Methods and uses for Anti-cd38 t cell engagers in treatment of peripheral t-cell lymphomas

Abstract

The disclosure provides methods for treating peripheral T-cell lymphoma (PTCL) using an anti-CD38 T-cell engager, as well as uses, compositions, and kits related thereto.

Description

METHODS AND USES FOR ANTI-CD38 T CELL ENGAGERS IN TREATMENT OF PERIPHERAL T-CELL LYMPHOMAS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. Provisional Application Serial No.63 / 529,942, filed on July 31, 2023; and EP Application No. EP24315126.3, filed on April 8, 2024; each of which is incorporated herein by reference in its entirety. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING

[0002] The content of the electronic sequence listing (183952035240seqlist.xml; Size: 274,177 bytes; and Date of Creation: July 24, 2024) is incorporated herein by reference in its entirety. FIELD OF THE INVENTION

[0003] The disclosure provides methods for treating peripheral T-cell lymphoma (PTCL) using an anti-CD38 T-cell engager, as well as uses, compositions, and kits related thereto. BACKGROUND

[0004] Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Despite the introduction of new chemotherapy protocols and a plethora of new agents, the progression-free survival of patients with PTCLs needs to be improved.

[0005] Immunotherapy has established itself in recent years as a major advance in the treatment of several cancers. Trispecific binding proteins that target CD38, CD3, and CD28 have been developed for treatment of multiple myeloma and chronic viral infections. See, e.g., International Publication Nos. WO2019074973 and WO2020076853 and U.S. Pat. Nos.11,186,649 and 11,530,268.

[0006] Therefore, there remains a need for improved treatments for PTCL. BRIEF SUMMARY

[0007] In one aspect, provided herein are methods for treating peripheral T-cell lymphoma (PTCL) in an individual in need thereof, comprising administering to the individual an effective amount of an anti-CD38 T-cell engager. 1

[0008] In some embodiments according to any of the embodiments described herein, the anti-CD38 T-cell engager is a bispecific binding protein comprising a first antigen binding site that specifically binds a CD38 polypeptide and a second antigen binding site that specifically binds a CD3 polypeptide. In some embodiments, the anti-CD38 T-cell engager is a trispecific binding protein comprising a first antigen binding site that specifically binds a CD38 polypeptide, a second antigen binding site that specifically binds a CD28 polypeptide, and a third antigen binding site that specifically binds a CD3 polypeptide.

[0009] In some embodiments according to any of the embodiments described herein, the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31) or GYTFTSYA (SEQ ID NO:37), a CDR- H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32) or IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34) or QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of LAS or GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). In some embodiments, the first antigen binding site comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). In some embodiments, the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:13, and a VL domain comprising the amino acid sequence of SEQ ID NO:14. In some embodiments, the first antigen binding site comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of 2ARTGGLRRAYFTY (SEQ ID NO:33); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34), a CDR-L2 sequence comprising the amino acid sequence of LAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). In some embodiments, the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:5, and a VL domain comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:17, and a VL domain comprising the amino acid sequence of SEQ ID NO:18. In some embodiments, the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:21, and a VL domain comprising the amino acid sequence of SEQ ID NO:18. In some embodiments, the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:23, and a VL domain comprising the amino acid sequence of SEQ ID NO:18. In some embodiments, the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARMFRGAFDY (SEQ ID NO:43); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO:44), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO:46). In some embodiments, the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:9, and a VL domain comprising the amino acid sequence of SEQ ID NO:10. In some embodiments, the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTLTEFS (SEQ ID NO:2), a CDR-H2 sequence comprising the amino acid sequence of FDPEDGET (SEQ ID NO:3), and a CDR-H3 sequence comprising the amino acid sequence of TTGRFFDWF (SEQ ID NO:4); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSVISRF (SEQ ID NO:7), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQDSNLPIT (SEQ ID NO:11). In some embodiments, the first antigen binding site comprises a VH domain comprising the 3amino acid sequence of SEQ ID NO:108, and a VL domain comprising the amino acid sequence of SEQ ID NO:109. In some embodiments, the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO:12), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO:15), and a CDR-H3 sequence comprising the amino acid sequence of ARYAYGY (SEQ ID NO:16); and (b) an antibody light chain variable (VL) domain comprising a CDR- L1 sequence comprising the amino acid sequence of QNVGTA (SEQ ID NO:19), a CDR- L2 sequence comprising the amino acid sequence of SAS, and a CDR-L3 sequence comprising the amino acid sequence of QQYSTYPFT (SEQ ID NO:22). In some embodiments, the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:110, and a VL domain comprising the amino acid sequence of SEQ ID NO:111. In some embodiments, the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:116, and a VL domain comprising the amino acid sequence of SEQ ID NO:117. In some embodiments, the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYSFTNYA (SEQ ID NO:24), a CDR-H2 sequence comprising the amino acid sequence of ISPYYGDT (SEQ ID NO:25), and a CDR-H3 sequence comprising the amino acid sequence of ARRFEGFYYSMDY (SEQ ID NO:26); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHSNGNTY (SEQ ID NO:27), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of SQSTHVPLT (SEQ ID NO:29). In some embodiments, the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:112, and a VL domain comprising the amino acid sequence of SEQ ID NO:113. In some embodiments, the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:118, and a VL domain comprising the amino acid sequence of SEQ ID NO:119. In some embodiments, the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARDPGLRYFDGGMDV (SEQ ID NO:106); and (b) an antibody light chain variable (VL) domain comprising a 4CDR-L1 sequence comprising the amino acid sequence of QGISSY (SEQ ID NO:107), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of QQLNSFPYT (SEQ ID NO:229). In some embodiments, the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:114, and a VL domain comprising the amino acid sequence of SEQ ID NO:115.

[0010] In some embodiments according to any of the embodiments described herein, the antigen binding site that binds a CD3 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHNNGNTY (SEQ ID NO:218), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130). In some embodiments, the third antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:84, and a VL domain comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHX1NX2X3TY, wherein X1 is E or Q, X2 is A or L, and X3 is Q, R, or F (SEQ ID NO:131), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130). In some embodiments, the CDR-L1 sequence of the VL domain of the antigen binding site that binds a CD3 polypeptide is selected from the group consisting of QSLVHNNANTY (SEQ ID NO:123), QSLVHQNAQTY (SEQ ID NO:124), QSLVHENLQTY (SEQ ID NO:125), QSLVHENLFTY (SEQ ID NO:126), QSLVHENLRTY (SEQ ID NO:127), and QSLVHDNAQTY (SEQ ID NO:128). In some embodiments, the VH domain of the antigen binding site that binds a CD3 polypeptide comprises the amino acid sequence of SEQ ID NO:53 or 138, and the VL domain of the 5antigen binding site that binds a CD3 polypeptide comprises the amino acid sequence of SEQ ID NO:54, 133, 134, 135, 136, or 137.

[0011] In some embodiments according to any of the embodiments described herein, the antigen binding site that binds a CD28 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO:139), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO:140), and a CDR-H3 sequence comprising the amino acid sequence of TRSHYGLDWNFDV (SEQ ID NO:141); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO:142), a CDR-L2 sequence comprising the amino acid sequence of KAS, and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO:144). In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises a VH domain comprising the amino acid sequence of SEQ ID NO:49, and a VL domain comprising the amino acid sequence of SEQ ID NO:50. In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFSLSDYG (SEQ ID NO:212), a CDR-H2 sequence comprising the amino acid sequence of IWAGGGT (SEQ ID NO:213), and a CDR-H3 sequence comprising the amino acid sequence of ARDKGYSYYYSMDY (SEQ ID NO:214); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVEYYVTSL (SEQ ID NO:215), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of QQSRKVPYT (SEQ ID NO:217). In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises a VH domain comprising the amino acid sequence of SEQ ID NO:51, and a VL domain comprising the amino acid sequence of SEQ ID NO:52. In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises a VH domain comprising the amino acid sequence of SEQ ID NO:49, and a VL domain comprising the amino acid sequence of SEQ ID NO:50, and the antigen binding site that binds a CD3 polypeptide comprises a VH domain comprising the amino acid sequence of SEQ ID NO:53 and a VL domain comprising the amino acid sequence of SEQ ID NO:54.

[0012] In some embodiments according to any of the embodiments described herein, the trispecific binding protein comprises four polypeptide chains that form the three antigen 6binding sites, wherein a first polypeptide chain comprises a structure represented by the formula: VL2-L1-VL1-L2-CL [I] and a second polypeptide chain comprises a structure represented by the formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3 [II] and a third polypeptide chain comprises a structure represented by the formula: VH3-CH1-hinge-CH2-CH3[III] and a fourth polypeptide chain comprises a structure represented by the formula: VL3-CL [IV] wherein: VL1is a first immunoglobulin light chain variable domain; VL2 is a second immunoglobulin light chain variable domain; VL3 is a third immunoglobulin light chain variable domain; VH1is a first immunoglobulin heavy chain variable domain; VH2 is a second immunoglobulin heavy chain variable domain; VH3 is a third immunoglobulin heavy chain variable domain; CLis an immunoglobulin light chain constant domain; CH1is an immunoglobulin CH1heavy chain constant domain; CH2 is an immunoglobulin CH2 heavy chain constant domain; CH3is an immunoglobulin CH3heavy chain constant domain; hinge is an immunoglobulin hinge region connecting the CH1and CH2domains; and L1, L2, L3 and L4 are amino acid linkers; wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair; wherein VH1and VL1form one of the three antigen binding sites; wherein VH2 and VL2 form another of the three antigen binding sites; and wherein VH3 and VL3 form another of the three antigen binding sites. In some embodiments, VH1 and VL1form the second antigen binding site that binds a CD28 polypeptide, VH2and VL2form the third antigen binding site that binds a CD3 polypeptide, and VH3and VL3form the first antigen binding site that binds a CD38 polypeptide. In some embodiments, VH1 and VL1 form the third antigen binding site that binds a CD3 polypeptide, VH2 and VL2 form the second antigen binding site that binds a CD28 polypeptide, and VH3and VL3form the first antigen binding site that binds a CD38 polypeptide. In some embodiments, VH1 and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2 and VL2 form the first antigen binding site that binds a CD38 polypeptide, and VH3and VL3form the third 7antigen binding site that binds a CD3 polypeptide. In some embodiments, VH1and VL1form the third antigen binding site that binds a CD3 polypeptide, VH2 and VL2 form the first antigen binding site that binds a CD38 polypeptide, and VH3 and VL3 form the second antigen binding site that binds a CD28 polypeptide. In some embodiments, VH1and VL1form the first antigen binding site that binds a CD38 polypeptide, VH2 and VL2 form the third antigen binding site that binds a CD3 polypeptide, and VH3 and VL3 form the second antigen binding site that binds a CD28 polypeptide. In some embodiments, VH1and VL1form the first antigen binding site that binds a CD38 polypeptide, VH2 and VL2 form the second antigen binding site that binds a CD28 polypeptide, and VH3 and VL3 form the third antigen binding site that binds a CD3 polypeptide. In some embodiments, L1comprises the sequence GQPKAAP (SEQ ID NO:58), L2comprises the sequence TKGPS (SEQ ID NO:57), L3 comprises the amino acid S, and L4 comprises the sequence RT. In some embodiments, L1 comprises the sequence GGGGSGGGGS (SEQ ID NO:55), L2 comprises the sequence GGGGSGGGGS (SEQ ID NO:55), L3is 0 amino acids in length, and L4is 0 amino acids in length. In some embodiments, L1 comprises the sequence GGSGSSGSGG (SEQ ID NO:59), L2 comprises the sequence GGSGSSGSGG (SEQ ID NO:59), L3 is 0 amino acids in length, and L4is 0 amino acids in length. In some embodiments, L1comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:56), L2is 0 amino acids in length, L3 comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:56), and L4 is 0 amino acids in length. In some embodiments, at least one of L1, L2, L3or L4comprises the sequence DKTHT (SEQ ID NO:147). In some embodiments, L1, L2, L3and L4comprise the sequence DKTHT (SEQ ID NO:147). In some embodiments, the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3domains each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A and L235A. In some embodiments, the hinge-CH2-CH3domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3domains, and wherein the hinge-CH2-CH3domains each comprise amino acid substitutions at positions corresponding to positions 233-236 of human IgG4 according to EU Index, wherein the amino acid substitutions are E233P, F234V, L235A, and a deletion at 236. In some embodiments, the hinge-CH2-CH3domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3 domains, and wherein the hinge-CH2- CH3 domains each comprise amino acid substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions 8are S228P and R409K. In some embodiments, the hinge-CH2-CH3domains of the second and the third polypeptide chains are human IgG1 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgG1 according to EU Index, wherein the amino acid substitutions are L234A, L235A, and P329A. In some embodiments, the hinge-CH2- CH3 domains of the second and the third polypeptide chains are human IgG1 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3domains each comprise amino acid substitutions at positions corresponding to positions 298, 299, and 300 of human IgG1 according to EU Index, wherein the amino acid substitutions are S298N, T299A, and Y300S. In some embodiments, the hinge-CH2-CH3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the hinge-CH2-CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the hinge-CH2-CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the hinge-CH2- CH3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, VH1 and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2and VL2form the third antigen binding site that binds a CD3 polypeptide, and VH3 and VL3 form the first antigen binding site that binds a CD38 polypeptide; VH1 comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO:139), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO:140), and a CDR-H3 sequence comprising the amino acid sequence of TRSHYGLDWNFDV (SEQ ID NO:141), and VL1 comprises a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO:142), a CDR-L2 sequence comprising the amino acid sequence of KAS, and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO:144); VH2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR- H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), 9and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122), and VL2 comprises a CDR-L1 sequence comprising the amino acid sequence of QSLVHNNANTY (SEQ ID NO:123), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130); and VH3 comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and VL3 comprises a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). In some embodiments, VH1 and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2 and VL2 form the third antigen binding site that binds a CD3 polypeptide, and VH3and VL3form the first antigen binding site that binds a CD38 polypeptide; wherein VH1 comprises the amino acid sequence of SEQ ID NO:49 and VL1 comprises the amino acid sequence of SEQ ID NO:50; wherein VH2 comprises the amino acid sequence of SEQ ID NO:53 and VL2comprises the amino acid sequence of SEQ ID NO:54; and wherein VH3comprises the amino acid sequence of SEQ ID NO:13 and VL3comprises the amino acid sequence of SEQ ID NO:14. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:62, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:65, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:67, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:68, 10and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:70, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:71, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:148, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:149, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:150, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:151. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:152, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:153, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:154, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:155. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:156, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:157, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:158, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:159. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:160, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:161, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:162, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:163. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:164, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:165, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:166, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:167. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:168, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:169, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:170, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID 11NO:171. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:172, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:173, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:174, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:175. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:176, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:177, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:178, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:179.

[0013] In some embodiments according to any of the embodiments described herein, the CD38 polypeptide is a human CD38 polypeptide. In some embodiments, the CD3 polypeptide is a human CD3 polypeptide. In some embodiments, the CD28 polypeptide is a human CD28 polypeptide. In some embodiments, the PTCL is angioimmunoblastic T- cell lymphoma (AITL), hepatosplenic T-cell lymphoma (HSTL), adult T-cell leukemia / lymphoma (ATLL), extranodal NK / T-cell lymphoma (ENKTCL), mycosis fungoides (MF), Sezary syndrome (SS), anaplastic large cell ALK- lymphoma (ALCL), PTCL-not otherwise specified (NOS), enteropathy-type T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), primary cutaneous CD4+ lymphoproliferative disorder, subcutaneous T-cell lymphoma panniculitis-like (SCTCL), or primary cutaneous ^ ^ T-cell lymphoma. In some embodiments, the PTCL is HSTL, SS, or MF. In some embodiments, the mycosis fungoides is transformed mycosis fungoides (tMF or MFt). In some embodiments, cells of the PTCL express CD38 and / or CD28. In some embodiments, the individual is a human.

[0014] In another aspect, provided herein is an anti-CD38 T-cell engager for use in a method for treating peripheral T-cell lymphoma (PTCL) in an individual in need thereof, said method comprising administering to the individual an effective amount of the anti- CD38 T-cell engager according to any one of the above embodiments.

[0015] In another aspect, provided herein is the use of an anti-CD38 T-cell engager according to any one of the above embodiments in the manufacture of a medicament for treating peripheral T-cell lymphoma (PTCL) in an individual in need thereof.

[0016] In another aspect, provided herein is a kit comprising an anti-CD38 T-cell engager (e.g., an effective amount thereof, optionally in combination with a pharmaceutically acceptable carrier) and instructions for administering to an individual with 12peripheral T-cell lymphoma (PTCL) an effective amount of the anti-CD38 T-cell engager according to the method of any one of the above embodiments.

[0017] It is to be understood that one, some, or all of the properties of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the invention will become apparent to one of skill in the art. These and other embodiments of the invention are further described by the detailed description that follows. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] FIGS.1A-1E show expression and distribution of CD38 (left in each subtype) and CD28 (right in each subtype) through PTCL subtypes by immunochemistry (IHC). Data per entity are expressed according to IHC score. Only cases with scoring for CD38 and CD28 on TC were considered (FIG.1A). Distribution of CD38 (left) and CD28 (right) expression with significant difference between PTCLs with a cytotoxic or non-cytotoxic profile (FIG.1B). Distribution of target expression pattern of CD38 and CD28 in tumour cells (FIG.1C). In FIG.1C, the letters A to J at the top of the figure show the following patterns of CD38 and CD28 expression for each tumor type (to be read from the bottom of the figure to the top): A: CD38+CD28+ and CD38-CD28+ ; B: CD38-CD28- and CD38- CD28+ ; C: CD38+CD28+, CD38-CD28- and CD38-CD28+; D: CD38+CD28+ and CD38+CD28-; E: CD38+CD28+, CD38+CD28- and CD38-CD28+; F: CD38+CD28+, CD38-CD28- and CD38+CD28-; G: CD38-CD28- and CD38+CD28-; H: CD38+CD28+, CD38-CD28-, CD38+CD28- and CD38+CD28-; I: CD38-CD28-, CD38+CD28- and CD38+CD28-; J: CD38-CD28-. Whole blood flow cytometry analysis of CD28 and CD38 surface expression in PTCL-TFH tumor cells (n=8) (FIG.1D) and in Sézary (n=6) or mycosis fungoides tumors cells (n=4) (FIG.1E). In FIG.1D, the letters A to C at the left of the figure show the following patterns of CD38 and CD28 expression for each patient (to be read from the left of the figure to the right): A: CD38-CD28+, CD38+CD28-, CD38+CD28+, CD38-CD28-; B: CD38-CD28+, CD38+CD28+, CD38-CD28-; C: CD38- CD28+, CD38-CD28-. In FIG.1E, the letters A to D at the left of the figure show the following patterns of CD38 and CD28 expression for each patient (to be read from the left of the figure to the right): A: CD38-CD28+, CD38+CD28-, CD38+CD28+, CD38-CD28-; B: CD38-CD28+, CD38-CD28-; C: CD38-CD28+, CD38+CD28+, CD38-CD28-; D: CD38-CD28+, CD38-CD28-. 13

[0019] FIGS.2A-2D show IHC analyses for CD38 and CD28 in four T-cell lymphoma subtypes and multiplex Immunofluorescence for CD38, CD28, and neoplastic cell markers such as PD-1. Representative example of angioimmunoblastic T-cell lymphoma (AITL) (FIG.2A); Sezary Syndrome (SS) (FIG.2B), Anaplastic Large Cell ALK+ Lymphoma (ALCL) (FIG.2C); extranodal NK / T-cell lymphoma (ENKTCL) in skin presentation (FIG. 2D). Shown in each are panels for CD28 IHC, CD38 IHC, and multiplex immunofluorescence IHC (targets as labelled), from left to right. All panels show 20X magnification.

[0020] FIGS.3A-3F show the cytotoxic effect of anti-CD38 / CD28xCD3 trispecific binding protein in different T-lymphoma cell lines (FIGS.3A-3C) or T-leukemia cell lines (FIGS.3D-3F). Cytolysis was also assessed with the indicated wild-type (circles) and null mutant (trispecific containing null mutant CD38 binding site, squares; trispecific containing null mutant CD28 binding site, triangles; and trispecific containing null mutant CD38 and CD28 binding sites, inverted triangles) trispecifics on the different cell lines in similar assays using human PBMCs (E:T = 10:1) as effector cells against the cell lines SEAX (N=3) (FIG.3A), H9 (N=6) (FIG.3B), DERL2 (N=5) (FIG.3C), MOLT4 (N=5) (FIG. 3D), JURKAT (N=4) (FIG.3E) and YT (N=5) (FIG.3F)) at the indicated concentrations. Lysis was evaluated by the percentage of CFSE+ apoptotic viability dye-positive (VD+ ) cells. Mean of data from different experiments with different donors are shown.

[0021] FIGS.4A-4E show a summary of IHC staining results for CD3, CD38 and CD28 through T-Cell lymphoma entities case by case (n=261). Shown are the IHC staining results for each marker (expressed as a percentage of positive cells in the sample) as well as intensity, proportion (%), and CD38 score, for each case. Cases are grouped by diagnosis; shown are cutaneous anaplastic large cell lymphoma (cALCL; FIG.4A top panel), lymphomatoid papulosis (FIG.4A top panel), mycosis fungoides (FIG.4A middle panel), transformed mycosis fungoides (MFt; FIG.4A bottom panel), Sezary syndrome (FIG.4B), primary cutaneous CD4+ TCL (FIG.4B), SCTCL (Subcutaneous T-cell lymphoma, panniculitis-like) (FIG.4B), Primary cutaneous γδ T-cell lymphoma (FIG.4B), extranodal NK / T-cell lymphoma (ENKTCL; FIG.4C top panel), enteropathy associated T-cell lymphoma (FIG.4C middle panel), MEITL (Monomorphic epitheliotropic intestinal T-cell lymphoma) (FIG.4C middle panel), hepatosplenic T-cell lymphoma (HSTL; FIG.4C bottom panel), angio-immunoblastic T-cell lymphoma (AITL; FIG.4D top panel), PTCL not otherwise specified (FIG.4D bottom panel), anaplastic lymphoma kinase (ALK)- negative anaplastic large cell lymphoma (ALCL; FIG.4E), anaplastic lymphoma kinase 14(ALK)-positive ALCL (FIG.4E), breast implant ALCL (FIG.4E), and adult T-cell leukemia / lymphoma (ATLL; FIG.4E).

