the costimulatory domain comprises a fragment of the hinge region of CD8 alpha or a fragment of the hinge region of CD28, wherein the fragment is anything less than the whole hinge region. In some embodiments, the fragment of the CDS alpha hinge region or the fragment of the CD28 hinge region comprises an amino acid sequence that excludes at least i, 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 ll, at least l2, at least 13, at least 'l4, at least 15, at least id, at least 17, at least ill, at least 19, or at least 20 amino acids at the Natern'iinus or ninus, or both, of the CD8 alpha hinge region of the CD28 hinge . [0264} In certain embodiments, the extracellular domain in the costiinulatory domain comprises an amino acid ce 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 1000/2: identical to the amino acid sequence LDNEKSNGTHHVKGKHLCPSPLFPGPSK? (SEQ ID NO: l67) or a fragment thereof. in some embodiments, the ellular domain in the costimulatory domain comprises the amino acid sequence of SEQ 1D NO: 167 or a fragment thereof. {0265] in certain embodiments, the ellular domain in the costinnilatory domain is encoded by a nucleotide 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 nucleotide ce CTTGATAATGAAAAGTCAAACGGAACAATCATT CACGTC‘rAAGGGCAAGCACC'I'CTG'I‘CCGTCACCCT’l‘G’lTCCC'l'GG’l'CCA’E‘CCAAG CCA (SEQ ID N0: tea) or a fragment thereof. In some embodiments, the extracellular domain in the costinnilatory domain is encoded by a tide sequence that ses the nucleotide sequence of SEQ ll) NO: use or a fragment thereof. {0266] in some embodiments, the CD281" domain is derived from a human CD28 hinge region. in other embodiments, the CD28T domain is derived from a rodent, inurine, or primate (rag, non—human primate) CD28 hinge region, in some embodiments, the CHEST domain is derived from a chimeric CD28 hinge region.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley {0267] In some embodiments, the extracellular domain ses some or all of a member of the imnmnoglobulin family such as lgGl, lgGZ, lgGS, lgG4, lgA, lgD, lgE, lgM, or t‘ragrn ent thereof. [0268} Tmmmembmne Domain: The eostimnlatory domain for the CAR or TCR of the invention can further eom prise a tran smemhrane domain, The transmeinbrane domain can he designed, to be timed to the extracellular domain in the costimulatory domain. lt can similarly be fused to the intracellular domain in the eostirnulatory domain. ln one embodiment, the transmemhrane domain that naturally is associated with one of the domains in a CAR is used, ln some instances, the transmernhrane domain can be selected or modified by amino acid substitution to avoid g of such domains to the transmemhrane domains of the same or ditt‘erent sur‘l‘aee membrane proteins to minimize interactions with other members of the receptor complex. The transmernbrane 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—hound or transmemhrane protein. In some ments, the transmemhrane domain is derived from CD28, DIX—40, 4—lBB/CDl37, CD2, CD3 (alpha, beta, delta, n, zeta), CD4, CDS, CD7, CDs, CDQ, Coin, CD22, CD27, CD30, CD 33, CD37, CD40, CD 45, CD64, CD80, CD86, CD134, CD137, CDlSLl, mmed Cleathwl (PD—l), lCOS, lymphocyte fimetion—associated antigen~l (LFA—l (CDl la/CDlll), CD3 gamma, CD247, CD276 (ET/$8), LlGHl‘ (tumor necrosis factor supelfamily rneniber l4, TNFSF14), NKGZC, lg alpha (CD79a), DARW, Fe gamma receptor, MHC class l molecule, 'l'NFr, integrin, signaling lyniphocytie activation le, BTLA, Toll ligand; receptor, lCAM—l, Ell-B, Cos, lCAM~l, one, BAFFR, LlGl-lT, r—rvnM (LlGl-lTR}, Kranszz, SLAB/H97, NKp80 {KLRFli}, 'NKpllll, NKp30, NKp46, CDl9, CD4, CDgalpha, CD8beta, lL2R beta, lL2R gamma, lL7R alpha, ITGA4, VLAl, CDzl-Qa, ‘l, 1A4, CD49D, lTGAD, VEDA—6, CD49f, l'l‘iCiAD, CDl~ld, l'l'GAE, , lTGAL, CDl~la, LEA—l, CREAM, CDl—lb, lTGAX, , rronr, CD29, rron2, CD18, LEA—l, rror37, memo, TINTR2, TRANCE/RANKL, DNAi‘t/ll (CD226), 'él (CD244, 2D4), CD84, CDQD ('l‘actile), CEACAMi, CRT AM, Lye (CD229), CD160 (BYSS),PSGL1, Come (Shaina-D), CD69, Sl_,Al‘vll76 (NTB-A, l_,yl08), SLAM (SLAMFl, CDlSO, IFS—3), BLAlVlE (SI...Ahll78), SELPLG (CD162), DEER, LAT, GADS, SLPJD, FAG/Clip, CDlQa, CD83 ligand, or a fragment thereof, {0269] Optionally, a short ollgo or polypeptide linker, preferably n 2 and; lt‘i amirDeids in length may form the e between the transmembrane domain and the [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley cytoplasmic signaling domain of the CAR. A glycinewserine doublet provides a particularly suitable linker, [0270} in one embodiment, the transmembi‘ane domain in the CAR of the invention comprises the CD8 transmembrane domain. In one embodiment, the CD8 embrane dorn ain comprises the transmembrane portion of the nucleic acid sequence of GCTGCAGCATTGAGCAACTCAATAATGTATTTTAGTCACTTTGTACCAGTGTTCT TGCCGGCTAAGCCTACTACCACACCCGCTCCACGGCCACCTACCCCAGCTCCTA CCA’I‘CGC"ETCACAGCC'l‘C'l‘G’lTCCCTGCGCCCAGAGGC'I"l'GCCGACCGGCCGCAG GGGGCGCTGTTCATACCAGAGGACTGGATTTCGCCTGCGATATCTATATCTGGG CACCCCTGGCCGGAACC'l‘GCGGCG'l‘AC'l'CC'l'GCTG’l'CCC'l‘GG'l‘CATCACGC'l'C'l' ATTGTAATCACAGGAAC (SEQ ll) NO: 269). In one embodiment, the CBS transmernbrane domain comprises the nucleic acid sequence that encodes the transmembrane amino acid sequence contained within Slh/lYli'Sl-lEVPViilPAKPTTTPA PEPPTPAPTIASQP LSLRPEACRPAAGGAVHTRGLDEACDlYl‘WAPLAGTCGVLLLSLVITLYCINWN (SEQ to no: 270), [0277i] in another embodiment, the transmembrane domain in the ulating dorn ain is a {1328 transmernbrane domain~ in some embodiments, the transmembrane domain ses 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 lC’OO/b identical to the amino acid sequence FWVLvvvoovLACY SLLVTVAF:E :1: E‘WV (SEQ ll) NO: l69). lin some embodiments, the transmernbrane domain comprises the amino acid sequence of SEQ lD NO: 169. {0272} In some embodiments, the transmembrane domain is encoded by a nucleotide sequence at least about 75%, at least about 89%, 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 nucleotide sequence TTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCA CCGTGGC'l"l"l"llA'l'AATC’ITC'l‘GGG'l'T (SEQ ll) NO: 168:). in some ments, the transmemhrane domain is encoded by a nucleotide sequence that comprises the nucleotide sequence of SEQ ll) N0: ins, [0273éed T cells of the ion can provide signaling to an activating domain, which tracelluier (signaling) Domain: The intracellular (signaling) domain of the [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley activates at least one of the normal effector functions of the immune cell. Effector function of a T cell, for example, can be cytolytic activity or helper ty including the secretion of cytolrines. [0274} In certain embodiments, suitable intracellular signaling domain e (to, comprise), but are not limited to CD28, Cl 283?, DX—zltl, 4-lBB/CDl 37, CDZ, CD7, CDZ7, CD30, CD40, programmed deathnl (PD~ l), inducible T cell costimulator (ICOS), lymphocyte function—associated antigen~l (LEA—l, CDl~la/CDl8), CD3 Gamma, CD3 delta, CD3 epsilon, CD247, 5 (B7—H3), ‘, ("l‘NFSFl4), NKGZC, lg, alpha (CD79a), one—re, Fc gamma receptor, Nil-{C class l molecule, TNF receptor proteins, an lrnmunoglobulin protein, cytoltine receptor, ins, ing cytic Activation Molecules (SLAM ns), activating NK cell receptors, BT1A, a Toll ligand receptor, lCAM~l, Bil-13, CD8, lCAlvl— l, Gl'l‘R, BAFFR, LIGHT, /l {LiGH'l‘R}, KHKDSZ, SLAl‘ylFK 'NKpSO (KLRFl), 19141044, NKp30, NKpi-lo, CDlQ, CD4, CDSalpha, CDBbeta, lL—ZR beta, Ban/"2R gamma, IL" 7R alpha, l’lKEAL’l, VLAl , (Illil9a, flail/34, 1A4, CDll9D, rrtztae, VLA—o, {EDIE-9f, {Kl/3d), CDl ld, lTGAE, cores, lTGAL, CDl la, LFA—l, lTGAM, CDl lb, lTGAX, our lc, lTGBl, (313329, i'l‘GBZ, CDl 8, l, li'l‘GB’i, NKGZD, 'llNli'RZ, CH,"RANK1_,, DNANll (CD226), SLAh/lF4 (CD244, 284), CD84, CD96 (Tactile), CEACAMl, CRT Al‘s/l, L379 (CD229), CDl‘oO (BYSS), PSGCLl, CDlOO (Slfil‘y/lAle), CD69, SLAh/lili'o (N'l'BwA, LleS), SLAh/l (SLAMFl, CDlSO, lPO~3), BLAh/lE (SLAMFS), SELPLG ((3le2}, LTBR, LAT, GADS, SLP—"x’o, FAG/Clap, CDl9a, a ligand that specifically binds with CD83, or any combination thereof. {0275] An example of a nucleotide sequence encoding the ellular signaling domain is set forth in SEQ ED ND. l70: AGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTC CACGCCGCCCTGGCCCCACAAGGAAAtfiiz-XC'l'ACCAGCC'l"l"ACGCACCACC TAGAGATTTCGCTGCCTATCGGAGC ln one embodiment, the cleotide encoding an intracellular signaling domain within a costimulatoiy domain comprises a nucleotide sequence at least about 60%, at least about 65943, 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 l 00% identical to the nucleotide sequence. of SEQ ID N0: l70.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley {0277] An example of an intracellular signaling domain is set forth in SEQ ll) NO.

RSKRSKidd-{SDYl‘leMITPER?(Ii’iP'l'RKl-l‘rQPYAPPRDFAAYRS. [0278} In one particular embodiment, the intracellular signaling donrain Within a ulatory 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 lOOll/o identical to the amino acid sequence of SEQ ll) NO: l7l. {0279} The ellular signaling sequences within the CAR of the inventi on can be linked to each other or to an activating domain in a random or specified order. ()ptionally, a short oligo~ or polypeptide linker, preferably between 2 and it) arnino acids in length may form the linkage. A glycine—serine doublet provides a particularly suitable linker. [0280} It will further be iated that where desired, the iulatory regions described herein can he expressed in a separate chain from the antigen g molecule (cg, scFv) and, activating deniains, in somcalled "trans" configuration.

[HE Activating Domain [028M in some embodiments, ellular domains for use in the engineered T cell of the ion include cytoplasmic sequences of the T cell receptor (TCR) and co—receptors that act in concert to initiate signal tr‘ai'isduction following antigen/receptor engagement, as well as any derivative or variant of these sequences and any synthetic sequence that has the sarne functional capability, CD3 is an element of the T cell receptor on native T cells, and has been shown to be an important ellular activating element in CARs. in one embodiment, the activating domain is CD3, eg, CD3 zeta, the nucleotide sequence of which is set forth in SEQ ll) NO l72: AGGG'l‘GAACl'l"l'"l"'l‘CCAGA'l‘C'l‘GCAGA'l‘GCACCAGCG'l‘ATCAGCAGGGCC AGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGAGTATG ACG’I"l7'l"l‘GGACAAGCGCAGAGGACGGGACCC'l'(LAGA'I'GGG'I'GGCAAACC AAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGA TAAGATGGC'l'GAAGC(fil'l‘A'l‘TCTGAAATAGGCA'l‘GAAAGGAGAGCGGAG AAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACTGCTACG AAGGA'l‘AC'll'l‘A'llClz-XCGC'E‘CTCCACA'l'GCAAGC(filtj’l‘GCCACCTA(36, [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley {0282] in some embodiments, the polynucleotide encoding an activating domain comprises a tide 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 1000/0: identical to the nucleotide sequence of SEQ [D NO}: NZ {0283} The corresponding amino acid of intracellular CBS. zeta is set forth in SEQ ID NO. l73: RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEh/lGGKPR RKNPQEGLYNElQK Dlib/lAEAYSElGMKGERRRGKGHDGLYQGLS"i‘A'l'KD"llYDALHl‘w/lQALPl’R. {0284] in some ments, the activating domain comprises an amino acid sequence at least about 70%, at least about 75%, at least about 80%, at least about 850/8, 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 1000/0: identical to the amino acid sequence of SEQ ll) NO: [0285} Additionally, in certain embodiments the activating domain comprises an amino acid sequence at least about 70%, at least about 750/8, 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 l00% identical to the amino acid sequence of a CD3 zeta variant as set forth in SEQ ll) NO: 412: SADAPAYKQGtQNQLYNELNLGRREEYDVLDKlUiGRDPEb/EGGKPRR LYNElQKDKhiAEAYSl3lGMKGERRRGKGl-lDGLXQGLSTATKDTY DA l_,l-ll\/lQALPPR 111’. C. Leader Peptide {0286} in some embodiments, the polynucleotide of the t invention encodes a CAR or a "l,"CR, wherein the CAR or the 'l'CR comprises an antigen binding le that specifically binds to BCMA, and wherein the CAR or the TCR further comprises a leader peptide (al so referred to herein as a l peptide"), ln 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 l000/ia identical to the amino acid sequence MAD"TALl_,l_.PLALLLl-lAAR? (SEQ ll) NO: l65), in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ll) NO: l65. in some embodiments, the [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley ation] eadley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley leader peptide is encoded by a nucleotide 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 950/25, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to SEQ ID NO: l6I-t. in some embodiments, the polynucleotide of the present invention s a CAR, wherein the CAR ses a leader peptide (P), an antigen binding molecule (B), a hinge domain (H), a. transm enibrane domain (T), a nulatory region (C), and an activation domain (A), wherein the CAR is configured according to the following: P—BwHu'lluC—A. In some embodiments, the antigen binding molecule comprises a VH and a VL, wherein the C AR is configured according to the following: PmVl'lmVLuHm'l‘mC—A or P—VL—VH—H—"l‘—CuA.

In some embodiments, the VB and the VL are connected by a linker (L), wherein the anti— BCMA CAR is configured according to the following, from N—terininus to inus: P— VHmLmVL—HmT—CMA or PnVHnLnVL—HnTnCnA. in some embodiments, the cleotide of the present 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 ofthe present invention encodes a CAR, wherein the CAR comprises an amino acid sequence selected from Table 2.

Table 2. Example CAR Sequences Anti— Nucleotide Sequence Amino Acid Sequence BCMA CAR 3:! S ,__ GCTGCC W ' MAQPVTALLLPlALLLHAA 21495CAR a" ‘T'c ’ ‘d SCA '"e 3T " LVQLLESC LVQPGGS PX? r , near GCCTGGG CTCC : 5* cans GF'l ES .3 YAMSW aCCTCTGGATTCACCTTx,GCAGCTATGCCnTGAGC TGiGTCCGCCAGGCTCCAGlGAAGGGGCTGGAGT‘CGiCralmq-‘(wv. Va. v, .

GCTATTAG"GG"PGTGGTGGTAGCACATACTKCGCAGACTCC GTGAACGGCCGGT"‘ACCATCWCCAGAGACAATTCC5‘~"" TATCTGVHAATGAAC,GCCTGAGPGCCGAGGACACG A CVSSG GCGG TACTACTGClCAAGZ‘CCGAGA.GGGA:CCGTATTC LJTKGEIV QQPATLSLS GAGA ATGGCC"CAG‘GTKCAATGGTCACCGTCTCCTCAGGG ‘ERATLSCRASQSVSRYL TCTACATCC CTCCGGGAAGCCCGGAAGTGGCGAAGGTAGT AWYQQKPGQAPRLLIYDAS ACAAAGGGCQAAA"GTCTTGACACAG"CTCCACCCACCCTG NRATGIPARFSGSGSGTDF V,WTTGT,T\K. m- xGAGCCACCZTCTCCTGCAGGGCC JSL QQ . V. TAGCAGUEACTTAGCCTGGTACCAACAGAAA RISWPFT :GGTKVEIKRA iiTGcCCAGGVT‘CCTGGC"CCTCA’"TATGKTwCATCCAAC AALDNEKSNGTIIHVKGKH GGCCKCK ‘CATCCCAGCCAGGT’TAGT'SCAGTGGGTNH LCPSPLF- ' GACAGACT CACCL’VAGCAG ifAGAGCCWGAA VGGVLACYSLLVTVAFITF " TTTTGCAGTCTATTACTGTCAGCAGAGAATCTCCTGGCCT WVRSKRS LLHSDYMNMTP [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] eadley Unmarked set by Anne.Headley C'TT'TTGGCCGATIJCGACCA TTI3G RmPGP RIXHYQI AP RDF GC‘TGCCCTTCATATTTT'I3ATA.AAG'T C7 F AC'GGAATC’3 F F .1" CA’ "TI’3AC ST -T T TIJKJGC1¢LAT33A CZGGGATCI’3 3’'GAGA'T GI3GFI" T..ATTNRTCTGGCAAACCAAGACG"37» _.A.AAACCCC"TN CAGGT TGG F'TC"FL‘CFTAT'FI'FAFL‘CLAG’3T‘GCAIAAT3I’3ATTAA’"F 1 (3 r; T G1 AGCCTTL TTCTGTI-I]ATAGC TATGAAAC 31- GAGCGG1>G1ITTTTC"F' GGAAAAG’ 3GCACCACGGTTCTACCAGG1-\.CTCALTCITCTG'C'T TATI’3.I3AATGGA’TATI’3TT1IT'FL‘GACGC" .T‘CCATCATAAC"’3 3’'GC‘CA CC"-GGTAA EFS" ATT'CIJ CZATC‘TCC"CC . CZ'1" 'TG3’F CZCGFT'TGGCAT'FLTG 177 -T"LPVT'ALLLPFIJATLF I--‘ \J CO 2 l 4 9 5 CAR CT 3CFL‘C3C.ACCv GC3AAAT'T F'TG"FL‘FL‘GACATCAC’3FL‘C.’T I<°"l"LT'"3 PLATES], LXI-I CCAGCCACC.L..TCTCTTTG . 7C3C GAAAGAGCCACCCTC RATE-SCRASCSVSRYIF‘ CC? '0CrAAGGUCCC’C'A pm A"1 TL: .L ‘3! .U' TGTT T1-\GCAG 3T1ATCTTAGCCTT GG 3r1 EWVLV1' ACGCT‘GTAT CFL‘GCTATAAT C3AAC,T T’3 3CFL‘C3AGAG’3CCGAGCrAI’3 TCG ‘V’GGVFIJAC' SLLVT‘VAFI T F C3CGGT-CzTT CTACT-C3CGC1F‘«AG1’-\CJC T'GAC: ’-.GC3CGF WVRS KRS RLLHSDYMNTP —A I3.1’.T1"-\.TGGGGTCATG' 3 TTAIJ1-\.1\TTGCTCITI CG lrfllfil"! .\/\4. TR/{NYC)PYAPPPTIF GI’3’F C‘CZC'T’TGATTATA '1‘ GAATATATGTCAAAJGGAACAATJAI«m n7 A.AY RS RFC/TESTI SATDZ—ITPAY:c’3 GT'I3ATFA A 3AC‘CF‘CT'G"C"GF"3ATCCCFI1‘GF"'TI’3CC _GC‘1N’QLYNELNFFGIPEE' ’3’I3FAri.CCAA "I FL‘CT' mam.LJ'JIJ G'FL‘FL‘GGT'C FL‘CIT3C-T' F'GAGF ‘C ‘V‘LI‘I ‘F‘ 3 <1)"" IGGKPRRFK CT JGCTTG . . 7LTTFTTCTCGTF1LCC‘GL'JGTTTTAIAATC NPQE-..ITY\IIFIIGKDT\ILI1A«IFAY TTCTGGGTF TCCIT 3CCGC'".3CTI3C1"-\TTATGCGA'. TRRRCI/G’IIJGIY FIAC 'TGATA 'TGACT'C G CGCCC"1‘GGCCI’3CF .CZAAGGAAA. FCLT'YDATF HM’QATL CZACFTATCCAGC"1C’"T ’TATI’3I "CI’3’FF GAGA"'T"'CCCFI‘GCCT'1LI CGGA-JCT/ITC'GC3FL‘G1YATG . .’ .LCZFL‘CC1Y..T/ITTL3'CACCATG T'G TATCATGCA JGGCCAGA 'TATAATCGAAGCTCAACLCTG dkjidiAhw(TEETH!"CA C GCAGGGATATGATG". TTTGGACATAG 'J'JZ‘ CGGGAGC‘CF‘GATGAFI‘G G'TGI3CAAACCATAGACCAAATAAA1"CCC CAGGAGGTCT T F"AFL‘AAT' L‘ GCTATGAAGC3ATTAT TGAFF C3GC.FT -GCC’FL‘AT LATATG , J'CT'AFL‘ G1’-\A.AGGAC3AG CL.GA1AGG GG '.ICCAGJCTTTCTACCATG JGAGTIJAGCAC '3CT 3' ‘T TAT GACCJ'C'TCTCCATC,’LTTGCAAGCCCTGCCA PC". -"TTGCGTT’3’F3""CC'TATT—ITCI'GCF"CT'I3CF'"CT 3CI’3I3TFI3‘GGCATT" FG 179 ILA ALLLPLALLLHATA 2 l4 97CALR "FF‘CCT'CCACGCCCATCGCC. C. 3’3TGG"FF"GCACCTGG"'FF"GGZ‘G'T 3T [a~VgLVE-SGGVVQPGRS I-LXL GG JGGATGC'CGFL‘GG CC'AGCC 'GG 3' «GGTCCCTGAGACTCT ,"C LTD..TT 3 CAASGFTFSS\GIVIHW TI3TGC"—G'C 3Tr:CT 3G7‘ITTG1TIJCTTCAGTAJCTATGGCITT'GCAC 7‘r‘-\ACETEIJI-TITV 115~~ CTFTI/ TV 1")G [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley AAGGGCCGATTGACCATCLC"‘ N"‘ 3-1 m ACGCTGTATCTGCAAATGAACAGCCTGAG1CCCCAGGACACG G'7:1‘3’1 LV‘I "7.3S13S’I‘SGS13’KP CGGTGTA"TACTCGGCCAGAGACGGTACTWAT"TAGCTGGT GEG’7’7 777’7FI7.73S CTCTCCTACTTCC1T.A1GGGG3A.ACCTACCTTGCTCAC" LI"TPGEPA... ISC' SSGSL GTCTCCT3ACGGTLTAC TCCGG: CCCCCAAGCCCGCAAGT GYIN'L’I1DWY.3Q1 CT"CTCG"CACCGTGCTTTT"TAATCTT"TGCTTAG"TCJ QKDKIV ‘.T_'1AYS E7IC’31VV1KGERR FFAACAAGCCGJCTGCTCCATA131TTACA -3AATATGACT RGKGHDGI1..LQGISI'A’IKQI‘ LCA.GCCG CCTGGCC CACA GJAAAC1C1A3C1C: TTAC V3111.}I7\/1)171I3PPR GCACCACG’ACAGATTTCGCTCCC’.TCGCAGCA.C3GGTGAAG ATCTGCAGATGCACCA 3CGTA"CAGCAGGGCCAG AACCAAGT"TAT .CGAGCTCAAC"TCKQCGCACCCAAGAG GTT11GGACAAGCGCAG1GUACGGGAJCCTG1CAT GGT3GLAAACCAACCAA’AAACCCCZAAGCCTCTCTAT AATGAGC CCAGAAGGATAAGA‘GCCTG -GCCTATTCTGAA ATA 3GCATGAAAGC3AGAGCG GGGAAAAGGCA.CGAC GGTTTCTACCLGGGACT’AGC"CTCCT""AGCAT-CTTAT 1’7/7..C"7 "77’7'77’/ )7\/_|. \,. .31.0711. 1301117118 lCCTGCCACC.Z‘1GC7-1’7117-11/71 PC— 3133211737 ..CC JGTAACTG ZTCI 3. . , 7GL3CG’ 2 I 4 9 7 CAP. TGCIL CCCCCCIL’I‘AII‘C 'IC’I'CCCTGCCCG"CACC’7C"3 pan G"r"r~u1V\/~1rl GAGCAmC«EGO/1T GH- KI7'1’3 7’13'L73AT’ ’3 ’1'7171;3’L3T’3 . 12‘1i3c (711-313(7131113 GVFD 7GATC’71I7. 7TG13G. CC D1777T13KILJR‘V’E3317‘ .GGTT1317-1G'1.GGL’73AG’.7GL337 .1 G. GI3L3I_ PI1"1FGGL3T. 3CAC3AG’ 71’31’3AGGC'". 17711313141" G71 TGGGG’I‘ ’17 "A TSGSGKPGSGEGSTK ‘17'AC’ GL3. "_7L3.’.3G GGACTCGG CCTCCC'I‘C’I‘C777"AC’7’7‘17"I'GGCGGA 11 Irv"s GGGNo 1‘611 GG3 1CCAAGGTTGAGA'IC11171171L3713GGGGI‘C’IA7A 'CCGGCT 3C GG’ 37171AG'L313CGG'7L1171GT GGCG’371371G 13’717-1. ‘7‘371C171AAGGGG' 3‘171G'L3TG GAGTGG" GG‘.7-‘1.G CTGGGG’ 37171G'L3C C3’7GGTCCAGCCTGGGAGG KYYAD. .

. . ’I‘CC "171317113 C777C’17’7’7"C"77(317113131773T C717GG1L1'777'CAGCi‘ITCAGI N’I' 1YLQMA SLRA ‘ AG(7’17A‘17"3GCA'T7G,1A"7’I‘G ‘_7CC1’3CCAGGC’I7 ’.3C1—\G’7’7FLAG-(31313 CAVDGT "LC-(3.7 7 L737TGG11113'1 S’GGTGGCA 3" 17171- 1‘CG ’Z‘1TGA'I'GG171171L31AATAAA GT Ifx’TVS SARAI.D IEKF.‘.NG T211377 mGCAGACTCC 37’7GAAGGG' C171CC171’I713TCCZ‘1G171 ’7 .IHVKGKHLCPSPLFPG’P 1 7’7?CCAAG1-11I71C3L1C‘L3CI7’7’77‘1TC‘113777.17-‘I‘G71ACIAC3CCTG S111PFWV.177‘1/7‘1’7/7GG71/LILC71'7SI3 ACCACAG’7GC’7’7"C’LAC’L1C"13CGCC17‘GA13ACG 7’17 L713IVAIIIEH"‘SKRSRLL 7‘ ’31’3"G’7'T7(7’17’7"'G G’I‘AC’I‘I‘CGA17371717173171.3-’7 1’36 GGAGA HSDY11NM"17717 RPGP’I‘RKHY GGTA‘" TCACC E''1. (7317113717’7 ; 7CT 1‘3T’L3AGCCGCTL73C .. QP\APPRIMAZ7RSR711’K1313 37117 ..GT 317.171.7‘1CCL3NACI17‘17CATI7C17-1CGTGMGGC‘C71171GCAC RSADPP371YQQG@710I3YN...I CT’ 1'G’71‘C3'371CL’313T’7G1.77CCCT7 3G"'C 3‘171’171313171GCCATTC NLGRPEEYDVIDKRRGRDP "77’7GC'77’7""‘C3717CG'17A13’.GGG’71’31’7AG I‘CCIC’7’7’I‘I3'71 ‘71717‘ACTC" EMGGKIRRKNPQEGLYNE7‘ (737711311317.’.31’3’‘"ACCL’3‘17'1’37"(73'1737’17‘17’7’171AL'I'AA’I‘C.’ 7" 7'1’3 71731717131» QKD 1V1 E71L‘LYSL7'17’77‘IK’7EPP 1111.1111/7.G"L737L7371;CCTC' "753713.31’717-1G JGAT’I‘A(3171.761712‘1A’ .7 .~G'KGIIDGLY’QC‘ISTA'I'KDT C1311 GCCGC‘CC’I‘GCCCC‘CACZ71GG71AACIACTZ‘1CCAG17 1f 1.. ALI-1111121711 P P R G13IL CAC TAG]GP1TT’7CGC. 'GC' JTAT13GG17-1L3'3‘171L’313G’ '717’1"’I"I‘CZC‘C7L71G17'171’3’‘GCAG17 'IGCAC’AGCG"A" CAGC111’313GC , CCAAC’KG‘I‘ .TACACGAGC’I‘CARP(3‘17"713131—1CGf71L‘L1’7-1’3G1—1A’A37 ATGZXCGGT"TT SGACAAGCC‘GAGAGGACCGLJAGCC1 617117331 TG [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley ionNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley ‘AA"GATl I3GC‘71 7AAGC C‘.‘AT"T C'T G 7C’ a {L rr. 'xI1 (a1 .‘ CAGA 7 1cTGAAAGGGAGCGCGA LGAAGGGGAAAAAGGGCAI:GAL3 ,I GTAL .CCAGL3G7-L.CTL'3AGC7ILC3T GCTAC G7—LAG GATACTTAT 'TCTCCACATG LAAGC CCLT"GCCAC I3TAG 3'T 1 A». {-3 p . 3 \3 x, 3GT7LAL .‘3'TL3Cr CT. G'C'TGCTGCC, 3r TALL A PLALL L-HAAL ACGCCG GC3CI3GC7GGTL GCAGETG 3 iTGCALC PPQV7QLVQSGLLE‘I/KKPGAS GGC GAGGIGALA’AAGLLL'GG GLL LL . "mm." L ,mer ,LCHC 3I‘GAAr34 ~r'J‘J YK37SCKAS GYTE'TSYYI‘VIHIA’II ‘I'CJCAAGGCAA ‘I'CTGGAT7‘ CACCTTCAIGCAGC"TACTAL'I'ATGC"I iRQAA\, AGOGLL‘I IGIINPG 3 TC3-G'G'TL'3CG7—\CL3AG' GCCCCTG SACAAG G. GGATGGGA GS SYAQKEQG VTMTRDT .AAAT‘LCAACCCT GGTGGT G 3'77‘LC3C7-\CAAG'CTACG3ALCAL3AAG STST‘CKI‘IIEIIL’A'SLSTLu )TAV . '. CCAGGGCAGPLGTCACCL. . . ACCAGG 33LLCAC"CLC3LLCL31LGC YYCAPEST’ITPMD‘ WGQGTTV :I-I-I r34 I-I-I‘r I C IAC-".TGGAGGTL"’3 AAGCAGCCT‘AG3A'T’7T‘CAGG3AL3ALG 'TVSSGSTSGSG LPGS‘GEG 7"7ACT’7’7GCCACAIG GAC3T‘ ‘G L3 AT‘GGACGTA ‘I' KG E TVMTI3 S PAT L SAL/7S P G AALL3L3L3AAAAL CTG7 AC3 lGTCTCCTCAL .G'L'3L3TCT7LC3'A .IA‘PATIISCRA.Qvac?L33L "33.13,?k/LJ \. _rAAG l‘l'CGG,-\7\LG‘7G'L'3L3CAA-L3GTA YQ’DKPGQAPLIT. YG7\ TATAZ‘L'JT'LL G7 TGACGCAGTC".7CIL’37‘LGCC7ICC3'CTGr 7\T3' PARFSGSGSGT ILLAUGCAT 7 7 .GAGCCACCC CTIL3’3 ’7'3‘I3CAG 3CCA3 "II S‘ ‘7QSEDI‘7AVYCQQYA ‘ GTTAGC L GCAACT‘T’TA 3’ 7A LCCAGCAGAAAAC7TGGC AYPT 77’7G GT‘KV AIKRAAAL GATES A». .NmL)‘\3_L"7\, CLLJ‘LLJG1 [‘1 mm—< r C'3. L, . .7’3'TAT CCT GCAT CGACCAGITL3L3CL. T‘ IEKSNG.’ "TGGTATCGL3 CAL A». .—A —A ' ."L)\3 ‘x, L . .7C7‘LGTGIL3L3AALGTL'3LGTCT ACA SPLFPGPSKPFVI7‘7L‘3TVA/7C3G CAG.TCALTCTCACCAT 3AC3L TG'3AC3T C3TG7 7 .GATTTT VLACTSLGV717VAFTIF‘JIVR GCAGTTTATIAC’lawn-It:I—l CA'TT'TT ‘7KRSPIALHSJYIVCNA'ITI‘I‘TP GscggsGGACCAHG"" (3'TACGCCGCC'TACCCA'I'CAA" ACGL3GC GCCCTT‘ EQ" YAPI3I I‘IAE'AAY GATAATCAAAACTCAAA AACAAT7 CA: I ' . AAGG 3C PSP.\7KE53RSADAPAYQ LGQ AAGCACCTCTGTCCLGTCAL33CTTGTTCLCT" NOLYNIlLi LGRRFEYDVLD CCATT‘TGGGTGTT‘G "ACG".GTGGIGTGI3AGTC 3'TCI3C’I I‘GT KT ..LC'CL'CLL7‘«CLAACCLLAATLTG‘T17TAAC'CLAGCTAACCL'TG CL'AGG-\.

CALGAG"1IA GACL‘ :TTT1TGGAC'AA3C GC’AGACLGACGG’LACCCT GAGATGGGKGGCAAACCAAGACGTTAAAACCCCAGGALb;,~,~4 Nr.

CTCTATAA.CAGCTGC GAAGGMTflAGA. 3GC"GAAG CTA: r"’""CA.ALTLAGCK‘""1""AAGGAGAGCGGAGA3GC3CAAZL‘CA«’3 G C7CG7CG$TTTCTACCAGGACTCAGCIC.GCTACCAAGG7T TT1— iL C7LLTC'Cjc.171,-: ‘T'CLIC. 7CLL7LLLT :KL'CLCL.'(T‘ 1"! 7CLCLLLT 'CLLLRCGULI.LLLLxCV"? pry-r rm: LGC T . . TIL-LIL? ITGCAGCTGCALGGAC4TCG RMQTGLGESCLPCJL7KPSET :sL CCCA‘GLCTGCTGAAGCCLICGCH3ACCCTG"CCC’GACCF"- LSLTCTvsGGS ssssyxw >CACTC"CT"T"CTQ3CTCATC‘GGAGTAGTDGT"‘TAC 3WTRQRPGKLENTGQIY LGGCIGGATLCGQCAGCLCCCAGGGAAGGGrLTGLAGIGG APLKSRVTISVD .TGCCAGTATCTCCTATAC.GGGAGCACTACT7CAACCCG TSKNQTCLKL33VTAADTA CCTGAACAGTCCAG’GACCAT ’CCGTAGACCGTCCAAG RGPGYAISLAEDTW AAC "CT""TCCCTGTTGCTCHGTTGTGTCAC" CCGCAGA GQGTMVI’OAP""SGSGKP .G(.Cf3STGTACTA"TGCGCCHGAGGCAC3GGATATCCAAC" assGS" GmIV’WQCPAT CTTzCLCTTcAIATCIrvGGTCACCCTACAATuCTCHLC LSLSPGERATLSCRASQSV ACJGTCIACATCCGGL CCCCCMAGCCCGCIAGT sYLAWYCQEPCCAPRLLI 1:50F)HAn GGTA.G’"TAALA’LGGC4LAALATCI'I3’I1GI LGLACACAC411 LT ‘I’DASNRATGILAI SGSGCL" GT)CCACCCTGT "CC‘AGGGCT TAG 3CCACCCL'TC G'TIW‘IE‘TL’ITSSLT FED TLALJY Argo_‘ .C4CL.( J;SL GCCCAGTCLL‘ ’TAG’IG"I1‘L1AT3CAG CTAC.T‘I'AGCC"I1GGVGC‘CI\I1\"IJP’3’ 1E'Gx’3G’I"K1\/LLETL'7‘«7‘«'CL.A 7.7.7.AC CL‘T GGCLCLAGGCJ‘.. CLCLACL G CL‘TC CE GATT CTAT1 I KR7—\7—\.A.ILDN EI SNGT I I III/T GA. GCLATCCAACLLLCLCL3 CLLICLTCLCLCA’TC'CL L‘AGCCAGG’TCTCAGT.1 C’PSPL'PGP’LIPEW GGCLT‘r3'T G13"LC'11 -".CLACTTCAGT11Cl1 ACCT .TIL‘C'AG’CAGC VL‘I'LVTTVTGVLACIS.LLVTVA C1"I1ACALC3a’L‘T‘r CAT ’I" rI""TLC3CLAGT ’I1TI AT‘TACTC—L’3’ "CAGCLAGAGA E'I I EI TVI‘1 KR.5 RT LES DYM CACG‘I‘C’I‘ T'GCC"1CL.’3'TI'AC""L‘"I1"1’173I3CGC4AGGGL’LCCAAGGT‘I'GAG 7‘«TC7—\7—7—CCLGCLCJCGCLL SCL'CTL'CTT1IL7TA7«ICAAAAGTCLAAACLG SA ‘I’LRRPC"""PKHY‘PYAP .AI‘E7‘«A\RS RV .ESRSADA ACAATCLATTCLAI G'3GC7-IAGCL'ACCTCTC3TCL‘CGTCAC'CLCL' PAYQCL'GGNQILYT‘IIT..AILGITR TCI'I3TI’ILGC'C"IT’3’3’"T1ATCCAA GC'A’IT'11’3’113C4’11G"ITTG3T"CG‘TI1LA EEDVLLYI GTG G4’IL‘GGLAGTCCI"LCL'G TCI'GT." IAC"1CTC’"CCTI1CC'I1’3ACGZGTG PRRKNPQEC4LYI\]E.LLQKDI.IVI GC’I‘TT‘T‘A’ 1AA'I' ’"IL‘C‘L1C3G’3"’"AC4""1’3CAAIAACLAAI’3’3CGCLC'1C AEAI..L3IG--KGEI‘"‘PGKGP L'CL'7‘«TAGC..L1\.TT7«AT-G3A.’-TAT GACLT1 CCACLGC CGCL L'CL'TGGC.. DGITYTQC'IL 3 TAT KDTYDALE CCLACAAGG T7CLC'A :CC. TAC’GCL‘ACCA CLTAGAGAT MQAI-PPP C 3CTGCCIL‘ATCGGA AGC’LCC'GAJLGTTTTTGCGATCTGCA GAT 3CLAC T‘T GC‘GTACI'C TGC‘A 3GGCCACLAACCAAC’IL‘GTLATAAC GAGCL‘I'CAAC""L1Cr3’3ACGCAG3’3AAG" C4‘L1AT’3AC TL""L"L1TT’3’ACL 7‘«AGG-~CL:AGAGGA. ’3G )L «CL‘CL T . GGCL'A7‘«ACC7-L7GA 7‘LA:CL' CCCCAG’ 3AGGGT GAGCL'TL GCACL‘AAC\. 3’3 ’L""GA " IAAG CCI'A . AGGCLATGAAAGGLA ’3AG CGGAGALTJ3GC3C4AAAAG TLGCAC G "."T‘T 3’11 ICC A L CL'AC3CL‘ACTGCLTACL‘GA7—\GC:’1—.T7‘«'CLTr1 7-TCATCC3CLTCTCLL'CACL7‘T1 . 1 GC'CL'CL.74741.31 7CLCLLLT L'CLLLRCGULILLLLLCV"? pry-r ("r7111 ....................................................................................................................................................................................................................n.

GGC. C. CLC’CL‘LTAA ' C . . 3CL‘AT 21 517 C?P .CL LTGCA GC'CLGCAC L‘GGAA7LTTG‘TT :TTGACLA.CLAGT3T.1 RPKI"ILTCLCL.

LZI LA3CCACCCT11G"IT"C"’I"TI4TC"1CCT GC4GGALAL .GA 4CCL'ACCC’1C RA’I‘L SCL'RLAS’S _‘."1’3.’3GGGCCA"3'I'C(\ 3""‘AGCAGCL‘I'ACTTAGCLCL'TI'GC3 QQKI’GQAPRLIIVATS}IA ACC7-\.7-\.CLAGA7AACCLT' LLGCLCLAGCvCLTCCL‘CAGGCLI CATCLTLL rT SGSGTDETLT .CL‘CL'AACAGG' 3TGG' LATCCCAGC’CLAGGTI".1 CLAGT -.VYYCQQPH\7 3GGTC. 4GGAC'AGACTTCL‘ACTCTCAC'CLATCACLAGCL' VEIKRGSTS G1TTALCI""AC’IL‘GTCALGCAGAGLA G51I {GQLQLQ [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by eadley [Annotation] eadley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley CACIG'TCT'GG 1TCGCCGAGCCA3C AG "'TCAG .LSLqu-r‘rVTC/ .".IL‘CL1LCAA’3J GG "CT'ACAT ‘ 3GGCI"C'C C‘GGGAATGCCCGGATAGT" SGGSgm I=I SSSSYYWGWTRQPP 1 1’3 I'TAG"‘1AC3AAA.GGGGC3GC3TGCTAGCT‘GCAGGAGII'CG EKG"17EWT GSTSYSGS’TYYN GGCCCAG 1ACTGGTCAAC3CCTTC‘GAGJAC CCL1 G .‘CL'CCTCACL'C 1. ..T1K /TT.S1TTSKI\TGL‘S 'T L3GACL‘T‘GTC'T CTGG'LT. GGCT'CCA' .T.‘ CL‘AGCAGTA.G‘ .AG TTTJACLTACL‘ LKL C" SIC/"TJAADTA\/YYC 1I-\1RG 'TGT3 GCI7‘GCAII'CGCCAGCCCCC'AGGGAA wGGGC'TGGACTGG h—r{GY 'TSL .IIDTTLT’3OT3T1‘V'NT AT'I‘ GGAG’TAT' 3I'CCTA1TA.T3T" GGGTAGCACCTAC’TA$3" I CCCG IiSSTAA1A13DT EKSNGI‘TIT'IHv" TCCCTCI‘AAGATGI ‘CLGA 31’ ‘CACCATA"’3’3GTACAC31‘"3’3" CL'CIL‘AAG KGKHLC’3 oPLEI‘‘3 PC3788 REIT/7 L'AGTT .LTC LC1.GJACA-JCLTGAGTTCL1 STGACC 'AGJAC \/LIvC/T’‘fG SIT/"TAGY S. LLVTVA ACGGCGGTGTACL‘TAC‘TGCG GAGGCAGGGGATATGCL‘AALCC FTTFWVRSKRSRLLHSDYIVT AGC’T'TAGCCT'IT CGAT'" TCTG A.GGG’TA1’3" I-TG "CATCC NT‘TT‘PRR. KHYICCPYACP GT C" I CCTl CACGCC 3CT'3TJCCC‘.C "T "T GATT‘AAT GATAAATGI." CAAAC GT3A. TITJEIAAYRS RACIKEISRSADA AGAATC TTTCAC‘C‘I‘GAAGGGCAAGC" GC‘." ‘C3LT’3T‘CCG" ‘C31 .CCCL PATYQQGQNOLYNEL JLCI‘C TTGTT1"CCCL'.C3C-TCCJ—.TCCAJAGCLCL1TTCTG1 E11ITLA/L1JKRGRDPLTVI-z3K GT'GGC‘"G' :1LC’3,T'T3C"‘CLGC'T T'GT"‘7-\.CL‘TCT'CTGCLTC :‘T CAT CLGTG PRRKNPFGLYI‘TFLKD IN’7" \ A"T1I‘ AT'CI" III"TGG’3T‘T-".CAT’3’3" " IACATAGCCGCCLIC I JTTKGLRRRCKGP CT'CCAIT‘IAGCGATT‘T"A.C'ATCAAT-".ITGA’3TCCACG ‘CGCCCI'II‘G1- C DGLYQGLSTATRDTYL-LH C3CCACL‘AAC1CA1AAC" C." ‘1"‘CL’3CA GCGT’T1’1CCGCACG." CLC3'II'1I—L'3I/‘ I"): gm*1" TTCL'GCL'TrCCiJJ‘C'GLJAGL1.C‘GCI3TG1\A.GTTTTCL1 3G}.‘1r.4 [L4 CAHTGC GT CAjGGCCAGAACCAACTGTAT )N GAGC'TCAACCTGCCACGAGGGAAGA".G"TA’"GATCGI ""‘GGAC ATAG 3GC.GAGGACGGGACC'C’"GACT3A.TGGG"GGCATATACCAATGA.

CL‘CAAAAAACLCGCC1.1JGAGC1G’T’3'I' TATAA’TCAGCTGC‘AGAAG ATAAGJLT‘GC3CT17-1117C‘CL’CJTJAI'TCT‘GJ‘AJACTAGGCL'ATGJAAAG SA GAG GGLAGA. GGCGAAP. L3GGCLLACL‘GACGTTT‘GTACLJI.GG3A CT'C GCAC’TG’3I A ...C"T’TAT'GACCACT C.AC‘"TG CAA wcccrr 3C1’37 C TS" AT'GGCAC‘T 3C’3CGT.IAA 3'TGCI‘ ‘GC'TGCI‘ CCG’T'TGGCA TG M LE’VT'ALLPLLTLLTTHAA ,__.-1 ‘CC‘ 1‘ 2 1522 CAR (3T3 C ‘ .' "CIL‘AC13’3’3CGC3AC1C3T’3C1AGI‘I7‘C1C3‘I'CGAG'77C3’T RI’EVGLATLCGG3LI1’V3PGGS HXL GG’ 3GGACGCTTC‘GTACA-JCLLTC3G-. GTCL'CL’CL'TGJ -7 TRLSCAASGFTFS SYS1TINT/7 . TCL'T LC TG’TGCGCCTCTCCATTCLLLCLLTTT31A.G‘TAGLTAT .GAJAC VRQ A.PG1\’I :LT_1E_.WIVIS ITSSSS TGGG'TCCGCCI"AGGCT‘CCA.GGGA1A.T3GGGC"TGGATGI"GG 3T'TT'CA. ST'I iT"Y".IAL‘1SVKGRETIT SRDN "CC3I‘TTAGTAG"1A’3'I'GI'3AG’T11CCATATAC3L‘I TCGCIL‘ACI‘C'I' T 1A1ICNSL "LLQMNSLRIAIETPTA)" G G’ SCL’CJGJAI' TCACLCL'AT.. 1CLCAGACJAC11LATGCCJAACLAAC IIfCLARGSCFRLTTTJY\IG’jG A73ATGAJACAG L‘CL‘TGACGACC‘TGAGGJACLZ‘ACL‘G TLVx/"TTISS-STCLCLGKPG\G .CCGC‘CLAJzAGGTTCLTCAGCL‘L7-‘.GCL‘AC3' GATT EGSTK'3TT..I"ILTCLCL.C 'LL. L 1.AT'T ’3T3CACACGT3I-".C'A’T'TGGT‘CAC'CG'T’3I‘CCCTCA SPGETRAT‘LSCRAS’SVSRY (31’3GT CTAC31" TCCGGG" ‘ C3 C31’3GGAAGCL C3’3GGAAG"‘GGCGAAGG’T T/TYI QQKPCQIAPRLLTV1JA AGTACL'J‘vAJAGGG SGALAA 'TG" GTTGACCL1.CLA’I'TCICCLAG‘CLCL'ACC SNRATG’I PARFSCS C‘SC3T1T‘ CTTTCTC"CL‘CAGGGGLLCLAGAGCCAL‘ LCTCT GCLAGG FTLTI‘TSLEPEDFAA\fYYCQ CLAGTCACHGTCTTAGCLAG :TACTTJ‘GCL‘CL‘TCGGI CL-C'L‘AACAG QRFI VETKR ATAA3C'TGGCCAG CAG CT'CCTCiA.‘C'TAT‘CAITGCAT' IVKGIIC AACL" "3-"3-1’3CCAC.3'_‘131’3-CI’I‘CC31AI’3’3CAGG"".‘CLAT’3I‘GGC GTG G HLCPS ’LEI'I‘CP KRE‘T'LTVL‘" TCTGGGACL'AGACTTCA’IL'TCTC1I\.CLCATCJA1GCAG L'CL’TAGAGCCL'T ‘CAJGGA/TJACY..~L1_.\/ 1. T GAAG T‘TTGCA TTATTA TG’TCL‘AGCA 7- GATTC. ACTAL 1'_‘TV?"RS KRSRLLE—TSDYTVINMT CCTTGC LCL‘I. ' GTTGAGATCAAz-CxLGG . CCGCAGGCACCLA PRR G.'.TPKHYCRYAPPRT‘ GCCGC T GCC’3II'I‘GA'ITAATCAATATIAGTCAAACCGGAL" CAAT‘CA"T’T EIAAYP‘3RV FS"SADAPAY C3 'TC "TGAAGC-GCAAGC‘"‘"3CI‘CTC"C3L’3’3I‘CA’I‘CC‘.’TT1’3TTCGC‘.’T QQGQI IQLYNELNLGPREI‘ 17CCL'ATCCAJGCCL'ATTCT SGGTCTTG17‘I’C3TJAGTCGGTGGA DV.1 .RRGRTJPTIVTC1'1K1RR L‘CL‘TCGCTTGTTACTC‘"CTCCLT'CC‘fCACLC‘CTJGC' .T.‘ T'T'TATJA. KNPQEG’ 1YT\T1_T.L.KTTT\1VA1_.A L‘ .TCTGGCTTAGAICCALCLAGAJA.GCCL‘GCL‘CCLTJCTCCL‘ATAGC YSTTGMCFRRRCIICTDGL I "‘"TAC.T‘GAA".1A'TGACTiCACGCCGCCCTCGCCCCACLTATTJC YQGL 'IT‘’TIxJT‘VDALHTQA I AAC3L1A’3 'II'1—\C C-AC1 C3L ’3 'II' I ‘AC GC3A1"3 CAG CTAGAGATTTT‘ C3Cr C3LT’3 CC3 LPPR LICGGAG‘CAGGGTCAAGT I'TCCL'AC3TTCTGCAGATL GCACCL'A T TCAGCAGGGCCLAG;«ACCAAC‘TL3T"ACT1I-\1.7-\.CL‘GAL3CTCLAACL‘ GCAL3GG1IA1L7-‘LGAGTAI GLACL :TTTTGGACLAAGC GCLLAGA ACC’3I‘ GI.‘ GGCTAAATCCATIA GAC"3A" ITIAAAC 13’3’3I‘CII3C'T1A‘IAA.‘GAGCLTGC I GAAGGA".'I'1—\T—\CAT TTCT G1\A.17..TAGGC1\T GAAAGGJAGAG L'GC3AGJ-\ [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley CAT'GCIAAGCGCI ‘G TS— """CIC3’."LJAJ’"I‘LLC‘CLCC‘IAALLIILIC"I"’"'I'GLLI'LIC‘.‘L"C3CLCG'ITC 3C_LAII'I‘G L L . PLALLLHAA 21.522CAR TGCLAL .‘CLLGCLJCC3CLA L'G'CZCCGC-AAAATTCTGTT'GAAC1\GTCLT . AA.TI_.S FJ LXH CL‘CJAGCLCLA/L-\J. L'CL'CL‘TGT'CLT TTC-3T LI' CLCAAGCJCerJAC1\1"\JG'A .G'CZ'CLLJA .LCLCL‘ C.L .~ . .I S L SQSLVIS' CIA-AW".

