CD38 and ICAM1 antibodies and their uses

Abstract

Disclosed herein are anti-CD38 antibodies, anti-ICAM1 antibodies, pharmaceutical compositions comprising the anti-CD38 antibodies and / or anti-ICAM1 antibodies, and methods for treating proliferative diseases. In certain embodiments, also disclosed herein are multispecific antibodies (e.g., bispecific antibodies) comprising a first targeting moiety that specifically binds to CD38 and a second targeting moiety that specifically binds to ICAM1, pharmaceutical compositions comprising the multispecific antibodies, and methods for treating proliferative diseases.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 768,566, filed on November 16, 2018, which is incorporated herein by reference in its entirety.

[0003] Sequence Listing

[0004] This application contains a sequence listing submitted electronically in ASCII format, which is hereby incorporated by reference in its entirety. The ASCII copy was created on November 14, 2019, is named 55429-701_601_SL.txt, and is 590,037 bytes in size. Background Art

[0005] Antibodies that bind to CD38 can be used to treat cancers that express CD38. Anti-CD38 antibodies are thought to kill cancer cells through various mechanisms, including antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. One such antibody, daratumumab, is approved for the treatment of adults with multiple myeloma. Reduced CD38 expression may limit the efficacy of anti-CD38 antibodies. Suggestions to overcome this limitation include treatment with antibodies that have higher affinity for CD38, treatment with antibodies that bind to different epitopes on CD38, treatment with antibodies that more effectively inhibit CD38 enzymatic activity, treatment with tetravalent anti-CD38 antibodies, and concomitant treatment with all-trans retinoic acid to increase CD38 expression.

[0006] Incorporation by reference

[0007] All publications, patents, and patent applications herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event of a conflict in a terminology herein and that of an incorporated reference, the terminology herein controls. Summary of the Invention

[0008] One embodiment provides a multispecific protein comprising a first component that specifically binds to CD38 and a second component that specifically binds to ICAM1. In some embodiments, the multispecific protein is bivalent, trivalent, or tetravalent. In some embodiments, the first component comprises an antibody or antigen-binding fragment thereof that specifically binds to CD38. In some embodiments, the second component comprises an antibody or antigen-binding fragment thereof that specifically binds to ICAM1. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to CD38 comprises the variable domain of an IgG heavy chain and the variable domain of an IgG light chain. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to ICAM1 comprises the variable domain of an IgG heavy chain and the variable domain of an IgG light chain. In some embodiments, the multispecific protein further comprises an Fc region. In some embodiments, the Fc region comprises a heterodimeric Fc region. In some embodiments, the Fc region comprises one or more mutations that increase the half-life of the multispecific protein. In some embodiments, the Fc region comprises one or more stabilizing mutations. In some embodiments, the Fc region comprises one or more mutations that modulate its interaction with an Fc receptor.

[0009] In some embodiments, multispecific proteins are provided, wherein the Fc region comprises one or more mutations that increase binding of the Fc region to Fc receptors. In some embodiments, the Fc region comprises one or more mutations that reduce glycosylation of the Fc region. In some embodiments, the one or more mutations that reduce glycosylation of the Fc region comprise a mutation at a position corresponding to position N297 of human IgG1, wherein numbering is according to the EU index of Kabat et al. In some embodiments, the Fc region is afucosylated. In some embodiments, the Fc region comprises one or more mutations that increase ADCC or CDC activity. In some embodiments, the Fc region comprises one or more mutations that increase ADCC, wherein the mutations that increase ADCC are at positions corresponding to positions 239, 332, and 330 of human IgG1, wherein the mutations are S239D, I332E, and A330L, and wherein amino acid numbering is according to the EU index of Kabat et al. In some embodiments, the heterodimeric Fc region comprises a knob chain and a hole chain, wherein the knob chain and the hole chain form a knob-in-hole (KIH) structure. In some embodiments, the knob chain comprises the mutation T366W, and the hole chain comprises the mutations T366S, L368A, and Y407V, wherein the amino acid positions are numbered according to the EU index of Kabat et al. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to CD38 comprises an anti-CD38 IgG, and the antibody or antigen-binding fragment thereof that specifically binds to ICAM1 comprises an anti-ICAM1 single-chain variable fragment (anti-ICAM1 scFv). In some embodiments, the anti-CD38 IgG comprises two light chains and each light chain is fused to a single anti-ICAM1 scFv. In some embodiments, the C-terminus of each light chain of the anti-CD38 IgG is fused to a single anti-ICAM1 scFv. In some embodiments, the N-terminus of each heavy chain of the anti-CD38 IgG is fused to a single anti-ICAM1 scFv. In some embodiments, the anti-CD38 IgG comprises two heavy chains and the C-terminus of each heavy chain is conjugated to a single anti-ICAM1 scFv.

[0010] In some embodiments, the first component comprises an anti-CD38 IgG and the second component comprises two anti-ICAM1 variable heavy chain domains and two anti-ICAM-1 variable light chain domains, wherein each variable heavy chain domain of the anti-CD38 IgG is fused to one of the anti-ICAM1 variable heavy chain domains, and each variable light chain domain of the anti-CD38 IgG is fused to one of the anti-ICAM1 variable light chain domains. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to CD38 is a monovalent anti-CD38 antibody or antigen-binding fragment thereof. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to ICAM1 is a monovalent anti-ICAM1 antibody or antigen-binding fragment thereof. In some embodiments, the monovalent anti-CD38 antibody or antigen-binding fragment thereof comprises an anti-CD38 Fab. In some embodiments, the monovalent anti-ICAM1 antibody or antigen-binding fragment thereof comprises an anti-ICAM1 scFv. In some embodiments, the multispecific protein comprises an anti-CD38 Fab, an anti-ICAM1 scFv, and an Fc region. In some embodiments, the Fc region is a heterodimeric Fc region comprising a KIH structure.In some embodiments, the monovalent anti-CD38 antibody or antigen-binding fragment thereof comprises a variable heavy chain domain (VH) and a variable light chain domain (VL), and wherein the monovalent anti-ICAM1 antibody or antigen-binding fragment thereof comprises a variable heavy chain domain (VH).

[0011] In some embodiments, the multispecific protein further comprises an Fc region. In some embodiments, the Fc region is a heterodimeric Fc region comprising a KIH structure, and wherein the multispecific protein has a common light chain bispecific format. In some embodiments, the first component that specifically binds to CD38 comprises a heavy chain comprising complementary determining regions CDR1, CDR2, and CDR3, wherein the CDR1, CDR2, and CDR3 of the heavy chain comprise a set of sequences selected from the group consisting of sequences of the following groups:

[0012] CDR1:CDR2:CDR3(SEQ ID No.1:SEQ ID No:2:SEQ ID No.3);

[0013] CDR1:CDR2:CDR3(SEQ ID No.4:SEQ ID No.5:SEQ ID No.3);

[0014] CDR1:CDR2:CDR3(SEQ ID No.6:SEQ ID No.2:SEQ ID No.7);

[0015] CDR1:CDR2:CDR3(SEQ ID No.1:SEQ ID No.2:SEQ ID No.7);

[0016] CDR1:CDR2:CDR3(SEQ ID No.4:SEQ ID No.5:SEQ ID No.7);

[0017] CDR1:CDR2:CDR3(SEQ ID No.4:SEQ ID No.2:SEQ ID No.7);

[0018] CDR1:CDR2:CDR3(SEQ ID No.6:SEQ ID No.2:SEQ ID No.3);

[0019] CDR1:CDR2:CDR3(SEQ ID No.8:SEQ ID No.5:SEQ ID No.3);

[0020] CDR1:CDR2:CDR3(SEQ ID No.9:SEQ ID No.2:SEQ ID No.10);

[0021] CDR1:CDR2:CDR3(SEQ ID No.11:SEQ ID No.12:SEQ ID No.13);

[0022] CDR1:CDR2:CDR3(SEQ ID No.14:SEQ ID No.15:SEQ ID No.16);

[0023] CDR1:CDR2:CDR3(SEQ ID No.17:SEQ ID No.18:SEQ ID No.19);

[0024] CDR1:CDR2:CDR3(SEQ ID No.20:SEQ ID No.21:SEQ ID No.22);

[0025] CDR1:CDR2:CDR3(SEQ ID No.23:SEQ ID No.24:SEQ ID No.25);

[0026] CDR1:CDR2:CDR3(SEQ ID No.26:SEQ ID No.27:SEQ ID No.28);

[0027] CDR1:CDR2:CDR3 (SEQ ID No.29:SEQ ID No.30:SEQ ID No.31);

[0028] CDR1:CDR2:CDR3 (SEQ ID No.32:SEQ ID No.33:SEQ ID No.34);

[0029] CDR1:CDR2:CDR3 (SEQ ID No.35:SEQ ID No.36:SEQ ID No.37);

[0030] CDR1:CDR2:CDR3 (SEQ ID No.38:SEQ ID No.39:SEQ ID No.40);

[0031] CDR1:CDR2:CDR3 (SEQ ID No.41:SEQ ID No.42:SEQ ID No.43);

[0032] CDR1:CDR2:CDR3 (SEQ ID No.44:SEQ ID No.45:SEQ ID No.46);

[0033] CDR1:CDR2:CDR3 (SEQ ID No.47:SEQ ID No.48:SEQ ID No.49);

[0034] CDR1:CDR2:CDR3 (SEQ ID No.50:SEQ ID No.51:SEQ ID No.52);

[0035] CDR1:CDR2:CDR3 (SEQ ID No.53:SEQ ID No.54:SEQ ID No.55);

[0036] CDR1:CDR2:CDR3 (SEQ ID No.56:SEQ ID No.57:SEQ ID No.58); and

[0037] CDR1:CDR2:CDR3 (SEQ ID No.59:SEQ ID No.60:SEQ ID No.61).

[0038] In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the first component comprise the following sequence: CDR1:CDR2:CDR3 (SEQ ID No. 14: SEQ ID No. 15: SEQ ID No. 16). In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the first component comprise the following sequence: CDR1:CDR2:CDR3 (SEQ ID No. 17: SEQ ID No. 18: SEQ ID No. 19). In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the first component comprise the following sequence: CDR1:CDR2:CDR3 (SEQ ID No. 1: SEQ ID No. 2: SEQ ID No. 7). In some embodiments, the first component that specifically binds to CD38 comprises a light chain comprising complementary determining regions CDR1, CDR2, and CDR3, wherein the CDR1, CDR2, and CDR3 of the light chain comprise a sequence selected from the group consisting of:

[0039] CDR1:CDR2:CDR3(SEQ ID No.62:SEQ ID No.63:SEQ ID No.64);

[0040] CDR1:CDR2:CDR3(SEQ ID No.65:SEQ ID No.66:SEQ ID No.67);

[0041] CDR1:CDR2:CDR3(SEQ ID No.68:SEQ ID No.69:SEQ ID No.70);

[0042] CDR1:CDR2:CDR3(SEQ ID No.71:SEQ ID No.72:SEQ ID No.73);

[0043] CDR1:CDR2:CDR3(SEQ ID No.74:SEQ ID No.75:SEQ ID No.76);

[0044] CDR1:CDR2:CDR3(SEQ ID No.77:SEQ ID No.78:SEQ ID No.79);

[0045] CDR1:CDR2:CDR3(SEQ ID No.80:SEQ ID No.81:SEQ ID No.82);

[0046] CDR1:CDR2:CDR3 (SEQ ID No.83:SEQ ID No.84:SEQ ID No.85);

[0047] CDR1:CDR2:CDR3 (SEQ ID No.86:SEQ ID No.78:SEQ ID No.87);

[0048] CDR1:CDR2:CDR3 (SEQ ID No.86:SEQ ID No.78:SEQ ID No.88);

[0049] CDR1:CDR2:CDR3 (SEQ ID No.89:SEQ ID No.90:SEQ ID No.91); !

[0050] [[ID=1>>12]]CDR1:CDR2:CDR3 (SEQ ID No.92:SEQ ID No.78:SEQ ID No.93);

[0051] CDR1:CDR2:CDR3 (SEQ ID No.94:SEQ ID No.84:SEQ ID No.95); !

[0052] CDR1:CDR2:CDR3 (SEQ ID No.96:SEQ ID No.81:SEQ ID No.97);

[0053] CDR1:CDR2:CDR3 (SEQ ID No.98:SEQ ID No.99:SEQ ID No.100);

[0054] CDR1:CDR2:CDR3 (SEQ ID No.77:SEQ ID No.72:SEQ ID No.101); and

[0055] CDR1:CDR2:CDR3 (SEQ ID No.102:SEQ ID No.84:SEQ ID No.103).

[0056] In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the first component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID No. 68: SEQ ID No. 69: SEQ ID No. 70). In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the first component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID No. 71: SEQ ID No. 72: SEQ ID No. 73). In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the first component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID No. 62: SEQ ID No. 63: SEQ ID No. 64).

[0057] In some embodiments, the first component comprises six CDRs comprising sequences as shown in any of the following groups of sequences:

[0058] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.1:SEQ ID No:2:SEQ IDNo.3)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64);

[0059] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.4:SEQ ID No:5:SEQ IDNo.3)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64);

[0060] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.6:SEQ ID No:2:SEQ ID No.7)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64);

[0061] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.1:SEQ ID No:2:SEQ IDNo.7)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64);

[0062] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.4:SEQ ID No:5:SEQ IDNo.7)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64);

[0063] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.4:SEQ ID No:2:SEQ IDNo.7)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64);

[0064] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.6:SEQ ID No:2:SEQ IDNo.3)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64);

[0065] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.8:SEQ ID No:5:SEQ IDNo.3)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64);

[0066] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.9:SEQ ID No:2:SEQ IDNo.10)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64);

[0067] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.59:SEQ ID No:60:SEQID No.61)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64);

[0068] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.11:SEQ ID No:12:SEQID No.13)-(SEQ ID No.65:SEQ ID No:66:SEQ ID No.67);

[0069] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.14:SEQ ID No:15:SEQID No.16)-(SEQ ID No.68:SEQ ID No:69:SEQ ID No.70);

[0070] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.17:SEQ ID No:18:SEQID No.19)-(SEQ ID No.71:SEQ ID No:72:SEQ ID No.73);

[0071] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.20:SEQ ID No:21:SEQID No.22)-(SEQ ID No.74:SEQ ID No:75:SEQ ID No.76);

[0072] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.23:SEQ ID No:24:SEQID No.25)-(SEQ ID No.77:SEQ ID No:78:SEQ ID No.79);

[0073] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.26:SEQ ID No:27:SEQID No.28)-(SEQ ID No.80:SEQ ID No:81:SEQ ID No.82);

[0074] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.29:SEQ ID No:30:SEQID No.31)-(SEQ ID No.83:SEQ ID No:84:SEQ ID No.85);

[0075] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.32:SEQ ID No:33:SEQID No.34)-(SEQ ID No.86:SEQ ID No:78:SEQ ID No.87);

[0076] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.35:SEQ ID No:36:SEQID No.37)-(SEQ ID No.86:SEQ ID No:78:SEQ ID No.88);

[0077] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.38:SEQ ID No:39:SEQID No.40)-(SEQ ID No.89:SEQ ID No:90:SEQ ID No.91);

[0078] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.41:SEQ ID No:42:SEQID No.43)-(SEQ ID No.92:SEQ ID No:78:SEQ ID No.93);

[0079] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.44:SEQ ID No:45:SEQID No.46)-(SEQ ID No.94:SEQ ID No:84:SEQ ID No.95);

[0080] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.47:SEQ ID No:48:SEQID No.49)-(SEQ ID No.96:SEQ ID No:81:SEQ ID No.97);

[0081] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.50:SEQ ID No:51:SEQID No.52)-(SEQ ID No.98:SEQ ID No:99:SEQ ID No.100);

[0082] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.53:SEQ ID No:54:SEQID No.55)-(SEQ ID No.77:SEQ ID No:72:SEQ ID No.101); and

[0083] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.56:SEQ ID No:57:SEQID No.58)-(SEQ ID No.102:SEQ ID No:84:SEQ ID No.103).

[0084] In some embodiments, the first component comprises six CDRs comprising the following group of sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID No. 14: SEQ ID No: 15: SEQ ID No. 16)-(SEQ ID No. 68: SEQ ID No: 69: SEQ ID No. 70). In some embodiments, the first component comprises six CDRs having the following sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID No. 17: SEQ ID No: 18: SEQ ID No. 19)-(SEQ ID No. 71: SEQ ID No: 72: SEQ ID No. 73). In some embodiments, the first component comprises six CDRs comprising one of the following group of sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID No.1:SEQ ID No:2:SEQ ID No.7)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64).

[0085] In some embodiments, the second component that specifically binds to ICAM1 comprises a heavy chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 of the heavy chain comprise a sequence selected from the group consisting of:

[0086] CDR1:CDR2:CDR3(SEQ ID No.208:SEQ ID No.209:SEQ ID No.210);

[0087] CDR1:CDR2:CDR3(SEQ ID No.211:SEQ ID No.212:SEQ ID No.213);

[0088] CDR1:CDR2:CDR3(SEQ ID No.214:SEQ ID No.215:SEQ ID No.216);

[0089] CDR1:CDR2:CDR3(SEQ ID No.217:SEQ ID No.218:SEQ ID No.219);

[0090] CDR1:CDR2:CDR3(SEQ ID No.214:SEQ ID No.220:SEQ ID No.221);

[0091] CDR1:CDR2:CDR3(SEQ ID No.222:SEQ ID No.223:SEQ ID No.224);

[0092] CDR1:CDR2:CDR3(SEQ ID No.225:SEQ ID No.223:SEQ ID No.224);

[0093] CDR1:CDR2:CDR3(SEQ ID No.222:SEQ ID No.223:SEQ ID No.226);

[0094] CDR1:CDR2:CDR3(SEQ ID No.222:SEQ ID No.227:SEQ ID No.224);

[0095] CDR1:CDR2:CDR3(SEQ ID No.228:SEQ ID No.229SEQ ID No.230);

[0096] CDR1:CDR2:CDR3(SEQ ID No.228:SEQ ID No.220:SEQ ID No.231);

[0097] CDR1:CDR2:CDR3(SEQ ID No.232:SEQ ID No.229:SEQ ID No.233);

[0098] CDR1:CDR2:CDR3(SEQ ID No.208:SEQ ID No.234:SEQ ID No.210);

[0099] CDR1:CDR2:CDR3(SEQ ID No.235:SEQ ID No.236:SEQ ID No.237);

[0100] CDR1:CDR2:CDR3(SEQ ID No.238:SEQ ID No.239SEQ ID No.240);

[0101] CDR1:CDR2:CDR3(SEQ ID No.241:SEQ ID No.242:SEQ ID No.243);

[0102] CDR1:CDR2:CDR3(SEQ ID No.241:SEQ ID No.244:SEQ ID No.245);

[0103] CDR1:CDR2:CDR3(SEQ ID No.241:SEQ ID No.246:SEQ ID No.245);

[0104] CDR1:CDR2:CDR3(SEQ ID No.247:SEQ ID No.248:SEQ ID No.249);

[0105] CDR1:CDR2:CDR3(SEQ ID No.250:SEQ ID No.251:SEQ ID No.252); and

[0106] CDR1:CDR2:CDR3 (SEQ ID No. 404: SEQ ID No. 405: SEQ ID No. 406).

[0107] In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the second component comprise the following sequence: (CDR1:CDR2:CDR3 (SEQ ID No. 228: SEQ ID No. 229: SEQ ID No. 230). In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the second component comprise the following sequence: CDR1:CDR2:CDR3 (SEQ ID No. 222: SEQ ID No. 223: SEQ ID No. 224). In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the second component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID No. 232: SEQ ID No. 229: SEQ ID No. 233). In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the second component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID No. 404: SEQ ID No. 405: SEQ ID No.406).

[0108] In some embodiments, the second component that specifically binds to ICAM1 comprises a light chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 of the light chain comprise a set of sequences selected from the group consisting of:

[0109] CDR1:CDR2:CDR3(SEQ ID No.253:SEQ ID No.254:SEQ ID No.255);

[0110] CDR1:CDR2:CDR3(SEQ ID No.256:SEQ ID No.257:SEQ ID No.258);

[0111] CDR1:CDR2:CDR3(SEQ ID No.259:SEQ ID No.260:SEQ ID No.261);

[0112] CDR1:CDR2:CDR3(SEQ ID No.262:SEQ ID No.263:SEQ ID No.264);

[0113] CDR1:CDR2:CDR3(SEQ ID No.265:SEQ ID No.260:SEQ ID No.266);

[0114] CDR1:CDR2:CDR3(SEQ ID No.267:SEQ ID No.263:SEQ ID No.264);

[0115] CDR1:CDR2:CDR3(SEQ ID No.268:SEQ ID No.263:SEQ ID No.264);

[0116] CDR1:CDR2:CDR3(SEQ ID No.269:SEQ ID No.263:SEQ ID No.264);

[0117] CDR1:CDR2:CDR3(SEQ ID No.270:SEQ ID No.260:SEQ ID No.271);

[0118] CDR1:CDR2:CDR3(SEQ ID No.272:SEQ ID No.260:SEQ ID No.266);

[0119] CDR1:CDR2:CDR3 (SEQ ID No.259:SEQ ID No.273:SEQ ID No.266);

[0120] CDR1:CDR2:CDR3 (SEQ ID No.274:SEQ ID No.275:SEQ ID No.276);

[0121] CDR1:CDR2:CDR3 (SEQ ID No.277:SEQ ID No.275:SEQ ID No.278);

[0122] CDR1:CDR2:CDR3 (SEQ ID No.279:SEQ ID No.280:SEQ ID No.281);

[0123] CDR1:CDR2:CDR3 (SEQ ID No.282:SEQ ID No.283:SEQ ID No.284);

[0124] CDR1:CDR2:CDR3 (SEQ ID No.62:SEQ ID No.63:SEQ ID No.64); and

[0125] CDR1:CDR2:CDR3 (SEQ ID No.407:SEQ ID No.408:SEQ ID No.409).