[0022] FIGS.5A & 5B show the cytotoxic effect of anti-CD38 / CD28xCD3 trispecific binding protein in two different T-leukemia cell lines (YTLT; FIG.5A, and MOLT4LT; FIG.5B) as target and with T-lymphocytes as effectors. Sorted CD3+ T-lymphocytes were used as effectors. Cytolysis was also assessed with wild-type and null mutant trispecific binding proteins on the different cell lines in similar assays using human sorted lymphocytes (E:T = 10:1). DETAILED DESCRIPTION

[0023] The disclosure provides, inter alia, methods for treating PTCLs with an anti- CD38 T-cell engager, as well as uses, compositions, and kits related thereto. These are based at least in part on the demonstration herein that anti-CD38 T-cell engagers (e.g., an anti-CD38 / CD28xCD3 trispecific binding protein) are able to induce cytotoxic lysis of various PTCL cell lines, including those from Sezary syndrome, MF (e.g., transformed MF), and hepatosplenic T-cell lymphoma in the presence of human T cells. I. General Definitions

[0024] As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings. Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. As used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and the like.

[0025] It is understood that aspects and embodiments of the present disclosure described herein include “comprising,” “consisting,” and “consisting essentially of” aspects and embodiments.

[0026] The term "polynucleotide" as used herein refers to single-stranded or double- stranded nucleic acid polymers of at least 10 nucleotides in length. In certain embodiments, the nucleotides comprising the polynucleotide can be ribonucleotides or deoxyribonucleotides or a modified form of either type of nucleotide. Such modifications 15include base modifications such as bromuridine, ribose modifications such as arabinoside and 2',3'-dideoxyribose, and internucleotide linkage modifications such as phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phoshoraniladate and phosphoroamidate. The term "polynucleotide" specifically includes single-stranded and double-stranded forms of DNA.

[0027] An "isolated polynucleotide" is a polynucleotide of genomic, cDNA, or synthetic origin or some combination thereof, which: (1) is not associated with all or a portion of a polynucleotide in which the isolated polynucleotide is found in nature, (2) is linked to a polynucleotide to which it is not linked in nature, or (3) does not occur in nature as part of a larger sequence.

[0028] An "isolated polypeptide" is one that: (1) is free of at least some other polypeptides with which it would normally be found, (2) is essentially free of other polypeptides from the same source, e.g., from the same species, (3) is expressed by a cell from a different species, (4) has been separated from at least about 50 percent of polynucleotides, lipids, carbohydrates, or other materials with which it is associated in nature, (5) is not associated (by covalent or noncovalent interaction) with portions of a polypeptide with which the "isolated polypeptide" is associated in nature, (6) is operably associated (by covalent or noncovalent interaction) with a polypeptide with which it is not associated in nature, or (7) does not occur in nature. Such an isolated polypeptide can be encoded by genomic DNA, cDNA, mRNA or other RNA, of synthetic origin, or any combination thereof. Preferably, the isolated polypeptide is substantially free from polypeptides or other contaminants that are found in its natural environment that would interfere with its use (therapeutic, diagnostic, prophylactic, research or otherwise).

[0029] Naturally occurring antibodies typically comprise a tetramer. Each such tetramer is typically composed of two identical pairs of polypeptide chains, each pair having one full-length "light" chain (typically having a molecular weight of about 25 kDa) and one full-length "heavy" chain (typically having a molecular weight of about 50-70 kDa). The terms "heavy chain" and "light chain" as used herein refer to any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity for a target antigen. The amino-terminal portion of each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids that typically is responsible for antigen recognition. The carboxy-terminal portion of each chain typically defines a constant domain responsible for effector function. Thus, in a naturally occurring antibody, a full-length heavy chain immunoglobulin polypeptide includes a variable domain 16(VH) and three constant domains (CH1, CH2, and CH3), wherein the VHdomain is at the amino-terminus of the polypeptide and the CH3 domain is at the carboxyl-terminus, and a full-length light chain immunoglobulin polypeptide includes a variable domain (VL) and a constant domain (CL), wherein the VLdomain is at the amino-terminus of the polypeptide and the CL domain is at the carboxyl-terminus.

[0030] Human light chains are typically classified as kappa and lambda light chains, and human heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including, but not limited to, IgG1, IgG2, IgG3, and IgG4. IgM has subclasses including, but not limited to, IgM1 and IgM2. IgA is similarly subdivided into subclasses including, but not limited to, IgA1 and IgA2. Within full-length light and heavy chains, the variable and constant domains typically are joined by a "J" region of about 12 or more amino acids, with the heavy chain also including a "D" region of about 10 more amino acids. See, e.g., FUNDAMENTAL IMMUNOLOGY (Paul, W., ed., Raven Press, 2nd ed., 1989), which is incorporated by reference in its entirety for all purposes. The variable regions of each light / heavy chain pair typically form an antigen binding site. The variable domains of naturally occurring antibodies typically exhibit the same general structure of relatively conserved framework regions (FR) joined by three hypervariable regions, also called complementarity determining regions or CDRs. The CDRs from the two chains of each pair typically are aligned by the framework regions, which may enable binding to a specific epitope. From the amino-terminus to the carboxyl-terminus, both light and heavy chain variable domains typically comprise the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0031] The term "CDR set" refers to a group of three CDRs that occur in a single variable region capable of binding the antigen. The exact boundaries of these CDRs have been defined differently according to different systems. The system described by Kabat (Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST (National Institutes of Health, Bethesda, Md. (1987) and (1991)) not only provides an unambiguous residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may be referred to as Kabat CDRs. Chothia and coworkers (Chothia and Lesk, 1987, J. Mol. Biol.196: 901-17; Chothia et al., 1989, Nature 342: 877-83) found that certain sub-portions within Kabat CDRs adopt nearly identical peptide backbone conformations, despite having great diversity at the level of amino acid sequence. These sub-portions were designated as L1, 17L2, and L3 or H1, H2, and H3 where the "L" and the "H" designates the light chain and the heavy chain regions, respectively. These regions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs. Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan, 1995, FASEB J.9: 133- 39; MacCallum, 1996, J. Mol. Biol.262(5): 732-45; and Lefranc, 2003, Dev. Comp. Immunol.27: 55-77. Still other CDR boundary definitions may not strictly follow one of the herein systems, but will nonetheless overlap with the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding. The methods used herein may utilize CDRs defined according to any of these systems, although certain embodiments use Kabat or Chothia defined CDRs. Identification of predicted CDRs using the amino acid sequence is well known in the field, such as in Martin, A.C. "Protein sequence and structure analysis of antibody variable domains," In Antibody Engineering, Vol.2. Kontermann R., Dübel S., eds. Springer-Verlag, Berlin, p. 33–51 (2010). The amino acid sequence of the heavy and / or light chain variable domain may be also inspected to identify the sequences of the CDRs by other conventional methods, e.g., by comparison to known amino acid sequences of other heavy and light chain variable regions to determine the regions of sequence hypervariability. The numbered sequences may be aligned by eye, or by employing an alignment program such as one of the CLUSTAL suite of programs, as described in Thompson, 1994, Nucleic Acids Res.22: 4673-80. Molecular models are conventionally used to correctly delineate framework and CDR regions and thus correct the sequence-based assignments.

[0032] In some embodiments, CDR / FR definition in an immunoglobulin light or heavy chain is to be determined based on IMGT definition (Lefranc et al. Dev. Comp. Immunol., 2003, 27(1):55-77; www.imgt.org).

[0033] The term "Fc" as used herein refers to a molecule comprising the sequence of a non-antigen-binding fragment resulting from digestion of an antibody or produced by other means, whether in monomeric or multimeric form, and can contain the hinge region. The original immunoglobulin source of the native Fc is preferably of human origin and can be any of the immunoglobulins. Fc molecules are made up of monomeric polypeptides that can be linked into dimeric or multimeric forms by covalent (i.e., disulfide bonds) and non- covalent association. The number of intermolecular disulfide bonds between monomeric subunits of native Fc molecules ranges from 1 to 4 depending on class (e.g., IgG, IgA, and IgE) or subclass (e.g., IgG1, IgG2, IgG3, IgA1, IgGA2, and IgG4). One example of a Fc is 18a disulfide-bonded dimer resulting from papain digestion of an IgG. The term "native Fc" as used herein is generic to the monomeric, dimeric, and multimeric forms.

[0034] A F(ab) fragment typically includes one light chain and the VH and CH1 domains of one heavy chain, wherein the VH-CH1heavy chain portion of the F(ab) fragment cannot form a disulfide bond with another heavy chain polypeptide. As used herein, a F(ab) fragment can also include one light chain containing two variable domains separated by an amino acid linker and one heavy chain containing two variable domains separated by an amino acid linker and a CH1 domain.

[0035] A F(ab') fragment typically includes one light chain and a portion of one heavy chain that contains more of the constant region (between the CH1and CH2domains), such that an interchain disulfide bond can be formed between two heavy chains to form a F(ab')2molecule.

[0036] A "recombinant" molecule is one that has been prepared, expressed, created, or isolated by recombinant means.

[0037] The term "anti-CD38 T-cell engager" as used herein refers to a multispecific (e.g., bispecific or trispecific) binding molecule that is able to specifically bind CD38 (e.g., expressed on the surface of a target cell) as well as one or more T cell-expressed surface proteins, including without limitation CD3 and / or CD28.

[0038] The term "binding protein" as used herein refers to a non-naturally occurring (or recombinant or engineered) molecule that specifically binds to at least one target antigen.

[0039] The term "bispecific binding protein" refers to a binding protein that specifically binds to two different antigen targets. In some embodiments, a bispecific binding protein binds to two different antigens. For example, the bispecific binding protein can comprise two antigen binding sites, each antigen binding site specifically binding to a different target antigen (e.g., CD38 and CD3).

[0040] The term "trispecific binding protein" refers to a binding protein that specifically binds to three different antigen targets. In some embodiments, a trispecific binding protein binds to three different antigens. For example, the trispecific binding protein can comprise three antigen binding sites, each antigen binding site specifically binding to a different target antigen (e.g., CD38, CD28, and CD3).

[0041] The term "trivalent binding protein" refers to a binding protein that has three antigen binding sites. In particular embodiments, the trivalent binding protein can bind to three antigen targets. For example, the trivalent binding protein can comprise three antigen binding sites, each antigen binding site specifically binding to a different target antigen 19(e.g., CD38, CD28, and CD3). In some embodiments, a binding protein can be trispecific and trivalent.

[0042] One embodiment of the disclosure provides binding proteins having biological and immunological specificity to two or three target antigens. Another embodiment of the disclosure provides nucleic acid molecules comprising nucleotide sequences encoding polypeptide chains that form such binding proteins. Another embodiment of the disclosure provides expression vectors comprising nucleic acid molecules comprising nucleotide sequences encoding polypeptide chains that form such binding proteins. Yet another embodiment of the disclosure provides host cells that express such binding proteins (i.e., comprising nucleic acid molecules or vectors encoding polypeptide chains that form such binding proteins).

[0043] The term "swapability" as used herein refers to the interchangeability of variable domains within the binding protein format and with retention of folding and ultimate binding affinity. "Full swapability" refers to the ability to swap the order of both VH1and VH2 domains, and therefore the order of VL1 and VL2 domains, in the polypeptide chain of formula I or the polypeptide chain of formula II (i.e., to reverse the order) while maintaining full functionality of the binding protein as evidenced by the retention of binding affinity. Furthermore, it should be noted that the designations VHand VLrefer only to the domain's location on a particular protein chain in the final format. For example, VH1 and VH2could be derived from VL1and VL2domains in parent antibodies and placed into the VH1and VH2positions in the binding protein. Likewise, VL1and VL2could be derived from VH1 and VH2 domains in parent antibodies and placed in the VH1 and VH2 positions in the binding protein. Thus, the VH and VL designations refer to the present location and not the original location in a parent antibody. VHand VLdomains are therefore "swappable."

[0044] The term "antigen" or "target antigen" or "antigen target" as used herein refers to a molecule or a portion of a molecule that is capable of being bound by a binding protein, and additionally is capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. A target antigen may have one or more epitopes. With respect to each target antigen recognized by a binding protein, the binding protein is capable of competing with an intact antibody that recognizes the target antigen.

[0045] "CD38" is a cluster of differentiation 38 polypeptide and is a glycoprotein found on the surface of many immune cells. In some embodiments, an anti-CD38 T-cell engager of the present disclosure binds the extracellular domain of one or more CD38 polypeptide(s). Exemplary CD38 extracellular domain polypeptide sequences include, but 20are not limited to, the extracellular domain of human CD38 (e.g., as represented by SEQ ID NO:1) and the extracellular domain of cynomolgus monkey CD38 (e.g., as represented by SEQ ID NO:30). In some embodiments, the CD38 polypeptide is a human CD38 polypeptide.

[0046] "CD28" is cluster of differentiation 28 polypeptide and is a T-cell surface protein that provides co-stimulatory signals for T-cell activation and survival. CD28 polynucleotide and polypeptide sequences are known in the art; see, e.g., NCBI Gene ID No.940 and NP_001230006. In some embodiments, the CD28 polypeptide is a human CD28 polypeptide.

[0047] "CD3" is cluster of differentiation factor 3 polypeptide and is a T-cell surface protein that is typically part of the T cell receptor (TCR) complex formed by TCR alpha / beta or gamma / delta heterodimers in complex with CD3-epsilon, -gamma, -delta, and -zeta. CD3 polynucleotide and polypeptide sequences are known in the art; see, e.g., NCBI Gene ID No.915 and NP_000723 for CD3-delta, NCBI Gene ID No.916 and NP_000724 for CD3-epsilon, NCBI Gene ID No.917 and NP_000064 for CD3-gamma, and NCBI Gene ID No.919 and NP_000725 for CD3-zeta. In some embodiments, the CD3 polypeptide is a human CD3 polypeptide.

[0048] An "isolated" binding protein is one that has been identified and separated and / or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would interfere with diagnostic or therapeutic uses for the binding protein, and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the binding protein will be purified: (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated binding proteins include the binding protein in situ within recombinant cells since at least one component of the binding protein's natural environment will not be present.

[0049] The terms "substantially pure" or "substantially purified" as used herein refer to a compound or species that is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition). In some embodiments, a substantially purified fraction is a composition wherein the species comprises at least about 50% (on a molar basis) of all macromolecular species present. In 21other embodiments, a substantially pure composition will comprise more than about 80%, 85%, 90%, 95%, or 99% of all macromolar species present in the composition. In still other embodiments, the species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.

[0050] The term "epitope" includes any determinant, preferably a polypeptide determinant, capable of specifically binding to an immunoglobulin or T-cell receptor. In certain embodiments, epitope determinants include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl groups, or sulfonyl groups, and, in certain embodiments, may have specific three-dimensional structural characteristics and / or specific charge characteristics. An epitope is a region of an antigen that is bound by an antibody or binding protein. In certain embodiments, a binding protein is said to specifically bind an antigen when it preferentially recognizes its target antigen in a complex mixture of proteins and / or macromolecules. In some embodiments, a binding protein is said to specifically bind an antigen when the equilibrium dissociation constant is ≤ 10-8M, more preferably when the equilibrium dissociation constant is ≤ 10-9M, and most preferably when the dissociation constant is ≤ 10-10M.

[0051] The dissociation constant (KD) of a binding protein can be determined, for example, by surface plasmon resonance. Generally, surface plasmon resonance analysis measures real-time binding interactions between ligand (a target antigen on a biosensor matrix) and analyte (a binding protein in solution) by surface plasmon resonance (SPR) using the BIAcore system (Pharmacia Biosensor; Piscataway, NJ). Surface plasmon analysis can also be performed by immobilizing the analyte (binding protein on a biosensor matrix) and presenting the ligand (target antigen). The term "KD," as used herein refers to the dissociation constant of the interaction between a particular binding protein and a target antigen.

[0052] The term "binds to" as used herein in reference to a binding protein refers to the ability of a binding protein or an antigen-binding fragment thereof to bind to an antigen containing an epitope with an Kd of at least about 1 x 10-6M, 1 x 10-7M, 1 x 10-8M, 1 x 10-9M, 1 x 10-10M, 1 x 10-11M, 1 x 10-12M, or more, and / or to bind to an epitope with an affinity that is at least two-fold greater than its affinity for a nonspecific antigen. In some embodiments, a binding protein of the present disclosure binds to two or more antigens, e.g., a human and a cynomologus monkey CD38 polypeptide. 22

[0053] In some embodiments, an antigen binding domain and / or binding protein of the present disclosure “cross reacts” with human and cynomolgus monkey CD38 polypeptides, e.g., CD38 extracellular domains, such as SEQ ID NO:1 (human CD38 isoform A), SEQ ID NO:105 (human CD38 isoform E) and SEQ ID NO:30 (cynomolgus monkey CD38). A binding protein binding to antigen 1 (Ag1) is “cross-reactive” to antigen 2 (Ag2) when the EC50s are in a similar range for both antigens. In the present application, a binding protein binding to Ag1 is cross-reactive to Ag2 when the ratio of affinity of Ag2 to affinity of Ag1 is equal or less than 10 (for instance 5, 2, 1 or 0.5), affinities being measured with the same method for both antigens.

[0054] A binding protein binding to Ag1 is “not significantly cross-reactive” to Ag2 when the affinities are very different for the two antigens. Affinity for Ag2 may not be measurable if the binding response is too low. In the present application, a binding protein binding to Ag1 is not significantly cross-reactive to Ag2, when the binding response of the binding protein to Ag2 is less than 5% of the binding response of the same binding protein to Ag1 in the same experimental setting and at the same antibody concentration. In practice, the binding protein concentration used can be the EC50or the concentration required to reach the saturation plateau obtained with Ag1.

[0055] The term "linker" as used herein refers to one or more amino acid residues inserted between immunoglobulin domains to provide sufficient mobility for the domains of the light and heavy chains to fold into cross over dual variable region immunoglobulins. A linker is inserted at the transition between variable domains or between variable and constant domains, respectively, at the sequence level. The transition between domains can be identified because the approximate size of the immunoglobulin domains are well understood. The precise location of a domain transition can be determined by locating peptide stretches that do not form secondary structural elements such as beta-sheets or alpha-helices as demonstrated by experimental data or as can be assumed by techniques of modeling or secondary structure prediction. The linkers described herein are referred to as L1, which is located on the light chain between the C-terminus of the VL2and the N- terminus of the VL1 domain; and L2, which is located on the light chain between the C- terminus of the VL1 and the N-terminus of the CL domain. The heavy chain linkers are known as L3, which is located between the C-terminus of the VH1and the N-terminus of the VH2 domain; and L4, which is located between the C-terminus of the VH2 and the N- terminus of the CH1 domain. 23

[0056] The term "vector" as used herein refers to any molecule (e.g., nucleic acid, plasmid, or virus) that is used to transfer coding information to a host cell. The term "vector" includes a nucleic acid molecule that is capable of transporting another nucleic acid to which it has been linked. One type of vector is a "plasmid," which refers to a circular double-stranded DNA molecule into which additional DNA segments may be inserted. Another type of vector is a viral vector, wherein additional DNA segments may be inserted into the viral genome. Certain vectors are capable of autonomous replication in a host cell into which they are introduced (e.g., bacterial vectors having a bacterial origin of replication and episomal mammalian vectors). Other vectors (e.g., non-episomal mammalian vectors) can be integrated into the genome of a host cell upon introduction into the host cell and thereby are replicated along with the host genome. In addition, certain vectors are capable of directing the expression of genes to which they are operatively linked. Such vectors are referred to herein as "recombinant expression vectors" (or simply, "expression vectors"). In general, expression vectors of utility in recombinant DNA techniques are often in the form of plasmids. The terms "plasmid" and "vector" may be used interchangeably herein, as a plasmid is the most commonly used form of vector. However, the disclosure is intended to include other forms of expression vectors, such as viral vectors (e.g., replication defective retroviruses, adenoviruses, and adeno-associated viruses), which serve equivalent functions.

[0057] The phrase "recombinant host cell" (or "host cell") as used herein refers to a cell into which a recombinant expression vector has been introduced. A recombinant host cell or host cell is intended to refer not only to the particular subject cell, but also to the progeny of such a cell. Because certain modifications may occur in succeeding generations due to either mutation or environmental influences, such progeny may not, in fact, be identical to the parent cell, but such cells are still included within the scope of the term "host cell" as used herein. A wide variety of host cell expression systems can be used to express the binding proteins, including bacterial, yeast, baculoviral, and mammalian expression systems (as well as phage display expression systems). An example of a suitable bacterial expression vector is pUC19. To express a binding protein recombinantly, a host cell is transformed or transfected with one or more recombinant expression vectors carrying DNA fragments encoding the polypeptide chains of the binding protein such that the polypeptide chains are expressed in the host cell and, preferably, secreted into the medium in which the host cells are cultured, from which medium the binding protein can be recovered. 24

[0058] The term "transformation" as used herein refers to a change in a cell's genetic characteristics, and a cell has been transformed when it has been modified to contain a new DNA. For example, a cell is transformed where it is genetically modified from its native state. Following transformation, the transforming DNA may recombine with that of the cell by physically integrating into a chromosome of the cell, or may be maintained transiently as an episomal element without being replicated, or may replicate independently as a plasmid. A cell is considered to have been stably transformed when the DNA is replicated with the division of the cell. The term "transfection" as used herein refers to the uptake of foreign or exogenous DNA by a cell, and a cell has been "transfected" when the exogenous DNA has been introduced inside the cell membrane. A number of transfection techniques are well known in the art. Such techniques can be used to introduce one or more exogenous DNA molecules into suitable host cells.