TCC 'G‘CLAGGGCCAGTCAGAGI LCCJCA3CTACL .T1CG ‘GG \ GCJPPLLIYDASI RA JACCL."-"LC'ACLAAACCEGCLGGACGC'. C’3IL‘AGCCLTCLCT CAI.L AT IPJAJRFS GSGSGT'DFII 'JT‘GLLC"ATCCAJACAGGGCCACI‘GG CCA—IGCCJ‘C"’3I‘ILCLAG’I" LL L D_'E"AVY GG’CAC3TCCGTC3‘"G'CJC3JAC1\J'AA.’CLLTT TCL'TCL'ACJCAI CLAAGLCL‘AGC LG'TI7.

CLTA. A’- JCT AAG'ATTT'TG'CL'AGTI J'-T TAACLLJ.CerCAG'CACJAGA " - DA'SG'F.GS TTCT CTJC "TCJC31CCIITTTGC3I C7‘GGCACLG1"-\G' 3LTTGAG CAECJAJAACG 3GGG’"CT'AC.ATC GGCILC"C"ZCL'CGGGAAGCCCGGAAGT SG "TFS GGCTGJACA G L'TAG'"J""AAAAGCICICCJAG GLTCC3C‘.AGCLII'G' GLTG 31‘ ’"'I' T GLETIJVS‘L" GG 3GG1AG' 3CLTTGGTACAC3'CL3 :G’ LGCJCerCCCLA GAC3ACI L I. "C' J.C; 'CLTCI"GGA/".TTCLACCTT AGCTA/"JTAGCJAI .' CLTCCAGC1".AGCCJC3CTCCGTGGGI" . . .I' T .L‘AGTJAJGI‘ GTAGTAG L CCATAT‘ACIIL‘ACGGAGAC. I‘CT . KSN G’ "I IJA ’"'I'GA—\AGGCIC‘L’_‘LI’3ATI"."CCL JT‘LLITL‘CC.C‘.J‘G'JGACL'LL1»CA‘L_""C3CCAAC3AAC HLCTPSPLETJGP.KPFCH ,1 CAACL'TGTJACTCLT SCLAAATI.LA/I.ACLLAGCCTG'AAGAGCIG1"-CGACLACG /\/GGCLAA.LLLYS VT"\1AE" .C LCLGTC3TJACiA/"JCLTC3CCGAGAGCTI'CLTCLAAG'CJAG\JCCTCJATT SECRCRLLHSDYD’JNE‘CT JTCGATTAI . GGGACAGG’ 3TACA:"TG’ LCG LTCCTCA PRRPGPTRKHYQPYJAPPRD C C 3CTGCC "GLAJT'AAIIL‘GAAJAAG .‘CAAACGG" L CAA’ "GATT FAAYRS RVI’LLLSPSAI‘AAY CACC‘I‘GAAGGCCLC ’"CA—IC‘C""C‘L‘I'GT‘CLLCGTC‘JL‘G"TI'LCL'"T’"’"T QG"\JQLVIL'L'L LGRREE" GGTC CL1"-JT'. L'CL'AJIAG.C -.I."TCLTG LT SITTGGI"CGTAAG'TCerGTG'3 C DVLIJDKRRGPCDPFIMGGKPI".I GTCC LG'CL'.TG . ."C'TC 3CLT L'GTCJACCCGT SGCL‘TI"TTATA FCTCPLFC;II.LCI\L_IJLKIJ CC CCAGG JJAG. I ACT"G GGACAGGGT'.AC‘ATJ'"GGT" CZACC LVSA"VC" T"P.VII" I TI’3 RAS GI CI.‘CCII"CACGI’3GI."CLLII"ACJJAJ'I'CCGCICTTCCG'G'GLL "AAGC‘LCLCG'GLL "AAGT ‘3 SiVII LA‘L‘JYC/QKPHAPKLLI GG’ L'GAAGCTATACLAAAGG' ATCCL'AAG'TTGACLCLCACJJ CT YGASSLQSGVPS. FSG’SGS CLCL'JATCTTCCC‘T 3LTCTG 1"-\.T L‘TGTJGGAGJCC‘AC3AACIICL'JLCC'CL1CTC GTDFTIJI." ISIS QCPFJDFATY ."-.CTTGTCGGCCGAGTCAGG 3I"ATT1"-\GCL'JAGCT GC'CLJGG YCQQIYTFPFTFGG 3T "7F TAT AGAAACGAGGG1AAGCCCC:TAA3CT'CCIIL‘CGA’"GT'AT' IKEAAAALLVLL‘VS" GTII H‘I’C GCITGCA'I' CACL'_"’"‘""’"CA—\AA’"GI’3G'GLLITL‘CC.C‘.C‘."‘TCAAGCITTCAGC KGKHLC"PSI"LFPGP"K'"LLTN GC3C1AGTC' ATCLTGGG'AACLLAGJA CACLJ CTC1IJCLCATCJAGC3/.GLCL VLV‘VA"Cer‘v’LIAA L'YSLLVTVAA.

CTGC1"—GCCTGA: TTTT1ACTTATTATG’TCAGCAGATA FIIFW‘VRS KPCRJJCASDYM TCL'JAC'TT. TGG' LGGAGGGACL'L‘JA GG 'TG'JAG "\WITPRRPCPJRMIYQP .

LCGGA [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] eadley Unmarked set by Anne.Headley ,—~1~\m {~71CIAPTTICPT’I‘T I GP -GGGCP TI3CPTC'CI‘CTG3"CCGI‘CPTCCC :PTYQQGQNQ.3 YN rI I‘G’ ‘TC1’3 3’'GGTCCA’I‘CCPPGC1’3PJI":‘C‘TGGGT'I’33’I‘TG "(313’ ‘P. "SYDVI DKI RGPDI’TT GTGT3GT1’3GPGT _‘.C‘1"CGCT'TGT TPTCTCTC’ ‘CG3TCAC’31’3’ ‘G 1911}KN""E’3~. ITYNEIT P.‘TP«P«T -TTCTGCTGT’ GP.TCC.3PTPTP\P.GPPGCC GCCT G fl 1—-\.EP1.Yb31.31 CTC CPTTAC C GPCT’. 'TPTC'TPjT GPCPC’. ' 71 -.—1 I1 an A T [-T .I. 'T CCHCu TITF‘ mf} 3 ij3G .1 C7 :1C YCIGILS TPTBDTYDP.TII AC:3PGCCTTPT1’3I3C.C.CACCT‘PTGPTCAT '> 'I1GAPTG’I‘T‘ ’.' T C‘ CAGPT’I‘ CT GCA GATG"CA’"CCTA‘I 1’CGAT CT‘I GCA " GUC‘ C31PT13PP.CCPCACT 1’3’ ‘P.ITAAC .11C‘CTCAPCCT SGGACGCLASSCTPCPGPTGTATACGTT'TTCJCPC -1.AGCGCAGZ.GG‘A .IGGGZ.CCJCCTa:ALGZALIL G :1 37G3I31-\.1\T.7‘1CCPPC31-\ C:GAAPAAACCC‘CCAGG -GG I" CT'C’ ".ITTAA’1GPTI3C’II‘GCAC3PTAG CATT AGCT GCiTGAAGCCTATT ’3’‘GPAATAGGCPI‘GA" APTGGP.

GAGCEGG‘GAAG j1.3GAT'LLAAGGG’3PCG"’3G \ 1 1 m m 31 I .1. IIIIIIM" C’3T" (313GP.

CTCACC?.C'TC'JCTJ-1CC1AACJCPTPCTTPTGP. ’3 ’3T ‘IJT C CPCPTT G :KTLIC~~7 ampv.1}: :CTTICA(«n-1'57 AT G 3CT-ITC, CCCG:i‘.7-‘11P:CT CTGCTT GCTGCCGTTT GGCTI- IVCPIITIF‘Vf‘rlTAT T J P EALL 11}{.7-\de ITJ.

CT'CC’I‘C G GIACPTT 1’3 CPTGII1 T GP‘TC 1’3 CP.GT CT RP:ITQLTQSTTSSISASVGD C1’3PT T T CCGT‘G’I‘C I‘GCPTT' C’.‘ CII1PTGGPCI3PTCPGPT3T1’3ACCT 1C RVT TCZPSQGTQGWLATY PTC’I‘ T GTCG3 PGTC‘TL‘C1’11’3G’7I111T‘AI’SCPTGCIII‘GGTTPTGCCTGG QQKPTVCPL’KELIV3P.’oVrv' f‘ .TQ TP TCPCTCP’31\TP.ACCAGGGPPAGCCCCTATTGCTCCT)IPJ7 C T.PTT' SG‘x/PSRFSGSGSG 1 GG". :CAT CCPTG"TTT GCPJ AGT r—. r1 IT‘31 7 TC: . 'C:i:TCGCI CCPX'T LIMP.GGTT CPCGC LLJLJJL: PF 2I3. PCT.

GGCPTI’3TG3I3 .TC". 3GGPTCPT’3A" TiTCP.CC- PCT 3PT1’3CI -II1’I'PTGIC3PCI3C EIF"FGGGTKV1 KRGST‘S CTGCPTG1’3 3’"GAA GPTT'T‘TTTGCPCPTI’331TII"II—1'11 TACTNI‘CPTGCAGPCTP. GS3K’1’3SCEGS’IK’3’3V"3V rE1A(\Ak(~(~1'rlrl CCC’1T‘1I"13TI’3\.C 111111TIT’31’3CGCAGGGT TCrGTT1’3T-1G 11‘NEP1’3‘PSLR S1’3PTP. mcNETINKCGCTGCTCTACITCCGGT .‘CCG :rGTI-ITPT T’-\.P.GI7 ". . AFGK GGCG C 731PCPTGC3GGCPYGGT C3I3PGC'1.GGT:IC:G1.C7T'C .T; .1 GITEWVPCVISYTIGSIVK T) G1’3I3GGGC’3T'I3C’II"CTLTG1 C’I‘GGGPTGG'I‘CCCTGPTG CT" CT CC SVFCI3'I’I‘ISAII\ SKN’I‘ LYL T1’3"G ATTCPCCI1'II1CTI‘ GT'PTI3CII1A‘I. 3’31’3PTI' GCAC QMAS'RAEDTAVVYCPRT" ‘1'1’3 I' 3' 1 "TC‘11P. 1’13CTGC3AG ' 1’31’3 IIT GGCP‘T FWSGS:PGLDYWGQGTTV" ‘TPTCTATGCCTACACT T C. VSSA -.P.LD.1JF1KSNCTTTH‘C11: CT 3TP3AGGGCCGITPT . TTCPCCCP.TCTTCICHGAG}LTCAPCITIIICCJLMLXKD'IT1.:CC K137 LCPSPLFPGPS{PFW I GCPTPP’ ‘G.A.ACPTGCCT GAGP‘TG GGP‘TC ACG VLVVVGG I ’LPTCY S :3 LVT‘V'PT C' 1G1’3I3CCAGP‘1PT1’3'II‘ PC"I1T TTGI3P.GCIGGPTT'C FT T FE IVTTTS KRSRT ITHSDYM ICCICNT .13,3 3. AGA'T ’IIIVICICJ'IJIJHK/III /3 f‘f GGGTT TG 31' 11’3PTC:II NIITPRRPC'3""PKHY"PVPP GTCTCCT1. CP«C3CCGC1. SCSCTT-3PT.P«P«T CPA!11167TAPTACG $P« T‘IFPPTYRSRV’ .T.FSR STI-ITUPT PCPPTCPTTCAGCTGALTCTGGCI-.\.-1.GCACCTCTC$TCIC'C3TCPTCCC PYQ,GQNQLY‘JF..1I\1LGRR TTGr .ippcqnwmpT TCCPPGC‘.JKJ CATTCI‘GGC'II1GTTGI3I'C’3TPT EEYLIVLLKRAGRDT EIV’IGGKh- r:UfrlIT3 G’II‘GGPTGT'CC’T'"CG rpm-1 ’ . ’ AC’ "CT'C’ ‘GCTCGTCPTCCGTG T .L (J . PRRKNT'91’JECLYNE3I OKDKM GC’I‘T’FTPT’ TAPT' 3’"1’"1131’3’3’".'AC1A’"’3CPPPP’3/3CL‘TI’3’3CGCC'1’3 AETAYTEIGKGEF'VPGKG‘F CT JCP«TPTC I P .T TP«CPT1’3IP1P1.’.PTTGPCT1 CGC JCTGCC DGI. IIQG.TSTATKDTYDP1T_1H CCCTPTCAPCC3G1.1 ATPTCACTP.CGP 3CCTTPTCGCTPTCCPC CTTPTGAGPCT MQPTPDF13.: 1.

’II‘TCC’3T’3CC’T.ATCG’3T .AGGG’3 TTI3PTAG‘T‘TTT 1’3CP.GAT CTG’3 CP. 3CPT1’3 TPTT' 3 .GC'TAGGGCCPTCAACI’3PTT—ITC’II‘GTATAPTC GAGCT1’3PTP.CC3T{:G’’3GPTCGCPTG ’3 P.GAG"-1’AT ’3-PTCG3TTTT’3 1’33P.C 1 1I\/ \, .. ’3IPITG «TI.TGGC: GGCP«P«TACCPTP.GP.

A ~ 7 ‘7‘ PXTLTC'v V T,"Cl-I‘01 ,-1 IIILI‘x'C:13G.r 'v 'CJRCH GAGCTGCAGPTPTC1.

GPT’I‘ TAGA‘I. 3I’31’3"G.I"TAAG CTA.Arrl‘r 7 I T"TGGPT T CI" GPTPP’ ‘P.GGCPTT 1’3 GPTGCGGPTGPC1’3GGC3TPCAPCP1’3 ' "’7' I11 GTT’TC CI’.GGGPT C'T.'CP«C)CACT13CTP«CCPTA-’36P. AC'CJC,TCTCASTTG CAPTGCCCT 3CC'TPT CTPGGTJDMZ‘X ....................................................................................................................................................................................................................11.

PTTGGC. (3131-CCCGTPP mp1 .1 C3 ,CTGCICCTCCC .me LIJEJIK Pi: ‘T.

C'T CCTGCPC GC’CGCPCCGCC'CGCAGGTGCATCTGGTGJAGTCT RF'C.JIVIOIV )SGPEC ‘1,I’IKITFGSS GGGGCTGPTG'I‘GPTPTGT I -GC'C’"GGGICCICCCTGP"G "CTCC VK‘IS’ PSGGI‘ESSYA III'GCTI‘ T’31’3CIII'TI11C'I IC7I: ITGGCACCVT TT"’CAGCTTTGCT'""PGC "RGADGQCLEWMGGIIPT3 TGCGTGCGP«CACGCC lcherfAC\a’:I‘TAL ()IxeerTITTIT/-‘TG 7 CJGPT1h/‘1‘30 $P« ’3. T C. _ GPTCATCCC ATCTTT'NJG {LLXGIC31NARCTACG'v:75d:AL7.733fo *- n. — ,0" 4.113. TGRCJI‘I ITLTC'JT;CTII'P-CCCCCzC—MCCGPXTC'I". K3 \3IAL GAGC GCCT’3AI3P.’"" "GT T1’3I3I.’"ACG . $51391 TM [Annotation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley "GCGCC 11’LL’ 'C .J A'TA'TGGCT C'I'A'."TAA1C" .CGGCAA1T'GG1'AC'GT1" 'TGGG S L ‘1/SI'JGFPA'T'1’T’LKS ACAL‘ C'1"GF 'CAC _‘.C'1'"LT'1J1'JLLLCLAI’L-GGT C'TACL1L"1"CCGGC.‘ 'CCGGG'L 113 U) L"Y S SNNKNYLAWYQQ J‘1A JCCCG 1L 1AGF'G-GCLG v11erTAGT'A1JAAAC’LG JLGJ‘11'JJ1 'C‘G. G :11] rrJ D 7710 ’11P.K11.L1'1. YI'AS FT RES G r-n ~r nnr: m«r 1 CLCLCJ1L1G1'1J.CCAAGJLM1'1J.'LCJ ...'L G! CL'1.GCCTCTCTCTC11JGGCG1L1C 'V' 111 1" ‘FSGSGSGTDFF "" ’L'CC1AG1J’LL CAGAG‘T G'T1T' T'T" 'TAC A 1GGGCCACCATl CAA-C"T GI’JAAG- (/1 t" mo1J‘)EDVAVYYCQOFAHFP F AGC’LT" 'GGTACCAGCA-G-AAA 1‘)-j1-.1 1 (.1 A 1GCT CCAACAA1A'T TA-CAACT'AC- "GG"Y"FTKRAAAFIN CCAGG GCTG’""L CLJ‘ '1" "1’" CJGGC 'L "LACL L I1 J .F U‘. 17'1""IIHVKKHL":6P CGCLGAA CAG.1'JGC11IJ1LGG1'JT I." _>-1 ’77.! U v _ 5: KP.FIF111." 1'13 131/"L P1!" ‘3, Elk? 1131\4. . CACJ‘C. .TCAGC'AGCCTGCAGGCTGAA ACYSLLVTVALFIFFWV SK AT I'TGGCACJTT'TAT"'A.C'TG"CAGC.'AGTT GCCCA.CA rpm wr' ’ WkMTI1REP TT CAC'TT'TTGGCCCAIJCGACCAA AGG1 1'GAGA'T'C -'A-'AC IGGCC1 CC .' PSR'L' PPVJVQPYAPPPD"MARS GCT LCCT'T CLATA'F' GAAAAC'T CAT—1A"L CrCrA. ‘CT'1"CAC RVKFF"ADAPYQ‘gomo T'CL111GG JLCLAJLAGC111LCT1J1'I1L1LGT1JACCCTFGTT'JCCLTG 1LT LYNETNL .11.I—.F1F.Y V11DKR.

CCA 13J1F'TCTC1JLJ TCCTAGFGC1J1G TC RGRDP ._.I\FG"L'PRRKI\1PQ CT'C AC'.'C.'TC'TG1’J’ 'CG‘TCACCGT JGC‘T'T'TT'ATA-ATC LYNELQF1DKMAEAA1YSIL1'GIVT 'TT'C'.'GGGT'TAA1G.'CCA.AAA113A-A-GCCGCC’ 'GC'TCCAT'AGCGLA'T GLERI‘RGKG IDGLYQGLST '1"ACATGAAT1A1TGACT CL.C 1CGCCGCL (LLCT GG CCC’LCi." CAAGGAAA A'L" 1' T‘I'1" YDALHMQAL P 1" R CACTJ‘1.1'JL'CJAGCCLT'TA’CJG 3:3CCJ'1A11'JL1'JT11G11GAT1..L CG1L1.1"1'LL'1'JLTJ1T CGCLAGCAGCJG'1"GA GTTT1‘TCCAGA.‘ CL'T'GCJ‘A1.11JATGCL11CCAL3CG TA" G1’LLA JGGCCAA1C7 ' .CCA‘I’LT'13T1'A-'L'AACGAGCCI‘CAACC"G GG CA3GAAGAG" -';'L ’LAC’L T'TT'F"GGACAA 113CGCA:AAGGACG J1J1 1 C'.'GAGA'1"1’J L 'TL‘GC1C1A1AJ—\C1'JAAC1AI’L1’JAJ—\AAACCC CAGGJ— GTCTCT1—1'1."AATGJ1GC'"1.1"1'LLJ‘1GJ1AC’L/LT'AAGJTGCGCT GAAJ’L’LF'A'T CTG1—117-‘1ATAL3G 1ATGAAAGGACJAG N'GGAJJ1A1J‘1.GG GGAA GGCACGCA C'GG'TT"' J'FL‘ LACCAA1GGGA-C'TC1AGCAC'FL‘G T 12111GA-AGGATAA1131111:.'TGACGCr 'C'TCCACATJCAAGI’L1’LL 'L'LGC‘ C1A I: (J1p.11AGG‘TAA AT 'LGCACL.‘‘L ' CLLCCC 'L"LAArLL'1"’L "IIV'F‘Y11CY(:D'l/3 VT "CC \rL 'Hl'lfs LCA‘T‘L VL C) ["1 T‘ALL' PTA1L1-"HAl—1 'j» '\.’\ 21528CJ-1R CT' J'CTG'CJA ..L-GCL J'G'1'JAC 1- ’LLCL J'GGACJ-1TC ST‘GATGJ—1C1LCA1JT JF" RPJJI‘MTQFPT‘JGAV’SLSF I.XH CLC'1L1GACTCCCLT'1GGCTG. GTC.1JTGGGCG11GAL3GGCC'1L1C1JJLTC RATINCI'SSCS'V'I "CCAJAC"'"'CAC’JC GAG'T’LT'TT'L-ATAC1GC" CCALACAAAr.' NY QQIKPGQ: AA JL‘A’L'F'ACTLTAG’J'TF 'GCLLT'AC’L1GCAGAAL‘ CCAGGACL.L‘AI’JCC'.' WAS'1'RE 5 (JVLL7‘R:F "GC C'CJF11111.:1LT'G'1J1 C.11TT""A1J1 GG-JCAT1J1AC .LCG JLGJ‘1AT .LCG ALG- TDFT111. SS.I1QAF.I)FA17‘Y‘. ~m~ Amp: 1 1,1. ~r./~.r1 r—..-—1rL '1: .LLJ CLI. C31L1C'1JG] i CJ1L1G'1 GGC!1U LJ. C70 :11Lx'xJJLAGA l CQC)FAIITPFTFGGGT "F ACF'CTCL11CCAT1AC11G1JCTGCLAGGCT JA1AC7‘1TC11JGC1T1G'."/'CLLC KRGS1 GS ,C CJQ‘1QL'V'OSCJAEVKKPGSSVE! FPGSGEGS 'TAA1T'T1'AAC'TG' ‘CAGCAGT' ‘CGCCCACACT'CCr.' T'T C1ACT'TT-'FL‘GGC ’L-GAGCJGACCAAG'L'FL'LL'JAI’L-AT'CAAACCGGGGTC"1‘" GGC K‘x/SCIKLAS GGl 'S‘.) AIVL TCL J'G'C-J'C-JAAGCCL J'GGAAGTC'CLCJCJAJ3G1.:1AC'"J‘11'JJ1J—11—1G SGGCJAG RQAPGQC I. F.I1MC ' IPIFG GCAGCF'GTGCAGF' TG JGGCTGAG JLTGAAGAA1)J‘CTGGG TAIF'XAQIFQ I .TADES .CGGF'G 7-‘1.G JTCF'CCLTGCAAGG LTTC. 'x: LLZFIAL F1I1S SI.RS F1II'IAVY GCT'A" GC‘TA'T’JAC’LTGG’LT'IJCJACALGCCCC'TGGACL ' YCA}TPEYSSSFHYYYGM GG JCT‘T‘GAGLTCJGA'1"1’JGGJ‘1G 11-11'1F'1—1'FL‘C' (LT11'1F' T T'L'GGT'ACA D'ILVFIFGQCJTTV'I'FSSAAA'JDR .AL'1JCJJ3C1111AA1J1TCL1L11CLG1JCJAG11GT'CA1GATTA LC E11131"1J1FI IHVK’GKHLCPS P J'AAT" "ACG1L1 JCACAGC J‘TACAT JG7‘1GCTL3AJCL17‘1GCxTxJCJ L:FPGPS V’IJ‘x/FLI’VJGVI1 SGGT JLTAC. TC 1GI CT JACL'YS VT"".7‘1FI I FWVPSF CC"G.'A-'A1L C’LACCAT'II'GGCA1’LL"TTACTACGGCATG POKGJHSLYMI I'TPPPPGP I’JAC 'L'I‘ALT'CKJI’J’LCCGGGAACAA"LL 'C'1" ’LACCCLTL (1'1" CCT‘ CAGCJC "LKKrIYQPYAPPRDFI—CA-11C .L1LT'1'JL'1'JL1'JLCJT. 1'1TAA1 JJ-1AAAL GT’CJAJ—1A1LGGAALJ1J-1I‘ CLATT’CJAC TS T‘GADAPAY1,1161;}.Q A111JJCA17-‘1GCACCTCG 1JCGTCL17-‘1CCJiiG. 'TC’CCTGGF" GRRF. DVIJDKR CCL'1L1T1J1JJAGCCL'1L1TTCTGGG‘ jJJLGC'T‘ GT111JTGGG'"GGAGTC DPFMGGKPRPJNP"JI._.G "L'CC’L'TT'IJ' L‘AC"CT'C" GC‘T L'GT'C C’LGTC’L’LLTT ATAATC LYNELQKDI’MAEAAYLSET GM r 1.11 (‘lrljljfsr Il' CA'"’L’LAJ—\AAG1AA1JC1JGCLCL'C’J'T CA'TA.rJCGA'.' KGB L<‘_RRG'I’J ID "LLYQGLST‘ 'GJ-1C'T'.J"1'LLJ‘1CJG .LCG LCCTGG..LCCCAC1~ AG-GAAA A 1. .1')T .’.')J1LAHMQAL P P R JC'JTTAC’GCACJzCCTAGAGJTTFCC1J1GCCLT1AT A GGTGJAGTTTTC A-1C311.1J1J7‘_"'L mmr‘CCACATGCAC 71G J‘G FLAGCAG A"I’L1’LLAA-C - G'TAT'AA GAGC'T1’LLT ' G ACLGCACYC'I'J 'A'1'"JA1/LLT'LTT'""’LGACAAC11LL’JCAGGGA 1L1) 1LGA1J1JC 'I.L1/1GAT1JGGTC'CLCJ‘AACLC1L1AAG 1'1'JLGAJ1JAA'CJL’CJ [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley CTATAA «13313». ~r. i 1313K, GAACCTATTC"TGAIAATAGGCATGAFLAGGAGTIGCGGAGAIAGG GGAAA GGC3AC‘.31 1CCGG"T7?"_‘C3‘I'AC3CA3ICGG17‘C'I'C31—IGC"’3AC1‘I'I’3 3T FI'C3GA-.GG'AT1I3TTFITG ICGCJCT 1'CFI'C3ATGGCFIIL .GCCCTGCCFI 1 D- .CCC 3 GTF11A.’73T’:TG‘CTG3TGCCGT1G.GCF-ITTG 3 -IJIJ‘VTALL. JPI..1IIJI..II.1-IIFI1A. 204 ZIBSOCFIR G' 3L3C3CC 3G7‘IGCIGCAGCTGCIGGFGTCT ‘VCIIVESGGCVIFQ GRS I.L . GCGTGC‘I7GCACCCrGGGA'GGTCGTGAGA SCAASGE" ‘E‘SSYGIVIHW ‘I'CT 'CACIC‘G‘I'GTGGAI‘T’ACCTTC.7‘AGTAG CTA‘7.‘ 3C3CAT .7 KQAE‘GKGLL‘I’I‘VCAIVI3Y‘7G .TkG'G‘GTCCGCCFIG‘GCT 3 FCI-3CC1IAGGI.3 1'TG'C3A (r. ."' . SIK. "‘{FJQ CVKG TIS RDN GTT ITFITC‘C1FI‘37-FITGC.F.F..37TFIATFIF-IF...TIACTA‘. ' -. .7 . ." KIITCYIJQNSLFIFIFJ )TAV GATTCFICC. ..‘ TCCF-IG.-I.GACAA’.7' G YYCVKG. T QEPP‘GYGMUV ATCZT GC31A1AATGAAC1A1GCC‘I7‘AGA’3’3CCAGGA ‘JIGCCTT‘IFTVSSCSG‘G 3SGK IC‘I'C'I'GTAC‘TGGG‘ICAAGGGG CCG‘7."7‘C3C1GGAGC.C1C3~ 3 EC SG3EGS’1‘RI’3T7'IIVI‘II‘CSA T1L.'C-3GAFITG' 37 ICGTATG’ 3 GGAFICAACTG. .JS‘I’SPC 'RFI.T1.ISC3R1I1‘.‘QG3 'CT’G T‘GC 1'GC3C3C SFIFIGCCCG' GFI VF 1GN1J1 FC" QAPRIJIJ GAFI'GGTFIG.‘ .TLICAAAAGGG 3GAA1AITF-IGTGATGFI GCAG IYSFISTRFITGI PARFSGSG C1T3TCC71‘GC11I’1’3.3‘7GCC3..A GACI"C‘I‘TAGCAGC‘AACTTAGC‘CAGCCACCCIGTCTG'7C‘I3GTCCAGGCAAAGA GCCZACC SGTEE‘TTIGSSLQSEA E‘A‘If YYCQC) I'IVWI’LT E'I’3GGT‘KV7 T1IC3’C3AGC1.GFI1IAC‘C1T5G7C'C3AGGCT1. C lCFIGG..1 1TC 1 I .7 E7..LKR1-.F.A1JI) JE.K1‘.‘IIGTJ.I .7FIC3C3GC3FITCCFIC3CI -GG’ 3TGC'3AI‘C'C3CF31GCCAGGT. .7 VKGKHIJCFSE‘LFEG’PSKE‘F ‘3C3CAG. 'GG3. CTGGG7‘CFIC3AG. 'TC3LI1‘TCTCF-ICCATCAGC WV .17I/T‘fl/7GG‘I/I11IC‘7GIJ.3VTV CC'I‘CGAC‘I7G1‘CA1AGA‘ AG ‘TATTACTGTCAGGAC AEIIE‘II‘IF‘SKRSRLLHSJY CACC1AC1I’3T '777‘C3C1C1C1'I'C‘I CAC‘.’1"17"TTGC3C3G 3AC3-C 7 ‘C3CTT MNIVITI’I RPGPTRKHYQE‘YA C1AG1ICFI1AFI'C3GCGCC1G7CTGCC...CT‘.‘GFITAAI. ‘. .7"- F11L.C RRRIMAF'RSR‘IFKE‘SRSFII) -\GFFTCATTCFICGTGAAG33'CFIAGCFICC1C. GTCCGTCFI -.I’F3AYQ'GQNQ .JYNF3LI LGR CCCT 1G3 l‘C‘CCT 3GTC3C31A1TCCFC GCCATTCTGGCTGT‘I3G‘TC D'LLKKRCIIJPEMG 3 GTAG‘I‘GG T‘C‘CTCGCT 7‘71‘1AICTCT C‘TGCTCGT C‘-AACC PQ G‘GLYNELQKDK GT 7‘77‘T71‘11'1'1—\37’—\.7I‘G7‘7‘G'rl ‘7 GGT7.‘17‘G TCCAAAAICAAGGC3C1C1 MAEAYSE‘C GAIKC‘L‘I‘PR31KG CT 37CTC3C3. ITFIG' lGFITTACFITG-FI1."1ITG'1AC'T'C3’C3F ...GC 1'G'C3C3C3T HDGLYQC1JSTATKDTYDAL GG JCCCACF-IFIG 3AA1AC1-\C.3LICC113 C'.‘TTFI 'GCFI CFICTAGF-I I-IMQFLFPR GATTTCGCTGC‘CTATC 3GAGC3AGG r"7GAACTTT‘IGGACATGT TGC G C'A~7CG'7 -T‘C‘AGCAG 3GC1C3AG1A1ACCFLAC37‘C3TAI7 AACTG 1:131. C7"1»C7AC_‘.C"I"3GG1"I7CGC‘ MG«7.AAGACJT. TGA,1 VIII-"3mg GAGAFIGCCCFIGAC3-I.1'GC1GF>C CC‘A’S'FIGATGGG.‘GC3C3AFIFICCFI 131ICG11I.LI3LIAACC CC JFI'GGAGGGTCT3 C. FITF-IFI.‘ .‘GAGCTGCA: T GA. A‘7.""3TGA1AATAGGGT I 7GAAA 1AIAGGA‘I‘AAAACATlGCG AGAGC‘GG1A1GT 7 .GGGGA1AT 7.GGGC3.A1CI3ACGG‘7.‘7‘TG'7 .C‘C‘AG ‘AC1.11.’3TGC"77C1C3AAGC3A7.‘17‘C1TT1ATC3AC.C3C1TC37’CC3..AC1C "IFIGCCCT 37CC3AC3CTF..G7GTAA RD— FTGG'C3FIC3T...CC JGTAA ...TG' 1TC3T :rCT1‘G"737C3CGTTG 37CFITTC MALPVT A.I.II..IJPLFIIJIJIJHAA 206 215 30CFIR GCFI GCCGCACGCCCG'GAAFITFIG‘.‘GATGFCG JFI'GTC. RPEI‘C'VITCG.I. 'LSVSPGF.

LZI CZC'ACCACCCTGTCTG‘7CTC7‘G’3ACGGGAA1IGA3C1C'AC3CC'7C [\ATLSCRAS’ AWY T‘CiC’A'GCAG 3GC1C3AC3TC.GAGT'GTT .GC'AGC1A .CTT‘AG CTGG QQK\PCQAL‘IILLIA’GAASTRA T‘ACC11ACCAG"AAC1C1TGG7GCAC‘GGTCGGACICC'I' "77‘GA7".1'I'1—\.7 ‘I'I’3II’ARSC3.3GSC1LE"I'.3T FIGCGCFT 1'CFII3C‘1IGG' 37CC3AC3. GG’I‘FITCC‘ C‘1I’.‘1GCFI'C3GTr CFIGT SSIJ)SEDFIF.‘VYYCQQHII‘F GGCF-ICTC3GGTCTGGGACA’3FAGT‘TCFICT CTCFICCATCFIGGAGC I’IFIJTFGGGTF.‘1’F3IKR.3STS CTGCAGTC‘"3AAC.".Tl‘TTGCACl‘l‘TATTAC‘I‘TCAGCAGC‘AC GSGI’E‘GSGEGSTKGO‘ QLV C1AC3GTCTCIC’3’3"CTC C1‘I"TT‘.7GC3ICC3’3GGGACTCJ‘ .I’3G‘.7T‘GAG ESGC’W’IQ’ IJGI SL} .S C_7 A F.TCFI1I1ICGGGG' CFIT 'CGGCTCCGG‘GFI1AG ...CCG7GFIAG.T' SGFI J.SQYGA’TI’T‘fRQFIFGI GG JGAAGGTFIGTLICAAFCGGGCAGGTG’CLIGCTGGTG 3FI'GTCT' IIEI'FV‘FI’IF3YI‘ GSNE’.YIAD GG 3GGAGGCGTG 3TCCF-IGC JTGGGFGGTCCCI31IG7‘ICTCTCC SVKGRFTI.G3RD? SFNTIJYII T"31‘ 3CAGC3"3’i CZAC3CTTCAG‘TAGCTAT 3GC'A"C3CAC WIFSLRALDTAV‘I’YCVKGP TGGC‘I‘CCG CC3AG3C1TCCAGGC11 .AGGGGCF‘GCGTGG 377C3I’3C3A LQEI’I’YDYGMD‘IfWGQC‘I‘T"! C3T. ATF.1. JGTAT GFT.GGFI1AG. 'F.FTFIFIATACTFT GCAG1IC1.1'C TfS SFI1AAI.1-DNFJ .SNG m 3GGCCGFIJT1‘CLICCATCT'CJIGAGAC TTCCFF .7-‘GI3LIC IIGMIII PSFIJFP 3ITCTGCF7-‘IATGFFCFIG 1CTGFI31IGCCCA3GFCFICG WVIJVV‘IIGGVIJLICYS GC1G7‘C.AGGG 7CCGTT3 CCGC‘C31A I SIILLHSDY [Annotation] Anne.Headley None set by eadley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] eadley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley TACGAALTT'T TGGAATGG GTA'TI’313 GCCA ~ 3AACAA1C'TG’3’ ‘C MNMTPAC ‘CGCCCT'T -.CCG'TCTCC’.CAGCCGCT‘ -ATAA’ATGAAT .AGT AAA—LC EPPDEAAYI‘5‘ PV’KFS RSAD GGAAGAATA" A 1" "ACACrCACC'T'CTGE‘C """'CA ALE'AYQQCQ'QQLYN‘"LNLGR CCCT .GCACJATT. ,, viGG'T GTE , 'TC LDKP.EG'RDPETVA G GTAG GG’GTGL ' . ‘GTTACTCTCTGCTCGC'CACC KERRKNPQEG’LYNELQKDK . ’3TGC C E‘T’TAT'AA-. C'i‘T’T CTGCC"w’E" CAAAAGAAGCCCGC EVEAEAYS ET GMKGERRRGKG CTl 13Cr‘C‘. CATAALI’3CG.A’E"TACATGAATA'TIGAC"C"C"1CCACG’3CGC‘. ’T HDGLYQGLSTA’TKDTYDAL ""CL/CCACi ‘AGGAAACAC'T'ACCAGC’""TACGCAC73ACCE‘AGA HMQAL E" PR "MTT3. CC-rCTGCC .ALTCG -..GCAAC-rGGTCAAGTLTTCCAGATCT CCACAT'GCACCLL 3CGTATCAi L 3CAGGGC A;LCAACCHAC GTAT AACG T‘CCAEACC'TI’3GGAC GCAAtGGGAEAGAG'T7T C.".C G’T'TT'TG GACAA CGCACAGGTCGGGAA C T .ACATGGIG’ ‘GGCAAA’3CA AGAC‘I’3uAAx-L—LACACC3CCAGCrAC TCT‘C‘C.’ ‘AA’TAATGA C’AGCAG [EAGC- xAL3'A'LGCTTGAA’TCC ‘AATTCZ’TL CAAA—'AGGCAT"/\AA 7‘-\ CLGGAGPJ'TEU :GAZAC:At;{7LCUGCACG]LCK’YK’] TTLJTITLCKukuAG "E‘C-AGCAAL3T ACCAACACGATACT'TrGACGCT'CTCCAC AALT'(3CAAGCCCT'(3CCACC'TAJ7I3GTAA"A in some embodiments, the cieotide of the present invention encodes a CAR, wherein the CAR comprises an amino acid sequence at ieast about 75% at least about 85%, at 1east about 85%, at least about 90%, at 1east about 95%, at least about 96%, at least about 97%, at ieast about 98%, at ieast about 99%, or 100% cal to an amino acid sequence seiected from the group ting of SEQ ED NGs: 1'76, 178, 180, 182, 184, 186, ms, 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 1D NQs: 176, 178, 180, 182, 1114, 186, ms, 190, 192, 194, 196, 19s, sec, 202, 204, and son. in one embodiment, the CAR comprises the amino acid sequence of SEQED NQ.176. in another embodiment, the CAR comprises the amino acid sequence of SEQ 1}) NO: 178. In r embodiment, the CAR ses the amino acid sequence. of SEQ TD NO: 180. In another embodiment, the CAR comprises the amino acid sequence of SEQ TD NO: 182. in another embodiment, the CAR comprises the amino acid sequence of SEQ TD NQ:1S4. in another embodiment, the CAR comprises the amino acid sequence of SEQ TD NC): 186. In another embodiment, the CAR comprises the amino acid sequence of SEQ 1}) NO: 188. In another embodiment, the CAR comprises the amino acid sequence of SEQ TD NO: 190. in another embodiment, the CAR comprises the amino acid sequence of SEQ TU NO: 192. in another embodiment, the CAR comprises the amino acid sequence of SEQ11) NC): 194. in r embodiment, the CAR comprises the amino acid sequence of SEQ 1}) NO: 196. In another embodiment, the CAR comprises the amino acid sequence of SEQ 1i) N0: 198. in r embodiment, the CAR comprises the amino acid sequence of SEQ TD NO: 200. in another emb nent, the CAR comprises the amino acid sequence of SEQ TD NO: 202. in another [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley embodiment, the CAR comprises the amino acid sequence of SEQ ll) NO: 204. in another embodiment, the CAR comprises the amino acid sequence of SEQ ID NO: 206. [0290} in some embodiments, the polyhucleotide of the present invention comprises an tide 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 lOO‘i/o identical to an amino acid sequence. selected ttoin the group consisting of SEQ tones;175,177,179,181,183,185,187,189,191,193,19s,'197,199,2o1,2o3,aad2os.

In n embodiments, the polynucleotide comprises a nucleotide ce ed from the group consisting of SEQ 11) N03; 175, 177, 179, 1st, 183, 1115, 187, 189, 191, 193, 195, l97, 199, 201, 203, and 205, in one embodiment, the polynucleotide comprises the nucleotide sequence of SEQ lD NO: 175. in another embodiment, the polynucleotide comprises the nucleotide sequence of SEQ ID NO: l77. in r embodiment, the polynucleotide comprises the nucleotide sequence of SEQ ll) NO: 179. in another embodiment, the cleotide comprises the nucleotide sequence of SEQ ID N0: lSl. ln another embodiment, the polynucleotide ses the nucleotide sequence of SEQ ll} bit): 183. in another ment, the polynucleotide comprises the nucleotide sequence of SEQ ll) NO: lSS. in another embodiment, the polynucleotide comprises the nucleotide sequence of SEQ ll) NQ: l87. in another embodiment, the polynucleotide comprises the nucleotide ce of SEQ ll) NO: l89. In another embodiment, the polynucleotide comprises the nucleotide sequence of SEQ lD NO: l9l. in another embodiment, the cleotide comprises the nucleotide sequence of SEQ ll) NQ: l93, in another embodiment, the polynucleotide comprises the nucleotide sequence of SEQ ll) NO: 195. in another embodiment, the polynucleotide comprises the nucleotide sequence of SEQ 1D N0: l9‘7. in another embodiment, the polynucleotide comprises the nucleotide sequence of SEQ ll} bit): 199. in another embodiment, the polynucleotide ses the tide sequence of SEQ ID NO: 20l. in another embodiment, the polynucleotide ses the nucleotide sequence of SEQ ID ND: 203. in another embodiment, the polynucleotide comprises the nucleotide sequence of SEQ ll) NO: 205.

[O29l] in r embodiments, the invention relates to Clone ESu26528 HC DNA (SEQ ll) NC): 271) as follows: ‘GCAGC'I'G'l'l'QGAGTC'l'GGGGGAGGC'l'TGGTACAGCC'I‘GGGGGGT DICCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGACGACTATGCC [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley A’IIGGCA'I'GGG’I‘CCGCCAGGC'I‘CCAGGGAAGGGGCTGGAG'I‘GGG’I‘C'I‘CAG GIGATGCAGGTGACAGAACATACTACGCAGACTCCGTGAGGGG CC(IIG‘I‘TCACCATCTC(fiAGAGACAA'l'TCCAAGAACACAC'I‘IIITA'I"CI(3CAA ATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGCAAGA GCCGAGA'I‘GIIGGAGCCG'I‘A’I‘TCGACA'l'ATGGGG'I‘CAGGG'I‘ACAATGG’I‘CA CCGTCTCCTCA {0292] In further embodiments, the invention relates t0 the Clone PEI—26528 I-IC amine acid sequence (SEQ ID NO: 272‘): EVQILESGGG LVQPGGSLRII SCAASGFTPD DYAMA‘NVRQA I’GKGLEWVSA ISDAGDR’I‘YY ADSVRGRFI'I KN'I‘LY LQI‘VINSLRAED TAVYYCARAB MGAVFDIWGQ GTMVTVSS In further embediments, the inventien relates te IIC CDRI thereef: FIFDDYAMA (SEQ ID N0: 273). In further embodiments, the inventien relates to I-IC CDRZ thereef: AISIL/AGDR'I'YY‘YADSVRG (SEQ ID NO: 274). In further embodiments, the lnventien s te HC CDR3 tllereel‘: ARAEMGAVFDI {SEQ ID ND: 275) [IIC CDR3] In further embedirnents, the invention relates t0 Clene 28 LC DNA (SEQ ID NO: 276): GAAA'I‘I'GI‘GT'I‘GACACAG'I‘C'I‘CCAGCCACCC'I‘G’I'C'I'ITG’I'C'I'CCAGGGGA AAGAGCCACCCTCTCCIGCAGGGCCAGTCAGAGTGTTAGCAGGTACTTA G‘CC'I‘GGI‘ACCAACAGAAACC'I'GGCCAGGC'I'CCCAGGC'I'CC'I‘CAICI7A'I'G‘ ATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGITCAGIGGCAGTGG G'ITC'ITGGGACAGAUYICACTCTCACCA'I‘CAGCAG’CC'I‘AGAGCCTGAAGAI‘ TTTGCAGTI‘TATIACTGTCAGCAGAGAAICTCCTGGCCTTTCACTTTTGGC GGAGGGACCAAGG’I‘TGAGA'I‘CAAAC(EEG [0295} In further embodiments, the ion s to Clene FSmf-16528 LC AA sequence (SEQ ID NO: 277): EIVITQSPAT GERAI" LSCRASQSVS RYLAWYQQEI’ GQAPRLLIYQ AS’NRATGIPA RFSGSGSGTD FTI_,TISSI_.EP YCQQ RISMPFTFGG G'I‘ICVEIKR {0296} In filrtlier ernbedirnents, the invention, relates t0 LC CDRI tl’ier'eef: RASQSVSRYLA (SEQ ID NO: 278). In further enibediments? the inventien relates te LC [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley CDR2 thereaf: DASNRAT (SEQ ID NO: 279). In further ments, the inventifln relates to the LC CDR3 : QQRESWPFT (SEQ ID NC): 280). [0297} En her embodimenta, the invention reiates to Clone FS—26528 CAR DNA HXL (SEQ ID NO: 281): ATGGCACTCCCCGTAACTGCTCTGUI‘GCTGCCG'HTGGCA'1"I"GC’E‘CCTGCA CGCCGCACGCCCGGAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTA CAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTT ’l‘GACGACTA'I‘GCCA'I‘GGCA'I'GGG'I‘CCGCCAGGC'I‘CCAGGGAAGGGGC'I‘G GAGTGGGTCTCAGCTATTAGTGATGCAGGTGACAGAACATACTACGCAG AC'I'CCG’I‘GAGGGGCCGGTTCACCA’I‘CTCCAGAGACAAT’E‘CCAAGAACAC ACTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTAC ’l‘AC'I‘GCGCAAGAGCCGAGA'I‘GGGAGCCG’I‘AT'ETCGACA'I‘ATGGGG’I‘CAGG GTACAATGGTCACCGTCTCCTCAGGGTCTACATCCGGCTCCGGGAAGCCC ETGG’CGAAGGTAG'I‘ACAAAGGGGGAAATT6'1‘GTTGACACAGTCTC CAGCCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGG 'E‘CAGA(:STE‘GT'E‘AGCAGG'I‘ACTTE‘AGCC’ETGGTE‘ACCAACAGAAACCTG GCCAGGC'I‘CCCAGGC'I‘CCTCATCTA'I‘GA'IGCA'I'CCAACAGGGCCAC'E‘GG CATCCCAGCCAGGTTCAGTGGCAGTGC‘rG'I‘ifii'I‘GGGA{LAGz-XCTTCACTCTC ACCATCAGCAGCC'I‘AGAGCCTGAAGA],"I"I"I‘GCAG],"I"I‘A'I"I‘AC’I‘G'I‘CAGCA GAGAATCTCCTGGCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAGATC AAACGGGCCGC'I'GCCCT'I‘GA'I‘AA'I'GAAAAG'I‘CAAACGGAACAA'I'CATI‘C ACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCC AAGCCA’E‘TCTGGG’E"GTTGC‘I’E‘CGI‘AGTGGG'I‘GGAG'I‘CCTCGC'I'TG'I‘TACTE‘C TCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAA GCCGCCTGCTCCA'E‘AGCGATE‘TACAT(3AAFATGACTCCACG’CCGCCC’EGGC CCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTG CCTATC(ZE'GAGCAGGGTGAAGT’ETTE‘TCCAGATCTGCAGATGCACCAGCGTA TCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGG GAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATG GGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCEC'LA’I'AA’l‘GAG CTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAG GAGAGCGGAGAAGGGGAAAAGGGCACGACGGT'I"I‘GTACCAGGGACTCA [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley C’I'ACGAAGGATACTI‘A'I‘GACGC’I‘C’I‘CCACATGCAAGCCC’R‘GCC ACCTAGG [0298} in [1111be ambodimems, the inventimn s [‘0 Clone FEB-26528 CAR Bx}...