[0126] In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the second component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID No. 270: SEQ ID No. 260: SEQ ID No. 271). In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the second component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID No. 267: SEQ ID No. 263: SEQ ID No. 264). In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the second component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID No. 259: SEQ ID No. 273: SEQ ID No. 266). In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the second component comprise sequences of the following group: (i) CDR1:CDR2:CDR3 (SEQ ID No. 407: SEQ ID No. 408: SEQ ID No. 409). In some embodiments, the second component comprises six CDRs comprising a sequence selected from the group consisting of sequences of the following groups:

[0127] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.208:SEQ ID No:209:SEQID No.210)-(SEQ ID No.253:SEQ ID No:254:SEQ ID No.255);

[0128] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.211:SEQ ID No:212:SEQID No.213)-(SEQ ID No.256:SEQ ID No:257:SEQ ID No.258);

[0129] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.214:SEQ ID No:215:SEQID No.216)-(SEQ ID No.259:SEQ ID No:260:SEQ ID No.261);

[0130] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.217:SEQ ID No:218:SEQID No.219)-(SEQ ID No.262:SEQ ID No:263:SEQ ID No.264);

[0131] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.214:SEQ ID No:220:SEQID No.221)-(SEQ ID No.265:SEQ ID No:260:SEQ ID No.266);

[0132] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.222:SEQ ID No:223:SEQID No.224)-(SEQ ID No.267:SEQ ID No:263:SEQ ID No.264);

[0133] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.225:SEQ ID No:223:SEQID No.224)-(SEQ ID No.268:SEQ ID No:263:SEQ ID No.264);

[0134] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.222:SEQ ID No:223:SEQID No.226)-(SEQ ID No.268:SEQ ID No:263:SEQ ID No.264);

[0135] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.222:SEQ ID No:227:SEQID No.224)-(SEQ ID No.269:SEQ ID No:263:SEQ ID No.264);

[0136] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.228:SEQ ID No:229:SEQID No.230)-(SEQ ID No.270:SEQ ID No:260:SEQ ID No.271);

[0137] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.228:SEQ ID No:220:SEQID No.231)-(SEQ ID No.272:SEQ ID No:260:SEQ ID No.266);

[0138] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.232:SEQ ID No:229:SEQID No.233)-(SEQ ID No.259:SEQ ID No:273:SEQ ID No.266);

[0139] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.208:SEQ ID No:234:SEQID No.210)-(SEQ ID No.274:SEQ ID No:275:SEQ ID No.276);

[0140] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.208:SEQ ID No:234:SEQID No.210)-(SEQ ID No.277:SEQ ID No:275:SEQ ID No.278);

[0141] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.235:SEQ ID No:236:SEQID No.237)-(SEQ ID No.279:SEQ ID No:280:SEQ ID No.281);

[0142] HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.238:SEQ ID No:239:SEQID No.240)-(SEQ ID No.282:SEQ ID No:283:SEQ ID No.284); <00044​​​​​​​​​​​​​​​In some embodiments, the second component comprises six CDRs comprising the following sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID No. 228: SEQ ID No. 229: SEQ ID No. 230)-(SEQ ID No. 270: SEQ ID No. 260: SEQ ID No. 271). In some embodiments, the second component comprises six CDRs comprising the following sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID No. 222: SEQ ID No: 223: SEQ ID No. 224)-(SEQ ID No. 267: SEQ ID No: 263: SEQ ID No. 264). In some embodiments, the second component comprises six CDRs comprising the following sequence: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID No. 232: SEQ ID No: 229: SEQ ID No. 233)-(SEQ ID No. 259: SEQ ID No: 273: SEQ ID No. 266). In some embodiments, the second component comprises six CDRs comprising a sequence of the following group: HC (CDR1: CDR2: CDR3) - LC (CDR1: CDR2: CDR3) (SEQ ID No. 404: SEQ ID No. 405: SEQ ID No. 406) - (SEQ ID No. 407: SEQ ID No. 408: SEQ ID No. 409. In some embodiments, the first component comprises a variable heavy chain domain and wherein the variable heavy chain domain comprises a sequence at least about 90% identical to a sequence selected from the group consisting of SEQ ID Nos. 104-129. In some embodiments, the first component comprises a variable light chain domain and wherein the variable light chain domain comprises a sequence at least about 90% identical to a sequence selected from the group consisting of SEQ ID Nos. 130-155. In some embodiments, the second component comprises a variable heavy chain domain and wherein the variable heavy chain domain comprises a sequence at least about 90% identical to a sequence selected from the group consisting of SEQ ID Nos. In some embodiments, the second component comprises a variable light chain domain, wherein the variable light chain domain comprises a sequence having at least about 90% identity to a sequence selected from the group consisting of SEQ ID Nos. 288-309. In some embodiments, the second component comprises a variable light chain domain, wherein the variable light chain domain comprises a sequence having at least about 90% identity to a sequence selected from the group consisting of SEQ ID Nos. 310-326.In some embodiments, the first component that specifically binds to CD38 comprises a full-length antibody comprising a light chain and a heavy chain, wherein the heavy chain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID Nos. 156-181. In some embodiments, the light chain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID Nos. 182-207. In some embodiments, the second component that specifically binds to ICAM1 comprises a full-length antibody comprising a light chain and a heavy chain, wherein the heavy chain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID Nos. 328-349. In some embodiments, the light chain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID Nos. 183 and 350-366.

[0149] One embodiment provides a multispecific protein comprising a heavy chain polypeptide (HC) comprising a VH and a light chain polypeptide (LC) comprising a VL, wherein the heavy chain polypeptide and the light chain polypeptide comprise a sequence that is at least about 90% identical to a sequence selected from the group consisting of:

[0150] HC: LC (SEQ ID No. 160: SEQ ID No. 397);

[0151] HC:LC(SEQ ID No.389:SEQ ID No.186);

[0152] HC: LC (SEQ ID No. 163: SEQ ID No. 395);

[0153] HC:LC(SEQ ID No.387:SEQ ID No.189);

[0154] HC: LC (SEQ ID No. 164: SEQ ID No. 396);

[0155] HC:LC(SEQ ID No.388:SEQ ID No.190);

[0156] HC: LC (SEQ ID No. 156: SEQ ID No. 393);

[0157] HC:LC(SEQ ID No.384:SEQ ID No.182);

[0158] HC: LC (SEQ ID No. 385: SEQ ID No. 182); and

[0159] HC: LC (SEQ ID No. 386: SEQ ID No. 394).

[0160] One embodiment provides a multispecific protein comprising a first heavy chain polypeptide (HC1), a light chain polypeptide (LC), and a second heavy chain polypeptide (HC2), wherein the HC1, LC, and HC2 comprise sequences that are at least about 90% identical to a sequence selected from the group consisting of:

[0161] HC1:LC:HC2(SEQ ID No.391:SEQ ID No.186:SEQ ID No.383);

[0162] HC1:LC:HC2(SEQ ID No.392:SEQ ID No.190:SEQ ID No.383); and

[0163] HC1:LC:HC2 (SEQ ID No. 156: SEQ ID No. 182: SEQ ID No. 383).

[0164] One embodiment provides a multispecific protein comprising a first heavy chain polypeptide (HC1), a first light chain polypeptide (LC1), a second heavy chain polypeptide (HC2), and a second light chain polypeptide (LC2), and wherein the HC1, LC1, HC2, and LC2 comprise sequences that are at least about 90% identical to a sequence selected from the group consisting of:

[0165] HC1:LC1:HC2:HC3(SEQ ID No.390:SEQ I No.189:SEQ ID No.348:SEQ IDNo.189);

[0166] HC1:LC1:HC2:HC3(SEQ ID No.390:SEQ ID No.189:SEQ ID No.349:SEQ IDNo.189);

[0167] HC1:LC1:HC2:HC3(SEQ ID No.391:SEQ ID No.186:SEQ ID No.348:SEQ IDNo.186); and

[0168] HC1:LC1:HC2:HC3 (SEQ ID No. 391: SEQ ID No. 186: SEQ ID No. 349: SEQ ID No. 186).

[0169] One embodiment provides a multispecific protein comprising a heavy chain sequence that is at least about 95% identical to the sequence shown in SEQ ID No. 410 and a light chain sequence that is at least about 95% identical to the sequence shown in SEQ ID No. 411.

[0170] In some embodiments, the heavy chain comprises CDR1, CDR2, and CDR3, wherein CDR1 has a sequence of SEQ ID No. 412 (GFSLSZ1Z2AMG), CDR2 has a sequence of SEQ ID No. 413 (GIIGSSZ3Z4TYYAZ5WAKG), and CDR3 has a sequence of SEQ ID No. 414 (VRDPYDSZ6Z7Z8Z9YRL). In some embodiments, the light chain comprises CDR1, CDR2, and CDR3, wherein CDR1 has a sequence of SEQ ID No. 415 (QASZ 10 Z 11 IYZ 12 YZ 13 Z 14 ) sequence, CDR2 has SEQ ID No.416 (DASKZ 15 AS), and CDR3 has SEQ ID No. 417 (QQAYSSZ 16 Z 17 Z 18 DNZ 19 In some embodiments, Z1 is serine or threonine; Z2 is histidine or tyrosine; Z3 is aspartic acid or glycine; Z4 is arginine or serine; Z5 is serine or threonine; Z6 is phenylalanine or tyrosine; Z7 is aspartic acid or glycine; Z8 is aspartic acid or alanine; Z9 is glycine or alanine; Z 10 is glutamine or glutamate; Z 11 is serine or asparagine; Z 12 is serine or arginine; Z 13 is cysteine ​​or leucine; Z 14 is serine or leucine; Z 15 is valine or leucine; Z 16 is serine or glycine; Z 17 is serine or asparagine; Z 18 is valine or isoleucine; and Z 19 It is valine or alanine.

[0171] In some embodiments, the multispecific protein induces an enhanced antigen-dependent cellular cytotoxicity (ADCC) effect on target cells compared to the ADCC effect induced on target cells by an otherwise identical multispecific protein that does not comprise an afucosylated Fc region.

[0172] In some embodiments, the multispecific protein induces an enhanced ADCC effect on target cells compared to the ADCC effect on target cells induced by an otherwise identical multispecific protein that does not comprise an Fc region, the Fc region comprising mutations at positions 239, 332, and 330 corresponding to human IgG1, wherein the mutations are S239D, I332E, and A330L, and wherein amino acid numbering is according to the EU index of Kabat et al.

[0173] In some embodiments, the amount of multispecific protein bound to cells expressing CD38 and ICAM1 is greater than the amount bound to cells by a monospecific protein comprising a first component that binds to CD38, wherein binding to cells is measured by flow cytometry. In some embodiments, the multispecific protein induces an enhanced ADCC effect on target cells compared to the ADCC effect on target cells induced by a monospecific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, the multispecific protein induces an enhanced CDC effect on target cells compared to the CDC effect on target cells induced by a monospecific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, the multispecific protein binds to target cells expressing CD38 and ICAM1 with enhanced affinity compared to a monospecific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raji cells. In some embodiments, the multispecific protein induces an enhanced ADCC effect on target cells expressing ICAM1 or CD38 as compared to the ADCC effect on target cells induced by a monospecific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, the cell expresses at least 5,000, 10,000, 15,000, 20,000, 30,000, 50,000, 100,000, 150,000, 200,000, 250,000, 300,000, 400,000, or 500,000 ICAM1 proteins on its surface. In some embodiments, the cell expresses at least 50,000 ICAM1 proteins on its surface. In some embodiments, the cell expresses at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on its surface. In some embodiments, the cell expresses at least 300 CD38 proteins on its surface. In some embodiments, the cell expresses fewer than about 350,000, 300,000, 250,000, 200,000, 150,000, 100,000, 50,000, 30,000, 20,000, 15,000, 10,000, or 5,000 CD38 proteins on its surface. In some embodiments, the cell expresses fewer than about 350,000 CD38 proteins on its surface.In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 10. In some embodiments, the cell expresses at least as much ICAM1 on its surface as NCI-H2291 cells. In some embodiments, the cell expresses at least as much CD38 on its surface as NCI-H2342 cells. In some embodiments, the cell expresses less CD38 on its surface than Daudi cells. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raji cells. In some embodiments, the multispecific protein induces an enhanced CDC effect on target cells expressing CD38 and ICAM1 compared to the complement dependent cytotoxicity (CDC) effect on target cells induced by a monospecific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raji cells. In some embodiments, the multispecific protein induces an enhanced apoptotic effect on target cells expressing CD38 and ICAM1 compared to the apoptotic effect on target cells induced by a monospecific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raji cells. In some embodiments, the multispecific protein has a reduced ability to kill NK (natural killer) cells in a population of fresh peripheral blood mononuclear cells compared to a monospecific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, the first component has a K of about 0.15 nM to about 64 nM as determined by surface plasmon resonance. DIn some embodiments, the first component binds to human CD38 with a K of about 0.42 nM to about 13.14 nM as determined by surface plasmon resonance. D In some embodiments, the first component binds to human CD38 with a K of about 0.15 nM to about 0.45 nM as determined by surface plasmon resonance. D In some embodiments, the second component binds to human CD38 with a K of about 0.2 nM to about 24.4 nM as determined by surface plasmon resonance. D In some embodiments, the second component binds to human ICAM1 with a K of about 0.2 nM to about 0.6 nM as determined by surface plasmon resonance. D Binds to human ICAM1.

[0174] One embodiment provides a pharmaceutical composition comprising a multispecific protein of the present disclosure. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or any combination thereof.

[0175] One embodiment provides a method for killing cells in a subject, comprising administering to the subject a multispecific protein of the disclosure or a pharmaceutical composition of the disclosure, wherein the cells express CD38 and ICAM1. In some embodiments, the cells are lysed. In some embodiments, the cells are tumor cells. One embodiment provides a method for treating cancer in a subject, comprising administering to the subject a multispecific protein of the disclosure or a pharmaceutical composition of the disclosure, wherein the cancer comprises cells that express CD38 and ICAM1. In some embodiments, the cancer comprises a solid tumor or a hematological malignancy. In some embodiments, the cancer comprises a hematological malignancy. In some embodiments, the hematological malignancy is multiple myeloma, leukemia, non-Hodgkin's lymphoma, or Hodgkin's lymphoma. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the cells express at least as much ICAM1 on their surface as NCI-H2291 cells. In some embodiments, the cells express at least as much CD38 on their surface as NCI-H2342 cells. In some embodiments, the cell expresses less CD38 on its surface than a Daudi cell. In some embodiments, the amount of CD38 on the surface of the cell is less than or equal to the amount of CD38 on the surface of a Raji cell. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is greater than the ratio of ICAM1 to CD38 on the surface of a Daudi cell.

[0176] In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raji cells. In some embodiments, the cell expresses at least 5,000, 10,000, 15,000, 20,000, 30,000, 50,000, 100,000, 150,000, 200,000, 250,000, 300,000, 400,000, or 500,000 ICAM1 proteins on its surface. In some embodiments, the cell expresses at least 50,000 ICAM1 proteins on its surface. In some embodiments, the cell expresses at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on its surface. In some embodiments, the cell expresses at least 300 CD38 proteins on its surface. In some embodiments, the cell expresses less than about 350,000, 300,000, 250,000, 200,000, 150,000, 100,000, 50,000, 30,000, 20,000, 15,000, 10,000, or 5,000 CD38 proteins on its surface. In some embodiments, the cell expresses less than about 350,000 CD38 proteins on its surface. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 10. In some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapeutic agent, a hormone-based therapeutic agent, a stem cell-based therapeutic agent, or radiation. In some embodiments, the additional therapeutic agent comprises at least one of lenalidomide, dexamethasone, bortezomib, or any combination thereof. In some embodiments, the additional therapeutic agent and the multispecific protein are administered simultaneously. In some embodiments, the additional therapeutic agent and the multispecific protein are administered sequentially. In some embodiments, the subject has received previous treatment. In some embodiments, the previous treatment comprises a proteasome inhibitor (PI) therapy and an immunomodulator. In some embodiments, the subject is dual refractory to a therapy comprising a proteasome inhibitor (PI) therapy and an immunomodulator. In some embodiments, the subject is human. One embodiment provides a kit comprising a multispecific protein according to the present disclosure or a pharmaceutical composition comprising the same.

[0177] In certain embodiments, disclosed herein are anti-CD38 antibodies, anti-ICAM1 antibodies, pharmaceutical compositions comprising anti-CD38 antibodies and / or anti-ICAM1 antibodies, and methods for treating proliferative diseases. In certain embodiments, disclosed herein are multispecific antibodies (e.g., bispecific antibodies) comprising a first targeting moiety that specifically binds to CD38 and a second targeting moiety that specifically binds to ICAM1, pharmaceutical compositions comprising multispecific antibodies, and methods for treating proliferative diseases.