[0059] The term "naturally occurring" as used herein and applied to an object refers to the fact that the object can be found in nature and has not been manipulated by man. For example, a polynucleotide or polypeptide that is present in an organism (including viruses) that can be isolated from a source in nature and that has not been intentionally modified by man is naturally-occurring. Similarly, "non-naturally occurring" as used herein refers to an object that is not found in nature or that has been structurally modified or synthesized by man.

[0060] As used herein, the twenty conventional amino acids and their abbreviations follow conventional usage. Stereoisomers (e.g., D-amino acids) of the twenty conventional amino acids; unnatural amino acids and analogs such as ^-, ^-disubstituted amino acids, N- alkyl amino acids, lactic acid, and other unconventional amino acids may also be suitable components for the polypeptide chains of the binding proteins. Examples of unconventional amino acids include: 4-hydroxyproline, ^-carboxyglutamate, ^-N,N,N- trimethyllysine, ^-N-acetyllysine, O-phosphoserine, N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine, ^-N-methylarginine, and other similar amino acids and imino acids (e.g., 4-hydroxyproline). In the polypeptide notation used herein, the left-hand direction is the amino terminal direction and the right-hand direction is the carboxyl- terminal direction, in accordance with standard usage and convention.

[0061] Naturally occurring residues may be divided into classes based on common side chain properties: (1) hydrophobic: Met, Ala, Val, Leu, Ile, Phe, Trp, Tyr, Pro; 25(2) polar hydrophilic: Arg, Asn, Asp, Gln, Glu, His, Lys, Ser, Thr ; (3) aliphatic: Ala, Gly, Ile, Leu, Val, Pro; (4) aliphatic hydrophobic: Ala, Ile, Leu, Val, Pro; (5) neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (6) acidic: Asp, Glu; (7) basic: His, Lys, Arg; (8) residues that influence chain orientation: Gly, Pro; (9) aromatic: His, Trp, Tyr, Phe; and (10) aromatic hydrophobic: Phe, Trp, Tyr.

[0062] Conservative amino acid substitutions may involve exchange of a member of one of these classes with another member of the same class. Non-conservative substitutions may involve the exchange of a member of one of these classes for a member from another class.

[0063] A skilled artisan will be able to determine suitable variants of the polypeptide chains of the binding proteins using well-known techniques. For example, one skilled in the art may identify suitable areas of a polypeptide chain that may be changed without destroying activity by targeting regions not believed to be important for activity. Alternatively, one skilled in the art can identify residues and portions of the molecules that are conserved among similar polypeptides. In addition, even areas that may be important for biological activity or for structure may be subject to conservative amino acid substitutions without destroying the biological activity or without adversely affecting the polypeptide structure.

[0064] The terms "patient," “individual,” or “subject” as used herein include humans and animals (e.g., mammals, such as dogs, pigs, horses, cats, cows, etc.).

[0065] The terms "treatment" or "treat" as used herein refer to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those having a disorder as well as those prone to have the disorder or those in which the disorder is to be prevented. In particular embodiments, binding proteins can be used to treat humans with cancer, or humans susceptible to cancer, or ameliorate cancer in a human subject. The binding proteins can also be used to prevent cancer in a human patient. In particular embodiments, the cancer is a PTCL.

[0066] The terms "pharmaceutical composition" or "therapeutic composition" as used herein refer to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a patient. 26

[0067] The term "pharmaceutically acceptable carrier" or "physiologically acceptable carrier" as used herein refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of a binding protein.

[0068] The terms "effective amount" and "therapeutically effective amount" when used in reference to a pharmaceutical composition comprising one or more binding proteins refer to an amount or dosage sufficient to produce a desired therapeutic result. More specifically, a therapeutically effective amount is an amount of a binding protein sufficient to inhibit, for some period of time, one or more of the clinically defined pathological processes associated with the condition being treated. The effective amount may vary depending on the specific binding protein that is being used, and also depends on a variety of factors and conditions related to the patient being treated and the severity of the disorder. For example, if the binding protein is to be administered in vivo, factors such as the age, weight, and health of the patient as well as dose response curves and toxicity data obtained in preclinical animal work would be among those factors considered. The determination of an effective amount or therapeutically effective amount of a given pharmaceutical composition is well within the ability of those skilled in the art.

[0069] One embodiment of the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a binding protein. II. Methods and Uses

[0070] Certain aspects of the present disclosure relate to methods of treating peripheral T-cell lymphoma (PTCL) in an individual, e.g., in need thereof. In some embodiments, the methods comprise administering to the individual an effective amount of an anti-CD38 T- cell engager of the present disclosure. In some embodiments, the individual is a human.

[0071] In some embodiments, the individual has or has been diagnosed with PTCL. In some embodiments, the PTCL is angioimmunoblastic T-cell lymphoma (AITL), hepatosplenic T-cell lymphoma (HSTL), adult T-cell leukemia / lymphoma (ATLL), extranodal NK / T-cell lymphoma (ENKTCL), mycosis fungoides (MF), Sezary syndrome (SS), anaplastic large cell ALK- lymphoma (ALCL), PTCL-not otherwise specified (NOS), enteropathy-type T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), primary cutaneous CD4+ lymphoproliferative disorder, subcutaneous T-cell lymphoma panniculitis-like (SCTCL), or primary cutaneous ^ ^ T-cell lymphoma. In 27some embodiments, the MF is transformed MF. In certain embodiments, the PTCL is HSTL, Sezary syndrome, or MF (e.g., transformed MF).

[0072] In some embodiments, cells of the PTCL express CD38 and / or CD28. In some embodiments, cells of the PTCL express CD38 and CD28. In some embodiments, cells of the PTCL express CD38. In some embodiments, cells of the PTCL express CD28. In some embodiments, expression of CD38 and / or CD28 by cells of the PTCL can be measured in a sample from the PTCL, e.g., a sample comprising PTCL cells. In some embodiments, a sample obtained from the PTCL of the individual comprises cells (e.g., PTCL cells) that express CD38 and / or CD28. In some embodiments, the methods of the present disclosure further comprise measuring expression of CD38 and / or CD28 in a sample obtained from the individual, e.g., a sample comprising PTCL cells. In some embodiments, the methods of the present disclosure further comprise obtaining a sample from the individual, e.g., a sample comprising PTCL cells. In some embodiments, the sample is from a tumor biopsy. A variety of methods known in the art are suitable for measuring expression of CD38 and / or CD28 in a sample, including without limitation immunohistochemistry (IHC), immunofluorescence (IF) microscopy, and flow cytometry.

[0073] Any of the anti-CD38 T-cell engagers, bispecific binding proteins, or trispecific binding proteins described herein may find use in the methods, uses, kits, and compositions of the present disclosure. Anti-CD38 T-cell engagers (TCEs)

[0074] Certain aspects of the present disclosure relate to anti-CD38 T-cell engagers. In some embodiments, the anti-CD38 T-cell engager binds to human CD38, e.g., expressed on the surface of a cell (such as a PTCL cell). In some embodiments, the anti-CD38 T-cell engager binds to human CD28, e.g., expressed on the surface of a cell (such as a PTCL cell). In some embodiments, the anti-CD38 T-cell engager binds to human CD3, e.g., expressed on the surface of a cell (such as a PTCL cell). In some embodiments, the anti- CD38 T-cell engager binds to human CD38 and human CD3. In some embodiments, the anti-CD38 T-cell engager binds to human CD38, human CD28, and human CD3. Exemplary human CD38, CD28, and CD3 polypeptides are known in the art and disclosed herein.

[0075] In some embodiments, the anti-CD38 T-cell engager is a bispecific binding protein (e.g., a bispecific antibody) comprising a first antigen binding site that specifically binds a CD38 polypeptide and a second antigen binding site that specifically binds a CD3 28polypeptide. For example, the anti-CD38 T-cell engager can be a bispecific antibody comprising at least a first antigen binding domain that specifically binds a CD38 polypeptide and at least a second antigen binding domain that specifically binds a CD3 polypeptide.

[0076] In some embodiments, the anti-CD38 T-cell engager is a trispecific binding protein. In some embodiments, the binding proteins comprise an antigen binding site that specifically binds a CD38 polypeptide, an antigen binding site that specifically binds a CD28 polypeptide, and an antigen binding site that specifically binds a CD3 polypeptide. In some embodiments, a binding protein induces apoptosis of a CD38+ cell. In some embodiments, a binding protein recruits a T cell to a CD38+ cell and optionally activates the T cell (e.g., though TCR stimulation and / or costimulation). Any of the anti-CD38 T- cell engagers described herein may find use in the methods, uses, kits, and compositions of the present disclosure. Anti-CD38 antigen binding sites

[0077] Exemplary antigen binding sites that specifically bind CD38 polypeptides and may find use in the anti-CD38 T-cell engagers of the present disclosure are described infra. Any of the anti-CD38 antigen binding sites and / or trispecific binding proteins described in International Appl. No. WO2019 / 074973 may find use in the methods, uses, kits, and compositions of the present disclosure. In some embodiments, the CD38 polypeptide is a human CD38 polypeptide, also known as ADPRC1. Human CD38 polypeptides are known in the art and include, without limitation, the polypeptide represented by NCBI Accession Number NP_001766.2, or a polypeptide produced from NCBI Gene ID Number 952. In some embodiments, the antigen binding site binds a human CD38 polypeptide, a non- human primate (e.g., cynomolgus monkey) CD38 polypeptide, or a human CD38 polypeptide and a non-human primate (e.g., cynomolgus monkey) CD38 polypeptide.

[0078] In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31) or GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32) or IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34) or QSVSSYGQGF (SEQ ID NO:39), a 29CDR-L2 sequence comprising the amino acid sequence of LAS or GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31) or GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32) or IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34) or QSVSSYGQG (SEQ ID NO:132), a CDR-L2 sequence comprising the amino acid sequence of LAS or GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: 1, 2, 3, 4, 5, or 6 CDRs from an antibody VH and / or VL domain sequence of an antigen binding site (e.g., mAb1, mAb2, mAb3, mAb4, mAb5, mAb6, hhy992, hu5739, hu6284, hhy1195, hhy1370, hyb5739, or hyb6284) as shown in Table A or B. In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: 1, 2, 3, 4, 5, or 6 CDRs from an antibody VH and / or VL domain sequence of a trispecific binding protein shown in Table E1 or E2.

[0079] In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31) or GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32) or IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34) or QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of LAS or GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).

[0080] In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); 30or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34), a CDR-L2 sequence comprising the amino acid sequence of LAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34), a CDR-L2 sequence comprising the amino acid sequence of LAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).

[0081] In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).

[0082] In some embodiments, the VH domain comprises the sequence, from N- terminus to C-terminus, FR1—CDR-H1—FR2—CDR-H2—FR3—CDR-H3—FR4; where FR1 comprises the sequence QVQLVQSGAEVVKPGASVKVSCKAS (SEQ ID NO:86), 31QVQLVQSGAEVVKSGASVKVSCKAS (SEQ ID NO:87), or QVQLVQSGAEVVKPGASVKMSCKAS (SEQ ID NO:88); where FR2 comprises the sequence MHWVKEAPGQRLEWIGY (SEQ ID NO:90) or MHWVKEAPGQGLEWIGY (SEQ ID NO:91); where FR3 comprises the sequence NYNQKFQGRATLTADTSASTAYMELSSLRSEDTAVYFC (SEQ ID NO:93) or NYNQKFQGRATLTADTSASTAYMEISSLRSEDTAVYFC (SEQ ID NO:94); and where FR4 comprises the sequence WGQGTLVTVSS (SEQ ID NO:96). In some embodiments, the VL domain comprises the sequence, from N-terminus to C-terminus, FR1—CDR-L1— FR2—CDR-L2—FR3—CDR-L3—FR4; where FR1 comprises the sequence DIVLTQSPATLSLSPGERATISCRAS (SEQ ID NO:97); where FR2 comprises the sequence MHWYQQKPGQPPRLLIY (SEQ ID NO:99); where FR3 comprises the sequence SRATGIPARFSGSGSGTDFTLTISPLEPEDFAVYYC (SEQ ID NO:101); and where FR4 comprises the sequence FGGGTKLEIK (SEQ ID NO:103).

[0083] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:5; and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:6. In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:17; and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:18. In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:21; and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at 32least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:18. In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:23; and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:18. In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:13; and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:14.

[0084] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:5; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:6. In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:17; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:18. In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 3391%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:21; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:18. In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:23; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:18. In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:13; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:14.

[0085] In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:5; and the VL domain comprises the amino acid sequence of SEQ ID NO:6. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:17; and the VL domain comprises the amino acid sequence of SEQ ID NO:18. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:21; and the VL domain comprises the amino acid sequence of SEQ ID NO:18. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:23; and the VL domain comprises the amino acid sequence of SEQ ID NO:18. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:13; and the VL domain comprises the amino acid sequence of SEQ ID NO:14.

[0086] In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence 34comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARMFRGAFDY (SEQ ID NO:43); or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO:44), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO:46). In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARMFRGAFDY (SEQ ID NO:43); and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO:44), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO:46).

[0087] In some embodiments, the VH domain comprises the sequence, from N- terminus to C-terminus, FR1—CDR-H1—FR2—CDR-H2—FR3—CDR-H3—FR4; where FR1 comprises the sequence QVQLVESGGGVVQPGRSLRLSCAAS (SEQ ID NO:89); where FR2 comprises the sequence MHWVRQAPGKGLEWVAV (SEQ ID NO:92); where FR3 comprises the sequence YYADSVKGRFTISGDNSKNTLYLQMNSLRAEDTAVYYC (SEQ ID NO:95); and where FR4 comprises the sequence WGQGTLVTVSS (SEQ ID NO:96). In some embodiments, the VL domain comprises the sequence, from N-terminus to C-terminus, FR1—CDR-L1—FR2—CDR-L2—FR3—CDR-L3—FR4; where FR1 comprises the sequence AIQMTQSPSSLSASVGDRVTITCRAS (SEQ ID NO:98); where FR2 comprises the sequence GWYQQKPGKAPKLLIY (SEQ ID NO:100); where FR3 comprises the sequence SLQSGVPSRFSGSGSGTDFTLTISGLQPEDSATYYC (SEQ ID NO:102); and where FR4 comprises the sequence WGQGTLVTVSS (SEQ ID NO:104).

[0088] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:9; and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 3593%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:10.

[0089] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:9; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:10. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:9; and the VL domain comprises the amino acid sequence of SEQ ID NO:10.

[0090] In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTLTEFS (SEQ ID NO:2), a CDR-H2 sequence comprising the amino acid sequence of FDPEDGET (SEQ ID NO:3), and a CDR-H3 sequence comprising the amino acid sequence of TTGRFFDWF (SEQ ID NO:4); or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSVISRF (SEQ ID NO:7), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQDSNLPIT (SEQ ID NO:11). In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTLTEFS (SEQ ID NO:2), a CDR-H2 sequence comprising the amino acid sequence of FDPEDGET (SEQ ID NO:3), and a CDR-H3 sequence comprising the amino acid sequence of TTGRFFDWF (SEQ ID NO:4); and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSVISRF (SEQ ID NO:7), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQDSNLPIT (SEQ ID NO:11).

[0091] In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO:12), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO:15), and a CDR-H3 sequence comprising the amino acid sequence of ARYAYGY (SEQ ID NO:16); 36or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QNVGTA (SEQ ID NO:19), a CDR-L2 sequence comprising the amino acid sequence of SAS, and a CDR-L3 sequence comprising the amino acid sequence of QQYSTYPFT (SEQ ID NO:22). In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO:12), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO:15), and a CDR-H3 sequence comprising the amino acid sequence of ARYAYGY (SEQ ID NO:16); and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QNVGTA (SEQ ID NO:19), a CDR-L2 sequence comprising the amino acid sequence of SAS, and a CDR-L3 sequence comprising the amino acid sequence of QQYSTYPFT (SEQ ID NO:22).

[0092] In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYSFTNYA (SEQ ID NO:24), a CDR-H2 sequence comprising the amino acid sequence of ISPYYGDT (SEQ ID NO:25), and a CDR-H3 sequence comprising the amino acid sequence of ARRFEGFYYSMDY (SEQ ID NO:26); or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHSNGNTY (SEQ ID NO:27), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of SQSTHVPLT (SEQ ID NO:29). In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYSFTNYA (SEQ ID NO:24), a CDR-H2 sequence comprising the amino acid sequence of ISPYYGDT (SEQ ID NO:25), and a CDR-H3 sequence comprising the amino acid sequence of ARRFEGFYYSMDY (SEQ ID NO:26); and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHSNGNTY (SEQ ID NO:27), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of SQSTHVPLT (SEQ ID NO:29).

[0093] In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 37sequence comprising the amino acid sequence of ARDPGLRYFDGGMDV (SEQ ID NO:106); or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QGISSY (SEQ ID NO:107), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of QQLNSFPYT (SEQ ID NO:229). In some embodiments, the antigen binding site that binds a CD38 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARDPGLRYFDGGMDV (SEQ ID NO:106); and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QGISSY (SEQ ID NO:107), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of QQLNSFPYT (SEQ ID NO:229).

[0094] In some embodiments, the VH domain comprises the sequence, from N- terminus to C-terminus, FR1—CDR-H1—FR2—CDR-H2—FR3—CDR-H3—FR4; where FR1 comprises the sequence QVQLVESGGGVVQPGRSLRLSCAAS (SEQ ID NO:89); where FR2 comprises the sequence MHWVRQAPGKGLEWVAV (SEQ ID NO:92); where FR3 comprises the sequence YYADSVKGRFTISGDNSKNTLYLQMNSLRAEDTAVYYC (SEQ ID NO:95); and where FR4 comprises the sequence WGQGTLVTVSS (SEQ ID NO:96). In some embodiments, the VL domain comprises the sequence, from N-terminus to C-terminus, FR1—CDR-L1—FR2—CDR-L2—FR3—CDR-L3—FR4; where FR1 comprises the sequence AIQMTQSPSSLSASVGDRVTITCRAS (SEQ ID NO:98); where FR2 comprises the sequence GWYQQKPGKAPKLLIY (SEQ ID NO:100); where FR3 comprises the sequence SLQSGVPSRFSGSGSGTDFTLTISGLQPEDSATYYC (SEQ ID NO:102); and where FR4 comprises the sequence WGQGTLVTVSS (SEQ ID NO:104).

[0095] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:108; and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 3893%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:109.

[0096] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:108; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:109. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:108; and the VL domain comprises the amino acid sequence of SEQ ID NO:109.

[0097] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:110; and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:111.

[0098] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:110; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:111. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:110; and the VL domain comprises the amino acid sequence of SEQ ID NO:111.

[0099] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:116; 39and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:117.

[0100] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:116; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:117. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:116; and the VL domain comprises the amino acid sequence of SEQ ID NO:117.

[0101] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:112; and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:113.

[0102] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:112; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:113. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:112; and the VL domain comprises the amino acid sequence of SEQ ID NO:113.

[0103] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, 40at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:118; and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:119.

[0104] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:118; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:119. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:118; and the VL domain comprises the amino acid sequence of SEQ ID NO:119.

[0105] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:114; and / or the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:115.

[0106] In some embodiments, the VH domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:114; and the VL domain comprises an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:115. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO:114; and the VL domain comprises the amino acid sequence of SEQ ID NO:115. 41

[0107] In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, 4, 5, or 6 CDR sequences of an antibody sequence shown in Table A. In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, 4, 5, or 6 CDR sequences, a VH domain sequence, and / or a VL domain sequence of an antibody sequence shown in Table B. In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, 4, 5, or 6 CDR sequences, a VH domain sequence, and / or a VL domain sequence of an antibody sequence shown in Table I1 or I2. In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, or 4 polypeptide sequences shown in Table I1 or I2. 4243Table B. Variable domain sequences of anti-CD38 (mAb1-7) and other binding proteins.44Note: Bolding and underlining in amino acid sequences above denotes CDR sequences.

[0108] In some embodiments, a binding protein of the present disclosure comprises an antigen binding site that binds an extracellular domain of a human CD38 polypeptide and an extracellular domain of a cynomolgus monkey CD38 polypeptide. Exemplary assays for determining whether an antigen binding site binds an antigen are described herein and known in the art. In some embodiments, binding is determined by ELISA assay, e.g., as described infra. In some embodiments, binding is determined by SPR assay, e.g., as described infra. In some embodiments, binding is determined by flow cytometry assay using cells expressing a CD38 polypeptide on their cell surface, e.g., as described infra. See, e.g., Examples 1, 3, and 4. 45

[0109] In some embodiments, a binding protein of the present disclosure binds a purified polypeptide or fragment thereof comprising the amino acid sequence of SEQ ID NO:1 and / or 30 (e.g., as measured by ELISA or SPR). In some embodiments, a binding protein of the present disclosure binds a polypeptide or comprising the amino acid sequence of SEQ ID NO:1 and / or 30 when expressed on the surface of a cell (e.g., as measured by flow cytometry).