AA sequences (SEQ [D NO: 282,): [\y/[ALPV'I'ALLL PE_,AL[;E_J[-[AAR PEVQE_,1_..ESGG (iiiN’QPG'éESLR 1.,SCAASGFTF DDYAl‘x/[AW’VRQ APGKGLE‘VVVS A[SDAGDRTY YADSVRGRET [SRDNSKNTL YLQMNSLRAE DTAVYYCARA D['WG V'I‘VSSG S'I'SGSGKPGS GEGS'I‘KGEEV L’I‘QSPATLSL SPGEELA’I‘LSC RASQSVSRYL A‘WYQQKPGQA PRLLEYDASN RATGIPARFS GSGSGTDFTL TISSLEPEDF AVYYCQQRIS ‘WPE'I‘EGGGTK VVEKRAAAALD NEKSNG'I‘HH VKGKH[_,CPSP [.FPGPSKPF‘W VLVVVGGVLA CYSLLVTVAF [[EW’VRSKRS YMCNN[ [PREPGP'I‘RK HYQPYAPPRD FAAYRSRVKE PAYQ QGQNQLYNEL NLGRREEYDV LDKRRGRDPE NiGGKPRRKNP Q[SGLYNELQK DKMCAEAYSEEEE GMKG’ERKRGK GEEDGLYQGLS TATKDTYDAL [EVEQALPPR [0299} En f1.1rther embodimenta, the invention reiates [0 Clone [18—26528 CAR DNA LXH. (SEQ [D NO: 283): A’ETGGCACTCCCC(ZETAACTGCTCTGCTGCTGCCG’E'TGGCA1"[GC’E‘CC’ETGiffiA CGCCGCACGCCCGGAAA'I"['G"[‘G’I"I‘GACACAG'I‘CTCCAGCCACCCTG’I‘C’I‘T TGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT TAGC[MEG'IACT’E‘AGCCTGG'I‘ACCAACAGAAACC'I‘GGCCAGGC'I‘CCCAGG CTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTT CACETGGCACETGGGTCTGGGACAGACTE‘TCAC'E'C'E'CACCATifiiAGCAG’CCTA GAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGAGAATCTCCTGGCC E‘(LA(Z'FET’E‘TGGCGGAGGGAC(3AAGGT'E‘GAGATCAAACGGS66TCTACA TCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAG G’EKSrQAGCTG’E‘TE‘GGAGTCT’C‘rGC‘rGC‘rAGGCT'I‘GG’I‘A(IAGCC[GGS66GTCCC TGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTGACGACTATGCCATG GCATGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTCTCAGCTA T'I‘AGI‘GA’I‘GCAGG'I‘GACAGAACA’I‘AC'I‘ACGCAGACTCCG’I‘GAGGGGCCG GTTCACCATCTCCAGAGACAATTCCAAGAACACACTGTATCTGCAAATG AACAGCC’l‘GAGAGCCGAGGACACGGCGG'I'GI‘ACTAC'I‘GCGCAAGAGCC DSAGATGGGAGCCGTATTCGACATATGGGGTCAGGGTACAATGGTCACCG [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley 'I‘C'I‘CC'I‘CAGCCGC'I‘GCCC'I‘TGA'I'AATGAAAAG’I‘CAAACGGAACAA'I‘CA'IT CACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATC (IAAGCCATTCT(ZEGGTG’EfE‘GGTCGTAGTGGG’I'GGAGTCCTCGC’37TE‘GT'37AC'I‘ CTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGA AGE?CGCCTGCTCCA’E‘AGCGATE‘TACAT’C‘rAA'E7A'I'GAC'I'CCACGCCGEXICTGG CCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCT GCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGT A'I‘C‘AGCAGGGCCAGAACCAAC'I‘GTA'I'AACGAGCTCAACC'I'GGGACGCAG GGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGAT GGGFGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCECEA'I'AATGA GCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAA GGAGAGCGGAGAAGGGGAAAAGGGCACGACGGT'IVI‘G'DXCCAGGGACTC AGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGC CACC'E‘AGG {0300} In further embodiments, the invention relates to the Clone FS—26528 CAR LxE-ii AA Sequence (SEQ [D N9: 284): MALPV'I‘ALLL PLALLLHAMK PER/L’l‘QSPA 'I'LSLSPGERA 'I‘LSCRASQSV YQQK PGQAPRMLEY DASNRATGIP [LXRFSGSGSGT DPTE‘EI‘ESSLE YYCQ QRISWPFTFG GG’R‘KVEIKRG STSGSGKPGS GEGS'I‘KGEVQ LLESGGGLVQ PGGSLRLSCA, ASGFTFDDYA MAWVRQAPGK GLEWVSAESD AGDR'I‘YYADS VRGRFFESRD NSK’N'I‘LYLQM NSLRAED'I‘AV YYCARALEMGA ETDIWGQGTM AALD TIH-i VKGKE-{LCPSP E_,}<"PGPSKPFW ‘V'LVVVGGVLA CYSLLVTVAF HFWVRSKRS YM’I‘H‘A TPRRPGPTRK HYQPYAPPRD FAAYRSRVKF SRSADAPAYQ YNEL NLGIZERREEEEYDV EJEKRRGRDPEEL MGGKPRRKNP QEGLYNELQK DKMAEAYSEI GMKGERRRGK DGLYQGlS Til-XTKD’E‘YDAL E-{MQALPPR {0301} In further embodiments, the ion relates to Clone PC—26534 HC DNA (SEQ ID NO: 285) as follows: CAGGI‘GCAGCTGG'I'GGAGTC’l‘GGGGGAGGCG'I‘GG’I‘CCAGCCTGGGAGGI‘ CCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTGAGCATGGC A’l‘GCAC'I‘GGG'I‘CCGCCAGGC’I‘CCAGGCAAGGGGC’I‘GGAGTGGG'IGGCAG D3TATATCTTATGATGGAAGGAATAAACACTATGCAGACTCCGTGAAGGG [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley CCGAI'I‘CACCATCTCCAGAGACAA'IVI‘CCAAGAACACGCIGI‘A'I‘C'I‘GCAA ATGAACAGCCIGAGAGCCGAGGACACGGCGGTGIACTACIGCGCCAGAG A{IfGtiil’IV-XCT’E‘A'I'C'I'AILIG’I‘GG'I‘C'I'C'I‘IIZI'GTACT'I‘CGACI'I‘ATE‘GIIIGIZZIGAGA GG’I‘ ACCITGGICACCGICICCTCA {O3 2] In further embodiment; the invention relates to Clone PC~26534 III: (SEQ II) NO: 286): QVQI_,VESGGG VVQPGRSIRL SLAA‘SGITI‘S IQIQMIIWVRQA E‘WVAA ISYDGRNKHY ADSVKGRF'II N’I'LY I_.QIVINSLRAED TAVYYCARDG TYLGGLW’YFD TLVIV SS, {0303] In further embodiments, the invention relates to BC CDRl f: FTFSEIIGMII (SEQ ID NO: 287), In further embodiments? the invention relates to EC CDRZ thereof: AISYDGRNKHYADSVKG (SEQ ID NO: 288). In further embodiments, the invention relates to EC CDR3 thereof: ARDGTYLGGLWYFDL (SEQ ID N0: 289).

In further embodiments) the invention relates to Clone IKE-26534 LC DNA (SEQ ID N0: 290) as follows: (IAIA'I'TGIRCSA'I‘IZZIAC'I‘CIAG'IC'I‘CCAC'I'CICCC'I‘GCCCGICACCCC’IGGAIZZIA GCCGGCC’I‘CCA'IC'ICCTGCAGG’ICTAGICAGAGCC’I‘CC'I‘GCA'I‘AG’I'AILYIG GA'I‘ACAACTA'I"I"l7(IGA'I‘IGGIACE?’I‘GCAGAAGCCAGGGCAG'I'C'I'CQMIA GC’I‘CC’IGA'I‘C'I'A'I"I'TGGG’I‘TC’I‘AATCGGGCCICCGGGGTCCC'IGACAGGI ICAGIGGCAGIGGATCAGGCACAGAIIITACACIGAAAATCAGCAGAGT GGAGGC'I‘GAGGATG'I'TGGGGTIVI‘AI'I‘AC'IGCA'IGCAGGGAC'I‘CGGCCTC CCICICACIIIIGGCGGAGGGACCAAGGTTGAGATCAAACGG In further embodiments, the invention relates to Clone PIE—26534 LC AA sequence (SEQ ID NO: 2%): DI‘Vh/I'I‘QSI’E_,S LPV'IPGEI’AS ISCRSSQSEJL GYNYLDW YLQKI’GQSI’Q LLIYLGSNRA fiGVPDRFSGS GSGTDFTLKI SRVEAEDVGV YYCIVIQGLGLP fiffifitt—‘ITKVE IICR. {0306} In further ments, the invention relates to LC CDRI AA sequence f: RSSQSLII-ISNGYNYLD (SEQ ID NO: 292). In further etnhotlirnente, the invention relates to LC CDRZ f: LGS’NRAS (SEQ ID N0: 293). In further ments, the invention reletee to LC CDR3 thereof: MQGI_,GLPI_.T (SEQ ID NC): 294). {0307] In further embodiments, the invention relates to Clone PIC—26534 CAR DNA Q ID NO: 295) as follows: [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley CAC'I‘CCCCG’I‘AAC'I‘GCTCTGCTGCTGCCG'I'TGGC.A'I"I'GCTCC’R‘GCA CGCCGCACGCCCGCAGGTGC‘AGCTGGTGGAGTCTGGGGGAGGCGTGGTC CAGCC'I‘GGGAGG'I'CCCTE‘GAGACTCTCC’E‘GTGCAGCGTC'I‘GGAT'I‘CACCTT CAGTGAGCATGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTG GAGTGGG'I'(IEGCAGCTATATCT’E‘A'I'Gz—X'ETGGAAGGAA'E,‘AAACACTATGCAG ACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACAC GCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTAC ’l‘AC'I‘GCGCCAGAGACGG'I‘ACTEA'IC'I‘AGG'I‘GG’I'C'I'C'I'GG’I‘AC'I‘TCGACTI‘ ATGGGGGAGAGGTACCTTGGTCACCGTCTCCTCAGGGTCTACATCCGGCT CCGGGAAGCCCGGAAGTGGCGAAGG'I‘AG'I'ACAAAGGGGGA'I'A'I"I‘G'I‘GA AGTCTCCACTCTCCCTGCCCGTCACCCCTGGAGAGCCGGCCTCC A'I‘C'I‘CCTGCAGG'I‘C'I‘AG'I'CAGAGCCTCCTGCATAG’I‘AA'I‘GGATACAACTA TTTGGATTGGTACCTGCAGAAGCCAGGGCAGTCTCCACAGCTCCTGATCT A'ETTE‘TGGG’E‘TC TE‘AATCGGGCC'I'CCGGGG'I‘ifiCC’E‘GACAGG'I'TCAGTGGCAGT GGATCAGGCACAGATTTTACACTGAAAATCAGCAGAGTGGAGGCTGAGG A'I‘GTTGGGG'I‘TTATTAC’E‘GCATGCAGGGACTCGGCCTCCCTCTQACT'ETTE‘T GGCGGAGGGACCAAGG'ITGAGA'I‘CAAAC‘GGGCCGC’R‘GCCC'IVI‘GA'I‘AA'I'G AAAAGTCAAACGGAACAA’E‘CATTCACG'HZEAAGGGCAAGCACCTC’ETG'I'CC G’l‘CACCC’l‘TG’ITCCC'I'GGTCCA'I‘CCAAGCCATTCTGGG'I'G'I"I‘GG'I'CGTAG GAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAA I‘GGG’l‘TAGA'ICCAAAAGAAGCCGC‘C'I‘GC'ICCATAGCG‘AT'I‘ACATG AATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTT ACGCACCACCTAGAGA’E‘TTCGCTGCCTATCGGAGCAGGG'I'GAAG'I’T’E‘TCC AGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATA ACGAGC'1'CAACCTGGGACGCAGGGA AGAGTATGACGTETFTGGACAAGCG CAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCC CCAGGAGGG’I'C'I'C'I’ATAATGAGC'ETGCAGAAGGATAAGA’E‘GGCTGAAGCC TATTCTGAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCAC GACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACG CTCTCCACA'I‘GCAAGCCC’l‘GC‘CACC'I‘AGG {0308} In furfl'xer ments, the invsntion relates to Clem EEC—26534 CAR HXL AA sequence (SEQ ID NO: 296‘): [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley MALPVTALLL PLALLLHAAR PQVQLVESGG G’VVQPGRSLR LSCAASGF'I‘F WVRQ EWVA AISYDGRNKE-i GRFT {SRDNSKNTL YLQM'NSE_,RAE ETAVYYCARD (ZETYLGGCLWY39‘ DLWGRGTLVT VSSGSTSGSG KPGSGEGSTK ATQSPL SLPVTPGEPA SESCRSSQSL LEESNGYNYLD WYLQKPGQSP QE_,1_..IYLGSNR ASGVPDRFSG SGSGTDFTLK ISRVEAEDVG VYYCMQGLGL PLTFGGGTKV EIKRAAALDN EKSNGTIH-fi/ KGKE-iLCPSPI... FPGPSKPFWV LVVVGGVLAC YSLLVTVAFI KRSR LLHSDYMNM'I‘ I‘RKH YQPYAPPRDF AAYRSRVKFS RSADAPAYQQ GQNQLYNEEN LGRREEYDVL DKRRGRDPEM GGKPRRKN?Q EGLYNELQKD KMAEAYSEEG MKGERRRGKG HDGLYQGLST ATKDTYDALH MQAI_,PPR In further emhediments, the im'emien relates is Clene PC—26534 CAR DNA LXH (SEQ ID NO: 297): A'iCGCACTCCCC(ZETAACTGCTCTGCTGCTGCCGHIWETGGCA'I‘TGC’E‘CCTGifiiA CGCCGCACGCCCGGATATTGTGATGACTCAGTCTCCACTCTCCCTGCCCG CTGC‘IAGAGCCGGCCTCCATCTCCTGCAGGTCTAGTCAGAGCCTC C'I'GCA'I'AGTAA'I‘GGA'I‘ACAACTATT'I‘GGA'I'TGG'I‘ACC'I'GCAGAAGCCAG GGCACETCTCCACAGCTCC’E‘GATCTA’HTGGC‘I’E‘TC'1‘AA'ICGGGCC'I‘CCGGG GI‘CCC'IGACAGG’IVI‘CAG'I‘GGCAG'I‘GGATCAGGCACAGAT‘E‘ITACACTGA AAATCAGCAGAGTGGAGGCTGAGGATGTTGGGGTTTATTACTGCATGCA GGGAC'I'CGGCC'I‘CCCTCTCAC‘TT'ITGGCGGAGGGACCAAGGI‘TGAGA'I‘C AAACGGGGGTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGT AG'I‘ACAAAGGGGCAGG’I'GCAGC’E‘GGTGGAGTCTGGGGGAGGCGTGGTC CAGCCTGGGAGGTCCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTT CAGTGAGCATGGCATGCAC’E‘GGGTCCGCCAGGC’E‘CCAGGCAAGGGGC’E‘G GAGTGGGTGGCAGCTATATCTTATGATGGAAGGAATAAACACTATGCAG 3TGAAGGGCCGATTCACCATCTCCAGAGACAA'ETTE‘CCAAGAACAC GCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTAC GCCAGAGACGGTACTTATCTAGGTGGTCTCTGGTACTTCGACTT A'I‘GGGGGAGAGG'I‘ACC'ITGGI‘CACCG’R‘C'R‘CC'I'CAGCCGC'I'GCCC'RTGA'I‘A ATGAAAAGTCAAACGGAACAATCATTCACGTGAAGGGCAAGCACCTCTG TCCG'I'CACCC'ITGT'I'CCC'IGG'I'CCATCCAAGCCATTCTGGGTG'IVI‘GG'I‘CGT DAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTAT [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley AA'I‘C'I‘TC'I'GGG'I‘TAGA'I‘CCAAAAGAAGCCGCC’I'GCTCCA'I'AGCGA'H‘AC ATGAATATGACTCCACGCCGCCCTGGCCCCACAAGGAAACACTACCAGC (IT'E‘ACC‘ICACCA{IfCTAG[Mb-X17131:GCTGCC'E,"ATCGfiAfiifl-XGGGT'C‘rflu-XG'YFF TCCAGATCTGCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGT A’ETAACGAGCTCAACC'EKKEGACGCAGGGAAGAGTA'I‘GACGT’E‘TTGGACAA GCGCAGAGGACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAA CCCCCAGGAGGGTCTCTATAATGAGCTGCAGAAGGATAAGATGGCTGAA ITCTGAAA'I‘AGGCA'I‘GAAAGGAGAGCGGAGAAGGGGAAAAGGG CACGACGGTTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATG ACGCTCTCCACA'I'GCAAGCCC'I‘GCCJMTC’I‘AGG {0310] In fhr’ther embodiments, the ilwerrtion relates t0 Clene 534 CAR LXH chain sequences (SEQ ID N0: 298): MALPVTALLL PLALLLHAAR PDIV‘MTQSPL SLPVTPGEPA SISCRSSQSL Li—ESNGYNYEJ) W YLQKPGQSP QLLIYLGSNR ASGVPDRLFSG SGSG’ETDFTE‘LK EDVG VYYCMQGLGL PLTFGGGTKV SGS GKPGSGEGST VESG (IE’GVVQPGRSL RQLSCAASGFT F SEHGMi-iw VR QAPGKGLE‘WV AAISYDGRNK HYADS‘VKGRP 'I‘ESRDNSKNI‘ LYLQMNSLRA E0TAVYYCAR DG'I"YLGG1...WY FDL‘WGRG’E‘LV 'I‘VSSAAALDN EKSNG’I‘HHV KGKHLCPSPL FPGPSKPFVVV LVVVGGVLAC YSLENTVAFE IFWVRSKRSR Lil-{SDYMNMT PRRPGPTRKH YQPYAPPRDF AAYRSR‘VKFS AYQQ GQNQLYNELN LGRREEYDVL DKRRGRDPEM GGKPRRKNPQ EGLYNELQKD KMAEAYSEIG MKGERRRC‘XKG E-{DGLYQGLST A'I‘KDTYDAU-i MQALPPR {0311} In further embediments, the invention relates to: Clone A3n26545 BC DNA (SEQ [D N0: 299): CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGGCCT CACETGAAGG’E‘TE‘TC(ITE‘GCAGGGC[LX'ETCTGGA'I'ACACCT'I‘CA’ETGGAGCACTAT TGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAG TAATCGGGCCTAGTGGTGGTAAGACAAGCTACGCACAGAAGTTCCAGGG CAGAG’I‘CACCA'I‘GACCAGGGACACG'I‘CCAC‘GAGCACAG’I‘C'I‘ACA'I‘GGAG CTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGAG AGAA'I‘TGGCCAA'I‘GGACG'I‘ATGGGGCCAGGGAAQAAC'I‘G’I‘CAC‘CG'I'C'I'C DSTCA [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley {03m In further embodiments, the invention relates to Clone 45 HC‘ AA sequence (SEQ ID NC): 300): QVQLVQSGAQE VKKPGASVKV SCRA SGY'I'FIVI liil-IYMI—lwVRQA PGQGLEWMGX IGPSGGKTSY AQKFQGR I’TM TRDTSISTVY MELSSIRSED ’IAVYYCARIES WPMI)VWGQG’I 'I'V'I‘VSS {03%} In further embodiments, the invention relates to BC CDRl thereof: YTFlleI-IYIVIII (SEQ ID NO: 30l). In further embodiments, the invention relates to I-IC CDRZ f: VIGPSGGK'I'SYAQKFQG (SEQ ID NO: 302). In further embodiments, the invention e to IIC CDR3 thereof: ARESWPNIDV (SEQ ID NO: 303), {03M} In further embodiments, the invention relates to Clone AI~26545 LC DNA (SEQ ID NO: 304): GAAATAG’I‘GA'I‘GACGCAG'I‘C'I'CCAGCCACCC'IG’I'C'I'G'I‘G’I‘C'I‘CCAGGGG AAAGAGCCACCCICTCCTGCAGGGCCAGICAGAGIGTTAGCAGCAACTT AGCCIGGTACCAGEL/MLAAACC'I‘GGCCAGGC'ICCCAGGC'ICC'I‘CA’ICTAT GGTGCATCCACCAGGGCCACTGGIATCCCAGCCAGGTTCAGIGGCAGTG 7GGGACAGAG’lIICACTCTCACCA’ICAGCADCC'I‘GCAG’IC’IGAAGA T'I"I‘I‘GCAG"I,"I"I‘A'I'I‘AC'I'GI‘CAGCAG’I‘ACGCCGCCTACCC'I‘AC'I'T'I'I‘GGCG GAGGGACCAAGG’I’l‘ILIAGA'IifiiAAz—KIGG {IBIS} In further embodiments, the invention s to Clone Ail—26545 LC AA sequence (SEQ ID NC): 305): EIXI’IVI'IQSI’A'I‘ LSVSI’GERA'I‘ LSCRASQSVS SNLAWYQQKI’ GQAPRLLIYQ ASTRAIGIPA RFSGSGSGTE FTLTISSLQS EDFAVYYCQQ YAAYPTFGGG 'I‘KVEIKR. {03 I6} In further embodiments, the invention relates to LC CDRl thereof: SSNLA (SEQ ID NO: 306). In further embodiments, the invention relates to LC CDRZ f: GASTRAI (SEQ ID NO: 307), In further embodiments, the invention relates to the LC (DDR3 thereof: QQYAAYP’I (SEQ ID N0: 308)" {03 I7} In further embodiments, the invention relates to Clone ALI-3,6545 CAR DNA I-IxL (SEQ ID NO: 309): A'I‘GGCAC'I'CCCCG’I'AAC'I‘GCTC'I‘GC'I'GC'I‘GCCG’I‘TGGCAT'IGC'I'CC'I‘GCA CGCCGCACGCCCGCAGGIGCAGCTGGTGCAGICTGGGGCTGAGGIGAAG AAGCC'IGGGGCC'I‘CAG'I‘GAAGG’I'I"I‘CC'I‘GCAGGGCA'ICTGGA'I‘ACACCT DICATGGAGCACTATAIGCACTGGGTGCGACAGGCCCCTGGACAAGGGCT [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley TGAG'I‘GGA’I‘GGGAG'I‘AA'I‘CGGGCC’I‘AGTGGTGGI‘AAGACAAGC'I‘ACGCA CAGAAGTTCCAGGGCAGAGTCACCATGACCAGGGACACGTCCACGAGCA CAGTCTACATGC‘rAGCTGAGCA(ZEC()’§7GAGA’E‘C’E‘GAGGACACGGCGG’I'G'E‘A CGCCAGAGAGAATTGGCCAATGGACGTATGGGGCCAGGGAACA ACTG'I‘CACC(:S'TE‘CTE‘CC’E‘CAGSG’E‘C’E‘ACA’E‘CCGGCTCCGGGAAGCCCGGAA GTGGCGAAGGTAGTACAAAGGGGGAAATAGTGATGACGCAGTCTCCAG CCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCC AG’R‘CAGAGTG’I"I‘AGCAGCAACTTAGCC'I‘GG’I'ACCAGCAGAAACCTGGCC AGGCTCCCAGGCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATC AGGI‘TCAG'I‘GGCAG'I‘GGG’I‘C'I‘GGGACAGAGTI‘CAC'I‘C’I'CACCA TCAGCAGCCTGCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTAC G‘CCGC‘CTACCCIACTTTIGGCGGAGGGACCAAGG’H‘GAGATCAAACGGG CCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAA GGGCAAGCACCTC7E‘G’ETCCGTE‘CACCCTE‘TG’E‘TCCC’ETGG’E‘CCA'I‘CCAAGCCA’ET TCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTC GTCACC(3TGCE'CTETFI'ATAATC'I‘TCTGGG'I‘TAGATC(3AAAAGAAGCCGCCT G‘CTCCATAGCGA’I'TACA’I‘CiAA'I‘A'I‘GACTCCACGCCGCCC'I‘GGCCCCACA AGGAAACACTACCAGCC'ITACGCACCACCTAC‘rAGATT’ETC(HZTGCC'I‘ATC GGAGCAGGGI‘GAAG'I‘T'ITCCAGA'I‘C'I‘GCAGA'I‘GCACCAGCGI‘ATCAGCA GGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGA G'I‘A'I‘GACG'I"1"fi,"'fGGACAAGCGCAGAGGACGGGACCC'IGAGA'I'GGG'I‘GGC AGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAG AAGQA’ETAAGATE‘GGC’E‘GAAGCC’E,"A'ITCTGAAA’ETAGGCA’ETGAAAGi‘xAGAG CGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTCAGCACT (3CTAC(IE’AAGGATACTI‘ATE‘GACGC'I‘C'E‘CCACATGCAAGCCCTG’CCAC(ETA In further embmdimems, the invention ralaiésa :0 Clone 45 CAR HXL AA sequence (SEQ [D NO: 310): MALPVTALLL PLALLLi-iAAR PQVQI_,VQSSA EVKKPGASVK VSCRASGY’I’F MEHYh/EHWVRQ APGQGLEWMG VEGPSGGK’I‘S YAQKFQGRV’T TMTRDTSTSTV YR/[EI_,SSI_.RSE DTAVYYCARE SWHVEDVWGQG TTVTVSSGS'I‘ SGSGKPGSGE GS’l‘KGEIVMT QSPA'I‘LSVSP LSCRA SQSVSS‘AEAW YQQKPGQAPR LLIYGASTRA TGH’ARFSGS [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley GSG’R‘EFTL'I‘E SSLQSEDPAV YYCQQYAAYF TFGGG'I‘KVEI KRAAALDNEK SNGTIH-[VKG KE-[LCPSHEP GPSKFFWVI_,V VVGGVLACYS [.LVTVAFHF WVRSKRSRLL [-[SDYMNM'I'PR RPGE’TRKHYQ PYAPPRDFAA YRSRVKFSRS QQGQ NQLYN‘ELNLG RREEYDVEDK RRGRDPELMGG NPQEG [XNELQKDKM ICHVHQ GERRRGKGHD GLYQGLSTAT KDTYDALHMQ ALPPR {0319] [n furthar embodimentg, [he invsntion reiates to Clans A[«26545 CAR DNA LXH. (SEQ [D [10:31]): ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAAA'[AG’I'GA’R‘GACG‘CAG’I‘CTCCAGCCACCCTGI‘CT GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTG T'I‘AGCAGCAACTTAGCC'I'GG’R‘ACCAGCAGAAAC‘C'I‘GGCCAGGC'I‘CCCAG GCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGT TCAG'I‘GGCAGIGGG’E‘CTGGGA(IAGACSTE‘TCACTCTCACCA’[CAGCA(ECCT GCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTACGCCGCCTACC CTACT'FITGGCGGAGGGACCAAGG’E‘TE‘GAGATCAAACGGGGG’E‘C’E‘ACA’E‘C CGGCTCCGGGAAGCCCGGAAG'I‘GGC{3AAGG’I'AGTACAAAGGGGCAGGI‘ GCAGCTGGTGCACETCTGGGGCTGA{EGI‘GAAGAAGCC'[GGG(KIC'I‘CAG'I‘G AAGG'I"["[CC’['GCAGGGCATC'I'GGA'I‘ACACC'["[‘CA'[GGAGCAC'[A'I'A'I‘GCA CTGGGTGCGACAGGCCCCTGGACAAGGGCTTGAGTGGATGGGAGTAATC GGGCC'[AGI‘GGTGG’I‘AAGACAAGC'R‘AC‘{3CACAGAAG’I"['CCAGGGCAGA GTCACCATGACCAGGGACACGTCCACGAGCACAGTCTACATGGAGCTGA DCAGCCTGAGA'[C'I'GAGGACACGGCGGTE‘GTAC'I‘ACTSCSCCAGAGAGAA TTGGCCAATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCA GC(3{3C'1‘{3CCC[TGA’ETAATGAAAAGTifiiAAACGSAACAA'1‘CAT[(3ACG’ETGA AGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCA TTC'[GGGTG’E‘TGGTCGTAC‘I’E‘GGGTGGA(ETCCTCGC’[7E‘GT’E‘AC'I‘C'[C'I‘CEC’E‘C GTCACCGTGGCTTTTATAATC[TCTGGGTTAGATCCAAAAGAAGCCGCCT GCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACA AGGAAACAC'[ACCAGCCT'I‘ACGCACCAC‘CTAGAGATH‘CGC’I'GCCTATC GGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCA GGGCCAfiAACCAAC'[G'I'A'I‘AACGAGC'['CAACC'I‘GGGACGCAGGGAAGA DSTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGC [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley AAACCAAGACGAAA‘LXJMXCCCCCAGGAGGG'I‘C'I‘C'I‘A'I‘AA'I‘GAGC'I'GCAG AAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAG CGGAGAAGGGGAAAAGGGCACGA(ISGTT'I‘GTE‘ACCAGGGACTCAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCIGCCACCTA {0320} In further embodiments, the inventinn relates t0 Clone AI—26545 CAR LXH AA Sequenee (SEQ ID NO: 312): MALPVI‘ALLL I’LALLLHAAR I’EIVMTQSPA 'I'LSVSI’GERA 'I‘LSCRASQSV SSNLAWYQQK PGQAPRI_,I_..IY GASTRATGIP ARFSGSGSGT EFTLTISSIQ SEDFAVYYCQ QYAAYIYI‘FGG G'I'KVEIKRGS 'I'SGSGKI’GSG EGS'I‘KGQVQL VQSGAEVKKP GASVKVSCRA SGYTFMEI-IYM I-IWVRQAPGQG LEWMGVIGI’S GGK’I‘SYAQKF QGR‘V'I‘IVI'IRD'I‘ S'I‘S’IIVYMELS TAVY YCARESWPMD VWVGQGITVTV SSAAALDNEK SNG’ITIIE-IVEQG KHLCPSPLFP GPSKFFWVLV VVGGVLACYS E_,I_..VITVAFIIF WVRSKRSRLL HSDYIVMITPR RPGPTRKHYQ PYAPPRDFAA YRSRVKFSRS QQGQ NQLYNEE_,NLG RRIELEYDVIIZIK RRGRDI’EMGG KPRRKNI)QEG KDKM AEAYSEIGMK CKICfiSiE—II) GE.XQGLS’I‘NE‘ I In further intents? the inventinn reintes tn CInne AL26554 LC DNA (SEQ ID N0: 3I8): GAAATAGTGATGACGCAGTCTCCAGCCACCCIGTCTGTGICTCCAGGGG AAAGAGCCACCC'I‘C'I'CC'I‘GCAGGGCCAG’I‘CAGAG'I‘GI‘I‘AGCAGCAACTI‘ AGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCAICIAT GG'I‘GCA'I‘CCACCAGGGCCAC'I‘GG'I‘A'I‘CCCAGCCAGGTI‘CAGI‘GGCAGI‘G GGTCTGGGACAGAGTICACTCTCACCAICAGCAGCCTGCAGICIGAAGA ’I‘T'I‘I‘GCAGI"I"I‘ATI‘AC'I'GI‘CAGCAG’I‘ACGCCGCCTACCC'I‘AC'I"I"I,"I‘GGCG GAGGGACCAAGGITGAGATCAAACGG In further enthndintents, the inventinn relates to Clnne A.E—26554 LC AA sequence (SEQ ID ND: 3L9): EIVMTQSPAT LSVSPGEILAT LSCRASQSVS SNLAWYQQKP GQAPRLLIYQ ASTRATGIPA RFSGSGSGTIE FTLTISSLQS EDFAVYYCQL} YAAYP'I‘FGGG 'I‘KVEIKR.

In r enthndintents? the inventinn I'eiates tn the LC CDRI thereof: ILASQSV’SSNLA (SEQ ID NO: 320). In further enthndintenta the ion relates to the LC CDRZ thereof: GASTRAT (SEQ ID NO: 321). In further etnbnditnents, the invention tetatee tn LC CDR3 f: QQYAAYPI‘ (SEQ ID NO: 322). {0327] In further emhndimentsa the nwentinn e tn Clone 54 CAR DNA I—IXL (SEQ ID NO: 323): ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATIGCTCCTGCA CGCCGCACCCCCGCAGG'IIIICAGC'IKEG'I‘GCAG'I‘C'I‘GGGGCTGA(:IG'IIIIAAG AAGCCTGGGGCCTCAGTGAAGGITTCCTGCAAGGCAICIGGATACACCT TCAC(ZIGAGCACTATATGCAC'I‘GGGTGCGACA(EGCCCCTGGACAAAGGC'1' TGAGTGGATGGGAGIAAICGGGCCTAGTGGTGGTAAGACAAGCIACGCA CAGAAGTTCCAGGGCAGAGICACCATGACCAGGGACACGTCCACGAGCA CAG'I'C'I'ACA'I'GGAGC'I‘GAGCAGCC'I‘GAGATCTGAGGACACGGCGG'I'G'I‘A CTACTGCGCCAGAGAGAGTTGGCCAATGGACGTATGGGGCCAGGGAACA AC'I'G'I‘CACCG’I‘C 'I‘CCTCAGGG’I‘CTACATCCGGC'I'CCGGGAAGCCCGGAA DSTGGCGAAGGTAGTACAAAGGGGGAAAIAGTGATGACGCAGTCTCCAG [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley CCACCC'I‘G'I'C'I'G'I'G'I‘CTCCAGGGGAAAGAGCCACCCTC'fiTCC'l‘GCAGGGCC AGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCC AGGCTCCCAGGCTCCTE‘CATC'I’A'I‘C‘rG'I‘GCA'I'CCACCAGGGCCAC'I‘GG'I'A'I‘C CCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCA 'I‘CAGCAGCCTGCAGTCTGAAGATE"I"1"TGCA(ZETE"1"I‘ATTAC'i‘G’I'CAGCAG'I‘AC GCCGCCTACCCTACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGG CCGCTGCCCTTGATAATGAAAAGTCAAACGGAACAATCATTCACGTGAA GGGCAAGCACCTC'I'G'I‘CCGTCACCC'IVI‘G'ITCCC'I‘GG'I'CC‘A’l‘CCAAGCCA'I‘ TCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACTCTCTGCTC G’l‘CACCG'IGGC'I"I"E,"I‘A’1‘AATCTTCTGGGTI‘AGA'I'CCAAAAGAAGCCGCC'I‘ GCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGGCCCCACA AGGAAACACTACCAGCC'fi7'I‘ACGCACCAC‘C'I‘AGAGATI"I‘CGC’I'GCCTATC GGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGCGTATCAGCA GGGCCAGAACCAAC’E‘GTA'I‘AACGAGC'I’CAACCTC‘IGC‘IACGCAGG’GAAGA GTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAGATGGGTGGC AAACCAAGACGAAAAAACCCCCAGGAGGGTCFCTATAATGAGCTGCAG AAGGA'I‘AAGA'IGGC'IGAAGCC'I‘ATI‘C'I‘GAAA'I‘AGGCA'I‘GAAAGGAGAG CGGAGAAGGGGAAAAGGGCLACGAC{KEEPTTG'I'ACCA66GACi‘ifiiAfiiii'CIACT GC’I'ACGAAGGATAC’I‘TA’IGACGCTCTCCACATGCAAGCCCTGCCACC'I'A In further embediments, the ien relates t0 Clane Ali—26554 CAR HXL AA saquénce (SEQ ID NO: 324): MALP‘V/TAiLL PLALLLE—E AAR LVQSGA ElVEiKPC‘rASVK VSCKASGYTF TEHYIVEWVRQ APGQRLEWMG V1GPSGGKTS YAQKFQGRVT MTE‘RD'I’S’I‘S’E‘V YMELSSLRSE, D’E‘AVYYCARE) ‘WGQG TTVTVSSGST SGSGKPGSGE GSTKGEIWVIT QSPATLSVSP GERA'I‘LSCRA NLAW YQQKPGQAPR 1.,141YGASTRA 'I‘GEPARFSGS GSGTEFTLTI DFAV YYCQQYAAYP KVEI D‘DEK SNGTIH-{VKG KE-{LCPSPEEP GPSKPFWVEA’ VVGGVLACYS LLVTVAFHF WVRSKRSRLL HSDYMNMTPR M’GP'I‘RKHYQ PYAPPRDFAA YRSRVKFSR8 ADAPAYQQGQ NQI_,YNEI_..NI_,G RREEYDVLDK RRGRDPEMGG KPRRKNPQEG LY’NELQKDKM IGMK DEERRRGKGHD GLYQGLSTAT KDTYDALHMQ ALPPR.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley ed set by Anne.Headley {0329] In further embadiments, the inventian relates 1:0 Clane AL26554 CAR DNA LxH (SEQ [D NO: 325): A'I‘GGCLACTCCCCGTAACTGCTCTGCTGCTGCCG’E‘TGGCAT’E‘GCTCC'I‘GCA ACGCCCGGAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCT GTGTC'I'CCAGGGGAAAGAGCCACCC'I‘C'I'CCTGCAGGGCCAG'I'CAGAGTG TTAGCAGCAACTTAGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAG GCTCCTCATCTATGGTGCATCCACCAGGGCCACTGGTATCCCAGCCAGGT TC.AG’R‘GGCAGTGGG’I‘C'IGGGACAGAG’H‘CACTCTCACCA'I'CAGCAGCC'I‘ GCAGTCTGAAGATTTTGCAGTTTATTACTGTCAGCAGTACGCCGCCTACC CTAC'I"E7'I"I‘GGCGGAGGGACCAAGGT'I'GAGATCAAACGGGGGTC'ILACA'I‘C CGGCTCCGG(’3AAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCAGGT GCAGCTGGI‘GCAG'I'CTGGGGCTGAGGTGAAGAAGCC'I‘GGGGCCTCAGTG AAGGTTTCCTGCAAGGCATCTGGATACACCTTCACGGAGCACTATATGC ACTGGGTGCGACAGGCCCC'I‘GGA(:3AAAGGCT'I‘GAGTGGA’ETGGGAG'I‘AAT CGGGCCTAGTGGTGGTAAGACAAGCTACGCACAGAAGTTCCAGGGCAGA G'I‘CACCA7E‘GACCAGGGACACG’E‘CCACGAGCACAGREE"ACATGGAGC’EKEA GCAGCC'l‘GAGA'I‘C'I‘GAGGACACGGCGG'I'GI‘AC’R‘ACTGCGCCAGAGAGAG 'IVI'GGCCAA'I'GGACGTATE‘GGGGCCAGGGAACAAC'I'G’E‘CACiKirTC’ETCC'I'CA GCCGCTGCCCTI‘GA'I‘AA'IGAAAAG’I‘CAAACGGAACAATCA'H‘CACG’I‘GA AGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCA TTC'I‘GGGTGTI'GGTCGTAG'IGGG’I‘GGAGTCCTCGC‘TTGH'ACTCTCTGC'I‘C GTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCT GCTCCA7E‘AGCGATE‘TACATGAA'ETA'IGAC'I'CCACCECCGCCC’EKEGCCCELACA AGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATC GGAGCAGGG’I'Gz-XAGT’E‘T'I‘CCAGATCTGCAGATGCACCAGCG’FA'I‘ifiiAGCA GAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGA GTAT(ZE'AC(ETEVITTGGA(3AAGCGCAGAGGACGGC‘rACCC’E‘GAGATGGGTGGC AAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAG AAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAG CGGAGAAGGGGAAAAGGGCACGACGG’I"I"I‘G’IACCAGGGAC’I‘CAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTA {033g [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley {0331] In further embediments, the inventien relates t0 Clene [XI—26554 CAR LXH AA Sequenee (SEQ ID NO: 326): Mil-XLPVTE‘ALLL PE_,ALLE_,}-IAAR PlEEiIVh/ITQSPA 'I'LSVSPGERA TLSCRASQSV SSNLAWYQQK LLIY GASTRATGIP ARFSGSGSGT EFTLTISSLQ SEDFAVYY(2Q; QYAAYP’ITEGG G'I'KVEIKRGS 'I'SGSGKPGSG EGSTE‘KGQVQL VQSGAEVKKP GASVKVSCKA SGYTFTEHY‘M HWVRQAPGQR LEWMGVIGPS GGKTSYAQKF QGRVTMTRDT STSTVYMELS 'I'AVY YCARESWPI‘VID ’I‘TV'I‘V SSAAALDNEK SNGTIIIIVKG KHIEPSPLFP GPSKFFWVLV VVGGW_,A,CYS LLVTVAFIIF WVRSKRSRLL H. SDYMNMTI‘I’R RPGP'I‘RKHYQ I’YAPI’RDFAA YRSRVKFSRS QQGQ NQLYNELNLG REEF.YDVI_,DK RRGRDI’EMGG KPRRKNI)QEG LYNELQKDKM AEAYSEIGMK KGHD GLYQGLSTAT KDTYDALHMQ ALPPR In further embediments, the invention reiates to {Home NM~26562 E-IC DNA (SEQ ID N0: 327): CAGGTGCAGC'IIIICACIGAG'I‘CC‘IGGCCCAGGACTC‘IG'I‘GAAGifiCT'I‘CACAGA CCC"I‘G’I‘CCC'I‘CACC"ITG'I'AC'I‘GTCTCTGG’I‘GGCTCCA'I‘C‘GGGAG’I‘GGTGGI‘ AGIVIACTE‘GG[LXGZZICTE‘GIIIATCCGCCAGCACCCAGGGAAGGGCC'I'GGAGTGGA 'I‘I'GGGI‘I‘GA'I'C’I'A'I"IACGA'IGGGAGC‘ACC’I'AC'I‘ACAACCCG’I'CCC'I‘CAAG AGTCGAGTTACCATATCAGTAGACACGTCTAAGAACCAGTTCTCCCTGA AGC'I'GAG'I‘IC'I'G'I‘GACCGCCGCAGACACGGCGGTG’I‘AC'I‘AC’I‘GCGC‘CAG AGGCAGGGGATATGAGACTTCTTTAGCCTTCGATATCTGGGGTCAGGGT [MIAATGG’E‘CACCG’I'C'I'CCI‘CLI-X {0333} In further embodiments, the invention relates t0 CIQhe NBA—26562 BC AA sequence (SEQ ID NO: 328:): QVQLQEESGPG SQTLSL 'I‘ifii'I‘VSGGSIG SGGSYWSWIR QIIPGKGLEWI GLIYYDGSTY ENI’SLKSRVT ISVDTSKNQF SLKLSSVTE‘AA DTAVYYCARG IAFD 1W(IQGTMVTV SS {0- 34-} In further intehts, the inventien relates to BC CDRI thereof: GSIGSGGSYWS (SEQ ID NO: 329), In thither ments? the hwentien relatee to I-IC CDRZ thereef: LIYYDGS'I‘YYNPSLKS (SEQ ID NO: 330). In further ments, the inventinn relatee to EC CDR3 thereof: ARGRGYETSLAFDI (SEQ ID NO: 331} {0335} In further emhediments, the inventien reIates t0 Ciene NMiu26562 LC DNA [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley GAAATTGI‘GT'I‘GACACAG'I‘C'I‘CCAGCCACCC'i‘G'I'CTLTGTC'I'CCAGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTA Gt:CTE‘GG’IACCAACAGAAACC'I‘GGC(fiiAGGC'I'CCCA(IiGC'I'C(I'I‘CA'E‘C’E‘ATG CCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG GLC’ETGGGACAC‘IAifiTI‘CACTCTCACCA'I‘CAGCAG’CC’i‘AGAGCCTGAAGAT TTTGCAGTTTATTACTGTCAGCAGAGACACGTCTGGCCTCCTACTTTTGG CGGAGGGACCAAGGTTGAGATCAAACGG in further ments, the inventinn relates t0 Clone 562 LC AA sequence (SEQ ID NO: 333): EIVL'I‘QSPA'I‘ LSLSPGERA'I‘ LSCRASQSVS SYLAWYQQKP GQAPRLLEYQ AS’NRATGEPA SGTD FTLTISSLEP EDFAVYYCQQ TFGG G'I‘KVEIKR [0337} In r embndiments, the inventien relates to LC CDR] AA sequence thereof: RASQSVSSYLA (SEQ {D NO: 334) in further embodiments, the inventinn reintes tn LC CDRZ AA sequence thereof: DASNRAT (SEQ [D ND: 33 5). In fiirther embodiments, the inventinn relates tn LC {313R}: AA sequence therenf: QQRE-EVW PPTE‘ (SEQ ED NO: 336) (LC CDR3).

In thither embediments, the invention relates to Clone Nix/3926562 CAR DNA HXL (SEQ in NO: 337); ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCG‘CACGCCCGCAGG'I‘GCAGCTGCAGGAGTCGGGCCCAGGAC'I‘GGTG AAGCCTTCACAGACCCTGTCCCTCACCTGTACTGTCTCTGGTGGCTCCAT {IfGGGAGTGG’E‘GCSTE‘AGZZETI‘AC’i‘GGA(:S'C’E‘GGATCCGCCAGCACCCAGGGz-XAG GGCCTGGAGTGGATTGGGTTGATCTATTACGATGGGAGCACCTACTACA A{IfCCG'E‘CCCTE‘CAAGAGTC(ZEAGTETACCATA’ETCAGTAGAifiiAC(ETC7E‘AAGAA CCAGTTCTCCCTGAAGCTGAGTTCTGTGACCGCCGCAGACACGGCGGTGT ACTACTGCGCCAti‘rAGGCACE’GGGATiI-X’ET(},A{},A{Z’ET’E‘CZ’E‘TTAGCCTI'CGA'E‘ATC TGGGGTCAGGGTACAATGGTCACCGTCTCCTCAGGGTCTACATCCGGCTC CGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAAATTGTGTT GACACAGTCTCCAGCCACCC'I'GI‘C'1"I"I'GI‘C'I‘CCAGGGGAAAGAGCCACC CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCTACTTAGCCTGGTACCA ACAGAAACC’l‘GGCCAGGC/TCCCAGGCTCCTCA'I‘C'I‘A'I‘GA'I‘GCA'I‘CCAAC QGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGGGTCTGGGACAG [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley C'I‘C'I‘CACC‘[YECAGCAGCC'ILAGAGCCTGAAGATTTTGCAGTTl‘A'l‘ TACTGTCAGCAGAGACACGTCTGGCCTCCTACTTTTGGCGGAGGGACCA AGG'lvl'GAGATCAAACGGGCCGC'llIZlCCCT’KlATE‘AA'l‘C‘rAAAAGTCAAACGG AACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCC CTGG'I‘CCATCCAAGCCATTC'l‘GGGTE‘GT’E‘GGTE‘CGTAG’llGC‘rG'l‘GG/AG'l'CC"l"C GCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGA TCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCAC GCCGCCC'I‘GGCCCCACAAGGAAACAC'l'ACCAGCC"l‘TACGCACCACC'I‘AG AGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATG CACCAGCG’I‘ATCAGCAGGGCCAGAACCAAC'I‘G'l7A'l'AACGAGCTCAACCT GGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGA CCC'l‘GAGA’l'GGGI‘GGCAAACCAAGACGAAAAAACCCCCAGGAGGGI‘C'I‘ CTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATA GGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGAC{}{:}’l‘7l"l‘{1}’E‘A(I CAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGC AAGCCC’EGCCACCTAGG, In further emlmdiments, the lnventlcn relates :0 Clone NEE—26562 CAR HXL (SEQ ll) NO: 338): l‘leLP‘v"l'ALLL PLALLLHAAR ESGP GLVKPSQTLS L'I‘C'I‘VSGGSI GSGGSYW’SWI RQHPGKGEEW IGLIYYDGST YYNPSEKSRV TESVDTSKNQ FSLKLSSVTA AD'l‘AVYYCAR GRGYE’I‘SLAP DRVGQGTMV'I‘ VSSGS'I‘SGSG KPGSGEGSTK GElVlTQSPA TLSLSPGERA RASQSV SSYI_,AWYQQK LE_,EY DASNRA’llGlP ARFSGSGSGT DF'E‘Ll‘lSSLE PEDFA‘V/YYCQ QRHVWPPTFG GGTKVEIKRA AALDNEKSNG GKBL CPSPLFPGPS KPFWVLVVVG GVLACYSLLV TE‘VAFHFWVR SKRSRLLEEESD YMNIVl’E‘PRRPG PTRKHYQPYA PPRDPAAYRS RVKESRSADA PAYQQGQNQL YNELLNMERRE EYDVLDKRRG RDPLEMGGKPR EGLYN ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLSTATKDT YDAll-ENIIQALP PR. {03%} In filr’thsr embgdimfints, the invention relates to Clone NMQéSéZ CAR. DNA LXH (SEQ ID NO: 339): [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAAATTGTGTTGACACAGTCTCCAGCCACCCTGTCTT TGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT TAGCAGCTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGG CTCCTCATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTF CAGTGGCAGTGGGTCTGGGACAGAETTCACTCTCACCATCAGCAGCCTA GAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGAGACACGTCTGGCC TCCTACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTACA TCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCAG GTGCAGCTGCAGGAGTCGGGCCCAGGACTGGTGAAGCCTTCACAGACCC TGTCCCTCACCTGTACTGTCTCTGGTGGCTCCATCGGGAGTGGTGGTAGT TACTGGAGCTGGATCCGCCAGCACCCAGGGAAGGGCCTGGAGTGGATTG GGTTGATCTATTACGATGGGAGCACCTACTACAACCCGTCCCTCAAGAGT CGAGTTACCATATCAGTAGACACGTCTAAGAACCAGTTCTCCCTGAAGCT GAGTTCTGTGACCGCCGCAGACACGGCGGTGTACTACTGCGCCAGAGGQ AGGGGA’E,"A'I‘GAGAC'1‘TCT"ETTE‘AGCC1‘TCGATE‘ATCTG’C‘rGC‘r’E‘CAGGG’ETACAAT GGTCACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTCAAACGGA ACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCC TGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCG CTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGAT CCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACG CCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGA I"F{I(3(37F(}(3(317fl\TF{3(}(}%X(}€3£&{3{}{3’F(}/A[X(35F3"E"F(I(I%\{}/XTF(21‘(}(Ifi\{}/XTF(}(I GTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTG GGA{3GCAGGGA AGAG'E‘A'I'Gz—XCGTE‘TTTGGA{3AAGCGCAGAGGACGGGAC CCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCT ATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGG CATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCA GGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAA CCACCTAGG {0342] In further @mbodimen‘ts, the invention relates t0 Cleric-5 DIM—26562 CAR LXH (SEQ ID NO: 340): [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley MALPVI'ALLL PLALLLHAAR PEIVLTQSPA 'I‘LSISPGERA ’I‘ISCRASQSV SSYIAWYQQK PGQAPRLIJY DASNRATGIP GSGT DFTLTISSLE PIELIIFA‘V'YYCQ QRI-IVWPP’I‘FG GGITKVEIKRG STE‘SGSGKPGS GEGSTKGQVQ LQESGPGLVK PSQTLSLTCT VSGGSIGSGG S‘erSWIRQIIP GKGLEWIGLI YYIXIS’IYYNP SIJKSRV'I‘ISV D'I‘SKNQFSLK LSSVTAADTE‘A ‘v’YYCARGRGY SDIWG QGTMVTVSSA AALDNEKSNG IIII-IVKGKHL CPSPLFPGPS NVVCi GVLACYSI_,LV TVAFIIFWVR SKRSRILI—ISD YMNMTPRRPG P'I‘RKHYQPYA PPRDFAAYRS R‘v’KFSRSADA PAYQQGQNQL Y’NI‘IMGRRP EYEV’IDKRRG RDPEMGGKPR RKNPQEGLYN ELQKDKMAEA YSEIGMKGER RRGKGHDGLY QGLS’I‘A'I'KDT YDAIHMQAIP PR In further enthedintents, the ien s to Clene "ISwZZéSéiI EEC DNA sequence (SEQ ID N0: 341): GAGG'I‘GCAGCTGGIGGAGI‘CI‘GGGGGAGGCI‘TE‘GG'I‘ACA(ICC'I‘IIIGGGGGT CCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTAIAGC A'I‘GAAC'E‘GGG’I'CC(ICCAGGCTCCAGGGAAGGGGC'I‘IIIGAG'I'GGGI"I"FCAA CCA'I7'I‘AG'I'AG'I'AG’I‘AG’I‘AG'I‘A'I'CA'I‘A'I7AC'I'ACGCA(IAC'I'C'I'GI‘GAAGGG C(IGA’ITCACCATCTCCAGAGACAATGCCAAILIAAC'I'CAC'E‘G’IA'I‘C'I‘GCAA A’I‘GAACAGCC'I‘GAGAGC'IGAGGACACGGCGG’I‘G’I‘AC'I‘AC’I‘GCGCCAGAG GTTCTCAGGAGCACCTGATTTTCGATTATTGGGGACAGGGTACATTGGTC ACCG’I'C’I'CC'I‘CA {0344] In tnrtner ernbodirnents, the. inventien relates to Clone "IS—26564 HC AA Sequence (SEQ ID N0: 342.): IEEVQLVESGGG INQPGGSLRI, FTFS SYSIVII‘WJVRQA PGKGLEWVS}: IIYY ADSVKGRFTI SRDNAKNSLY LQMNSLRAELD 'IZAVYYCARGS (IEli-ELIE)WVG QC‘x’I‘IA/"IVS S [0345} In further embodiments, the invention relates to EC CDRI AA sequence f: FTE‘FSSYSMN (SEQ ID NI}: 3435). In further enrbediments? the invention relates tn HC CDRLZ AA sequence therenf: TISSSSSIIYYADSVKG (SEQ ID NO: 34-4). In further embediments, the inventien relates to I-IC CDR3 AA sequenee tI'lereef: I-ILIFDY (SEQ ID NO; 345), {0346] In further lI’IIeIIISy the invention relates to Clone ITS—26564 LC DNA (SEQ ID NO: 346): [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley GAAA'l"l'(i'l‘G’l"l‘GACACAG'I‘C'l‘CCAGCCACCC'l‘G’l'C’l'TTG’l'C'l'CC‘AGGGGA AAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGGTACTTA Gt:CTE‘GG’l‘z-XCCAACAGAAACC'l‘GIZlGC(fiiAGGC'l'CCCAGGC'l'CC'l'ELA’E‘C’E‘ATG ATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTTCAGTGGCAGTGG G’llC’llGG’GACAGAC"PFCACTCTCA(ICATCAGCAG’CC’lTAGAGC(ITGz-XAC‘IA'I‘ TTTGCAGTTTATTACTGTCAGCAGAGATTCTACTACCCTTGGACTTTTGGC GGAGGGACCAAGGTTGAGATCAAACGG In further embediments, the lnventlen relates t0 Clone TS~26564 LC AA eequence (SEQ ID NO: 347): ElVL'I‘QSl’A'l‘ LSLSPGERA’I‘ LSCRASQSVS RYLAWYQQKP GQAPRLUYQ AS’NRATGIPA RFSGSGSGTD FTLTISSlEP EDFAVYYCQQ TFGG G'l‘KVElKR [0348} In further ments, the lnventlen relates to LC CDRl AA sequence f: RASQSVSRYLA (SEQ ll) NO: 348). In fintber emlmcllrnenls, the invention relates to LC CDRZ AA sequence thereof: DASNRAT {SEQ [D ND: 34-9). In further embodiments, the inn s t0 LC (DDR3 AA sequence therenf: QQRQFYYPWT (SEQ ll) NO: 3:30).