[0178] In certain embodiments, disclosed herein is a bispecific antibody comprising a first targeting portion that specifically binds to CD38 or ICAM1 and has an enhanced CDC effect compared to the complement dependent cytotoxicity (CDC) effect of the reference antibody daratumumab. In certain embodiments, also described herein is a bispecific antibody comprising a first targeting portion that specifically binds to CD38 or ICAM1 and has an enhanced ADCC effect compared to the antibody dependent cell-mediated cytotoxicity (ADCC) effect of the reference antibody daratumumab. In certain embodiments, additionally described herein is a bispecific antibody comprising a first targeting portion that specifically binds to CD38 or ICAM1 and has a reduced immune cell killing effect compared to the immune cell killing effect of the reference antibody daratumumab. In some embodiments, the bispecific antibody further comprises a second targeting portion that specifically binds to CD38 or ICAM1. In some embodiments, the enhanced CDC is at least 2 times, 3 times, 4 times or more that of the CDC effect of the reference antibody daratumumab. In some embodiments, the enhanced CDC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more greater than the CDC effect of the reference antibody daratumumab. In some embodiments, the enhanced ADCC is at least 2-fold, 3-fold, 4-fold, 5-fold or more greater than the ADCC effect of the reference antibody daratumumab. In some embodiments, the enhanced ADCC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more greater than the ADCC effect of the reference antibody daratumumab. In some embodiments, the immune cells are natural killer cells. In some embodiments, the immune cell viability is increased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to the immune cell viability in the presence of the reference antibody daratumumab. In some embodiments, the bispecific antibody is a bivalent antibody or binding fragment thereof. In some embodiments, the bivalent antibody or its binding fragment comprises an IgG-scFv (LC) C-terminal fusion form, an IgG-HC-scFv C-terminal fusion form, an scFv-HC-IgG N-terminal fusion form, or a DVD-Ig form. In some embodiments, the bispecific antibody is a monovalent antibody or its binding fragment. In some embodiments, the monovalent antibody or its binding fragment comprises a Fab-scFv-Fc (KIH) form or a Biclonics common LC form. In some embodiments, the scFv portion of the bispecific antibody specifically binds to ICAM1. In some embodiments, the first targeting moiety specifically binds to CD38 and the second targeting moiety specifically binds to ICAM1. In some embodiments, the first targeting moiety has a K of about 1 nM to about 100 nM. DIn some embodiments, the first targeting moiety has a K of at least 1 nM, 2 nM, 3 nM, 3.15 nM, 3.2 nM, 3.39 nM, 3.5 nM, 4 nM, 4.5 nM, 5 nM, 5.32 nM, 5.5 nM, 6 nM, 6.5 nM, 7 nM, 7.5 nM, 8 nM, 8.5 nM, 9 nM, 9.5 nM, 10 nM, 15 nM, 18 nM, 20 nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, or 100 nM. D In some embodiments, the second targeting moiety has a K of about 0.1 to about 20 nM. D In some embodiments, the second targeting moiety has a K of about 0.15 nM, 0.2 nM, 0.24 nM, 0.25 nM, 0.29 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.7 nM, 0.8 nM, 0.9 nM, 1 nM, 1.5 nM, 1.72 nM, 2 nM, 2.28 nM, 2.5 nM, 3 nM, 3.5 nM, 4 nM, 4.5 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, or 20 nM. D In some embodiments, the bispecific antibody induces apoptosis similar to that induced by the reference antibody daratumumab. In some embodiments, the first targeting moiety comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises: CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from P, S or D; X4 is selected from F, L or A; X5 is selected from D, G, S, N or T; X6 is selected from V, A, T, R, S, I or N; X7 is selected from Y, I, N, R, A, G or D; X8 is selected from A, Y, D, G, W, C or T; X9 is selected from M, V, I, W, D or Y; X 10 Selected from S, T, M, C, I, Y, A or G; X 11 is present or absent, and if present, is selected from C or M; and X 12 Present or absent, if present, C; CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 ; where X 13 Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from S, I, L, T or M; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P, V or Y; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from F, Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25 Selected from D, T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from V, A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 Present or absent, if present, selected from G or K; X 31 Present or absent, if present, G; and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X46X 47 X 48 X 49 ; and where X 32 Selected from A, G or V; X 33 Selected from K, A, R, T, G or S; X 34Selected from R, A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, A, T or R; X 36 Selected from T, P, A, Y, D, G, S, R, V or E; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, A, S, D, K, F, L or Y; X 39 Selected from Y, T, A, G, S or I; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, if present, selected from P, L, Y, F, G or T; X 43 Present or absent, if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, if present, selected from G, L, S, T or F; X 45 Present or absent, if present, selected from F, L, E, N or S; X 46 Present or absent, if present, selected from D, S, L or R; X 47 Present or absent, if present, selected from Y or L; X 48 is present or absent, and if present, is D; and X49 is present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR1 sequence GFPFX5X6YAMS, wherein X5 is selected from D or G; and X6 is selected from V, A, or T. In some embodiments, the VH region comprises a CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from S or D; X4 is selected from L, F or A; X5 is selected from S, N or T; X6 is selected from R, S, N, I or T; X7 is selected from Y, I, N, R, A, D or G; X8 is selected from Y, D, G, A, W, T or C; X9 is selected from V, M, I, W, Y or D; X 10 Selected from T, S, M, C, I, Y, A or G; X 11 is present or absent, and if present, is selected from C or M; and X 12 Present or absent, if present, C. In some embodiments, the VH region comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11wherein X5 is selected from S or N; X6 is selected from R, S or N; X7 is selected from Y, I or N; X8 is selected from Y, D, G or A; X9 is selected from V, M or I; X 10 is selected from T, S or M; and X 11 Present or absent, if present, C. In some embodiments, the VH region comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 wherein X4 is selected from F or A; X5 is selected from S, T or N; X6 is selected from S, T or N; X7 is selected from Y, R, A or G; X8 is selected from W, Y or C; X9 is selected from I, W, Y or D; X 10 Selected from C, I, Y or M; X 11 is present or absent, and if present, is selected from C or M; and X 12 Present or absent, if present, C. In some embodiments, the VH region comprises the CDR2 sequence AISGSGGSTX 22 YADSVKG, where X 22 is selected from F or Y. In some embodiments, the VH region comprises a CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 ; where X 13 Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from I, L, M or T; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P or V; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24Selected from A or Y; X 25 Selected from T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 Present or absent, if present, G. In some embodiments, the VH region comprises a CDR2 sequence X 13 X 14 IX 16 X 17 X18X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 ; where X 13 Selected from A or G; X 14 selected from I, F, Y, V, S or C; X 16 Selected from G, Y, S, T or L; X 17 Selected from S, I, K, Y, T or G; X 18 Selected from G, S or T; X 19 Selected from G, A, D or S; X 20 Selected from T, I, N or G; X 21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Select from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Select from W or T; X 27 Select from A or W; X 28 Selected from K, R, Q or A; X 29 is selected from G or K; and X 30 Present or absent, if present, G. In some embodiments, the VH region comprises a CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 ; where X 13 Select from A or S; X 15 Selected from I, L or T; X 16 Selected from Y or V; X 17 Selected from S, T or A; X 18 Selected from G, P or V; X 19 Selected from D, S or T; X 20 Selected from S, T or G; X 21 Selected from D, N, S or A; X 22 Selected from T, I or S; X 23 Selected from Y, K or I; X 25 Selected from A or Y; X 26 Selected from S, T, A or N; X 27 Selected from W, N or S; X 28 Select from A or W; X 29 Select K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 Present or absent, if present, G. In some embodiments, the VH region comprises the CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY, where X 38 Selected from A or G; X 41 is selected from F or Y. In some embodiments, the VH region comprises a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X38X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X 32 Selected from A, G or V; X 33 Selected from A, R, T, S or G; X 34 Selected from A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, R or A; X 36Selected from P, A, Y, D, G, S, R, V, E or T; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, S, D, K, F, L or Y; X 39 Selected from T, A, G, S, I or Y; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from V, D, Y, A, N, G, L or E; X 42 Present or absent, if present, selected from L, Y, F, T or G; X 43 Present or absent, if present, selected from P, F, V, N, S or Y; X 44 Present or absent, if present, selected from L, S, T, G or F; X 45 is present or absent, and if present is selected from L, F, E, S or N; and X 46 Present or absent, if present, selected from S, L or R; X 47 Exist or not, if it exists, it is L; X 48 exists or does not exist, if it exists, it is D; and X 49 is present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 ; where X 32 Selected from A or G; X 33 Selected from A, R or T; X 34 Selected from A, V, T, P, I, E or D; X 35 Selected from G, W, D, L, K or P; X 36 Selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X 38 Selected from G, S, D or K; X 39 Selected from T, A, G, S or I; X 40 Selected from S, Y, G, R or W; X 41 Selected from V, D, Y, A, N or G; X 42 Selected from L, Y or F; X 43Present or absent, if present, selected from P, F, V or N; X 44 is present or absent, and if present is selected from L, S or T; and X 45 is present or absent, and if present is selected from L or F. In some embodiments, the VH region comprises the CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 ; where X 33 Selected from R or G; X 34 Selected from E, D or S; X 35 Selected from G, L, P, S or A; X 36 Selected from D, S or R; X 37 Selected from Y, T, N or G; X 38 Selected from G, S, F or L; X 39 Selected from A, G, S or I; X 40 Selected from Y, N or L; X 41 Present or absent, if present, selected from V, Y or E; X 42 Exist or not, if it exists, it is G; X 43 Exists or does not exist, if exists, then it is Y; X 44 Exist or not, if it exists, then F; X 45 is present or absent, and if present, is selected from E or N; and X 46 Present or absent, if present, selected from S or L. In some embodiments, the VH region comprises the CDR1 sequence GFPFX5X6YAMS, the CDR2 sequence AISGSGGSTX 22 YADSVKG and CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY; wherein X5 is selected from D or G; X6 is selected from V, A or T; X 22 Selected from F or Y; X 38 is selected from A or G; and X 41 Selected from F or Y. In some embodiments, the VH region comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 , CDR2 sequence X 13 X 14 IX 16X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X25X 26 X 27 X 28 X 29 X 30 and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 wherein X5 is selected from S or N; X6 is selected from R, S or N; X7 is selected from Y, I or N; X8 is selected from Y, D, G or A; X9 is selected from V, M or I; X 10 Select from T, S or M; X 11 Exist or not, if it exists, then C; X 13 Selected from A or G; X 14 selected from I, F, Y, V, S or C; X 16 Selected from G, Y, S, T or L; X 17 Selected from S, I, K, Y, T or G; X 18 Selected from G, S or T; X 19 Selected from G, A, D or S; X 20 Selected from T, I, N or G; X 21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Select from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Select from W or T; X 27 Select from A or W; X 28 Selected from K, R, Q or A; X 29 Selected from G or K; X 30 Exist or not, if it exists, it is G; X 32 Selected from A or G; X 33 Selected from A, R or T; X 34 Selected from A, V, T, P, I, E or D; X 35 Selected from G, W, D, L, K or P; X 36Selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X 38 Selected from G, S, D or K; X 39 Selected from T, A, G, S or I; X 40 Selected from S, Y, G, R or W; X 41 Selected from V, D, Y, A, N or G; X 42 Selected from L, Y or F; X 43 Present or absent, if present, selected from P, F, V or N; X 44 is present or absent, and if present is selected from L, S or T; and X 45 is present or absent, and if present is selected from L or F. In some embodiments, the VH region comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 , CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 and CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 wherein X4 is selected from F or A; X5 is selected from S, T or N; X6 is selected from S, T or N; X7 is selected from Y, R, A or G; X8 is selected from W, Y or C; X9 is selected from I, W, Y or D; X 10 Selected from C, I, Y or M; X 11 Present or absent, if present, selected from C or M; X 12 Exist or not, if it exists, then C; X 13 Select from A or S; X 15 Selected from I, L or T; X16 Selected from Y or V; X 17 Selected from S, T or A; X 18 Selected from G, P or V; X 19 Selected from D, S or T; X 20 Selected from S, T or G; X 21 Selected from D, N, S or A; X 22 Selected from T, I or S; X 23 Selected from Y, K or I; X 25 Selected from A or Y; X 26 Selected from S, T, A or N; X 27 Selected from W, N or S; X 28 Select from A or W; X 29 Select K or A; X 30 Present or absent, if present, selected from G or K; X 31 Exist or not, if it exists, it is G; X 33 Selected from R or G; X 34 Selected from E, D or S; X 35 Selected from G, L, P, S or A; X 36 Selected from D, S or R; X 37 Selected from Y, T, N or G; X 38 Selected from G, S, F or L; X 39 Selected from A, G, S or I; X 40 Selected from Y, N or L; X 41 Present or absent, if present, selected from V, Y or E; X 42 Exist or not, if it exists, it is G; X 43 Exists or does not exist, if exists, then it is Y; X 44 Exist or not, if it exists, then F; X 45 is present or absent, and if present, is selected from E or N; and X 46 is present or absent, and if present, is selected from S or L. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X38X 39 X40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X 32 Selected from A, G or V; X 33 Selected from K, A, R, T, G or S; X 34 Selected from R, A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, A, T or R; X 36 Selected from T, P, A, Y, D, G, S, R, V or E; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, A, S, D, K, F, L or Y; X 39 Selected from Y, T, A, G, S or I; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, if present, selected from P, L, Y, F, G or T; X 43 Present or absent, if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, if present, selected from G, L, S, T or F; X 45 Present or absent, if present, selected from F, L, E, N or S; X 46 Present or absent, if present, selected from D, S, L or R; X 47 Present or absent, if present, selected from Y or L; X 48 exists or does not exist, if it exists, it is D; and X 49is present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 3, 7, and 10. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58.In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NO: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103. In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 71, 77, 83, 94, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 72, 78, and 84; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 73, 79, 85, 95, and 103. In some embodiments, the first targeting moiety comprises a VH sequence selected from the group consisting of SEQ ID NOs: 104-128 and a VL sequence selected from the group consisting of SEQ ID NOs: 130-154. In some embodiments, the second targeting moiety comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises: CDR1 sequence X. 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 ; where X 1 Selected from G or E; X 2 Selected from F or Y; X 3 Select from S or T; X 4 Selected from L, F or S; X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y, H or G; X 8 Selected from G, A, Y, W or F; X 9 Selected from M, W, Y or I; X 10 is selected from S, G, N, M or I; and X 11Present or absent, if present, C; CDR2 sequence X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 ; where X 12 Selected from G, T, A, I or Y; X 13 Selected from W, I, Y or C; X 14 Selected from I, S or Y; X 15 Selected from S, G, T, D or P; X 16 Selected from F, S, D, T or A; X 17 Selected from S, R, G or D; X 18 Selected from G, D or S; X 19 Selected from S, R, T, N, Y, A, D or P; X 20 Selected from T, A, G or Y; X 21 Selected from Y, H, A, S or T; X 22 Select from Y or N; X 23 Selected from A, P, Y or S; X 24 Selected from S, T, N, D, Y, A or P; X 25 Selected from W, S, A or D; X 26 Selected from A, V, T, W, F or S; X 27 Selected from K, W, A, Q or V; X 28 Selected from G, A or K; X 29 is present or absent, and if present, is selected from K or G; and X 30 Present or absent, if present, G; and CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X46 X 47 X 48 X 49 ; where X 31 Selected from A or V; X 32 Selected from R or I; X 33 Selected from G, D, P, A or V; X 34 Selected from G, P, W, D, N or R; X 35 Selected from D, Y, S, L, G, F or W; X 36 Selected from Y, D, V, L, S, G or P; X 37 Selected from G, S, D, V or E; X 38 Selected from G, Y, F, S or D; X 39 Selected from S, D, G, T, N, A or V; X 40 Selected from T, A, D, S, Y, L or F; X 41 Present or absent, if present, selected from Y, A, G, I or D; X 42 Present or absent, if present, selected from I, Y, R, P, V or G; X 43 Present or absent, if present, selected from L, R, Y, G or A; X 44 Present or absent, if present, selected from N, L, Y, S or W; X 45 Present or absent, if present, selected from L, Y, F or C; X 46 Present or absent, if present, selected from D, A or F; X 47 Present or absent, if present, selected from M, P, Y or N; X 48 is present or absent, and if present, is selected from D or L; and X 49 Present or absent, if present, L. In some embodiments, the VH region comprises the CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 , where X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y or H; X 8 is selected from G, A or Y; and X 10 Selected from S, G or N. In some embodiments, the VH region comprises the CDR2 sequence GX 13 IX 1 5 X 16 X 17 X 18 X 19 X 20 YYAX24 WAKG, where X 13 Selected from W, I or Y; X 15 Selected from S or G; X 16 Selected from F, S, D or T; X 17 Selected from S or R; X 18 Select from G or D; X 19 Selected from S, R, T or N; X 20 is selected from T or A; and X 24 is selected from S, T or N. In some embodiments, the VH region comprises a CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , where X 31 Selected from A or V; X 33 Select from G or D; X 34 Selected from G, P, W or D; X 35 Selected from D, Y, S or L; X 36 Selected from Y, D, V or L; X 37 Selected from G, S or D; X 38 Selected from G, Y, F or S; X 39 Selected from S, D, G or T; X 40 Selected from T, A, D, S or Y; X 41 Selected from Y, A, G or I; X 42 selected from I, Y or R; X 43 Selected from L, R, Y or G; X 44 Selected from N, L, Y or S; X 45 Present or absent, if present, selected from L, Y or F; X 46 Exist or not, if it exists, then D; X 47 Present or absent, if present, selected from M or P; X 48 exists or does not exist, if it exists, it is D; and X 49is present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 243, 245, 249, and 252. In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284. In some embodiments, the second targeting moiety comprises a VH sequence selected from the group consisting of SEQ ID NOs: 289-309 and a VL sequence selected from the group consisting of SEQ ID NOs: 311-326 and 155. In some embodiments, the bispecific antibody comprises a humanized antibody or binding fragment thereof or a chimeric antibody or binding fragment thereof.In some embodiments, the bispecific antibody comprises an IgG-scFv, a nanobody, a BiTE, a diabody, a DART, a TandAb, a scDiabody, a scDiabody-CH3, a triple body, a mini-antibody, a minibody, a TriBi minibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, F(ab')2, F(ab')2-scFv2, scFv-KIH, Fab-scFv-Fc, a tetravalent HCAb, scDiabody-Fc, a diabody-Fc, a tandem scFv-Fc, or an intrabody. In some embodiments, the bispecific antibody comprises an IgG1 framework sequence. In some embodiments, the bispecific antibody comprises an IgG2 framework sequence. In some embodiments, the bispecific antibody comprises an IgG4 framework sequence. In some embodiments, the bispecific antibody further comprises a payload. In some embodiments, the payload comprises a small molecule, a peptide, or a protein.

[0179] In certain embodiments, disclosed herein are anti-CD38 antibodies comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises: CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 , wherein X1 is present or absent, and if present, is S; X2 is selected from F or I; X3 is selected from P, S or D; X4 is selected from F, L or A; X5 is selected from D, G, S, N or T; X6 is selected from V, A, T, R, S, I or N; X7 is selected from Y, I, N, R, A, G or D; X8 is selected from A, Y, D, G, W, C or T; X9 is selected from M, V, I, W, D or Y; X 10 Selected from S, T, M, C, I, Y, A or G; X 11 is present or absent, and if present, is selected from C or M; and X 12 Present or absent, if present, C; CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X26 X 27 X 28 X 29 X 30 X 31 ; where X 13 Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from S, I, L, T or M; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P, V or Y; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from F, Y, N, T, I or S; X 23 is selected from Y, D, K or I; X24 is selected from A or Y; X 25 Selected from D, T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from V, A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 Present or absent, if present, selected from G or K; X 31 Present or absent, if present, G; and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X42X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X 32 Selected from A, G or V; X 33 Selected from K, A, R, T, G or S; X 34 Selected from R, A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, A, T or R; X 36 Selected from T, P, A, Y, D, G, S, R, V or E; X 37selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, A, S, D, K, F, L or Y; X 39 Selected from Y, T, A, G, S or I; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, if present, selected from P, L, Y, F, G or T; X 43 Present or absent, if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, if present, selected from G, L, S, T or F; X 45 Present or absent, if present, selected from F, L, E, N or S; X 46 Present or absent, if present, selected from D, S, L or R; X 47 Present or absent, if present, selected from Y or L; X 48 exists or does not exist, if it exists, it is D; and X 49 In some embodiments, the VH region comprises a CDR1 sequence of GFPFX5X6YAMS, wherein X5 is selected from D or G; and X6 is selected from V, A or T. In some embodiments, the VH region comprises a CDR1 sequence of X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from S or D; X4 is selected from L, F or A; X5 is selected from S, N or T; X6 is selected from R, S, N, I or T; X7 is selected from Y, I, N, R, A, D or G; X8 is selected from Y, D, G, A, W, T or C; X9 is selected from V, M, I, W, Y or D; X 10 Selected from T, S, M, C, I, Y, A or G; X 11 is present or absent, and if present, is selected from C or M; and X 12 Present or absent, if present, C. In some embodiments, the VH region comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 wherein X5 is selected from S or N; X6 is selected from R, S or N; X7 is selected from Y, I or N; X8 is selected from Y, D, G or A; X9 is selected from V, M or I; X 10 is selected from T, S or M; and X 11Present or absent, if present, C. In some embodiments, the VH region comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 wherein X4 is selected from F or A; X5 is selected from S, T or N; X6 is selected from S, T or N; X7 is selected from Y, R, A or G; X8 is selected from W, Y or C; X9 is selected from I, W, Y or D; X 10 Selected from C, I, Y or M; X 11 is present or absent, and if present, is selected from C or M; and X 12 Present or absent, if present, C. In some embodiments, the VH region comprises the CDR2 sequence AISGSGGSTX 22 YADSVKG, where X 22 is selected from F or Y. In some embodiments, the VH region comprises a CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 ; where X 13 is selected from A, G or S; X14 is selected from I, F, Y, V, S or C; X 15 Selected from I, L, M or T; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P or V; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25 Selected from T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from A, W, N or S; X 28Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 Present or absent, if present, G. In some embodiments, the VH region comprises a CDR2 sequence X 13 X 14 IX 16 X17X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 ; where X 13 Selected from A or G; X 14 selected from I, F, Y, V, S or C; X 16 Selected from G, Y, S, T or L; X 17 Selected from S, I, K, Y, T or G; X 18 Selected from G, S or T; X 19 Selected from G, A, D or S; X 20 Selected from T, I, N or G; X 21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Select from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Select from W or T; X 27 Select from A or W; X 28 Selected from K, R, Q or A; X 29 is selected from G or K; and X 30 Present or absent, if present, G. In some embodiments, the VH region comprises a CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X31 ; where X 13 Select from A or S; X 15 Selected from I, L or T; X 16 Selected from Y or V; X 17 Selected from S, T or A; X 18 Selected from G, P or V; X 19 Selected from D, S or T; X 20 Selected from S, T or G; X 21 Selected from D, N, S or A; X 22 Selected from T, I or S; X 23 Selected from Y, K or I; X 25 Selected from A or Y; X 26 Selected from S, T, A or N; X 27 Selected from W, N or S; X 28 Select from A or W; X 29 Select K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 Present or absent, if present, G. In some embodiments, the VH region comprises the CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY, where X 38 is selected from A or G; and X 41 is selected from F or Y. In some embodiments, the VH region comprises a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X 32 Selected from A, G or V; X 33 Selected from A, R, T, S or G; X 34 Selected from A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, R or A; X 36 Selected from P, A, Y, D, G, S, R, V, E or T; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38Selected from G, S, D, K, F, L or Y; X 39 Selected from T, A, G, S, I or Y; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from V, D, Y, A, N, G, L or E; X 42 Present or absent, if present, selected from L, Y, F, T or G; X 43 Present or absent, if present, selected from P, F, V, N, S or Y; X 44 Present or absent, if present, selected from L, S, T, G, F; X 45 Present or absent, if present, selected from L, F, E, S or N; X 46 Present or absent, if present, selected from S, L or R; X 47 Exist or not, if it exists, it is L; X 48 exists or does not exist, if it exists, it is D; and X 49 is present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 ; where X 32 Selected from A or G; X 33 Selected from A, R or T; X 34 Selected from A, V, T, P, I, E or D; X 35 Selected from G, W, D, L, K or P; X 36 Selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X 38 Selected from G, S, D or K; X 39 Selected from T, A, G, S or I; X 40 Selected from S, Y, G, R or W; X 41 Selected from V, D, Y, A, N or G; X 42 Selected from L, Y or F; X 43 Present or absent, if present, selected from P, F, V or N; X 44 is present or absent, and if present is selected from L, S or T; and X 45is present or absent, and if present is selected from L or F. In some embodiments, the VH region comprises the CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 ; where X 33 Selected from R or G; X 34 Selected from E, D or S; X 35 Selected from G, L, P, S or A; X 36 Selected from D, S or R; X 37 Selected from Y, T, N or G; X 38 Selected from G, S, F or L; X 39 Selected from A, G, S or I; X 40 Selected from Y, N or L; X 41 Present or absent, if present, selected from V, Y or E; X 42 Exist or not, if it exists, it is G; X 43 Exists or does not exist, if exists, then it is Y; X 44 Exist or not, if it exists, then F; X 45 is present or absent, and if present, is selected from E or N; and X 46 Present or absent, if present, selected from S or L. In some embodiments, the VH region comprises the CDR1 sequence GFPFX5X6YAMS, the CDR2 sequence AISGSGGSTX 22 YADSVKG and CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY; wherein X5 is selected from D or G; X6 is selected from V, A or T; X 22 Selected from F or Y; X 38 is selected from A or G; and X 41 Selected from F or Y. In some embodiments, the VH region comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 , CDR2 sequence X 13 X 14 IX16X 17 X 18 X 19 X 20 X 21 X 22X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 wherein X5 is selected from S or N; X6 is selected from R, S or N; X7 is selected from Y, I or N; X8 is selected from Y, D, G or A; X9 is selected from V, M or I; X 10 Select from T, S or M; X 11 Exist or not, if it exists, then C; X 13 Selected from A or G; X 14 selected from I, F, Y, V, S or C; X 16 Selected from G, Y, S, T or L; X 17 Selected from S, I, K, Y, T or G; X 18 Selected from G, S or T; X 19 Selected from G, A, D or S; X 20 Selected from T, I, N or G; X 21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Select from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Select from W or T; X 27 Select from A or W; X 28 Selected from K, R, Q or A; X 29 Selected from G or K; X 30 Exist or not, if it exists, it is G; X 32 Selected from A or G; X 33 Selected from A, R or T; X 34 Selected from A, V, T, P, I, E or D; X 35 Selected from G, W, D, L, K or P; X 36 Selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X 38 Selected from G, S, D or K; X39 Selected from T, A, G, S or I; X 40 Selected from S, Y, G, R or W; X 41 Selected from V, D, Y, A, N or G; X 42 Selected from L, Y or F; X 43 Present or absent, if present, selected from P, F, V or N; X 44 is present or absent, and if present is selected from L, S or T; and X 45 is present or absent, and if present is selected from L or F. In some embodiments, the VH region comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 , CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X27X 28 X 29 X 30 X 31 and CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 wherein X4 is selected from F or A; X5 is selected from S, T or N; X6 is selected from S, T or N; X7 is selected from Y, R, A or G; X8 is selected from W, Y or C; X9 is selected from I, W, Y or D; X 10 Selected from C, I, Y or M; X 11 Present or absent, if present, selected from C or M; X 12 Exist or not, if it exists, then C; X 13 Selected from A, or S; X 15 Selected from I, L or T; X 16 Selected from Y or V; X 17 Selected from S, T or A; X 18 Selected from G, P or V; X 19Selected from D, S or T; X 20 Selected from S, T or G; X 21 Selected from D, N, S or A; X 22 Selected from T, I or S; X 23 Selected from Y, K or I; X 25 Selected from A or Y; X 26 Selected from S, T, A or N; X 27 Selected from W, N or S; X 28 Select from A or W; X 29 Select K or A; X 30 Present or absent, if present, selected from G or K; X 31 Exist or not, if it exists, it is G; X 33 Selected from R or G; X 34 Selected from E, D or S; X 35 Selected from G, L, P, S or A; X 36 Selected from D, S or R; X 37 Selected from Y, T, N or G; X 38 Selected from G, S, F or L; X 39 Selected from A, G, S or I; X 40 Selected from Y, N or L; X 41 Present or absent, if present, selected from V, Y or E; X 42 Exist or not, if it exists, it is G; X 43 Exists or does not exist, if exists, then it is Y; X 44 Exist or not, if it exists, then F; X 45 is present or absent, and if present, is selected from E or N; and X 46 is present or absent, and if present, is selected from S or L. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X32X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X46 X 47 X 48 X 49 ; where X 32 Selected from A, G or V; X 33 Selected from K, A, R, T, G or S; X 34 Selected from R, A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, A, T or R; X 36 Selected from T, P, A, Y, D, G, S, R, V or E; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, A, S, D, K, F, L or Y; X 39 Selected from Y, T, A, G, S or I; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, if present, selected from P, L, Y, F, G or T; X 43 Present or absent, if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, if present, selected from G, L, S, T or F; X 45 Present or absent, if present, selected from F, L, E, N or S; X 46 Present or absent, if present, selected from D, S, L or R; X 47 Present or absent, if present, selected from Y or L; X 48 exists or does not exist, if it exists, it is D; and X 49is present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 3, 7, and 10. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58.In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NO: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103. In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 71, 77, 83, 94, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 72, 78, and 84; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 73, 79, 85, 95, and 103. In some embodiments, the anti-CD38 antibody comprises a VH sequence selected from the group consisting of SEQ ID NOs: 104-128 and a VL sequence selected from the group consisting of SEQ ID NOs: 130-154. In some embodiments, the anti-CD38 antibody is a multispecific antibody comprising a second targeting moiety. In some embodiments, the second targeting moiety specifically binds to ICAM1. In some embodiments, the second targeting moiety comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises: CDR1 sequence X. 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 ; where X 1 Selected from G or E; X 2 Selected from F or Y; X 3 Select from S or T; X 4 Selected from L, F or S; X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y, H or G; X 8 Selected from G, A, Y, W or F; X 9 Selected from M, W, Y or I; X10 is selected from S, G, N, M or I; and X 11 Present or absent, if present, C; CDR2 sequence X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 2 3 X 24 X 25 X 26 X 27 X 28 X 29 X 30 ; where X 12 Selected from G, T, A, I or Y; X 13 Selected from W, I, Y or C; X 14 Selected from I, S or Y; X 15 Selected from S, G, T, D or P; X 16 Selected from F, S, D, T or A; X 17 Selected from S, R, G or D; X 18 Selected from G, D or S; X 19 Selected from S, R, T, N, Y, A, D or P; X 20 Selected from T, A, G or Y; X 21 Selected from Y, H, A, S or T; X 22 Select from Y or N; X 23 Selected from A, P, Y or S; X 24 Selected from S, T, N, D, Y, A or P; X 25 Selected from W, S, A or D; X 26 Selected from A, V, T, W, F or S; X 27 Selected from K, W, A, Q or V; X 28 Selected from G, A or K; X 29 is present or absent, and if present, is selected from K or G; and X 30 Present or absent, if present, G; and CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X 31 Selected from A or V; X 32 Selected from R or I; X 33 Selected from G, D, P, A or V; X 34 Selected from G, P, W, D, N or R; X 35 Selected from D, Y, S, L, G, F or W; X 36 Selected from Y, D, V, L, S, G or P; X 37 Selected from G, S, D, V or E; X 38 Selected from G, Y, F, S or D; X 39 Selected from S, D, G, T, N, A or V; X 40 Selected from T, A, D, S, Y, L or F; X 41 Present or absent, if present, selected from Y, A, G, I or D; X 42 Present or absent, if present, selected from I, Y, R, P, V or G; X 43 Present or absent, if present, selected from L, R, Y, G or A; X 44 Present or absent, if present, selected from N, L, Y, S or W; X 45 Present or absent, if present, selected from L, Y, F or C; X 46 Present or absent, if present, selected from D, A or F; X 47 Present or absent, if present, selected from M, P, Y or N; X 48 is present or absent, and if present, is selected from D or L; and X 49 Present or absent, if present, L. In some embodiments, the VH region comprises the CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 , where X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y or H; X 8 is selected from G, A or Y; and X 10 Selected from S, G or N. In some embodiments, the VH region comprises the CDR2 sequence GX 13 IX 15 X 16 X 17 X18 X 19 X 20 YYAX 24 WAKG, where X 13 Selected from W, I or Y; X 15 Selected from S or G; X 16 Selected from F, S, D or T; X 17 Selected from S or R; X 18 Select from G or D; X 19 Selected from S, R, T or N; X 20 is selected from T or A; and X 24 is selected from S, T or N. In some embodiments, the VH region comprises a CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 3 7 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , where X 31 Selected from A or V; X 33 Select from G or D; X 34 Selected from G, P, W or D; X 35 Selected from D, Y, S or L; X 36 Selected from Y, D, V or L; X 37 Selected from G, S or D; X 38 Selected from G, Y, F or S; X 39 Selected from S, D, G or T; X 40 Selected from T, A, D, S or Y; X 41 Selected from Y, A, G or I; X 42 selected from I, Y or R; X 43 Selected from L, R, Y or G; X 44 Selected from N, L, Y or S; X 45 Present or absent, if present, selected from L, Y or F; X 46 Exist or not, if it exists, then D; X 47 Present or absent, if present, selected from M or P; X 48 exists or does not exist, if it exists, it is D; and X 49present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 243, 245, 249, and 252. In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284. In some embodiments, the second targeting moiety comprises a VH sequence selected from the group consisting of SEQ ID NOs: 289-309 and a VL sequence selected from the group consisting of SEQ ID NOs: 311-326 and 155. In some embodiments, the anti-CD38 antibody comprises a humanized antibody or binding fragment thereof or a chimeric antibody or binding fragment thereof. In some embodiments, the anti-CD38 antibody comprises a bispecific antibody or a binding fragment thereof.In some embodiments, the bispecific antibody or binding fragment thereof comprises an IgG-scFv, a nanobody, a BiTE, a diabody, a DART, a TandAb, a scDiabody, a scDiabody-CH3, a triabody, a minibody, a minibody, a TriBi minibody, a scFv-CH3 KIH, a Fab-scFv-Fc KIH, a Fab-scFv, a scFv-CH-CL-scFv, a F(ab')2, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a diabody-Fc, a tandem scFv-Fc, or an intrabody. In some embodiments, the anti-CD38 antibody comprises an IgG1 framework sequence. In some embodiments, the anti-CD38 antibody comprises an IgG2 framework sequence. In some embodiments, the anti-CD38 antibody comprises an IgG4 framework sequence. In some embodiments, the anti-CD38 antibody comprises an HC sequence selected from SEQ ID NOs: 157-181 and an LC sequence selected from SEQ ID NOs: 183-207. In some embodiments, the anti-CD38 antibody further comprises a payload. In some embodiments, the payload comprises a small molecule, a peptide, or a protein.