[0110] In some embodiments, a binding protein of the present disclosure binds to a CD38 isoform A polypeptide (e.g., comprising the amino acid sequence of SEQ ID NO:1). In some embodiments, a binding protein of the present disclosure binds to a CD38 isoform E polypeptide (e.g., comprising the amino acid sequence of SEQ ID NO:105 and not comprising the full amino acid sequence of SEQ ID NO:1, consisting of the amino acid sequence of SEQ ID NO:105, or consisting essentially of the amino acid sequence of SEQ ID NO:105). In some embodiments, a binding protein of the present disclosure binds to a CD38 isoform A polypeptide (e.g., comprising the amino acid sequence of SEQ ID NO:1) and a CD38 isoform E polypeptide (e.g., comprising the amino acid sequence of SEQ ID NO:105 and not comprising the full amino acid sequence of SEQ ID NO:1, consisting of the amino acid sequence of SEQ ID NO:105, or consisting essentially of the amino acid sequence of SEQ ID NO:105). Without wishing to be bound to theory, it is thought that binding to a CD38 isoform E polypeptide can be advantageous, e.g., in targeting a binding protein of the present disclosure to cell(s) expressing a CD38 isoform E polypeptide. Human CD38 isoform A extracellular domain polypeptide sequence RWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCN ITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDL TWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRFAEAACDVVHVMLNGSR SKIFDKNSTFGSVEVHNLQPEKVQTLEAWVIHGGREDSRDLCQDPTIKELESIISKRNI QFSCKNIYRPDKFLQCVKNPEDSSCTSEI (SEQ ID NO:1) Human CD38 isoform E polypeptide sequence RWRQQWSGPGTTKRFPETVLARCVKYTEIHPEMRHVDCQSVWDAFKGAFISKHPCN ITEEDYQPLMKLGTQTVPCNKILLWSRIKDLAHQFTQVQRDMFTLEDTLLGYLADDL TWCGEFNTSKINYQSCPDWRKDCSNNPVSVFWKTVSRRHFWECGSP (SEQ ID NO:105) 46

[0111] In some embodiments, the extracellular domain of a human CD38 polypeptide comprises the amino acid sequence of SEQ ID NO:1. In some embodiments, the extracellular domain of a cynomolgus monkey CD38 polypeptide comprises the amino acid sequence of SEQ ID NO:30. Cynomolgus monkey CD38 polypeptide sequence RWRQQWSGSGTTSRFPETVLARCVKYTEVHPEMRHVDCQSVWDAFKGAFISKYPC NITEEDYQPLVKLGTQTVPCNKTLLWSRIKDLAHQFTQVQRDMFTLEDMLLGYLAD DLTWCGEFNTFEINYQSCPDWRKDCSNNPVSVFWKTVSRRFAETACGVVHVMLNG SRSKIFDKNSTFGSVEVHNLQPEKVQALEAWVIHGGREDSRDLCQDPTIKELESIISKR NIRFFCKNIYRPDKFLQCVKNPEDSSCLSGI (SEQ ID NO:30) Anti-CD28 antigen binding sites

[0112] Exemplary antigen binding sites that specifically bind CD28 polypeptides and may find use in the anti-CD38 T-cell engagers of the present disclosure are described infra. Any of the anti-CD28 antigen binding sites and / or trispecific binding proteins described in International Appl. Nos. WO2019 / 074973, WO2017 / 180913, or WO2020 / 210392 may find use in the methods, uses, kits, and compositions of the present disclosure. In some embodiments, the CD28 polypeptide is a human CD28 polypeptide, also known as Tp44. Human CD28 polypeptides are known in the art and include, without limitation, the polypeptides represented by NCBI Accession Numbers XP_011510499.1, XP_011510497.1, XP_011510496.1, NP_001230007.1, NP_001230006.1, or NP_006130.1, or a polypeptide produced from NCBI Gene ID Number 940.

[0113] In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO:139), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO:140), and a CDR-H3 sequence comprising the amino acid sequence of TRSHYGLDWNFDV (SEQ ID NO:141) and / or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO:142), a CDR-L2 sequence comprising the amino acid sequence of KAS, and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO:144). In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY 47(SEQ ID NO:139), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO:140), and a CDR-H3 sequence comprising the amino acid sequence of TRSHYGLDWNFDV (SEQ ID NO:141) and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO:142), a CDR-L2 sequence comprising the amino acid sequence of KAS, and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO:144).

[0114] In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:49, and / or an antibody light chain variable (VL) domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:50. In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:49, and / or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:50. In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:49, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:50.

[0115] In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFSLSDYG (SEQ ID NO:212), a CDR-H2 sequence comprising the amino acid sequence of IWAGGGT (SEQ ID NO:213), and a CDR-H3 sequence comprising the amino acid sequence of ARDKGYSYYYSMDY (SEQ ID NO:214) and / or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVEYYVTSL (SEQ ID NO:215), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of QQSRKVPYT (SEQ ID NO:217). In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFSLSDYG (SEQ ID NO:212), a CDR-H2 sequence comprising the amino acid sequence 48of IWAGGGT (SEQ ID NO:213), and a CDR-H3 sequence comprising the amino acid sequence of ARDKGYSYYYSMDY (SEQ ID NO:214) and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVEYYVTSL (SEQ ID NO:215), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of QQSRKVPYT (SEQ ID NO:217).

[0116] In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:51, and / or an antibody light chain variable (VL) domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:52. In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:51, and / or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:52. In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:51, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:52.

[0117] In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, 4, 5, or 6 CDR sequences of an antibody sequence shown in Table C. In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, 4, 5, or 6 CDR sequences, a VH domain sequence, and / or a VL domain sequence of an antibody sequence shown in Table C. In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, 4, 5, or 6 CDR sequences, a VH domain sequence, and / or a VL domain sequence of an antibody sequence shown in Table C. In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, or 4 polypeptide sequences shown in Table C. 49Table C. Anti-CD28 antigen binding site sequences.Anti-CD3 antigen binding sites

[0118] Exemplary antigen binding sites that specifically bind CD3 polypeptides and may find use in the anti-CD38 T-cell engagers contemplated herein are described infra. Any of 50the anti-CD3 antigen binding sites and / or trispecific binding proteins described in International Appl. Nos. WO2019 / 074973, WO2017 / 180913, or WO2020 / 210392 may find use in the methods, uses, kits, and compositions of the present disclosure. In some embodiments, the CD3 polypeptide is a human CD3 polypeptide, including CD3-delta (also known as T3D, IMD19, and CD3-DELTA), CD3-epsilon (also known as T3E, IMD18, and TCRE), and CD3-gamma (also known as T3G, IMD17, and CD3-GAMMA). Human CD3 polypeptides are known in the art and include, without limitation, the polypeptides represented by NCBI Accession Numbers XP_006510029.1 or NP_031674.1, or a polypeptide produced from NCBI Gene ID Numbers 915, 916, or 917.

[0119] In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122) and / or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHX1NX2X3TY, wherein X1 is E or Q, X2is A or L, and X3is Q, R, or F (SEQ ID NO:131), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130). In some embodiments, the antigen binding site that binds a CD28 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122) and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHX1NX2X3TY, wherein X1 is E or Q, X2 is A or L, and X3 is Q, R, or F (SEQ ID NO:131), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130). In some embodiments, the CDR-L1 sequence is selected from the group consisting of QSLVHNNANTY (SEQ ID NO:123), QSLVHQNAQTY (SEQ ID NO:124), QSLVHENLQTY (SEQ ID NO:125), QSLVHENLFTY (SEQ ID NO:126), QSLVHENLRTY (SEQ ID NO:127), and QSLVHDNAQTY (SEQ ID NO:128).

[0120] In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence 51comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122) and / or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHNNGNTY (SEQ ID NO:218), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130). In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122) and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHNNGNTY (SEQ ID NO:218), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130). In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122) and / or an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHNNANTY (SEQ ID NO:123), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130). In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122) and an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHNNANTY (SEQ ID NO:123), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130). 52

[0121] In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:53 or 138, and / or an antibody light chain variable (VL) domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO: 54, 133, 134, 135, 136, or 137. In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 53 or 138, and / or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 54, 133, 134, 135, 136, or 137. In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 53 or 138, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 54, 133, 134, 135, 136, or 137.

[0122] In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:84, and / or an antibody light chain variable (VL) domain comprising an amino acid sequence that is at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to the amino acid sequence of SEQ ID NO:85. In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:84, and / or an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:85. In some embodiments, the antigen binding site that binds a CD3 polypeptide comprises: an antibody heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:84, and an antibody light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO:85. 53

[0123] In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, 4, 5, or 6 CDR sequences of an antibody sequence shown in Table D. In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, 4, 5, or 6 CDR sequences, a VH domain sequence, and / or a VL domain sequence of an antibody sequence shown in Table D. In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, 4, 5, or 6 CDR sequences, a VH domain sequence, and / or a VL domain sequence of an antibody sequence shown in Table D. In some embodiments, a binding protein of the present disclosure comprises 1, 2, 3, or 4 polypeptide sequences shown in Table D. Table D. Anti-CD3 antigen binding site sequences.5455Trispecific binding protein formats

[0124] In some embodiments, an anti-CD38 T-cell engager of the present disclosure is a trispecific binding protein comprising an antigen binding site that binds one or more CD38 polypeptides, a second antigen binding site that binds a CD28 polypeptide, and a third antigen binding site that binds a CD3 polypeptide. Any of the antigen binding sites described supra may find use in the anti-CD38 T-cell engagers of the present disclosure.

[0125] In some embodiments, the trispecific binding protein comprises four polypeptide chains that form the three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula: VL2-L1-VL1-L2-CL[I] and a second polypeptide chain comprises a structure represented by the formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3 [II] and a third polypeptide chain comprises a structure represented by the formula: VH3-CH1-hinge-CH2-CH3[III] and a fourth polypeptide chain comprises a structure represented by the formula: VL3-CL [IV] wherein: VL1is a first immunoglobulin light chain variable domain; VL2 is a second immunoglobulin light chain variable domain; VL3is a third immunoglobulin light chain variable domain; VH1is a first immunoglobulin heavy chain variable domain; VH2 is a second immunoglobulin heavy chain variable domain; VH3 is a third immunoglobulin heavy chain variable domain; CLis an immunoglobulin light chain constant domain; CH1 is an immunoglobulin CH1 heavy chain constant domain; CH2 is an immunoglobulin CH2 heavy chain constant domain; CH3is an immunoglobulin CH3heavy chain constant domain; hinge is an immunoglobulin hinge region connecting the CH1and CH2domains; and L1, L2, L3 and L4 are amino acid linkers.

[0126] In some embodiments, the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair. In some embodiments, VH1and VL1form a binding pair and one of the three antigen binding sites; VH2and VL2form a binding pair and another of the three antigen binding sites; and VH3 and VL3 form a binding 56pair and another of the three antigen binding sites. In some embodiments, the first polypeptide chain and the second polypeptide chain have a cross-over orientation that forms two distinct antigen binding sites. In some embodiments, the VH1 and VL1 form a binding pair and form the first antigen binding site. In some embodiments, the VH2 and VL2 form a binding pair and form the second antigen binding site. In some embodiments, the first antigen binding site binds a CD3 polypeptide (e.g., human CD3), and the second antigen binding site binds a CD28 polypeptide (e.g., human CD28). In some embodiments, the second antigen binding site binds a CD3 polypeptide (e.g., human CD3), and the first antigen binding site binds a CD28 polypeptide (e.g., human CD28). In some embodiments, the third polypeptide and the fourth polypeptide form a third antigen binding site. In some embodiments, the VH3 and VL3 form a binding pair and form the third antigen binding site. In some embodiments, the third antigen binding site binds a CD38 polypeptide (e.g., human and optionally cynomolgus monkey CD38). Exemplary binding protein formats with cross-over orientations contemplated for use herein are also described in U.S. Pat. Appl. Ser. No.15 / 487,243 and International Application No. PCT / US2017 / 027488.

[0127] The three antigen binding sites may be arranged in any combination that includes an antigen binding site that binds a CD38 polypeptide, an antigen binding site that binds a CD28 polypeptide, and an antigen binding site that binds a CD3 polypeptide. In some embodiments, VH1 and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2and VL2form the third antigen binding site that binds a CD3 polypeptide, and VH3and VL3form the first antigen binding site that binds a CD38 polypeptide. In some embodiments, VH1 and VL1 form the third antigen binding site that binds a CD3 polypeptide, VH2 and VL2 form the second antigen binding site that binds a CD28 polypeptide, and VH3 and VL3form the first antigen binding site that binds a CD38 polypeptide. In some embodiments, VH1 and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2 and VL2 form the first antigen binding site that binds a CD38 polypeptide, and VH3and VL3form the third antigen binding site that binds a CD3 polypeptide. In some embodiments, VH1and VL1form the third antigen binding site that binds a CD3 polypeptide, VH2 and VL2 form the first antigen binding site that binds a CD38 polypeptide, and VH3 and VL3 form the second antigen binding site that binds a CD28 polypeptide. In some embodiments, VH1and VL1form the first antigen binding site that binds a CD38 polypeptide, VH2 and VL2 form the third antigen binding site that binds a CD3 polypeptide, and VH3 and VL3 form the second antigen binding site that binds a CD28 polypeptide. In some embodiments, VH1and VL1form the first antigen binding site that binds a CD38 polypeptide, 57VH2and VL2form the second antigen binding site that binds a CD28 polypeptide, and VH3and VL3 form the third antigen binding site that binds a CD3 polypeptide. Linkers

[0128] In some embodiments, the linkers L1, L2, L3and L4range from no amino acids (length=0) to about 100 amino acids long, or less than 100, 50, 40, 30, 20, or 15 amino acids or less. The linkers can also be 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acids long. L1, L2, L3 and L4in one binding protein may all have the same amino acid sequence or may all have different amino acid sequences.

[0129] Examples of suitable linkers include a single glycine (Gly) residue; a diglycine peptide (Gly-Gly); a tripeptide (Gly-Gly-Gly); a peptide with four glycine residues; a peptide with five glycine residues; a peptide with six glycine residues; a peptide with seven glycine residues; and a peptide with eight glycine residues. Other combinations of amino acid residues may be used such as the peptide GGGGSGGGGS (SEQ ID NO: 55), the peptide GGGGSGGGGSGGGGS (SEQ ID NO: 56), the peptide TKGPS (SEQ ID NO: 57), the peptide GQPKAAP (SEQ ID NO:58), and the peptide GGSGSSGSGG (SEQ ID NO:59). The examples listed above are not intended to limit the scope of the disclosure in any way, and linkers comprising randomly selected amino acids selected from the group consisting of valine, leucine, isoleucine, serine, threonine, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine, glycine, and proline have been shown to be suitable in the binding proteins. For additional descriptions of linker sequences, see, e.g., WO2012135345 and International Application No. PCT / US2017 / 027488.

[0130] The identity and sequence of amino acid residues in the linker may vary depending on the type of secondary structural element necessary to achieve in the linker. For example, glycine, serine, and alanine are best for linkers having maximum flexibility. Some combination of glycine, proline, threonine, and serine are useful if a more rigid and extended linker is necessary. Any amino acid residue may be considered as a linker in combination with other amino acid residues to construct larger peptide linkers as necessary depending on the desired properties.

[0131] In some embodiments, at least one of L1, L2, L3 or L4 is independently 0 amino acids in length. In some embodiments, L1, L2, L3 or L4 are each independently at least one amino acid in length. In some embodiments, the length of L1is at least twice the length of L3. In some embodiments, the length of L2is at least twice the length of L4. In some embodiments, the length of L1 is at least twice the length of L3, and the length of L2 is at least 58twice the length of L4. In some embodiments, L1is 3 to 12 amino acid residues in length, L2is 3 to 14 amino acid residues in length, L3 is 1 to 8 amino acid residues in length, and L4 is 1 to 3 amino acid residues in length. In some embodiments, L1 is 5 to 10 amino acid residues in length, L2is 5 to 8 amino acid residues in length, L3is 1 to 5 amino acid residues in length, and L4 is 1 to 2 amino acid residues in length. In some embodiments, L1 is 7 amino acid residues in length, L2 is 5 amino acid residues in length, L3 is 1 amino acid residue in length, and L4is 2 amino acid residues in length. In some embodiments, L1is 10 amino acid residues in length, L2 is 10 amino acid residues in length, L3 is 0 amino acid residue in length, and L4 is 0 amino acid residues in length. In some embodiments, L1, L2, L3, and L4 each have an independently selected length from 0 to 15 amino acids (e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids), wherein at least two of the linkers have a length of 1 to 15 amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 amino acids). In some embodiments, L1, L2, L3, and L4 are each 0 amino acids in length.

[0132] In some embodiments, L1, L2, L3, and / or L4comprise a sequence derived from a naturally occurring sequence at the junction between an antibody variable domain and an antibody constant domain (e.g., as described in WO2012 / 135345). For example, in some embodiments, the linker comprises a sequence found at the transition between an endogenous VHand CH1domain, or between an endogenous VLand CLdomain (e.g., kappa or lambda). In some embodiments, the linker comprises a sequence found at the transition between an endogenous human VHand CH1domain, or between an endogenous human VLand CLdomain (e.g., human kappa or lambda).

[0133] In some embodiments, L1, L2, L3 and L4 each independently are zero amino acids in length or comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO:55), GGGGSGGGGSGGGGS (SEQ ID NO:56), S, RT, TKGPS (SEQ ID NO:57), GQPKAAP (SEQ ID NO: 58), and GGSGSSGSGG (SEQ ID NO:59). In some embodiments, L1, L2, L3 and L4 each independently comprise a sequence selected from the group consisting of GGGGSGGGGS (SEQ ID NO:55), GGGGSGGGGSGGGGS (SEQ ID NO:56), S, RT, TKGPS (SEQ ID NO:57), GQPKAAP (SEQ ID NO: 58), and GGSGSSGSGG (SEQ ID NO:59).

[0134] In some embodiments, L1 comprises the sequence GQPKAAP (SEQ ID NO: 58), L2comprises the sequence TKGPS (SEQ ID NO:57), L3comprises the sequence S, and L4comprises the sequence RT. In some embodiments, L1 comprises the sequence GGGGSGGGGS (SEQ ID NO:55), L2 comprises the sequence GGGGSGGGGS (SEQ ID NO:55), L3is 0 amino acids in length, and L4is 0 amino acids in length. In some 59embodiments, L1comprises the sequence GGSGSSGSGG (SEQ ID NO:59), L2comprises the sequence GGSGSSGSGG (SEQ ID NO:59), L3 is 0 amino acids in length, and L4 is 0 amino acids in length. In some embodiments, L1 comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:56), L2is 0 amino acids in length, L3comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:56), and L4 is 0 amino acids in length.

[0135] In some embodiments, at least one of L1, L2, L3 or L4 comprises the sequence DKTHT (SEQ ID NO:147). In some embodiments, L1, L2, L3and L4comprise the sequence DKTHT (SEQ ID NO:147). Fc regions and constant domains

[0136] In some embodiments, an anti-CD38 T-cell engager or binding protein of the present disclosure comprises a full-length antibody heavy chain or a polypeptide chain comprising an Fc region. In some embodiments, the Fc region is a human Fc region, e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region. In some embodiments, the Fc region includes an antibody hinge, CH1, CH2, CH3, and optionally CH4domains. In some embodiments, the Fc region is a human IgG1 Fc region. In some embodiments, the Fc region is a human IgG4 Fc region. In some embodiments, the Fc region includes one or more of the mutations described infra.

[0137] In some embodiments, an anti-CD38 T-cell engager or binding protein of the present disclosure includes one or two Fc variants. The term "Fc variant" as used herein refers to a molecule or sequence that is modified from a native Fc but still comprises a binding site for the salvage receptor, FcRn (neonatal Fc receptor). Exemplary Fc variants, and their interaction with the salvage receptor, are known in the art. Thus, the term "Fc variant" can comprise a molecule or sequence that is humanized from a non-human native Fc. Furthermore, a native Fc comprises regions that can be removed because they provide structural features or biological activity that are not required for the antibody-like binding proteins of the invention. Thus, the term "Fc variant" comprises a molecule or sequence that lacks one or more native Fc sites or residues, or in which one or more Fc sites or residues has be modified, that affect or are involved in: (1) disulfide bond formation, (2) incompatibility with a selected host cell, (3) N-terminal heterogeneity upon expression in a selected host cell, (4) glycosylation, (5) interaction with complement, (6) binding to an Fc receptor other than a salvage receptor, or (7) antibody-dependent cellular cytotoxicity (ADCC).

[0138] In some embodiments, the Fc region comprises one or more mutations that reduce or eliminate Fc receptor binding and / or effector function of the Fc region (e.g., Fc receptor- 60mediated antibody-dependent cellular phagocytosis (ADCP), complement-dependent cytotoxicity (CDC), and / or antibody-dependent cellular cytotoxicity (ADCC)).

[0139] In some embodiments, the Fc region is a human IgG1 Fc region comprising one or more amino acid substitutions at positions corresponding to positions 234, 235, and / or 329 of human IgG1 according to EU Index. In some embodiments, the amino acid substitutions are L234A, L235A, and / or P329A. In some embodiments, the Fc region is a human IgG1 Fc region comprising amino acid substitutions at positions corresponding to positions 298, 299, and / or 300 of human IgG1 according to EU Index. In some embodiments, the amino acid substitutions are S298N, T299A, and / or Y300S.

[0140] In some embodiments, the Fc region is a human IgG4 Fc region comprising one or more mutations that reduce or eliminate Fc ^I and / or Fc ^II binding. In some embodiments, the Fc region is a human IgG4 Fc region comprising one or more mutations that reduce or eliminate Fc ^I and / or Fc ^II binding but do not affect FcRn binding. In some embodiments, the Fc region is a human IgG4 Fc region comprising amino acid substitutions at positions corresponding to positions 228 and / or 409 of human IgG4 according to EU Index. In some embodiments, the amino acid substitutions are S228P and / or R409K. In some embodiments, the Fc region is a human IgG4 Fc region comprising amino acid substitutions at positions corresponding to positions 234 and / or 235 of human IgG4 according to EU Index. In some embodiments, the amino acid substitutions are F234A and / or L235A. In some embodiments, the Fc region is a human IgG4 Fc region comprising amino acid substitutions at positions corresponding to positions 228, 234, 235, and / or 409 of human IgG4 according to EU Index. In some embodiments, the amino acid substitutions are S228P, F234A, L235A, and / or R409K. In some embodiments, the Fc region is a human IgG4 Fc region comprising amino acid substitutions at positions corresponding to positions 233-236 of human IgG4 according to EU Index. In some embodiments, the amino acid substitutions are E233P, F234V, L235A, and a deletion at 236. In some embodiments, the Fc region is a human IgG4 Fc region comprising amino acid mutations at substitutions corresponding to positions 228, 233-236, and / or 409 of human IgG4 according to EU Index. In some embodiments, the amino acid mutations are S228P; E233P, F234V, L235A, and a deletion at 236; and / or R409K.