In further em’bndiments, the inventinn relates te Clnne 'l‘S—26564 CAR DNA l-lXL (SEQ ll) NO: 351): A’l‘GGCAC'I‘CCCCGI‘AAC'I‘GCTC'I'GC'I‘GC'I'GCCG'l"l"GGCA'l‘l'GC'lTCCTGCA CGCCGCACGCCCGGAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTA CAGCC'l‘GGGGGG’l'CCC'l‘GAGAC'l‘CTCC'lTG’I'GCAGCC’l‘C’l‘GGA'lTCACCTT CAGTAGCTATAGCATGAACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTG GAG’llGG’G'lTlTCAACCATE‘l‘AG'l‘AGTAGTAti‘x’E‘AGTE‘ATCATA’E‘AC'I‘ACGCAG ACTCTGTGAAGGGCCGATTCACCATCTCCAGAGACAATGCCAAGAACTC Atif'l‘G’l‘A'l'C'l'GCAAA'I'GAACAGCCTGAGAGCTGAtfi‘sz-XCAC(lGCGG’lTG'l‘AC TACTGCGCCAGAGGTTCTCAGGAGCACCTGATTTTCGATTATTGGGGACA GGG’ETACA’E‘Tl‘tfi‘niil’l‘ifiiACCG’EETCCTCAGGGTCTACATC(ICEGC'I‘CCGCEGAAGC CCGGAAGTGGCGAAGGTAGTACAAAGGGGGAAATTGTGTTGACACAGTC CACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCA GGGCCAGTCAGAG’I‘G’I‘TAGCAGG'I‘AC"ll'l‘AGrCC’l‘GG’lLACCAACAGAAACC TGGCCAGGCTCCCAGGCTCCTCATCTATGATGCATCCAACAGGGCCACTG GCA'I‘CCCAGCCAGGTI‘CAGI‘GGCAGI‘GGG’l‘CTGGGACAGAC'l‘l‘CAC'l'C'l' DIACCATCAGCAGCCTAGAGCCTGAAGATTTTGCAGTTTATTACTGTCAGC [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley AGAGATI‘CTACTACCCTTGGACTTT'[GGCGGAGGGACCAAGGTTGAGAT CAAACGGGCCGCTC?CCCTTGATAATGAAAAGTCAAACGGAACAATCATT CACGTGAAG€ZEG(IAA(3CACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATC CAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCGCTTGTTACT CTCTGCTC(ZE'TCACCG'E‘GGCTTTTATAATCTTCTGGGTTAGATCCAAAAGA AGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCTGG CCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCT GCCTATCGGAGCAGGGTGAAGTT'[TCCAGATC'[GCAGATGCACCAGCGT ATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAG GGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCC"[7GAGAT GGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGA GCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAA GGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACTC AGCACTGCTAC(3AAGGATACTTATGACGCTCTCCACATGCAACCCCT(3C CACCTAGG [0350} in Timber embodiments, the invention relates to Cione TEE-26564 CAR .

AA sequence (SEQ [D N0: 352): TATLL _JT_..[-[AAR PEVQTN’ESGG GE_,VQT’GGSLR LSCAASGFTF SSYSNTN‘WVRQ APGKGLE‘WVS TISSSSSHY YADSVKGRET [SRDNAKNSL Y[_.Q[V[NS[_;RAE DTAVYYCARG SQET-[[_..[EDYV\/ TVSS GKPG SGEGSTKGEI VLTQSPATLS LSPGERATLS CRASQSVSRY [_.,A,W7YQQKPGQ APRLLTYDAS NRATGTPARF SGSGSGTDET LTTSSLEPED FAVYYCQQRP YYPWTFGGGT KV’EiifliRAAAL DNEKSNGTH E-[VKGKT-[LCPS PLFPGPSKPF TNVLVVVGGVI ACYSLLVTVA ETEWVRSKR SRLLHSDYAW MTPRRPGPTR [(E-[YQPYAPPR DFAAYRSRVK APAY QQGQNQLYNE LNLGRREEYD VLDKRRGRDP EMGGKPRRKN YNELQ KDKMAEAYSE [GMKGERRRG KGHTBGLYQGL STATKDTYDA ALPPR {0351] [n fizrther embndiments, the inventim relates to Clene TSm26564 CAR DNA LXH (SEQ [D [101353) ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAAAT"T'G"['G’I"T‘GACACAGTCTCCAGCCACCCTGTCTT DTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGT [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley TAGCAGGTACTTAGCCTGGTACCAACAGAAACCTGGCCAGGCTCCCAGG ATCTATGATGCATCCAACAGGGCCACTGGCATCCCAGCCAGGTT CAGTGGCAGTGGGTCTGGGACAGACTTCACTCTCACCATCAGCAGCCTA GAGCCTGAAGATTTTGCAGTTTATTACTGTCAGCAGAGATTCTACTACCC 'FflflkfiiflfiTfifiCfiGAGGGACCAAGGTTGAGATCAAACGGGGGTCTACA TCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGAG GTGCAGCTGGTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCC TGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTAGCTATAGCATG AACTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCAACCA TTAGTAGTAGTAGTAGTATCATATACTACGCAGACTCTGFGAAGGGCCG ATTCACCATCTCCAGAGACAATGCCAAGAACTCACTGTATCTGCAAATG AACAGCCTGAGAGCTGAGGACACGGCGGTGTACTACTGCGCCAGAGGTF CTCAGGAGCACCTGATTTTCGATTATTGGGGACAGGGTACATTGGTCACC GTC’EKZCTCAGCCGCTGCCC’ETTE‘GATAA'HZE'AAAAGTCAAA()GC‘IAACAATCA TTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCA "ETCCAAGCCATTCT(ZEGSIZETG’E‘TE‘GG'E‘CG’E,"AGE‘GGGTGGAGTCCTCGC"ETTE‘GT’E‘A CTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAA GAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACGCCGCCCT GGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCG CTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGCACCAGC GTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGC AGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGACCCTGAG ATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATG AGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAA GCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCAGGGACT CAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTG CCACCTAGG {0352} In r msnts, the invention reiatss t0 Clans: TS—26564 CAR LXH ‘ijgequence(SE%}]I)?J{t'354) MALPVI‘ALLL PLALLLHAAR PEIVLTQSPA 'I'LSLSPGERA 'I‘LSCRASQSV SRYLAWW’QQK PGQAPRillY DASNRATGEP ARESGSGSGT DPTLTISSLE PEDFAVYYCQ ‘W'I‘FG GG'I‘KVEIKRG S'I‘SGSGKPGS GEGS'I'KGEVQ QV'ESGGGLVQ PGGSLRLSCA ASGFTPSSYS MNWVRQAPGK GLEWVSTISS [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley SSSIIYYADS "V’ICGRFTISRD NAK’NSLYLQM NSLRAED'I‘AV YYCARGSQEH LIFDYWGQGT LVTVSSAAAL DNEKSNGIII IIVKGKI-ILCPS PI_,FPGPSKPF WVLVVVGGVIJ AC‘i’SIIA/"ITVA I? E EIIWVRSK R SiRI,iE_JI-ISI)YMN M'I‘PRRPGPI‘R KHYQI’YAPI’R DFAAYRSRVK FSRSADAPAY LYI‘HE LNLGRREEYI) VLDKRRGRDI’ I3MGG€KPRRKN I’QIEGIXNEIQ KDKMAEAYSE IGMI‘ZGERRRG KGHDGLYQGL SIATKDTYDA LI-IMQALPPR In r embodiments, the invention s to Cione EEK—26568 HC DNA (SEQ ID NC): 355): I'GCAGC'I‘GGI‘GGAG'I‘C'I‘GGGGGAGGCG’I‘GG’ICCAGCC'I'GGGAGG’I‘ CCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCGGGAGCTATGGC A'I‘GCAC'I‘GGGTCCGCCAGGC'I‘CCAGGC‘AAGGGGCTGGAG’I‘GGGTGGCAG "ITATACATTATGATGGAAGTGTTGAATACTATGCAGACTCCGTGAAGGG CC(IA’E‘TCACCz-XTCTCCAGAGACAATE‘TifiiCAAGGACz-XCGC'E‘GTA'I‘CI‘GCAA AGCCTGAGAGCCGAGGACACGGCGGTGIACTACIGCGCCAGAA CTGACTTC'E‘GGAGC(IGAI‘CCCCTCCAAGC’E‘TAGA’E‘TE‘AC'I'GGGGACAGGG ’I‘ACA’II'I‘GGI‘CACCG’IC’I‘CC’I‘CA In thither embodiments, the invention s to Gene RY—26568 I—IC AA Sequence (SEQ ID NO: 356): QVQLVESGGG VVQI’GRSLRL SCAA SGF'I‘IFG EXQMIIWVRQA PGKGLEWVAM IIIXQIQIEMEXX ADSWXGRTH SRDNSKDTLY LQI‘VINSLRAED YCAR’I‘D I’SLD XWGQG'I'LV'I'V SS {0355] In further embodiments, the invention relates to EC CDRI tI'ieteof: FTFGSYGIVII-I (SEQ ID NI}; 357)" In further embodiments, the invention reiates to Hi: CDR2 thereof: VIIIYDGSVEYYADSVKG (SEQ ID NO: 358). In finther ments, the invention relates to I-IC CDR3 thereof: ARTDFWSGSPI’SIJDY {SEQ ID NO: 359). {0356;} In further embodiments, the invention relates to Clone RY—26568 LC DNA (SEQ II) NO: 360): GACATCCAGITGACCCAGICTCCATCTTCCGTGTCTGCATCTGTAGGAGA CAGAGTCACCATCACTTGTCGGGCGAGTCGGGGTATTAGCAGCTGGTTA G‘CC'I‘GGI‘A’I‘CAGCAGAAACCAGGGAAAGCCCC'I‘AAGC’I'CC"I‘GA'I'C’I‘A'I‘G GTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGG ATC’I‘GGGACAGA'I‘TTCACTCTCACCA'I'CAGCAGC‘C'I‘GCAGCC'I‘GAAGA'IVI‘ [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley AAC'i7'I‘A’1Vi7ACTGTCAGCAGA'I‘ATACACC’1'"i,‘CCC'I"1TCAC'I"i"ITGGCG GAGGGACCAAGGTTGAGATCAAACGG [0357} in further enibedinienis? the invention reieies in Clone RY—26568 LC AA sequence (SEQ ID N0: 361): DEQLXFQSPSS VSASVGDRVT iTC ASRGIS SWLAWYQQKP Li‘i’Q ASSLQSG‘W’S RFSGSGSGTD FTLTISSLQP EDFATYYCQQ IYTFPFTFGG GTKVEIKR, in further embodiments, the invention relates to LC CDRi AA sequence thereef: SSWLA (SEQ ED NO: 362). in further embodiments? the invention s t0 LC CADRE AA sequence thereef: GASSLQS (SEQ 1D NO: 363‘). in further embodiments, the inventien relates in LC CDR3 AA sequence thereof: QQIYTFPFT (SEQ ID NC): 364) (LC CDR3). [0359} In further embediments, the inventien relates to Ciene RY~26568 CAR DNA HXL (SEQ 11) NO: 365): ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA GCACCCCC(3CAGGTGCA{3CTGG’E‘GGAGTE‘CTGGGGGAG(ZiCGTGG’i’C CAGCCTGGGAGGTCCC'I‘GAGAC'i‘C'I‘CCTG’I‘GCAGCG'I‘C'IGGA'I‘TCACCTI' CGGGAGC'I‘ATGGCATGCAC'i‘GGGTCCGCCAGGC'i‘CifihAGGCAAGGGGCTG GAGTGGG'IGGCAGITA'I‘ACA'ITA'I‘GA'I‘GGAAGTG'ITGAATAC"i‘A'I'GCAG ACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGGACAC GC'I‘G’l‘A'i'C'i'GCAAA'i'GnAACAGCC'I'GAGAGCCGAGGACACGGCGG'I‘G’I‘AC TACTGCGCCAGAACTGACTTCTGGAGCGGATCCCCTCCAAGCTTAGATTA CTGGGGACAGGGTACA'i'TGG'E‘CACCGTCTCCTCAGGGTCTACATCC66CT AGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGGACATCCAGT ’37GACCCAGTC'E'CC1ATC’E7TC(ZG'i‘iCETE‘CTE‘6CATCTE‘GTAGGAGACAGAGTCACC ATCACTTGTCGGGCGAGTCGGGGTATTAGCAGCTGGTTAGCCTGGTATCA GCAGAAACCA66GAAAGCCCCTAAGC'1'CCT(EATC'i'ATGGTGCATCCAGT TTGCAAAGTGGGGTCCCATCAAGGTTCAGCGGCAGTGGATCTGGGACAG ATTTCACTCTCACCATCAGCAGCCTGCAGCCTGAAGATTTTGCAACTTAT TACTGTCAGCAGATATACACCTTCCC'i"I"i,‘CACTT'I'TGGCGGAGGGACCAA GGTTGAGATCAAACGGGCCGCTGCCCTTGATAATGAAAAGTCAAACGGA ACAA'I'CA'I‘TCACGI‘GAAGGGCAAGCACCTCTGI‘CCG'i'CACCC'i'TGTFCCC DTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGGAGTCCTCG [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley CTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAGAT GAAGCCGCCTGCTCCATAGCGATTACATGAATATGACTCCACG CCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTAGA GCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCTGCAGATGC ACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGCTCAACCTG GGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGGACGGGAC ATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGAGGGTCTCT 'I'GAGC'I‘GCAGAAGGA'ELLXAGA'I‘GGC'I‘GAAGCCEA'ITCTGAAATAGG AGGAGAGCGGAGAAGGGGAAAAGGGCACGACGGTTTGTACCA GGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATGCAA GCCCTGCCACCTAGG In further embodiments, the invention relates to Clone RYu26568 CAR HXL AA sequence (SEQ ID NO: 366): B/iALP‘V/"I'ALLL PLAiEiLE-iEAAR PQVQL I’ESGG (WVQPGRSLR GFTF GSYGREQNVRQ APGKGLEWWUX VHfKDGSVEY YADSVKGRFT {SRDNSKDTL XEXHfiNSLRAE iDTAVYYCART DFWSCEPPSL DYWGQG'I‘LV'I‘ VSSGSTSGSG KPGSGEGS'I‘K GDEQL'ETQSPS SVSASVGDRV THC ASRGE SSWLAWYQQK LLEY GASSLQSGVP SRFSGSGSGT DFTL’R‘ESSLQ PEDFA'I‘YYCQ Qi‘i’TFPF‘i‘FG GGTKVEEKRA AALDNEKSNG TIME/KGKE-{L CPSPEEPGPS KPFWVLVVVG GVLACYSI_,I_.V TVAFHFWVR SKRSRLLHSDEfiflNNHPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADA PAYQQGQKKHI YNELNLGRRE EYDVLDKRREE RDPHWGGKPR CHXN ELLQKDKMAEA YSEIGMKGER RRGKGHDGLX QGLSTATKDTYTMfljHflQALPPR [0361} in further embediments, the invention relates 10 Cinne RYwZ‘éSéfi CAR DNA LXH (SEQ ID NO: 367): ATGGCACTCCCC(ZETAA{IfTGCTCTGUI‘GCTGCCKSrTTGGCAT'I"GC’E"CC'§7Gill-X CGCCGCACGCCCGGACATCCAGTTGACCCAGTCTCCATCTTCCGTGTCTG CATCTGTAGGAGACAGAGTCACCATCACTTGTCGGGCGAGTCGGGGTAT TAGCAGCTGGTTAGCCTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAG CTCCTGATCTATGGTGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTT CAGCGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGCCTG DIAGCCTGAAGATTTTGCAACTTATTACTGTCAGCAGATATACACCTTCCC ation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley 'I"I"I'CAC'1"I"I"I'GGCGGAGGGACCAAGG’RTGAGATCAAACGGGGG’I‘C'I‘ACA TCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAGGGGCAG GTGCAGCTGGE‘GGAG’E‘C’E‘GGGGGAGGC(3'1"(EG'I'CCAGifiCTGGGAG€ZiT<fi1CC TGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCGGGAGCTATGGCATG CAC'I‘GGGTCC(SrCCAGGC'I‘CCAGGCAAGGGGC'I‘GGAGIGGCETGGCACETI‘A TACATTATGATGGAAGTGTTGAATACTATGCAGACTCCGTGAAGGGCCG ATTCACCATCTCCAGAGACAATTCCAAGGACACGCTGTATCTGCAAATG AACAGCCTGAGAGCCGAGGACACGGCGGTG’I‘AC'I‘AC'I'GCGCCAGAAC'I‘G ACTTCTGGAGCGGATCCCCTCCAAGCTTAGATTACTGGSGACAGGGTAC ATTGGI‘CACCG'R‘CTCC’R‘CAGCCGCTGCCCTTGA'I‘AA’IGAAAAG'I'CAAACG GAACAATCATTCACGTGAAGGGCAAGCACCTCTGTCCGTCACCCTTGTTC CC'I‘GG’I‘CCA'I‘CCAAGCCATE"C'I'GGG'I‘GTI‘GG'I'C‘GTAG’I‘GGG’I‘GGAGTCCT CGCTTGTTACTCTCTGCTCGTCACCGTGGCTTTTATAATCTTCTGGGTTAG AFCCAAAAGAAGCCQCCTGC’E‘CCATAGCGA'1"1"A(IA'I‘GAATA’ETGACTCCA CGCCGCCCTGGCCCCACAAGGAAACACTACCAGCCTTACGCACCACCTA (LAGAETTE‘TCGCTGCC’E‘A'I’CGGAGCAGSGTGAAGFFF’E‘CCAGA'I‘C'I‘GCAGA'I‘ GCACCAGCG'I'A'I‘CAGCAGGGCCAGAACCAAC'I‘GTA'I'AACGAGCTCAACC 'I‘GGGACGCAGGGAAGA(STE‘A’ETGAC(ZETFFFGGACAAGCGCAGAGGACGGG ACCC‘TGAGA’IGGGI‘GGCAAACCAAGACGAAAAAACCCCCAGGAGGGI‘C TCTATAATGAGCTGCAGAAGGATAAGATGGCTGAAGCCTATTCTGAAAT AGGCA'I'GAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGG’R‘TI‘GTA CCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCCACATG CAAGCC{3TGCCACC'I’AGG {0362} In further embediments, the inventien relates t0 Clone Rme-16568 CAR LXH AA Sequenca (SEQ [D NO}: 368): ALLL PLALLLHAAR QSPS SVSASVGDRV TITCRASRGI SSWLAWYQQK PGKAPKLLEY GASSLQSGVF SREQ‘SGSGSGT DFTLTISSLQ PEDFATYYCQ QIYTFPFTEG GGTKVEIKRG STSGSGKPGS GEGSTKGQVQ LVESGGGVVQ PGRSLRLSCA ASGFTFGSYG MHWVRQAPGK GLEWVAVEHY DGSVEYYADS VKGRF’HSRD NSKD'I‘LYLQM NSLRAQEDTAV YYCARTDPWS _,DYWG QGTLVTVSSA AALDNEKSNG 'I'HHVKGKHL PGPS KPFWVLVVVG GVLACYSLLV DTVAFHFWVR SKRSRLLHSD YMNNETPRRPG PTRKHYQPYA PPRDFAAYRS — 100 - [Annotation] Anne.Headley None set by eadley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley R‘VKFSRSADA PAYQQGQNQL YNELNLGRRE EYDVLDKRRG REPEMGGKPR GI...YN ELQKDKI‘VIAEA YSEIGIVIKGER RRGE‘IGE-IDGLY QGLSTA'E‘KDT YI)AI_..I-IMQALP PR [0363} In thither embodiments, the invention relates tn Ciene PP~26575 BC DNA (SEQ II) NI): 369): CAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCT CGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCCTCAGCAGCCTGGC TA'I'CAGC'I‘GGG’I‘GCGACAGGCCC‘C'I‘GGACAAGGGC'I‘TGAG’I‘GGA'IGGGA GGGGTCATCCCTATCTTGGGTCGGGCAAACTACGCACAGAAGTTCCAGG GCAGAG'I'CACGA'IVI‘ACCGCGGACGAG’I‘CCACGAGCAC‘AGCC'I‘ACA'I‘GGA GCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGTACTACTGCGCCAGA AC'I‘CC"ITGAA’I'AC'I‘CC’I‘CCAGCA'I‘A'IGGCAC'I‘A'I7'I‘AC’I'ACGGCA'I‘GGACG'I‘ CCAGGGAACAACTGTCACCGTCTCCTCA In further embodiments, the invention s te Cinne PP-26575 I-IC AA ce (SEQ ID NO: 370): QVQL‘VQSGALE VKKI’GSSVKV SCICASGGTE‘IS SLAISWVRQA PGQGLE‘Wh/IGQ VII’ILGRANY AQKFQGR‘VTI 'I'ADES'I'S'I‘AY h/IELSSLRSED 'IIAVYYCARTP EYSSSE‘i/VI-IYY YGMDVWCi'QG’i‘ TVI‘VSS. {0365] In further einbndiinents, the inventinn relates to EC CDRI AA sequence thereof: GTI_,SSLAIS (SEQ II) NO: 37I). In filt’théjt‘ embodiments, the invention relates to EC {DDR2 AA ce thei‘enf: GVII’ILGRANYAQKFQG (SEQ ID NO: 372). In further embodiments, the invention reintes to I-IC CDR3 thereof: ARTPEYSSSIWIIYYYGMDV (SEQ II) NO: 373). {0366} In further einbndiinents, the invention relates tn Clone PPm26575 LC DNA (SEQ ID NO: 374): GACATCGTGATGACCCAGICTCCAGACTCCCTGGCTGTGTCTCTGGGCGA GAGGGCCACCA'I‘CAAC’E‘GCAAti‘r’E‘CCA(ICCAGAG'I‘G’I"IVI'TA'I‘ACAGCTCC AACAATAAGAACTACTTAGCTTGGTACCAGCAGAAACCAGGACAGCCTC CTAAGCTGCTCATTTACTGGGCATCTACCCGGGAATCCGGGGTCCCTGAC CGATTCAG'I‘GGCAGCGGGI‘C'I‘GGGACAfiA'ITICAC'I‘C"I‘CACCA'ITCAGCA GCC'I‘GCAGGCTGAAGATGTGGCAGTTTATTACTGICAGCAGTTCGCCCAC AC’I‘CC’I’TTCAC'I"I"I"I‘GGCGGAGGGACCAACiG’I"I‘G.AGA'I‘CAAACGG — 101 - [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley {O367} In " einbednnents, the inventien relates to Clene PP—26575 LC AA sequence (SEQ ID NC): 375): DIVM'I‘QSPDS IAVSLGERATE‘ INCKSSUSVL NYIA WYQQKPGQPP KLLIYWASTR fiGVPDRFSG SGSGTDEILT ISSLQAEDVA VYYCQQEAHT PIFI‘FGGG'I'KV EIKR. {0368} In further embodiments, the inventien relates to LC CDR I AA sequence theft-30f: KSSQSVIYSSNNKNYLA (SEQ ID NO: 376). In further embodiments, the inventien relates to LC CDR2 AA ce thereef: WAS'I‘RES (SEQ ID NO: 377). In further enlbedinlenm the invention relates to LC CDR3 AA sequence th erenf: QQFAI—ITFFT (SEQ ID NO: 373). {0369] In further mente, the invention reiates to Clene PPv26575 CAR DNA HXL (SEQ ID N0: 379): ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCICCTGCA CGCCGCACGCCCGCAGG’I‘GCAGC'I‘GG'I‘GCAGTC’ITGGGGC'I‘GAGG’I‘GAAG AAGCCIGGGTCCTCGGTGAAGGTCTCCTGCAAGGCTTCTGGAGGCACCC TCAGCAGCC'I‘GGCTA'I‘CAGC’IKIGG'I'GCGACA66CCCCTGGACAAGGGC'I" ’I‘GAG’IGGA'I‘GGGAGGGGI‘CA'I'CCC'I'A'I‘C'I‘I‘GGG’ITCGGGCAAAC'I’ACGCA CAGAAGT’E‘CCAGGGCAGAG'I‘CACGA’ITTE‘ACCGCGGACGAG'I‘CCACGAGCA CAGCCTACA’I‘GGAGC’I‘GAGCAGCC'ITGAGA'I‘C'I‘GAGGACACGGCGG’I‘G'I‘A CTACTGCGCCAGAACTCCTGAATACTCCTCCAGCATATGGCACTATTACT ACGGCA'IGGACG’I'A'I‘GGGGCCAGGGAACAAC'I'G'I‘CACCG’ITC'ITCC’I‘CAGG GTCTACATCCGGCTCCGGGAAGCCCGGAAGTGGCGAAGGTAGTACAAAG GGGGACATCGTGA'ITGACCCAGI‘C'I‘CCAGACTCCC'I‘GGC'I‘G’E‘G’ICTCTGGG CGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTGTTTIATACAGC '3,"CCAACAA'I'AAGAAC’E‘AC'ITAGCT’I‘GCETEA(ICAGCAGAAACCAGGACAGC CTCCTAAGCTGCTCATTIACTGGGCATCTACCCGGGAAICCGGGGTCCCT TE‘TCAGTGGCAGCGGG’I'C'I'GGGACAGA’E‘TE‘TCACTCTCACCA'I‘CA GCAGCCTGCAGGCTGAAGATGIGGCAGITTATTACTGTCAGCAGTTCGCC CACACTCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAGATCAAACGGG CCGCTGCCCTI‘GA'I‘AA'IGAAAAG’I‘CAAACGGAACAA’I‘CA'I‘I'CACG'I‘GAA GGGCAAGCACCTCTGTCCGTCACCCTTGITCCCTGGICCATCCAAGCCAT 'I‘C'I‘GGG’I‘G’I‘I‘GGI‘CG'I'AG’I‘GGGI'GGAG'I'CC'I‘CGC'I'IG’ITAC'I‘C'I‘C'I‘GCTC DSTCACCGTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCT —102- [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley GC'I'CCA'I‘AGCGATI‘ACA'I‘GAA’l‘A'I'GAC'I'CCACGCCGCCCTGGCCC‘CACA AGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATC GGAGCAGGG'I'fiAAGT'E‘T'I‘CCAGATCTGCAGATGCACCAGE?GTA'I‘QAGCA GGGCCAGAACCAACTGTATAACGAGCTCAACCTGGGACGCAGGGAAGA G’ETA'E'GAC(Ii*7E"I"I‘TGGA(3AAGCGCAGAGGACGGC‘IACCC'E‘GAGATGGGTGC‘IC AAACCAAGACGAAAAAACCCCCAGGAGGGTCTCTATAATGAGCTGCAG AAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAG CGGAGAAGGGGAAAAGGGCACGACGG’IWH‘G’I‘ACCAGGGAC’I'CAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTA {0370] In fhrther embodimel'rtsg the inventim reiates to Clone EFF—26575 CAR HXL AA sequence (SEQ [D N0: 380): MALPVTALLL PLALLLHAAR PQVQLVQSGA EVKKPGSSVK VSCKASGGTL SSLAESWVRQ APC‘IQC‘ILEEWMG GVEPILGRAN YAQKFQGRVT ETADESTSTA YEWELSSLRSE DTAVYYCART PEYSSSIWHY YYGMDVWGQG 'ETTE‘VTVSSC‘IS'I‘ GSGE GSTKGDEVIVET QSPDSE...AVSE_, GERA’E‘ENCKS SQSVLYSSNN KNYLAWYQQK PGQPPKLLEY WAS'I'RESGVP DRFSGSGSGI‘ I)§9"I‘L'§7§iSSLQ AEEEDVAVYYCQ QFAEEE'I‘PFTFG GGTKVEiifliRA AALDNEKSNG 'I‘HHVKGKHL CPSPLFPGPS KPFWVLV‘V’VG GVLACYSLLV 'I'VAFHFWVR SKRSRLI_,HSD YMNMTPRRPG QPYA PPRDFAAYRS RVKFSR8ADA QNQL YNELNLGMKE EYD‘VLDKRRG RDPEMGGKPR RKNPQEGLYN ELQKDKMAEA YSEIGMKGER RRGKGHDGLX {LEGLSTE‘ATEHYE‘ YDA E_,}-{MQALP PR {0371} In further embodiments, the invention relates to Clnne PEI-3,6575 CAR DNA LxE-I (SEQ [D N0: 383): ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGC‘IACATCGTGA'I'GACC{IfACETCTCCAGAC'I‘CC(ITE‘GGC’E‘ GTGTCTCTGGGCGAGAGGGCCACCATCAACTGCAAGTCCAGCCAGAGTG TTTTATACAGCTCCAACAATAAGAACTACTTAGCTTGGTACCAGCAGAA ACAGCC'I‘CC'I‘AAGCTGC‘TCAT’EVI‘AC'I'GGGCA'I'C’l‘ACCCGGGAA'I‘ CCGGGGTCCCTGACCGATTCAGTGGCAGCGGGTCTGGGACAGATTTCAC 'I‘C'I‘C‘ACCA'I‘CAGCAGCC'I‘GCAGGCTGAAGATG’I‘GGCAG'I"1"IEA'I'TAC'I‘GTC DAGCAGTTCGCCCACACTCCTTTCACTTTTGGCGGAGGGACCAAGGTTGAG — 103 - [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ATCAAACGGGGG’I'C'I‘ACATCCGGCTCCGGGAAGCCCGGAAG’I‘GGCGAAG GTAGTACAAAGGGGCAGGTGCAGCTGGTGCAGTCTGGGGCTGAGGTGAA GAAGCC'IGGGTCCTCGGTGAAGGTCTCCT(ZE’CAAGGCTTCTGGAGGCACC CTCAGCAGCCTGGCTATCAGCTGGGTGCGACAGGCCCCTGGACAAGGGC TT(IiAGTGGATGGGAGGGG'E‘CATCCCTE‘A’ETCTTGGGTC(ZE’GGCAA C ACAGAAGTTCCAGGGCAGAGTCACGATTACCGCGGACGAGTCCACGAGC ACAGCCTACATGGAGCTGAGCAGCCTGAGATCTGAGGACACGGCGGTGT AC'I‘AC'I'GCGCCAGAACTCCTGAATACTCCTCCAGCA'I‘A’l‘GGCAC'I‘AT'I‘AC TACGGCATGGACGTATGGGGCCAGGGAACAACTGTCACCGTCTCCTCAG CCGC'1‘GCCCTTG‘A’l‘AA'I‘GAAAAG’I‘CAAACGGAACAA'I‘CA’RVECACG’l‘GAA GGGCAAGCACCTCTGTCCGTCACCCTTGTTCCCTGGTCCATCCAAGCCAT TC"R‘GGG'I'G'I"I'GG'I'CGTAG'I‘GGGTGGAGTCCTCGC'IVI'G'I‘TACTCTCTGCTC GTGGCTTTTATAATCTTCTGGGTTAGATCCAAAAGAAGCCGCCT 7E‘AG’CGATE‘TACATGAA'ETA'I'GACTCCACGCCGCCCTGGCCCCACA AGGAAACACTACCAGCCTTACGCACCACCTAGAGATTTCGCTGCCTATC GGG'I'GAAGT'EVI‘TCCAGATCTGCAGATGCACCAGCGTAT(LAGCA GAACCAAC'1'G'I‘A’l‘AACGAGCTCAACC'I'GGGACGCAGGGAAGA G'ETA'E'GAC(355"???GGACAAGCGCAGAGGACGGGACCC’E‘GAGATGGGTGGC AAACCAAGACGAAAAAACCCCCAGGAGGG'I‘CTC'I‘A'I‘AA'I‘GAGCTGCAG AAGGATAAGATGGCTGAAGCCTATTCTGAAATAGGCATGAAAGGAGAG CGGAGAAGGGGAAAAGGGCACGACGG’I"I"I‘G’IIACCAGGGACTCAGCACT GCTACGAAGGATACTTATGACGCTCTCCACATGCAAGCCCTGCCACCTA {0372} In further embodiments, the inventmn relates t0 Clone PIP—26575 CAR LXH AA Sequenca (SEQ [D NO}: 382): REALPVTALLL PLALLLHAAR PDIVMTQSPD SLAVSLGERA TINCKSSQSV LYSSNNKNYL AWYQQKPGQP PKLLEYWAST REEESGVPDRFS GSGSG'I‘DFTL TISSLQAEDV AVYYCQQFAH TPFTFGGGTK VEIKRGSTSG SGKPGSGEGS TKGQVQLVQS GAEVKKPGSS VKVSCKASGG TLSSLAESWV GLE‘W BAGGVIPILGR ANYAQKFQGR V'I‘I’I'ADES'I‘S 'I'AYh/IELSSLR SEDTAVYYCA RTPEYSSSEW HYYYGB/{DVWG QGTTVTVSSA AALDNEKSNG 'I'HHVKGKHL CPSPLFPGPS KPFWVLVVVG GVLACYSLLV DTVAFHF‘WVR SKRSRLLHSD YB/INNITPRRPG PTRKHYQPYA PPRDFAAYRS —104- [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley RVKFSRSADA PAYQQGQNQL YNELNLGRRE EYD'VLDKRRG GKPR RKNPQEGI...YN ELQKDKMAEA YSEIGMKGER RRGEiGE-IDGIX QGLS’I‘A’E‘KDT IMQALP PR [0373} In further embednnents, the inventien relates te Clone RID—265% HC DNA (SEQ II) NO: 383): CAGGTGCGGCTGGTGGAGTCTGGGGGGGGCGTGGTCCAGCCTGGGAGGT CCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCTATGGC A'I‘ACAC'I‘GGGTCCGCCAGGC'I‘CCAGGCAAGGGGCTGGAG'I‘GGG’ITGGCAG TTATAGGGTATGATGGACAGGAGAAATACTATGCAGACTCCGTGAAGQG CCGATICACCA’I‘C’I‘CCAGAGACAA'IVI‘CCAAGAACACGC"ITG'I'A'I‘C'I‘GCAA ATGAACAGCCTGAGAGCCGAGGACACGGCGGTGTACTACTGCGTCAAGG GGCCG’I‘TGCAGGrAGrCCGCCA'I‘ACGCT'I"ITGGGA'I‘GGACGTA’I'GGGGCCA GGGAACAACTGTCACCGTCTCCTCA In finther embediments, the invention relates te Chane RIB—26576 I-IC AA sequence (SEQ ID NO: 384-): QVRIJVIELSGGG VVQI’GRSIJRIJ SET/AASIZZIF'ITFS SYGII—IWVRQA PGKGLEWVAE IG’YDGt EEKYY RIYI‘I SRDNSICN’I’LY I‘VQIVINSIJRAQEI) YCVKGP I4 IELI’ PYAIIGIVI gym/{IQG’E‘TVIT VSS. {0375] In r embednnents, the inventien relates to EC CDRI AA sequence thereof: FTFSSYGIII (SEQ ID NO: 385). In further embednnents, the invention relates to EC CDRZ AA ce thereof: QEKYYADSVKG {SEQ ID NO: 386). In further embodiments, the nwention relates t0 the IIC CDR3 AA sequence tI'tereef: VICGPLQEPPY/Aih'tifithI)V (SEQ II) NO: 387). {0376} In further embodiments; the invention relates t0 Clone RID—265% LC DNA (SEQ ID NO: 388): GAAATAGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGG AAAGAGCCACCC’E‘C'I‘CC'IKICAGGGCCAG’E‘CAGAG’E‘GTTA(K)AGCAAC‘I‘T AGCCTGGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTAT AGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTG GG’I‘C’I‘GGGACAGAGTTCAC'I‘C'I‘CACCA'IEAGCAGCC'IGCAGIETGAAGA TTTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGG CGGAGGGACCAAGG'I‘I‘GAGA’I’CAAACGG — 105 - [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley {O377} In further embodiments, the inventinn i‘eiates t0 Cinne RDu26576 LC AA sequence (SEQ ID ND: 389): ISIVIVI’IQSPAT LSVSPGIE AI 1.,SCILASQSVS SNLAWYQQKP GQAPRI.LIY§ ASTRAIGII’A SGTE SLQS EDFAVYYCQQ IIHVWPLTFGG GIKVIEIKR. {0378} In further einbndiinents, the inventinn reiates tn LC CDRI AA sequence thereof: RASQSVSSNLA (SEQ ID NO: 390). In further embodiments, the invention reiates t0 LC CDRZ AA sequence thereef: SAS'IRA'I‘ (SEQ ID NO: 391). In further enthndiments, the inventien reietes tn LC CHRIS AA sequence f: QQI-IIIVWPI_,I (SEQ ID NO: 392). {0’ 79]LN In further embodiments, the inn relates tn Cione RID—26576 CAR DNA I-IxL (SEQ ID NO: 393): A'I‘GGC‘AC'I'CCCCG’I‘AAC'I‘GCTC'I‘GC'I'GC'I‘GCCG’I‘TGGCAT'IGC'I'CC'I‘GCA CGCCGCACGCCCGCAGGIGCGGCTGGTGGAGICIGGGGGGGGCGIGGIC {IfAIIICC’IGGGAGGICCC'IGZ—XGAC'IC'ICC'I'EITGCAGCG’ICIGGATICACC’IT CAGIAGCTATGGCAIACACTGGGICCGCCAGGCTCCAGGCAAGGGGCTG GAG'I‘G’GGIGGCAGITA’IAGGGTATGA’IGGACAGGAGAAA'IACIA'I‘IIICAG AC'I‘CCG'IGAAGGGCCGA'I‘I‘CACCATCICCAGAGAC‘AA'I‘I'CC‘AAGAACAC GCTG'IATICIGCAAAIGAACAGCCTC‘IAC‘IAGCCGAGGACACGGCGG’IG’IA{If 'I‘ACTGC‘G'ICAAGGGGCCG'I'I‘GCAGGAGCCGCCA'I‘ACGC'I‘I‘TTGGGA'I‘GG: ACGTATGGGGCCAGGGAACAACIGTCACCGICICCICAGGGICIACAIC 'CCGGGAAGCCCGGAAG'I‘GGCGAAGG’IAGIACAAAGGGGGAAA'I AGTGAIGACGCAGICICCAGCCACCCTGICIGTGTCTCCAGEGGGAAAGA GCCACCC'IC'ICCI‘GCAGGGCCAG'ICAGAGIGTIZAGCAGCAACITAGCC’I GGTACCAGCAGAAACCIGGCCAGGCTCCCAGGCICCICAICIATAGCGC ATCCACCAGGGCCAC'I‘G’G'I‘ATCCCAGCCAGG’ITCAGTGGCAGIITIGIIIGTCT GGGACAGAGITCACTCTCACCATCAGCAGCCTGCAGTCTGAAGAITTIGC AGI'ITAI"'IACIGTCAGCAGCACCACGI‘CI‘GGCCTCTCAC'I'I’ITGGCGGAG GGACCAAGGITGAGATCAAACGGGCCGCIGCCCTIGATAATGAAAAGIC AAACGGAACAAICAITCACGTGAAGGGCAAGCACCICIGICCGICACCC ’FICCC'I'GGTCCA'I‘CCAAGCCA'ITCTGGG’I'GI‘I‘GG’ICG'I‘AGI‘GGGTGG AGTCCTCGCITGTIACTCICTGCTCGTCACCGIGGCIITTAIAATCTTCTG GG'I‘I'AGA'I‘CCAAAAGAAGCCGCCTGC'I‘CCA'I'AGCGA'ITACATGAA'I‘A'I‘G QCTCCACGCCGCCCTGGCCCCACAAGGAAACACIACCAGCCIIACGCAC —106- [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley CACC‘TAGAGA'ITI‘CGC’I‘GCC'I‘A'I'CGGAGCAGGG’IGAAG'I'ETI‘CCAGA'I‘C'I‘ SCAGATGCACCAGCGTATCAGCAGGGCCAGAACCAACTGTATAACGAGC TCAACCTGGGACGCAGGGAAGAGTATGACG'ITE,"E‘GGACAAGCGCAGAGG ACGGGACCCTGAGATGGGTGGCAAACCAAGACGAAAAAACCCCCAGGA GGGTC’KZ’E‘A'I’AA'ETGAGCTGCAGAAGGATAAGATGGC'I‘GAAGC(ITE‘A'ET’E‘C’E‘ GAAATAGGCATGAAAGGAGAGCGGAGAAGGGGAAAAGGGCACGACGG TTTGTACCAGGGACTCAGCACTGCTACGAAGGATACTTATGACGCTCTCC ACA'I'GCAAGCCC'I‘GCCACC’I‘AGG {0380} In further embodimentg the invention relates to Clone REE—26576 CAR HXL AA sequence (SEQ ID NO: 394); MALPVTALLI_, PLALLLE-{AAR PQVRLVESGG GVVQFGRSLR LSCAASGFTF SSYGIHWVRQ EWVA VIGYDGQEKY YADSVKGRF'I‘ ISRDNSKNTL YLQMNSLRAE CVKG PLQEPPYAFG MDVWGQGTTV 'I‘VSSGSTSGS GKPGSGEEEGST KGEWMTQSP A’E‘LSVSPGESER ATLSCRASQS VSSNLAWYQQ KPGQAPRLLI YSASTRATGI PARFSGSGSG 'ETEEF'ETEJTISSL QSEDFAVYYC QQE-{E-IVVV’PL'I‘F GGG’I'KVMKR AAALDNEKSN VKGKH LCPSPLFPGP SKI?FVVVLV 7V CYSLL VFVAFHFW V RSKRSRLLEEES DYMNMTPRRP GPTRKE—EYQPY APPRDFAAYR SRVKFSRSAD APAYQQGQNQ LYNELNLGEGK EEYDVLDKMK GRDPEh/EGGKP RRKNPQEGLX NELQKDKMAE AYSEIGMKGE RRRGKGHDGL I‘ATKD 'I‘YDALHMQAL PPR. {0381} In firmer embodiments, the inventien relates to Clone RED-26576 CAR DNA iLxE-i’ (SEQ 11) NO: 395): ATGGCACTCCCCGTAACTGCTCTGCTGCTGCCGTTGGCATTGCTCCTGCA CGCCGCACGCCCGGAAATE‘AGTGA'I‘GACGCAGTC'I'CCAGCCACCCTE‘G’FCT GTGTCTCCAGGGGAAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTG '1"I'AGCAGCAACTTAGCCTGG'I‘ACCAGCAGAAACCTGGCCAGGCFCCCAG GCTCCTCATCTATAGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGT TCAGTGGCAGTGGGTCTGGGACAGAGTTCACTCTCACCATCAGCAGCCT CTGAAGA'E,"I"I"I‘GCAG"???A'fi7'I‘AC'I'G'I‘CAGCAGCACCACGTCTGGC CTCTCACTTTTGSCGGAGGGACCAAGGTTGAGATCAAACGGGGGTCTAC ATCCGGC’I'CCGGGAAGCCCGGAAGI‘GGCGAAGG'I'AGTACAAAGGGGCA DSGTGCGGCTGGTGGAGTCTGGGGGGGGCGTGGTCCAGCCTGGGAGGTCC —107- [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley C'I‘GAGAC'I‘C'I‘CC'I‘G'I'GCAGCG'I'C'IGGA'I‘TCACCTTCAG’I‘AGC'I'A'I'GGC‘A’R‘ ACACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTGGAGTGGGTGGCAGTT ATAGGG’I'ATC‘XATGGACAGGAGAAATAC'I‘A'E‘GCAGACTCCGTE‘GAAGGGCC GATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAAT GAACAGCC'I‘GAGAGCC(IS'AGGACACGG’CGGTE‘GT[A(:13‘,A{I'F{}(ii(}'i"{lAAGGG GCCGTTGCAGGAGCCGCCATACGCTTTTGGGATGGACGTATGGGGCCAG GGAACAACTGTCACCGTCTCCTCAGCCGCTGCCCTTGATAATGAAAAGTC AAACGGAACAA'I‘CA'I‘TCMTG'IGAAGGGCAAGCACCTCTG’FCCGTCACCC TTGTTCCCTGGTCCATCCAAGCCATTCTGGGTGTTGGTCGTAGTGGGTGG AG’I‘C‘C'I‘CGCTI'G'ITACTCTC'I‘GC'I'CGI‘CACC‘G’R‘GGC’1"I"I"I‘A'I‘AATC'I"I'C'I'G GGTTAGATCCAAAAGAAGCCGCCTGCTCCATAGCGATTACATGAATATG ACTCCACGCCGCCC'IGGCCCCAC‘AAGGAAACACTACCAGCCT'I‘ACGCAC CACCTAGAGATTTCGCTGCCTATCGGAGCAGGGTGAAGTTTTCCAGATCT GCAGATGCACCAGCGIZE’EDA’EKIAGCAGGGCCAGAACCAACTG'I'ATz-XACGAGC TCAACCTGGGACGCAGGGAAGAGTATGACGTTTTGGACAAGCGCAGAGG CCCTGAGA’iKSrGGTGGCAAACCAAGAC(3AAAAAACCCCCAGSA GGG'I‘C'I‘C'I'A'I‘AA'I‘GAGC’I‘GCAGAAGGA’I‘AAGATGGC’R‘GAAGCC'I'A'I‘TC'I‘ ‘AGGCA'I‘GAA AGSAGAGCGGAGz-XAGGGGAAAAGGGCACGACGG 'I"I"I'G'I'ACCAGGGAC'I‘CAGCAC'I‘GC’I‘ACGAAGGA'I‘AC'ITA'I'fiACGCTCTCC ACATGCAAGCCCTGCCACCTAGG [O3 82} In r embodiments, the invention relates to Clone RDu26576 CAR LXH AA sequence (SEQ ID NO: 396): MALPVTA}...LL PLA:E.3..LE€EAAR PEWMTQSPA TE‘LS‘V/SPGERA TLSC ASQSV SS‘E‘VEAWYQQK PGQAPRLLIY TGIP ARFSGSGSGT EFTLTISSLQ SELDFAVYYCQQi-{E€E\7WP1_..'I‘FGGGTKVEEKRG STSC‘ISGKPGS (ZE’EEGS’I‘KGQVR LVESGGGVVQ PGRSLRLSCA ASGFTESSYG EWV’RQAPGK GLEWVAVIGY I)GQ{SKYYALE)S VKGRF'E,"HERD NSKN'I'LYLQM N SLRALED'E,"AV YYCVKGPLQE PPYAEGh/[DVW GQGTTVTVSS AAALDNEKSN GTIH-{VKGKH 1.,CPSPLFPGP SKPFWVLVVV GGVLACYSIL VTVAFHFWV RSKRSRLLHS ‘PRRP GP'I'RKHYQPY APPRDFAAYR SRVKFSRSAD APAYQQGQNQ I...YNELNI_..GRR EEYDVLDKRR GRDPEMGGKP QEGLY NELQKDKMAE MKGE EQUKGKGHDGL DJKQGLSTATKD TYDALHEWQAL PPR. — 108 - [Annotation] eadley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley {O383} ln futther embodiments, the lnventlnn relates to Clone 578 HC‘ DNA (SEQ ll.) NO: 397): CAGC'l'GGTGGAGTC’l7GGGGGAGGCG'I‘GG'I‘CCAGE?C’E‘GGGAGGT CCCTGAGACTCTCCTGTGCAGCGTCTGGATTCACCTTCAGTAGCCGTGGC A’ETGCACTGGG'I‘CCGCCAGGCTCCAGG’CAAGGGGCTGGAGTGGG'I‘GGCAG TTATAGGGTATGATGGACAGGAGAAATACTATGCAGACTCCGTGAAGGG CCGATTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAA A'l‘GAACAGCC'l'fiAGAGCCGAGGACACGGCGGI‘GTAC'I‘AC'lTGCGTCAAGG GGCCGTTGCAGGAGCCGCCATACGATTATGGAATGGACGTATGGGGCCA GGGAACAAC’l'GI‘CACCG’l‘C’l‘CC’I‘CA {0384] In further embodiments? the invention relates to Clone RID—26578 HC AA ce (SEQ ll) NO: 398): QVQLV’ESGGG VV’QPGRSLRL SCAASGmS SRGMHW‘V’RQA PGKGLEWVAX EGYDGE EEKYY ADSVKGRF'I‘I SRI)NSKNTE‘1_,Y LQMNSLRAED TAVYYCVKGP Lg EEPPYDYGM mfw’GQGTTK/T V88. [0385} in further embodiments, the ion relates tn HC CDRl AA sequence therenf: F'I'FSSRGMH (SEQ ll) N0: 399). in further ments, the invention relates to l-lC CDRZ AA sequence therenl‘: VEGYDGQEKYYADSVKG (SEQ ll) NE); 400): ln further embodiments, the invention relates to HC‘ CDR3 thereof: VKGPLQEPPYDYGMDV (SEQ ID NO: 401).