[0180] In certain embodiments, disclosed herein are anti-ICAM1 antibodies comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises: CDR1 sequence X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 ; where X 1 Selected from G or E; X 2 Selected from F or Y; X 3 Select from S or T; X 4 Selected from L, F or S; X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y, H or G; X 8 Selected from G, A, Y, W or F; X 9 Selected from M, W, Y or I; X 10 is selected from S, G, N, M or I; and X 11 Present or absent, if present, C; CDR2 sequence X 12 X 13 X 14 X15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 ; where X 12 Selected from G, T, A, I or Y; X 13 Selected from W, I, Y or C; X 14 Selected from I, S or Y; X 15 Selected from S, G, T, D or P; X 16 Selected from F, S, D, T or A; X 17 Selected from S, R, G or D; X 18 Selected from G, D or S; X 19 Selected from S, R, T, N, Y, A, D or P; X 20 Selected from T, A, G or Y; X 21 Selected from Y, H, A, S or T; X 22 Select from Y or N; X 23 Selected from A, P, Y or S; X 24 Selected from S, T, N, D, Y, A or P; X 25 Selected from W, S, A or D; X 26 Selected from A, V, T, W, F or S; X 27 Selected from K, W, A, Q or V; X 28 Selected from G, A or K; X 29 is present or absent, and if present, is selected from K or G; and X 30 Present or absent, if present, G; and CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X31 Selected from A or V; X 32 Selected from R or I; X 33 Selected from G, D, P, A or V; X 34 Selected from G, P, W, D, N or R; X 35 Selected from D, Y, S, L, G, F or W; X 36 Selected from Y, D, V, L, S, G or P; X 37 Selected from G, S, D, V or E; X 38 Selected from G, Y, F, S or D; X 39 Selected from S, D, G, T, N, A or V; X 40 Selected from T, A, D, S, Y, L or F; X 41 Present or absent, if present, selected from Y, A, G, I or D; X 42 Present or absent, if present, selected from I, Y, R, P, V or G; X 43 Present or absent, if present, selected from L, R, Y, G or A; X 44 Present or absent, if present, selected from N, L, Y, S or W; X 45 Present or absent, if present, selected from L, Y, F or C; X 46 Present or absent, if present, selected from D, A or F; X 47 Present or absent, if present, selected from M, P, Y or N; X 48 is present or absent, and if present, is selected from D or L; and X 49 Present or absent, if present, L. In some embodiments, the VH region comprises the CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 , where X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y or H; X 8 is selected from G, A or Y; and X 10 Selected from S, G or N. In some embodiments, the VH region comprises the CDR2 sequence GX 1 3 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG, where X 13 Selected from W, I or Y; X 15Selected from S or G; X 16 Selected from F, S, D or T; X 17 Selected from S or R; X 18 Select from G or D; X 19 Selected from S, R, T or N; X 20 is selected from T or A; and X 24 is selected from S, T or N. In some embodiments, the VH region comprises a CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , where X 31 Selected from A or V; X 33 Select from G or D; X 34 Selected from G, P, W or D; X 35 Selected from D, Y, S or L; X 36 Selected from Y, D, V or L; X 37 Selected from G, S or D; X 38 Selected from G, Y, F or S; X 39 Selected from S, D, G or T; X 40 Selected from T, A, D, S or Y; X 41 Selected from Y, A, G or I; X 42 selected from I, Y or R; X 43 Selected from L, R, Y or G; X 44 Selected from N, L, Y or S; X 45 Present or absent, if present, selected from L, Y or F; X 46 Exist or not, if it exists, then D; X 47 Present or absent, if present, selected from M or P; X 48 exists or does not exist, if it exists, it is D; and X 49is present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , where X 31 Select from A or V; X 32 Selected from R or I; X 33 Selected from G, D, P, A or V; X 34 Selected from G, P, W, D, N or R; X 35 Selected from D, Y, S, L, G, F or W; X 36 Selected from Y, D, V, L, S, G or P; X 37 Selected from G, S, D, V or E; X 38 Selected from G, Y, F, S or D; X 39 Selected from S, D, G, T, N, A or V; X 40 Selected from T, A, D, S, Y, L or F; X 41 Present or absent, if present, selected from Y, A, G, I or D; X 42 Present or absent, if present, selected from I, Y, R, P, V or G; X 43 Present or absent, if present, selected from L, R, Y, G or A; X 44 Present or absent, if present, selected from N, L, Y, S or W; X 45 Present or absent, if present, selected from L, Y, F or C; X 46 Present or absent, if present, selected from D, A or F; X 47 Present or absent, if present, selected from M, P, Y or N; X48 is present or absent, and if present, is selected from D or L; and X 49present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NO: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; a CDR2 sequence selected from the group consisting of SEQ ID NO: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 241, 247, and 250; a CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252. In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284. In some embodiments, the second targeting moiety comprises a VH sequence selected from the group consisting of SEQ ID NOs: 289-309 and a VL sequence selected from the group consisting of SEQ ID NOs: 311-326 and 155. In some embodiments, the anti-ICAM1 antibody is a multispecific antibody comprising an additional targeting moiety. In some embodiments, the additional targeting moiety specifically binds to CD38.In some embodiments, the additional targeting moiety comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises: CDR1 sequence X1GX2X3X4X5X6X7X8X9X. 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from P, S or D; X4 is selected from F, L or A; X5 is selected from D, G, S, N or T; X6 is selected from V, A, T, R, S, I or N; X7 is selected from Y, I, N, R, A, G or D; X8 is selected from A, Y, D, G, W, C or T; X9 is selected from M, V, I, W, D or Y; X 10 Selected from S, T, M, C, I, Y, A or G; X 11 Present or absent, if present, selected from C or M; X 12 Present or absent, if present, C; CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X20X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 ; where X 13 Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from S, I, L, T or M; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P, V or Y; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from F, Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25 Selected from D, T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27Selected from V, A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 Present or absent, if present, selected from G or K; X 31 Present or absent, if present, G; and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; and where X 32 Selected from A, G or V; X 33 Selected from K, A, R, T, G or S; X 34 Selected from R, A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, A, T or R; X 36 Selected from T, P, A, Y, D, G, S, R, V or E; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, A, S, D, K, F, L or Y; X 39 Selected from Y, T, A, G, S or I; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, if present, selected from P, L, Y, F, G or T; X 43 Present or absent, if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, if present, selected from G, L, S, T or F; X 45 Present or absent, if present, selected from F, L, E, N or S; X 46 Present or absent, if present, selected from D, S, L or R; X 47 Present or absent, if present, selected from Y or L; X 48 exists or does not exist, if it exists, it is D; and X 49In some embodiments, the VH region comprises a CDR1 sequence of GFPFX5X6YAMS, wherein X5 is selected from D or G; and X6 is selected from V, A or T. In some embodiments, the VH region comprises a CDR1 sequence of X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from S or D; X4 is selected from L, F or A; X5 is selected from S, N or T; X6 is selected from R, S, N, I or T; X7 is selected from Y, I, N, R, A, D or G; X8 is selected from Y, D, G, A, W, T or C; X9 is selected from V, M, I, W, Y or D; X 10 Selected from T, S, M, C, I, Y, A or G; X 11 is present or absent, and if present, is selected from C or M; and X 12 Present or absent, if present, C. In some embodiments, the VH region comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 wherein X5 is selected from S or N; X6 is selected from R, S or N; X7 is selected from Y, I or N; X8 is selected from Y, D, G or A; X9 is selected from V, M or I; X 10 is selected from T, S or M; and X 11 Present or absent, if present, C. In some embodiments, the VH region comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 wherein X4 is selected from F or A; X5 is selected from S, T or N; X6 is selected from S, T or N; X7 is selected from Y, R, A or G; X8 is selected from W, Y or C; X9 is selected from I, W, Y or D; X 10 Selected from C, I, Y or M; X 11 is present or absent, and if present, is selected from C or M; and X 12 Present or absent, if present, C. In some embodiments, the VH region comprises the CDR2 sequence AISGSGGSTX 22 YADSVKG, where X 22 In some embodiments, the VH region comprises a CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 ; where X 13 Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from I, L, M or T; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P or V; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25 Selected from T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 is present or absent, and if present, is G. In some embodiments, the VH region comprises a CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X19X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 ; where X 13 Selected from A or G; X 14 selected from I, F, Y, V, S or C; X 16 Selected from G, Y, S, T or L; X 17 Selected from S, I, K, Y, T or G; X18 Selected from G, S or T; X 19 Selected from G, A, D or S; X 20 Selected from T, I, N or G; X 21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Select from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Select from W or T; X 27 Select from A or W; X 28 Selected from K, R, Q or A; X 29 is selected from G or K; and X 30 is present or absent, and if present, is G. In some embodiments, the VH region comprises a CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 ; where X 13 Select from A or S; X 15 Selected from I, L or T; X 16 Selected from Y or V; X 17 Selected from S, T or A; X 18 Selected from G, P or V; X 19 Selected from D, S or T; X 20 Selected from S, T or G; X 21 Selected from D, N, S or A; X 22 Selected from T, I or S; X 23 Selected from Y, K or I; X 25 Selected from A or Y; X 26 Selected from S, T, A or N; X 27 Selected from W, N or S; X 28 Select from A or W; X 29 Select K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 Present or absent, if present, G. In some embodiments, the VH region comprises the CDR3 sequence AKRGTYX 38 YSX 41PTGFDY, where X 38 is selected from A or G; and X 41 In some embodiments, the VH region comprises a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X 32 Selected from A, G or V; X 33 Selected from A, R, T, S or G; X 34 Selected from A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, R or A; X 36 Selected from P, A, Y, D, G, S, R, V, E or T; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, S, D, K, F, L or Y; X 39 Selected from T, A, G, S, I or Y; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from V, D, Y, A, N, G, L or E; X 42 Present or absent, if present, selected from L, Y, F, T or G; X 43 Present or absent, if present, selected from P, F, V, N, S or Y; X 44 Present or absent, if present, selected from L, S, T, G or F; X 45 Present or absent, if present, selected from L, F, E, S or N; X 46 Present or absent, if present, selected from S, L or R; X 47 Exist or not, if it exists, it is L; X 48 exists or does not exist, if it exists, it is D; and X 49 is present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR3 sequence X 32 X 33 X 34 X35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 ; where X 32 Selected from A or G; X 33 Selected from A, R or T; X 34 Selected from A, V, T, P, I, E or D; X 35 Selected from G, W, D, L, K or P; X 36 Selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X 38 Selected from G, S, D or K; X 39 Selected from T, A, G, S or I; X 40 Selected from S, Y, G, R or W; X 41 Selected from V, D, Y, A, N or G; X 42 Selected from L, Y or F; X 43 Present or absent, if present, selected from P, F, V or N; X 44 is present or absent, and if present is selected from L, S or T; and X 45 is present or absent, and if present is selected from L or F. In some embodiments, the VH region comprises the CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 ; where X 33 Selected from R or G; X 34 Selected from E, D or S; X 35 Selected from G, L, P, S or A; X 36 Selected from D, S or R; X 37 Selected from Y, T, N or G; X 38 Selected from G, S, F or L; X 39 Selected from A, G, S or I; X 40 Selected from Y, N or L; X 41 Present or absent, if present, selected from V, Y or E; X 42Exist or not, if it exists, it is G; X 43 Exists or does not exist, if exists, then it is Y; X 44 Exist or not, if it exists, then F; X 45 is present or absent, and if present, is selected from E or N; and X 46 Present or absent, if present, selected from S or L. In some embodiments, the VH region comprises the CDR1 sequence GFPFX5X6YAMS, the CDR2 sequence AISGSGGSTX 22 YADSVKG and CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY; wherein X5 is selected from D or G; X6 is selected from V, A or T; X 22 Selected from F or Y; X 38 is selected from A or G; and X 41 Selected from F or Y. In some embodiments, the VH region comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 , CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X43X 44 X 45 wherein X5 is selected from S or N; X6 is selected from R, S or N; X7 is selected from Y, I or N; X8 is selected from Y, D, G or A; X9 is selected from V, M or I; X 10 Select from T, S or M; X 11 Exist or not, if it exists, then C; X 13 Selected from A or G; X 14selected from I, F, Y, V, S or C; X 16 Selected from G, Y, S, T or L; X 17 Selected from S, I, K, Y, T or G; X 18 Selected from G, S or T; X 19 Selected from G, A, D or S; X 20 Selected from T, I, N or G; X 21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Select from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Select from W or T; X 27 Select from A or W; X 28 Selected from K, R, Q or A; X 29 Selected from G or K; X 30 Exist or not, if it exists, it is G; X 32 Selected from A or G; X 33 Selected from A, R or T; X 34 Selected from A, V, T, P, I, E or D; X 35 Selected from G, W, D, L, K or P; X 36 Selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X 38 Selected from G, S, D or K; X 39 Selected from T, A, G, S or I; X 40 Selected from S, Y, G, R or W; X 41 Selected from V, D, Y, A, N or G; X 42 Selected from L, Y or F; X 43 Present or absent, if present, selected from P, F, V or N; X 44 is present or absent, and if present is selected from L, S or T; and X 45 is present or absent, and if present is selected from L or F. In some embodiments, the VH region comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 , CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X21X 22 X 23 YX 25 X 26 X27 X 28 X 29 X 30 X 31 and CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 wherein X4 is selected from F or A; X5 is selected from S, T or N; X6 is selected from S, T or N; X7 is selected from Y, R, A or G; X8 is selected from W, Y or C; X9 is selected from I, W, Y or D; X 10 Selected from C, I, Y or M; X 11 Present or absent, if present, selected from C or M; X 12 Exist or not, if it exists, then C; X 13 Select from A or S; X 15 Selected from I, L or T; X 16 Selected from Y or V; X 17 Selected from S, T or A; X 18 Selected from G, P or V; X 19 Selected from D, S or T; X 20 Selected from S, T or G; X 21 Selected from D, N, S or A; X 22 Selected from T, I or S; X 23 Selected from Y, K or I; X 25 Selected from A or Y; X 26 Selected from S, T, A or N; X 27 Selected from W, N or S; X 28 Select from A or W; X 29 Select K or A; X 30 Present or absent, if present, selected from G or K; X 31 Exist or not, if it exists, it is G; X 33 Selected from R or G; X 34 Selected from E, D or S; X 35 Selected from G, L, P, S or A; X 36 Selected from D, S or R; X 37 Selected from Y, T, N or G; X 38 Selected from G, S, F or L; X 39 Selected from A, G, S or I; X 40 Selected from Y, N or L; X41 Present or absent, if present, selected from V, Y or E; X 42 Exist or not, if it exists, it is G; X 43 Exists or does not exist, if exists, then it is Y; X 44 Exist or not, if it exists, then F; X 45 is present or absent, and if present, is selected from E or N; and X 46 is present or absent, and if present, is selected from S or L. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X 32 Selected from A, G or V; X 33 Selected from K, A, R, T, G or S; X 34 Selected from R, A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, A, T or R; X 36 Selected from T, P, A, Y, D, G, S, R, V or E; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, A, S, D, K, F, L or Y; X 39 Selected from Y, T, A, G, S or I; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, if present, selected from P, L, Y, F, G or T; X43 Present or absent, if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, if present, selected from G, L, S, T or F; X 45 Present or absent, if present, selected from F, L, E, N or S; X 46 Present or absent, if present, selected from D, S, L or R; X 47 Present or absent, if present, selected from Y or L; X 48 exists or does not exist, if it exists, it is D; and X 49is present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 3, 7, and 10. and a CDR3 sequence selected from the group consisting of SEQ ID NO: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58.In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NO: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103. In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 71, 77, 83, 94, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 72, 78, and 84; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 73, 79, 85, 95, and 103. In some embodiments, the anti-CD38 antibody comprises a VH sequence selected from the group consisting of SEQ ID NOs: 104-128 and a VL sequence selected from the group consisting of SEQ ID NOs: 130-154. In some embodiments, the anti-ICAM1 antibody comprises a humanized antibody or a binding fragment thereof, or a chimeric antibody or a binding fragment thereof. In some embodiments, the anti-ICAM1 antibody comprises a bispecific antibody or a binding fragment thereof. In some embodiments, the bispecific antibody or binding fragment thereof comprises an IgG-scFv, a nanobody, a BiTE, a diabody, a DART, a TandAb, a scDiabody, a scDiabody-CH3, a triabody, a minibody, a minibody, a TriBi minibody, scFv-CH3KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, F(ab')2, F(ab')2-scFv2, scFv-KIH, Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a diabody-Fc, a tandem scFv-Fc, or an intrabody. In some embodiments, the anti-ICAM1 antibody comprises an IgG1 framework sequence. In some embodiments, the anti-ICAM1 antibody comprises an IgG2 framework sequence. In some embodiments, the anti-ICAM1 antibody comprises an IgG4 framework sequence.In some embodiments, the anti-ICAM1 antibody comprises an HC sequence selected from SEQ ID NOs: 329-349 and an LC sequence selected from SEQ ID NOs: 351-366 and 182. In some embodiments, the anti-ICAM1 antibody further comprises a payload. In some embodiments, the payload comprises a small molecule, a peptide, or a protein.