[0141] In some embodiments, an anti-CD38 T-cell engager or binding protein of the present disclosure comprises one or more mutations to improve purification, e.g., by modulating the affinity for a purification reagent. For example, it is known that heterodimeric binding proteins can be selectively purified away from their homodimeric 61forms if one of the two Fc regions of the heterodimeric form contains mutation(s) that reduce or eliminate binding to Protein A, because the heterodimeric form will have an intermediate affinity for Protein A-based purification than either homodimeric form and can be selectively eluted from Protein A, e.g., by use of a different pH (See e.g., Smith, E.J. et al. (2015) Sci. Rep.5:17943). In some embodiments, the mutation comprises substitutions at positions corresponding to positions 435 and 436 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are H435R and Y436F. In some embodiments, the binding protein comprises a second polypeptide chain further comprising a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; and wherein only one of the first and the second Fc regions comprises amino acid substitutions at positions corresponding to positions 435 and 436 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are H435R and Y436F. In some embodiments, a binding protein of the present disclosure comprises knob and hole mutations and one or more mutations to improve purification. In some embodiments, the first and / or second Fc regions are human IgG1 Fc regions. In some embodiments, the first and / or second Fc regions are human IgG4 Fc regions.

[0142] To improve the yields of some binding proteins (e.g., bispecific or trispecific binding proteins), the CH3domains can be altered by the "knob-into-holes" technology which is described in detail with several examples in, for example, International Publication No. WO 96 / 027011, Ridgway et al., 1996, Protein Eng.9: 617-21; and Merchant et al., 1998, Nat. Biotechnol.16: 677-81. Specifically, the interaction surfaces of the two CH3domains are altered to increase the heterodimerisation of both heavy chains containing these two CH3 domains. Each of the two CH3 domains (of the two heavy chains) can be the "knob," while the other is the "hole." The introduction of a disulfide bridge further stabilizes the heterodimers (Merchant et al., 1998; Atwell et al., 1997, J. Mol. Biol.270: 26-35) and increases the yield. In particular embodiments, the knob is on the second pair of polypeptides with a single variable domain. In other embodiments, the knob is on the first pair of polypeptides having the cross-over orientation. In yet other embodiments, the CH3domains do not include a knob in hole.

[0143] In some embodiments, an anti-CD38 T-cell engager or binding protein of the present disclosure (e.g., a trispecific binding protein) comprises a “knob” mutation on the 62second polypeptide chain and a “hole” mutation on the third polypeptide chain. In some embodiments, a binding protein of the present disclosure comprises a “knob” mutation on the third polypeptide chain and a “hole” mutation on the second polypeptide chain. In some embodiments, the “knob” mutation comprises substitution(s) at positions corresponding to positions 354 and / or 366 of human IgG1 or IgG4 according to EU Index. In some embodiments, the amino acid substitutions are S354C, T366W, T366Y, S354C and T366W, or S354C and T366Y. In some embodiments, the “knob” mutation comprises substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index. In some embodiments, the amino acid substitutions are S354C and T366W. In some embodiments, the “hole” mutation comprises substitution(s) at positions corresponding to positions 407 and, optionally, 349, 366, and / or 368 and of human IgG1 or IgG4 according to EU Index. In some embodiments, the amino acid substitutions are Y407V or Y407T and optionally Y349C, T366S, and / or L368A. In some embodiments, the “hole” mutation comprises substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index. In some embodiments, the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

[0144] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitution(s) at positions corresponding to positions 366 and optionally 354 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are T366W or T366Y and optionally S354C; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitution(s) at positions corresponding to positions 407 and optionally 349, 366, and / or 368 and of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y407V or Y407T and optionally Y349C, T366S, and / or L368A.

[0145] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitution(s) at positions corresponding to positions 407 and optionally 349, 366, and / or 368 and of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y407V or Y407T and optionally Y349C, T366S, and / or 63L368A; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitution(s) at positions corresponding to positions 366 and optionally 354 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are T366W or T366Y and optionally S354C.

[0146] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitution at position corresponding to position 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitution is T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitution(s) at positions corresponding to positions 366, 368, and / or 407 and of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are T366S, L368A, and / or Y407V.

[0147] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitution(s) at positions corresponding to positions 366, 368, and / or 407 and of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are T366S, L368A, and / or Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitution at position corresponding to position 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitution is T366W.

[0148] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the third polypeptide chain further comprises a second Fc region 64linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W. In some embodiments, the first and / or second Fc regions are human IgG1 Fc regions. In some embodiments, the first and / or second Fc regions are human IgG4 Fc regions.

[0149] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 354, 366, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, S354C, T366W, and R409K; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 228, 349, 366, 368, 407, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, Y349C, T366S, L368A, Y407V, and R409K. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 349, 366, 368, 407, and 409 of human IgG4 according to EU Index, wherein the amino acid 65substitutions are S228P, Y349C, T366S, L368A, Y407V, and R409K; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 228, 354, 366, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, S354C, T366W, and R409K.

[0150] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, 354, and 366 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A, L235A, S354C, and T366W; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, 349, 366, 368, and 407 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A, L235A, Y349C, T366S, L368A, and Y407V. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, 349, 366, 368, and 407 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A, L235A, Y349C, T366S, L368A, and Y407V; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 234, 235, 354, and 366 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A, L235A, S354C, and T366W.

[0151] In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant 66domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 234, 235, 354, 366, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, F234A, L235A, S354C, T366W, and R409K; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 228, 234, 235, 349, 366, 368, 407, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, F234A, L235A, Y349C, T366S, L368A, Y407V, and R409K. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, wherein the first Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first Fc region comprises amino acid substitutions at positions corresponding to positions 228, 234, 235, 349, 366, 368, 407, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, F234A, L235A, Y349C, T366S, L368A, Y407V, and R409K; and wherein the third polypeptide chain further comprises a second Fc region linked to CH1, wherein the second Fc region is a human IgG4 Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the second Fc region comprises amino acid substitutions at positions corresponding to positions 228, 234, 235, 354, 366, and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P, F234A, L235A, S354C, T366W, and R409K.

[0152] In some embodiments, an anti-CD38 T-cell engager or binding protein of the present disclosure comprises one or more mutations to improve serum half-life (See e.g., Hinton, P.R. et al. (2006) J. Immunol.176(1):346-56). In some embodiments, the mutation comprises substitutions at positions corresponding to positions 428 and 434 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are M428L and N434S. In some embodiments, the binding protein comprises a second polypeptide chain further comprising a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first and / or second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 or IgG4 67according to EU Index, wherein the amino acid substitutions are M428L and N434S. In some embodiments, a binding protein of the present disclosure comprises knob and hole mutations and one or more mutations to improve serum half-life. In some embodiments, the first and / or second Fc regions are human IgG1 Fc regions. In some embodiments, the first and / or second Fc regions are human IgG4 Fc regions.

[0153] In some embodiments, an anti-CD38 T-cell engager or binding protein of the present disclosure comprises one or more mutations to improve stability, e.g., of the hinge region and / or dimer interface of IgG4 (See e.g., Spiess, C. et al. (2013) J. Biol. Chem. 288:26583-26593). In some embodiments, the mutation comprises substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P and R409K. In some embodiments, the binding protein comprises a second polypeptide chain further comprising a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions are human IgG4 Fc regions; and wherein the first and the second Fc regions each comprise amino acid substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P and R409K. In some embodiments, a binding protein of the present disclosure comprises knob and hole mutations and one or more mutations to improve stability. In some embodiments, the first and / or second Fc regions are human IgG4 Fc regions.

[0154] In some embodiments, an anti-CD38 T-cell engager or binding protein of the present disclosure comprises one or more mutations to improve purification, e.g., by modulating the affinity for a purification reagent. For example, it is known that heterodimeric binding proteins can be selectively purified away from their homodimeric forms if one of the two Fc regions of the heterodimeric form contains mutation(s) that reduce or eliminate binding to Protein A, because the heterodimeric form will have an intermediate affinity for Protein A-based purification than either homodimeric form and can be selectively eluted from Protein A, e.g., by use of a different pH (See e.g., Smith, E.J. et al. (2015) Sci. Rep.5:17943). In some embodiments, the mutation comprises substitutions at positions corresponding to positions 435 and 436 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are H435R and Y436F. In some embodiments, the binding protein comprises a second polypeptide chain further comprising a first Fc region 68linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2and CH3 immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2and CH3immunoglobulin heavy chain constant domains; and wherein only one of the first and the second Fc regions comprises amino acid substitutions at positions corresponding to positions 435 and 436 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are H435R and Y436F. In some embodiments, a binding protein of the present disclosure comprises knob and hole mutations and one or more mutations to improve purification. In some embodiments, the first and / or second Fc regions are human IgG1 Fc regions. In some embodiments, the first and / or second Fc regions are human IgG4 Fc regions.

[0155] In some embodiments, an anti-CD38 T-cell engager or binding protein of the present disclosure comprises one or more mutations to improve serum half-life (See e.g., Hinton, P.R. et al. (2006) J. Immunol.176(1):346-56). In some embodiments, the mutation comprises substitutions at positions corresponding to positions 428 and 434 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are M428L and N434S. In some embodiments, the binding protein comprises a second polypeptide chain further comprising a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, wherein the first and / or second Fc regions comprise amino acid substitutions at positions corresponding to positions 428 and 434 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are M428L and N434S. In some embodiments, a binding protein of the present disclosure comprises knob and hole mutations and one or more mutations to improve serum half-life. In some embodiments, the first and / or second Fc regions are human IgG1 Fc regions. In some embodiments, the first and / or second Fc regions are human IgG4 Fc regions.

[0156] In some embodiments, an anti-CD38 T-cell engager or binding protein of the present disclosure comprises one or more mutations to reduce effector function, e.g., Fc receptor-mediated antibody-dependent cellular phagocytosis (ADCP), complement- dependent cytotoxicity (CDC), and / or antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2and CH369immunoglobulin heavy chain constant domains; wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions are human IgG1 Fc regions; and wherein the first and the second Fc regions each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG1 according to EU Index, wherein the amino acid substitutions are L234A and L235A. In some embodiments, the Fc regions of the second and the third polypeptide chains are human IgG1 Fc regions, and wherein the Fc regions each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG1 according to EU Index, wherein the amino acid substitutions are L234A and L235A. In some embodiments, the second polypeptide chain further comprises a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the third polypeptide chain further comprises a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains; wherein the first and second Fc regions are human IgG1 Fc regions; and wherein the first and the second Fc regions each comprise amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgG1 according to EU Index, wherein the amino acid substitutions are L234A, L235A, and P329A. In some embodiments, the Fc regions of the second and the third polypeptide chains are human IgG1 Fc regions, and wherein the Fc regions each comprise amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgG1 according to EU Index, wherein the amino acid substitutions are L234A, L235A, and P329A. In some embodiments, the Fc regions of the second and the third polypeptide chains are human IgG4 Fc regions, and the Fc regions each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A and L235A. In some embodiments, the binding protein comprises a second polypeptide chain further comprising a first Fc region linked to CH1, the first Fc region comprising an immunoglobulin hinge region and CH2 and CH3 immunoglobulin heavy chain constant domains, and a third polypeptide chain further comprising a second Fc region linked to CH1, the second Fc region comprising an immunoglobulin hinge region and CH2and CH3immunoglobulin heavy chain constant domains; and wherein the first and the second Fc regions each comprise amino acid substitutions at positions corresponding to positions 234 70and 235 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A and L235A.

[0157] In some embodiments, an anti-CD38 T-cell engager or binding protein of the present disclosure comprises knob and hole mutations and one or more mutations to reduce effector function. In some embodiments, the first and / or second Fc regions are human IgG1 Fc regions. In some embodiments, the first and / or second Fc regions are human IgG4 Fc regions. For further description of Fc mutations at position 329, see, e.g., Shields, R.L. et al. (2001) J. Biol. Chem.276:6591-6604 and WO1999051642.

[0158] In some embodiments, the types of mutations described supra can be combined in any order or combination. For example, a binding protein of the present disclosure can comprise two or more of the “knob” and “hole” mutations, the one or more mutations to improve serum half-life, the one or more mutations to improve IgG4 stability, the one or more mutations to improve purification, and / or the one or more mutations to reduce effector function described supra.

[0159] In some embodiments, an anti-CD38 T-cell engager or binding protein of the present disclosure comprises an antibody fragment, including but not limited to antibody F(ab), F(ab’)2, Fab’-SH, Fv, or scFv fragments.

[0160] Exemplary full chain polypeptide sequences for trispecific binding proteins are provided herein and are contemplated for use in any of the methods, uses, kits, and compositions of the present disclosure. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:62, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:63. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:65, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:63. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:61, the 71second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:67, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:63. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:68, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:69. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:70, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:69. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:71, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:69. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:148, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:149, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:150, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:151. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:152, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID 72NO:153, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:154, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:155. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:156, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:157, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:158, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:159. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:160, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:161, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:162, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:163. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:164, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:165, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:166, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:167. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:168, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:169, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:170, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:171. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:172, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:173, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of 73SEQ ID NO:174, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:175. In certain embodiments, the first polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:176, the second polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:177, the third polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:178, and the fourth polypeptide chain comprises a polypeptide sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:179.

[0161] In certain embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:62, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63. In certain embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:65, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63. In certain embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:67, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63. In certain embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:68, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69. In certain embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:70, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69. In certain embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:71, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69. In some embodiments, the first polypeptide chain comprises the amino acid 74sequence of SEQ ID NO:148, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:149, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:150, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:151. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:152, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:153, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:154, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:155. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:156, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:157, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:158, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:159. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:160, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:161, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:162, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:163. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:164, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:165, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:166, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:167. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:168, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:169, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:170, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:171. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:172, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:173, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:174, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:175. In some embodiments, the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:176, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:177, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:178, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:179.

[0162] In some embodiments, a trispecific binding protein comprises 1, 2, 3, or 4 polypeptide chains shown in Table E1 or E2. In some embodiments, a trispecific binding 75protein comprises 1, 2, 3, or 4 polypeptide chains of a single trispecific binding protein shown in Table E1 or E2. In some embodiments, a trispecific binding protein comprises 1, 2, 3, or 4 polypeptide chains encoded by a polynucleotide sequence shown in Table F1 or F2. In some embodiments, a trispecific binding protein comprises 1, 2, 3, or 4 polypeptide chains encoded by the polynucleotide sequence(s) of a single trispecific binding protein shown in Table F1 or F2. Table E1. Full-length sequences of trispecific binding proteins.7677787980818283848586Table F1. Full-length polynucleotide sequences of binding proteins.87888990919293949596979899100101102103104105106107K N K M K K K K N K K K N W108V Y G Q V A H V G A G N W V V Y D K V G A A R A V G K109123

[0163] Standard recombinant DNA methodologies are used to construct the polynucleotides that encode the polypeptides which form the anti-CD38 T-cell engagers, incorporate these polynucleotides into recombinant expression vectors, and introduce such vectors into host cells. See e.g., Sambrook et al., 2001, MOLECULAR CLONING: A LABORATORY MANUAL (Cold Spring Harbor Laboratory Press, 3rd ed.). Enzymatic reactions and purification techniques may be performed according to manufacturer's specifications, as commonly accomplished in the art, or as described herein. Unless specific definitions are provided, the nomenclature utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Similarly, conventional techniques may be used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, delivery, and treatment of patients.

[0164] Certain aspects of the present disclosure relate to kits of polynucleotides. In some embodiments, one or more of the polynucleotides is a vector (e.g., an expression vector). The kits may find use, inter alia, in producing one or more of the anti-CD38 T-cell engagers described herein. For example, a kit of the present disclosure may include one or more polynucleotides encoding 1, 2, 3, or 4 polypeptides of an anti-CD38 T-cell engager. In some embodiments, a kit of the present disclosure comprises one or more polynucleotides encoding 1, 2, 3, or 4 polypeptide chains of a single trispecific binding protein, e.g., as shown in Table F1 or F2.

[0165] In some embodiments, the isolated nucleic acid is operably linked to a heterologous promoter to direct transcription of the binding protein-coding nucleic acid sequence. A promoter may refer to nucleic acid control sequences which direct transcription of a nucleic acid. A first nucleic acid sequence is operably linked to a second nucleic acid sequence when the first nucleic acid sequence is placed in a functional relationship with the second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence of a binding protein if the promoter affects the transcription or expression of the coding sequence. Examples of promoters may include, but are not limited to, promoters obtained from the genomes of viruses (such as polyoma virus, fowlpox virus, adenovirus (such as Adenovirus 2), bovine papilloma virus, avian sarcoma virus, cytomegalovirus, a retrovirus, hepatitis-B virus, Simian Virus 40 (SV40), and the like), from heterologous eukaryotic promoters (such as the actin promoter, an immunoglobulin promoter, from heat- shock promoters, and the like), the CAG-promoter (Niwa et al., Gene 108(2):193-9, 1991), the phosphoglycerate kinase (PGK)-promoter, a tetracycline-inducible promoter (Masui et al., 124Nucleic Acids Res.33:e43, 2005), the lac system, the trp system, the tac system, the trc system, major operator and promoter regions of phage lambda, the promoter for 3- phosphoglycerate kinase, the promoters of yeast acid phosphatase, and the promoter of the yeast alpha-mating factors. Polynucleotides encoding binding proteins of the present disclosure may be under the control of a constitutive promoter, an inducible promoter, or any other suitable promoter described herein or other suitable promoter that will be readily recognized by one skilled in the art.

[0166] In some embodiments, the isolated nucleic acid is incorporated into a vector. In some embodiments, the vector is an expression vector. Expression vectors may include one or more regulatory sequences operatively linked to the polynucleotide to be expressed. The term "regulatory sequence" includes promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Examples of suitable enhancers may include, but are not limited to, enhancer sequences from mammalian genes (such as globin, elastase, albumin, α-fetoprotein, insulin and the like), and enhancer sequences from a eukaryotic cell virus (such as SV40 enhancer on the late side of the replication origin (bp 100-270), the cytomegalovirus early promoter enhancer, the polyoma enhancer on the late side of the replication origin, adenovirus enhancers, and the like). Examples of suitable vectors may include, for example, plasmids, cosmids, episomes, transposons, and viral vectors (e.g., adenoviral, vaccinia viral, Sindbis-viral, measles, herpes viral, lentiviral, retroviral, adeno-associated viral vectors, etc.). Expression vectors can be used to transfect host cells, such as, for example, bacterial cells, yeast cells, insect cells, and mammalian cells. Biologically functional viral and plasmid DNA vectors capable of expression and replication in a host are known in the art, and can be used to transfect any cell of interest.

[0167] Other aspects of the present disclosure relate to a vector system comprising one or more vectors encoding a first, second, third, and fourth polypeptide chain of any of the anti- CD38 T-cell engagers described herein. In some embodiments, the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first and second polypeptide chains of the binding protein, and a second vector encoding the third and fourth polypeptide chains of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first and third polypeptide chains of the binding protein, and a second vector encoding the second and 125fourth polypeptide chains of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first and fourth polypeptide chains of the binding protein, and a second vector encoding the second and third polypeptide chains of the binding protein. In some embodiments, the vector system comprises a first vector encoding the first, second, third, and fourth polypeptide chains of the binding protein. The one or more vectors of the vector system may be any of the vectors described herein. In some embodiments, the one or more vectors are expression vectors.

[0168] Other aspects of the present disclosure relate to an isolated host cell comprising one or more isolated polynucleotides, polynucleotide kits, vectors, and / or vector systems described herein. In some embodiments, the host cell is a bacterial cell (e.g., an E. coli cell). In some embodiments, the host cell is a yeast cell (e.g., an S. cerevisiae cell). In some embodiments, the host cell is an insect cell. Examples of insect host cells may include, for example, Drosophila cells (e.g., S2 cells), Trichoplusia ni cells (e.g., High Five™ cells), and Spodoptera frugiperda cells (e.g., Sf21 or Sf9 cells). In some embodiments, the host cell is a mammalian cell. Examples of mammalian host cells may include, for example, human embryonic kidney cells (e.g., 293 or 293 cells subcloned for growth in suspension culture), Expi293TM cells, CHO cells, baby hamster kidney cells (e.g., BHK, ATCC CCL 10), mouse sertoli cells (e.g., TM4 cells), monkey kidney cells (e.g., CV1 ATCC CCL 70), African green monkey kidney cells (e.g., VERO-76, ATCC CRL-1587), human cervical carcinoma cells (e.g., HELA, ATCC CCL 2), canine kidney cells (e.g., MDCK, ATCC CCL 34), buffalo rat liver cells (e.g., BRL 3A, ATCC CRL 1442), human lung cells (e.g., W138, ATCC CCL 75), human liver cells (e.g., Hep G2, HB 8065), mouse mammary tumor cells (e.g., MMT 060562, ATCC CCL51), TRI cells, MRC 5 cells, FS4 cells, a human hepatoma line (e.g., Hep G2), and myeloma cells (e.g., NS0 and Sp2 / 0 cells).

[0169] Other aspects of the present disclosure relate to a method of producing any of the anti-CD38 T-cell engagers described herein. In some embodiments, the method includes a) culturing a host cell (e.g., any of the host cells described herein) comprising an isolated nucleic acid, vector, and / or vector system (e.g., any of the isolated nucleic acids, vectors, and / or vector systems described herein) under conditions such that the host cell expresses the anti-CD38 T-cell engager; and b) isolating the anti-CD38 T-cell engager from the host cell. Methods of culturing host cells under conditions to express a protein are well known to one of ordinary skill in the art. Methods of isolating proteins from cultured host cells are well known to one of ordinary skill in the art, including, for example, by affinity chromatography 126(e.g., two step affinity chromatography comprising protein A affinity chromatography followed by size exclusion chromatography).