In further enthedlntents, the invention relates to Clone RID—26578 LC DNA (SEQ ID NC): 402): GAAATAG'l'GATGAC(EECAG’E‘CTl‘CCAGCCACCC'IGTCTG’ETG’l'C'l'CCAGGGG AAAGAGCCACCCTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTT AlfiiCC'l'GGTACCAGCAGAAACC’E‘GGCCAlliGCTl‘CCCAGtiil'CTl‘CC’E‘CA'l'CTA'l‘ AGCGCATCCACCAGGGCCACTGGTATCCCAGCCAGGTTCAGTGGCAGTG GG'I‘C'l‘G’GGACARAG'I‘TCACTCTCAC(IATCAGCAGCC’E‘GCAG'I‘C'l‘GIZlAAGA TTTTGCAGTTTATTACTGTCAGCAGCACCACGTCTGGCCTCTCACTTTTGG CGGAGGGACCAAGGTTGAGATCAAACGG In further embedlments, the lnventlon relates t0 Clone RD—26578 LC AA nequenee (SEQ ll) NO: 403): — 109- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley EIVM'I'QSPA'I' LSVSPGERA'I‘ LSCRASQSVS YQQKP GQAPRLUYSZ ASTRATGIPA SGTE PTI_,TISSLQS EDFAVYYCQQ ffl-iV‘NPI..TFGG EIKR, [0388} In further embediments, the inventinn relates to LC CDRI AA sequence: RASQSVSSNE_,A (SEQ [D NO: 404) in further embodiments) the in‘ventien rebates to LC CDR2 AA sequence therenf: SASTRAT (SEQ [D NO: 4-05). In further embodiments, the invention reiates :0 LC CDR3 AA sequence thereof: QQI-HIVWFEI (SEQ ID NO: 406).

In further embediments? the ien relates t0 Chane Emaesv’n CAR DNA HXL (SEQ ID N0: 407): A’l‘GGCAC'I‘CCCCGI‘AAC'I‘GCTC'I'GC'I‘GC'I'GCCGTI'GGCA'I‘TGCTCCTGCA CGCCGCACGCCCGCAGGTGCAGCTGGTGGAGTCTGGGGGAGGCGTGGTC CAGCC'I‘GGGAGG’I'CCC'I‘GAGACTCTCCTG’I‘GCAGCG'I‘C'I'GGA'I‘TCACCTF CAGTAGCCGTGGCATGCACTGGGTCCGCCAGGCTCCAGGCAAGGGGCTG GAG'ETGGGT(ZEGCAG'E'TA'I‘AGGGTATGATGGACAGGAGAAA’E,‘ACTA’E‘GCAG ACTCCGTGAAGGGCCGATTCACCATCTCCAGAGACAATTCCAAGAACAC GCTG’ETA'E'C'E'GCAAA’I'GAACAG’CCTGAGAGCCGAGGAiLACGGCGGTGTAC GCG'I'CAAGGGGCCGTFGCAGGAGCCGCCATACGAT'I'A'I‘GGAA'I‘GG ACGTA'EKSrGGGCCAGGGAACAACTGE‘CACCGTCTCCTCAGGG'I‘CTACATC CGGC'I‘CCGGGAAGCCCGGAAGTGGCGAMEGTAG’I‘ACAAAGGGGGAAA'I‘ AGTGATGACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGA GCCACCCTC'I‘CCTGCAGGGCCAG’I‘CAGAG’I‘G’YEAGCAGCAAC'I'TAGCC'I‘ GGTACCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATAGCGC A'ETCCACCA66SCCAC'ETGG’E‘ATCCCAGCCAGG'I‘TCAGTGGCAG'I'GGGTCT GGGACAGAGTTCACTCTCACCATCAGCAGCCTGCAGTCTGAAGATTTTGC AG’ETTE‘TA’E‘TE‘AC’I'GT Suitable techniques include use of inducible caspase-9 (US Appl. Kill/0286980) or a thymidine kinase, before, after or at the same time, as the cells are transduced with the CAR construct of the present invention. onal s for introducing suicide genes and/or "on" switches include TALENS, zinc fingers, RNAi, siRNA, shRNA, antisense logy, and other techniques ltnown in, the art in accordance with the invention, onal on—off or other types of control switch techniques may be incorporated herein. These techniques may employ the use of dimerization domains and optional tors of such domain dirnerization. These techniques include, eg, those described by Wu et al., Science 20% 350 (6258) utilizing PKBP/Rapalog dirnerization systems in certain cells, the contents of which are incorporated by reference herein in their entirety Additional dimerization technology is described in, cg, Fegan et al.

Chem Rev. ZOlO, llO, 33l5---3336 as well as US. Patent Nos. 5,830,462., 5,334,266, ,869,337; and til 65,787, the contents of which are also incorporated by reference herein in their entirety. Additional dinieiization pairs may include cyclosporine~A/cyclophilin, receptor, estrogen/estrogen receptor (optionally using tamoxifen), gl ucocorti coid s/gl ucocorticoi d receptor, tetracycli n ex’tetracycl in e receptor, vitaniin ill/’vitarni n l} receptor. Further examples of dimerization technology can he found in e. g, VVQZUl/l/l2726l, ‘WOZQlS/QQOZE.

, USZOld-l0286987, USZOl5/0266973, trszcra’ccaemo, us. Patent No. 8,486,693, oszeizi/ciri 649, and trszcrzmrseme, the contents of which are further orated by nce herein in their entirety. ill/Z Vectors? Cells, and Pharmaceutical Compositions {0396} In certain aspects, provided herein are vectors sing a polynucleotide of the present ion, iln some embodiments, the present invention is directed to a vector or a set of vectors sing a polynucleotide encoding a CAR or a TCR, as described herein in other embodiments, the present invention is ed to a vector or a set of vectors comprising —ll3- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley a poiynucieotide encoding an antibody or an antigen binding molecuie f that specifically binds to BCMA, as disciosed herein, [0397} Any vector known in the art can be suitable for the present invention, in some embodiments, the vector is a viral vector. In some embodiments, the vector is a retrovirai vector (such as pMSVGi), a DNA vector, a marine Eenkeinia virus , on SFG vector, a plasmid, a RNA vector, an irai vector, :1 hacuiovirei vector, an Epstein Barr viral vector, 3 papovevirai vector, 25. vaccinie viral vector, 21 herpes simpiex viral vector, an adenovirus associated vector (AAV‘), a ientiviral vector (such as pGAR), or any combination thereof.

The pGAR sequence is as foilows: CGCCCTGTAGCGGCGCATTAAGCGCGGCGGGTGTGGTGG 'i"I'ACGCGCAGCGI‘GACCGCTACAC'1"i‘GCCAGCGCCC'I‘AGCGCCCGCTCC’IT TCGCTTTCTTCCCTTCCTTTCTCGCCACGTTCGCCGGCTTTCCCCGTCAAGC 7E‘CTE‘AAATC(ItG(ZtG(ZtCTE‘CCCTTTAGGGTTCCGA"FHAGTGCYF'FACGG’CACCT CGACCCCAAAAAACTTGATTAGGGTGATGGTTCACGTAGTGGGCCATCGC C(fii’i‘ti‘xA'I‘AGACGG’ETTT'E‘TCGCCC'iT’E‘GACGI‘TGGAG’ETCCA(:3G'FFCT’ET'E‘AATA GTGGAC'i'C’i"I'G'I"I'CCAAAC’I‘GGAACAACAC’R‘CAACCC'I‘A'ETCTCGGTC"i‘A’iT C’E‘TE‘T'E‘GAT’ETTE‘ATAAGGGz—X’ET’E‘T'I‘GCC(ItAT’iTTE‘CGGCCTATTGG’ET'E‘AAAAAATE‘G GATH'AACAAAAA’F’E'I‘AACGCGAA"i,"'i"1"i'AACAAAATA'I‘TAACGC’I‘TA CAATTTGCCATTCGCCATTCAGGCTGCGCAACTGTTGGGAAGGGCGATCG G'I‘GCGGGCC'I'C'ITCGC'I‘AT'I‘ACGCCAGC'i'GGCGAAAGGGGGATG'I‘GCTGC AAGGCGATTAAGTTGGGTAACGCCAGGGTTTTCCCAGTCACGACGTTGTA AAACGACGGCCAti‘r’E‘GAA'i‘TG'I‘AA'i‘ACGACTCACTATAGGGCGACCCGGGG CGCCAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATG (EAGTE‘TCCGCG’E‘TE‘ACATE‘AACTE‘TACSIZEGTAAA'I‘GGCEXIGCC1‘6th7E‘GACCGCCC AACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCATAGTAACG CCAATAGGGACTTTCCA’ETTE‘GACGTCAAT(ZiGG’i‘GGA{ETATE‘TTA(I(§t3’i,‘AAA(I"I" GCCCACTTGGCAGTACATCAAGTGTATCATATGCCAAGTACGCCCCCTATT GACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGAC C'I‘TA'I‘GGGAC'I"I"I'CC'I'ACT'I‘GGCAGI‘ACATCTACGI‘ATTAGI‘CA’I‘CGCTA’I‘T ACCATGCTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTT GAC’R‘CACGGGGA’ITI‘CCAAG'I‘CTCCACCCCA’i‘TGACGTCAA'I‘GGGAGT’PI‘G D‘TTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCC —ii4- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by eadley [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley CCATTGACGCAAATGGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAG CAGAGCTGGTTTAGTGAACCGGGGTCTCTCTGGTTAGACCAGATCTGAGCC TGGGAGCTCTCTGGCTAACTAGGGAACCCACTGCTTAAGCCTCAATAAAG CTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCCGTCTGTTGTGTGACTCTGGT AACTAGAGATCCCTCAGACCCTTTTAGTCAGTGTGGAAAATCTCTAGCAGT CGAACAGGGACTTGAAAGCGAAAGGGAAACCAGAGGAGCTCTC TCGACGCAGGACTCGGCTTGCTGAAGCGCGCACGGCAAGAGGCGAGGGG CGGCGACTGGTGAGTACGCCAAAAATTTTGACTAGCGGAGGCTAGAAGGA GAGAGATGGGTGCGAGAGCGTCAGTATTAAGCGGGGGAGAATTAGATCG CGA"R‘GGGAAAAAATTCGGTFAAGGCCAGGGGGAAAGAAAAAA'I'A'I‘AAAT TAAAACATATAGTATGGGCAAGCAGGGAGCTAGAACGATTCGCAGTTAAT CC'I‘GGCCTG’I‘TAGAAACATCAGAAGGC'I'G'I‘AGACAAA'I‘ACTGGGACAGCT ACAACCATCCCTTCAGACAGGATCAGAAGAACTTAGATCATTATATAATA CAGTAGCAACCCTCTATTGTGTGCATCAAAGGATAGAGATAAAAGACACC AAGGAAGCTTTAGACAAGATAGAGGAAGAGCAAAACAAAAGTAAGACCA CCGCACAGCAAGCCGCCGCTGATCTTCAGACCTGGAGGAGGAGATATGAG GGACAATTGGAGAAGTGAATTATATAAATATAAAGTAGTAAAAATTGAAC CATTAGGAGTAGCACCCACCAAGGCAAAGAGAAGAGTGGTGCAGAGAGA AAAAAGAGCAGTGGGAATAGGAGCTTTGTTCCTTGGGTTCTTGGGAGCAG CAGGAAGCACTATGGGCGCAGCGTCAATGACGCTGACGGTACAGGCCAGA CAATTATTGTCTGGTATAGTGCAGCAGCAGAACAATTTGCTGAGGGCTATT GAGGCGCAACAGCATCTGTTGCAACTCACAGTCTGGGGCATCAAGCAGCT CCAGGCAAGAATCCTGGCTGTGGAAAGATACCTAAAGGATCAACAGCTCC TGGGGATTTGGGGTTGCTCTGGAAAACTCATTTGCACCACTGCTGTGCCTT GGAATGCTAGTTGGAGTAATAAATCTCTGGAACAGATTTGGAATCACACG ACCTGGATGGAGTGGGACAGAGAAATTAACAATTACACAAGCTTAATACA CTCCTTAATTGAAGAATCGCAAAACCAGCAAGAAAAGAATGAACAAGAAT TATTGGAATTAGATAAATGGGCAAGTTTGTGGAATTGGTTTAACATAACA AATTGGCTGTGGTATATAAAATTATTCATAATGATAGTAGGAGGCTTGGTA GGTTTAAGAATAGTTTTTGCTGTACTTTCTATAGTGAATAGAGTTAGGCAG GGATATTCACCATTATCGTTTCAGACCCACCTCCCAACCCCGAGGGGACCC GACAGGCCCGAAGGAATAGAAGAAGAAGGTGGAGAGAGAGACAGAGAC DEATCCATTCGATTAGTGAACGGATCTCGACGGTATCGGTTAACTTTTAAA [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley AGAAAAGGGGGGATTGGGGGGTACAGTGCAGGGGAAAGAATAGTAGACA TAATAGCAACAGACATACAAACTAAAGAATTACAAAAACAAATTACAAA ATE‘TCAAAATT‘TTATCGCGATCGCGGAATGAAAGACCCCACCTGTAGGTTTG GCAAGCTAGCTTAAGTAACGCCATTTTGCAAGGCATGGAAAATACATAAC TGAGAATAGAGAAGTTCAGA’ECAAGGTTAGGAACAGAGAGACAGCAGAA TATGGGCCAAACAGGATATCTGTGGTAAGCAGTTCCTGCCCCGGCTCAGG GCCAAGAACAGATGGTCCCCAGATGCGGTCCCGCCCTCAGCAGTTTCTAG ATCAGATGT'TTCCAGGG’TGCCCCAAGGACCTGAAAATGACCCTG TGCCTTATTTGAACTAACCAATCAGTTCGCTTCTCGCTTCTGTTCGCGCGCT TCTGCTCCCCGAGCTCAATAAAAGAGCCCACAACCCCTCACTCGGCGCGC CAGTCCTTCGAAGTAGATCTTTGTCGATCCTACCATCCACTCGACACACCC GCCAGCGGCCGCTGCCAAGCTTCCGAGCTCTCGAATTAATTCACGGTACCC ACCATGGCCTAGGGAGACTAGTCGAATCGATATCAACCTCTGGATTACAA AATTTGTGAAAGATTGACTGGTATTCTTAACTATGTTE‘GCTCCTTTTACGCTA TGTGGATACGCTGCTTTAATGCCTTTGTATCATGCTATTGCTTCCCGTATGG CTTTCATTTTCTCCTCCTTGTATAAATCCTGGTTGCTGTCTCTT‘TATGAGGA GTTGTGGCCCGTTGTCAGGCAACGTGGCGTGGTGTGCACTGTGTTTGCTGA CGCAACCCCCACTGGTTGGGGCATTGCCACCACCTGET:AGCTCCTTTCCGG GACT'TTCGCTTTCCCCCTCCCTATTGCCACGGCGGAACTCATCGCCGCCTG CCTTGCCCGCTGCTGGACAGGGGCTCGGCTGTTGGGCACTGACAATTCCGT GGTGTTGTCGGGGAAGCTGACGTCCTTTTCATGGCTGCTCGCCTGTGTTGC CACCTGGATTCTGCGCGGGACGTCCTTCTGCTACGTCCCTTCGGCCCTCAA TCCAGCGGACCTTCCTTCCCGCGGCCTGCTGCC(IS'GCTCTGCGGCCTCTTCC GCGTCTTCGCCTTCGCCCTCAGACGAGTCGGATCTCCCTTTGGGCCGCCTC TGGT‘TAAT’E‘AAAGTACCTTTAAGACCAATGACTTACAAGGCAGCT GTAGATCTTAGCCACTTTTTAAAAGAAAAGGGGGGACTGGAAGGGCGAAT CCAACGAAGACAAGATCTGCTTTTTGCTTGTACTGGGTCTCTCTG GTTAGACCAGATCTGAGCCTGGGAGCTCTCTGGCTAACTAGGGAACCCAC TGCTTAAGCCTCAATAAAGCTTGCCTTGAGTGCTTCAAGTAGTGTGTGCCC GTCTGTTGTGTGACTCTGGTAACTAGAGATCCCTCAGACCCTTTTAGTCAG TGTGGAAAATCTCTAGCAGGCATGCCAGACATGATAAGATACATTGATGA GTTTGGACAAACCACAACTAGAATGCAGTGAAAAAAATGCTTTATTTG’TG QATTTGTGATGCTATTGCTTTATTTGTAACCATTATAAGCTGCAATAAAC —116- ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley AAGTTAACAACAACAATTGCATTCATTTTATGTTTCAGGTTCAGGGGGAGG TGTGGGAGGTTTTTTGGCGCGCCATCGTCGAGGTTCCCTTTAGTGAGGGTT AATTGCGAGCTTGGC(ETTAATCATGCTCATAGCTGTTTCCT(ISTE‘GTGAAA'E‘TG TTATCCGCTCACAATTCCACACAACATACGAGCCGGAAGCATAAAGTGTA AAGCCTG6G6TCCCTAATGAGTGAGCTAACTCACATTAATTGCGTTGCGCT CACTGCCCGCTTTCCAGTCGGGAAACCTGTCGTGCCAGCTGCATTAATGAA TCGGCCAACGCGCGGGGAGAGGCGGTTTGCGTATTGGGCGCTCTTCCGCTT CCTCGCTCACTGACTCGCTGCGCTCGGTCGTTCGGCTGCGGCGAGCGGTAT ACTCAAAGGCGGTAATACGGTTATCCACAGAATCAGGGGATAAC GCAGGAAAGAACATGTGAGCAAAAGG‘CCAGCAAAAGGCCAGGAACCGTA AAAAGGCCGCGTTGCTGGCGTTTTTCCATAGGCTCCGCCCCCCTGACGAGC ATCACAAAAATCGACGCTCAAGTCAGAGGTGGCGAAACCCGACAGGACTA TAAAGATACCAGGCGTTTCCCCCTGGAAGCTCCCTCGTGCGCTCTCCTGTT CCGACCCTGCC(3C'37TACCGGA'E‘ACCTGTCCGCCTTTCTCCCTTCGGGAAGC GTGGCGCTTTCTCATAGCTCACGCTGTAGGTATCTCAGTTCGGTGTAGGTC GTTCGCTCCAAGCTGGGCTGTGTGCACGAACCCCCCGTTCAGCCCGACCGC TGCGCCTTATCCGGTAACTATCGTCTTGAGTCCAACCCGGTAAGACACGAC TTA’E‘CGCCACT(IS'GCAGCAGCCACTGGTAACAGGATTAGCAGAGCGAGGTA TGTAGGCGGTGCTACAGAGTTCTTGAAGTGGTGGCCTAACTACGGCTACA CTAGAAGAACAGTATTTGGTATCTGCGCTCTGCTGAAGCCAGTTACCTTCG GAAAAAGAGTTGGTAGCTCTTGATCCGGCAAACAAACCACCGCTGGTAGC GGTGGTTTTTTTGTTTGCAAGCAGCAGATTACGCGCAGAAAAAAAGGATC TCAAGAAGATCCTTTGA'E‘CTTTTCTACGGGG’E‘C'E‘GACGCTCAGTGGAACGA AAACTCACGTTAAGGGATTTTGGTCATGAGATTATCAAAAAGGATCTTCAC CTAGATCCTTTTAAATTAAAAATGAAGTI‘TTAAATCAATCTAAAGTATATA TGAGTAAACTTGGTCTGACAGTTACCAATGCTTAATCAGTGAGGCACCTAT CTCAGCGATCTGTCTATTTCGTTCATCCATAGTTCCCTGACTCCCCGTC(ZE'TG TAGATAACTACGATACGGGAGGGCTTACCATCTGGCCCCAGTGCTGCAAT GCGAGACCCACGCTCACCGGCTCCAGATTTATCAGCAATAAACC AGCCAGCCGGAAGGGCCGAGCGCAGAAGTGGTCCTGCAACTTTATCCCCC CAGTCTATTAATTGTTGCCGGGAAGCTAGAGTAAGTAGTTCGCCA GTTAATAGTTTGCGCAACGTTGTTCCCATTGCTACAGGCATCGTGGTGTCA DECTCGTCGTTTGGTATGGCTTCATTCAGCTCCGGTTCCCAACGATCAAGG —117- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley CGAGTTACATGATCCCCCATGTTGTGCAAAAAAGCGGTTAGCTCCTTCGGTCC TCCGATCGTTGTCAGAAGTAAGTTGGCCGCAGTGTTATCACTCATGGTTATGG CAGCACTGCATAATTCTCTTACTGTCATGCCATCCGTAAGATGCTTTTCTGTGA CTGGTGAGTACTCAACCAAGTCATTCTGAGAATAGTGTATGCGGCGACCGAGT TGCTCTTGCCCGGCGTCAATACGGGATAATACCGCGCCACATAGCAGAACTTT AAAAGTGCTCATCATTGGAAAACGTTCTTCGGGGCGAAAACTCTCAAGGATCT TGTTGAGATCCAGTTCGATGTAACCCACTCGTGCACCCAACTGATCT TCAGCATCTTTTACTTTCACCAGCGTTTCTGGGTGAGCAAAAACAGGAAGGCA AAATGCCGCAAAAAAGGGAATAAGGGCGACACGGAAATGTTGAATACTCATA CTCTTCCTTTTTCAATATTATTGAAGCATTTATCAGGGTTATTGTCTCATGAGC GGATACATATTTGAATGTATTTAGAAAAATAAACAAATAGGGGTTCCGCGCA CCCGAAAAGTGCCAC (SEQ ID NO: 413) The pGAR vector map is set forth below: Suitable additional exemplary vectors include e.g., puro, pBABE-neo largeTcDNA, pBABE-hygro-hTERT, pMKO.1 GFP, MSCV-IRES-GFP, pMSCV PIG (Puro IRES GFP empty d), pMSCV-loxp-dsRed-loxp-eGFP-Puro-WPRE, MSCV IRES Luciferase, pMIG, MDH1-PGK-GFP_2.0, TtRMPVIR, pMSCV-IRES-mCherry FP, pRetroX GFP T2A Cre, pRXTN, pLncEXP, and pLXIN-Luc.

[Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley {0402] In other aspects, provided herein are cells comprising a polynucleotide or a vector of the present invention, in some embodiments, the present invention is directed to cells, in vitro cells, comprising a polynucleotide encoding a CAR or a TCR, as described herein. In some ments, the present invention is directed to cells, eg, in vitro cells, comprising a, polynucleotide encoding an antibody or an antigen binding molecule thereof that specifically binds to BCMA, as disclosed herein. in other embodiments, the present invention is directed to in vitro cells sing a polypeptide encoded by a cleotide encoding a CAR or a TCR, as disclosed herein. ln other embodiments, the present invention is directed to cells, in vitro cells, sing a polypeptide encoded by a polynucleotide encoding an antibody or an n binding molecule thereof that specifically binds to BCMA, as sed l'ierein.

Any cell maybe used as a host cell for the polynucleotides, the vectors, or the polypeptides of the present invention. in some embodiments, the cell can be a prolraryotic cell, fungal cell, yeast cell, or higher eukaryotic cells such as a mammalian cell. Suitable prolraryotic cells e, without limitation, eubacteria, such as Gram—negative or Gram— positive organisms, for example, Enter/'obucichaccac such as Escherichia, cg, E coil, Emarobacrcr, Emr’inia, Klebsiella, Proteus; Salmonella, e.g Salmonella typi/iimurium; Sermon, e. g., Sermon marcescans, and Shigeit’a, Bacillz such as B whims and B.

Itcizei'zgformis; Psettdomonas such as P. acrttginosa, and Srrcpromyces. in some embodiments, the cell is a l'iun'ian cell. In some enibodin’ients, 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 ating lyinpl'iocyte (TIL), a TCR sing cell, a l lciller (Nlti) cell, a dendritic cell, a granulocyte, an innate lymphoid cell, a raryocyte, a monocyte, a macrophage, a platelet, a yte, and a myeloid cell. in one embodiment, the immune cell is a l cell, in another embodiment, the immune cell is an NK cell. in certain ments, the T cell is a tumorminfiltrating lymphocyte (TlL), autologous T cell, engineered autologous Tl‘ cell (eACTTM), an allogeneic T cell, a heterologous 'l‘ cell, or any combination thereof. {0404} The cell of the t invention can be obtained through any source known in the art, For example, T cells can be differentiated in Vin/o from a hematopoietic stem cell population, or T cells can be obtained from a subject. '1" cells can he obtained from, agi, 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 addiD, the T cells can be derived from one or more T cell lines available in the art. T cells —ll9- [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley can also be obtained from a unit of blood collected from a subject using any number of techniques known to the skilled n, such as FlCOLLTM separation and/or sis. In certain embodiments, the cells collected by apheresis are washed to remove the plasma fraction, and placed in an appropriate buffer or media for subsequent 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, eg the CQBETM 299i cell processor, the Baxter CYTOMATETM, or the lilre. In some embodiments, the washed cells are resuspended in one or more npatible buffers, or other saline solution with or without butler. In certain embodiments, the undesired components of the apheresis sample are removed. onal methods of isolating T cells for a T cell therapy are disclosed in US Patent ation No, ZOE/0287748, which is herein incorporated by references in its entirety. [0405} In n embodiments, T cells are ed from PBMCs by lysing the red blood cells and depleting the m onocytes, ega, by using centri t‘ugation through a, PlELRCtIlLl_,W gradient. In some embodiments, a specific ulation of T cells, such as C3281", CDA‘P‘, Cllllll, CD45RA+, and CEMSRO+ T cells is further isolated by positive or negative selection techniques known in the art. For example, enrichment of a T cell population by negative selection can be accomplished with a combination of antibodies directed to surface niarlters unique to the negatively selected cells. in some embodiments, cell sorting and/or selection via negative magnetic immunoadherence or flow cytometry that uses a cocktail ofrnonoclonal antibodies directed to cell surface markers present on the cells negatively selected can be used. For example, to enrich for CD4+ cells by i'iegative selection, a monoclonal antibody cocktail typically includes antibodies to (El 4, (3)20, Clitl lb, (sore, DR, and CD8. in certain embodiments, flow cytometry and cell sorting are used to isolate cell populations of interest for use in the present invention. [(34le In some embodiments, PBMC s are used directly for genetic modification with the immune cells (such as CARs or 'l‘tjlils) using methods as described herein, in certain embodiments, after isolating the PBMCs, T cytes are further isolated, and both cytotoxic and helper T lymphocytes are sorted into naive, , and eflector T cell subpopulations either before or after genetic modification and/or expansion. {0407] In some embodiments, CD8" cells are further sorted into naive, central memory, and effector cells by fying cell surface antigens that are associated with each ypes of CD8+ cells. In some embodiments, the expression of phenotypic markers of — lle - [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley central memory T cells includes CD45RO, CDbZL, CCR7, CD28, CD3, and CDl27 and are negative for granzynie B. In some embodiments, central memory T cells are CDdSROl', (Ille’llf, (EDS+ T cells. in some embodiments, effector T cells are negative for CD62L, CCR’i’, CD28, and CDlZ’i’ and, positive for me B and perform. in certain embodiments, CHM+ T cells are further sorted into subpopulations. For example, CD4+ T helper cells can be sorted into naive, central memory, and effector cells by identifying cell populations that have cell surface antigens. ln some embodiments, the immune cells, cg, "l7 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, eg, T cells, are genetically modified with the chimeric antigen receptors described herein (egg transduced with a viral vector sing one or more nucleotide sequences encoding a CAR) and then are activated and/or expanded in vitro. Methods for activating and expanding ’l‘ cells are known in the art and are described, cg, in US. Patent Nos. 6,905,874; 6,867,04l, and 5l4; and PCT Publication No. W0 20l2/O79tl00, the contents of which are hereby incorporated by reference in their ty.

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 e, in a culture medium with appropriate cytol [Ii/ll ll In some embodiments, the composition includes more than one ent antigen binding molecule to BMCA. In some embodiments, the composition included more than one antigen g molecule to BCMA, wherein the antigen binding molecules to BCMA bind more than one epitope. In some embodiments, the antigen binding molecules will not compete with one another for g to BC‘h/IA. In some ments, any of the antigen binding les provided herein are combined together in a pharmaceutical composition. {04%} In other embodiments, the composition is selected for parenteral delivery, for inhalation, or for delivery h the digestive tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the ability of one d in, the art. In, certain embodiments, s are used to maintain the composition at physiological pI—I or at a slightly lower pH, typically within a pH range of from about 5 to about 8. In certain embodiments, when parenteral administration is contemplated, the composition is in the form of a nnfree, parenterally acceptable aqueous on comprising a desired antigen binding molecule to BCMA, with or without onal therapeutic agents, in a pharmaceutically acceptable vehicle. In certain embodiments, the vehicle for parenteral injection is sterile distilled ‘l. titer in, which an antigen binding molecule to BCMA, with or without at least one additional therapeutic agent, is formulated as a sterile, isotonic solution, properly preserved. In certain embodiments, the preparation involves the ation of the desired molecule with polymeric compounds (such as polylactic acid or polyglycolic acid), bean liposomes, that provide for the controlled or sustained release of the product, which —l22- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley are then be delivered via a depot injection In certain embodiments, implantable drug delivery devices are used to introduce the desired m oiecule.

I". M’etheds (tithe Invention {04B} 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 polynucieotide disciosed herein under suitable conditions. In some embodiments the method comprises transducing a cell with a, cleotide encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding ie that specifically binds to BCMA, as disclosed herein. In some embodiments, the method comprises transducing a cell with a vector comprising the polynucieotide encoding a CAR or a TCR, wherein the CAR or the ICE; comprises an antigen binding rnoiecuie that caliy binds to BCMA. In other embodiments, the method comprises transducing a cell with a polynucleotide encoding an antibody or an antigen binding moiecuie thereof that specifically binds to BCMA, as disclosed herein. In some embodiments, the method ses transducing a cell with a vector comprising the poiynucieotide encoding an antibody or an n binding molecule thereof that cally binds to BCMA, as described herein in some embodiments, the method further comprises ing the celi. {041i 4] Another aspect of the t ion is directed to a method of ng an immunity against a tumor sing administering to a subject an effective amount of a cell comprising a polynucieotide described herein, a vector described herein? or a CAR or a 'I'CR described herein. In one embodiment, the method comprises stering to a subject an etiective amount of a. cell comprising a poiynucleotide encoding a CAR. or a TCR, wherein the CAR or the TCR comprises an antigen binding moiecuie that specificaiiy binds to BCMA, as disclosed herein. In an other embodiment, the method comprises stering to a subject an effective amount of a cell comprising a vector comprising a polynucleotide encoding a CAR or a TCRc wherein the CAR. or the TCR. comprises an antigen binding molecule that specifically binds to BCMA, as disciosed herein. In another embodiment, the method comprises administering to a subject an effective amount of a cell comprising a CAB: or a 'I'CR encoded by a poiynucieotide disclosed , wherein the CAR or the ICE comprises an antigen binding le that speciticaiiy binds to BCMA. In other embodiments, the method comprises administering to a subject an effective amount of a ceii comprising a polyDieotide encoding an dy or an antigen binding molecuie thereof that specifically —l23- ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley 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 cleotide encoding an antibody or an antigen binding molecule thereof that specifically binds to BCMA, as sed herein. in another embodiment, the method comprises administering to a, subject an effective amount of a cell sing an antibody or antigen binding molecule thereof encoded by a polynucleotide disclosed herein, wherein the antibody or antigen binding molecule thereof specifi cally binds to BCMA, [Odlij Another aspect of the present invention is directed to a method of ng an immune response in a subject comprising administering an ive amount of the engineered immune cells of the present application. ln some embodiments, the immune response is a T cell—mediated immune se. In some embodiments, the T cell~niediated immune response is directed against one or more target cells. ln some embodiments, the engineered immune cell comprises a CAB: or a TCR. in some ments, the target cell is a tumor cell. will 6] Another aspect of the present 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 molecule bed herein or at least one immune cell, wherein the immune cell comprises at least one CAR, TCR, and/or an isolated antigen binding molecule as described ~ {04 l 7] Another aspect of the t invention is directed to a method of treating a hypeiproliferative er or an intlamm atory 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 sed herein, In some embodiments, the matory disease is ed 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 present invention may be useful to treat diabetes, particularly Type l diabetes.

{Gill 8] Another aspect of the present invention is directed to a method of treating a cancer in a subject in need f 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 sed herein. ln one embodiment, the method comprises administering a polynucleotide ng a CAR or a TCR, wherein the CAR or the TCR. comprises an antigen binding molecule that specifically binds to BCMA, as disclosed herein.

In pher embodiment, the method comprises administering a vector comprising a —l24- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley poiynucieotide encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molecule that specifically binds to BCMA, as disclosed herein. in another embodiment, the method comprises administering a CAR or a TCR encoded by a poiynucieotide sed herein, wherein the CAR or the TCR comprises an antigen binding moiecuie that speciii caliy binds to BCMA. in another embodiment, the method comprises administering a cell sing the cieotide, or a vector comprising the bolyhucieotide, encoding a CAR or a TCR, wherein the CAR or the TCR comprises an antigen binding molecule that specifically binds to BCMA, as disclosed herein. in other ments, the method comprises adrnini stering a bolynocleotide encoding an ai'itibody or an antigen binding le f that specifically binds to BCMA, as disclosed herein. in another embodiment, the method comprises administering a vector comprising a poiynucieotide encoding an antibody or an antigen binding le thereof that specifically binds to BCMA, as disclosed herein. in another embodiment, the method comprises administering an antibody or an antigen binding rnoiecuie thereof encoded by a polynucieotide disciosed herein, wherein the antibody or the antigen binding molecule thereof specifically binds to BCMA. in another ment, the method comprises administering a cell comprising the polynucieotide, or a vector comprising the polynucieotide, encoding an dy or an n binding le thereof th at ically binds to Bil/MA, as disclosed herein. {04W} in some embodiments, an antigen binding molecule to BCMA is administered atone, in certain embodiments, an antigen binding molecule to BC‘MA is stered as part of a CAR, TCR, or other immune cell. in such irnrntme ceiis, the n binding le to BCh/iA can be under the control of the same promoter region, or a separate promoter. in certain embodiments, the genes encoding protein agents and/or an antigen binding molecule 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 "l" cell therapy of the t invention is engineered Antoiogons Ceil Therapy (eACTTM). According to this embodiment, the method can inciude collecting blood ceiis from, the patient, The isolated blood cells (eg 1' cells) can then be engineered to express an antinCMA CAR ofthe present invention ("anth BCMA CAR T ) In a particular embodiment, the anti—BCMA CAR T cells are administered to the patient. in some embodiments, the anti—BCMA CAR 1' ceiis treat a tumor [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley or a cancer in the patient. in one embodiment the anti—BCMA CAR T cells reduce the size of a tumor or a cancer. {04%} in some embodiments, the donor T cells for use in the T cell y are obtained from the t (eg, for an autologous T cell y). 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 tl’ierapeutically effective amount of the T cells can be at least about l04 cells, at least about l05 cells, at least about l06 cells, at least about ll)!" cells, at least about l08 cells, at least about l09 cells, at least about l010 cells, or at least about 10" cells. In another embodiment, the therapeutically effective amount of the T cells is about l04 cells, about l05 cells, about l06 cells, about l07 cells, or about if)8 cells. Tn one particular embodiment, the therapeutically ive amount of the anti—BCh/TA CAR T cells is about 2 X l ()6 cells/kg, about 3 X if)6 cells/leg, about 4 X l06 cells/leg, about 5 X l06 cells/kg, about 6 X it)6 cells/kg, about 7 X lOl’ cells/leg, about 8 X lt ‘3 cells/leg, about 9 X l06 cells/kg, about l X l07 cells/kg, about 2 X l07 cells/kg, about 3 X l07 cells/kg, about 4 X l07 cells/kg about 5 X it)7 cells/kg, about ‘6 X ll)7 cells/ltg, about 7 X l07 cells/leg, about 8 X l07 cells/kg, or about 9 X l07 cells/kg.

Another aspect of the present invention is ed to methods of diagnosis, detection, or validation. in some embodiments, the antigen binding molecule is used as a stic or validation tool. in certain embodiments, the antigen binding molecules disclosed herein are used to assay the amount ofBCMA present in a sample and/or subject. in some embodiments, the diagnostic antigen binding molecule is not neutralizing. in some ments, the antigen binding molecules sed herein are used or provided in an assay kit and/or method for the detection ofBCMA in mammalian tissues or cells in order to screen/diagnose for a, disease or disorder ated with changes in levels of BCMA. in some embodiments, the hit comprises an antigen g molecule that binds BCMA, along with means for ting the binding of the antigen g molecule with BCMA, if t, and optionally BCMA protein levels. Various means for indicating the presence of an antigen binding molecule can be used. For example, tluorophores, other molecular probes, or enzymes can be linked to the antigen binding molecule and the presence of the antigen binding molecule. can be observed in a variety of ways. As will be appreciated by one of skill in the art, the degree of antigen binding molecule binding can be used to ine how muth/TA is in a sample. —l26- [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley VA Cancer" Hemmer/rt {0424] The methods of the invention can, he used to treat a cancer in a subject, reduce the size of a tumor, l Cancers that may he treated include tumors that are not arized, not yet substantially vascularized, or arized The cancer may also include solid or non~solid tumors. In some embodiments, the cancer is a hematologic 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. ln certain embodiments, the cancer is multiple myeloma, Hodgkinls Disease, non~Hodgkin‘s lymphoma (NHL), primary mediastinal large B cell lymphoma (PMBC), diffuse large B cell ma (DLBCL), follicular lymphoma (FL), ormed, follicular lymphoma, splenic marginal zone lymphoma (SMZL), chronic or acute leukemia, myeloicl diseases including but not limited to acute myeloid leukemia (AML), c d leukemia (CML), acute lyrnphohlastic leukemia (ALL) (including non T cell ALL), chronic cytic leulcernia (CLL), Tucell lymphoma, one or more of B—cell acute lymphoid leukemia ("BALL"), 'l‘ucell acute lymphoid leukemia ("TALL"), acute lymphoid leulcemia (ALL), chronic rnyelogenous leukemia (CML), B cell prolymphocytic leukemia, hlastic plasmacytoid dendritic cell neoplasm, Burkitt’s lymphoma, ditiuse large B cell lymphoma, follicular ma, hairy cell leukemia, small cell- or a large ollicular lymphoma, malignant lymphoprolit‘eratiye ions, MALT lymphoma, mantle cell ma, Marginal zone lymphoma, myelodysplasia and myelodysplastic me S), hemophagocytic syndrome (Macrophage Activating Syndrome (MAS), and hemophagocytic lymphohistocytosis (l-lLl-lfl, chronic or acute granulomatous e, large cell oma, leukocyte adhesion deficiency, plasmahlastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom rnacroglohulinemia, plasma cell proliferatiye disorders (eg, asymptomatic myeloma (smoldering multiple myeloma or nt myeloma), monoclonal gammapathy of undetennined significance (MGUS), plasmacytomas (eg, plasma cell dyscrasia, solitary myeloma, ry plasmacytoma, extramedullary plasmacytoma, and multiple plasnytoma), systemic aniyloid light chain amyloidosis, POEMS syndrome (Crowlultase —l27- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley me, 'l‘akatsuiti e, PEP me), or combinations thereof. in one embodiment, the cancer is a myelorna. in one particular embodiment, the cancer is multipie rnyeloma [0426} in some ments, the methods further comprise administering a chemotherapeutic. in certain embodiments, the chemotherapeutic selected, is a lymphodepleting (preconditioning) chemotherapeutic Beneficiai preconditioning treatment regimens, aiong with correlative beneficial hiomarlrers are described in US. Provisional Patent Applications 62/262, M3 and 62/167,750 which are hereby incorporated by reference in their entirety herein These describe, cg, metheds of conditioning a patient in need of a T celi therapy comprising administering to the patient speciiied beneticiai doses of cyciophosphaniide (between 200 2/day and 2000 ing/m2,"day) and specified doses of fludarahine (between 20 mg/rn2/day and 900 mg/mz/day). A preferred dose regirn en involves treating a t comprising administering daiiy to the patient about 500 mg/an/day of cyciophosphamide and, about 60 nig/mZ/day of fiudarabine for three days prior to administration of a therapeuticaiiy effective amount of engineered T ceiis to the patient, {0427} In other embodiments, the n binding molecule, transduced {or otherwise engineered) ceiis (such as CARs or TCRs), and the herapeutic agent are stered each in an anrcunt effective to treat the disease or conditien in the subject. in certain embodiments, compositions comprising CAR~ and/or TER— sing ininiune effector celis discicsed herein may be stered in conjunction with any number of chei'notherapeutic agents. Examples of chemotherapeutic agents include ting agents such as thiotepa and cyclophosphamide (CE/"lTOXANTM‘j; aikyi sulfonates such as husuifan, ii'nprosuit‘an and piposuli‘an; aziridines such as henzodopa, carhoquone, meturedopa, and uredopa; nimines and methyiameiamines including anrine, triethyienemeiamine, trietylenephosphoramide, triethylenethiophosphaoraniide and trimethylolomelamine resume; nitrogen ds such as chioramhucii, chlornaphazine, cholophosphamide, estramustine, ifosfamide, inechlorethamine, mechiorethamine oxide hydrochloride, meiphaian, novernhichin, phenesterine, prednirnustine, trofcsfamide, uracil d; nitrosureas such as carinustine, chlorozotecin, foteniustine, iomustine, nimustine, ranirnustine; antibiotics such as aciacinomysins, actinornycin, authramycin, azaserine, bieeniycins, cactinoniycin, caiieheamicin, carabicin, carminomycin, carzinophiiin, chrcrnoniycins, dactinornycin, daunorubicin, detoruhicin, 6~diazo—S~o>ro—L—norieucine, dexorubicin, epiruhicin, escrubicin, icin, mareeiloniycin, mitomycins, mycophenolic acid, igaianiycin, olivomycins, peploniycin, pottironiycin, purornycin, quelainycin, —128- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] eadley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by eadley i‘cdcruhicin, streptcnigrin, sti‘eptczccin, tubercidih, ubeniniex, zinnstatin, zomhicin; anti— metabolites such as methotrexate and 5~fluurouracil (SvFU); fclic acid analogues such as dencpterin, methctrexate, pterepteriii? ti‘imetrexate; purine s such as t‘ludarahine, 6- mercaptepuiine, thiamiprine, thinguanine; pyrimidine anaiegs such as bine, azacitidine, 6—azauridine, carincfui; cytarahine, didecxyuridine, dcxit‘hiridiiie, enecitabine, idii‘te, S—FU; androgens such as caiustercne, dremostaneiene prcpicnate, epitinstanci, mepitinstane, testoiactcne; anti—adrenals such as ainirteglutethiinide tnitetane, tt‘iicstane; felic acid replenisher such as ic acid; acegiatcne; aldcphosphamide giyceside; amineievuiinic acid; ine; hestrahucii; bisantrene; edatraxate; defot‘amine; demeculcine; diaziqucne; eifermithine; elliptiniuni acetate; etngiucid; ni nitrate; hydrcxyutea; ientinan; icnidamine; n'iitcguazone; mitoxanti‘one; mepidamci; nitracrine; pentostatin; phenainet; biciii; podnphyliinic acid; Zuethyihydi‘azide; pi‘ccarhazine; PSK®; i‘azoxane; sizeih‘an; spircgermanium; tenuazenic acid; triaziqunne; 2, 2',2"mtrichinrctriethylamine; urethan; vindesine; dacarhazine; manncmustine; mitehrenitoi; mitclactci; pipehreinan; gacytesine; arabineside ("AranC"); cyeicphesphamide; thictepa; taxcids, eg. paciitaxei (TAXGLTM, clwh/Eyers Squibb) and dexetaxel ('I‘A.X()TE‘ELREL®, Rhone—Pmtlenc Rerer); chloramhucii; gemcitabine; guaiiihe; mercaptepui‘iiie; i‘exate; piatinuin analegs such as cispiatin and cai'heplatin; vinbiastiiie; piatinum; etupeside (vein); mide; niitcmycin C; mitoxantrone; vincristine; vincreihine; navelhine; tievantrene; teniposide; daunemvcin; amineptetin; xeicda; ihandrunate; CPT~1l; emei‘ase inhibitor RPSZOOO; dititicromethylnmithine (DMFO); i‘etinoic acid derivatives such as Targretih 'l‘M (hexaretene), Partretiit'i‘Nfl (aiitretinoin); ONTAKTM (denileukin diftitox); esperarnicins; capecitahine; and pharmaceuticaily acceptabie saits, acids or tives cf any of the above. in same embodiments, eompesiticns ccmprising CAR" and/er TCR—expressing immune ei‘feetcr ceiis disciesed herein may be administered in conjunction with an hcrineiial agent that acts to regulate or inhibit hermene actien en tunicrs such as anti—estrcgens including fer example tainexifen, rainxifene, ase inhibiting 4(5)—imidazeles, 4—hydi‘0xytamcxifen, triuxifeiie, ene, LY} 17018, cnapristcne, and teremifene (Faresten); and antimandregens such as fiutantide, nihttainide, hicaiutaniide, ieuprciideg and gesereiin') and phainlaceutically acceptabie salts, acids 01‘ derivatives of any cf the abeve. Ccmhinations of chemetherapeutic agents are alse administered Where apprcpria‘te, ii'iciuding, but not limited to CHOP, ire, Cyciephcsphamide xan®), Doseruhicin (hydrcxvdexcrubicin), Vinci‘istine (ancviri® , and Diniscne. —l29- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley {0429] In some ments, 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 I to 4 weeks or from 1 week to l month, I week to 2 months, I week to 3 , l week to 6 , i week to 9 months, or l week to l2 months after the administration ot‘the engineered cell or nucleic acid, In some embodiments, the chemotherapeutic agent is administered at least I month before administering the oeii or nucleic acid. In some en'ihodinients, the n'iethods r comprise administering two or more chemotherapeutic agents. {043 0] A, vari ety of additional th erapeuti e agents may he used in eonj unetion with the compositions described herein. For exampie, potentially usefui additional therapeutic agents include I’D—l inhibitors such as nivoiurnah (Updivog’), pem‘orolizumah (Keytruda®), pembroiizumab, pidiiizumah (Cure’l'eeh), and atezolizuniah (Roche). {04%} Additionai therapeutic agents suitahie for use in combination with the invention include, but are not d to, ihrutinih (Inihnwica.®), oi‘atuniuniah (Arzerra‘g’), rituximah (Rdtuxangfi, hevaeizumah in®), trastuzurnab (Heroeptin®), trastuzumah emtansine YLA®), innatinih (Gieeveegi), cetuximab (:Eiirhituxgi), panituniumah (Vending); oatuniaxomah, ibritunioma‘o, ofatumumab, tositunioniah, hrentuximah, aiemtuzumah, gemtuzumah, eriotinih, getitinib, vandetanih, afatinih, lapatinih, neratinih, axitinih, masitinih, pazopanih, sunitinih, nih, toceranih, iestaurtinih, axitinih, cediranih, ienvatinib, nintedanih, pazopani‘o, regorafem‘o, semaxanih, sorafeni‘o, sunitinih, ni‘o, tocerani‘o, vandetani‘o, tinih, cabozantinih, imatinih, dasatinih, nilotinih, ponatinih, radotinih, hosutinih, iestaur’tinih, tinih, paeritinih, eohinietinib, selumetinih, trametini‘o, hinimetinih, nih, ceritinih, crizotinih, afiibereept,adipotide, deniieukin diftitox, m'l‘QR inhibitors such as Everoiirnus and Tenisiroiirnus, hedgehog inhibitors such as sonidegih and Vismodegih, CDK inhibitors such as CDK inhibitor (paibocieiib). [0432} In onal embodiments, the composition comprising CAR— and/or TCRn containing immune are administered with an anti—inflammatory agent, Anti—inflammatory agents or drugs can ineiude, but are not limited to, steroids and giuoooorticoids (including hetaniethasone, hudesonide, thasone, hydroeortisone acetate, ortisone, hydroeortisone, lprednisoione, prednisoione, prednisone, trianioinolone), nonsteroidai anti—inflammatory drugs (NSAIDS) including aspirin, ibuprofen, naproxen, methotrexate, suifasaiazine, ieflttnomitle, anti—INF medications, eyeiophosphamide and nolate. Exemplary NSAIDs include ibuprofen, naproxen, naproxen sodium, Cox—2 — l30- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by eadley [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley inhibitors; and sialylates. ary analgesics include acetaminophen, oxycodone; tramadol of xyphene hydrochloride. Exen'iplary glucocorticoids include cortisone? dexarnethasone, hydrocoitisone; methylprednisolone, prednisolone; or prednisone.

Exemplary biological response modifiers include molecules directed against cell surface markers (erg, CDL‘l, (EDS; etc); cytolrine inhibitors, such as the TNF antagonists, (eg; etanercept (ERE%L@>); adalimumah (nice/nitrate and infliximah (RENllCADE®); chemolrine inhibitors and on molecule inhibitors) The biological response ers include onal antibodies as well as recombinant forms of molecules. Exemplary DMARDs include azathioprine, cyclophosphamide, cyclosporine; methotrexa‘re, penicillamine; leflunomide; sulfasalazine, hydroxychloroquine; Gold (oral (auranofin) and intramuscular); and minocycline. in certain embodiments; the compositions described herein are administered in conjunction with a cytolrine. "Cytoltine" as used herein is meant to refer to proteins released by one cell population that act on another cell as intercellular mediators. Examples of cytolrines are lympliolrines; monolrines; and traditional polypeptide hormones. included among the cytokines are growth hormones such as human growth hormone; ionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; axin; glycoprotein es such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH); and luteinizlng hormone (LB); hepatic growth factor (HGF); fibroblast growth factor (PGP); prolactin; placental en; mullerianuinhibiting substance; mouse gonadctropin—associated peptide; inhihin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth s (NGili's) such as NGililbeta; platelet—growth factor; transforming growth factors ('l‘tilili's) such as TSP—alpha and TGFnhcta; insulinnlilte growth factorml and, mil; erythropoietin (BPS); osteoinductive factors; interferons such as interferon—alpha, beta; and gamma; colony stimulating factors (CSFs) such as macrophage—CS}? (M—CSF); granulocytcnmacrophagem CSF (GM—CSF); and ocyte—CSF (G-CSF); interle'ultins (its) such as IIx‘l; lL—lalpha; m2, m3, lL—r-l, m5, m6, m7, lL—B, m9, mic, lL—‘ll, lL—l2; lL—lS, a tumor necrosis factor such as Tmealpha or TNF—heta; and other polypeptide factors ing LlF and kit ligand (KL). As used herein; the term cytolrine includes proteins from natural sources or from recombinant cell culture, and 1oiologically active equivalents of the native sequence cytolrines. —l3l- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by eadley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley {0434] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and dually indicated to he 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 present invention. To the extent that any of the definitions or terrns provided in the references incorporated by reference differ from the terrns and discussion provided herein, the present terms and definitions control.

The present invention is further illustrated by the following examples which should not he construed as further limiting The contents of all references cited tl'ironghout this application are expressly orated herein by reference.