[0181] In certain embodiments, disclosed herein are nucleic acid polymers encoding a bispecific antibody described herein, an anti-CD38 antibody described herein, or an anti-ICAM1 antibody described herein.

[0182] In certain embodiments, disclosed herein are vectors comprising a nucleic acid polymer encoding a bispecific antibody described herein, an anti-CD38 antibody described herein, or an anti-ICAM1 antibody described herein.

[0183] In certain embodiments, disclosed herein is a pharmaceutical composition comprising: a bispecific antibody described herein, an anti-CD38 antibody described herein, or an anti-ICAM1 antibody described herein; and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for systemic administration. In some embodiments, the pharmaceutical composition is formulated for parenteral administration.

[0184] In certain embodiments, disclosed herein is a method of treating cancer in a subject in need thereof, comprising administering to the subject a bispecific antibody described herein, an anti-CD38 antibody described herein, an anti-ICAM1 antibody described herein, or a pharmaceutical composition described herein, thereby treating the subject's cancer. In some embodiments, the subject has a solid tumor. In some embodiments, the solid tumor is bladder cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, eye cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the hematological malignancy is a B-cell lymphoma or a T-cell lymphoma. In some embodiments, the hematological malignancy is a Hodgkin lymphoma or a non-Hodgkin lymphoma. In some embodiments, the hematological malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt lymphoma, non-Burkitt high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma or lymphomatoid granuloma. In some embodiments, the cancer is a metastatic cancer. In some embodiments, the cancer is a recurrent or refractory cancer. In some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapy agent, a hormone-based therapy agent, a stem cell-based therapy agent, or radiation. In some embodiments, the additional therapeutic agent comprises a first-line therapy agent. In some embodiments, the additional therapeutic agent and the antibody are administered simultaneously. In some embodiments, the additional therapeutic agent and the antibody are administered sequentially. In some embodiments, the additional therapeutic agent is administered before the antibody. In some embodiments, the additional therapeutic agent is administered after the antibody is administered. In some embodiments, the additional therapeutic agent and the antibody are administered as separate doses. In some embodiments, the subject has undergone surgery. In some embodiments, the subject is human.

[0185] In certain embodiments, disclosed herein is a kit comprising a bispecific antibody described herein, an anti-CD38 antibody described herein, an anti-ICAM1 antibody described herein, or a pharmaceutical composition described herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0186] The novel features of the present invention are set forth with particularity in the appended claims. The features and advantages of the present invention will be better understood with reference to the following detailed description which sets forth illustrative embodiments in which the principles of the invention are utilized, wherein:

[0187] Figure 1A-1B Exemplary bispecific antibody formats contemplated herein are shown. Figure 1A and Figure 1B Adapted from Figure 2 of Brinkmann and Kontermann, “The making of bispecific antibodies,” MABS 9(2):182–212 (2017).

[0188] Figure 2 shows exemplary bispecific formats described herein. Figure 2A : Light chain C-terminal fusion; Figure 2B : Heavy chain C-terminal fusion; Figure 2C : Heavy chain N-terminal fusion; Figure 2D : DVD format; Figure 2E : three-chain knob-in-hole structure (KIH); and Figure 2F : Common light chain bispecific.

[0189] Figures 3A-3B Shown are the CD38 ( Figure 3A ) and ICAM1( Figure 3B ) level.

[0190] Figure 4A-4B The effects of selected monoclonal and bispecific antibodies on Daudi cells ( Figure 4A ) and Raji cells ( Figure 4B ) by complement-dependent cytotoxicity (CDC)-mediated lysis.

[0191] Figures 5A-5F Shown using NK92 / CD16A as effector cells, Daudi cells ( Figure 5A ), DU145 cells ( Figure 5B ), NCI-H2444 cells ( Figure 5C ), HCC44 cells ( Figure 5D ), NCI-H2291 cells ( Figure 5E ) and NCI-H2342( Figure 5F ) cells through antibody-dependent cellular cytotoxicity (ADCC)-mediated lysis.

[0192] Figures 6A-6D Shown using fresh PBMC as effector cells, Daudi cells ( Figure 6A ), DU145 cells ( Figure 6B ), HCC44 cells ( Figure 6C ) and NCI-H2444 cells ( Figure 6D ) by ADCC-mediated cleavage.

[0193] Figure 7 Shown is the induction of cell death and apoptosis in Daudi cells by selected monoclonal and bispecific antibodies in the presence (grey bars) or absence (black bars) of cross-linkers.

[0194] Figure 8A-8B NK92 / CD16a cells ( Figure 8A ) and NK cells in fresh PBMCs ( Figure 8B ) antibody-induced cell death. HC N fusion and three-chain KIH antibodies showed reduced NK killing compared to anti-CD38 BMK clones (or the reference antibody daratumumab).

[0195] Figure 9A-9B An exemplary anti-CD38 rabbit-human chimeric clone is shown with recombinant human CD38 ECD ( Figure 9A ) and cynomolgus monkey CD38 ECD ( Figure 9B ) by ELISA binding.

[0196] Figures 10A-10B An exemplary anti-ICAM1 rabbit-human chimeric clone is shown with recombinant human ICAM1 ECD ( Figure 10A ) and rhesus ICAM1 ECD ( Figure 10B ) by ELISA binding.

[0197] Figure 11 Binding of exemplary anti-CD38 rabbit-human chimeric clones to Daudi cells as determined by flow cytometry is shown.

[0198] Figure 12 Shown is the binding of anti-ICAM1 rabbit human chimeric clone to DU145 cells as determined by flow cytometry.

[0199] Figure 13 CDC-mediated lysis of Daudi cells by benchmark and exemplary rabbit-human chimeric anti-CD38 antibodies is shown.

[0200] Figures 14A-14B Using NK92 / CD16A as effector cells, anti-CD38 antibodies were shown to inhibit Daudi cells ( Figure 14A ) and HuNS1 cells ( Figure 14B ) by ADCC-mediated cleavage.

[0201] Figures 15A-15B Benchmark and exemplary rabbit-human chimeric anti-CD38 antibodies are shown for Daudi cells ( Figure 15A ) and HuNS1 cells ( Figure 15B ) by ADCC-mediated cleavage.

[0202] Figures 16A-16C The results show that NK92 / CD16A cells were used as effector cells, anti-ICAM1 clone G12 and an exemplary rabbit human chimeric anti-ICAM1 antibody were used to treat DU145 ( Figure 16A ), Daudi cells ( Figure 16B ) and HuNS1 cells ( Figure 16C ) by ADCC-mediated cleavage.

[0203] Figures 17A-17C Shown are exemplary high affinity anti-CD38 4618_1_12 bispecific antibodies ( Figure 17A ), exemplary medium affinity anti-CD38 32218_1 bispecific antibody ( Figure 17B ) and an exemplary low affinity anti-CD3833218_2 bispecific antibody ( Figure 17C ) ADCC-mediated lysis of DU145 cells.

[0204] Figures 18A-18C The results of the immunohistochemistry of Raji ( Figure 18A )、DU145( Figure 18B ) and HCC44( Figure 18C ) by ADCC-mediated cleavage.

[0205] Figures 19A-19B The use of CD38 / ICAM1 KIH bispecific antibody with Fc mutation (ADCC-high) for Raji ( Figure 19A ) and KMS26( Figure 19B ) cells by increased ADCC-mediated lysis.

[0206] Figure 20A-Figure 20B The use of afucosylated CD38 / ICAM1 KIH bispecific antibody to Raji ( Figure 20A ) and KMS26( Figure 20B ) cells by increased ADCC-mediated lysis.

[0207] Figure 21Shown are the mean volumes of Raji cell-derived xenograft tumors treated with monospecific CD38 or ICAM1 antibodies or three-chain KIH CD38 / ICAM1 bispecific antibodies.

[0208] Figure 22 Shown are the average volumes of Raji cell-derived xenograft tumors treated with a monospecific CD38 antibody, a three-chain KIH CD38 / ICAM1 bispecific antibody having an anti-CD38 binding domain from an anti-CD38 BMK, or a three-chain KIH CD38 / ICAM1 bispecific antibody having a CD38 binding domain from 32218_1 (three-chain KIH (medium)).

[0209] Figure 23 Shown are the mean volumes of HuNS1 cell-derived xenograft tumors treated with monospecific CD38 or ICAM1 antibodies or the three-chain KIH CD38 / ICAM1 bispecific antibody.

[0210] Figure 24 Shown are the mean volumes of HCC44 cell-derived xenograft tumors treated with fucosylated and afucosylated versions of the bispecific antibody having the CD38 binding domain derived from 18E4 and the ICAM1 binding domain derived from 11F2, monospecific antibodies with the same binding domains, and a monospecific anti-CD38 reference antibody (anti-CD38 BMK). DETAILED DESCRIPTION

[0211] Due to the specificity and affinity of antibodies for target binding and the ease of chemical and molecular modification, antibody-based therapies have become an effective cancer treatment option. For example, approved antibody-based therapies include monoclonal antibodies such as rituximab, tositumomab, and trastuzumab; and bispecific T cell engagers such as belintumomab.

[0212] In some cases, low receptor copy number on target cells or low affinity for the antigen have hindered the efficacy of antibody-based therapies.In some cases, the antibody is nonspecific for the target antigen, or the target is present in both cancer and non-cancerous cells, further limiting the use of antibody-based therapies.

[0213] CD38, also known as cyclic ADP ribose hydrolase, is a type II transmembrane glycoprotein with a long C-terminal extracellular domain and a short N-terminal cytoplasmic domain. CD38 mediates cytokine secretion and activation and proliferation of lymphocytes (Funaro et al., J Immunology 145: 2390-6, 1990; Guse et al., Nature 398: 70-3, 1999), and regulates extracellular NAD+ levels through its NAD glycohydrolase activity, which is related to regulating regulatory T cell compartments (Adriouch et al., 14: 1284-92, 2012; Chiarugi et al., Nature Reviews 12: 741-52, 2012). In some cases, CD38 is upregulated in different types of cancer, particularly in hematological malignancies such as multiple myeloma.

[0214] ICAM1, also known as CD54, is an Ig-like cell adhesion molecule. ICAM1 is an endothelial and leukocyte-associated transmembrane protein involved in stabilizing cell-cell interactions and promoting leukocyte endothelial migration. ICAM1 is expressed in a variety of cell types, including endothelial cells and leukocytes, and can be expressed and / or overexpressed in different cancer cells, such as myeloma, pancreatic cancer, glioma, lung cancer, melanoma, colorectal cancer, and lymphoma.

[0215] In some embodiments, disclosed herein are anti-CD38 antibodies, anti-ICAM1 antibodies, and multispecific antibodies comprising a CD38-targeting moiety, an ICAM1-targeting moiety, or a combination thereof. In some embodiments, also described herein are bispecific antibodies comprising a first CD38-targeting moiety and a second ICAM1-targeting moiety. In additional embodiments, methods of treating cancer using anti-CD38 antibodies, anti-ICAM1 antibodies, or multispecific antibodies (e.g., bispecific CD38 / ICAM1 antibodies) are also described herein.

[0216] Multispecific proteins

[0217] In certain embodiments, disclosed herein are multispecific proteins comprising a first component that binds to CD38 and a second component that binds to ICAM1. In some cases, the first component is a CD38 binding protein, such as an anti-CD38 antibody or an anti-CD38 antibody mimetic. In some cases, the second component is an ICAM1 binding protein, such as an anti-ICAM1 antibody or an anti-ICAM1 antibody mimetic. See, e.g., Yu et al., Annu Rev Anal Chem (Palo Alto Calif). 2017 Jun 12; 10(1): 293-320.

[0218] In some cases, the multispecific protein is bispecific, trispecific, or tetraspecific. In some cases, the multispecific protein is bivalent, trivalent, tetravalent, or more than tetravalent. In some cases, the multispecific protein has more than one binding site that binds to CD38. In some cases, the multispecific protein has more than one binding site that binds to ICAM1. In some cases, the multispecific protein has more than one binding site for each of 1, 2, 3, or 4 different target proteins. In some cases, the multispecific protein binds to more than one epitope on CD38 and / or ICAM1. In some cases, the multispecific protein is bivalent for CD38 and univalent for ICAM1. In some cases, the multispecific protein is bivalent for ICAM1 and univalent for CD38.

[0219] In some embodiments, the first component comprises an antibody mimetic comprising a specific binding site for CD38 and is an affibody, an adnectin (also known as a monobody), an affimer, an affitin (also known as a nanofitin), an anticalin, an atrimer, an avimer, a fyonmer, an antibody mimetic comprising an armadillo repeat domain, a kuntiz domain, a knottin, a DARpin, or any combination thereof. In some embodiments, the second component comprises an antibody mimetic comprising a specific binding site for ICAM1 and is an affibody, an adnectin (also known as a monobody), an affimer, an affitin (also known as a nanofitin), an anticalin, an atrimer, an avimer, a fyonmer, an antibody mimetic comprising an armadillo repeat domain, a kuntiz domain, a knottin, a DARpin, or any combination thereof.

[0220] In some embodiments, the first component comprises an anti-CD38 antibody or an antigen-binding fragment thereof. Non-limiting examples of anti-CD38 antibodies include: an anti-CD38 IgG antibody comprising two polypeptides (each comprising a heavy chain (HC) and a light chain (LC)), a single domain antibody (sdAb), a VHH domain (or camelized) antibody, a variable heavy chain domain (VH), a variable light chain domain (VL), Fab, F(ab')2, a single chain variable fragment (scFv), a scFv comprising an Fc region (scFv Fc), a monovalent IgG, a V-NAR, an IgGNAR, a camelid heavy chain IgG (hcIgG), and a scFv fused to a CH3 domain (scFv-CH3).

[0221] In some embodiments, the second component comprises an anti-ICAM1 antibody or an antigen-binding fragment thereof. Non-limiting examples of anti-ICAM1 antibodies include: an anti-ICAM1 IgG antibody comprising two polypeptides (each comprising a heavy chain (HC) and a light chain (LC)), a single domain antibody (sdAb), a VHH domain (or camelized) antibody, a variable heavy chain domain (VH), a variable light chain domain (VL), Fab, F(ab')2, a single chain variable fragment (scFv), a scFv comprising an Fc region (scFv Fc), a monovalent IgG, a V-NAR, an IgGNAR, a camelid heavy chain IgG (hcIgG), and a scFv fused to a CH3 domain (scFv-CH3).

[0222] In some embodiments, a multispecific protein comprising a CD38-binding first component and an ICAM1-binding second component has different affinities (K D ), as measured by surface plasmon resonance. In some cases, the first component has a K D Binding to human CD38: from about 0.1 nM to about 100 nM, from about 0.15 nM to about 95 nM, from about 0.2 nM to about 90 nM, from 0.25 nM to about 85 nM, from about 0.3 nM to about 80 nM, from about 0.35 nM to about 75 nM, from about 0.4 nM to about 70 nM, from about 0.5 nM to about 70 nM, from about 0.6 nM to about 60 nM, from about 0.7 nM to about 50 nM, from about 0.8 nM to about 40 nM, from about 0.9 nM to about 30 nM, from about 1 nM to about 20 nM, from about 1.5 nM to about 10 nM, about 0.01 nM to about 25 nM, about 0.01 nM to about 20 nM, about 0.01 nM to about 10 nM, about 0.01 nM to about 5 nM, about 0.02 nM to about 20 nM, about 0.04 nM to about 20 nM, about 0.06 nM to about 20 nM, about 0.08 nM to about 20 nM, or about 0.1 nM to about 20 nM.

[0223] In some cases, the second component is K DBinding to human ICAM1: from about 0.1 nM to about 100 nM, from about 0.15 nM to about 95 nM, from about 0.2 nM to about 90 nM, from 0.25 nM to about 85 nM, from about 0.3 nM to about 80 nM, from about 0.35 nM to about 75 nM, from about 0.4 nM to about 70 nM, from about 0.5 nM to about 70 nM, from about 0.6 nM to about 60 nM, from about 0.7 nM to about 50 nM, from about 0.8 nM to about 40 nM, from about 0.9 nM to about 30 nM, from about 1 nM to about 20 nM, from about 1.5 nM to about 10 nM, from about 0.15 nM to about 30 nM, from about 0.16 nM to about About 25nM, about 0.17nM to about 20nM, 0.18nM to about 15nM, about 0.19nM to about 10nM, about 0.1nM to about 6nM, about 0.2nM to about 6nM, about 0.2nM to about 4nM, about 0.2nM to about 2nM, about 0.2nM to about 1.5nM, about 0.2nM to about 1nM, about 0.2nM to about 0.8nM, about 0.2nM to about 0.6nM, or about 0.2nM to about 0.4nM.

[0224] In some embodiments, the multispecific proteins provided herein bind to target cells that express higher levels of ICAM1 than CD38 on the surface of the target cells. For example, the ratio of ICAM1 to CD38 protein expression on the surface of the target cells is about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200, as measured by flow cytometry. For example, based on quantification of surface expression of the proteins, the ratio of ICAM1 to CD38 protein expression on the surface of the target cells is about 1.1 to 700, e.g., about 2.5, 14.2, 29.1, 64.5, 34.0, 50.3, 357.1, 666.7.

[0225] In some cases, the target cell expresses at least 500, 1000, 2000, 3000, 5000, 10000, 15000, 20000, 30000, 50000, 100000, 150000, 200000, 250000, 300000, 400000, or 500000 ICAM1 proteins on its surface as measured by flow cytometry.

[0226] In some cases, the target cell expresses at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on its surface as measured by flow cytometry. In some cases, the target cell expresses fewer than 350,000, 300,000, 250,000, 200,000, 150,000, 100,000, 50,000, or 25,000 CD38 proteins on its surface as measured by flow cytometry. In some cases, the amount of CD38 protein on the surface of a target cell is 100 to 350,000, 100 to 300,000, 100 to 250,000, 100 to 200,000, 100 to 150,000, 100 to 100,000, 100 to 80,000, 100 to 60,000, 100 to 50,000, 100 to 40,000, 100 to 30,000, 100 to 20,000, 00,000, 300 to 20,000, 300 to 150,000, 300 to 100,000, 300 to 80,000, 300 to 60,000, 300 to 50,000, 300 to 40,000, 300 to 30,000, 300 to 20,000, or 300 to 10,000. In some cases, the target cells have less CD38 protein on their surface than Daudi cells, Raji cells, KMS-26 cells, HuNS1 cells, HCC44 cells, NCI-H2444 cells, or DU145 cells. In some cases, the target cell has at least 200 CD38 proteins on its surface, but has fewer CD38 proteins on its surface than a Daudi cell, a Raji cell, a KMS-26 cell, a HuNS1 cell, a HCC44 cell, an NCI-H2444 cell, or a DU145 cell.

[0227] In some embodiments, the target cell is a transformed cell wherein the ratio of ICAM1 to CD38 protein is at least 1, 2, 5, 10, 15, 20, 35, 40, 50, or 200. In some cases, the transformed cell expresses at least 100, 200, 300, 400, 500, 750, 1000, 1250, 1500, 2000, 3000 CD38 cells on its surface. In some cases, the target cell is a myeloma cell, a lymphoma cell, a pancreatic cancer cell, a lung adenocarcinoma cell, or a prostate cancer cell wherein the ratio of ICAM1 to CD38 protein is at least 0.15, 0.20, 0.3, 0.4, 0.5, 1.0, 2.5, or 5.0. In other cases, the target cell is derived from a lung adenocarcinoma wherein the ratio of ICAM1 to CD38 protein is at least 1, 2, 5, 10, 15, 20, 35, 40, 50, or 200. In some cases, the myeloma cell, lymphoma cell, pancreatic cancer cell, lung adenocarcinoma cell, or prostate cancer cell express at least 100, 200, 300, 400, 500, 750, 1000, 1250, 1500, 2000, 3000 CD38 cells on its surface.

[0228] In some embodiments, a multispecific protein having a CD38 binding domain and an ICAM1 binding domain has an enhanced affinity for cells expressing CD38 and ICAM1 compared to a monospecific protein having a CD38 binding domain and / or a monospecific protein having an ICAM1 binding domain. In some cases, the multispecific protein has a 1.5, 2, 3, 4, 5, or 10-fold higher affinity for cells expressing CD38 than a monospecific protein that binds to CD38 or a monospecific protein that binds to ICAM1. In some embodiments, a multispecific protein having a CD38 binding domain and an ICAM1 binding domain has an enhanced affinity for cells expressing CD38 at a higher level than ICAM1 compared to a monospecific protein having a CD38 binding domain. In some cases, the multispecific protein has a 1.5, 2, 3, 4, 5, or 10-fold higher affinity for cells expressing ICAM1 than CD38 compared to a monospecific protein that binds to CD38.

[0229] In some embodiments, a multispecific protein having a CD38 binding domain and an ICAM1 binding domain binds to the surface of cells expressing CD38 and ICAMs in greater amounts than a monospecific protein having a CD38 binding domain and / or a monospecific protein having an ICAM1 binding domain. In some cases, the multispecific protein binds to cells expressing CD38 at 1.5, 2, 3, 4, 5, or 10 times more than the monospecific protein that binds to CD38 or the monospecific protein that binds to ICAM1. In some embodiments, a multispecific protein having a CD38 binding domain and an ICAM1 binding domain binds to the surface of cells expressing ICAM1 at a higher level than CD38 at a higher level than the monospecific protein that has a CD38 binding domain. In some cases, the multispecific protein binds to cells expressing ICAM1 at a higher level than CD38 at a 1.5, 2, 3, 4, 5, or 10 times more than the monospecific protein that binds to CD38.

[0230] In some embodiments, compared with a monospecific protein with a CD38 binding domain and / or a monospecific protein with an ICAM1 binding domain, a multispecific protein with a CD38 binding domain and an ICAM1 binding domain has a higher immunoreactivity against cells expressing CD38. In some cases, the immunoreactivity that the multispecific protein has is 1.5, 2, 3, 4, 5 or 10 times higher than that of a monospecific protein with a CD38 binding domain and / or a monospecific protein with an ICAM1 binding domain. The various immunological activities of the multispecific protein can be measured by in vitro assays (e.g., ADCC assays and CDC assays). In some cases, the ADCC activity that the multispecific protein has is 1.5, 2, 3, 4, 5 or 10 times higher than that of a monospecific protein with a CD38 binding domain and / or a monospecific protein with an ICAM1 binding domain. In some cases, the multispecific protein has CDC activity that is 1.5, 2, 3, 4, 5, or 10 times greater than a monospecific protein with a CD38 binding domain and / or a monospecific protein with an ICAM1 binding domain.