[0170] In some embodiments, an anti-CD38 T-cell engager of the present disclosure is purified by protein A affinity chromatography, kappa light chain affinity chromatography (e.g., using a KappaSelect resin according to manufacturer’s instructions; GE Healthcare), and optionally lambda light chain affinity chromatography (e.g., using a LambdaFabSelect resin according to manufacturer’s instructions; GE Healthcare). In some embodiments, a binding protein of the present disclosure is purified by Protein A affinity chromatography, lambda light chain affinity chromatography (e.g., using a LambdaFabSelect resin according to manufacturer’s instructions; GE Healthcare), and optionally kappa light chain affinity chromatography (e.g., using a KappaSelect resin according to manufacturer’s instructions; GE Healthcare). In some embodiments, the binding protein comprises two Fc regions, each comprising a CH3 domain, and only one of the CH3 domains comprises amino acid substitutions at positions corresponding to positions 435 and 436 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are H435R and Y436F. In some embodiments, a binding protein of the present disclosure is purified by protein A affinity chromatography, then kappa light chain affinity chromatography (e.g., using a KappaSelect resin according to manufacturer’s instructions; GE Healthcare), then optionally lambda light chain affinity chromatography (e.g., using a LambdaFabSelect resin according to manufacturer’s instructions; GE Healthcare) in sequence. In some embodiments, a binding protein of the present disclosure is purified by Protein A affinity chromatography, then lambda light chain affinity chromatography (e.g., using a LambdaFabSelect resin according to manufacturer’s instructions; GE Healthcare), then optionally kappa light chain affinity chromatography (e.g., using a KappaSelect resin according to manufacturer’s instructions; GE Healthcare) in sequence. For example, in some embodiments, the binding protein is contacted with Protein A, eluted from Protein A under conditions suitable for isolating the binding protein away from binding proteins comprising either 0 or 2 CH3domains comprising the amino acid substitutions are H435R and Y436F, contacted with a kappa light chain affinity medium (e.g., as used in the KappaSelect resin; GE Healthcare), and eluted from the kappa light chain affinity medium under conditions suitable for isolating the binding protein away from binding proteins comprising only lambda CLdomains (e.g., according to manufacturer’s instructions). Conditions suitable for the Protein A elution are known in the art, including without limitation a stepwise elution gradient from pH4.5-2.8. In some embodiments, Protein A or a Protein A variant useful for protein purification is employed. In 127some embodiments, the Protein A is attached to a substrate or resin, e.g., as part of a chromatography medium. In some embodiments, after elution from the kappa light chain affinity medium, the binding protein is contacted with a lambda light chain affinity medium (e.g., as used in the LambdaFabSelect resin; GE Healthcare), and eluted from the lambda light chain affinity medium under conditions suitable for isolating the binding protein away from binding proteins comprising only kappa CL domains (e.g., according to manufacturer’s instructions). In some embodiments, a binding protein of the present disclosure is detected using HIC chromatography. In some embodiments, the binding protein comprises: a first polypeptide chain that comprises a lambda CL domain; a CH3 domain of a second polypeptide chain that comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4according to EU Index, wherein the amino acid substitutions are S354C and T366W; a CH3 domain of a third polypeptide chain that comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, 407, 435, and 436 of human IgG1 or IgG4according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, Y407V, H435R, and Y436F; and a fourth polypeptide chain that comprises a kappa CL domain. In some embodiments, the binding protein is produced by a host cell. In some embodiments, the binding protein is purified from a cell culture medium or host cell extract. In some embodiments, the binding proteins are secreted by a host cell or produced and extracted from a host cell (e.g., before being contacted with Protein A). In some embodiments, the binding protein is in a cell culture medium or host cell extract when contacted with Protein A. In some embodiments, the binding protein is purified away from other binding proteins, polypeptides, and / or other cellular components. III. Therapeutic compositions, kits, and administration thereof

[0171] In some embodiments, provided herein is the anti-CD38 T-cell engager of the present disclosure for use in any of the methods described herein. In some embodiments, the methods comprise administering an effective amount of the anti-CD38 T-cell engager to an individual in need thereof, e.g., to an individual that has or has been diagnosed with PTCL for treatment of PTCL.

[0172] In some embodiments, an anti-CD38 T-cell engager of the present disclosure is used in the manufacture of a medicament for treating PTCL in an individual, e.g., according to any of the methods described herein.

[0173] In some embodiments, a kit or article of manufacture is provided. In some embodiments, the kit comprises an anti-CD38 T-cell engager of the present disclosure and, 128optionally, instructions for administering the T-cell engager to an individual, e.g., according to any of the methods described herein.

[0174] In some embodiments, a pharmaceutical composition is provided. In some embodiments, the pharmaceutical composition comprises an effective amount of an anti- CD38 T-cell engager of the present disclosure and a pharmaceutically acceptable carrier. In some embodiments, the composition is for use according to any of the methods of the present disclosure.

[0175] Therapeutic or pharmaceutical compositions comprising anti-CD38 T-cell engagers or binding proteins are within the scope of the disclosure. Such therapeutic or pharmaceutical compositions can comprise a therapeutically effective amount of a T-cell engager or binding protein, or T-cell engager / binding protein-drug conjugate, in admixture with a pharmaceutically or physiologically acceptable formulation agent selected for suitability with the mode of administration.

[0176] Acceptable formulation materials preferably are nontoxic to recipients at the dosages and concentrations employed.

[0177] The pharmaceutical composition can contain formulation materials for modifying, maintaining, or preserving, for example, the pH, osmolarity, viscosity, clarity, color, isotonicity, odor, sterility, stability, rate of dissolution or release, adsorption, or penetration of the composition. Suitable formulation materials include, but are not limited to, amino acids (such as glycine, glutamine, asparagine, arginine, or lysine), antimicrobials, antioxidants (such as ascorbic acid, sodium sulfite, or sodium hydrogen-sulfite), buffers (such as borate, bicarbonate, Tris-HCl, citrates, phosphates, or other organic acids), bulking agents (such as mannitol or glycine), chelating agents (such as ethylenediamine tetraacetic acid (EDTA)), complexing agents (such as caffeine, polyvinylpyrrolidone, beta-cyclodextrin, or hydroxypropyl-beta-cyclodextrin), fillers, monosaccharides, disaccharides, and other carbohydrates (such as glucose, mannose, or dextrins), proteins (such as serum albumin, gelatin, or immunoglobulins), coloring, flavoring and diluting agents, emulsifying agents, hydrophilic polymers (such as polyvinylpyrrolidone), low molecular weight polypeptides, salt-forming counterions (such as sodium), preservatives (such as benzalkonium chloride, benzoic acid, salicylic acid, thimerosal, phenethyl alcohol, methylparaben, propylparaben, chlorhexidine, sorbic acid, or hydrogen peroxide), solvents (such as glycerin, propylene glycol, or polyethylene glycol), sugar alcohols (such as mannitol or sorbitol), suspending agents, surfactants or wetting agents (such as pluronics; PEG; sorbitan esters; polysorbates such as polysorbate 20 or polysorbate 80; triton; tromethamine; lecithin; cholesterol or 129tyloxapal), stability enhancing agents (such as sucrose or sorbitol), tonicity enhancing agents (such as alkali metal halides – preferably sodium or potassium chloride – or mannitol sorbitol), delivery vehicles, diluents, excipients and / or pharmaceutical adjuvants (see, e.g., REMINGTON'S PHARMACEUTICAL SCIENCES (18th Ed., A.R. Gennaro, ed., Mack Publishing Company 1990), and subsequent editions of the same, incorporated herein by reference for any purpose).

[0178] The optimal pharmaceutical composition will be determined by a skilled artisan depending upon, for example, the intended route of administration, delivery format, and desired dosage. Such compositions can influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the binding protein.

[0179] The primary vehicle or carrier in a pharmaceutical composition can be either aqueous or non-aqueous in nature. For example, a suitable vehicle or carrier for injection can be water, physiological saline solution, or artificial cerebrospinal fluid, possibly supplemented with other materials common in compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles. Other exemplary pharmaceutical compositions comprise Tris buffer of about pH 7.0-8.5, or acetate buffer of about pH 4.0-5.5, which can further include sorbitol or a suitable substitute. In one embodiment of the disclosure, binding protein compositions can be prepared for storage by mixing the selected composition having the desired degree of purity with optional formulation agents in the form of a lyophilized cake or an aqueous solution. Further, the binding protein can be formulated as a lyophilizate using appropriate excipients such as sucrose.

[0180] The pharmaceutical compositions of the disclosure can be selected for parenteral delivery or subcutaneous. Alternatively, the compositions can be selected for inhalation or for delivery through the digestive tract, such as orally. The preparation of such pharmaceutically acceptable compositions is within the skill of the art.

[0181] The formulation components are present in concentrations that are acceptable to the site of administration. For example, buffers are used to maintain the composition at physiological pH or at a slightly lower pH, typically within a pH range of from about 5 to about 8.

[0182] When parenteral administration is contemplated, the therapeutic compositions for use can be in the form of a pyrogen-free, parenterally acceptable, aqueous solution comprising the desired binding protein in a pharmaceutically acceptable vehicle. A particularly suitable vehicle for parenteral injection is sterile distilled water in which a 130binding protein is formulated as a sterile, isotonic solution, properly preserved. Yet another preparation can involve the formulation of the desired molecule with an agent, such as injectable microspheres, bio-erodible particles, polymeric compounds (such as polylactic acid or polyglycolic acid), beads, or liposomes, that provides for the controlled or sustained release of the product which can then be delivered via a depot injection. Hyaluronic acid can also be used, and this can have the effect of promoting sustained duration in the circulation. Other suitable means for the introduction of the desired molecule include implantable drug delivery devices.

[0183] In one embodiment, a pharmaceutical composition can be formulated for inhalation. For example, a binding protein can be formulated as a dry powder for inhalation. Binding protein inhalation solutions can also be formulated with a propellant for aerosol delivery. In yet another embodiment, solutions can be nebulized.

[0184] It is also contemplated that certain formulations can be administered orally. In one embodiment of the disclosure, binding proteins that are administered in this fashion can be formulated with or without those carriers customarily used in the compounding of solid dosage forms such as tablets and capsules. For example, a capsule can be designed to release the active portion of the formulation at the point in the gastrointestinal tract when bioavailability is maximized and pre-systemic degradation is minimized. Additional agents can be included to facilitate absorption of the binding protein. Diluents, flavorings, low melting point waxes, vegetable oils, lubricants, suspending agents, tablet disintegrating agents, and binders can also be employed.

[0185] Another pharmaceutical composition can involve an effective quantity of binding proteins in a mixture with non-toxic excipients that are suitable for the manufacture of tablets. By dissolving the tablets in sterile water, or another appropriate vehicle, solutions can be prepared in unit-dose form. Suitable excipients include, but are not limited to, inert diluents, such as calcium carbonate, sodium carbonate or bicarbonate, lactose, or calcium phosphate; or binding agents, such as starch, gelatin, or acacia; or lubricating agents such as magnesium stearate, stearic acid, or talc.

[0186] Additional pharmaceutical compositions of the disclosure will be evident to those skilled in the art, including formulations involving binding proteins in sustained- or controlled-delivery formulations. Techniques for formulating a variety of other sustained- or controlled-delivery means, such as liposome carriers, bio-erodible microparticles or porous beads and depot injections, are also known to those skilled in the art. Additional examples of sustained-release preparations include semipermeable polymer matrices in the form of shaped 131articles, e.g. films, or microcapsules. Sustained release matrices can include polyesters, hydrogels, polylactides, copolymers of L-glutamic acid and gamma ethyl-L-glutamate, poly(2-hydroxyethyl-methacrylate), ethylene vinyl acetate, or poly-D(-)-3-hydroxybutyric acid. Sustained-release compositions can also include liposomes, which can be prepared by any of several methods known in the art.

[0187] Pharmaceutical compositions to be used for in vivo administration typically must be sterile. This can be accomplished by filtration through sterile filtration membranes. Where the composition is lyophilized, sterilization using this method can be conducted either prior to, or following, lyophilization and reconstitution. The composition for parenteral administration can be stored in lyophilized form or in a solution. In addition, parenteral compositions generally are placed into a container having a sterile access port, for example, an intravenous solution bag or vial having a stopper pierceable by a hypodermic injection needle.

[0188] Once the pharmaceutical composition has been formulated, it can be stored in sterile vials as a solution, suspension, gel, emulsion, solid, or as a dehydrated or lyophilized powder. Such formulations can be stored either in a ready-to-use form or in a form (e.g., lyophilized) requiring reconstitution prior to administration.

[0189] The disclosure also encompasses kits for producing a single-dose administration unit. The kits can each contain both a first container having a dried protein and a second container having an aqueous formulation. Also included within the scope of this disclosure are kits containing single and multi-chambered pre-filled syringes (e.g., liquid syringes and lyosyringes).

[0190] The effective amount of a pharmaceutical composition to be employed therapeutically will depend, for example, upon the therapeutic context and objectives. One skilled in the art will appreciate that the appropriate dosage levels for treatment will thus vary depending, in part, upon the molecule delivered, the indication for which the binding protein is being used, the route of administration, and the size (body weight, body surface, or organ size) and condition (the age and general health) of the patient. Accordingly, the clinician can titer the dosage and modify the route of administration to obtain the optimal therapeutic effect.

[0191] Dosing frequency will depend upon the pharmacokinetic parameters of the binding protein in the formulation being used. Typically, a clinician will administer the composition until a dosage is reached that achieves the desired effect. The composition can therefore be administered as a single dose, as two or more doses (which may or may not 132contain the same amount of the desired molecule) over time, or as a continuous infusion via an implantation device or catheter. Further refinement of the appropriate dosage is routinely made by those of ordinary skill in the art and is within the ambit of tasks routinely performed by them. Appropriate dosages can be ascertained through use of appropriate dose-response data.

[0192] The route of administration of the pharmaceutical composition is in accord with known methods, e.g., orally; through injection by intravenous, intraperitoneal, intracerebral (intraparenchymal), intracerebroventricular, intramuscular, intraocular, intraarterial, intraportal, or intralesional routes; by sustained release systems; or by implantation devices. Where desired, the compositions can be administered by bolus injection or continuously by infusion, or by implantation device.

[0193] The composition can also be administered locally via implantation of a membrane, sponge, or other appropriate material onto which the desired molecule has been absorbed or encapsulated. Where an implantation device is used, the device can be implanted into any suitable tissue or organ, and delivery of the desired molecule can be via diffusion, timed- release bolus, or continuous administration. IV. Items