EXAlVlPl.ES EXAMPLE l [0436} BCMA expression was measured in various cell lines, BCMA was found to he expressed, with a fragnients/lrilohase of exon/niillion reads mapped (FPKh/l) greater than , in 99% of multiple na tnrnor cell lines tested (HG 2A), BCMA expression was greater than that of CD79, CS—l, CLL~l, DLL—l and FL]? (F 1G. 2A). To further terize the expression of BCMA, EoL~l (Sigma), NCl—l-l929 (Molecular lniaging), and MMlS (Molecular linaging) cells were stained with an antinCl‘le dy conjugated to PE (Biolegend, San Diego, CA) in stain buffer (Bl) Pl’iarrningen, San lose, CA) for 30 s at 40C. Cells were then washed and ended in stain huffer with propidiunn iodide (Bl) Pharniingen) prior to data acquisition. Samples were then acquired by flow cytonietry and data analyzed {Fle 3). BCMA expression was observed in the niyelorna cell lines lvlh/llS {Flt}. 2C) and NCl~H929 (), but not in the human eosinophil cell line Eolfl (FIG, 2B), in addition, little to no BCMA expression was observed in normal irnrnune cells (). exits/tern 2 {0437] A third generation lentiviral transfer vector containing the BCMA CAR. ucts was used along with the ViraPowerm Lentiviral Packaging Mix (Life gies, FlXTM) to generate the lentiyiral atants, Briefly, a transt‘ection mix was generated by mixing lSng of DNA and 22.5pl of polyethileneiinine (Polysciences, —l32- ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ling/nil) in ot‘iOul of ()ptiMEM media. The transfection mix was incubated for 5 minutes at roorn temperature. Simultaneously, 293T cells (ATCC) were trypsinized and counted A total of ill X l06 total 293T cells were then plated in a T75 flask with the tran sfection rnix.

Following culture for three days, supernatants were collected and filtered h a 0.45 urn filter and stored at —llOOC {0-438} Peripheral blood rnononuclear cells (PBMCs) were isolated from two different y donor leukopalrs (l-lemacare) using licoll—padue density centrifugati on according to the manufacturer’s instructions. PBMCs were stimulated using Qli'l‘B (lyluronionah—CD3, Sling/nil, Miltenyi Biotec) in RlO rnedia supplemented with, ll_,~2 /rnl, Proleulrin® 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 (MOT) of lt‘l. Cells were maintained at 0.5 x l06 w 2.0 X 'l 06 cells/ml prior to use in activity assays.

At day 12 timulation, transduced T cells were stained with recombinant BCMA—Fc {R&D Systems) in stain buffer (ED Pharniingen) for 30 minutes at 40C. Cells were then washed and stained with goat anti—human lgG llc PE. (Jackson lnrnrunollesearch, West Grove, PA) in stain buffer for 39 minutes at 4°C. Cells were then washed and resuspended in stain buffer with propidiurn iodide (Bl) Pharnringen) prior to data acquisition. All experiments were performed in two different donors. BCMA CAR expression was observed for each of the constructs in both Donor l (EEG. 3A) and Donor 2 {Fit}. BB) transduced cells.

Ett‘ector cells, egg anti—BCMA CAR T cells. were. cultured with target cells at a l:l effector cell to target cell {ET} ratio in El 0 media l2 days after T cell stimulation.

Cell lines tested included, Eolfl, NClnH929 and MMlS. Sixteen hours o—culture, supernatants were ed by l_,uniiner< (EMD Millipore), according to the manufacturer’s instructions; for tion of the ines TEN"): (Fle. rilA—ZlB), TNFd {Flt}. 404D), and ills-2 (FlG. zl-Ewll-F). TEN"); {FiGs llA—Jllil), ’llNFu {FTC}. [Evil—49)? and lid—2 (FIG: aiii—ill?) were observed in the supernatant of NCl~H929 and MMlS target cell concultures for each anti— BCMA CAR T cell tested in both donors (Fle) 4A,'4B); however; lFNy (Fler 4A—4B), TNFd (FIG 404D), and le2 (FlG. dB—dF) were only observed in the supernatant ofthw l target cell co~cultures above background for the 1R ve control T cells (): {fiddll Target cell viability was assessed by tlow tric analysis of propidium ion (Pl) uptake of CD3 negative cells. The anti—BCMA CAR T cells were concultured —l33- [Annotation] Anne.Headley None set by eadley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley with EeLl (FIGS. SA—SB), NCl~H929 (Fle. 505D), er MMlS (PIGS. SEAS?) target cells fer l6 hours, 40 heurs, 64 hours, 88 heurs, or 112 hours. little eytelytie activity was ehseryed in the EQEri era—cultures at any tirne period fer the anti—BCMA CAR Tl‘ eell s {Flt}.

SA—SB). Heweyer, ture ef the anti—BCMA CAR T cells and the NCl—HQZ9 er Mlyll S target cells resulted in a decrease in the percentage of viable target cells at eaeh time point measured for each ef the antimBCh/lA CAR T cells. {04-42} To examine proliferation, anti—BCMA CAR T cells were labeled witl'i cai‘hexyi’luereseein sueeiniinidyl ester (CFSE) prior to ee—eulture with EeL—l, NCl—H929, er MMlS target eells at a 1:1 ET ratio in Kit) media. Five days later, T cell preliferatien was assessed by flew eyternetrie analysis of CFSE dilutinn. Data was analyzed and platted as hi stegram using Flnw‘lem (Fle. (SA—68). All ments were perferrned in two different deners.

EXAh/lPLE 3 Antigens were hietinyiated using the liiZ-link SuifewNil-lS—Bintinylatien liit from Pieree/ThernieFisher (Walthani, MA). Seat anti—human F(ab’)2 kappa—FlTC (LC— Fil'l‘C), Extravidin—PE (EA-PE) and streptayidin-633 (SA—633) were ehtained freni Snuthern Bieteeh (Birmingham, AL), Sigma (St. Leuis, MO) and Molecular Prehes/lnyitregen (Waltharn, MA), respectively, Streptavidin Miernlieads and MACS LC separatien eeluinns were purchased from yi Bietee aehn, y). [0444} Eight naive hunian synthetic; yeast lihraries each of ~10?) ity were prepagated as deserihed l'ierein (see "762009036379, WQZOlGlOSZSe, and W020i 2009568 to Xu emf.) Fer the first twe rounds of selection, a magnetic head setting technique utilizing the Miltenyi MACS system was performed, as described (Siegel , 2004), Briefly, yeast cells (~l010 cells/library) were incubated with 3 ml 0f 100 nM hietinylated neric antigen er l0 nit/l hintinylated Fe fusinn antigen fer l5 minutes at reeni temperature in li‘ACS wash buffer (phesphate—lniffered saline (PBS/Ollie bovine serum albumin {BSA)). After washing once with 50 ml ice—celd wash buffer, the cell pellet was resuspended in 40 m L wash buffer, and Streptayidin MiereBeads (500 pl) were added tn the yeast and incubated for 15 minutes at 40C. Next, the yeast were pelleted, resuspended in 5 iii wash buffer, and leaded onto a Miltenyi LS n. After the 5 iii was loaded, the eeluinn was washed 3 times with 3 rnl FACS wash buffer. The eeluinn was then reled freni the magnetic field, and the yeast were eluted, with 5 mL at growth media and —l34- [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley then grown overnight. The ing rounds of sorting were med using flow try Approximately l> Affinity Maturation {0446} Binding optimization of naive clones was carried out using three maturation strategies: light chain diversiticatiorg diversification of Vii-l l/Cl)l{l-le and performing "v’Hmut/Vlémut selections.

Light Chain Diversification: l-leavy chain plasmids were extracted and transformed into a light chain library with a diversity of l X 106. Selections were med as described above with one round ofMACS sorting and two rounds ofFACS g using l 0 old or 1 nM ylated antigen for respective rounds.

CDRl—l l and CDRHZ Selection: A ed donor CDRl-B was recombined into a preinade lihrary with CDRl-ll and CDRl-lZ variants of a, diversity of l x l08 and selections were performed as described, above. Affinity pressures were applied, by incubating the biotinylated antigen—antibody yeast complex with unhiotinylated antigen for varying amounts of time to select for the highest ty antibodies.

Vl-lmut/VKniut Selection: This round of affinity maturation ed error prone PCRMbased niutagenesis of the heavy chain and/or light chain. ions were performed similar to previous cycles, but employing FACE; sorting for all selection rounds, Antigen concentration was reduced and cold antigen competition times were increased to pressure tirrther for optimal atlinity.

[Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Antibody Production and Purification {0450} Yeast clones were grown to saturation and then induced for 48 h at 300C with g After induction, yeast cells were pelleted and the supernatants were harvested for purification. lgGs 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 KappaSeleetTM (GE Healthcare LifeScienoes, Pittsburg, PA).

ForteBio KT) Measurements {04%} ForteBio ty measurements were performed generally as previously described {Estep at 6251., 20l3). Briefly, ForteBio affinity measurements were performed by loading lgGs on-line onto Al-lQ sensors. Sensors were equilibrated off—line in assay buffer for 30 minutes and then red e for 60 seconds for baseline establishment.

Sensors with loaded lgGs were exposed to l00 nM antigen for 5 minutes, afterwards they were transferred to assay buffer for 5 minutes for offwrate measurement. Kineties were analyzed, using the l:l binding model.

MSDnSET Kl) ements [0452' Equilibrium affinity rneasurern ents performed generally as previously described (Estep er (1].; 20l3). Briefly, solution equilibrium titrations (SET) were performed in PBS ~l- 0l% lgG—ili'ree BSA (PEST?) with antigen (BCMA monomer) held constant at lO—lOO pM and incubated with 3—to Sufold serial ons of Fab or mAhs starting at l0ph4lmlOnM (experimental condition is sample dependent). Antibodies (20 nM in PBS) were coated onto standard bind MSD—ECL plates overnight at 4°C or at room temperature for 30 minutes. Plates were then blocked by BSA for 30 minutes with shaking at 700 rpnn followed by three washes with wash buffer {Pl-ESE? v-l- 0.05% Tween 20). SHEET s were applied and incubated on the plates for l50 seconds with shaking at 700 rpm followed by one wash. Antigen ed on a plate was detected with 250ng/rnL sulfotagm—labeled avidin in PBSF by incubation on the plate for 3 s. The plates were washed three times with wash buffer and then read on the M89 Sector liniager 24-00TM instrument using ls: Read, Buffer T with surfactant. The percent free n was d as a function of titrated antibody in Pri srnTM and lit to a quadratic: equation to extract the RD. To improve throughput, liquid handling robots were used throughout MiSDuSET exfintents? ing SET sample preparation —l36- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Qctet Red3 84 Epitope ginning/ligand blocking {0453} Epitope binning/ligand 1clocking was performed using a standard sandwich forinat cross—blocking assay. Control anti-target lgG was loaded onto All-lQ sensors and pied Fcnbinding sites on the sensor were blocked with an irrelevant nuinan lgGl 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 '70. Additional binding by the second antibody or ligand after antigen association indicates an unoccupied epitope (noiiucompetitor‘), while no binding tes epitope blocking titor or ligand blocking) iiias:__iEastusinnfihtoinatnarannt {@454} A TSngl SuperSW inAh HTP column (22855) was used for fast SEC analysis of yeast produced inAbs at 0,4 rnl_,/rnin,ute with a cycle time ofo minutes/run) 200 mM Sodium ate and 250 mM Sodium de was used as the mobile phase: Dynamic Scanning Fluorimetry [0455} ll) uL ot‘ZOx Sypro OrangeTM is added to 20 uL of ng/rnL rnAb or Fab on. A R in strurn ent (BioRad CFXQé RT PCR) is used to ramp the sample plate temperature front 40° to 95° C at QSC increment, with 2 minutes to equilibrate at each temperature. The negative of first derivative for the raw data is used to extract Tin. —i37- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Clcne FSm26528 HC DNA (SEQ ID NO: 271} GAGGTCAGCTGT GAGTC’GGGGGAGGC'TGG'ACAGCCT1GGG1GTC CCTGTGCACLCTTTCGATTCACCTTCACCACTATCCTTGG ATG GTC AGGC-1AAG ‘1GCC‘L ’1' CI CSAC-‘1TC-3 -1C-1"TCCI'T CTAG ‘L’T'TAT 'TAC‘ r"CATC1C‘ACSC1 C‘1LACJT- C—‘1T-A\T‘T‘TT1’T ‘L‘T'AC ‘1C‘TGTCTCCCTGACGGGZCCA'TCAZCATCTGGTGAGTCA'TTCCAACAA ACTCTATCTG AATTGAACGCGT1ALLGCGGACGLG.GGCGETCTLTTAGTCGTCAAGAGCJCLATGG? A1GCCTLTTCGAC.1ATATGGG.tCGCT.CAA GGTCACC1TCT CTCA Clcne FSm25528 HG (SEQ ID NO: 272). CDRS l, 2, and 3 are underlined. hVCHTESGCGLWPGG?TRL"TAAGG1"\I1 .T'T"1T‘TC1TLT11/TI \L’DT’TTT‘11~L1 1n1111-L1w1-111l1AGUKT’ 1111-1 1111,1 l ALSVRC‘"'SRPRS ETYTFQP"ELSLSPGERATLSCRASQSVSRYLAWKPGVAPPLTTTDASWRATGPN P 7 " UTSNPFTFGU. . VETKR —138- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley (Ilene 28 CAR DNA HXL (SEQ ID NO: 281) I.TG1C. CTCL‘CC‘CT .ATCT1C‘ CTC1CTGC‘.‘CC‘CT GGCATTG ITCC'. CCAHCf’GCCGC.CGC CGGA1L1GTGL‘,I1—"1.GC.TGTTGGAG TC' GGG 4GAG 4CTTCGTACAC’I‘CTGG4GGTCCCTGAC4ACT TGTGCAGCCT‘J‘T'CLISA"'T‘LIJZ CCT'T‘T'GAT‘JL‘1T"1LJ'TAT‘ ‘JCIAT1.-TL‘TTL1LI.1‘LII'."L.‘LIJLII 1C1G1CT CLIAJT TGLT‘r-TAI‘rGLGCT-1L.-‘1AG'1‘1LSG'TL‘T‘LIJZCTA‘T'TIL-‘TLT‘T'CTL‘T 11.JTL‘\L1.1T‘G;7L ‘""‘AL‘TA CI L1." CTC .‘.G‘T‘CAGGCGCC‘CGITCACC‘A‘T'CTCL‘JA'I‘GA AAT‘TL‘CI.A.GAIL I‘L.‘.I L‘J'T‘L‘1‘T‘.TTL.‘.T GCAAATCAAC'T‘GCTGAGAGCC‘CACGACC‘IC—GGLCT 1TAC'. ATCT C‘CCIAAGACCGIAGATG GGAGC 'GTAT.'C "CATITTJGG‘GTCATGG 1TAC. .IATTG . C.ACC‘C—T ITCCTCAG1‘GTCTACAT CC‘G‘CTCCGGL—AAGC’I‘CGL—AATG 4CGAAGGTAGTACIZLAGGGG4AATTGTGTTGACT-CA G'IT‘CTLJ,AGLJ "TALJCCT G"TL.‘TT"T1L.-‘1‘LJT‘ ‘CCIL-‘TG1-1.‘GAAAGZL1.JLJZ- CCLJT C‘ CTGLIJAL-rGLII TCII- G'IT‘ LAG. L-I'."GTTA.TLIJZ1GT‘ACT‘TT‘AL1.JLJ"-L‘T‘T.T.-IL‘TACT"1GZTALJ ‘J‘T'GG G 1CTLJ TCII-G1CTLJL‘ T .‘.ATL‘J'T‘ATCA'T GCAIIICCAI .LJ'AL.-‘1L_1GCCA -‘1 .1C'ATCC‘L‘AL1C'CAL1GTTCAL‘ T SG 3A.; TI‘ .1L_‘1 ETC T‘GG 1ACAL1AL‘'ITTT L‘AC T CTL‘A.CL.‘JI.TCAGC‘AL‘1CC‘T‘A.L1A.CL.‘JL- TGAI.L AT'TTT TG AL‘TT TAT TAC T‘GTCAL‘CIACACILI TCTCC'. GGC. TCA.CTTT. .'G C‘CAAGG‘. TGACIATCAIAAC C‘GGAG‘GGI.

CGG ICCC‘TGATTA. AAAAGTC‘.AAC‘GG. ACA. .TCA.. L‘ACCTGIA. ..... G1CAAGC CCTCTGTC‘CG'CAC CTTGT CTG 4TCC T371. GLI‘ ATTTCTGGCTGTTGGTCGTAGTG L‘GTG-1T-_L.4‘TCCTCGC' TGT' ACT ‘TCT 4C.‘ 'CGTCACCGTGGCTTTTATAATCI‘ 'TCTGGGTTA -IATAAG7TAG-LJ ‘,GCLJ"L.11CT ‘,CI1‘1.T‘7-TL1.JLISA"'T‘TL‘TL‘AT‘GAATA‘GALJTC LIJA ‘GLIJLJ 1C LIJLJ'IT‘GG CCC .‘.A ,‘AI‘L1GAAACAL‘J'ITACL‘JI.GL‘,L‘J'T"I‘AL.‘J .1C'AL‘JCA.CL‘J'ITAGAGATT"TCGCTG .‘.CT .TL.‘ SGAGC L1CL1TL1AL1T‘"’T"I.ICL:A.L_1AL‘T‘ CTGL‘.AL1A.‘.L.‘1CALL‘,L.‘,II3L‘.L.‘1TAL‘.CII3CAGGCCCAL‘1AI LJSAI CTGT ATA CAACL‘ GLTAC’TCACGCGAGTITTGA‘CTTT .'CJ1ATCAIA’GCGCAGAG’G. .CG GGA‘CCTGA ATGGGCGCZ‘TAATC’I‘AI L—ACL‘I-‘LAAI ATACC. LCC AGGAGCTTCTCTATITTTGA ' L‘TL‘LJMGAAG I-1TAATL—7‘TTGC' L‘AACCCTATT’I" L‘ATAZ TAG CATCAAT’TGC-TAL‘CTGAAA ‘1GG/1TZUTAI‘L-1SLJZ- CTTTL‘T ‘L‘1CT'T‘T'1T]-...JTL‘TL1.‘1LTTL‘TL,"T'CTL‘TL4CT"1LJ"L1.JT‘Z-L..G.r-TAL1GA"‘AL‘TTA‘T‘L‘IA ,~ ,~.T.I,.C:A(T ATGL‘ AACL‘L‘w T‘ALI‘L‘T‘I" r: .

I'Ca .1. ‘\/ .T'. \.....,4. T Lu T, x, \/ . '3 x, \/ .z x, J. LJ 3 Clans: FS26528 CAR HXL (SEQ ID NO: 282) TLLAL "TAL E'T ALT.LT—TAAT RE‘L‘QI.LESGGCLVL‘RGCSL. LSCASCRTTTRYATVTAWVRQA RGKGLE'1/11'TTAICDACTRYTADSVRG \TTTTG'LDTLGRT TLTVLLI‘T‘TNSLRATTTA‘LYVARAZTVT GA‘/CSLVS"‘1T...I"1I1’1"1I‘QL,_RR’1L‘1IDT‘WGL T‘T‘L'rLTVSSGS‘T'GLISSGT/PLTGGEGGKL‘ITVT‘T‘T'QEIE’AT‘L T1LI5‘JLL1I‘PJ-T'T" SLIJRAG T-ILRT1TTTI1II YTIALITRATCTRARTSGSGL '3‘..1‘.‘1‘I"T‘TIP‘T C [1T1IIT‘TI'ZII‘DTI‘A‘VY‘1I "DRIIS'WPTLTFGGG‘T‘TVEIT...ILA ‘.\IT..T.I'IST\IL.-1TITI.ITIII‘TKCRHTTLPSR"‘P T ., T T ‘ILVVI G 1‘1fT1A.C.YST_1.1_1VTI‘7LI.1. .T. E W‘IL."S RSRTTT. S_)‘.{].VTT\JTvTT t'RR.RG.T-."T.'RTLIIYQT: TAIL. 1:RTPAAV RVRTCRS-TJATRAYQOTCTQLYNEIILNLGRRET‘LD17._.DKRRGRDT'ET‘LTGGKRRR LT\TRQ.LGTT‘TT1E LQKDKTVTAEAT ST-.GTI/GE‘RRRG LGT—TDGLYQGLSTATKGT‘LDATTTT‘TL‘TLPRR[AT —139- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ClQne F3726528 CAR DNA LXH (SEQ ID NO: 283) ATG7 CTCCCCZT.ACTC CTC7CTGC.‘CCTT GGCATTG ITCC'. GCAGCC7C CGCC CGCAAATT.TTTGACACAGTC'CACCCACCCTCTGTTTGT TCCAwCGALAr-TGATCCAL, CTL7T C ‘T C C TGL7AT.7TS-CG YCA.G"C1A.GAT.7‘GTCTT"T'LA.GCAT7C7TAC T‘ 'TAT7T, T GTC7'T1-TTJT7.‘A1-‘-T L‘AGALATA 7C.T CCT‘ ZCLAG -7CTC ,‘T'CZ-‘TT‘C‘TZ-‘T'L‘ T.-7LA.T‘C"TCCT‘ACAGG7 -.-L/‘TC1GC.C1‘TT‘C "LCL- G 1C2- G7.TCLCTCGCAGTGG7TCTGGCACACTCCLCCCTCTCCACILTC7CJ‘.G‘CJCTGA TCCACT.TATTACT.TCACCAG GAATCTCITTCCCTTCACTTTTG’GGAGCG ACCAAGGTTGAG.T.AAACG GGGTCTAC TC GGC'. CCG7GAA. 7CCCG.AAGT GZGAAG AGTAG1TAGGCGGAGGTC ACC'GTTCGAG'C'CCGGGCCTTCCTACACTGGG GTCCCTGL CTLTCC' TSCAGTCTCT-CAT'CACTTTTA.GZ"TATCCCA1GCATGG CLGGCT7CAG7GA-TGGGCTGGZMT GTTTCAGZTATTATTTTCCAGCTG?A GAAC.LL. .7 m. ,m. "NT. "Wm mm. mm. "mm -ATWW.TCAT.7A7 T .A ,3, W -..7 ..

T.I. A. ,T‘AT,GT,AT_7.. .1. T. TLG.1.T.71T 77GT.7GT,-GGT , .1. ‘T..AA . ,LLAAGAA.

C.. r. NWVVTAWVWNN T (LN. (71,. mm.» . "my. mm," LL. .1...

L77. \/..:.'_‘I T.. CTKJ ., f1.ALT‘C‘JPTLT..,L. TTJK,TL'.,.LKJA'JJLD‘bk,.MCJPTKJTJL. J'KJK/xj TCG LLT‘ \/ .'..11 ST..Jk. J‘\/.lzl AGA 7"CGAGC GCC 7TAT'. CCJACA.TATGGG 7TC.’AGGGTI. CAATGTCA-\,GTCTCGT CAG LCC3CTGCCCTT.GATTA. .1. AAAATJTC.AACGG. .ACA. .‘T‘CA.. CAC’GTGA. ..... G7CAAGC CCTCTGTCCG"CA'C CTT‘GT TC CTG 7TCC TCCA GC ATTCTGGCTGTTGGTCCTAGTG CGTG_GTCCTCGC' TGT' ACT ‘TCT‘ 7C" 'CGTCACCGT‘GGCTTTTATAATC‘ 'TCTGGGTTA L-TCCL-LATAAG1TAG"I 7C7CC"T.7CT‘ 7CLA.T‘7TT.7GGA‘TI TL/‘TCATGAA‘TA ‘T.7LA.CT‘-TC-CA 7C7TL'C 7C- GG CCC CA.

SALAGGAAACAC'LTACCLL.GCC'LTT‘AC 7CACCACC'LTAGAGATT}.T'TCGCTG JCT TTC SCAGC T7CT7TT7ACT".'T'L.‘CEAGATCTGCAGACGCACCL"SCGTACCLL3T7AT7GT7C7T,AT7ALT,CALL. CTGT ATA GACCTCAAC 7GGACCCACGGGAGT7TTTJA‘GTTT .'G 7.ACAAGCGCAGAGG. .CG GGATCCTGA ATCGC—CGCAAACCAL T—ACCT-‘TAALL 7-‘J—‘TCC CC AGGAGGCTCT‘CTATMGTGA ‘ CC‘CCHGAAG 171AAf—7‘TTGC' CAACCCTATTC' CT—‘TAZ TAG CATCAL‘G’TGCILCACTCGAAA 7C7T3/7TA1TL‘T7G7C} CCA 7C7GT‘T‘T7T‘17-.TT.L7-‘TC-7~.7TTL/‘TT,‘l'CL/‘TCCLAC' ‘17-CG1-TAT7G/3"‘ACT'C‘AT‘CA w. ~r~< 7-7 L~ "AFC/AFDC"an AIL/ATCFCW,mr TNT r'17‘ (:7 ~ .I\_1 .1. ‘\L/ .L'. x.....,1 T ...u .L x, \/ . .J x, \/ .z x, J_ \J J Clcne FS"?6528 CAR LXH (SEQ 13 NO: 284) MAL T’TAL LP ALLLT-TAAT RCTVTCC(/1 PGE RASx "SL‘JSRVLAWVGCRP T—QAPR_.L T TRAGTL'TATGTPARFGS (3C; G)TT'FTTTLLCSLTPTDF’WTYCATRTS‘VPFT FGG TV‘I‘I‘T'LRGST‘SGSGKPGLJGECEL ‘KG1,T‘ITILESGGGLVGRGSST.RLS’CALL SGFTFDT YAMAW VR")ARGKC7E‘LIT"\J’S TJACTT.’TVATJSVRGRFTT SRDR7’5KT T171. LCMNS 1.739733"‘JYYCA AM1.7 L\fTL‘DLLLLTLGT‘TH‘JTVCSAAA..... L‘T\T1_7.'ICTXT.7TLTT11LTT71GETTCPSP‘CP T T T ’T‘JTFT"W G 7VT7ACYSLLfT‘ITv 7. T E WVT"S1. RSRTTT. 3.3‘.{].VTT\JTvTT PRR.PGT-."T1 Qv;"\J1_JS(TI\\I VQPGI IP13ULIIA.AIvGrII, THU. III I T . I: IIIIA I IIIIIIIIIIII -I..,II .. "II .I I. mm I . I I'I QILIAIGIJIHIMAL AIIJGIGIIIIN 1" IQYIICR"!III.IN, ADSVKG{7111‘ SAI‘I‘IS<\I'I'I.II’IICIV111’3131’ T \ILYYCAI‘DGT' IIGGIMJTTUITIGP I‘IfiI/TTVS I C CDIL '. I I I I |. J Clone PC"26534 LC DNA {SEQ ID NC): 290) ATAITGTCAIGA'.1CAC11C".".3ICI‘1"I’3’I'C.‘1I1"ICCT’3CCC’3’I'CACCCC".".33A3L‘C3C3I.3IG.3C.3I‘1.1I3L3I'.A 111C111I3C3I'I1C33I.. 3171’3ITIACI C’C".3ICI‘I11’3CIA111G'1A.AT .3GATI ATTT .3GA"11G 31‘.A CCTGCCAACCCAGCACTCT .CAC. 3C3T CTGATCTATTGGGT'."TAATCCGCCI'CC GGGG‘TCCCTGACAG3TTCGATG CAG'GGATCAG 3CAC[ GATTT TACACTGAZ—L’-\.ATCA 'CA CACTGGAIGC' CI7—‘G A 'GT3GCGT TATITCATG 1ATG AGG ACT 3CCTCTCA TTTTGG1GCACGL—7‘ICCA7‘ICGTCAL—AICAAACCC Giana PC~26534 LC (SEQ ID NO: 291). CDRs 1, 2, and 3 are ined.

DIW’MIQS UHBVTEG1BTC GZRSSOC’LHQNYNYLDLW{LQIP m GVPHxFSCS'GCTD'TLKIGRVALDV‘LYYCNDCTGLPLTF"G4 SCICII13IISNC31I’1XYLI) (SEQ II}__. NC": 292) [113C CD1 I] Giana PC~26534 CAR DNA HXL (SEQ ID NO: 295) ATGJIIAICTC 'CC 3T7‘IACTI GC' CTG TGCTGCCGT. TGCTCCTGCACG 1CG ACCGCC’ C 'CI-CG'IGCACC'L3TCCI‘3G'CTGGGGGAIGGC 3'TGG'3CLAGCCCGLIr-GCTC1CTGAGI;CT C'I‘C 13T C3IL13CIL’3CI3TCT1-3C3I1'1‘T'ICACC’I‘TC]T C3]GIIIL‘I L3I3CZA’I'I3CJZC 33GTCI1‘ 3CCCIAGL13CI'I1 AGCCAI IIC3G3C3I1I'C3C3AC3TC3 3C3TG 3CAC3 3I’I'I1‘17171I'CT'IAT C3]’I'C3C3AAL’[M"T‘AJMI13"I3"I'I- TG CI‘.1‘C3I1. CTC AIACGGCCGAT’I'L‘ACCA111’3’I'L‘LIAGI.3A.IIA1".’I'CCAAC3I 3C'I1C'I1ATC'I‘ G 3AA. I'I‘GAACI.GCCTGIASIA.GCCGAGGI .C.C.3GGCG 3T1C3’I'I.C1TAIITCC3I .3C.3I1‘ 3A. ..3A JG TATCTAGGTGGTCT TGG' ACT' C.JACTTATGGG GAGA13TACL1 TCAIIIGTCTCCT CI-_C1 CTALIAT3’11CGL CGG 3f7-‘IGCCG 3IL7-‘IG'GCGC 3AI-‘G TII‘CIAAAAGG L32..AI TGT IGAICT AGT TCCACTCTCCC'GCCCGTCA3’11CTL3G CAG CGG CTCCATCTC3 —141- [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ‘.GCJ.V.GGTC‘..A. A .'GGJV.’ 'ACJVLACTAL' .'T'V'GGATTGGTACCTGC JT. CA .ALGC ITCC. CATAL;T .

GGCJVrLGTCT 'A CAAGCJVTC ITC~C LCALTG 'TC'T.7‘.’TCGGGCC‘.‘CCGGCGTLJ V CT-GACV 7‘LCTGG AGT = GATCAGG ACAGATT'TACACTGAZLAJ—LTCAGCAGAGTG r" .’Vva-inZA''JC'JIALL/llV/Nr‘ilr‘ r m \r'1n' .nL'JLJG'J Lx ITI. "I" ITI. 1 ‘(Dl \ I-Jy J1-J CWCITL'JLJQIZCJ 2JIC JCxxJI\ I-Jy \ I-q , 1 q \ I-L.

'C'JI ITL IFLCJLCJVIZTXLL, /\-1I‘|r1/\r‘1r‘L/IK/LV—LIK/PL‘C-nTr mIVL ITS JLJCJILGCJCJILL,.‘ (I CAAGT VGAG2".TV VJA.".A VJGGG VJCGLJ V'GCCJCVTIGA’T'2"-L' -JA..AAGTC2 AVC-VJG AAC ‘AJTCAITVJACGZL.GAALA’VJG ECAAGCJ'ACCT’V'T'GTCC .1TC7 T TCC‘ V‘IIf’VTCC...J\- ..... . \J \JKJ. K/ -J 1LJJ. CJ .LJTCJCK.

JL‘XK‘JC\IJL\ .LT.3':JN‘N rTINIIN :m :I’" . mINIIN TTIINIIN mTINrTINmINmN FTTHATJ:.

..J TTG UTAGJ. .30 1_:_ ':J. GTC .J.'JTI’NIIN..J'L:J TLJ. J..r‘\K_J.L Ci. CLLJCTCLJliq-INT".K_JJ.L‘L IN 'NmmK_JC.(J.L KJC‘JKJL-Nrn. .L . .1. 17 mININ 17 -r1—1NINr—IN , J. ‘.JK_J .LKJCJEL. .AL"\F‘IA . LATCT .2\:T{.J'\J.TINNIN m7 C4ININ J. PM; LJ. ..J\_J. LJ..L1’\.\A.GJL1’\KJ ~J\_/ CGAI.mr-[L TATGT‘ CCACGCCV VCCC'GGCCCACVJILGCAJJALCACTACCA 'CCTTACGCACC‘A CC‘I'AC-JAC-VJ2- ICJ-JC'VICSCVJC'VIA' V'CGGAGCAG «.VJ.-TCA."«G'I’V'I'VV VJCAGA’T'CTV‘ 1C2- LJAIGCJACV CVALVJ- {J V .J.J2‘\CA.'\CJCVVLACJ'.1J'VIAIAACJGAG IC2"-LCVJCIG -J ‘I'ATV‘ V‘ZLCSG C7JVJ2"LCJV‘ VJ-C2-C7-J1VJG2- ALGAGTV‘A TGA JVC-T‘.TT.VJGACA 7SCGLJACAC1LJAJGGGACCCT .1AGA TGGG'TGGCAA.. CC.) . .JAAAAV a JVLJVKJJ.I~. «(a JD‘LJ‘IKJ'LJ \JI L2.J.I..IAJJLKJACWLJ.JCJHLKJAIJKJAIPL.f-‘.L'LJJ.D\ L~ IIWfN.-Arb\r'1/N ~AJr n 1mm »D‘rE'IerV N'\ mm ‘1': ~ _, JLJC..JI12L.- K; \I \_Jfirm-1 J. . Li. ,IIJ AAATAGCCATCAA.’ GAGACGCJLJ GGG.J..LAAAG'GGACGGGT’.‘TCTACLJJLLCJGALCT\4 CAGCACTGCTACGAACwCATJVLTJLTGAGC'. CTC 'ACATCAAGCC . C'AJKJLAGC (Ilene PC-"26534 CAR HXL (SEQ ID NO: 296) MATRIX"..LTJIJIJILJJAIJIJ-IJHAARE 2 VC1GGVV"TC)'RCJRLJ7JRIJ'VVAJA.CGFTFEV PGKG.JEWVV'AALT.{VV2L2JCTVI KHYA1271?’RGRIT TSR LJI’VK‘ JQIIRSLJRAEIJ'T"V2J’YCARIV\_J .IJGGIJW .VFL.I.JTJ\I7GRCTIJVTJ.AqSGSTSGSGKPGS LCSTKC-TLZIITCSPIJLJTJPVTJ‘JFPASIS CVRSSC]SLLHENGYNYLIW’LV'YLCJ'CPGQCTV"'LTYLGSNu 3G‘JPDRFSGSGSGTDFTLK:SRV(A LA". "JGVYYCM"GLC—LPLTFGGC—TKT.LLKRAAALDNZ CSNGTCTHV .GKIILCV SP F' PS' ‘JVJVJL/VK/CJVLACVJCIJVT\fAIIII'I'V‘LVTV'S’RS PLLI—ISD MJT'V'IPPRP" PTV‘R .IGIVL7V2..2-LPI} PIVRTAAY. CR‘ITI ATJVAPAYQ’VCI .. TIJGRRFFLTYDVLDKRRGR.EPIJTVI K IVPQIJCLYNETJQKIKMA.EJ‘AYSET. .1?iKGILRRR.1KG-II)'J1JYQG1JSTATKIVIYDJJALI.JTI{CAIRIJ_J.. —142- [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley Clarita PCw26534 CAR DNA LXH (SEQ IT} NO: 297) ATG7 CTCCCCZT .ACT.7CI CTC7CTGC.'CCITT GGCAT.TG ITCC". GCAIG -C7C. .CGCC TATTGT 7IATGAC 'CAGTC' 'CCACTCTCTCCCTCTCACCCT' GGAGAGCIGGCC‘TC T—T‘C‘T‘ TC'T‘C'ITTGT T’T'TTG' "CTTGAGCC' I'CCT-CAT‘T TAA’T'GGAT‘TCZ—TAL'ITAT'TI‘T TGT— T"T‘GG ‘T'A'CCTGCAK-rTKTAITCCAGGGCAGT T’T'CCACTTG ,‘T'CC TGTTT T’T'TTT‘T’T'GC-3GT'TC'T‘ATTTCGGG "CT CCG.3G 3TT‘CC ITIGA.CAG .I7TT."CA.G"G .I7CAGT G'TATCTG 3C7 CT GATYTT.CACTGAAAATCAG VACATTCJAGCC GAGGATG". TCCCCT"".TTACTGATG IAGG7. CTCG CT-7,CTCTC ACTT . TGGC CACCI 7.GTT. 77.ATCI7" GGCG'CCTACATCC7ICTCCJCGAACC CCCGAZTGTCGCTAAGG'AKI[CAAZCZ—G CAGCTC—C TGGTG AK—TCTACGAG-.CCT GTCCAr-ICC'T‘GGfiAGG CCC' "GTTGZ-C’ TC CCT‘ T’T'GCAGCGTCTC(ATTCACCT LIA G CATGGCATG TTTC' "GGG' "CCG TCTTG CTCCTCCTAGTGGC' TC’T'CCGTGGCAGC'T‘ATAT CT TAT" GATG.~AACGA"AT"AAACAC T? T .I7CAGT .‘C'T."CCGT GAA’TG ECCGA."T‘CTC3ATCTGCAT‘ AGAC.AATTCJA.AGATHCTC.I7CT."G"I.IATT.IT. GCATAI".ACAGCC'T'GACAGCSGT"ACACGGC‘ TCT 7.CC~C IAGH 7.ACG .TACTTACTAG .TCCTCIT.-TG'CTACTCGA,TTATC GJAGAJCTACC 7. TCACCCK‘IETITCCTCA‘GCCGCTGCC ITTG. A.TG .AACTCAAA G AACIAATCZTTCACT' TGCTCCT ITGT I 3T IACCCT TGTACICTACTCCFTCC ATK-_GICCATTCTGGC—T7TTG7ITCG' T CK CTGCT' GTTZ CTCTCTCCTCGTCA CCC'T‘GGC'T‘T'TII'TATT/‘TA’T'CT'T CTG TGTTAGTATCAAAAKCT/‘TAG.T\T(CCT‘ TCTC‘ "[‘TA j7CGTAKT'T" "A CAT"GAATATGACACCAGCC TCCCTGCCCCCAAAGGA AC’T'AC’CSCJ‘TTACGCACCT C. ,ITf‘GT ATTT C TGTGCCTA"CGGT."SCAGGC'T'GA."IITTTCC..7T.TC‘T SCI‘CTTIAT‘ .SCACCAG CGTATCAGCAGG7.CK .GAAC IAAC".TATAA7- 7.AG.C" CIT‘ACCIT 7.G.AC7ICAGGGAAGAGTA TGACGTTTTGC—AC AGCGK-ACTGGCGG ACCICTCACAT 7GTG CAAKTACCAAC_CGAA_A-K.A .ACCC ICTK--GI G CTATT T‘TCACCI'GCAGZTAGGATAZ GATCGCTGAACCCTATTCTG TA TG'IAT'TITTT/‘TAAGGZGTTG VTGT/KATTG«.TTTT/‘TAATTGTGCA GTT'TIGTJI TCT—GTGT— CT CAK.7CAC ‘T TCTT.,7 7 7 7 7.77 ,77 GAT.’7 GGATACT "TA". G.,7.7 7 7777. A, "‘27 ,77 7,7. 7,77, ,77 7 7 ,7 7 ,7 7,7 T 7,7 7,7.77 7_,7 . -CACATGCAT'GC.T‘TC. 77.C..C7_.TAT Clcne PC~26534 CAR LXH (SEQ ID NO: 298) WKALPT’TA. L PLATTLLTTAAR '5ID--T'T’TTQSPL SLPVTPGJTPA STSCRSSQSL YRKYLD VKKYLC’TTPGCIST‘K QLTTYLCCWTR ASGVPPRTTSG SCSGTDFT ToRV'IKTT. ‘VG f‘II’TT/TgGIG'T. PLTTfi-GT1 V ETK .GS’T'SGS GRTGSGEGST‘ KGQ‘V’CTAIETSG G TVVQPGRSTT RLSC F’TTHGTTTTWVR QAPGTCGLTT'JT/I AAT NTC THADR‘J; GRIT" TTSRTDT‘TSKTXT'T'GTKIT TTYTTCITA SLRA .TTJTAIVIYYCT R DGTYT.GGTTWY FDLWGRGTLV TTK’SSAAALDN EUST GTTTHV (GKHTICRSPL TPCPS‘x’P?\TV \LIK. KGG‘ZLAC YCITLVT‘.T .L TTTWVRSR SR. LLT—TSDYM TMT PP\RPGIPTR.KTT YQPY-APPRTKP TITAYRSRVKTTS T SAHAR—T' QQ GQNKKKTTYNT-TKTt*2", ..GRP'TYL‘ DKR .G TT‘IT‘I'T'I‘T‘T GCKPRRKTTPT‘LYNLL KD WTATSAYSET{'\~ T‘TTGERRRGKG TTT‘G'TIYCGTIG'T 'TTKT‘T'T‘ATPT VQTAK-PD" [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Clans.- AJm26545 HC DNA (SEQ ID NO: 299) C.A.GGTGCACCGCTCCAGTCTGCGGC GAG1TG GAAGCCT1GGG'CTCIGTGAAGGTTT CCTGCz-_GCJTZT GATITCAC TCTTTGGAGCA TATJ TCCA.TC GTGCGACTGGCCCC ‘T'CSCTZ1T1’T1-71T1GCC"'TGZGGA'TC GAG'TAT'TT CCTT7‘TCT’1'G Gr:""7Tz-TLTr-CAT'TTiC"T'AC 1C}- -’ CAAL‘T'"C"Z111TSGCTZTCT’1'CT/‘T 1C"TCACAGGC-121 CAC 1’T'TSCZ1CGATC}- AG'T‘CTACA'T‘I’1G A 1C'I‘CTTAGCCTAG;T'I'C1ACC1J C.CC.1GCG .1TG’I'TC'TACTCCT .1CCAC1AV1A.1.AA‘"TG.1CC, AATGCACGTATCJGGGC 'ACGG 1AAC. TACT C TITCC'. CA Clcne 45 HG (SEQ ID NO: 300). CDRs 1, 2, and 3 are ined.

QVQITV 38G. TTTT‘VT KPGAS‘V’KVT’SCkASG‘:TFT’TJA'YNHTN""3QTAGQGTTTTPC/ .1TTTCPSGCKTST .AQTKEC‘QGR'V'TTV’T’T CTS TUTTME ZSSTTRS .T‘TD'"‘"TVYYCrT 1’ .1QG‘TTVTVC‘So YTFMEHYMT—T (SEQ TD NO: 301) (EC CDRT) VTGPSGGK‘TSYAQl TQG (SEQ ID NO: 30'-) (HC CDRZ) ARESWTMDV (SEQ TD NC): 3'03) (HC CDRB) Clone AJMZSBAS LC DNA {SEQ ID NO: 304) AAATGTCATGrT .1CACTC".’JCT‘AC’JCAC’JCT‘T’1'I'CT'1’I' .1T’1'I'CCAC.-1.1G1AAACAGCT1A SC .1 TCTCCTGCACC1’CC. GTC. GAG' ’G’.‘TAGKAGCAATCTAGCCT1GTACCAGCAGAAATCTCG TCC AGGCT’CC T'AT‘C'.'A’.‘G... 1T3C. .TCC. C 'ACT CTATCTCAC TCAGG TTCTCTCGCACTC—GCTCGf—ACAf—ACTCACTC' CAC ATCGACZ—‘T1CCTGCT-_GTCTGAAG AT’TTGCAGT'"T"T'TACTCT’l'CT/‘TCCAG'TTLTCG1CGC1’1'T1‘TCCCTT7-‘TC’T"TT'GGC1G2—G1GL-CCAT GG" TGE—C1A‘TCAATTC-TG Giana AJ~26545 LC (SEQ ID NO: 305), CDRs 1, 2, and 3 are underlined. ~_ ~ . T; .v SSTTTTAWVCCKPCCAPRLLTL GASTRATGTPAR T':CTSGT‘T‘CTLT TCSLC/S Tj' ,T’TTVY'TCQ)YAAYPTT‘G«-1C"‘K‘\/}T‘' Kl‘ ’1‘AS 'TAT‘ —144- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ClQne 45 CAR DNA HXL (SEQ ID NO: 309) ATC33‘ CTCCCC3T ACT4C‘ CTCCTGC‘.‘CC3T CGICATT.LT TLTLL .JKJ ITCIC'. GCA'GCCCCGCC.LKJ -./.

CGCAI.GGTGCAGC CT3’3GTC' GGI’G 4CTGAG 3T AGAZTC’L‘CTGGGG3CTCAGTGAr-GCT 'T‘CCTGCZTGG1C""‘C‘1'GT13Z ‘TLI'TCZ- CCT'T CLI'TT‘1GAGCZTCT‘T‘TLI'"T‘ 13CL7‘TC'T 7-3LL311L'I‘C 3GZTCL 373C ICCT 3GL-I11ZTZTGGGCT" «C—‘3AG' ‘GTSZ-‘T' (‘3T3GZ‘TCTZ‘TTTT'CG«T3TJC'TZTCT‘CT3(131131'ITr-TGZTL3TZTI-rL‘TZT CL'1 L IT.CLAAGTTCCAGCGTLATCZTGTCCC7‘T'C4ATCCLGGGAC7 C .3TCCL.CGA3'13." CL GTC‘T‘ACAT GGALGCTGAGCAGCC‘T'GAGATCT3ACGACCGGGC3T 3TACTATCTGCGCCAGAGAGAA CG CCAATGG. .CGTA.TGGG4C‘CACG'3AAC.ATCC T'.ATCC 4TCT C"TC GGGTCTACA.T, GCT CCCGGAAGC iCG AL74-TG"GCGC AL74-TG 4TL7-‘TG3' ACZ‘TAZT'3GCGf—7‘TZT7TT7‘CT3ZTTGL-_C C'LI-_GTCTC 73 an «73 :/\L«3.—TT'JL‘TLT ‘T ‘T‘LCL L‘TLT3-4 1'1 {a 3 -L "EAT/JCST'1 , -,\ {TL-n «TL/an «an 3-4ATLL’TCLTATL L‘CLT ‘ {a Tm IT '11LLI-‘T «/T '1/‘LxLZT'C'IixLZT''11 K: Lfirm» r ‘~ 'L'\:JL’LZTIM'JL’TCS TL‘:1Li"Jul-1v;{a-n‘r m '11:! («rm-- V «A '1 1.31"." «an 3"‘(JCATL ‘(Ti ’3'" «Y4 T-q '1\ Tm TIL-T7 V {-4 {a T» 'N/‘I'I’I/NL«.— ~4373r|r3 (L L L‘ JVZTZ‘TL‘ 3'iL"(L(LATJVIZT/T‘ZTL".C/‘LITTLTLLT\JTLxLI‘TT‘ZTTJxL‘ VELVET:'ITJ'CLT‘TT- L1LLTCZ‘TT'CLT .TTG 3T1‘.3CLLATCCATCCAGCGCC7'LTGGTL .T‘CLCTLATCCTLL"'3C3r"’3ZTC3‘T7’3C3TLAT3TGGGT T‘3G 3AC AGA..3.‘TCL ’3TCTCACC.TCATGCL.3C’.3LTGCAC4TC'7'C4AT..3L.TT‘7'TGCACTTATT.L3T‘ GTCAG ACTACG GCC‘TAC‘CT. .C‘TT T3’3CGC3.’..GGC C.C‘7‘.AGGT' TGATLATCAAATC.3G 3CCGCTG CCTT‘GATAATGAAAAZT T.T7‘.ACG3AAC.ATC‘7‘HTTC‘LZLC AGGGCAAGCACCTCTGTCC CTCZTCCCTTGTT3’3CTGGTCCZ-‘TTCCZ-‘TACCATTC'GGG' GT'TGGTC 4TAGTGGGTGGA 'T’3 TGTACTC'CTG TCG' G4CT'T'TATAATCTCT4GGTTAGZTTL3AZTAA GL7— A31C3. CGCCT13CTCCZTTAGLTTZ‘TT‘l'L'TCZ‘T'GZ—‘TZT‘T'LI"T‘GZTCT‘ 13CCG3-CCT 3G'3'11L‘ 3-CL-I11L‘ZTZTG IT.GLLAA‘ L.'13L‘TA ZCA 3CCT'L.ATCGCATCCL.CCTL .GAGL.TT‘ TCGCTGCCL'T'L..TCG 3AGCL<3C3TCZTAG TTT‘ 'T‘CCACATCT 3CAGL.TGCL.7"3ZTGCCTATAGC.3GGCCAGITACCZTAJ'TGTATZTACCL GC TCAACCTGGATLCCAGAGA. 3AT3T. .T3ACC T3’3AC.AGC3C. .GAGGACGGG. .C 'CTGA TGGGTG3G ‘CI'3I’L3AG'I—3AGG'I3—T TCT ‘Z‘LZ-‘TACCAZ GL7-TC 4AAL7-TAZ 7-TC TATATGLI-CCTGCZCAr-TG "‘3T7\r-TGATGGIT Z7-TG CTZ‘TTTT4 7-‘J—TTAGG 7TGCZTI—7TCCGG3GAL/TGGGAAALAG G13-CL-I11C3ZTC11LC3T‘T'3TZ-‘T 3CL‘TG13GAC' ‘CAGCZTCT 13CTZ—‘T 3LGLI"L-T «(-133L7‘TTZTCTTZT‘T'GA 373L3TCTC11L TLATmwmaw’JTLZTZ—T\«AwwmmnTmmn. mm"LJK/ TLC T TTL.TLLTP. 3kg Clcne AJ26545 CAR HXL (SEQ ID NO: 310) VALE/"T"T L PLALLLHAAR QVG‘TL-VQSGA BKPCA3T7K VSCRASGYTF TITEIT-TYEITHT/T7R3 ZPG3C2GLET/‘TTI'TJ3 SGGTT S ‘T’AQKFQGRVT MTRDTSTSTV YML’T'LSSLRSE TTZ‘x‘x/‘YTCZTKT TVTTW‘NC’ T'TZT‘VSSCEL L. SGGTT: 3SGTi ITTSTKIGTHLL VMT 11"AT T3SC'RA. SOST/TSS TTIAT‘ILITLI TIE/Ir: (:ITVTA GS .3TE‘E"TILT.1 SS STTCTTHV .G KHTLCPSPL.;P O) L" T"‘VTVAELLTE‘ WVRGKRSAHL TTS ‘Y‘QNVTPR RPG'TT .KT-TYT_ ETTA-TAT Y \.LRVTE ABIZTPAVC‘CC" NQLYNLELNLG RT 7HTTPT7 - RPIGTTDP GG KPRLTTTTTTPQETG -TI .T’TTTE'Z'T.{L'KT‘ ZTFTATLYSTL‘LC-3TI/T311/TGEQTRPGTTGT-TD T K)‘T‘YDZTTTTT'V'KL. LI"TL‘TL PR [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by eadley Clans: AJGZSSIQB CAR DNA LXH (SEQ ID NO: 311) A. c. CiCCCC,TmT . ""T‘ ‘HJ. JJHKGElf-4TC1, CTC"‘CTGC‘77Cp—Tm GGCATTG "TV-Tm..J. K/‘KJ CGGAAATAGT 4ATGAC3‘34CGATC' rTI 73::le‘ ./\_, CACCCACCCTCT3TCT3T GGGGAA_AGAG3 r‘GCAC GIL-Tr1711K7I‘K1KJL'CIX‘ZTKJK7'JT '1/‘.ITI/:':7 T T, T,T-,\,G1-1KJ {Tn T7G11KJI-KCM].1,-T.-31"."’-1KJK,1KC2K31X1LKCi-TT-4 ,-T7 Tm.-TAGCjCTG-C'*1112mm ""i‘1-1K11‘ T /\ r71 J‘G- J. r4 «,1KJT,K11KJGKTKJ,G1-1KJ'J .J'1K ,T‘CJ1/‘ki13113‘3 1iT «,4 T -T T,T-,\ -T {T 1 -T m T .-4.,T.11- ,T Tm 3/37"" T,T-,\,.,1-1K,-T CAGG:CGJ‘LK TKJK‘JI T -T,4 ITI'[\r‘1/‘.