[0231] Immune activity can also be measured in cell line-derived xenograft assays, in which transformed cells are injected into mice and form tumors. In some cases, a multispecific protein having a CD38 binding domain and an ICAM1 binding domain inhibits the growth of tumors containing cells expressing CD38 to a greater extent than a monospecific protein having a CD38 binding domain and / or a monospecific protein having an ICAM1 binding domain. In some cases, the multispecific protein exhibits 1.5, 2, 3, 4, 5, or 10-fold greater xenograft tumor growth inhibition than a monospecific protein having a CD38 binding domain and / or a monospecific protein having an ICAM1 binding domain.

[0232] As used herein, "antibody-dependent cell-mediated cytotoxicity" and "ADCC" refer to a cell-mediated reaction in which nonspecific cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages) recognize bound antibodies on target cells, subsequently leading to target cell lysis. In one embodiment, the target cell is a human cell, such as a tumor cell (e.g., a myeloma cell). Although not wishing to be bound by any particular mechanism of action, cytotoxic cells that mediate ADCC typically express Fc receptors (FcRs). NK cells that mediate ADCC express FcγRIII, while monocytes express FcγRI, FcγRII, FcγRIII, and / or FcγRIV. FcR expression on hematopoietic cells is summarized in Ravetch and Kinet, Annu. Rev. Immunol., 9:457-92 (1991).

[0233] To assess the ADCC activity of a multispecific protein as described herein, in some embodiments, an in vitro ADCC assay is performed, such as a cytotoxicity assay using a cancer cell line. Useful effector cells for such assays include, but are not limited to, peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively, or additionally, in some embodiments, the ADCC activity of the multispecific protein of interest is assessed in vivo (e.g., in an animal).

[0234] "Complement-dependent cytotoxicity" or "CDC" refers to the ability of a molecule to initiate complement activation and lyse a target in the presence of complement. The complement activation pathway is initiated by the binding of the first component of the complement system (C1q) to a molecule (e.g., an antibody) complexed with a cognate antigen. To assess complement activation, in some embodiments, a CDC assay is performed, for example, as described in Gazzano-Santaro et al., J. Immunol. Methods, 202:163 (1996).

[0235] In some embodiments, a multispecific protein as described herein that binds CD38 and ICAM1 mediates complement dependent lysis of at least 50% of the cells in an exponentially growing Raji cell population at a concentration of about 2 nM. In some embodiments, a multispecific protein as described herein that binds CD38 and ICAM1 mediates ADCC of PBMC cells in 40% of the cells in an exponentially growing NCI-H2444 cell population at a concentration of about 1 nM. In certain embodiments, a multispecific (e.g., bispecific), multivalent (e.g., bivalent, trivalent, tetravalent) protein as described herein that binds CD38 and ICAM1 does not induce apoptosis in the absence of cross-linking.

[0236] anti-CD38 antibody

[0237] In certain embodiments, an anti-CD38 antibody is disclosed herein. In some cases, the anti-CD38 antibody comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises a CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from P, S or D; X4 is selected from F, L or A; X5 is selected from D, G, S, N or T; X6 is selected from V, A, T, R, S, I or N; X7 is selected from Y, I, N, R, A, G or D; X8 is selected from A, Y, D, G, W, C or T; X9 is selected from M, V, I, W, D or Y; X 10 Selected from S, T, M, C, I, Y, A or G; X 11 is present or absent, and if present, is selected from C or M; and X 12 Present or absent, if present, C; CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X29X 30 X 31 ; where X 13 Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from S, I, L, T or M; X16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P, V or Y; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from F, Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25 Selected from D, T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from V, A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 Present or absent, if present, selected from G or K; X 31 Present or absent, if present, G; and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X 32 Selected from A, G or V; X 33 Selected from K, A, R, T, G or S; X 34 Selected from R, A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, A, T or R; X 36 Selected from T, P, A, Y, D, G, S, R, V or E; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, A, S, D, K, F, L or Y; X 39 Selected from Y, T, A, G, S or I; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41Present or absent, if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, if present, selected from P, L, Y, F, G or T; X 43 Present or absent, if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, if present, selected from G, L, S, T or F; X 45 Present or absent, if present, selected from F, L, E, N or S; X 46 Present or absent, if present, selected from D, S, L or R; X 47 Present or absent, if present, selected from Y or L; X 48 exists or does not exist, if it exists, it is D; and X 49 Exists or does not exist, if it exists, it is L

[0238] In some instances, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFPFX5X6YAMS (SEQ ID No. 423), wherein X5 is selected from D or G; and X6 is selected from V, A, or T.

[0239] In some cases, the VH region of the anti-CD38 antibody comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from S or D; X4 is selected from L, F or A; X5 is selected from S, N or T; X6 is selected from R, S, N, I or T; X7 is selected from Y, I, N, R, A, D or G; X8 is selected from Y, D, G, A, W, T or C; X9 is selected from V, M, I, W, Y or D; X 10 Selected from T, S, M, C, I, Y, A or G; X 11 is present or absent, and if present, is selected from C or M; and X 12 It exists or it doesn't exist, if it exists, then it is C.

[0240] In some cases, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (SEQ ID No. 426); wherein X5 is selected from S or N; X6 is selected from R, S or N; X7 is selected from Y, I or N; X8 is selected from Y, D, G or A; X9 is selected from V, M or I; X 10 is selected from T, S or M; and X 11 It exists or it doesn't exist, if it exists, then it is C.

[0241] In some cases, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (SEQ ID No. 419); wherein X4 is selected from F or A; X5 is selected from S, T or N; X6 is selected from S, T or N; X7 is selected from Y, R, A or G; X8 is selected from W, Y or C; X9 is selected from I, W, Y or D; X 10 Selected from C, I, Y or M; X 11 is present or absent, and if present, is selected from C or M; and X 12 It exists or it doesn't exist, if it exists, then it is C.

[0242] In some instances, the VH region of the anti-CD38 antibody comprises the CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID No. 418), wherein X 22 Select from F or Y.

[0243] In some cases, the VH region of the anti-CD38 antibody comprises a CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X24X 25 X 26 X 27 X 28 X 29 X 30 X 31 ; where X 13 Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from I, L, M or T; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P or V; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25Selected from T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 It exists or it doesn't exist, if it exists, it is G.

[0244] In some cases, the VH region of the anti-CD38 antibody comprises a CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X24X 25 X 26 X 27 X 28 X 29 X 30 ; where X 13 Selected from A or G; X 14 selected from I, F, Y, V, S or C; X 16 Selected from G, Y, S, T or L; X 17 Selected from S, I, K, Y, T or G; X 18 Selected from G, S or T; X 19 Selected from G, A, D or S; X 20 Selected from T, I, N or G; X 21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Select from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Select from W or T; X 27 Select from A or W; X 28 Selected from K, R, Q or A; X 29 is selected from G or K; and X 30 It exists or it doesn't exist, if it exists, it is G.

[0245] In some cases, the VH region of the anti-CD38 antibody comprises a CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X20 X 21 X 22 X 23 YX25X 26 X 27 X 28 X 29 X 30 X 31 ; where X 13 Select from A or S; X 15 Selected from I, L or T; X 16 Selected from Y or V; X 17 Selected from S, T or A; X 18 Selected from G, P or V; X 19 Selected from D, S or T; X 20 Selected from S, T or G; X 21 Selected from D, N, S or A; X 22 Selected from T, I or S; X 23 Selected from Y, K or I; X 25 Selected from A or Y; X 26 Selected from S, T, A or N; X 27 Selected from W, N or S; X 28 Select from A or W; X 29 Select K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 It exists or it doesn't exist, if it exists, it is G.

[0246] In some instances, the VH region of the anti-CD38 antibody comprises the CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY (SEQ ID No. 421), wherein X 38 is selected from A or G; and X 41 Select from F or Y.

[0247] In some cases, the VH region of the anti-CD38 antibody comprises a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X43X 44 X 45 X 46 X 47 X 48 X 49 ; where X 32Selected from A, G or V; X 33 Selected from A, R, T, S or G; X 34 Selected from A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, R or A; X 36 Selected from P, A, Y, D, G, S, R, V, E or T; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, S, D, K, F, L or Y; X 39 Selected from T, A, G, S, I or Y; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from V, D, Y, A, N, G, L or E; X 42 Present or absent, if present, selected from L, Y, F, T or G; X 43 Present or absent, if present, selected from P, F, V, N, S or Y; X 44 Present or absent, if present, selected from L, S, T, G, F; X 45 Present or absent, if present, selected from L, F, E, S or N; X 46 Present or absent, if present, selected from S, L or R; X 47 Exist or not, if it exists, it is L; X 48 exists or does not exist, if it exists, it is D; and X 49 It exists or not, if it exists, it is L.

[0248] In some cases, the VH region of the anti-CD38 antibody comprises a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X43X 44 X 45 ; where X 32 Selected from A or G; X 33 Selected from A, R or T; X 34 Selected from A, V, T, P, I, E or D; X 35 Selected from G, W, D, L, K or P; X 36 Selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X38 Selected from G, S, D or K; X 39 Selected from T, A, G, S or I; X 40 Selected from S, Y, G, R or W; X 41 Selected from V, D, Y, A, N or G; X 42 Selected from L, Y or F; X 43 Present or absent, if present, selected from P, F, V or N; X 44 is present or absent, and if present is selected from L, S or T; and X 45 Present or absent, if present, selected from L or F.

[0249] In some cases, the VH region of the anti-CD38 antibody comprises the CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X43X 44 X 45 X 46 (SEQ ID NO: 422); wherein X 33 Selected from R or G; X 34 Selected from E, D or S; X 35 Selected from G, L, P, S or A; X 36 Selected from D, S or R; X 37 Selected from Y, T, N or G; X 38 Selected from G, S, F or L; X 39 Selected from A, G, S or I; X 40 Selected from Y, N or L; X 41 Present or absent, if present, selected from V, Y or E; X 42 Exist or not, if it exists, it is G; X 43 Exists or does not exist, if exists, then it is Y; X 44 Exist or not, if it exists, then F; X 45 is present or absent, and if present, is selected from E or N; and X 46 It may be present or absent, and if present, it is selected from S or L.

[0250] In some instances, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFPFX5X6YAMS (SEQ ID NO: 423), the CDR2 sequence AISGSGGSTX 22YADSVKG (SEQ ID NO: 418) and CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY (SEQ ID NO: 421); wherein X5 is selected from D or G; X6 is selected from V, A or T; X 22 Selected from F or Y; X 38 is selected from A or G; and X 41 Select from F or Y.

[0251] In some instances, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (SEQ ID NO: 426), CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 and CDR3 sequence X 32 X 33 X 34 X 35 X36X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 wherein X5 is selected from S or N; X6 is selected from R, S or N; X7 is selected from Y, I or N; X8 is selected from Y, D, G or A; X9 is selected from V, M or I; X 10 Select from T, S or M; X 11 Exist or not, if it exists, then C; X 13 Selected from A or G; X 14 selected from I, F, Y, V, S or C; X 16 Selected from G, Y, S, T or L; X 17 Selected from S, I, K, Y, T or G; X 18 Selected from G, S or T; X 19 Selected from G, A, D or S; X 20 Selected from T, I, N or G; X21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Select from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Select from W or T; X 27 Select from A or W; X 28 Selected from K, R, Q or A; X 29 Selected from G or K; X 30 Exist or not, if it exists, it is G; X 32 Selected from A or G; X 33 Selected from A, R or T; X 34 Selected from A, V, T, P, I, E or D; X 35 Selected from G, W, D, L, K or P; X 36 Selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X 38 Selected from G, S, D or K; X 39 Selected from T, A, G, S or I; X 40 Selected from S, Y, G, R or W; X 41 Selected from V, D, Y, A, N or G; X 42 Selected from L, Y or F; X 43 Present or absent, if present, selected from P, F, V or N; X 44 is present or absent, and if present is selected from L, S or T; and X 45 Present or absent, if present, selected from L or F.

[0252] In some instances, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (SEQ ID NO: 419), CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 and CDR3 sequence AX 33X34X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 422); wherein X4 is selected from F or A; X5 is selected from S, T or N; X6 is selected from S, T or N; X7 is selected from Y, R, A or G; X8 is selected from W, Y or C; X9 is selected from I, W, Y or D; X 10 Selected from C, I, Y or M; X 11 Present or absent, if present, selected from C or M; X 12 Exist or not, if it exists, then C; X 13 Select from A or S; X 15 Selected from I, L or T; X 16 Selected from Y or V; X 17 Selected from S, T or A; X 18 Selected from G, P or V; X 19 Selected from D, S or T; X 20 Selected from S, T or G; X 21 Selected from D, N, S or A; X 22 Selected from T, I or S; X 23 Selected from Y, K or I; X 25 Selected from A or Y; X 26 Selected from S, T, A or N; X 27 Selected from W, N or S; X 28 Select from A or W; X 29 Select K or A; X 30 Present or absent, if present, selected from G or K; X 31 Exist or not, if it exists, it is G; X 33 Selected from R or G; X 34 Selected from E, D or S; X 35 Selected from G, L, P, S or A; X 36 Selected from D, S or R; X 37 Selected from Y, T, N or G; X 38 Selected from G, S, F or L; X 39 Selected from A, G, S or I; X 40 Selected from Y, N or L; X 41 Present or absent, if present, selected from V, Y or E; X 42 Exist or not, if it exists, it is G; X 43Exists or does not exist, if exists, then it is Y; X 44 Exist or not, if it exists, then F; X 45 is present or absent, and if present, is selected from E or N; and X 46 Present or absent, if present, selected from S or L.

[0253] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1, CDR2, and CDR3 sequence selected from Table 1.

[0254] Table 1. Heavy chain complementarity determining regions of exemplary anti-CD38 antibodies

[0255]

[0256]

[0257] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X 32 X 33 X 34 X35X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X 32 Selected from A, G or V; X 33 Selected from K, A, R, T, G or S; X 34 Selected from R, A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, A, T or R; X 36 Selected from T, P, A, Y, D, G, S, R, V or E; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, A, S, D, K, F, L or Y; X 39Selected from Y, T, A, G, S or I; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, if present, selected from P, L, Y, F, G or T; X 43 Present or absent, if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, if present, selected from G, L, S, T or F; X 45 Present or absent, if present, selected from F, L, E, N or S; X 46 Present or absent, if present, selected from D, S, L or R; X 47 Present or absent, if present, selected from Y or L; X 48 exists or does not exist, if it exists, it is D; and X 49 It exists or not, if it exists, it is L.

[0258] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 2 and 5; and a CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY (SEQ ID NO: 421), wherein X 38 Selected from A or G and X 41 Select from F or Y.

[0259] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X41X 42 X 43 X 44 X 45 X 46 X47 X 48 X 49 , where X 32 Selected from A, G or V; X 33 Selected from A, R, T, S or G; X 34 Selected from A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, R or A; X 36 Selected from P, A, Y, D, G, S, R, V, E or T; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, S, D, K, F, L or Y; X 39 Selected from T, A, G, S, I or Y; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from V, D, Y, A, N, G, L or E; X 42 Present or absent, if present, selected from L, Y, F, T or G; X 43 Present or absent, if present, selected from P, F, V, N, S or Y; X 44 Present or absent, if present, selected from L, S, T, G or F; X 45 Present or absent, if present, selected from L, F, E, S or N; X 46 Present or absent, if present, selected from S, L or R; X 47 Exist or not, if it exists, it is L; X 48 exists or does not exist, if it exists, it is D; and X 49 It exists or not, if it exists, it is L.

[0260] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 , where X32 Selected from A or G; X 33 Selected from A, R or T; X 34 Selected from A, V, T, P, I, E or D; X 35 Selected from G, W, D, L, K or P; X 36 Selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X 38 Selected from G, S, D or K; X 39 Selected from T, A, G, S or I; X 40 Selected from S, Y, G, R or W; X 41 Selected from V, D, Y, A, N or G; X 42 Selected from L, Y or F; X 43 Present or absent, if present, selected from P, F, V or N; X 44 is present or absent, and if present is selected from L, S or T; and X 45 Present or absent, if present, selected from L or F.

[0261] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence AX 33 X 34 X 35 X 36 X37X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 422), wherein X 33 Selected from R or G; X 34 Selected from E, D or S; X 35 Selected from G, L, P, S or A; X 36 Selected from D, S or R; X 37 Selected from Y, T, N or G; X 38 Selected from G, S, F or L; X 39 Selected from A, G, S or I; X 40 Selected from Y, N or L; X 41 Present or absent, if present, selected from V, Y or E; X 42 Exist or not, if it exists, it is G; X 43 Exists or does not exist, if exists, then it is Y; X44 Exist or not, if it exists, then F; X 45 is present or absent, and if present, is selected from E or N; and X 46 It may be present or absent, and if present, it is selected from S or L.

[0262] In some embodiments, the VH region of the anti-CD38 antibody comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 , wherein X1 is present or absent, and if present, is S; X2 is selected from F or I; X3 is selected from P, S or D; X4 is selected from F, L or A; X5 is selected from D, G, S, N or T; X6 is selected from V, A, T, R, S, I or N; X7 is selected from Y, I, N, R, A, G or D; X8 is selected from A, Y, D, G, W, C or T; X9 is selected from M, V, I, W, D or Y; X 10 Selected from S, T, M, C, I, Y, A or G; X 11 Present or absent, if present, selected from C or M; X 12 present or absent, and if present, C; a CDR2 sequence selected from the group consisting of SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.

[0263] In some embodiments, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFPFX5X6YAMS (SEQ ID NO: 423), wherein X5 is selected from D or G and X6 is selected from V, A or T; a CDR2 sequence selected from SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10.

[0264] In some embodiments, the VH region of the anti-CD38 antibody comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 , wherein X1 is present or absent, and if present, is S; X2 is selected from F or I; X3 is selected from S or D; X4 is selected from L, F or A; X5 is selected from S, N or T; X6 is selected from R, S, N, I or T; X7 is selected from Y, I, N, R, A, D or G; X8 is selected from Y, D, G, A, W, T or C; X9 is selected from V, M, I, W, Y or D; X 10Selected from T, S, M, C, I, Y, A or G; X 11 Present or absent, if present, selected from C or M; X 12 present or absent, and if present, C; a CDR2 sequence selected from the group consisting of SEQ ID NO: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.

[0265] In some embodiments, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (SEQ ID No. 426), wherein X5 is selected from S or N; X6 is selected from R, S or N; X7 is selected from Y, I or N; X8 is selected from Y, D, G or A; X9 is selected from V, M or I; X 10 Select from T, S or M; X 11 is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52.

[0266] In some embodiments, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (SEQ ID No. 419), wherein X4 is selected from F or A; X5 is selected from S, T or N; X6 is selected from S, T or N; X7 is selected from Y, R, A or G; X8 is selected from W, Y or C; X9 is selected from I, W, Y or D; X 10 Selected from C, I, Y or M; X 11 Present or absent, if present, selected from C or M; X 12 is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58.

[0267] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, and 59; a CDR2 sequence X 13 X 14 X 15 X 16 X17X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 , where X 13 Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from S, I, L, T or M; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P, V or Y; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from F, Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25 Selected from D, T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from V, A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 Present or absent, if present, selected from G or K; X 31 is present or absent, and if present, is G; and a CDR3 sequence selected from SEQ ID NO: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.

[0268] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NO: 1, 4, 6, 8, and 9; a CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID No. 418), wherein X 22 is selected from F or Y; and a CDR3 sequence selected from SEQ ID NO: 3, 7 and 10.

[0269] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X23X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 , where X 13 Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from I, L, M or T; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P or V; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25 Selected from T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30is present or absent, and if present, is selected from G or K; and X 31 is present or absent, and if present, is G; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.

[0270] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 , where X 13 Selected from A or G; X 14 selected from I, F, Y, V, S or C; X 16 Selected from G, Y, S, T or L; X 17 Selected from S, I, K, Y, T or G; X 18 Selected from G, S or T; X 19 Selected from G, A, D or S; X 20 Selected from T, I, N or G; X 21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Select from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Select from W or T; X 27 Select from A or W; X 28 Selected from K, R, Q or A; X 29 is selected from G or K; and X 30 is present or absent, and if present, is G; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52.

[0271] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence X13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 , where X 13 Select from A or S; X 15 Selected from I, L or T; X 16 Selected from Y or V; X 17 Selected from S, T or A; X 18 Selected from G, P or V; X 19 Selected from D, S or T; X 20 Selected from S, T or G; X 21 Selected from D, N, S or A; X 22 Selected from T, I or S; X 23 Selected from Y, K or I; X 25 Selected from A or Y; X 26 Selected from S, T, A or N; X 27 Selected from W, N or S; X 28 Select from A or W; X 29 Select K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 is present or absent, and if present, is G; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58.

[0272] 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.

[0273] In some instances, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 3, 7, and 10.

[0274] and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.

[0275] In some instances, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52.

[0276] In some instances, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58.

[0277] In some embodiments, the VL region of the anti-CD38 antibody comprises a CDR1, CDR2, and CDR3 sequence selected from Table 2.

[0278] Table 2. Light chain complementarity determining regions of exemplary anti-CD38 antibodies

[0279]

[0280] 14618_1 shares the same VL CDR1, CDR2 and CDR3 sequences with 4618_5, 4618_12, 4618_1_12, 4618_5_12, 4618_5F_12, 32218_1, 32218_2, 32018_7, G1F4_VL, c05G01, c06F06, c05G07, 81618_3 and 62218_13.

[0281] In some embodiments, the VL region of the anti-CD38 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NO: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103. In some instances, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100. In some instances, the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 71, 77, 83, 94, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 72, 78, and 84; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 73, 79, 85, 95, and 103.

[0282] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X 32 Selected from A, G or V; X 33 Selected from K, A, R, T, G or S; X 34 Selected from R, A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, A, T or R; X 36 Selected from T, P, A, Y, D, G, S, R, V or E; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, A, S, D, K, F, L or Y; X 39 Selected from Y, T, A, G, S or I; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, if present, selected from P, L, Y, F, G or T; X 43 Present or absent, if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, if present, selected from G, L, S, T or F; X 45 Present or absent, if present, selected from F, L, E, N or S; X 46 Present or absent, if present, selected from D, S, L or R; X 47 Present or absent, if present, selected from Y or L; X 48 exists or does not exist, if it exists, it is D; and X 49 is present or absent, and if present, is L; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NO: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0283] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from SEQ ID NOs: 2 and 5; and a CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY (SEQ ID No. 421), wherein X 38 Select from A or G, X 41 Selected from F or Y; and wherein the VL region comprises a CDR1 sequence consisting of SEQ ID NO: 62, a CDR2 sequence consisting of SEQ ID NO: 63, and a CDR3 sequence consisting of SEQ ID NO: 64.