[0194] The following exemplary items are representative of some aspects of the invention: 1. An anti-CD38 T-cell engager for use in the treatment of peripheral T-cell lymphoma (PTCL) in an individual in need thereof. 2. The anti-CD38 T-cell engager for use according to Item 1 characterized in that it is a trispecific binding protein comprising a first antigen binding site that specifically binds a CD38 polypeptide, a second antigen binding site that specifically binds a CD28 polypeptide, and a third antigen binding site that specifically binds a CD3 polypeptide. 3. The anti-CD38 T-cell engager for use according to Item 1 characterized in that it is a bispecific binding protein comprising a first antigen binding site that specifically binds a CD38 polypeptide and a second antigen binding site that specifically binds a CD3 polypeptide. 1334. The anti-CD38 T-cell engager for use according to Item 2 or Item 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31) or GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32) or IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34) or QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of LAS or GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). 5. The anti-CD38 T-cell engager for use according to Item 4, wherein the first antigen binding site comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR- L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). 6. The anti-CD38 T-cell engager for use according to Item 4 or Item 5, wherein the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:13, and a VL domain comprising the amino acid sequence of SEQ ID NO:14. 7. The anti-CD38 T-cell engager for use according to Item 4, wherein the first antigen binding site comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31), a CDR-H2 sequence 134comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34), a CDR- L2 sequence comprising the amino acid sequence of LAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). 8. The anti-CD38 T-cell engager for use according to Item 4 or Item 7, wherein the first antigen binding site comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:5, and a VL domain comprising the amino acid sequence of SEQ ID NO:6; (b) a VH domain comprising the amino acid sequence of SEQ ID NO:17, and a VL domain comprising the amino acid sequence of SEQ ID NO:18; (c) a VH domain comprising the amino acid sequence of SEQ ID NO:21, and a VL domain comprising the amino acid sequence of SEQ ID NO:18; or (d) a VH domain comprising the amino acid sequence of SEQ ID NO:23, and a VL domain comprising the amino acid sequence of SEQ ID NO:18. 9. The anti-CD38 T-cell engager for use according to Item 2 or Item 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARMFRGAFDY (SEQ ID NO:43); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO:44), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO:46). 13510. The anti-CD38 T-cell engager for use according to Item 9, wherein the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:9, and a VL domain comprising the amino acid sequence of SEQ ID NO:10. 11. The anti-CD38 T-cell engager for use according to Item 2 or Item 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of gytltefs (SEQ ID NO:2), a CDR-H2 sequence comprising the amino acid sequence of fdpedget (SEQ ID NO:3), and a CDR-H3 sequence comprising the amino acid sequence of ttgrffdwf (SEQ ID NO:4); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSVISRF (SEQ ID NO:7), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of qqdsnlpit (SEQ ID NO:11). 12. The anti-CD38 T-cell engager for use according to Item 11, wherein the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:108, and a VL domain comprising the amino acid sequence of SEQ ID NO:109. 13. The anti-CD38 T-cell engager for use according to Item 2 or Item 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO:12), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO:15), and a CDR-H3 sequence comprising the amino acid sequence of ARYAYGY (SEQ ID NO:16); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QNVGTA (SEQ ID NO:19), a CDR-L2 sequence comprising the amino acid sequence of SAS, and a CDR-L3 sequence comprising the amino acid sequence of QQYSTYPFT (SEQ ID NO:22). 14. The anti-CD38 T-cell engager for use according to Item 13, wherein the first antigen binding site comprises: 136(a) a VH domain comprising the amino acid sequence of SEQ ID NO:110, and a VL domain comprising the amino acid sequence of SEQ ID NO:111; or (b) a VH domain comprising the amino acid sequence of SEQ ID NO:116, and a VL domain comprising the amino acid sequence of SEQ ID NO:117. 15. The anti-CD38 T-cell engager for use according to Item 2 or Item 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYSFTNYA (SEQ ID NO:24), a CDR-H2 sequence comprising the amino acid sequence of ISPYYGDT (SEQ ID NO:25), and a CDR-H3 sequence comprising the amino acid sequence of ARRFEGFYYSMDY (SEQ ID NO:26); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHSNGNTY (SEQ ID NO:27), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of SQSTHVPLT (SEQ ID NO:29). 16. The anti-CD38 T-cell engager for use according to Item 15, wherein the first antigen binding site comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:112, and a VL domain comprising the amino acid sequence of SEQ ID NO:113; or (b) a VH domain comprising the amino acid sequence of SEQ ID NO:118, and a VL domain comprising the amino acid sequence of SEQ ID NO:119. 17. The anti-CD38 T-cell engager for use according to Item 2 or Item 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARDPGLRYFDGGMDV (SEQ ID NO:106); and 137(b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QGISSY (SEQ ID NO:107), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of QQLNSFPYT (SEQ ID NO:229). 18. The anti-CD38 T-cell engager for use according to Item 17, wherein the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:114, and a VL domain comprising the amino acid sequence of SEQ ID NO:115. 19. The anti-CD38 T-cell engager of any one for use according to any one of Items 2 to 18, wherein the antigen binding site that binds a CD3 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHX1NX2X3TY, wherein X1 is E or Q, X2is A or L, and X3is Q, R, or F (SEQ ID NO:131), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130). 20. The anti-CD38 T-cell engager for use according to Item 19, wherein the CDR- L1 sequence of the VL domain of the antigen binding site that binds a CD3 polypeptide is selected from the group consisting of QSLVHNNANTY (SEQ ID NO:123), QSLVHQNAQTY (SEQ ID NO:124), QSLVHENLQTY (SEQ ID NO:125), QSLVHENLFTY (SEQ ID NO:126), QSLVHENLRTY (SEQ ID NO:127), and QSLVHDNAQTY (SEQ ID NO:128). 21. The anti-CD38 T-cell engager for use according to Item 19 or Item 20, wherein the antigen binding site that binds a CD3 polypeptide comprises a VH domain comprising the amino acid sequence of SEQ ID NO:53 or 138, and a VL domain comprising the amino acid sequence of SEQ ID NO:54, 133, 134, 135, 136, or 137. 13822. The anti-CD38 T-cell engager for use according to Item 21, wherein the antigen binding site that binds a CD3 polypeptide comprises a VH domain comprising the amino acid sequence of SEQ ID NO:53 and a VL domain comprising the amino acid sequence of SEQ ID NO:54. 23. The anti-CD38 T-cell engager for use according to any one of Items 2-18, wherein the antigen binding site that binds a CD3 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHNNGNTY (SEQ ID NO:218), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130). 24. The anti-CD38 T-cell engager for use according to Item 23, wherein the third antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:84, and a VL domain comprising the amino acid sequence of SEQ ID NO:85. 25. The anti-CD38 T-cell engager for use according to any one of Item 2 and 4- 24, wherein the antigen binding site that binds a CD28 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO:139), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO:140), and a CDR-H3 sequence comprising the amino acid sequence of TRSHYGLDWNFDV (SEQ ID NO:141); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO:142), a CDR-L2 sequence comprising the amino acid sequence of KAS, and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO:144). 13926. The anti-CD38 T-cell engager for use according to Item 25, wherein the antigen binding site that binds a CD28 polypeptide comprises a VH domain comprising the amino acid sequence of SEQ ID NO:49, and a VL domain comprising the amino acid sequence of SEQ ID NO:50. 27. The anti-CD38 T-cell engager for use according to any one of Items 2 and 4- 24, wherein the antigen binding site that binds a CD28 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFSLSDYG (SEQ ID NO:212), a CDR-H2 sequence comprising the amino acid sequence of IWAGGGT (SEQ ID NO:213), and a CDR- H3 sequence comprising the amino acid sequence of ARDKGYSYYYSMDY (SEQ ID NO:214); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVEYYVTSL (SEQ ID NO:215), a CDR- L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of QQSRKVPYT (SEQ ID NO:217). 28. The anti-CD38 T-cell engager for use according to Item 27, wherein the second antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:51, and a VL domain comprising the amino acid sequence of SEQ ID NO:52. 29. The anti-CD38 T-cell engager for use according to any one of Items 2 and 4- 28, wherein the trispecific binding protein comprises four polypeptide chains that form the three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula: VL2-L1-VL1-L2-CL [I] and a second polypeptide chain comprises a structure represented by the formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3[II] and a third polypeptide chain comprises a structure represented by the formula: VH3-CH1-hinge-CH2-CH3 [III] and a fourth polypeptide chain comprises a structure represented by the formula: VL3-CL[IV] 140wherein: VL1 is a first immunoglobulin light chain variable domain; VL2 is a second immunoglobulin light chain variable domain; VL3 is a third immunoglobulin light chain variable domain; VH1is a first immunoglobulin heavy chain variable domain; VH2is a second immunoglobulin heavy chain variable domain; VH3 is a third immunoglobulin heavy chain variable domain; CL is an immunoglobulin light chain constant domain; CH1 is an immunoglobulin CH1 heavy chain constant domain; CH2is an immunoglobulin CH2heavy chain constant domain; CH3is an immunoglobulin CH3heavy chain constant domain; hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and L1, L2, L3 and L4 are amino acid linkers; wherein the polypeptide of formula I and the polypeptide of formula II form a cross-over light chain-heavy chain pair; wherein VH1and VL1form one of the three antigen binding sites; wherein VH2 and VL2 form another of the three antigen binding sites; and wherein VH3and VL3form another of the three antigen binding sites. 30. The anti-CD38 T-cell engager for use according to Item 29, wherein: (a) VH1 and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2 and VL2 form the third antigen binding site that binds a CD3 polypeptide, and VH3 and VL3 form the first antigen binding site that binds a CD38 polypeptide; or (b) VH1and VL1form the third antigen binding site that binds a CD3 polypeptide, VH2 and VL2 form the second antigen binding site that binds a CD28 polypeptide, and VH3and VL3form the first antigen binding site that binds a CD38 polypeptide. 31. The anti-CD38 T-cell engager for use according to Item 29, wherein: 141(a) VH1and VL1form the second antigen binding site that binds a CD28 polypeptide, VH2and VL2 form the first antigen binding site that binds a CD38 polypeptide, and VH3 and VL3 form the third antigen binding site that binds a CD3 polypeptide; or (b) VH1and VL1form the third antigen binding site that binds a CD3 polypeptide, VH2 and VL2 form the first antigen binding site that binds a CD38 polypeptide, and VH3 and VL3 form the second antigen binding site that binds a CD28 polypeptide. 32. The anti-CD38 T-cell engager for use according to Item 29, wherein: (a) VH1and VL1form the first antigen binding site that binds a CD38 polypeptide, VH2and VL2 form the third antigen binding site that binds a CD3 polypeptide, and VH3 and VL3 form the second antigen binding site that binds a CD28 polypeptide; or (b) VH1and VL1form the first antigen binding site that binds a CD38 polypeptide, VH2 and VL2 form the second antigen binding site that binds a CD28 polypeptide, and VH3 and VL3 form the third antigen binding site that binds a CD3 polypeptide. 33. The anti-CD38 T-cell engager for use according to Item 29, wherein: VH1 and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2and VL2form the third antigen binding site that binds a CD3 polypeptide, and VH3and VL3form the first antigen binding site that binds a CD38 polypeptide; VH1 comprises a CDR-H1 sequence comprising the amino acid sequence of gytftsyy (SEQ ID NO:139), a CDR-H2 sequence comprising the amino acid sequence of iypgnvnt (SEQ ID NO:140), and a CDR-H3 sequence comprising the amino acid sequence of trshygldwnfdv (SEQ ID NO:141), and VL1 comprises a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO:142), a CDR-L2 sequence comprising the amino acid sequence of KAS, and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO:144); VH2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122), and VL2 comprises a CDR-L1 sequence 142comprising the amino acid sequence of QSLVHNNANTY (SEQ ID NO:123), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130); and VH3comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and VL3comprises a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36). 34. The anti-CD38 T-cell engager for use according to Item 29, wherein VH1and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2 and VL2 form the third antigen binding site that binds a CD3 polypeptide, and VH3 and VL3 form the first antigen binding site that binds a CD38 polypeptide; wherein VH1comprises the amino acid sequence of SEQ ID NO:49 and VL1 comprises the amino acid sequence of SEQ ID NO:50; wherein VH2 comprises the amino acid sequence of SEQ ID NO:53 and VL2 comprises the amino acid sequence of SEQ ID NO:54; and wherein VH3comprises the amino acid sequence of SEQ ID NO:13 and VL3comprises the amino acid sequence of SEQ ID NO:14. 35. The anti-CD38 T-cell engager for use according to any one of Items 29-34, wherein: (a) L1comprises the sequence GQPKAAP (SEQ ID NO:58), L2comprises the sequence TKGPS (SEQ ID NO:57), L3 comprises the amino acid S, and L4 comprises the sequence RT; (b) L1 comprises the sequence GGGGSGGGGS (SEQ ID NO:55), L2 comprises the sequence GGGGSGGGGS (SEQ ID NO:55), L3is 0 amino acids in length, and L4is 0 amino acids in length; (c) L1 comprises the sequence GGSGSSGSGG (SEQ ID NO:59), L2 comprises the sequence GGSGSSGSGG (SEQ ID NO:59), L3is 0 amino acids in length, and L4is 0 amino acids in length; or 143(d) L1comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:56), L2is 0 amino acids in length, L3 comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:56), and L4 is 0 amino acids in length. 36. The anti-CD38 T-cell engager for use according to any one of Items 29-34, wherein at least one of L1, L2, L3 or L4 comprises the sequence DKTHT (SEQ ID NO:147). 37. The anti-CD38 T-cell engager for use according to Item 36, wherein L1, L2, L3 and L4comprise the sequence DKTHT (SEQ ID NO:147). 38. The anti-CD38 T-cell engager for use according to any one of Items 29-37, wherein the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3domains, and wherein the hinge-CH2-CH3domains each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A and L235A. 39. The anti-CD38 T-cell engager for use according to any one of Items 29-37, wherein the hinge-CH2-CH3domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 233-236 of human IgG4 according to EU Index, wherein the amino acid substitutions are E233P, F234V, L235A, and a deletion at 236. 40. The anti-CD38 T-cell engager for use according to any one of Items 29-37, wherein the hinge-CH2-CH3domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3domains, and wherein the hinge-CH2-CH3domains each comprise amino acid substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P and R409K. 41. The anti-CD38 T-cell engager for use according to any one of Items 29-37, wherein the hinge-CH2-CH3domains of the second and the third polypeptide chains are human IgG1 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgG1 according to EU Index, wherein the amino acid substitutions are L234A, L235A, and P329A. 14442. The anti-CD38 T-cell engager for use according to any one of Items 29-37, wherein the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG1 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 298, 299, and 300 of human IgG1 according to EU Index, wherein the amino acid substitutions are S298N, T299A, and Y300S. 43. The anti-CD38 T-cell engager for use according to any one of Items 29-42, wherein the hinge-CH2-CH3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the hinge-CH2-CH3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W. 44. The anti-CD38 T-cell engager for use according to any one of Items 29-42, wherein the hinge-CH2-CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the hinge-CH2-CH3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V. 45. The anti-CD38 T-cell engager for use according to Item 29, wherein: (a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:62, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63; (b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:65, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63; 145(c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:67, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63; (d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:68, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69; (e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:70, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69; (f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:71, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69; (g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:148, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:149, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:150, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:151; (h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:152, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:153, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:154, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:155; (i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:156, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:157, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:158, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:159; 146(j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:160, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:161, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:162, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:163; (k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:164, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:165, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:166, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:167; (l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:168, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:169, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:170, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:171; (m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:172, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:173, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:174, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:175; or (n) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:176, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:177, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:178, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:179. 46. The anti-CD38 T-cell engager for use according to any one of Items 2-45, wherein the CD38 polypeptide is a human CD38 polypeptide. 47. The anti-CD38 T-cell engager for use according to any one of Items 2-46, wherein the CD3 polypeptide is a human CD3 polypeptide. 48. The anti-CD38 T-cell engager for use according to any one of Items 2 and 4- 47, wherein the CD28 polypeptide is a human CD28 polypeptide. 49. The anti-CD38 T-cell engager for use according to any one of Items 1-48, wherein the PTCL is angioimmunoblastic T-cell lymphoma (AITL), hepatosplenic T-cell lymphoma (HSTL), or adult T-cell leukemia / lymphoma (ATLL), extranodal NK / T-cell 147lymphoma (ENKTCL), mycosis fungoides (MF), Sezary syndrome (SS), anaplastic large cell ALK- lymphoma (ALCL), PTCL-not otherwise specified (NOS), enteropathy-type T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), primary cutaneous CD4+ lymphoproliferative disorder, subcutaneous T-cell lymphoma panniculitis-like (SCTCL), or primary cutaneous ^ ^ T-cell lymphoma. 50. The anti-CD38 T-cell engager for use according to any one of Items 1-48, wherein the PTCL is hepatosplenic T-cell lymphoma (HSTL), Sezary syndrome (SS), or mycosis fungoides (MF). 51. The anti-CD38 T-cell engager for use according to Item 50, wherein the mycosis fungoides is transformed mycosis fungoides. 52. The anti-CD38 T-cell engager for use according to any one of Items 1-51, wherein cells of the PTCL express CD38 and / or CD28. 53. The anti-CD38 T-cell engager for use according to any one of Items 1-52, wherein the individual is a human. 54. Pharmaceutical composition comprising an anti-CD38 T-cell engager for use according to any one of Items 1-53. EXAMPLES

[0195] The Examples that follow are illustrative of specific embodiments of the disclosure, and various uses thereof. They are set forth for explanatory purposes only, and should not be construed as limiting the scope of the invention in any way. Example 1: Treatment of PTCL with anti-CD38 / CD28xCD3 trispecific binding proteins

[0196] Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Despite the introduction of new chemotherapy protocols and a plethora of new agents, the progression-free survival of patients with PTCLs needs to be improved. Immunotherapy has established itself in recent years as a major advance in the treatment of several cancers. Trispecific binding proteins that 148target CD38, CD3, and CD28 have been developed for treatment of multiple myeloma and chronic viral infections.

[0197] This Example describes the investigation of anti-CD38 / CD28xCD3 trispecific binding proteins comprising the polypeptides of SEQ ID Nos:60-63 in the treatment of PTCL. Materials and Methods Cell lines and culture

[0198] The human cell lines SEAX, H9 (derived from Sezary Syndrome) DERL-2 (derived from HepatoSplenic T-cell lymphoma), YT (derived from T / NK cell leukemia), JURKAT and MOLT4 (derived from Acute T-cell leukemia) Mac2a and Mac2b were established from clinical specimens of one patient each. All cell lines, except DERL-2, were grown in RPMI1640 Glutamax-I medium, supplemented with 10% fetal calf serum, 100 U / ml penicillin-streptomycin (all from Thermo Fisher Scientific) at 37 °C with 5% CO2. DERL-2 is grown in RPMI1640 Glutamax-I medium, supplemented with 20% fetal calf serum, 100 U / ml penicillin-streptomycin (all from Thermo Fisher Scientific) and 20ng / ml Human IL-2 (Biolegend). Immunohistochemistry (IHC)

[0199] IHC analysis was performed in PTCL (n = 261) tissue sections. IHC was carried out on FFPE tissue sections, as previously described [ref], using antibodies against CD3 (mouse mAb, clone F7.2.38, 1: 50; Agilent Dako), CD38 (mouse mAb, clone SCP32, 1: 100; Leica Biosystems), CD28 (rabbit mAb, clone D2Z4E, 1: 50; Cell Signaling Technology). IHC was performed on a BOND III or a BOND-MAX (Leica Biosystems) automated stainer platform for CD3 and CD38. After appropriate antigen retrieval with EDTA buffer, pH 9 (DiaPath), deparaffinized tissue sections were stained manually for CD28 staining using a two-step indirect immunoperoxidase method (ImmPRESS Anti-rabbit; Vector Laboratories). CD28 and CD38 expression were evaluated on tumor cells and by a pathologist. For the both markers internal control were evaluated, respectively reactive T-Cell for CD28 and plasma cells for CD38. Expression was semi-quantified with a score for calculating by intensity (between 1 to 3, three corresponding to the intensity of internal control such as plasma) cells and proportion (percentage) of stained tumor cells using the formula: Score = intensity x proportion of tumor cells stained 149H Score = intensity x percentage of tumor cells stained Multiplex immunofluorescence

[0200] The TSA-based Opal method was used in this study for immunofluorescence (IF) staining (Akoya Biosciences). Multiplex immunofluorescence analysis was performed in FFPE tissue sections PTCL-TFH (N=6), Sezary Syndrome (N=7), ALCL ALK+ (N=2), ENKTCL (N=2) according to the manufacturer’s instructions after appropriate antigen retrieval with EDTA buffer pH 9 (Zytomed). Low-expressing markers were coupled to more intense Opals to facilitate spectral acquisition, and vice versa. The Opal fluorophores were used at 1: 200. For Multiplex staining CD28 (1:200; Cell Signaling Technology), CD38 (1:100, Leica Biosystems), PD1 (1:200; Abcam), ICOS (1:200; Abcam), ALK1 (1:200; Agilent Dako) antibodies were used. Flow cytometry

[0201] For flow cytometry on primary cells, eighteen blood samples were prospectively collected in EDTA tubes, shipped at room temperature and analyzed locally in the Immunology laboratory of Henri Mondor's hospital within 24 hours. Fresh whole blood (100 µL) was stained for 10 min at room temperature with a mix of antibodies directed against CD45-Krome Orange (Beckman Coulter), CD3-ECD (Beckman Coulter), CD4-PB (Beckman Coulter), CD8-AA700, CD14-FITC (Beckman Coulter), CD38-PC5.5 or isotype control (Beckman Coulter) and CD28-APC-H7 or isotype control (BD Pharmingen). The following additional antibodies were added depending on the T-cell lymphoma sub-type: anti-CD10 PE (Beckman Coulter), anti-CD7 PE (Beckman Coulter) and anti-KIR3DL1 / DL2 (Miltenyi Biotec). Red blood cells where then lysed using VersaLyse reagent (Beckman Coulter) according to manufacturer’s instructions. Samples where then washed in 1 mL phosphate- buffered saline (PBS) and immediately acquired on a Navios flow cytometer (Beckman Coulter). Data were analyzed with the Kaluza 2.1 software. Lymphocytes were gated on CD45+ CD14-and low-side scatter cells. Tumor T cells were defined according to the T-cell lymphoma sub-type: for PTCL-TFH tumor T cells were defined as CD4+CD3+ / -CD10+ / - CD7+ / - cells, and for Cutanous T cell lymphoma tumor T cells were defined as CD4+CD3+CD7-KIR3DL2+ cells. The expression of CD38 and CD28 was then studied on gated tumor cells and threshold of expression was set according to isotype controls. 150

[0202] For flow cytometry on cell lines, multiparametric flow cytometric immunofluorescence analyses were performed on cell lines. Multicolour analyses were carried out using a combination of monoclonal fluorochrome- labelled antibodies on LSRFortessaTMX-20 (BD Biosciences) using the FlowJo software. For cell lines phenotype CD28-PE (Clone CD28.2; Biolegend), CD38-APC (Clone HIT2; Biolegend), CD3-BV510 (Clone SK7; Biolegend) antibodies were used according to the manufacturer’s instructions with corresponding isotype controls, and Fixable Viability Dye eFluor™ 780 (1:1000; ThermoFisher Scientific). Cytotoxicity assays

[0203] For cytotoxicity assays on cell lines, human healthy volunteers’ PBMCs, isolated from normal human donors by Ficoll separation, were incubated with CFSE (1:50000; Biolegend) labelled tumor cell lines (SEAX, H9, DERL 2, MOLT-4, JURKAT or YT) in the presence of a dose range (0, 8, 40, 200, 1000, 5000, 25000pM) of anti-CD38 / CD28xCD3 trispecific antibody or indicated single mutants (∆) or double-mutant (∆∆) negative controls using an effector-to-target ratio of 10:1 with 20000 target cells per well (96-well plate). Spontaneous lysis was measured, in culture medium alone. After a 12 hours incubation. Target cell line lysis by PBMCs was monitored with flow cytometry (MACSQuant Analyzer 16; Miltenyi Biotec) by measuring the percentage of CFSE and Fixable Viability Dye (eFluor™ 780; 1:1000; ThermoFisher Scientific) double positive cells. Specific lysis of target cells was calculating by by subtracting the value of spontaneous lysis in medium alone.

[0204] For cytotoxicity assays with T-lymphocytes as effectors, isolation of mononuclear cells from PBMCs by Pan T cell isolation kit (Miltenyi Biotec). The T-cells were inoculated in at a rate of 2×105 / well according to effector-to-target ratio of 10:1 with CFSE labelled tumor cell lines. Cytotoxicity assay was performed as previously described. Effector and target activation

[0205] To address the PBMC or target (cell lines) activation mediated by either anti-CD38 / CD28xCD3 trispecific binding protein or indicated single mutants (∆) or double- mutant (∆∆) negative controls. PBMCs and were incubated with tumor cell lines (JURKAT or SEAX) or alone for 24 h or 96h in the presence of a dose range of the anti- CD38 / CD28xCD3 trispecific binding protein or controls antibodies, using an effector-to- target ratio of 10:1 similar at cytotoxicity assay. After a 24 h incubation, the activation of 151PBMC cells was monitored by flow cytometry with an anti CD25-PE anti body and CD69- BV421 antibody (Biolegend). After a 96 h incubation, the activation of cells was monitored with an anti HLA.DR-APC antibody (BDpharmagen) and PD1-PECy7 antibody (Biolegend). Data were acquired on a FACS MACSQuant Analyzer 16 (Miltenyi Biotec) and analysed with FlowLogic software v7.2.1. Results

[0206] CD38 and CD28 were investigated as potential targets in PTCL. A cohort of FFPE tissue samples (n=250) was analyzed by IHC and / or fluorescent multiplex labeling with tumor cell markers. CD28 and CD38 showed heterogenous expression among the different entities of PTCL (FIG.1A). Significantly higher CD38 expression was observed in entities from the innate immune system containing more cytotoxic cells like natural killer (NK) cells than those entities with no cytotoxic cells, whereas CD28 expression showed significant differences in the opposite pattern (FIG.1B). FIG.1C summarizes the percentage of samples showing co-expression of CD38 and CD28, expression of only a single marker, or expression of neither marker, as measured by IHC semi-quantitative scoring. CD38 and CD28 expression pattern on circulating tumor cells was also analyzed by flow cytometry with blood samples from PTCL-T follicular helper (TFH) (FIG.1D) and non- PTCL-TFH patients (e.g., Sezary syndrome and mycosis fungoides; FIG.1E). Rarer cases with co-expression of both markers were identified. IHC staining results for CD3, CD28, and CD38 in various PTCL entities are summarized in FIGS.4A-4E.

[0207] Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. AITL has a rich tumor microenvironment (TME) that typically harbors plenty of CD4+tumor infiltrating lymphocytes, (TIL)-T-cells. Analysis was more complicated for this PTCL entity but, thanks to multiplex labelling with tumor markers like PD-1 or ICOS, several cases with CD28 expression and some cases with co-expression of CD28 and CD38 were observed (FIGS.2A- 2D). CD28 staining was detected in atypical lymphoid cells and in tumor microenvironment cells. CD38 staining was detected in lymph node (FIG.2A middle panel and FIG.2C middle panel) or skin (FIG.2B middle panel and FIG.2D middle panel) with lymphoma. CD38 staining was heterogeneous in neoplastic cells and strongly positive in plasma cells for AITL (FIG.2A middle panel) and negative for SS (FIG.2B middle panel). PD1 staining highlighted numerous neoplastic cells sparing the diffuse polymorphic infiltrate (FIG.2A 152right panel). Multiplex staining in AITL (FIG.2A right panel) showed different configurations: one with some negative neoplastic cells, one with some double positive (CD28 and CD38) positive cells, and one with some neoplastic cells with either target. Multiplex staining in SS showed mostly co-expression between CD28 and PD1 (FIG.2B right panel). ALCL presented positive staining in tumor cells for CD28 (FIG.2C left panel) but not for CD38 (FIG.2C middle panel). ALK staining highlighted numerous neoplastic cells. Multiplex staining showed the co-expression of CD28 and ALK without co-expression with CD38 (FIG.2C right panel) in neoplastic cells. CD28 (FIG.2D left panel) and CD38 (FIG.2D middle panel) staining in skin presentation of ENKTCL showed numerous and strongly positive skin neoplastic cells with obvious angiotropism. Granzyme B (GrB) staining highlighted numerous neoplastic cells. Immunofluoresecence multiplex CD38, CD28 and GrB staining showed the co-expression of CD38 and CD28 in the GrB positive cells (FIG. 2D right panel).