J‘G-1 ,1 T ,1.T._,T (-1 .T. KT...::C;1K,AC:IJ_TIT Tr1nTrT ~r’1/~ K/ .1. K3 I K73 \/ K_u.

GGAGAAT TGGCHATJUAKJr’lvfi JiAimvm 4G‘34GCC‘AG1GAACIAAC'. GTC.C3131CT’3CTCAr"CM CCGCTG CCTTGA..AATGAAAAGT . m 7‘ 11. .1. . ACG34AAC‘7‘.ATC‘7‘TTCAC.37‘7‘3AAGGGCAAGCA3T,‘. .Cfl‘3(3‘ CTTGTT3CCTGGTC‘I3AT C (:I"ATT/"I. GT'j—GI.GTTGGTC 4TAGTGGG("r1 .3GA ‘T'3 CTCGCTTGTiACTC'CTG rTI ("{GI CACCGTG4CTT .YTI’"i1-3TAATC'T ‘3T4GGTTAGA33L, AAAA rT- 1 T -4 .-.. (1‘ £11" ".L 'K/K3K11GLGJ7K7].7. TC«,4 {44.1,1(AL/‘CGZ-‘T4(4 h"l7\,"17ilTl,’\ 4 :- 13.1131C-4A11",:an1 ,zT r'1l «(44 'r\ {'1 4/44 ‘(f\ V/T .. GT) .. -1 \J .\.J TiJ. [MG/11K, 34.,CG, 3T '1 K'! 1K1 wG-1 [U1 (‘1 ‘T‘ 1. TIT T ,1, [T ‘T'- v. [T (Tr-/\ /~< [‘4 ,Ax /~< )Tl KJA(31A(4 .143K,.3T- 143K,3.. \K,.‘J. Ar," rJ-zi’T' (T,KJ K,'"1/‘(1T|CN,,mCu-rl r11 /‘ K_qJAA.‘ Cu. K/ .I1’! ,K,A 3K1Kz'1 '1 J. ,K_‘.' J 1'T_u. J. K}.AAG 7.1’4 r71 I]HT! r‘1 f\ r71 /~< m ~ .1, 7‘ f" ’ r71 r’< f‘ VGAGCJKJ .,,T 'G‘r—‘L T ,»T ,T (TA i'T_C,.A‘:J.A iK,... :rK,A:J1 .J_KJ.11 ,A1VITA(3C (: 7:71AJL]r711 .‘G3AAC C7AA. ,‘ T 3TAT7‘AACG TCAACCTGGnGCC‘nGGAA. 717. .T3ACGEAC'T3’3AC.AGCCC. GAGGACGGG :CTrT—n. 'TJJF‘.

TGGGTG3G '17-‘_AAC‘3A[ r1 7\ {’1 [111‘\11 4A?_AA. 7-‘3C ‘C‘I3CAGC3AGGC3—T ‘T‘I3T z-"‘CTGCZCAAG GPfiTZ-LAGAT GG‘I3‘7‘3 10 CTATTEMF" T4 Z‘LZ‘iTAKEG A‘TAX71GCAf—ACC‘3G3GAE-1.GGGPJLZLAG G3C1}- GACCGTT'3"l.7-‘.T V... 1 ,.,. ,.T,. 1T3 , .,.-«.(3-3.3.41. ‘G1‘1KJK,AC 1 4’31‘1‘. 3G.7"7-. 7"«.T11CTTATGA V‘C‘TCTL CAT 3 C"AA T1 1 "WT/T NT -. ,1," 3L, -,C 3 13.,C}4..K,., T14. 3.3 Clcne AJ26545 CAR LXH (SEQ ID NO: 312) LPTIFT7‘7‘, 1. P'.GALLLHPJB RETVMTOC‘TA TLSVG‘ 3511:. 31".YQQK PG‘7‘APRLLTY GASTRA "3G7: P ARFSG ‘1‘VFTTIi . "AN" /’ .‘JGM" YYCQ C4 T17VE3‘7 KRC.1 m (T (T1T ,-T- \471- J 0‘1:) \J .LKJQl 1\K'J-1 «(T-.4 r‘ obiu': ".K,’ vsTKH [V’D‘ GVK‘VTQ/‘(W’N’KYJJKJJL (4. (Tx‘7?" 7-14,"- -1 H7 74M:- _,.

I TTl-TrT 344GT k) K;‘./.. C) ‘\J. J. .1. .L 1..14.4. .1. 1' E.l OVGKE‘SGAT TKTCGACWKV YTTT VRC PGQRLEWMGV TCTSCTiTSY ER‘JTM IRATSTCT‘T MTLGSLLGCF TA..LCARES WPMDJWC‘GT TVTVSS YTFTE"YMH (SEQ ID NO: 315) (HC CDRI) VTCPSGCKTSYAQKFQE (SEQ ID NO: 31‘) (AC CDRZ) ARESTTPMDV (SEQ ID NO: 317) (EC CDRB) Clcne AJ~26554 LC DNA (SEQ ID NO: 318) MAATACLC GACCCAGTCT 'AZCZACCZTGTZTGTvTCT CAGCCJAAAGAGCA'CC TCTCCTGCACCCC. GTC. GAG' GTT LCAGCAMACTAG‘CT GTACLACCAGAAACTGG CCAGMCICCAG"CTCCT‘ATCTA'CCTGCATZCACKLCGCC ACT CTATCCCZGCCAGG TTCJ STYLECIKJIG‘JICZKxTCK£¥k(JI‘CZ’Iq'CLACC¥XICZ~JCflJS"I ICLLJICELJTAG ‘T'TIGCACT'T"TIACTCTCCCAGIACGTCCIZTACCCTACWIT"SCEGLSEGL-LCAA ""ECYXEZT‘ICAZLAC(3 Clone AJ~26554 LC (SEQ ID NO: 319). CDRS 1, 2, and 3 are underlined. ngxrrL'. MIQQEALUQIOVGIRAILOVKAQ RASQSVSSILA (SEQ ID NO: 3"O) (LC CDRI) GASTRAT (SEQ ID NO: 321) (LC CDRZ) —147- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley CTQne AJm26554 CAR DNA HXL (SEQ ID NO: 323) ATG1CTCCCCCT ACTC CTCCTGC.‘CCCT CGCATT ITCC' C C.JT TLTD .JKJ .xxJ -./. CGCC CGCA—GTGCAGC. CTCCGTC' GGG 4C.TGAG 3T 7-‘1GAACCCTGGGGCCTCAGTCAr-GCT 'TCCTGCAA.(C"TCTGGZTACZGCTTCACGAGCACTT"T4CACTGGCTCCCA "CC T—iAAALGGT'GAG'GCA.GGGZTAATCGGGGTACTfiGGGTAAGACTAGCTA CLC’TAACTTCCLGCGCACAGTCCCTTGACCLGCGACTCETCCLCC3C'C,GTCTACAT GGAGCTGAGCAGCCT'GAGATCTCACGACCGGKT1TACTACTGGCCAGAGAGAGTIGG CCAATGG.CGTATGGGCCACGCAACMAC C.T'ACC TCT CTCGGGTCTACALC GCT CCCGGAAGCiCG AAG'GCGC AAG TAC'ACAAAGGCGFAAATTCTCTTCC CLCTCTC 7\ «f1 '17\ :4ka«.—TC‘J'TC, IT T'C, T,1-4 1w {a 1 '1 JC:\‘1V‘df -,\ .1 «(a 1-4 «‘(f‘dn {a 1m «f1 '1/‘ r ‘~ 'JL'J1‘ELEM111(3f‘d'y‘ {a-n‘r r‘r‘v‘ m 'J‘~L,I‘T AG1‘1(,(,C, TC, I CAT/,T"AC/1".\'1 TC! ,\,ZT'~:1T\,ZT"I1‘ \"J - 14 «A ,1." «1m 1-47 1m ‘4""7 1a {-4 {a \r‘ VYrU/‘II’I 'VJ -(«rm--1C\4C11LJ\/.ZA1‘(1Il".(l(z‘v-r(ls'li1".(,(ACJVIZT/T01".C/‘JTC/C,T(‘CJxxK/ICT‘ZTxJVC' CALVZAM:C1LJ\,.:.G-,TC1‘\tT\.,-Turn-'1" «an 1 '1\ «rm/1L«.— TTGTTGCATCCACCAGCGCCTTGCTATCCCACCCACGTCAGTCGCACTGGCT‘CEGTAC AGA.TCLCTCTCACC.TCACCLGCCTGCAGTCTGA.TATTTTGCACTTATTJTCTCAC ACTACG CCTAC‘CT.CT.TCCCGGLGGC CCAmAGGTTCATATCAAACJC1CGCTG CCTTGATAATGAAAAZTIAAACGZAACmATCATTCAC.TC'GGCAACCAJCTCTGTCC CTCACCCTTGTTCCCTGGTCCATCCAACCATTC'GGG'GTTGGTC4TAGTGGGTGGA'TC CTCGCTTGTACTC'CTG TCC'CACCGTGCTTTATAATC'TCT4CGTTAGATTPAAA G} A;jCCGCCT-EC’CTCATAGGCL/‘TT’l'ACZTGAATL"TGACT CCG"CCT EGCJC‘ :Ci—iAAG GAA GLCTAJCAiCCTACGCACCLCCTLGJLTTTCGCTGCCTATCGTAGC,ECTGAAG TT'TCCAGATCTECAGATCCLCCAGCCTATAGC.GGCCLGAACCAAITJTATAACC GC TCAACCTGGACCCAGGAA AZTTTCAC TCCACmAGCGC. GAGGACGGG.C'CTGA CCGTCC'AAA.CA1GAC AA_AAJAC CCCAfACGCT TCT TA_ATGrCCTGCZCAAG GAT7\r-TGA‘T‘GGKT AAG CTATTT4 7-‘_ATAGG ATACL71GCAf—7‘TCCf3GAGAJ-TGGGAJLAJ-TG CEC-CACCCTT'TACCAGGAC'CAGCACTvCTACGD' GATTCTTATGA‘CCTCTCC LAATmwmaw’J'G.A11.;1'GVC T J,CHTKA,T.\1A11mmn1mmn. mm"J'C‘J Clcne AJ26554 CAR HXL (SEQ ID NO: 324) WALT/"T"T L PLALLLHAAR V‘T7OCC BKPCACVK VSCKASGYTF TEHYMHWTRC APGQRLEWMG TTCPSGGA S YAQKFQGRVT MTRDTSTSTV YPHLLSGLRSE CZLW.T bWPbDVVT" "WT/TVSGCL SE'GKITGGL GSTKGELVMT T CT‘ATLSM. SQGVGGILAH TT.CST1A CG‘TFTTLTT SS bkCTT HT? .G KHLCPSPL P O) L" T"‘[VTVAFTTF WVRGKRSQHL ES‘YMNVTPR RPGLT.KHYC 7 V ' ETTA YxGRvKLGE TTTPAVQCC" LNLG RTUTTD GG KPRIKNPQTG -1' KD AFAYSE Cu? GEKRPGAGHD T‘ K)TTELDTTTTW', T-TLT.PPL —148- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Clans: AJm26554 CAR DNA LXH (SEQ ID NO: 325) A. c. 1L1CCCC,wma . "r71 EFTC‘ CGGAZLATAGT {.5}. 1mm"..J. ./"\_z :7.GCC .1..1./ CTCCTCCCp1~m TG ./\_, CG1T—CGATC'{LACCKLACCCTCT3TGTCTT rTI '\/'!A1 GTGGZLA_AGAG'TCCAC CT CTC T CC‘TG L‘AGGG TCAG' CAGA’1’11'1 TAGCA"CAACT '1Af’3TC’T'GCT'1ACCLA’1 "AGA.T,’1"C.7‘1."1"C"1TAT1’.-T1G’1‘-1’..TAT TCACCAG" GLACJGC'"ATC‘ 44 f‘ m A..- .L TGCCAGCCl'T TCAG -1’..TT’L‘ .1-.- G 3.‘TC... ’T'T"TGCAGT’1G 1TC'T'GGGAACAGT’C. C’JC'TCACCA.’.‘1’.T..'.GCA3C 3‘11" 1C"p r41 w. 'T‘ r11:: .1. k, .1. 1.

A.GAT‘.‘T‘_CCA1TT TATT7.TT ‘AG ACGCGC ZTACCC‘TAC T‘.TJGGC GAGGG AAGGTTGAG1L1T1L..1.T.AC G'GGC'TLTT CAT C‘GG ZTCC1G'1TA.G'CC GKTTAC1G1CG’r1111:7\~1\"\:GTA GTAC1AATCG1T’T C7‘1GCTGG'G13Z‘1GTKI3 TGGGGC‘TGAGGT’GAAG. AGCCTGGG CCTC AGlGAAGG’T'1‘1T’TC’1'CGZ5113(-SCA’CT /‘.1AACCTTCACGGAGGZ’T "117‘.TZ‘-1’1GC2-‘1CT- '13 T (1 ,L‘ /\ er --~1 (w. 44 IA r71 (‘1 r\ '1 7 r\ '1 ’T'T TCAf’T T ,1. 11-1 k.('11tIn '1 LT 1-1.«1L111L1G-1 TQM"."In rnJ. 31131-1".'1' i.’1 CCC;CCTACTCCT L \L bu"AMA ’TAAGCTA LTG —T1AA.G'T"."CCAGGCCAG.A1.-T1"1'C..7 1’..T.CA.’.‘1’T'JJ TCACGCCAJGTCJA AGCA.C AG ‘T ,Tr1‘ACA1‘GGAG1.1 ,.,. .GAGCAG’.T.1.TCACAT 1’3"." G7r411.-JCTHLKLA71 [WAscc:C*C1ACTCTG (-4 ~1 (T I '\J \z '\_u.

GAGAG1T‘TGGCHAT1.0thr17 P1 1J_.[’1.1m7 m 1G'GGCC‘AG1GAACIA..AC'. CTC CCG. CTGCTCACCGC TG CC}.TTGATAATGAAAAGT . m 7‘ 41. .1. . AC GGAAC‘7‘FLATC‘7‘TTC‘ACTZAAGGGCAAGC’AL1.1 .Cfl'(T'T ’TTCACCC‘TTGTT'3CCTGGTCCATCCAAG'\("AY’IT("I Gfij—G"GTTGGTC 4T.A.GTGGG("r1 GGA ‘T ’T CTCGCTTGT1ACTC'CTG rTI («Irv CACCGTG4 .YTITY\i.-1.TAATC'TTT4GGTTAG.r\.1.1, -\.AZLA_ /~- 1 LL" ".1 '71 TCK'11PLIV}Cj‘v rwr‘i .wI'(Al./‘(GALw "TM-17imp-1 A AA: :GA111-". IA r'17 *1/44" {’1 .L .L ._,-\... .L -1. -K/ -x... 1.;4_ A‘GJ‘V 31/44 (\II{T if: 3T er .-.‘ {T C» \4‘ \J '1 LT 1&1 wG-l AI: I": 'T‘ 7‘ 1m 1 F1 /~< 'TI- 7‘ /~< (T‘f71 /~< [41 IT‘ /~< m (1 ~1(T 71-. (-4 k.T113131" C... .‘x/ .1.2" ,KAZA :r‘vkz'.. JAG1:11.PA»..... \LKLJL \JA.14TTTCGCTCCCT.TCG.ACC .1. 'KJ.AAG '1’1 r11 1]HT! f‘.1.'_CLA.1:12" 1K,...f\ 1’?! /~< ’T' ~ "‘1 7‘ f" ’ J'\/.!‘\3.:1. .1b'-4r71 1’1 f‘ IT‘\L/TA(3C (: 'IIJAJL}r711CAC:C.AGGCC.GAACCAAJT .11TA1AAC’T' TC'AACCTGGACC’TAGGAA 1ACGT .TTACG TT"ACmAGC::C G.AGGACGGG Cmn—n.1GA TGGGTGTG ‘.I7-‘_7-‘1ACK3A! r" 71 {’1 \Jl'l‘u 4AA_7-‘1A.L A.C CCCArACGCT TCT TA_ATC-GC TGCA'GAE-1G GAATAJ-TGATGG"31 7LI-1G CTATTEMF" T4 ZLATAGG A.—‘’nr""1UCAf—ACCGGTGAE-'1 AG’T-TG GT1CT1- GALLCGTT'311.731.. .,.},\ -. ,.},\ .,.},\1...-«.G(AC 1«1.. -1’T TA «p4 '1" ' r‘ '1" , ...-«.G-11.1.1.1. / ‘:.1.L-‘ 31:11.11ACTTATGA T C ‘1"1' CAT 3 C".AA .,~ 1 mm. N. 1fr. .11, -,C 1 ~11...CA.1L1... '1.. 11.1 Clcne AJ26554 CAR LXH (SEQ ID 13103326) "J'ALPTITTTI‘I 1. P7.GALLLHAAR KEPT/TMTOC‘TA TLSVG QA-1YQQK PGQAPRLLTY GASTRA "T\J: P ARFSG. ‘1MFT111 . "A ~1— /’ "J"AVTVCC GTKVETTKRGS 7? (‘1 p4q { -1 «m-.4 r‘ \17- i Q‘21..) \J .L(101 LUV} 11:? 17Cumvmwl GASVKV (:1 r1 x.1’71 717' ‘1 7 7 771V" .1. J’Z‘_I'1’\'I’1‘.'C1\J. I «Ti-rr41-3741 .) '13. J. 1. .1..1f‘1.1 .1 . O (3.1 <~A(\-:E-1 QC1RC/‘7'1V1’1‘RD'1' (:1 rm 1 1’."IT ' > - (a 4..) .1. k J. ‘17.. 17.11.. .1.J O. :{CA119.13.1191V11T) VWGQGTT‘V7TT/7 CSAAA.»1:11 STQGT'T'J. 717.17. HA7 .13 GPSKPH/11VL117 LLVTVAF:1 1 WE7R.LKRST{.1L Y‘QNVTPR RPf—PTR41‘73 YRSRVKFSRS ALT—UAPAVQ’VTH ELNLG R1 TTYDVLDK KPR '.l11\1PQ‘~71G "4 .1’111‘9'1'1’QK1‘ A171AYS" Cuk GL{RRGKGMQ L’T'YT'11111'V'G ALT PR. —149- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley ClQne NMm26562 HC DNA (SEQ ID NO: 327) C1—CC17TCrCP1-CCT3ACCAG'C K3—G 3‘AGKI3—ACTKl3—C' CKI3TTCACAC1C'C CTGT CCCTC1—- C 1‘TC71-1C7'T‘C7T ,TCTC7CC71 T,CATC1C7C1P1C7TC C7T1’TC7TT1’-C"TC7C17ACC,'."CL7P1TC CC7 7C1- C3A7C3A7C’TAC’717CCT1CAC'GCATTC‘T’SATCTATTAYCATCJ7A7C-C11CTAL ALCJCSJCC‘CCAACACTCCJ3"T C7IAGACCG’CPXTCAACC74TT7TCCC TGAACCTCA7_1"T, C 7P1CC 7CCG '773AC773G CC3—G".TACTAC'.1C3G 'CAGACCCACC7C7 7 AT..TGAC. CTTCT1TAC‘CT CATATCT'CG.C.AGC’TACA’1dCTCA3CCTCTCCTCA Clone NMMZSBEZ HG {SEQ ID N0: 328). CDRS 1, 2, and 3 are underlined.

)VCKUES"P3CTKPSQTLSLTCTVTG7C1.GCS‘N" 1. SLTYYDC 8T1): YWPCLVQ'fT!V1UbKNQhaLATaQVTAADT""Y .JCWCJQGJ‘MVTVS 7L>TC7>CC7CYE73 (SEQ TD NC): 329) (RC CDR') T71Y‘1’DC‘3T‘. 111.1PC'LK (SEQ ID ND: 330) (EC CDRZ, 1—TRC-7LC'C7YL1C,731«TD=7x'r)/~V'~r""'1r71cqv 'r\ 7- \QLQ[pm-7 \ "'r\T73! NC:'Vr ,1‘ .1\ ’T_T 7 331; (IR, C,=31Rj,vN'r\' fi\ Clcne NMMZSESE LC DNA (SEQ ID NO: m332} TCT'.CACAC."AGTCTC 'P13—C 'PCCC ITK‘.3 . CTCTCA‘GGCC7PAAAAGAGCCACCC TCTCCTCCACCUCCGTCACAC' 'CTTACCA 7CTACTTAGCK’3TGCTACC1—rTCAGP AJTCCTCC CCACCTCC3CACK'3—C'CCK ,m 1 ATCTATCTTK3K'3'C T3’3AAK3ACC7K3 AK3T 7CCATC’3CA1CCCA1 1' T 'C,‘P CT C17 7CAC7 TC3 17TC TC7C7C7PTCAC7PTC,1"'1"TC1’1CC TC, 1C1":CCATCATxC7C3PTC7C. CTPT'1 C177CT CAPTC PT r"T‘1T C 1 T1"T TAC T C7 TCTC7C1A.CAC7AC1’- «CCTT C, TC3C3C"TC,3 CT" T T T 7C7 '17 C7 C71TC C7 C7AC CAP.GGT ‘.717.13.17'I'Ci"AACGG Clone NMM26562 LC (SEQ ID NO: 333). CDRS 1, 2, and 3 are underlined.

L—z-rxV-n‘FELTSE'\RTIHPL.1- 'KLSS‘TT\C3ET\1-ll\rr11r(\rTVT7AS5(\C31\1/(T1T13v777C1’WV‘T/PC17Q1—"1RLLTV17C\IRATC7TP1 RTSCC 7SCT.‘TTTL ’W1I’Pl19TTC7C7CTRVPKR RASQSVSSTEA (SEQ ID NO: 331') (LC CDRT) D1- SNRAT {SEC T11) NC): 335) (LC CDRZ \ 1.

QQ IIVY/T PPT (SEQ TD NO: 331.6) (LC CDRB) Clone Wm25562 CAR DNA HXL (SEQ ID NO: 331?} mn 7A» AMA 7 7,m,7,7_-. 1T|~,"~!r {7. (777,77 7p" .r7 m. 1,~/N(~<*D\r'1r.f~4 "77,7(7. 7,-7. 7,7 7,-7. "‘f‘ 777» 7A 7 17.11 TC C,C'CC CAPCC CCTC/T t1.,l'\:IK/.i.(3'\, . 'JC3lk/K) . _'Cjb'A." . 'JC3 1 , 3. \J V11 ,\3 CA. ’JC.;1CC, .~ Nr‘~J'\_u.<13’:71.~.7-1 INC/.AC'X’k/‘1'" ~,-n— -f" ‘7‘ INfV’ [a ,«rwfx ‘IA1l—X )Tl,‘1f.fVJD\‘/\ erN ‘r'1r.f~< > ‘(f‘ir’WINITlfw Thu-r! . '3C3HC ALA GT .«(J’KJK’J3C3\3.(IPCK,...CI'C:I.ATHCUT13C . .,11.D\7C(111.CC,'C3 .L C" .7. C, ,C i.

CC. TG . LV‘VI‘FIETC.'. G'J.moNrE'! 1m’jG1 lN/N. .CwN,.,.A.C.‘Jk311d31.1\3'3N/N ‘n Nrr! f". .IN m7,~.1r—17\,~47\ ‘Nmr‘ 7., J. .U’J’xJ. 1... no J_.1"\\_, GGn.C71\/.'1. UGA.1.'K_, C,CACGCAACCCC IT3GCTG 77ATTGCK3T'.jCATC'TAT".’ACG GGACACCTACT ACP T C3CGTCCC"3AAC—A7T_CCACT1ATCCATATC TACAK3ACC7TCTA1C37P1ACCPCTTCTC CCT C7C TC!11ACT TCTCTCACC17CCC1-7C3ACPx CACCPZ1CCC7 CTPT YTPCT C-7CC7 7C1- C7PTC-7CC,‘PTC7C '7CP1TTTC7PT'7AC’11'T 3TTTP1CCCT'1CCP1TAT "CCSG 7TCP1CC77T1’TC1"11T’7L7T CACC, 71C‘TCCT — 15(F- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley [Annotation] eadley None set by Anne.Headley [Annotation] eadley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley LPLKJC‘ITJm r‘ "'VF'W/"F‘I:L AFJANiC'NH (3‘fir?! {"an rim/fl r1," "(N K_, \w‘JKJ’11.YAKJCC b'\J 11.AAKJ G‘J'V 17/" mum . ‘Ttfl "\‘n J11 J. thTA‘flnfixA. (JCTJ‘HJ. , Al.

TGCAG.TG‘TCJCACL:CTCC CC.CCC'G'CTT1GTCTC'AGG GAAACAGCJC C'CTCTCC{’5‘ f‘ wCCCTCTCACAfTGTTAGCAG TAC'TAG CTG TACACAGz-J CTGGACAGG CTCjCYCGCTCCTCZTGT’TCA_GCA.CGAACAGGGCZ’T C"TTCCA}CCA}GTTCAG TEGCTCT GACZGAC'TCACTCTCXCCZTCACCAGCCTAGIGCCTGGAGTTTTT _ ACTTTATTTGCCJGCAGACACGTCCG4CCTCCTACTTTTGCC3GAG3G‘CCA‘GG .TCACATCAAACC'GCC'CTCCC' TCATAAGAAA C 4GAACAATCATTCACGT CAAGCC'AAGCACCfC'GTC GTC.CCCTJ31TCCCTGCTCCAT CAA7CCATCTTGGTG TTGGTCGTAGT 4AGT 'C CTT GT' TACTGT TGC'C 3T ACCGTGCCTTTATAA GGCTTALAT4 Eflfimh(GGGCCTCTGCZTAGZGTTTACATG?ATXTCACTCC A,"CCC "1-"‘CCTGG YCGCZ- C" GAJQYCACTACCZGGCTTACCCACC'VXCC'"ALJr-YC-‘T"'"CGC'." CCTATC§CAGC.J1G"CAACTTTCCCACATGCGCACATGCACCTGCCTATC J ‘AACJA,TGT.TAACGAGCTCAACCTCCGACGC"GGGA.J;TAT' TTTTC‘ACJA CJCCAGACC.GGGACCC' GAG ATGG 4.TZ~G TIEAJCCCA ACGJAAAAAJCCAC GTGT CTCTATHTCACT CAGAAZCATAACHTJGCTAAGCITATTCTGAAATACATGAAAC GAGAGCGGAGAFGG4CA_AAAGG 4CAC 4ACGGT TT 4TAC AGG CACTGCTAGAA GCATA.TTA_CACCCT CACATGCAACC'CTC CAC TAG4 Giana NM~26562 CAR HXL (SEQ ID NO: 338) MILFKTLLJL PLALLLHAAR FGVCLGGSG? 'TVTFQTLSLg; LTCTVSGGST TSWT GLEW :GLTYYDG3T TYNPSTACQV TTSV "S RLGSVTA.ADTAVYYCAR GR4YTTS A5 DLTCQJTMVT VSSGSTSGSG KFGGCEGSTK G'TVLTC ‘A TLSLS PGER-\ TLSCRASQSV SSYLAWYGQK FGQLFRLLTY UASWRATITR ALFSSSGSST DFTLTTSS'J QRTJW°RTPC GGTAVFTKRAALTNGKGE TTTHVKGKHL CF‘FLF‘FGFS KFFWVL\7VVG GVLLYSTLV TVATTTFTR SKRSFLLHSD YMTVTFFRP JTKKHYQFYA FFRJFAAYRS VKTSRbALH PAYQQGQNQL YNLJTTGRHF 'VDVLDFRG RDPEMGGKFR RKJFQNGLYL ELQKDKMAEA YSTCGMKGER KRGKGHDGLY LSTATKTT YDALHMQALF FR —151- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Clan? NMm26562 CAR DNA LXH (SEQ ID NO: 339) ATG7 CTCCCTZT .LACT1C CTC7CTGCJCC1TT GGCATTG ITCC' GCACCC7C. .CGCC ATT.T CAGTC'KCACCKCACCKCTCTCTTTTT TCCATCGALAr-LGATT‘CAL, CL1T C T CC'LI‘G TAGGG 'L T.17"TC "I'LAGCAGL1TACT TAT11CTGTL1TACCAAL1ALGALALA 1T1"11 1GCCAGCCI1 TCLAG 71CTC T’I'CL/AL'TCTLL/AL'L" GLALT71C"TCT1K"\C1TT1L1 .LLLL/‘LCTLLSCLCATC TCL- G TC}- G 3."I‘CL ’I'I‘T1GCAGT'TG .17TCTC7GCAALTTAT1IL1I.T.TL .'CIJC'LTCACCALI.T.TL.GCA3C .T‘ITLL.G.L1‘T.17 )C'I‘GLA AGATTTTCJCLAGT'. TATTLILCT AG T ITKTCCTT ITACTTTTGGCGGAGC1G ACCAAGGTTGAG. CAALACG GGGTTTAC TC GGC' CCG7C7AA 77CCCACAGT GZGAAG ZTXGTACLI;AAGGGGCAGGTG AG'C' GCAGTAG' CGG1CKC'TC1AGK'37-‘TCTCT1TT1ArT "TCL-_CA ZG'TC TC'I‘GT C TCT TACCTT3TACTGT 7.7"1 1L1C"TCL1 TATC «.17CL/‘LTL’I'CCL'I‘GGTAT‘TTACTCG LT17CTG17ATC‘ TGTL)CAGC:71 LCCAHGGAAGL1 1L1CCT-L1GLAG'L «17CL/‘LI"I'GL1 71T"' 1’1A1LL1T1AT'"71L’1 TGL- TG C..17A'I' KTT1.)T‘ACTACLAALCCCGI." CCCI.TTLAALCAGTCGLLGT-'TL.JC’TTA'TALTJCA.C'I‘A 7ACA )C'I‘CT.A CAA. )C.‘T.17TTC'L.1CCT.T'L.17AAT1CI.T.17LLTI.'I'T)IL1C’I'T1ALTTT.T 1CCGCALCAA)LCG .7C 17T1TC'I1" )TL‘CTC- .T CICCLA': .GGC.GGGG .TATCLLLAC '.'C'IT. .'AGC1CT'CTALL.CTGGGCTCAGGTLAC ATCG TCA.. TCTCCTCACCCG .T.GC C.‘'TGA .'.A AGTCAAACGGAACA.LATCAT TCA..

GAJTGGTT‘AACCAK"’L1TT1TTTTTKC’TTC7-7C CTTGT CTG 1TKCC ATT1CA TCTTCGTC TTGGTCGTAGTGGG'GK—A1TCC' CGC' TGT' ACT 1TCT1'TL1CTC7TCGTGG Tr-L.ALI\ TC"TCTG 17(17TT"AGL7-‘L'L CCAAAAGAAGT TC7KC)C'L"GKC)T1 TCAT’Tx7CGA’1'TL/‘LCATCTTJT'I‘GL? CTCC TA)C~ .TC 1.'L1'TT.17CCCT.TL .CAATmrTAA'IL'TTT'LTALCCL.GCC'LTTAT.) CA.CT.1.TAC’"CA'I‘TTCJCT T.17 )C'I‘ATC.TGLATTTTLA.GCT.-17'L.TAAT1I'L1I"T"LICTTAT1ALTT.TIGCACALT.T.17CALCT.TLAGCGT L'I‘CL C -LACC.J 'x_L I AGAACCAATTTZT .TAA. A CK 7GGACT'I1ACC7KLGAGTLLTCLACTTTT=. GGAC.’.

GCr-LGAGGACG1GACC 'GAGATCGKCGKCAAAKCCAL K—ACTZ-TAALALw.ICCAGGACC ALATGI‘TCTTC CAACCAIAAK—ATGC' T1L7‘77TCCCTL1ATT’L1' T1L7-‘x_r’-\.ATAGGT1ATGAY-LALTG‘IlJ CAT-7L7TT17GA7A TLG7-7.1GAAL"_!‘\-L11T;7GCZ1T.L.LL/‘L TGG T T "I'STA CCAG /‘LC"I'KC)- 17CL- C'I‘G L1TACGAA K’I‘L..17ATAC TTA'I‘T1ALCT1T1T’TTT‘ATTLAIL1’TT1AALCCCCI.T.17CCAT1T1TT G . J x, J. / ... Lu L, \, .17 Clans: NM26562 CAR LXH (SEQ ID NO: 340) EJLALPV’T? I i_. PLALLLHAAR #ELLVTIOC TLSLSP (3) SSLTL YQQ/ PGQAPRLLTY PASNRA 'GLL'LIP ARFSGS G) U1 L) BL Ur11 P‘ T" 7 O) PE=LLLJLLYLT‘JYYCC‘ TQ LLHVL’TIP ‘LT"E1GT«-7TV‘"LLI S'L "SGS 1L1IL\L.I1GSL: TSEGST G. LL‘JG LC LLST.1.1CIL\IK PSCLjTLSLTCT JGG’TIGC'TG V78"!RQL1PJ: .7L CL .7'LL'N IT--1 r Y1'"LJGSTYYNP SI7KS7I1.‘JTISL‘J ITI'STTCJITSILK L’TSLJTrTATTA L‘JY TTTLARGRL Y ETCLILATL' IW71 .AA..7.7LLIT..LKSTTG TTIHIVKC(IITL CPSILFPGPS KPFWL‘ LV‘FJG GL\.7 ACLQGT.vTI‘J'.':TSSALL‘J TIJAFLLTFWV'T1h S .RSRLLHSD YACETVTILTRPG PTRKHYQPYA PRADPAAYRS RIJKFSRSADA PAVQT‘CT‘NQT. YNILITMTGR?{7: EYDLL‘JLDL'LRRG RDPETVT71GT/PR RRNPQEGLYN REVQKP VT=Z1T‘rL’L‘.LKA. YSLKIT 17I\’II~LTL-L1T4L'.R RTGKGI-II)LY QGLSTATTDT LIALHIV’IQALP PR —152- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] eadley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ClQne TSm26564 HC DNA (SEQ ID NO: 341) GA.GGTCAGCTGCm «GAGTC'TGGGGGAGGC' GCCT GGG1GTC CCTGTGCACCCTCTCGATTCAC TCATACCTATAGCTT"AA.TG GTC AGCC1AAC 1C1CSC’T'GGAC1TG 1C1T'T‘TCCA-T1C1A" rT"T1TC1C‘TT‘AC1T1-‘TI 1’1'L'\G'T1TC"T‘A’T""T'T‘ATA 1"TAC 1CLTC11-G'1 ‘C T GT C1A1T~1GG 1CG1-‘T'T ’1' C1‘1 1C1A" 'T‘C T 11CAC1L'\C111C,CL'\-T C1TSCA1TC1‘L1TC‘ T CAC T GTAT C, '1‘ C1 AATTGAACGCCT1A1LGCTGACGLG.GGCG1TCT1GTAGTCC1CCGACCTTCTCAGGA GCACCTGATTTT GATTATGGGGACAG NGTACA' GTC CCGTC .'CCTCA Clcne 64 HG (SEQ ID NO: 342). CDRs 1, 2, and 3 are underlined.

EVQTVESGCGLCAPGGGTRLGC1AGC. .SYSHWWVAQXDCAGLGWVSTZCGCTCT?"T ALSVKC‘T'SA1NAKNSLTCCMTCJR"EDTAVYVCATG ffiTFTfiT’WGLCTLVTVSS FTFSSYSMN (SEQ TD NO: 343) (EC CDRT) TTSSSSSTTYYADSVKG (SEQ TD NO: 344) (flC CDRZ) ATGSQGHLTHTY (Sm) Tu NO: 345) (EC CDRB) Clone TSu26564 LC DNA {SEQ ID N8: 346) CTGA11C.TGCCCACCGACCCTGTCTTTGTCTCC.1C1AAACAGCJAICJ TCTCCTGCACC1CC. GTC. TAGCA GTACT. TAGCCT CTAC'AACAGAAAJCTGJ TCCAGGCTCC1'ATCUALATZCTTCCTAAC'GC'ACTCATCCCAGCCAG1 TTCKGTCGCACTGGCTCGGACAGACTCACTC'CAC ATCAGCAGGCTA CTGAAG ‘T’TTGCAGT'T"TTACTCTCACCAG1GTTTCTAJTACCCTTCGACTTTT1GCCGAGCGAC C11- r"-TC1 C1'7‘ T C11-TGA’T G1 Giana TS~26564 LC (SEQ ID NO: 347), CDRs 1, 2, and 3 are underlined.

IVLTQSPATLSLSPCETATLSCRASQS‘7SRTLAWYQQKPGAPRLLZYDAQNRATGT [J»\PIJT REFSSGGGTFTLTTSSL.PL‘fivV‘m)RTYYDWTTG‘"TVE‘TR RAGQCVSRYLA (SEQ TU NO: 348) (LC CDTT) DLL SNR1 T (SEQ T3 N0: 349) (LC CD32) [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley ation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Clcne T$~26564 CAR DNA HXL (SEQ ID NO: 351) ATGEC CTCCCC3T.ACTC CTCECTGC.‘CC3T GGCATTG iTCC1GCACGCCGC.C3GC CGGAGGTGCAGC 4T3GAGTC'GL3G GAG TACACCCTGG4~GTCCCTGACACT CTCCTGTGCXLCCTZTCGATTCZ3CTTCAGTAG"TATALC"TLAACTGGCTCCC3C1CECT CL3A1 EGLSr-JTIEGLCECT-EGAG' «ESCE'T"'TCAACCATTA. E’l'AG'TACZT’ETAGIATCXTATAL‘TA AT » A r71 A. .T13~. r71 A IAK3 .C‘f IA1A E TT1 A .

T IA1 AL1T. T TT1 A A3‘..33LD‘.\r.-‘j..!‘\3.'\.‘13.fl‘.\3.!‘\3£‘\3 KJ K3.33APLK3A33.1.IA r A IA1 7T 71" A A T A A..T1ATA..T13~ r71 '1" r~< r71 C13. .K;. C. .L K3 .1. C‘1 .L KJA3..K KJ C‘JrL3K3KKJA.l3. K3AK3x3- ... (3'3'. C13. K.3 .l. ':1 i. .L.1. k3'.L GCAAATCAACAGCCGAGAGCT3ACGACVGGlTETAC1ACTGGCCAGAGCTTC.CAG GACCA'3TGAT.T3G.1TA'_GG GAC A1LGGTCAC CTCCTCA TCTA C3G CCAACT3CGA_AGGTA TACALACCGGGAAATTCTCTTGAC nCAGTClCCAGLCACC3TGT TZCAGGCAAA.AL3CAECCTC1CCTGTAEGGCC AGE"AEAGTC‘T’GCALGTALTTALCCTLGTACCA‘CXAAACC'GGCCAGCCTCCCAGCC 1-TC3C1iK3.Al~1r~ T CTCTCACC GAG.TTCTACTA‘CC .T3CCGG/CGGACAAGGTTGAGATC.

AAC, CT'3CITC1.TAATCAAAGTIAAACG3AACmATCATTCAGTGAACJCCAA GCA CTCTCT‘ 3T ACCCT'C'T3CCTGGTCCATCCAA3CATTC'CTCTTGCTCGTA CTG 'GTGGAGTCCTLCGCT' GT1ACTC'CTG CCGTGCTTTTATAATCTTCTGG T'TA.EXTCCYQLTA.AJMEQCLCI3TL/3TCTXTAKESCALPTACI’TCAJT""TLZQTTL3LLC33CCC1¥3C TiCJCJCfC.GGA ACTACCAECCTACGCACCLTCTLG3LTTTCC3"EC3"TCGG QCACQCTCAATTTTCC. TCTEC.3ATCCLTCAGCCTATAGC.G§C3C.GAA3CAAC ACGAGC1CAACCT GACCCAGGAA A3T.T3AC 1 T3CACAA G GGACCCT3ACAT 4GTG CHAA.CA[GAC 4A1A_AALAC CL3CAGGGA 'GGTCTCTATA_AT GACTGCLCAAG ATAZGATCGK AG CTATT3TC AATAGG A.'GAA1-fGGAG’W’GGA GAAGG EGAAAAG-E1’.E.JA‘31’.EL"\.CGG’TTT'I TA. ECAG-EGAC' CAGCACT EC TA. 33G}- A. EGA TACT TA (~T\113KTIA. A -. T1—T. C3K3PTK3A.T KJK3A3..\ZIK3..3(33_~1 T-A A 1 IAA AAA "71’1" T min K3 -31 3 3..3C3HLK3..3 J...T-A An. JC‘J Clcne TSm26564 CAR HXL (SEQ ID NO: 352) NALP\’TALLL PLALLTHAAR PEVQL ESGG GLVQPGGSLR LSCAASGFTF1Q SSYSMNWARQTCKCTEVVC,1.) TTSSSSSTZY YADSVKGRFT LCPDWAKKSL YYUMRGLC"T DTAVYYCARG CQTHLTPDYT GQC‘TLVTYSS GS' 'SGSGK ‘C SGP‘STKLTT VLTQSPATLS LSPGEPATLS RASCCVSRY TATK‘GKPGQ APRLLTAJAS NPATGTPRP SGSGSGTDFT LTTSSLEPEJ TAVYYCQGRT YYP‘T/‘TTPGGGT K‘17E._K:LA1AA.T_1 DNEISNGTT T LCPS P._1P 1.‘TCKPF WVLVVVGGVL ACYSLLVTVA FTZFWVRSKR SRLLKSDYMN MTPRP\PGPTR PLP DFAAL\SRVK FSASADAPAY COCGDOLYAT TNMCRR+TVD TLFKRPGRDP EMGGRPRIKN PQEGLYNELQ KDKMAEAYST MKGETR’G KGH‘GLYGGL STATK‘TYTT LHMGALTPR T154- [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ClQne T$m26564 CAR DNA LXH (SEQ ID NO: 353) ATG CTCCCCCT1ACTC C.‘CCGT GGCATTG ITCC1GCAGCCC CGCC CGCAAATT.TTTGACACAGTC'CACCCACCCTCTCTTTCT TCCA"CGAAAGAGCCAC CLL‘,T C ‘T C C 'T‘ G,L‘A""113CG ",CA.G ' TCTuCTT'TAGCAGCC1T"AC T‘ TAGCC, T G(C1'T1-TCCA11T L‘AGA1TA ‘CLT ‘GCCAGCCT‘ZCAGvCTC,TCATCTALGATC"TCCA‘CTG‘GGACTGCCATCiCLG1C1 G§.TCLCTCGCAGTGG§TCTGGCACACTCCLCCCTCTCCACILGC§CC1.G‘CJCTGA AGATTTTCCACT.TATTACT.TCACCAG GATTCTACTACCCTTCGACTTTTG’GGAGCG ACCAAGGTTGAG.L.AAACG GGGTCTAC TC GGAA CCCGAAGT GfGAAG AGTAC1TAGGCGGAGGTC AGC'GCX CAG'C'CCGGGCCTTCCTACACTGGG GTCCCTGL 'GTCCCTCLGGCTZCAG1GA-CSCAGC,CTCT1CTT'CAC,TTCMTACCTPTAGCATGAACTCG (GGGCTGGZMT GTTTC"3C"TTA.TACTAGLGTAGTA TCATATA1TAGCAGACTCTCTGA.GGCCGATTCACCATCTCCAGAGWCALTGZCAAGAA CTCLCTGCATCTCCA.TGATGLGCCT1AJLGCTGACGLCTGGCGvTCT CTA‘TECTCC AGAGGTTCTCAGC.GCACITCALTTT GATTHTGGGGACAG GTACATTGCTCACJGTCT CCTCAGCCT'CC.TG1TA’1GAAAAGTIAAACGCAACmATCATTCAGTGAAGJCCAA GC CTCTCT' 3T ACCC'T'C'TCCCTGGTCCATCCAA"CATTC'CTCTTGCTCGTA GTG CTCGAGTCKTCGCT' GT1ACTC'CTG" TCC'CACCGTGCTTTTATAATCTTCTG ‘TTATETTCCYCLTA.TGm1CCfiflCTfif‘TCYT‘TAT1GCTLFTACI’TC!¢T""T(ZTCTCLLLC,1CCC1¥CC TTCCCZCLC.GGAL ACTACCA1CCTACGCACCLCCTLGJLTTTCCC1§CC1TCGG TCACTCTCAATTTTCC. TCTEC.JLTCCLCCAGCCTATAGC.G§CCCLGAAJCAAC TGTATAACGAGC1CAACCT GACCCAGGAA ACT1TCAC 1 TCGACAA GCAGAGG TCACAT 4GTG A1GAC AC A 'GGTCTCTATA_AT GACTGCLCAAG ATAZGATCGK 1AG CTATTCTC A_ATAGG A.'GAA1-fGGAG’W’GGA GAAGG 1G1AA1'T—(1311GCA3G1'TCGGTTTTL/‘LTC1'TG11G15TC' CAGCACT 14CT1-. "G1- A 1G1 TACT TA ~1er w -. u—T. ("CPA/A.l \‘jk,THC,w 1-11 A «A «AA "AAANCLHLK,.1, TH1-1 An. 71 An \3 GT , JTJ Clcne TS26564 CAR Lxfi (SEQ ID NO: 354) "ALP"TT1 L PLALLLHAAR #EPVTTOC TLSLSPGLEPUT TLSCRAS QSV SRYLAT»TYQQK PGQAPRLL _Y DAGLRA'CTP ARFSGSGSGT DT"TLT LS .1 PEDRAVYYCQ QRE‘YYPWTFG (GTVVCT S' 'SGSGKPGS GECSTKGCVC LVLGGTGL1_ PGGGTPLGCL,ASGFTFSSYS DNTTRO PGK GLLWVCTLCS SSSTIYTADS VKGRFTTSRD NA'WCL1LDM PGTPAFDAV {YCARCGQE LT FPYT/T’GCCT LVTVS .... DNCTLbTxC1. T1 KTKCKHLCPS PT. FR. TPCKPF WTL‘FVVGGVL ACYSLLVTVA FILL FWVRSKL; SRLLT—TS DYT’TN T’TLPRP\PGRTR KKYQRYAPLR DF1AYRSRVK FSKSADAPAY COCGTOLYL? DARRGC'ED 2w}grthi>KNJ\..—J.\.J_ . 1 t- f‘. 1J:EGLYNELQ KDKMAEAYST LNLGRRETYDMKGET'Lw YGCL ‘TATDTYCT LHTQALPPR [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley ionNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Clans: RY~26568 HG DNA (SEQ ID NO: 355) CA.GGTCAGCTGCT GAGTC’’3GG'GGAGGC 3TGC3 C3CAAGC'CT G'CACCTCCCTGTGLACTCT CCTGTGCA-CCCTCTCGATTCAC GCTATG3’33LT3’3A.TG 3GTCCGCCALGGCTCC AGGCAAG 3C3C33C3L’TGC3AC3TC3 3CL3TC3 3CAG''T'1'\LT"'-TC"T'TAT C317TGGZ'T'LTTGT‘G ’T'TC3A1—‘T7'A3LT1 ’3 3C1 C31-C'T'C 3CL'T'C3AAJ3C3G 3CGATTCA 3C1-"T‘ 3LTLSCAGAG} C31"T'I'CCAAGCSZC3.L 'C"L3CTC3 'T'ATC'T'G": ALA. LT. CJLALACLLT"C1CL.LL.mp. A «AA. 1'CJA'SILD‘'CJKLLLGHLK'L'CJL 'CL.»AAA -n An» ALT C(J'CJKLU JTC'JT...3~A1A,~ ~rf1r~ )‘VQTFv’TL‘JSGGC‘ VVQE>GRSL:LL- AASGF’I'FG 5511"SM:ITJVRC,1.. L PG'iG-1LFWVA: THYLCSJGT ADSVLGRFTI SRRLSKRTLI LCMNSLRAED TAVTYCARTR FHRCRPDLD YWGGTLVT] SS GT’TTT (SEC) TD NC]: 357) (HC CDRT) HYILTGCTTTYATQTL’KG (SFQ ID NO: 358) (HC’ CDRZ) WSCS PSLE I (SEQ TD NO: 359) ’HC C R3) Clcne RYMZSESB LC. DNA (SEQ ID NO: 360} G .CAT CAGT'L GACCCAGTCT 'ATCTTCC .T.3T IT3.C. LTCT 3TAGGAC3ACAC3AGTCACCA.ELI—1' TCACTTGTCGGCCG. GTC .GGG'L'ATTAGCAGC‘TC3GTTLAGCCT CTATCACCAGAAALCTCG G1-_ALA3CCCLAACCTCCT 3ATCTA 'GGTGC TTGCAAAGT 3G"CTCCC1TCAL-.—.G TTCLAGCJCL 3CACL’3L'GC31’TCT‘G«3C1‘LC3A3AT’3'T CZC "TC CACCATCAC3LLAC3C C3T3‘ 3C1-C3'3CTC3AAC3 1-‘TT'T'TCSCLAA'"’1'"'T"TACT‘CL’I'CC3CAC317- TATACACTTCLC3LC3TT3'TT'CAC'T‘TTT 3C3'3CC313C33CLC3AC ,1-;33GLLLLWG1TMTTCALC¥;G3.LWHL..T. .L Clone R3326568 LC (SEQ ID NO: 361). CDRS 1, 2, and 3 are underlined.