[0284] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X 32 X 33 X 34 X35X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , where X 32 Selected from A, G or V; X 33 Selected from A, R, T, S or G; X 34 Selected from A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, R or A; X 36 Selected from P, A, Y, D, G, S, R, V, E or T; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, S, D, K, F, L or Y; X 39 Selected from T, A, G, S, I or Y; X 40 Selected from S, Y, G, R, W, N, L, D or F; X41 Present or absent, if present, selected from V, D, Y, A, N, G, L or E; X 42 Present or absent, if present, selected from L, Y, F, T or G; X 43 Present or absent, if present, selected from P, F, V, N, S or Y; X 44 Present or absent, if present, selected from L, S, T, G or F; X 45 Present or absent, if present, selected from L, F, E, S or N; X 46 Present or absent, if present, selected from S, L or R; X 47 Exist or not, if it exists, it is L; X 48 exists or does not exist, if it exists, it is D; and X 49 is present or absent, and if present, is L; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NO: 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0285] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from SEQ ID NO: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 , where X 32 Selected from A or G; X 33 Selected from A, R or T; X 34 Selected from A, V, T, P, I, E or D; X 35 Selected from G, W, D, L, K or P; X 36 Selected from P, A, Y, D or G; X37 is selected from Y, V, T, S, N, A or G; X 38 Selected from G, S, D or K; X 39 Selected from T, A, G, S or I; X 40 Selected from S, Y, G, R or W; X 41 Selected from V, D, Y, A, N or G; X 42 Selected from L, Y or F; X 43 Present or absent, if present, selected from P, F, V or N; X 44 is present or absent, and if present is selected from L, S or T; and X 45 is present or absent, and if present is selected from L or F, and wherein the VL region comprises a CDR1 sequence selected from SEQ ID NO: 65, 68, 80, 86, 89, 92 and 98; a CDR2 sequence selected from SEQ ID NO: 66, 69, 78, 81, 90 and 99; and a CDR3 sequence selected from SEQ ID NO: 67, 70, 82, 87, 88, 91, 93 and 100.

[0286] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 (SEQ ID No. 422), wherein X 33 Selected from R or G; X 34 Selected from E, D or S; X 35 Selected from G, L, P, S or A; X 36 Selected from D, S or R; X 37 Selected from Y, T, N or G; X 38 Selected from G, S, F or L; X 39 Selected from A, G, S or I; X 40 Selected from Y, N or L; X 41 Present or absent, if present, selected from V, Y or E; X 42 Exist or not, if it exists, it is G; X43 Exists or does not exist, if exists, then it is Y; X 44 Exist or not, if it exists, then F; X 45 Present or absent, if present, selected from E or N; X 46 Present or absent, if present, selected from S or L, wherein the VL region comprises a CDR1 sequence selected from SEQ ID NO: 71, 77, 83, 94 and 102; a CDR2 sequence selected from SEQ ID NO: 72, 78 and 84; and a CDR3 sequence selected from 73, 79, 85, 95 and 103.

[0287] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 , wherein X1 is present or absent, and if present, is S; X2 is selected from F or I; X3 is selected from P, S or D; X4 is selected from F, L or A; X5 is selected from D, G, S, N or T; X6 is selected from V, A, T, R, S, I or N; X7 is selected from Y, I, N, R, A, G or D; X8 is selected from A, Y, D, G, W, C or T; X9 is selected from M, V, I, W, D or Y; X 10 Selected from S, T, M, C, I, Y, A or G; X 11 is present or absent, and if present, is selected from C or M; and X 12 is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58, and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: NO:63, 66, 69, 72, 75, 78, 81, 84, 90 and 99; and a CDR3 sequence selected from SEQ ID NO:64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101 and 103.

[0288] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence GFPFX5X6YAMS (SEQ ID No. 423), wherein X5 is selected from D or G and X6 is selected from V, A or T; a CDR2 sequence selected from SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from SEQ ID NOs: 3, 7 and 10; and wherein the VL region comprises a CDR1 sequence consisting of SEQ ID NO: 62, a CDR2 sequence consisting of SEQ ID NO: 63, and a CDR3 sequence consisting of SEQ ID NO: 64.

[0289] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 , wherein X1 is present or absent, and if present, is S; X2 is selected from F or I; X3 is selected from S or D; X4 is selected from L, F or A; X5 is selected from S, N or T; X6 is selected from R, S, N, I or T; X7 is selected from Y, I, N, R, A, D or G; X8 is selected from Y, D, G, A, W, T or C; X9 is selected from V, M, I, W, Y or D; X 10 Selected from T, S, M, C, I, Y, A or G; X 11 Present or absent, if present, selected from C or M; X 12 is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: NO: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101 and 103.

[0290] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11(SEQ ID NO: 426), wherein X5 is selected from S or N; X6 is selected from R, S or N; X7 is selected from Y, I or N; X8 is selected from Y, D, G or A; X9 is selected from V, M or I; X 10 is selected from T, S or M; and X 11 is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 78, 81, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.

[0291] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (SEQ ID NO: 419), wherein X4 is selected from F or A; X5 is selected from S, T or N; X6 is selected from S, T or N; X7 is selected from Y, R, A or G; X8 is selected from W, Y or C; X9 is selected from I, W, Y or D; X 10 Selected from C, I, Y or M; X 11 is present or absent, and if present, is selected from C or M; and X 12 is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 71, 77, 83, 94, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 72, 78, and 84; and a CDR3 sequence selected from the group consisting of 73, 79, 85, 95, and 103.

[0292] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, and 59; and a CDR2 sequence X 13 X 14 X 15 X16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 , where X 13 Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from S, I, L, T or M; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P, V or Y; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from F, Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25 Selected from D, T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from V, A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 Present or absent, if present, selected from G or K; X 31is present or absent, and if present, is G; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101 and 103.

[0293] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 1, 4, 6, 8, and 9; and a CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID No. 418), wherein X 22 selected from F or Y; and a CDR3 sequence selected from SEQ ID NO: 3, 7 and 10; and wherein the VL region comprises a CDR1 sequence consisting of SEQ ID NO: 62, a CDR2 sequence consisting of SEQ ID NO: 63, and a CDR3 sequence consisting of SEQ ID NO: 64.

[0294] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; and a CDR2 sequence X 13 X 14 X 15 X16X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 , where X 13 Selected from A, G or S; X 14selected from I, F, Y, V, S or C; X 15 Selected from I, L, M or T; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P or V; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25 Selected from T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 is present or absent, and if present, is G; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0295] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 11, 14, 26, 32, 35, 38, 41, and 50; and a CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25X 26 X27X 28 X 29 X 30 , where X 13 Selected from A or G; X 14 selected from I, F, Y, V, S or C; X 16 Selected from G, Y, S, T or L; X 17 Selected from S, I, K, Y, T or G; X 18 Selected from G, S or T; X 19 Selected from G, A, D or S; X 20 Selected from T, I, N or G; X 21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Select from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Select from W or T; X 27 Select from A or W; X 28 Selected from K, R, Q or A; X 29 is selected from G or K; and X 30 is present or absent, and if present, is G; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 78, 81, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.

[0296] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 17, 23, 29, 44, and 56; and a CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 , where X 13Select from A or S; X 15 Selected from I, L or T; X 16 Selected from Y or V; X 17 Selected from S, T or A; X 18 Selected from G, P or V; X 19 Selected from D, S or T; X 20 Selected from S, T or G; X 21 Selected from D, N, S or A; X 22 Selected from T, I or S; X 23 Selected from Y, K or I; X 25 Selected from A or Y; X 26 Selected from S, T, A or N; X 27 Selected from W, N or S; X 28 Select from A or W; X 29 Select K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 is present or absent, and if present, is G; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 71, 77, 83, 94, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 72, 78, and 84; and a CDR3 sequence selected from the group consisting of 73, 79, 85, 95, and 103.

[0297] In some instances, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: NO: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98 and 102; a CDR2 sequence selected from SEQ ID NO: 63, 66, 69, 72, 75, 78, 81, 84, 90 and 99; and a CDR3 sequence selected from SEQ ID NO: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101 and 103.

[0298] In some instances, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 3, 7, and 10; and wherein the VL region comprises a CDR1 sequence consisting of SEQ ID NO: 62, a CDR2 sequence consisting of SEQ ID NO: 63, and a CDR3 sequence consisting of SEQ ID NO: 64.

[0299] In some instances, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: NO: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98 and 102; a CDR2 sequence selected from SEQ ID NO: 66, 69, 72, 75, 78, 81, 84, 90 and 99; and a CDR3 sequence selected from SEQ ID NO: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101 and 103.

[0300] In some instances, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 78, 81, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.

[0301] In some instances, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 71, 77, 83, 94, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 72, 78, and 84; and a CDR3 sequence selected from the group consisting of 73, 79, 85, 95, and 103.

[0302] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the sequence of the VH region comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 104-128, and the sequence of the VL region comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 130-154.

[0303] In some embodiments, the VH region comprises a sequence selected from Table 3 and the VL region comprises a sequence selected from Table 4.

[0304] Table 3. Heavy chain variable domains of exemplary anti-CD38 antibodies. The underlined regions represent the respective CDR1, CDR2 or CDR3 sequences.

[0305]

[0306]

[0307]

[0308] Table 4. Light chain variable domains of exemplary anti-CD38 antibodies. The underlined regions represent the respective CDR1, CDR2 or CDR3 sequences.

[0309]

[0310]

[0311]

[0312] In some embodiments, the anti-CD38 antibodies are full-length antibodies. In other embodiments, the anti-CD38 antibodies are binding fragments. In some cases, the anti-CD38 antibodies comprise antibodies or binding fragments thereof, chimeric antibodies or binding fragments thereof, monoclonal antibodies or binding fragments thereof, or bispecific antibodies or binding fragments thereof. In some cases, the anti-CD38 antibodies comprise monovalent Fab, bivalent Fab'2, single-chain variable fragment (scFv), diabodies, minibodies, nanobodies, single domain antibodies (sdAb), or camelid antibodies or binding fragments thereof.

[0313] In some embodiments, the anti-CD38 antibody comprises a bispecific antibody or a binding fragment thereof. In some cases, the bispecific antibody or binding fragment thereof is a bispecific antibody conjugate, a hybrid bispecific IgG, a variable domain-only bispecific antibody, a CH1 / CL fusion protein, a Fab fusion protein, a non-immunoglobulin fusion protein, an Fc-modified IgG, an attached and Fc-modified IgG, a modified Fc and CH3 fusion protein, an attached IgG-HC fusion, an Fc fusion, a CH3 fusion, an IgE / IgM CH2 fusion, or a F(ab')2 fusion.

[0314] In some embodiments, the bispecific antibody or binding fragment comprises a knob-in-hole structure (KIH), asymmetric reengineered technology-immunoglobulin (ART-Ig), Triomab quadroma, bispecific monoclonal antibody (BiMAb, BsmAb, BsAb, bsMab, BS-Mab or Bi-MAb), FcΔAdp, XmAb, Azymetric, T cell receptor-based antibody bispecific engagement (BEAT), bispecific T cell engager (BiTE), Biclonics, Fab-scFv-Fc, Two-in-one / bifunctional Fab (DAF), Finomab, scFv-Fc-(Fab)-fusion, Dock-aNd-Lock (DNL), Adaptir (formerly SCORPION), tandem diabody (TandAb), Dual-affinity-ReTargeting (DART) or nanobody.

[0315] In some embodiments, variable domain-only bispecific antibodies include tandem scFv (taFv), triabodies, diabodies (Db), dsDb, Db (KIH), scDb, dsFv-dsFv', tandAbs, triple heads, tandem dAb / VHH, triple dAb / VHH, or tetravalent dAb / VHH.

[0316] In some embodiments, the CH1 / CL fusion protein comprises scFv2-CH1 / CL or VHH2-CH1 / CL.

[0317] In some cases, the Fab fusion protein comprises Fab-scFv (diabody), Fab-scFv2 (triabody), Fab-Fv, Fab-dsFv, Fab-VHH, or orthogonal Fab-Fab.

[0318] In some instances, the non-immunoglobulin fusion protein comprises scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, minibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine 2, or ImmTAC (TCR-scFv).

[0319] In some cases, the Fc-modified IgG includes IgG (KIH), IgG (KIH) common LC, ZW1 IgG common LC, Biclonics common LC, CrossMAb, scFab-IgG (KIH), Fab-scFab-IgG (KIH), orthogonal Fab IgG (KIH), DuetMab, CH3 charge pair + CH1 / CL charge pair, hinge / CH3 charge pair, DuoBody, four-in-one-CrossMab (KIH), LUZ-Y common LC, LUZ-Y scFab-IgG or FcFc.

[0320] In some cases, the appended and Fc-modified IgG includes IgG(KIH)-Fv, IgG(HA-TF-FV), IgG(KIH)-scFab, scFab-Fc(KIH)-scFv2, scFab-Fc(KIH)-scFv, half DVD-Ig, dual variable domain-immunoglobulin (DVD-Ig) or CrossMab-Fab.

[0321] In some cases, the modified Fc and CH3 fusion proteins include scFv-Fc (KIH), scFv-Fc (CH3 charge pair), scFv-FC (EW-RVT), scFv-Fc (HA-TF), scFv-Fc (SEEDbody), taFv-Fc (KIH), scFv-Fc (KIH)-Fv, Fab-Fc (KIH)-scFv, Fab-scFv-Fc (KIH), Fab-scFv-Fc (BEAT), DART-Fc, scFv-CH3 (KIH) or TriFabs.

[0322] In some cases, the additional IgG-HC fusion antibody includes IgG-HC-scFv, IgG-dAb, IgG-taFv, IgG-CrossFab, IgG-orthogonal Fab, IgG-(CαCβ)Fab, scFv-HC-IgG, tandem Fab-IgG, Fab-IgG(CαCβFab), Fab-IgG(CR3) or Fab-hinge-IgG(CR3).

[0323] In some cases, the additional IgG-LC fusion antibody comprises IgG-scFv(LC), scFv(LC)-IgG, or dAb-IgG.

[0324] In some cases, the additional IgG-HC & LC fusion antibody includes DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, or Zybody.

[0325] In some instances, the Fc fusion antibody includes Di-diabody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-Ig, or scFv2-Fcab.

[0326] In some cases, the CH3 fusion antibody comprises a diabody or scDb-CH3.

[0327] In some instances, the IgE / IgM CH2 fusion antibody comprises scFv-EHD2-scFv or scFv-MHD2-scFv.

[0328] In some instances, the F(ab')2 fusion antibody comprises F(ab')2-scFv2.

[0329] In some cases, the CH1 / CL fusion protein comprises scFv2-CH1-hinge / CL.

[0330] In some cases, modified IgG includes DAF (two-in-one-IgG), DutaMab or mAb 2 .

[0331] In some instances, the non-immunoglobulin fusion antibody comprises DNL-Fab4-IgG.

[0332] In some cases, anti-CD38 antibodies include, for example Figure 1A or Figure 1B The bispecific antibody or binding fragment thereof is shown.

[0333] In some embodiments, the anti-CD38 antibodies described herein comprise an IgG framework, an IgA framework, an IgE framework, or an IgM framework. In some cases, the anti-CD38 antibodies comprise an IgG framework (e.g., IgG1, IgG2, IgG3, or IgG4). In this case, the anti-CD38 antibodies comprise an IgG1, IgG2, IgG3, or IgG4 framework.

[0334] In some cases, the anti-CD38 antibody further comprises one or more mutations in the framework region (e.g., in the CH1 domain, CH2 domain, CH3 domain, hinge region, or a combination thereof). In some cases, the one or more mutations are used to stabilize the antibody and / or increase half-life. In some cases, the one or more mutations are used to modulate Fc receptor interactions to increase ADCC or complement dependent cytotoxicity (CDC). In other cases, the one or more mutations are used to reduce or eliminate Fc effector functions, such as FcγR binding, ADCC, or CDC. In another example, the one or more mutations are used to modulate glycosylation.

[0335] In some cases, anti-CD38 antibodies include IgG1 frameworks. In some embodiments, the constant region of anti-CD38 antibodies is modified at one or more amino acid positions to change Fc receptor interactions. Exemplary residues that regulate or change Fc receptor interactions include but are not limited to G236, S239, T250, M252, S254, T256, K326, A330, I332, E333A, M428, H433, or N434 (Kabat numbering; EU index of Kabat et al. 1991 immunology target protein sequences (Sequences of Proteins of Immunological Interest)). In some cases, mutations include G236A, S239D, T250Q, M252Y, S254T, T256E, K326W, A330L, I332E, E333A, E333S, M428L, H433K, or N434F.

[0336] In some embodiments, modifications at one or more amino acid positions in the IgG1 constant region that alter Fc receptor interactions result in increased half-life. In some cases, modifications at one or more amino acid positions include T250, M252, S254, T256, M428, H433, N434, or a combination thereof; for example, including T250Q / M428L or M252Y / S254T / T256E and H433K / N434F.

[0337] In some embodiments, the modification for changing Fc receptor interactions at one or more amino acid positions in the IgG1 constant region causes ADCC and / or CDC to increase. In some cases, the modification at one or more amino acid positions includes S239, K326, A330, I332, E333 or a combination thereof. In some cases, the modification at one or more amino acid positions for increasing ADCC and / or CDC includes, for example, E333A, S239D / A330L / I332E or K326W / E333S. In some cases, the modification at one or more amino acid positions for increasing ADCC includes S239D / A330L / I332E. In some cases, the modification at one or more amino acid positions for increasing CDC includes K326W / E333S.

[0338] In some embodiments, modifications at one or more amino acid positions in the IgG1 constant region that alter Fc receptor interactions result in increased macrophage phagocytosis.

[0339] In some cases, modifications at one or more amino acid positions include G236, S239, I332, or a combination thereof. In some cases, modifications at one or more amino acid positions for increasing macrophage phagocytosis include the combination S239D / I332I / G236A.

[0340] In some embodiments, the IgG1 constant region is modified at amino acid N297 (Kabat numbering), e.g., to N297C.

[0341] In some embodiments, the anti-CD38 antibody comprises an IgG2 framework. In some cases, one or more amino acid positions in the IgG2 framework are modified to alter Fc receptor interactions, for example, to increase ADCC and / or CDC. In some cases, one or more amino acid positions in the IgG2 framework are modified to stabilize the antibody and / or increase half-life. In some cases, one or more amino acid positions in the IgG2 framework are modified to regulate glycosylation. In some cases, the IgG2 constant region is afucosylated.

[0342] In some embodiments, the anti-CD38 antibody comprises an IgG3 framework. In some cases, one or more amino acid positions in the IgG3 framework are modified to alter Fc receptor interactions, for example, to increase ADCC and / or CDC. In some cases, one or more amino acid positions in the IgG3 framework are modified to stabilize the antibody and / or increase half-life. In some cases, one or more amino acid positions in the IgG3 framework are modified to regulate glycosylation. In some cases, the constant region of the antibody is modified at amino acid R435 to extend half-life, for example, R435H (Kabat numbering). In some cases, the constant region is afucosylated.

[0343] In some embodiments, anti-CD38 antibodies include IgG4 frameworks. In some cases, one or more amino acid positions in the IgG4 framework are modified to change Fc receptor interactions, for example, for increasing ADCC and / or CDC. For example, in some embodiments, mutations for increasing ADCC include S239D, I332E, and A330L (amino acid numbering according to the EU index of Kabat et al.), such as described in U.S. Patent No. 8,093,359. In some cases, one or more amino acid positions in the IgG4 framework are modified to stabilize the antibody and / or increase half-life. In some cases, one or more amino acid positions in the IgG4 framework are modified to regulate glycosylation. In some cases, the constant region is modified at the hinge region to prevent or reduce chain exchange. In some cases, the modified amino acid is S228 (e.g., S228P).

[0344] In some embodiments, the human IgG constant region is modified for ADCC and / or CDC, e.g., with amino acid modifications as described in Natsume et al., 2008 Cancer Res, 68(10):3863-72; Idusogie et al., 2001 J Immunol, 166(4):2571-5; Moore et al., 2010 mAbs, 2(2):181-189; Lazar et al., 2006 PNAS, 103(11):4005-4010, Shields et al., 2001 JBC, 276(9):6591-6604; Stavenhagen et al., 2007 Cancer Res, 67(18):8882-8890; Stavenhagen et al., 2008 Advan. Enzyme Regul., 48:152-164; Alegre et al., 1992 J Immunol, 148:3461-3468; reviewed in Kaneko and Niwa, 2011 Biodrugs, 25(1):1-11.

[0345] In some embodiments, the human IgG constant region is modified to induce heterodimerization. For example, the CH3 domain has an amino acid modification at Thr366, which, when replaced by a bulkier amino acid (e.g., Trp (T366W)), can preferably pair with a second CH3 domain having amino acid modifications that produce smaller volumes at Thr366, Leu368, and Tyr407, such as Ser, Ala, and Val (T366S / L368A / Y407V). In some cases, the heterodimerization performed by CH3 modification is further stabilized by introducing a disulfide bond, for example, by replacing Ser354 on the opposite CH3 domain with Cys (S354C) and Y349 with Cys (Y349C) (reviewed in Carter, 2001 Journal of Immunological Methods, 248: 7-15).

[0346] In some cases, the anti-CD38 antibodies described herein have reduced glycosylation or lack glycosylation but are unmodified at amino acid Asn297 (Kabat numbering). In these cases, glycosylation is eliminated, for example, by producing the antibody in a host cell that lacks post-translational glycosylation capabilities (e.g., a bacterial or yeast-derived system or a modified mammalian cell expression system). In certain aspects, such a system is a cell-free expression system.

[0347] In some embodiments, the anti-CD38 antibodies described herein are full-length antibodies comprising a heavy chain (HC) and a light chain (LC). In some cases, the heavy chain (HC) comprises a sequence selected from Table 5. In some cases, the light chain (LC) comprises a sequence selected from Table 6.

[0348] Table 5. Heavy chains of exemplary anti-CD38 antibodies

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357] Table 6. Light chains of exemplary anti-CD38 antibodies

[0358]

[0359]

[0360]

[0361]

[0362] In some embodiments, the anti-CD38 antibodies described herein have enhanced ADCC and / or CDC compared to daratumumab as a reference antibody. In some cases, the enhanced ADCC and / or CDC is an increase of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400% or more compared to daratumumab. In some cases, the enhanced ADCC and / or CDC is an increase of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400% or more compared to daratumumab.

[0363] In some cases, the enhanced ADCC and / or CDC is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold or more compared to the reference antibody daratumumab. In some cases, the enhanced ADCC and / or CDC is about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold or more compared to the reference antibody daratumumab.