[0208] Next, functional studies were undertaken to examine the cytotoxic effects of anti- CD38 / CD28xCD3 trispecific binding proteins on relevant cells. In vitro administration of anti-CD38 / CD28xCD3 binding protein induced cytotoxic lysis in several PTCL cell lines, including SEAX (a Sezary syndrome cell line; FIG.3A), H9 (MF transformed cell line; FIG. 3B), DERL2 (hepatosplenic T-cell lymphoma or PTCL of the innate immune system cell line; FIG.3C), and several leukemia cell lines, including MOLT4 (acute lymphoblastic leukemia cell line; FIG.3D), Jurkat (acute T-cell leukemia; FIG.3E), and YT (T / NK cell leukemia; FIG.3F) cell lines. Mutant forms of the trispecific binding protein with null CD38 and / or CD28 binding sites were also tested to demonstrate the specificity of the effects on the presence of the CD3, CD28, and CD38 binding sites. Administration of anti- CD38 / CD28xCD3 binding protein also stimulated effector PBMC-specific activation (without T-cell target activation). The cytotoxic effect of anti-CD38 / CD28xCD3 trispecific binding protein was also demonstrated in two different T-leukemia cell lines, YTLT (FIG. 5A) and MOLT4 (FIG.5B), using the cell lines as the target and sorted CD3+ T- lymphocytes as the effectors (E:T = 10:1). Expression of CD3, CD28, and CD38 in various cell lines as determined by flow cytometry is shown in Table 1.

[0209] Collectively, these data indicate a potential therapeutic of the tri-specific anti- CD38 / CD28xCD3 binding protein as a new immunotherapy strategy for PTCL treatment. 153Table 1. Summary of CD3, CD28, CD38 phenotype for cell lines derived from T-lymphoma or T-leukemia (Phenotype was determined by Flow Cytometry).

[0210] While the disclosure includes various embodiments, it is understood that variations and modifications will occur to those skilled in the art. Therefore, it is intended that the appended claims cover all such equivalent variations that come within the scope of the disclosure. In addition, the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0211] Each embodiment herein described may be combined with any other embodiment or embodiments unless clearly indicated to the contrary. In particular, any feature or embodiment indicated as being preferred or advantageous may be combined with any other 154feature or features or embodiment or embodiments indicated as being preferred or advantageous, unless clearly indicated to the contrary.

[0212] All references cited in this application are expressly incorporated by reference herein. 155

Claims

CLAIMS What is claimed is:

1. A method for treating peripheral T-cell lymphoma (PTCL) in an individual in need thereof, comprising administering to the individual an effective amount of an anti-CD38 T- cell engager.

2. The method of claim 1, wherein the anti-CD38 T-cell engager is a trispecific binding protein comprising a first antigen binding site that specifically binds a CD38 polypeptide, a second antigen binding site that specifically binds a CD28 polypeptide, and a third antigen binding site that specifically binds a CD3 polypeptide.

3. The method of claim 1, wherein the anti-CD38 T-cell engager is a bispecific binding protein comprising a first antigen binding site that specifically binds a CD38 polypeptide and a second antigen binding site that specifically binds a CD3 polypeptide.

4. The method of claim 2 or claim 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31) or GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32) or IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34) or QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of LAS or GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).

5. The method of claim 4, wherein the first antigen binding site comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence 156comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).

6. The method of claim 4 or claim 5, wherein the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:13, and a VL domain comprising the amino acid sequence of SEQ ID NO:

14.

7. The method of claim 4, wherein the first antigen binding site comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSFN (SEQ ID NO:31), a CDR-H2 sequence comprising the amino acid sequence of IYPGNGGT (SEQ ID NO:32), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVDSYGNGF (SEQ ID NO:34), a CDR-L2 sequence comprising the amino acid sequence of LAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).

8. The method of claim 4 or claim 7, wherein the first antigen binding site comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:5, and a VL domain comprising the amino acid sequence of SEQ ID NO:6; (b) a VH domain comprising the amino acid sequence of SEQ ID NO:17, and a VL domain comprising the amino acid sequence of SEQ ID NO:18; (c) a VH domain comprising the amino acid sequence of SEQ ID NO:21, and a VL domain comprising the amino acid sequence of SEQ ID NO:18; or (d) a VH domain comprising the amino acid sequence of SEQ ID NO:23, and a VL domain comprising the amino acid sequence of SEQ ID NO:

18. 1579. The method of claim 2 or claim 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARMFRGAFDY (SEQ ID NO:43); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QGIRND (SEQ ID NO:44), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of LQDYIYYPT (SEQ ID NO:46).

10. The method of claim 9, wherein the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:9, and a VL domain comprising the amino acid sequence of SEQ ID NO:

10.

11. The method of claim 2 or claim 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTLTEFS (SEQ ID NO:2), a CDR-H2 sequence comprising the amino acid sequence of FDPEDGET (SEQ ID NO:3), and a CDR-H3 sequence comprising the amino acid sequence of TTGRFFDWF (SEQ ID NO:4); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSVISRF (SEQ ID NO:7), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQDSNLPIT (SEQ ID NO:11).

12. The method of claim 11, wherein the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:108, and a VL domain comprising the amino acid sequence of SEQ ID NO:

109.

13. The method of claim 2 or claim 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: 158(a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYAFTTYL (SEQ ID NO:12), a CDR-H2 sequence comprising the amino acid sequence of INPGSGST (SEQ ID NO:15), and a CDR-H3 sequence comprising the amino acid sequence of ARYAYGY (SEQ ID NO:16); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QNVGTA (SEQ ID NO:19), a CDR-L2 sequence comprising the amino acid sequence of SAS, and a CDR-L3 sequence comprising the amino acid sequence of QQYSTYPFT (SEQ ID NO:22).

14. The method of claim 13, wherein the first antigen binding site comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:110, and a VL domain comprising the amino acid sequence of SEQ ID NO:111; or (b) a VH domain comprising the amino acid sequence of SEQ ID NO:116, and a VL domain comprising the amino acid sequence of SEQ ID NO:

117.

15. The method of claim 2 or claim 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYSFTNYA (SEQ ID NO:24), a CDR-H2 sequence comprising the amino acid sequence of ISPYYGDT (SEQ ID NO:25), and a CDR-H3 sequence comprising the amino acid sequence of ARRFEGFYYSMDY (SEQ ID NO:26); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHSNGNTY (SEQ ID NO:27), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of SQSTHVPLT (SEQ ID NO:29).

16. The method of claim 15, wherein the first antigen binding site comprises: (a) a VH domain comprising the amino acid sequence of SEQ ID NO:112, and a VL domain comprising the amino acid sequence of SEQ ID NO:113; or 159(b) a VH domain comprising the amino acid sequence of SEQ ID NO:118, and a VL domain comprising the amino acid sequence of SEQ ID NO:

119.

17. The method of claim 2 or claim 3, wherein the first antigen binding site that binds a CD38 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFSSYG (SEQ ID NO:41), a CDR-H2 sequence comprising the amino acid sequence of IWYDGSNK (SEQ ID NO:42), and a CDR-H3 sequence comprising the amino acid sequence of ARDPGLRYFDGGMDV (SEQ ID NO:106); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QGISSY (SEQ ID NO:107), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of QQLNSFPYT (SEQ ID NO: 229).

18. The method of claim 17, wherein the first antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:114, and a VL domain comprising the amino acid sequence of SEQ ID NO:

115.

19. The method of any one of claims 2-18, wherein the antigen binding site that binds a CD3 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHX1NX2X3TY, wherein X1is E or Q, X2is A or L, and X3 is Q, R, or F (SEQ ID NO:131), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130). 16020. The method of claim 19, wherein the CDR-L1 sequence of the VL domain of the antigen binding site that binds a CD3 polypeptide is selected from the group consisting of QSLVHNNANTY (SEQ ID NO:123), QSLVHQNAQTY (SEQ ID NO:124), QSLVHENLQTY (SEQ ID NO:125), QSLVHENLFTY (SEQ ID NO:126), QSLVHENLRTY (SEQ ID NO:127), and QSLVHDNAQTY (SEQ ID NO:128).

21. The method of claim 19 or claim 20, wherein the antigen binding site that binds a CD3 polypeptide comprises a VH domain comprising the amino acid sequence of SEQ ID NO:53 or 138, and a VL domain comprising the amino acid sequence of SEQ ID NO:54, 133, 134, 135, 136, or 137.

22. The method of claim 21, wherein the antigen binding site that binds a CD3 polypeptide comprises a VH domain comprising the amino acid sequence of SEQ ID NO:53 and a VL domain comprising the amino acid sequence of SEQ ID NO:

54.

23. The method of any one of claims 2-18, wherein the antigen binding site that binds a CD3 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid sequence of RGVYYALSPFDY (SEQ ID NO:122); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QSLVHNNGNTY (SEQ ID NO:218), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130).

24. The method of claim 23, wherein the third antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:84, and a VL domain comprising the amino acid sequence of SEQ ID NO:

85.

25. The method of any one of claims 2 and 4-24, wherein the antigen binding site that binds a CD28 polypeptide comprises: 161(a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO:139), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO:140), and a CDR-H3 sequence comprising the amino acid sequence of TRSHYGLDWNFDV (SEQ ID NO:141); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO:142), a CDR-L2 sequence comprising the amino acid sequence of KAS, and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO:144).

26. The method of claim 25, wherein the antigen binding site that binds a CD28 polypeptide comprises a VH domain comprising the amino acid sequence of SEQ ID NO:49, and a VL domain comprising the amino acid sequence of SEQ ID NO:

50.

27. The method of any one of claims 2 and 4-24, wherein the antigen binding site that binds a CD28 polypeptide comprises: (a) an antibody heavy chain variable (VH) domain comprising a CDR-H1 sequence comprising the amino acid sequence of GFSLSDYG (SEQ ID NO:212), a CDR-H2 sequence comprising the amino acid sequence of IWAGGGT (SEQ ID NO:213), and a CDR-H3 sequence comprising the amino acid sequence of ARDKGYSYYYSMDY (SEQ ID NO:214); and (b) an antibody light chain variable (VL) domain comprising a CDR-L1 sequence comprising the amino acid sequence of ESVEYYVTSL (SEQ ID NO:215), a CDR-L2 sequence comprising the amino acid sequence of AAS, and a CDR-L3 sequence comprising the amino acid sequence of QQSRKVPYT (SEQ ID NO:217).

28. The method of claim 27, wherein the second antigen binding site comprises a VH domain comprising the amino acid sequence of SEQ ID NO:51, and a VL domain comprising the amino acid sequence of SEQ ID NO:

52.

29. The method of any one of claims 2 and 4-28, wherein the trispecific binding protein comprises four polypeptide chains that form the three antigen binding sites, wherein a first polypeptide chain comprises a structure represented by the formula: 162VL2-L1-VL1-L2-CL[I] and a second polypeptide chain comprises a structure represented by the formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3 [II] and a third polypeptide chain comprises a structure represented by the formula: VH3-CH1-hinge-CH2-CH3 [III] and a fourth polypeptide chain comprises a structure represented by the formula: VL3-CL[IV] wherein: VL1 is a first immunoglobulin light chain variable domain; VL2is a second immunoglobulin light chain variable domain; VL3is a third immunoglobulin light chain variable domain; VH1 is a first immunoglobulin heavy chain variable domain; VH2 is a second immunoglobulin heavy chain variable domain; VH3is a third immunoglobulin heavy chain variable domain; CL is an immunoglobulin light chain constant domain; CH1 is an immunoglobulin CH1 heavy chain constant domain; CH2is an immunoglobulin CH2heavy chain constant domain; CH3is an immunoglobulin CH3heavy chain constant domain; hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and L1, L2, L3and L4are amino acid linkers; wherein the polypeptide of formula I and the polypeptide of formula II form a cross- over light chain-heavy chain pair; wherein VH1 and VL1 form one of the three antigen binding sites; wherein VH2 and VL2 form another of the three antigen binding sites; and wherein VH3 and VL3form another of the three antigen binding sites.

30. The method of claim 29, wherein: (a) VH1 and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2and VL2form the third antigen binding site that binds a CD3 polypeptide, and VH3and VL3form the first antigen binding site that binds a CD38 polypeptide; or (b) VH1 and VL1 form the third antigen binding site that binds a CD3 polypeptide, VH2 and VL2 form the second antigen binding site that binds a CD28 polypeptide, and VH3 and VL3 form the first antigen binding site that binds a CD38 polypeptide. 16331. The method of claim 29, wherein: (a) VH1 and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2 and VL2 form the first antigen binding site that binds a CD38 polypeptide, and VH3 and VL3form the third antigen binding site that binds a CD3 polypeptide; or (b) VH1 and VL1 form the third antigen binding site that binds a CD3 polypeptide, VH2 and VL2 form the first antigen binding site that binds a CD38 polypeptide, and VH3 and VL3 form the second antigen binding site that binds a CD28 polypeptide.

32. The method of claim 29, wherein: (a) VH1 and VL1 form the first antigen binding site that binds a CD38 polypeptide, VH2 and VL2form the third antigen binding site that binds a CD3 polypeptide, and VH3and VL3form the second antigen binding site that binds a CD28 polypeptide; or (b) VH1 and VL1 form the first antigen binding site that binds a CD38 polypeptide, VH2 and VL2 form the second antigen binding site that binds a CD28 polypeptide, and VH3 and VL3 form the third antigen binding site that binds a CD3 polypeptide.

33. The method of claim 29, wherein: VH1 and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2 and VL2form the third antigen binding site that binds a CD3 polypeptide, and VH3and VL3form the first antigen binding site that binds a CD38 polypeptide; VH1 comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYY (SEQ ID NO:139), a CDR-H2 sequence comprising the amino acid sequence of IYPGNVNT (SEQ ID NO:140), and a CDR-H3 sequence comprising the amino acid sequence of TRSHYGLDWNFDV (SEQ ID NO:141), and VL1 comprises a CDR-L1 sequence comprising the amino acid sequence of QNIYVW (SEQ ID NO:142), a CDR-L2 sequence comprising the amino acid sequence of KAS, and a CDR-L3 sequence comprising the amino acid sequence of QQGQTYPY (SEQ ID NO:144); VH2 comprises a CDR-H1 sequence comprising the amino acid sequence of GFTFTKAW (SEQ ID NO:120), a CDR-H2 sequence comprising the amino acid sequence of IKDKSNSYAT (SEQ ID NO:121), and a CDR-H3 sequence comprising the amino acid 164sequence of RGVYYALSPFDY (SEQ ID NO:122), and VL2comprises a CDR-L1 sequence comprising the amino acid sequence of QSLVHNNANTY (SEQ ID NO:123), a CDR-L2 sequence comprising the amino acid sequence of KVS, and a CDR-L3 sequence comprising the amino acid sequence of GQGTQYPFT (SEQ ID NO:130); and VH3 comprises a CDR-H1 sequence comprising the amino acid sequence of GYTFTSYA (SEQ ID NO:37), a CDR-H2 sequence comprising the amino acid sequence of IYPGQGGT (SEQ ID NO:38), and a CDR-H3 sequence comprising the amino acid sequence of ARTGGLRRAYFTY (SEQ ID NO:33), and VL3 comprises a CDR-L1 sequence comprising the amino acid sequence of QSVSSYGQGF (SEQ ID NO:39), a CDR-L2 sequence comprising the amino acid sequence of GAS, and a CDR-L3 sequence comprising the amino acid sequence of QQNKEDPWT (SEQ ID NO:36).

34. The method of claim 29, wherein VH1 and VL1 form the second antigen binding site that binds a CD28 polypeptide, VH2 and VL2 form the third antigen binding site that binds a CD3 polypeptide, and VH3and VL3form the first antigen binding site that binds a CD38 polypeptide; wherein VH1 comprises the amino acid sequence of SEQ ID NO:49 and VL1 comprises the amino acid sequence of SEQ ID NO:50; wherein VH2 comprises the amino acid sequence of SEQ ID NO:53 and VL2comprises the amino acid sequence of SEQ ID NO:54; and wherein VH3comprises the amino acid sequence of SEQ ID NO:13 and VL3comprises the amino acid sequence of SEQ ID NO:

14.

35. The method of any one of claims 29-34, wherein: (a) L1comprises the sequence GQPKAAP (SEQ ID NO:58), L2comprises the sequence TKGPS (SEQ ID NO:57), L3 comprises the amino acid S, and L4 comprises the sequence RT; (b) L1comprises the sequence GGGGSGGGGS (SEQ ID NO:55), L2comprises the sequence GGGGSGGGGS (SEQ ID NO:55), L3is 0 amino acids in length, and L4is 0 amino acids in length; (c) L1comprises the sequence GGSGSSGSGG (SEQ ID NO:59), L2comprises the sequence GGSGSSGSGG (SEQ ID NO:59), L3is 0 amino acids in length, and L4is 0 amino acids in length; or 165(d) L1comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:56), L2is 0 amino acids in length, L3 comprises the sequence GGGGSGGGGSGGGGS (SEQ ID NO:56), and L4 is 0 amino acids in length.

36. The method of any one of claims 29-34, wherein at least one of L1, L2, L3or L4comprises the sequence DKTHT (SEQ ID NO:147).

37. The method of claim 36, wherein L1, L2, L3 and L4 comprise the sequence DKTHT (SEQ ID NO:147).

38. The method of any one of claims 29-37, wherein the hinge-CH2-CH3domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3domains each comprise amino acid substitutions at positions corresponding to positions 234 and 235 of human IgG4 according to EU Index, wherein the amino acid substitutions are F234A and L235A.

39. The method of any one of claims 29-37, wherein the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3domains, and wherein the hinge-CH2-CH3 domains each comprise amino acid substitutions at positions corresponding to positions 233-236 of human IgG4 according to EU Index, wherein the amino acid substitutions are E233P, F234V, L235A, and a deletion at 236.

40. The method of any one of claims 29-37, wherein the hinge-CH2-CH3domains of the second and the third polypeptide chains are human IgG4 hinge-CH2-CH3 domains, and wherein the hinge-CH2-CH3domains each comprise amino acid substitutions at positions corresponding to positions 228 and 409 of human IgG4 according to EU Index, wherein the amino acid substitutions are S228P and R409K.

41. The method of any one of claims 29-37, wherein the hinge-CH2-CH3 domains of the second and the third polypeptide chains are human IgG1 hinge-CH2-CH3domains, and wherein the hinge-CH2-CH3domains each comprise amino acid substitutions at positions corresponding to positions 234, 235, and 329 of human IgG1 according to EU Index, wherein the amino acid substitutions are L234A, L235A, and P329A.

42. The method of any one of claims 29-37, wherein the hinge-CH2-CH3domains of the second and the third polypeptide chains are human IgG1 hinge-CH2-CH3 domains, and 166wherein the hinge-CH2-CH3domains each comprise amino acid substitutions at positions corresponding to positions 298, 299, and 300 of human IgG1 according to EU Index, wherein the amino acid substitutions are S298N, T299A, and Y300S.

43. The method of any one of claims 29-42, wherein the hinge-CH2-CH3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the hinge-CH2- CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W.

44. The method of any one of claims 29-42, wherein the hinge-CH2-CH3domain of the second polypeptide chain comprises amino acid substitutions at positions corresponding to positions 354 and 366 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are S354C and T366W; and wherein the hinge-CH2-CH3domain of the third polypeptide chain comprises amino acid substitutions at positions corresponding to positions 349, 366, 368, and 407 of human IgG1 or IgG4 according to EU Index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

45. The method of claim 29, wherein: (a) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:62, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63; (b) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:65, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63; (c) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:67, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:63; 167(d) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:60, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:68, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69; (e) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:64, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:70, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69; (f) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:61, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:66, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:71, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:69; (g) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:148, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:149, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:150, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:151; (h) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:152, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:153, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:154, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:155; (i) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:156, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:157, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:158, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:159; (j) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:160, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:161, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:162, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:163; 168(k) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:164, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:165, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:166, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:167; (l) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:168, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:169, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:170, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:171; (m) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:172, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:173, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:174, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:175; or (n) the first polypeptide chain comprises the amino acid sequence of SEQ ID NO:176, the second polypeptide chain comprises the amino acid sequence of SEQ ID NO:177, the third polypeptide chain comprises the amino acid sequence of SEQ ID NO:178, and the fourth polypeptide chain comprises the amino acid sequence of SEQ ID NO:

179.

46. The method of any one of claims 2-45, wherein the CD38 polypeptide is a human CD38 polypeptide.

47. The method of any one of claims 2-46, wherein the CD3 polypeptide is a human CD3 polypeptide.

48. The method of any one of claims 2 and 4-47, wherein the CD28 polypeptide is a human CD28 polypeptide.

49. The method of any one of claims 1-48, wherein the PTCL is angioimmunoblastic T- cell lymphoma (AITL), hepatosplenic T-cell lymphoma (HSTL), adult T-cell leukemia / lymphoma (ATLL), extranodal NK / T-cell lymphoma (ENKTCL), mycosis fungoides (MF), Sezary syndrome (SS), anaplastic large cell ALK- lymphoma (ALCL), PTCL-not otherwise specified (NOS), enteropathy-type T-cell lymphoma (EATL), monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), primary cutaneous CD4+ 169lymphoproliferative disorder, subcutaneous T-cell lymphoma panniculitis-like (SCTCL), or primary cutaneous ^ ^ T-cell lymphoma.

50. The method of any one of claims 1-48, wherein the PTCL is hepatosplenic T-cell lymphoma (HSTL), Sezary syndrome (SS), or mycosis fungoides (MF).

51. The method of claim 49 or claim 50, wherein the mycosis fungoides (MF) is transformed mycosis fungoides.

52. The method of any one of claims 1-51, wherein cells of the PTCL express CD38 and / or CD28.

53. The method of any one of claims 1-52, wherein the individual is a human.

54. An anti-CD38 T-cell engager for use in a method for treating peripheral T-cell lymphoma (PTCL) in an individual in need thereof, said method comprising administering to the individual an effective amount of the anti-CD38 T-cell engager.

55. Use of an anti-CD38 T-cell engager in the manufacture of a medicament for treating peripheral T-cell lymphoma (PTCL) in an individual in need thereof.

56. A kit, comprising an anti-CD38 T-cell engager and instructions for administering to an individual with peripheral T-cell lymphoma (PTCL) an effective amount of the anti-CD38 T-cell engager according to the method of any one of claims 1-53. 170

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