FSGVLAGVCDRVTTTCI SLGGGWLA""’"TPC""TKLTVG1SCLGS3V‘SR TGGGCGCLTL K-LGLLDEIYYCHW3n. r~"1 rwr~r71v "1.1 r: 1- - C V' {\1 ) V‘ r\ r11 3 / 1-\ 'PHTFGGG AVLTARr-IrV1V-1/V \ W. .17' "1"1'7- 3LCLLC:34r3. . 3 \ 34 TGLQ/ --«.- -| /\ -v- 1) Nu:---~ 303)r P. \ ,' 'v- \LC{a CDR-4' 3 1') ) QQTYTFT'F‘T (SFQ LTD NO: 364) (LC CDTC Clone RTE-25568 CAR DNA HXL (SEQ ID NO: 365} SCLZ CTC 3CG 3’TAL-C3LTG CL3'T' C3'TC3C3TG’L C3LJCC3T LAT" C3CT‘C3LC3'TC-C33ACC-3 3CC33CACC33CC3 CC.3CL GGT 'C L3 3T"3GAC3’ 'C3'LTGGG EGAG 3C’3TGGT CCAC3CL3LCL3T"3G 3A .3GTC‘ L3LC3L'TG." GLC‘T CTC. STG‘T .3CAGC’C'I'CTCGATI.CLCCT''C’CGCACCTAT ECA'I' EC.TCTG.3GTC‘ L3G SCAG SCT CCA.3 CAAGC3GGCT GAGTG'GG'L G'GC. LGTT. LTAC. LTTA'L GAT GAAGTGLCAAACTA .‘G ACACTCC3T .AAGGGCC .LTTCACCALTCT 'C'LAG. LGAC. LATTCCLAA..GACACGCTGTATCT GCAT TGAACAGCC' C 3A’3GCACCGCCCTALCTACT3’3 3CCr-LGAACT11-LCTTC TC33C3 JC3C31‘T 3C3CC' CCT‘LAGLST'TA3A' TAC' «3513CAAC3CCZT‘T-CAT" 3GTC31TCJCL 3"T'C3T3C3CT /\-2Vf‘r‘1I/‘I"I’I m C {-1 ,3 \m LTC'C'JGTL‘LCJ\ w n -. V,‘ALLCLCJGCL‘LCJ' \JCJCLCTL(JG i’iCj'T.Z‘XL/I‘ELZAJCXTCJVJC -. n -. ,3 n--. w .-.-,L «L «,L. NY m ‘- - JJTCLTTTKATCLCL'"JCT 'Lr'C'ICC31-‘CLT'T —156- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley CCAG.TGEACCCAJETCTCC .TCT'T CCG'. GT'C'.'GCA.'TC .'G'. AGG. GACAC:AGTC .CCATCACT TGTCGGC 3G. TCGCGCT .T.TA.GC.AGCTAC'ATAGCCTG ETAT CAJZEC. AACCA EGGAAAG r-GCY GAT3TJ TGG' 'GKI3ATCKI3AGTTTGCZ—‘LAAG GGGC—T CAATCJ-JAGGTTCAG CECCACETGCEATCT CEAT'T‘T'CT‘IC‘T'C'L‘CACJA‘T'CACECACECCTCACECCTCEILA/EAT" 1'T A’LACTTATT"CJTG TCAC-ECACATATACACG'"T'CCJE"'TTCACT'TTT ECCECAIECECAE A’LAI-ILE T'TGf‘C'a.EIAT‘ .E A.AACCEGCCCGC’I'GC'C’E"T’EATA..’T'GA 'GTCAATC.EG'GAACA.LA‘TC. .TT. CA.EC_E'T GAAGGGCAAAGCACC .'C'. GT'C G .'C."ETTATTCC' GGT CATCAAGACA..I .‘C‘ EG‘T‘G ‘. TGCTCGTAGG GTGEAJET .CC'C ECT CYTACTCT .YGCTCAT 'A.CCG‘T.‘ ..‘T‘ T TAA TC 'TCTGGCTTACATCJAJ—V CZ—‘LAGCCG 'GA T'3C TAG GATTACATC‘AAZTXTGACTC A EGCCJ ECCCJTCECE ECCJCJACCA GAIL: CACJTACCJACECJCJT"TACJCECACJCACC'"ACEA EA'TT TCCECJT GECTA'T‘CCECACECJAxECECE' "GATG‘T" "T" CCACA'TCJ' «EGACATECACECJA«ECJCTATCZEAA C EA.AC, .EA.TC.T-TAACGAGC’I'C‘AA’ECT C’E .EACGCA’.EGGAAGACET'A'TC; ETT ‘T'TG.EACA..A G .EG EAGA GGACCC'."'GAGAT'EG .ET"EGCA.AACCAAGACGAAAAACC EC.EA EGAG EGT CTCT. CTCCAG .AJZEG. .TAAGA.TCEGCTG..A.GC ITATTCTGAAATAGCAT EAAAG G GEAGCCGACAEAQ’E EGAAAAJZEG ECAC EACG ETTT ETAC '.A.:CCACTCAC CTGCT CGAA.

GETZXCTTZXCACCCT CAGATC—CAIA—C CTGA CAC TAGE Clene REY-E26568 CAR HXL (SEQ ID NO: 366) MAT. PV'TAITELL PLATE?.ELHAAF PQ‘JQT‘J’FELEGG 'G\7‘\J’QFGRSLR LSCAI‘EGFrTF‘ GSYGF’THTI’TVR ‘ APGKGLETIV. . VTHY .GSVEY YA1_.ISV..G\F.' .LSR.1.T\T‘3K1T.T...I TTSLPAE T)" J ' DFATSGS PPSL DYWCQATLVT VSSGS‘ 'SGSG SGL'GS'T‘T’ GDTQL'T‘QSPS SVSASVGDRV TIIT RAS AG: SSFILATI’FI’QQK PGKAPKLLTV CEAS SE LQ SCEVP SRFSCES EGG-T 3:1 L‘T‘ AEE‘ELQ TEEJFA‘T'VY EC Q .T Y rT FP F rT FG 'G GT. "IVF.‘ FIRA AATETDT 3K9) "G T. ITH‘J’FI'G 'C‘IL 7PSTIDYWG ’T7 SSA AA 7N:'ICNG TTTH KGTAT C99’3?ITPGT‘C KPFTT‘TVLVVVG GVGACT STLV‘7 1'7‘VAt 1.1.‘TTI’MTVK SKLLHSJ) Y"J'7\J3T\’TT.L‘T QvGLT‘SG.EVKKPGJ""RVTCRATGLTTSSL..SYRQTPGQCIPT3CVTPTTCCAJTA VFQ3RV TTCTAYMELSCLRGL mATTYVCTP‘..ESTIYVYGVPVWCGCT_V TVQSL.- GT SPLAT? (SAG TD NC: 371) (HC CDRT) CRANYAC&FQG (SEQ TD NO: 372) (HC CDRZ) TRTELYSSSIWHYYTCMD (SEQ TD NC: 373) (HC CD1&&3) Clcne PPMZSS75 LC DNA (SEQ ID NO: 374) GACATCTGATGACCCnGTCTC CCITGC..TCTCTITGG ECGAGAGGECCACCA AJCTCCAACTCCGCC CAG' GTT 'TAT GTA CTCCAGATAC3AGGACAG C'C TATAGCCAG TCCAACAATAACAACTACTTACTTGTCATTTACTGGGCATCTACiL3CGAA ’T CC EGG G'T’TT3L.'3 3’1'C1‘T 3CC3A'T ’"T'C1‘TC’1'T33CTATT3L'G (EC T C ’"T' C L3GEAT3AGEATT" T3T- L.'I’CT 3L.'3AT'T’CTT- G3AEC3TECTLECTLAAGZTCTLCCCW‘merACTCTCTmJJTCCCCCCA3AC1CCT'C f‘i’ ~"117711- ~Ir~ .LJ'L:J.RTL:I L1'LT1TL/wpw I‘i/Nf" Im/x (‘1/‘(1TI-C rr1x~< -/\ l~ "T"MTCQRTSLAVSRGTRPWTRCKCCC‘m VMYLAWVQKPGGPBKLLTVWAST '7zerN’ \-1"](1 ~I rr1- (L L ‘17— 7/1 L" TTED'L:13in;T'. L50 ..JL L31.T'L:J..'./‘1."iiTJJ."CDSTTIQIATT‘ETJJA ngf AHTPTTFCGETKVECKR I‘irjf‘r17‘17‘1rfl‘r KSSQSVLYS "WTKRTLA (SEQ TD 10: 376) (LC CDRT) WTTSTRES (SEC TD NC: x. 377) (LC CDRZ) QQFAHTPFT (SEQ TD NO: 378) (LC CDRB) Clone PPm25575 CAR DNA HXL (SEQ ID NO: 379} 'TT r‘ L .~ rw r71 .~ w (LIA: (L ’T'.TRTRLC ’T’ LIA" ,L. I~1~<1T| LIA" .rL VAULT. «papa Liv.rL meIrL. Tm.LJL'J.T..R\ LII‘ L.-I. La» LIA. L T! L_1 ;1L. ‘L...LL. T.L-L.L «(L ... C1L.TT.TL.1L.... (.1L. . 'LT‘JC.\/L . . 'L:JC.i . .T.. L: Vb .LJ T.L. .1L..‘ .1L. T. .~ ~er . ~71T JL/.ACJ\/.*f" ~ Imr f~ .J_.'—Ti.CEJAAACLJIKJ GG'LJTLIC LJL‘TL...'CRT1GC CCTCACAAGGG’CT'GAGTgCAT’GGG’GGETL.AT‘TCTHT T GGGTCGEGAAACTACE CACACAnGTTCCAGCGCAGAGT ACCATTACGCE3CAC EAGT CACCAGCACT CTAWCAk; T. f'T 1r"‘\7_\ wL'3'ZT'1. T\T'JL.L.I TLjr-T TTCTTLTLTCWLJIT-T.T’\TL.'3"T'JLTLj ETCTiITC’TTR‘TLz'lr‘dn -<7 m Lrn L -<7 3 {a-n w m \rr17_ 7 ’1" L /i\r\C1‘L.L'3TC.I-‘T:3.TL1}‘TT‘TTA. ....,L ka—KI‘V-L171wa"1r TACTC3TCCATCATATGCACTTTTA3TACEGCA GCA3CTAG3G3C3AEGGAAnCT —159- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by eadley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley TCCITCA.GCKCTCITAC.1.TCCGCT IC.IGG .AAGCCCG.1.TAG3CGCG.AGGT GTAC AAACIGGGGACATCG'. GAT ACC IAGT ITCC. GAC'. CCC'. GGC'. G.'GT’CTCT ICACTACG(myL1) JCTG AG' KCACAKTGT T'TTATACACC'KCAACATATATAGAACTACT ‘T'AC-3C‘ITI‘T‘GG‘ITIA KCSATAAKCJCA«3TTATCAGC‘IT'CC'TATAG 3TGC C"T'TTTI C'T‘GGCCATC'T‘AL CCG 3G} A'T‘CCGGTSG' ‘CCC' ‘GAC 3GTKA'T‘IT CTKAG' ‘1’3T3CA-CG13G‘CT «"3T31TGZC.T-GA‘T'TT‘CACTC‘T‘C AICA‘TCA..3CACCCTGCJ'GCCZIC«AAGATTGTGCC.C"TTATCT C’.".—3TC.G JAG‘CTC..3C 3C? CA CTCCTTTCACTTTGG GKCACGKCACC CTTCATCAAACGG .CCGCTGC 'CTTGATAA TGAAAACTCAAAICGIGAACA.ATCAT'.CAC 4.TG.AG‘GG IAAGCACC'. C .GTCCCTCAC'CTTG TTCCCTCGTCATCKICAAGCCATTC'GGG'GTTGGTC GG'GGAGT CC‘TCCGCTTGTT r-TCTC’TCT GC'T‘CG'T CAC 3GTG 13CT'T"TATAAT C'T‘T'CT31’;3T3'T"TAGAT' CCTTAATAEAAGC 3GCC5'T‘ GC‘T' CCATAG 3GAT'T TACA‘T'CATA‘T'KArT‘GACT 3CTIKAC13CCG 3CC'T‘GGCC 3CT".CA1TGCAAACZ C‘T‘AC CAG ,ICTT C..3CATCCJCCTJJGAAGATT‘ TCGC‘I'GC‘C‘T'ATCG EAGCA'GGG'.ICAAC T‘T‘."TCCACT CTG ,AGATC .3;CCAGC‘CT. .TCAGCAfEGGCCATAACC‘AACTC’T'. TAACCAC ,IT‘ .3"ACCTCC3 CGCAGGGAA .AGT. .TG. GTT1.TC’3ACA.A.CGC. GAG .ACG GAC ICTGAGAT TGGTGGF AAAI'CCAAGACC....AATAACICC. ’CGT.ITCT. .TAA'. GAGCITGCAGAAGGAT‘AAGATGG CCTATTT 4AATATAGG IATGA AG GGG TAACGGGAAAr-TGGCACGACIG TTTGT-_CICAGGGACTCAG IAKICTGCTACICZ-LAGCATACT1TATK'C—ACGKICTCTCCACTAT GCC C‘T‘1 3CT- AGCG (Elaine REL-26575 CAR HXL (SE ID NO: 380) TVTALPVTALLL PTKATLC-TTT- AR CESGAEVE(KPGSSVK VSKICKASGGTL SSLACSWC‘V7RQ AACOCC-"WMG GV T) LGRAxT YA’C‘KFQG \VT :TATBESTSTA YMELSSI RSE II'TAT/C' CAT‘1'T T3EIYSEISCIT‘T-IY YYGT‘TT‘»WCCI 'T‘T'VTVSSGS‘I" £3 .38GKPGC‘GE. G’3TKGDTI‘I’TTT.‘ ..RAT TKCKS KYC‘ CNN KN LAW? QQK TCGa."RPKTTTTTY TJRFCGT 'GCGT TUTTSCLQ AVYTCK QTA... Tl:12"1 fK~ GG'J.'K‘JJ__‘...K. ‘A .AALDNf. VKG..

CRAY/LT1. ‘IITCI: I}?{TIA/.TT‘JC‘FJKE CVLACTGTTLV T‘T/TART .‘SRTTngJ YM TMTPRRRG PT1'KMY’W T PPRTE TLA‘T’ A? RVKFS TYQ C'GQNQL YNEL TLGRRE YC‘JLDTTRRG REPET/TGKlC—KPR RKNPQ 0,Q‘2: LC’KDKTVTAG’T YS‘ETKMKGEI' RRG GHDGLY (3T1CTATITTTCDT YDALTT K’\.\Jfr: -<. j '1 r 1- P —160- [Annotation] Anne.Headley None set by Anne.Headley ation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by eadley [Annotation] eadley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Clans: PPm26575 CAR DNA LXH (SEQ IE NO: 381) ATGE CTCCCC3T .ACTEC CTCECTGC.‘CC3T GGCAT.TG ETCC'L GCA.’GCC ‘CLACGCC CGCACATC-.L EAT’GACCCAGTC 'CCAGACTCCCTGGCTGTT T3T EGGCGAC3AGGGCCAC -" LI-‘TCEALT- 7TACT ECLAG CET G'TT' ‘TAT‘ TALCACTCC1‘\CAL"T 7-TZITGAAC rTL’T E‘TTr’T EC'T ‘T GGTACCZ"E '317-«ELALZ‘LLTLLLLL/‘xEGLACAGLEC' CCTAAG’ ATT'TLLTCTCCEGCA1CTA"3 C’C‘ EGG AATCC 3"EECTCCCT '3’CC'EA'1"T "3ACET "EGLLACC EGC 'I'C T "ECLE EACACEAT ‘13'T'1E.'" CTCTCLCLEAT CAGCAGCCTECAG'CTC.LALE .T.3TEG'CACLTTALTACCCA3C G'TT'LCCACACTLCL . TCL r‘m. .mr7. 7C7A'C7 .7\,~ l7\/7< '7‘7v1.LxA\JG_E_TI\J. GLATCLETAIr‘IL./7< .7 . 7TJCL '17 r‘ {cm/7‘ CLL TIN/74 . 1L. L :TGJTJ 7G..«n PTLLrTTCTfl"""<7\FTI"‘< \JGGLLT ’\ V" "/74 {V'Wm (‘4. 4 «(w «(w _f~4m 4 A A_AGTG 7CbAAUbiAUTACfZLAGGbU AbU'ULA7CT:Gi JCTITCI~bC{NEW (74 mf‘rl'fi‘f‘mr‘mr‘ "(/71 hmri—n -.LEG 1Gr’ELA"-rL ALGCC' "x"EL3G' 'CCT ALAG L’1'CTC"3TECALAG ECTT E'1'C’3AGL'313LACCCTCL—TCEE L’T E-."3. CT‘ EG 3TAT13;7«"LELET-EGGTELLLLL/‘L133TG’3 ECCC' «ELLACALAG«"ELELET' «"ELALC'T'CEG/EL'TGGCATEGCG T ECTA'I‘CTTLE EGGGCAAA"LETACGLLACACEAL .GGGC..3EA 3T3‘CLLA EGATTAC "3'CLEC 3G3"".3GACLE'."CCALL1ET"ECACACEC"3L’I'ACrT’I'GGrTGCTCACECLELECT/3"EAT ET EA 3G3" 13G ECGGTGTACTAC'CCE'CC. GAACTCC'L T CTC AGC. .TLATCCCACTATLACTACE GCTLTG EACC3T. .TCGGCE'CC. G'GG. CAAC.‘ECACCCJCTCCT AC—CCCTG'CCCTT‘GALAA TGAAAAGTCLIAALACGE' 7-‘"3AAT’3ATT’3ALC' "3CGTLZ‘T[AL 3ACCTC' 'GTCCGTC3LCCCTTC 'TC CTCGTCCATC:LZ‘LG CATTCTGEGTGTT3GT"3CTATG GGAGT CTCGCLTGTT ACTC1CTGCT EGTCZ- "LECG' «ELECT '1' ‘T7TTL'A-T'"3TTC'1'C’3 'T'L‘AGAT’3CALAL/ELAGL A E-."3.C13E EC'T CE ETCCAT" G EGA'TTA"LEATEEAL T’I'CE3"L"3,’I'CL3C'LT C .ECCGCCCT .EGC"LECL3CLT CLAA’ECEAA '1ETAC CL C LECT'. CGCACCACCTTGA3GAT11TCCLECL3T"E"LECL3T'I'CGCACEC'LG LEGI"..EAAG‘3T".TCCAGAT CLCCAGAICE 'LAC AT3C ETLAT CA.3C.GGGCCLAG. .ACC. .ACT ETLAT. .ACCACCTCAACTGGG A EGCAGGGA}TGA TATCACCTTTGGACAAGC ECAGAGGACGGGACCCTGLTCCGATGGGTC3G AACr-LC7‘ —AA.7—‘7-TAC.T'3’C3 "3CAGEE. GGGTC3'T TATAAT’3TAGC: EC.AGAAGGATArTGATC C'1' (EL? AE3C ('3T3‘A'T1"7CL'1'CL/‘LLTLTTTLl‘xfi «LELLLT‘L (EL'L!‘LLTxELLLl‘\(AT"3 EGLAGAA'"E Ex";ELTALT’ETAAG 13E ECL— CGACCG T TT3T." CCAGGGACTCAGCACTGCTAC\ErTACEGTLLCI.‘TATGAC(3’3, ’I' C TCCL CAT 3'1EAA 3'1E LE mmn ‘ffi’ r~< w~.»\ Va \/ .1. C: IV. 'CL , TACK] Clcne PPm26575 CAR LXH (SEQ ID NO: 382) MALPT’TALLL PLALLLHAA? PCIVMTQSPD C3TLT/7C3TGTPLA.TTT\TCT\LSSQSV TSCNNKMYT T’""CTP(CP PKLLTVVATT RESGVPDAFC 3360GTDTTL TTSTTCATI' A'VYCCCP.fl TPPTTCEGGTK VPHKRC51SE SGKTGCEEEGS '392VCLV’ 3 HRPCSS ACCG TLoSLATSWV PQTTCQCLEW MG3UTPTCC' AHT'CTPQGT AITTTATTPTTQ TAVMLTSLR SCDTAVYYCA RTTEYSSSIN HYY :GMDVWG QCTTVTVSSA AALDNTRSNS TTLLHTFKGK L ("L PET (/1 Trj tLL Pt] kr- CT) TU C!) TE T11 '3;2<11":51E?-Li NG) C N 1"‘ L!(/1 :9ON C1)3 T:V TVAFTIFWVR GBROTLHHGD YMAMTPRPP PTRTH"GPYAL PP' UFAAIRS< RVRFSASADA PAYQEGCAC TEIRCJR E E DVLQKRRG RDPEMGEKPT RKNPGTCLIN ELQKDRMJT- TTJLCMTG_ R.GIGTDGLY QG13TTTVPT YUALHMQALP TI/ —161- [Annotation] Anne.Headley None set by eadley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley ClQne RDm26576 HG DNA (SEQ ID NO: 383) CA.GGT CTGCT GCGGGCGGC1TGG CCAAGCCT GCACCTVCCTGTGACTCT CCTGTGCACCCTCTCGATTCAC TCATGTAGCTATGGC TACACTG GTCCGCCAGGCTCC G 1C1CSCTGGAC1"TG 1G’TG 1CAG'"1'L'TTJ«TCSG'TJTTGJTGGJ- CAGCAGAAJ3‘TA ",‘T'J- T 1C1? GJ- CTC 3CL'LT‘C1AA11CSG ZCGA'T ’T'CA T,CLK«." TLZTCJCAGL’TGJ- CATT" TCCAJTCAJT ATCTC1'3 AACTGAACGCCTTAJLGCCGACGLCTGGCG1TCTLTTACTCC1TCAL1G1C3GTT1CA GGAGCZ’LVLTAC'CTTLT GAT GAC TATGGGCCAG GAACAACTCTCLGTCTCZ Clone RD_26576 HG {SEQ ID N0: 384). CDRS 1, 2, and 3 are underlined.

QV1T_1T\I1TLL‘SC1C.71VVCQT3C1RSTETLSCAA’TGE‘TT‘SSYGTHWTCTQAPGCGTL-EIWVA\«TGYDGQE3CYYA LJbV'xGHTT T bRLL‘ATQTCTVT'T1YT_1KQTVTT SLRAEDTAVYYCV. GEL E11:r’Y TCT’TDVW.QG‘TTVTTv’S ET TK‘SSYG TTT (S\JJ TC) TD N31:’\ 385) (T-TC CDRT) VTGYDG TKYYASVKG (SEQ :1-1 13 NO: 38.") THC CDR2‘) TKGFLUTE-LL-TCmDV ("SEQ TD NO: .387) (EC, CDR3, Clcne @"26576 LC DNA (SEQ ID NO: 388} ATACLGTGACGCJ‘PTGTCTC 'ACGC IACCC ITGT, KL.TCTCT CAGGGGAAAGAGCCAC(9‘)) TCTCCTGCAGCGKCCG GAG' 'GTTAGKI3ACC7-‘1ACTAGC TGGTACCL-_GCJTGAAA’OCT-CG.1? CCAGCTCCCAGGC'C T ATCTATACCCC TCCACKLACGC—C ACT 1GTATCCCJGCCA-C'0 TTCLAGTCL TCACLTG‘ 1’TCTC‘1‘11C1CJ‘LCJTAC‘1’T ‘CJHC,C "TC CACCJTTCZJC1CLAC‘1CCT 1CL- CL'LT‘CTCLAA ATT"'T‘TGCLACT' TL"T'TJTCTCL’l'CACvCAGC‘TCLCZJ CGTC’TGGCC'TC CAC'T T T T 1C1'3CLC1AGCLC1JTC CLAACCT'TGAGA’T'CAAACGG Clone RD126576 LC (SEQ ID NO: 389). CDRS 1, 2, and 3 are underlined.

LVCMTT"T ‘ QS L.".'T"T1E>\/’S1PGEPATLS CJRAG CIL'T‘RETYSL- STRLrTGTPA RESGS T‘TL‘TL’T'LS’T1QS’LL‘DETCTK/L_ KLV‘\"T?._1TTTC1GC’T'T\\/TKTKR RASCQST‘JSS TEA (SEQ ID NO: 390) (LC CDRT) SASTL-T" (SEQ TLC) NC): 391) (DC CDRZ) Clone Rflm25575 CAR DNA HXL (SEQ ID NO: 393} .LTG SC.‘ CTC‘ CTCCCTAA’TGCT CTGCTC1CT.C71CC'7'.T'GGCAT"T.C71CL‘TL‘C,C,."C 3A. ,‘G 3C C.1CCT, ,..71CLCC" 3C7 ‘TGC.17 1 _1T’71GACGT 'C7,'‘GCGGGCGGC’CTGGCCACCCTGG 1AC71C‘TCC1CTGL‘GLC'T‘ CTCCTJTGC.GCGT ZTKTCALTACCT'.CC‘GTFQCT . GGCJ‘TACAC' GGGTCC CAG1‘CT CCA1‘GCAAGGGGCT 1GAGTGGGGGC GTT LTAGCCTATG. 1GAC GJAGAAAACTATJ 1‘T TCCCTC 1ATTCAKI3CACTKI3T CAGAGACAATTCCAACAACAC CCTGTATCT C1'L‘A TAC‘J-CC1CJC' "GAGACC1CJCLC-LJTC1GACL'TC‘1CC1CLC1 1TGTAC.,'TAC,’T'GCGTC-LAK1GCL 1CCGT"'G C GAGC,‘G'CC‘JTTA ‘GCT'TTT 1CC1L".'TL‘1GL'\C 1TL".T-‘CC1CS-C1T,CL5\G-L‘CC1L"\C‘JTACL'LT‘GTCLACCGTCT —162- ation] Anne.Headley None set by Anne.Headley [Annotation] eadley ionNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley CCTCACCATCTAC‘CGCGTiGGG.AJZ—CZCGG.3A3~T1G’CG.3A3GTAGTAC AACCCAC.1) AATACTCTTC.C:3C G. CCA 3.CCACCCTCCCTFC :TCC. GGGCAAAGAGCACC iTC CCTGCAGGGCCAG' CACAC TAC 1 TACCCCCC' A1::CAC,-3CAA,-:CTC 'CG2 ACCCTL’JCCACCCTCTCATCTATAC:CCAT :CACCAC‘CCAC,’1'G"'I[ATC, :C2C3ZCL-i:CT GTGTGGCZGT1GCTCTC"(A.AfiACT'CACIGICZCCAICAGGXGCI‘GCZ GTCTGLHQAW TTITG,GT"TTIA’TGTCAGCIGCACGJGGTCTGGCCGGIGTITTIT§GJG§AEG§ACGA AGATCAAACGGCC1CTG ‘GT.GAT3ATGAAAA.IAAACCGAACAATCA T.CA CGTGAAGJC'YACGACiTCT T3C1T:CGGTTGGCCCT1GTC ' CAAGC TTCTGG GTGTTGGTGGIACTGG 1TGGAG T‘I3G T 'G' TAC'GC TCGTAC3G'TGGCTTTA TAATCTIGIGG"'TAGATCCAAAAfiAAGZCC3LTG3'CCATAG(ATTA.ICAATATGAG I‘CCE—i‘GGCTH3C'«LL:ZCCKKWAAC(TULACACITACCKA,CCTITVCGCGVCC‘"IZA1I§ZA‘ITI‘C G3"§C3TAICGGAGCAGG§TCAJGGTYTCCJGATCTGGJJATECTCCHEGIATCHEC,3G GJCJCAAJCAAGGGI"IAJ"GAGCGGAACGTGCGJCCGJGGGACACTATGACGTITT§GA CAA1’CGCAG 1GAC1GG CGCT AG .TGGG' GGCAAACIAAG. AAAAAACCC’CA.GGAG GGTCTCTATA.3T3A.GGTG 'A3AAGGAGAAG3TITGAA'CCTATTCTGAA IGGA.TG AAGGAGAWCGGAGAAGGG1A1AAAGGG AGGAGGG"TG'AGCAGGG CTCAGLACTGCTAC TACT' ATGAGGC' C. ACATGCAAGGGCTV‘ ACC' AGG Giana RD~26576 CAR HXL (SEQ ID NO: 394) NALP\7T1LLL .LAGJLEAAI PQVT LVHSGG GVWQP~R'LR LSCAASGJTF SSYGTHWVRQ APG GLEWVA /TGYDGQ"K~ ADSVK \FTH YLQMNSLRAE GTTVVYGV/G PLQFLPYAEG VDPYGO"TV .:3 DNSKNTL‘7SSGSTSGS EST GCI ATLSGLC‘R ATLSCRASQS VSS"‘WYQ( PGQAP3CQI ’GAGTRAIGI PARTSGGGCJ TFPILIISCL QSFDT’VYYC )GHHVJPLIP GGGTKVEIKR AAALDNSKSN G‘_TIH\KGKH LCPSPLE'GL CKPEWVIVVV GGVLACYSLL VTVAETIPWV SKRPLLHC DYMVMTPRRP GPTRKEYQGVAP .RUFAAY" SRVKFSKSAD .PAYQ)GQNQ LYTELNLGRA EEYDVLDYRR G DPEMG1NP TGLT NTLQKDKMAG AYSG:GMKG*A.

‘AJ'M’1 73 CD. 5' C} HHU G. [:"lC_ YQGLSTATK TYDALEM’AL PP: —163- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley Clans: RTDm26576 CAR DNA LXH (SEQ ID NO: 395) ATG7 CTCCCCGTTACTC CTC7CTGC."CCGT G ITCC1GCA'GCC7CHCGCC CGCAAATACT‘ATGACGCAGTC'CACCCACCCTCTGTCTGT TCCAGCGAAAGAGCCAC CL7‘T C ‘17' C C 'TG7‘A7"7GCG "CAG ' "CAGA"7'7L7TCT"’17'T7AGCAG CZ-TAC T TAfGC,’17'fG-GT1--TCCAG 7‘AGZ-71.7- 7"TZC T CC1‘7CAG7CTC,TCATCTATAG C"T7CACCXG‘GGAC1GCTTTC7C1G‘CG G7_TC,CTCGCAGTGG7TCTGGCACAGTTCDCTCTGTCCATIDGC7C377C’GTCTGA AGATTTTCCACT.TATTAGT.TCACCAGCAGCCTCTGCCC'CTCACTTTTGC:GGAGCG ACCAAGGTTGAGTT.AAAGG GGGTCTAC TC GGC1CCG7GAA 7CCCGAAGT‘ GfGAAG AGTACTTAGGCGCAGGTGCGGC'GG CAG'C'CCGGGCGCC TCCTCGCCTGGAG CTCCCTGL CT,TCG' CSCAGCGTCT-GTT'CAC,TTCACTACCTATCGCATACTCG L7-7'7T‘CL7JC7CTCGCT‘CTAGCC'A(GGGCTGGZMT E'TGCAG'TAT’GGCTTTCA1GCGG AGAAAT TATGCAGAGTCCCTGA.GGCCGATTCACCATGTCCAJJC'GAATTJCAAGAA C C7CTGTATCTCCA.TGATJDGCCG7A7JGCCGACGJGTGGCG7TCT CTA‘T7CTC AAG7 CCGT1 GfGA 7GAG CGCTATTACC7CTTT 'G EAT GAC7TATCG7 AACAA GTGTGCGT'TGC CAGC‘GCGCCTTGTTA’1GAAAAGT1AAA GGAAC ATC TTC CGTGAAGGC7CATL GCATCCT TGT ' G—T ACCCT 'G' TGCCTGGTCCATCATCCCATTCTCG CTCTTGCTCGTAfTGGGT 7G7-‘7.G"CC.f' TCGCT' GTTTCATC'CTG TCG'TCTICCGTCGCTT TA._.7 "'17'2- "T'T‘CTTC17GGTT‘A77TATCAAAACT/‘TAGGCLCCT‘C—7C'7CT,CATT7-‘TGGTTT/\TTAA1GI’ATA17ATC7AL 171ZC‘I‘CJSCGG JCCGGCCCCCAAAGGA ACTACCA 7CCT1ACGCACCJL,T,17 ’ T."7AT‘T‘TC C7 ,‘TT7C. STAT 77CAC7GC'7'C7A..7TTT7GT"TCCAT rA77C,T ECAGI. .TGCJ.CC"AGC‘G TAT" GA. SC." GG ACAACCIACTATAAC 7.AGC1 CAACCTG EACGCAG EAAGAfTG1‘ATGACGTTT.L TCGGA CAAGCGCTI;GAGGACGG fGAGATG 7GTG 7C.C7-‘7_7-‘TACCA! GAC 7A7-‘7_AAAACCCCCAGGA ' GGTCTCTATAATCACC'GCAGTLAAGGATAZ GATGGCT TAG CTATTfGTGATArAGGCATGA AAGL;r-TC71TG C 7GACATA.G-«.7CfTITATAG«-7G 7,7";7T7'ACG"G'TTTT T1‘T 7CT7AG-CAC'T‘C. GC,ACT 7C TA 7 b.7121. jLJZ‘TT(‘1*'\"\ 7,7. 7 ..77. Ar [772‘ A7/7r7. 7A" 7,7 777 ,7 «,7 ~7/7,7 77:7,7f7 777 ,7,7. m ,7r7 .11%. 'JACk;.., . A..1 flak/AT}\‘jk,MC, .., .1714. 77:1 Clans: RDm26576 CAR LXH (SEQ ID NO: 396) "JIALPY’T’A-LLL HAAR RETAIT‘TTCDCTA TLSVSPGERA TLSCRASCS‘J YQQK PGCAPRLLTY SASTRA 'GTP ARFSGSGSGT AFTLTGSSLQ TDTA‘J77 YYC-Q CIHH‘I'1PLT‘T57‘G (GTV‘TT 5,7 SGSGKRGS GEGSTKGT ‘JR LVESG SGVV _" PGT’7T7P.7_7’7(.7.A OFT}SS TC: Q’ PG.T\TST'TATVD ’T‘T’DALTTT’TQTAL PPT —164- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley ed set by Anne.Headley Clcne RD~26578 HG DNA (SEQ ID NO: 397} CA.GGT1CAGCTGGT GAGTCTC: GGG.j;GGC1TGG" CCAGCCT GGACCTL'CTGIGACTC CCTG‘TGCACCCTCTCGAm CAC TTC 'CGCATZCACTC1GTCiGCCAGGCTCC Z1C1 C1 CALTC1 1C1C1C’I'GC1ZTC1 T C1C1C1 T G-1CLAG''IL'ATZTC1G-LC1'1AT C1ZT'I' G C1ZTCLTC1C1AL'11AZTZTTAC ‘T'AI‘ 1CA GI- C1'TC C1C1'I‘ C1LTLrTx’1GC1 1LCGA'T 'I'CA 1LCAT"1 1ZTC1L-TC1ZTCAZ-‘T'1 TC C1ZTAGAAAC1 1C T C1'1'AT C1'1'C1C1 AALTGAACAGCCT1A1LGCCGACGLG.GGCG1TCTLCTACTCCGTCAL43G1CJGTT1CA GAGC'GCLATACGATTAT1AAT GAC TA GGGCCAG CIGTCACCGTCTCZ Clone RD_26578 HG {SEQ ID N0: 398) CDRS l, 2, and 3 are underlined.

)VQTVESGCTVVPGR"IPLTCLATGFTFSSACNHW‘.FAPGIGLEWTAVICYTGQEYTA Jvax511T LbRLLIIQILIVILYLQMNGLRAEDI..\rYYCVKgrLQELLA’TI".L'YC"IIDVWCJQGTTVTVS TTFGSRCMH (5\Jq.1 1 —."(L H. U HQ:7 393) (HC CDRI) VIGYDG SVKG (SEQ ID NO: 400) (HC CDRZ) TVGPLCAPVD"CMDV (CEQ ID NO: 401) (HC CD 3) CIQne RDm26578 LC DNA (SEQ ID NO: 402} GAAATAGTGZ-‘ GACGCAGTCTC AGC ACCCTCTCTGTCTSTCCAG1~GAAAAG) C) C2‘51fl. (1 G CCAGCGCCTCAGAG'GTIAGCACCAACTAGC:TCGTACCLCAGAAA1CTGG'1 C1CA 1C1C1 T C C 1G C1 'T C C T CA"'LTCL'TATACCG C1ZT’I' C C1Z-TCGAG C1G C1CACT1'1C-1TA'1' C C1 C1ZTC1C1 C1ZTC1C1 ‘T' T C1Z GT C1 1CLTC1 ’I' G C1 C1 ’I' C TC1C1GACAGAC1 ’I' T C1ZTC "'LTCL'T CAC1CAT C1ZTC1CA 1CL'1LT" 1CL-L1'T C T C1ZTZ‘TC1 I1LII'11Am" m T J\LA'\_‘I I«A. r~r71r. 'I' rf1rIZ-TCLI LICHTKJ.._LLAT'CJKLZ-TCLTL.C:CJIKLICJ'LJKL.L‘rn/Nrrl 1m ALTA ,«A 1p, EIVMTflRPAmR"QZS "(J 6‘) [1;] 'ZU 3d L{I {-4 U)\. _. . (‘1 _ 7):! U) IO CQ 4 U) CG {-4[131:: L<:QCII"QARRLLTYS ASTRL.TGIT‘ARFSGSGSGTEFT.1T SSTQSETL‘FAIJYYC. >...( H )Q..11VI’\II‘111TFGCG‘KVFTKR RASQSVSS ILA (SEC, TD NC): 404) (LC C1DR1) SHUTJL‘TT (SEC; ID NO: 405) (LC CDRZ‘) ICHR‘JWIIT (SEQ IT1 "IO: 406‘) (LC CDR'B) —165- [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley Clans: RDR26578 CAR DNA HXL (SEQ ID NO: 407) ATGEC 3T ACTC CTCCTCCCCTT CCCATTC :TCC CACCCCCCCCCC CCCA;CTCCACC 4T<3CAC'C'C3C 4CAC4C TCCTC ACC T<3CCACCTCCCTCAC:ACT CT:CTCTCCATCCTZTCCATTCTCCTTCACTAC22CT CEGGCTCCC1CTC}GG CCA 3CL:CT(TAC'ETCC'ETCCTT"""VTACixJEfx CA1:GACZVTLNCGIL ATTCCTTCTC C.C’CTCCCTCA."CCCCCATCCACC.TCTCCA3T AATCCC.ACA; C:CTCT.TCT CAACTCCCCACACCCTACCACCCC1xT1TAC ACT4CCTCAAC;C.C'TTTC CACJAjC ATACC.TTATCCA.TCC C:T TCCCCC CCC.AC1ACTCTC C'CTCT CCTCAJCCTCTACATCCCCC'CCC C.ACCCCCAACCCC‘CAACCTACTCAATC C.CCA .ATACTCLTCAC4CACTCTCA67:CACC,TCT TCCCTCTZCACCCAAACA3CATCTC ECCTCCAGngCZ7ECZGAG'"m’flCfivCSI7"1A7CCT7G1A1CALCAGAAACCTCGCC AgC,.CCCArCTiCCCCATCTATACC:CATCCACCACC:CCACTCCTATCJCACJC’C.TT C’CTCTC.CTTCCTCTCCCACACACT‘CTTTKC.TCATCTCCACCCTTC.CTCTCAACAT TTTCCACT_T..TACCCT'ACCCK:CCACCCCTCCC CTC CWTTC C3A3CCACT AJCITCACATCAAAC'CCCCCCCC:TTG.TA’ CAAAACT1AAA :CCAAC ATC TTC GGCCATGGXGGG TGT'C 3T ACCCT'G'GGGCGGGTGLAICRJICCCATTCGGG GTGGTGGGGGTAfTGGGm GAG'G:TCGCT' GTEGACTC'GTG T:GTC1NCQTFGGLTTA Ti- "T'E‘CT’ECE5GG"TA712‘"‘7‘Z‘J-‘TAAC[CLARACCTGC’CICATAGCCT/‘VE'TKAlG/LAINEGAL TZC'WECJGJCGTGCGCCGAAACEGA ACGAGCARCCTACGCACCJCCE C GJTSGJTAH'XXIGCAGGCwafi‘GGMTTCCT"""TECTJLTCGJGW‘CKF‘EREJnQC GG ACARCGIACTATAAC AGC' G1ACGT GACGCAG GRACH3 ATGACGGTETJCA AAGGGC;GPGGAGG AGGCGGACAT GTG CHAA.DA[GAC KTEAARCTCCZGGA' GGTCTCTDTERGCAGG'GCAGTHGCATAJGAGCG‘ 1G CTATGGTGAA,AGGCATGA AAGGr-CGAGC, JCfi7A$GGCJ‘IALLLDG37;}CSADGZ‘1CGGE‘G'l‘j‘IDCZ‘EG-GAC'E‘CT GCAE‘T SCTAD 77.71.21. 373.911.1"." 4" «(C-I «4 ATE. Ar .r~4 Al/Nffl.1w~1r.f~< w‘ /~< «m «Mn "Ewan w‘ /~ DG T<"YAUC VRGRFTTSRD NSRNTLYLQM AGLRAETA TPTGE PPTDYG‘DVW TVCG AAALDATKSA RGRH TC'TC'PLPGP SRPFWVLVVV G4VLACYSLL VTVAPTTFWV RSI{RSRLLRS DYMTMTPRRP CPTARHYCPY PRATTTTR STVRPETAAC APA ’QGCTQ LTNELTLGR LTYD'LDRRR TTPPTGT/1-CCRP RRRNPQT'GLTT' NPUCA’D/T‘TAT' AYESTTCTITRG PERTTJGL TUGLCTATRP TYDALAMTAL PPT —167-

Claims (28)

Claims

1. An ed polynucleotide encoding a polypeptide that comprises an antigen binding molecule that specifically binds to B-cell maturation antigen (BCMA), wherein the antigen binding molecule comprises: (a) a VH CDR1 region comprising the amino acid sequence of SEQ ID NO: 16; a VH CDR2 region comprising the amino acid ce of SEQ ID NO: 32; a VH CDR3 region comprising the amino acid sequence of SEQ ID NO: 48; a VL CDR1 region comprising the amino acid sequence of SEQ ID NO: 88; a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 104; and a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 120; (b) a VH CDR1 region comprising the amino acid sequence of SEQ ID NO: 385; a VH CDR2 region comprising the amino acid ce of SEQ ID NO: 386; a VH CDR3 region comprising the amino acid sequence of SEQ ID NO: 387; a VL CDR1 region comprising the amino acid sequence of SEQ ID NO: 390; a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 391; and a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 392; (c) a VH CDR1 region comprising the amino acid sequence of SEQ ID NO: 399; a VH CDR2 region comprising the amino acid sequence of SEQ ID NO: 400; a VH CDR3 region sing the amino acid sequence of SEQ ID NO: 401; a VL CDR1 region comprising the amino acid sequence of SEQ ID NO: 404; a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 405; and a VL CDR3 region sing the amino acid sequence of SEQ ID NO: 406; or (d) a VH CDR1 region comprising the amino acid sequence of SEQ ID NO: 357; a VH CDR2 region comprising the amino acid sequence of SEQ ID NO: 358; a VH CDR3 region comprising the amino acid sequence of SEQ ID NO: 359; a VL CDR1 region comprising the amino acid sequence of SEQ ID NO: 362; a VL CDR2 region comprising the amino acid sequence of SEQ ID NO: 363; and a VL CDR3 region comprising the amino acid sequence of SEQ ID NO: 364.

2. The polynucleotide of claim 1, wherein the antigen binding molecule comprises: (a) a VH comprising the amino acid ce of SEQ ID NO: 72; and a VL comprising the amino acid sequence of SEQ ID NO: 144; (b) a VH comprising the amino acid sequence of SEQ ID NO: 384; and a VL comprising the amino acid sequence of SEQ ID NO: 389; (c) a VH comprising the amino acid sequence of SEQ ID NO: 398; and a VL comprising the amino acid sequence of SEQ ID NO: 403; or (d) a VH sing the amino acid sequence of SEQ ID NO: 356; and a VL comprising the amino acid sequence of SEQ ID NO: 361.

3. The polynucleotide of claim 1 or 2, which comprises a nucleotide 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% cal to a nucleotide sequence selected from the group consisting of SEQ ID NOs: 64, 136, 383, 388, 397, 402, 355 and 360.

4. The polynucleotide of any one of claims 1 to 3, wherein the n binding molecule is selected from the group consisting of scFv, Fab, Fab', Fv, F(ab')2, and any combination thereof.

5. The polynucleotide of any one of claims 1 to 4, n the antigen binding molecule comprises an scFv, wherein the VH and the VL are connected by a linker.

6. The polynucleotide of claim 5, wherein the linker comprises an amino acid sequence at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 174.

7. The polynucleotide of any one of claims 1 to 6, wherein the antigen binding molecule binds to BCMA with a KD of less than about 1 x 10-6 M, less than about 1 x 10-7 M, less than about 1 x 10-8 M, or less than about 1 x 10-9 M.

8. The polynucleotide of any one of claims 1 to 7, wherein the ptide is a chimeric antigen receptor (CAR) or a T cell receptor (TCR).

9. The polynucleotide of claim 8, wherein the CAR or TCR further comprises a transmembrane domain.

10. The polynucleotide of claim 9, n the transmembrane domain is a transmembrane domain of CD28, 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 zeta chain of a T cell receptor, or any combination thereof.

11. The polynucleotide of claim 10, wherein the transmembrane domain is a CD28 transmembrane domain.

12. The polynucleotide of claim 11, 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% cal to SEQ ID NO: 169 or is encoded by a nucleotide 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.

13. The polynucleotide of any one of claims 8 to 12, wherein the CAR further comprises a hinge region between the transmembrane domain and the antigen binding molecule, n the hinge region is of IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, IgM, CD28, or CD8 alpha.

14. The polynucleotide of claim 13, wherein the hinge region is of CD28.

15. The polynucleotide of claim 14, wherein the hinge region of CD28 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: 167 or is encoded by a tide ce 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:

16. The polynucleotide of any one of claims 8 to 15, wherein the CAR or TCR further ses a costimulatory region, wherein the costimulatory region is a signaling region of CD28, OX-40, CD137, CD2, CD7, CD27, CD30, CD40, programmed death-1 (PD- 1), inducible T cell costimulator (ICOS), lymphocyte function-associated antigen-1 (LFA- 1)(CD11a/CD18), CD3 gamma, CD3 delta, CD3 epsilon, CD247, CD276 ), LIGHT (tumor necrosis factor superfamily member 14; TNFSF14), NKG2C, Ig alpha (CD79a), DAP- 10, Fc gamma receptor, MHC class I molecule, TNF receptor proteins, Immunoglobulin-like proteins, cytokine receptors, integrins, signaling lymphocytic tion molecules (SLAM proteins), activating NK cell receptors, BTLA, a Toll ligand receptor, B7-H3, CDS, 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, IA4, CD49D, ITGA6, VLA-6, CD49f, ITGAD (CD11d), ITGAE (CD103), ITGAL (CD11a), LFA-1, ITGAM (CD11b), ITGAX (CD11c), (ITGBl), CD29, ITGB2, CD18, ITGB7, NKG2D, TNFR2, TRANCE/RANKL, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile), CEACAM1, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), CD69, SLAMF6 , Lyl08), SLAM 1, CD150, , BLAME (SLAMF8), SELPLG (CD162), LTBR, LAT, GADS, SLP-76, PAG/Cbp, CD19a, a ligand that specifically binds with CD83, or any combination thereof.

17. The polynucleotide of claim 16, wherein the costimulatory region is a CD28 costimulatory region or is a 4-1BB/CD137 costimulatory region.

18. The polynucleotide of claim 17, wherein the costimulatory region 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 or is encoded by a nucleotide 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.

19. The cleotide of any one of claims 8 to 18, wherein the CAR or TCR further comprises an activation domain.

20. The polynucleotide of claim 19, wherein the activation domain is a CD3 zeta domain.

21. The polynucleotide of claim 19, wherein the CD3 zeta 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: 173 or is encoded by a tide ce 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.

22. The polynucleotide of any one of claims 8 to 21, wherein the CAR or TCR further comprises a leader peptide comprising 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: 165 or is encoded by a tide 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: 164.

23. A vector comprising the polynucleotide of any one of claims 1 to 22, which is a retroviral vector, a DNA vector, a plasmid, a RNA vector, an adenoviral vector, an adenovirus associated vector, a lentiviral vector, or any combination thereof.

24. A polypeptide encoded by the polynucleotide of any one of claims 1 to 22 or the vector of claim 23.

25. A cell comprising the polynucleotide of any one of claims 1 to 22, the vector of claim 23, or the ptide of claim 24, or any combination thereof.

26. The cell of claim 25, wherein the cell is a tumor-infiltrating lymphocyte (TIL), autologous T cell, engineered autologous T cell (eACT), an allogeneic T cell, or any combination thereof.

27. Use of the polynucleotide of any one of claims 1 to 22, the vector of claim 23, or the polypeptide of claim 24 in the manufacture of a medicament for inducing immunity t a tumor in a subject in need thereof, or for treating a cancer in a subject in need thereof.

28. The the use of claim 27, wherein the cancer is multiple myeloma, Hodgkin's Disease, non-Hodgkin's lymphoma (NHL), y mediastinal large B cell lymphoma (PMBC), diffuse large B cell lymphoma ), follicular lymphoma (FL), transformed follicular lymphoma, splenic marginal zone lymphoma (SMZL), chronic or acute leukemia, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic ia (ALL) ding non T cell ALL), chronic lymphocytic ia (CLL), T-cell lymphoma, one or more of B-cell acute lymphoid ia ("BALL"), T-cell acute lymphoid leukemia ("TALL"), acute id leukemia (ALL), chronic myelogenous leukemia (CML), B cell prolymphocytic leukemia, c plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B cell ma, follicular ma, hairy cell leukemia, small cell- or a large cell-follicular lymphoma, ant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, Marginal zone lymphoma, myelodysplasia and myelodysplastic syndrome, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom macroglobulinemia, a plasma cell proliferative disorder, asymptomatic myeloma, smoldering multiple myeloma, indolent myeloma, monoclonal gammapathy of undetermined significance (MGUS), plasmacytomas, plasma cell dyscrasia, solitary myeloma, solitary plasmacytoma, extramedullary plasmacytoma, and multiple plasmacytoma, systemic amyloid light chain amyloidosis, POEMS me, (Crow-Fukase syndrome, Takatsuki disease, PEP me), or a combination thereof. [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by eadley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley ionNone set by Anne.Headley ation] Anne.Headley Unmarked set by Anne.Headley FIG. lA—Anti-BCMA BlIldln Molecules FS 2 PC-2 97_v AJ-22508 V VM-22517 V ‘V‘ .v. A .\ \ .‘\ \v “ .; ..- . TS -2 522_V QY-22527 V PP— 2 528_V \-. .~ » g )— 2 530 V PC-2 —97 VH AJ-22508 VH VM-2L517 VH ~.- .., h. m , ft‘. TS-22522 ‘ \E‘: \2‘, ,3 '\1 VH {\31:: V" QY-22527 VH :l \..vtn. PP-22528 VH y .x,‘x). q D-2L530 VH FS -2 PC -2 AJ— 2 508 V WM-2 517_v TS -2 522_v RY— 2 527_v PP 2 528_V q 3-2 530 V SEQ ID NOn AJ-ZISOB VH NM~21517 V3 TS“21522 VH 33-2152? VB FP~21528 V3 RD* 21530 VH ation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley [Annotation] Anne.Headley None set by Anne.Headley [Annotation] Anne.Headley MigrationNone set by Anne.Headley [Annotation] Anne.Headley Unmarked set by Anne.Headley — Anti-BCMA Binding les ‘- x '\\\:4.\.'\270VNab. a».1A.! ’11o4 2.9222223? “ __95 v _ 97W .508W .517W .522