[0364] In some embodiments, ADCC activity is determined by an in vitro cytotoxicity assay, e.g., using PBMC effector cells and targeting cancer cells, e.g., B lymphoblastoid cells from a lymphoma, e.g., Daudi cells, and the anti-CD38 antibodies described herein have a cytotoxicity of about 1×10 -6 nM to about 2 nM (e.g., about 4×10 -6 nM, about 0.00001 to about 0.00003 nM, 0.1 nM, about 0.2 nM, about 0.3 nM, about 0.4 nM, about 0.5 nM, about 0.6 nM, about 0.7 nM, about 0.8 nM, about 0.9 nM, about 1.0 nM) or an EC of about 0.00001 to about 0.00003 nM. 50.

[0365] In some embodiments, the anti-CD38 antibodies described herein have an improved cell killing effect compared to a reference antibody, daratumumab. In some cases, the improved cell killing effect is an increase of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400% or more compared to a reference antibody, daratumumab. In some cases, the improved cell killing effect is an increase of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400% or more compared to a reference antibody, daratumumab.

[0366] In some cases, the improved cell killing effect is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold or more compared to the reference antibody daratumumab. In some cases, the improved cell killing effect is about 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold or more compared to the reference antibody daratumumab.

[0367] In some embodiments, the anti-CD38 antibodies described herein have improved serum half-life compared to the reference antibody daratumumab. In some cases, the improved serum half-life is at least 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or longer than the reference antibody daratumumab.

[0368] In some instances, the serum half-life of an anti-CD38 antibody described herein is at least 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or longer. In some instances, the serum half-life of an anti-CD38 antibody described herein is about 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or longer.

[0369] Anti-ICAM1 antibody

[0370] In certain embodiments, anti-ICAM1 antibodies are disclosed herein. In some cases, the anti-ICAM1 antibody comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises a CDR1 sequence X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 ; where X 1 Selected from G or E; X 2 Selected from F or Y; X 3 Select from S or T; X 4 Selected from L, F or S; X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y, H or G; X 8 Selected from G, A, Y, W or F; X 9 Selected from M, W, Y or I; X 10 is selected from S, G, N, M or I; and X 11 Present or absent, if present, C; CDR2 sequence X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 ; where X 12 Selected from G, T, A, I or Y; X 13 Selected from W, I, Y or C; X 14 Selected from I, S or Y; X 15 Selected from S, G, T, D or P; X 16 Selected from F, S, D, T or A; X 17 Selected from S, R, G or D; X 18 Selected from G, D or S; X 19 Selected from S, R, T, N, Y, A, D or P; X 20 Selected from T, A, G or Y; X21 Selected from Y, H, A, S or T; X 22 Select from Y or N; X 23 Selected from A, P, Y or S; X 24 Selected from S, T, N, D, Y, A or P; X 25 Selected from W, S, A or D; X 26 Selected from A, V, T, W, F or S; X 27 Selected from K, W, A, Q or V; X 28 Selected from G, A or K; X 29 is present or absent, and if present, is selected from K or G; and X 30 Present or absent, if present, G; and CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 4 4 X 45 X 46 X 47 X 48 X 49 ; where X 31 Select from A or V; X 32 Selected from R or I; X 33 Selected from G, D, P, A or V; X 34 Selected from G, P, W, D, N or R; X 35 Selected from D, Y, S, L, G, F or W; X 36 Selected from Y, D, V, L, S, G or P; X 37 Selected from G, S, D, V or E; X 38 Selected from G, Y, F, S or D; X 39 Selected from S, D, G, T, N, A or V; X 40 Selected from T, A, D, S, Y, L or F; X 41 Present or absent, if present, selected from Y, A, G, I or D; X 42 Present or absent, if present, selected from I, Y, R, P, V or G; X 43 Present or absent, if present, selected from L, R, Y, G or A; X 44 Present or absent, if present, selected from N, L, Y, S or W; X 45Present or absent, if present, selected from L, Y, F or C; X 46 Present or absent, if present, selected from D, A or F; X 47 Present or absent, if present, selected from M, P, Y or N; X 48 is present or absent, and if present, is selected from D or L; and X 49 It exists or not, if it exists, it is L.

[0371] In some cases, the VH region of the anti-ICAM1 antibody comprises the CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 (SEQ ID NO: 425), wherein X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y or H; X 8 is selected from G, A or Y; and X 10 Selected from S, G or N.

[0372] In some instances, the VH region of the anti-ICAM1 antibody comprises the CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG (SEQ ID NO: 420), wherein X 13 Selected from W, I or Y; X 15 Selected from S or G; X 16 Selected from F, S, D or T; X 17 Selected from S or R; X 18 Select from G or D; X 19 Selected from S, R, T or N; X 20 is selected from T or A; and X 24 Selected from S, T or N.

[0373] In some instances, the VH region of the anti-ICAM1 antibody comprises the CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 4 2X 43 X 44 X 45 X 46 X 47 X 48 X 49 (SEQ ID NO: 424), wherein X 31 Select from A or V; X 33 Select from G or D; X 34 Selected from G, P, W or D; X 35 Selected from D, Y, S or L; X 36 Selected from Y, D, V or L; X 37 Selected from G, S or D; X 38 Selected from G, Y, F or S; X 39 Selected from S, D, G or T; X 40 Selected from T, A, D, S or Y; X 41 Selected from Y, A, G or I; X 42 Selected from I, Y or R; X 43 Selected from L, R, Y or G; X 44 Selected from N, L, Y or S; X 45 Present or absent, if present, selected from L, Y or F; X 46 Exist or not, if it exists, then D; X 47 Present or absent, if present, selected from M or P; X 48 exists or does not exist, if it exists, it is D; and X 49 It exists or not, if it exists, it is L.

[0374] In some cases, the VH region of the anti-ICAM1 antibody comprises the CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 (SEQ ID NO: 425), CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG (SEQ ID NO: 420) and CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 (SEQ ID NO: 424), wherein X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y or H; X 8 Selected from G, A or Y; X 10 Selected from S, G or N; X 13 Selected from W, I or Y; X 15 Selected from S or G; X 16 Selected from F, S, D or T; X 17 Selected from S or R; X 18 Select from G or D; X 19 Selected from S, R, T or N; X 20 Select from T or A; X 24 Selected from S, T or N; X 31 Selected from A or V; X 33 Select from G or D; X 34 Selected from G, P, W or D; X 35 Selected from D, Y, S or L; X 36 Selected from Y, D, V or L; X 37 Selected from G, S or D; X 38 Selected from G, Y, F or S; X 39 Selected from S, D, G or T; X 40 Selected from T, A, D, S or Y; X 41 Selected from Y, A, G or I; X 42 selected from I, Y or R; X 43 Selected from L, R, Y or G; X 44 Selected from N, L, Y or S; X 45 Present or absent, if present, selected from L, Y or F; X 46 Exist or not, if it exists, then D; X 47 Present or absent, if present, selected from M or P; X 48 exists or does not exist, if it exists, it is D; and X 49 It exists or not, if it exists, it is L.

[0375] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1, CDR2, and CDR3 sequence selected from Table 7.

[0376] Table 7. Heavy chain complementarity determining regions of exemplary anti-ICAM1 antibodies

[0377]

[0378]

[0379] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , where X 31 Selected from A or V; X 32 Selected from R or I; X 33 Selected from G, D, P, A or V; X 34 Selected from G, P, W, D, N or R; X 35 Selected from D, Y, S, L, G, F or W; X 36 Selected from Y, D, V, L, S, G or P; X 37 Selected from G, S, D, V or E; X 38 Selected from G, Y, F, S or D; X 39 Selected from S, D, G, T, N, A or V; X 40 Selected from T, A, D, S, Y, L or F; X 41 Present or absent, if present, selected from Y, A, G, I or D; X 42 Present or absent, if present, selected from I, Y, R, P, V or G; X 43 Present or absent, if present, selected from L, R, Y, G or A; X 44Present or absent, if present, selected from N, L, Y, S or W; X 45 Present or absent, if present, selected from L, Y, F or C; X 46 Present or absent, if present, selected from D, A or F; X 47 Present or absent, if present, selected from M, P, Y or N; X 48 is present or absent, and if present, is selected from D or L; and X 49 It exists or not, if it exists, it is L.

[0380] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and a CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 4 6 X 47 X 48 X 49 (SEQ ID NO: 424), wherein X 31 Selected from A or V; X 33 Select from G or D; X 34 Selected from G, P, W or D; X 35 Selected from D, Y, S or L; X 36 Selected from Y, D, V or L; X 37 Selected from G, S or D; X 38 Selected from G, Y, F or S; X 39 Selected from S, D, G or T; X 40 Selected from T, A, D, S or Y; X 41 Selected from Y, A, G or I; X 42 selected from I, Y or R; X 43 Selected from L, R, Y or G; X 44 Selected from N, L, Y or S; X 45 Present or absent, if present, selected from L, Y or F; X46 Exist or not, if it exists, then D; X 47 Present or absent, if present, selected from M or P; X 48 exists or does not exist, if it exists, it is D; and X 49 It exists or not, if it exists, it is L.

[0381] In some embodiments, the VH region of the anti-ICAM1 antibody comprises the CDR1 sequence X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 , where X 1 Selected from G or E; X 2 Selected from F or Y; X 3 Select from S or T; X 4 Selected from L, F or S; X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y, H or G; X 8 Selected from G, A, Y, W or F; X 9 Selected from M, W, Y or I; X 10 Selected from S, G, N, M or I; X 11 present or absent, and if present, C; a CDR2 sequence selected from the group consisting of SEQ ID NO: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252.

[0382] In some embodiments, the VH region of the anti-ICAM1 antibody comprises the CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 (SEQ ID NO: 425), wherein X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y or H; X 8 is selected from G, A or Y; and X 10selected from S, G or N; a CDR2 sequence selected from SEQ ID NO: 209, 212, 218, 220, 223, 227, 229, 234, 236 and 239; and a CDR3 sequence selected from SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237 and 240.

[0383] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 , X 12 Selected from G, T, A, I or Y; X 13 Selected from W, I, Y or C; X 14 Selected from I, S or Y; X 15 Selected from S, G, T, D or P; X 16 Selected from F, S, D, T or A; X 17 Selected from S, R, G or D; X 18 Selected from G, D or S; X 19 Selected from S, R, T, N, Y, A, D or P; X 20 Selected from T, A, G or Y; X 21 Selected from Y, H, A, S or T; X 22 Select from Y or N; X 23 Selected from A, P, Y or S; X 24 Selected from S, T, N, D, Y, A or P; X 25 Selected from W, S, A or D; X 26 Selected from A, V, T, W, F or S; X 27 Selected from K, W, A, Q or V; X 28 Selected from G, A or K; X 29 is present or absent, and if present, is selected from K or G; and X30 is present or absent, and if present, is G; and a CDR3 sequence selected from SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249 and 252.

[0384] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; a CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG (SEQ ID NO: 420), wherein X 13 Selected from W, I or Y; X 15 Selected from S or G; X 16 Selected from F, S, D or T; X 17 Selected from S or R; X 18 Select from G or D; X 19 Selected from S, R, T or N; X 20 is selected from T or A; and X 24 is selected from S, T or N; and a CDR3 sequence selected from SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237 and 240.

[0385] and 252. In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NO: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252.

[0386] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, and 412; a CDR2 sequence selected from the group consisting of SEQ ID NO: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, and 413; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, and 414.

[0387] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 243, 245, 249, and 252.

[0388] In some embodiments, the VL region of the anti-ICAM1 antibody comprises a CDR1, CDR2, and CDR3 sequence selected from Table 8.

[0389] Table 8. Light chain complementarity determining regions of exemplary anti-ICAM1 antibodies

[0390]

[0391] In some embodiments, the VL region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 415; a CDR2 sequence selected from the group consisting of SEQ ID NO: 254, 257, 260, 263, 273, 275, 280, 283, and 416; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 417.

[0392] In some embodiments, the VL region of the anti-ICAM1 antibody comprises the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 62-64, respectively.

[0393] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , where X 31 Selected from A or V; X 32 Selected from R or I; X 33 Selected from G, D, P, A or V; X 34 Selected from G, P, W, D, N or R; X 35 Selected from D, Y, S, L, G, F or W; X 36 Selected from Y, D, V, L, S, G or P; X 37 Selected from G, S, D, V or E; X 38 Selected from G, Y, F, S or D; X 39 Selected from S, D, G, T, N, A or V; X 40 Selected from T, A, D, S, Y, L or F; X 41 Present or absent, if present, selected from Y, A, G, I or D; X 42 Present or absent, if present, selected from I, Y, R, P, V or G; X 43 Present or absent, if present, selected from L, R, Y, G or A; X 44 Present or absent, if present, selected from N, L, Y, S or W; X 45 Present or absent, if present, selected from L, Y, F or C; X 46 Present or absent, if present, selected from D, A or F; X 47 Present or absent, if present, selected from M, P, Y or N; X48 is present or absent, and if present, is selected from D or L; and X 49 is present or absent, and if present, is L; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62; a CDR2 sequence selected from the group consisting of SEQ ID NO: 254, 257, 260, 263, 273, 275, 280, 283, and 63; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 64.

[0394] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and a CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 (SEQ ID NO: 424), wherein X 31 Select from A or V; X 33 Select from G or D; X 34 Selected from G, P, W or D; X 35 Selected from D, Y, S or L; X 36 Selected from Y, D, V or L; X 37 Selected from G, S or D; X 38 Selected from G, Y, F or S; X 39 Selected from S, D, G or T; X 40 Selected from T, A, D, S or Y; X 41 Selected from Y, A, G or I; X 42 Selected from I, Y or R; X 43Selected from L, R, Y or G; X 44 Selected from N, L, Y or S; X 45 Present or absent, if present, selected from L, Y or F; X 46 Exist or not, if it exists, then D; X 47 Present or absent, if present, selected from M or P; X 48 exists or does not exist, if it exists, it is D; and X 49 is present or absent, and if present, is L; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279 and 282; a CDR2 sequence selected from the group consisting of SEQ ID NO: 254, 257, 260, 263, 273, 275, 280 and 283; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 255, 258, 261, 264, 266, 271, 276, 278, 281 and 284.

[0395] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 , where X 1 Selected from G or E; X 2 Selected from F or Y; X 3 Select from S or T; X 4 Selected from L, F or S; X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y, H or G; X 8 Selected from G, A, Y, W or F; X 9 Selected from M, W, Y or I; X 10 Selected from S, G, N, M or I; X 11is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62; a CDR2 sequence selected from the group consisting of SEQ ID NOs: NO:254, 257, 260, 263, 273, 275, 280, 283 and 63; and a CDR3 sequence selected from SEQ ID NO:255, 258, 261, 264, 266, 271, 276, 278, 281, 284 and 64.

[0396] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 (SEQ ID NO: 425), wherein X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y or H; X 8 is selected from G, A or Y; and X 10 selected from the group consisting of S, G or N; a CDR2 sequence selected from the group consisting of SEQ ID NO: 209, 212, 218, 220, 223, 227, 229, 234, 236 and 239; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237 and 240; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279 and 282; a CDR2 sequence selected from the group consisting of SEQ ID NO: 254, 257, 260, 263, 273, 275, 280 and 283; and a CDR3 sequence selected from the group consisting of SEQ ID NO: NO: 255, 258, 261, 264, 266, 271, 276, 278, 281 and 284.

[0397] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; and a CDR2 sequence X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 , where X 12 Selected from G, T, A, I or Y; X 13 Selected from W, I, Y or C; X 14 Selected from I, S or Y; X 15 Selected from S, G, T, D or P; X 16 Selected from F, S, D, T or A; X 17 Selected from S, R, G or D; X 18 Selected from G, D or S; X 19 Selected from S, R, T, N, Y, A, D or P; X 20 Selected from T, A, G or Y; X 21 Selected from Y, H, A, S or T; X 22 Select from Y or N; X 23 Selected from A, P, Y or S; X 24 Selected from S, T, N, D, Y, A or P; X 25 Selected from W, S, A or D; X 26 Selected from A, V, T, W, F or S; X 27 Selected from K, W, A, Q or V; X 28 Selected from G, A or K; X 29 is present or absent, and if present, is selected from K or G; and X 30and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, 283, and 63; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: NO: 255, 258, 261, 264, 266, 271, 276, 278, 281, 284 and 64.

[0398] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; and a CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 1 9 X 20 YYAX 24 WAKG (SEQ ID No. 420), wherein X 13 Selected from W, I or Y; X 15 Selected from S or G; X 16 Selected from F, S, D or T; X 17 Selected from S or R; X 18 Select from G or D; X 19 Selected from S, R, T or N; X 20 is selected from T or A; and X 24selected from S, T or N; and a CDR3 sequence selected from SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237 and 240; and wherein the VL region comprises a CDR1 sequence selected from SEQ ID NO: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279 and 282; a CDR2 sequence selected from SEQ ID NO: 254, 257, 260, 263, 273, 275, 280 and 283; and a CDR3 sequence selected from SEQ ID NO: 255, 258, 261, 264, 266, 271, 276, 278, 281 and 284.

[0399] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, or 251; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: NO:210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249 and 252; and wherein the VL region comprises a CDR1 sequence selected from SEQ ID NO: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282 and 62; a CDR2 sequence selected from SEQ ID NO: 254, 257, 260, 263, 273, 275, 280, 283 and 63; and a CDR3 sequence selected from SEQ ID NO: 255, 258, 261, 264, 266, 271, 276, 278, 281, 284 and 64.

[0400] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: NO: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279 and 282; a CDR2 sequence selected from SEQ ID NO: 254, 257, 260, 263, 273, 275, 280 and 283; and a CDR3 sequence selected from SEQ ID NO: 255, 258, 261, 264, 266, 271, 276, 278, 281 and 284.

[0401] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 243, 245, 249, and 252; and wherein the VL region comprises the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 62-64, respectively.

[0402] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the sequence of the VH region comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NOs: 289-309, and the sequence of the VL region comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to SEQ ID NOs: 311-326 and 155.

[0403] In some embodiments, the VH region comprises a sequence selected from Table 9 and the VL region comprises a sequence selected from Table 10.

[0404] Table 9. Heavy chain variable domains of exemplary anti-ICAM1 antibodies. The underlined regions represent the respective CDR1, CDR2 or CDR3 sequences.

[0405]

[0406]

[0407]

[0408] Table 10. Light chain variable domains of exemplary anti-ICAM1 antibodies. The underlined regions represent the respective CDR1, CDR2 or CDR3 sequences.

[0409]

[0410]

[0411] In some embodiments, the anti-ICAM1 antibody is a full-length antibody. In other embodiments, the anti-ICAM1 antibody is a binding fragment. In some cases, the anti-ICAM1 antibody comprises an antibody or a binding fragment thereof, a chimeric antibody or a binding fragment thereof, a monoclonal antibody or a binding fragment thereof, or a bispecific antibody or a binding fragment thereof. In some cases, the anti-CD38 antibody comprises a monovalent Fab, a bivalent Fab'2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single domain antibody (sdAb), or a camelid antibody or a binding fragment thereof.

[0412] In some embodiments, the anti-ICAM1 antibody comprises a bispecific antibody or a binding fragment thereof. In some cases, the bispecific antibody or binding fragment thereof is a bispecific antibody conjugate, a hybrid bispecific IgG, a variable domain-only bispecific antibody, a CH1 / CL fusion protein, a Fab fusion protein, a non-immunoglobulin fusion protein, an Fc-modified IgG, an attached and Fc-modified IgG, a modified Fc and CH3 fusion protein, an attached IgG-HC fusion, an Fc fusion, a CH3 fusion, an IgE / IgM CH2 fusion, or a F(ab')2 fusion.

[0413] In some embodiments, the bispecific antibody or binding fragment comprises a knob-in-hole structure (KIH), asymmetric reengineered technology-immunoglobulin (ART-Ig), a triomab tetravalent, a bispecific monoclonal antibody (BiMAb, BsmAb, BsAb, bsMab, BS-Mab or Bi-MAb), FcΔAdp, XmAb, Azymetric, bispecific engagement of T cell receptor-based antibodies (BEAT), bispecific T cell engager (BiTE), Biclonics, Fab-scFv-Fc, two-in-one / bifunctional Fab (DAF), Finomab, scFv-Fc-(Fab)-fusion, docking and locking (DNL), Adaptir (formerly SCORPION), tandem diabodies (TandAb), dual affinity retargeting (DART) or nanobody.

[0414] In some embodiments, the variable domain-only bispecific antibodies include tandem scFv (taFv), triabodies, diabodies (Db), dsDb, Db(KIH), scDb, dsFv-dsFv', tandAbs, triple heads, tandem dAb / VHH, triple dAb / VHH, or tetravalent dAb / VHH.

[0415] In some embodiments, the CH1 / CL fusion protein comprises scFv2-CH1 / CL or VHH2-CH1 / CL.

[0416] In some cases, the Fab fusion protein comprises Fab-scFv (diabody), Fab-scFv2 (triabody), Fab-Fv, Fab-dsFv, Fab-VHH, or orthogonal Fab-Fab.

[0417] In some instances, the non-immunoglobulin fusion protein comprises scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, minibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine 2, or ImmTAC (TCR-scFv).

[0418] In some cases, the Fc-modified IgG includes IgG(KIH), IgG(KIH) common LC, ZW1 IgG common LC, Biclonics common LC, CrossMAb, scFab-IgG(KIH), Fab-scFab-IgG(KIH), orthogonal Fab IgG(KIH), DuetMab, CH3 charge pair + CH1 / CL charge pair, hinge / CH3 charge pair, DuoBody, four-in-one-CrossMab(KIH), LUZ-Y common LC, LUZ-Y scFab-IgG or FcFc*.

[0419] In some cases, the appended and Fc-modified IgG includes IgG(KIH)-Fv, IgG(HA-TF-FV), IgG(KIH)-scFab, scFab-Fc(KIH)-scFv2, scFab-Fc(KIH)-scFv, half DVD-Ig, dual variable domain-immunoglobulin (DVD-Ig) or CrossMab-Fab.

[0420] In some cases, the modified Fc and CH3 fusion proteins include scFv-Fc (KIH), scFv-Fc (CH3 charge pair), scFv-FC (EW-RVT), scFv-Fc (HA-TF), scFv-Fc (SEEDbody), taFv-Fc (KIH), scFv-Fc (KIH)-Fv, Fab-Fc (KIH)-scFv, Fab-scFv-Fc (KIH), Fab-scFv-Fc (BEAT), DART-Fc, scFv-CH3 (KIH) or TriFabs.

[0421] In some cases, the additional IgG-HC fusion antibody includes IgG-HC-scFv, IgG-dAb, IgG-taFv, IgG-CrossFab, IgG-orthogonal Fab, IgG-(CαCβ)Fab, scFv-HC-IgG, tandem Fab-IgG, Fab-IgG(CαCβFab), Fab-IgG(CR3) or Fab-hinge-IgG(CR3).

[0422] In some cases, the additional IgG-LC fusion antibody comprises IgG-scFv(LC), scFv(LC)-IgG, or dAb-IgG.

[0423] In some cases, the additional IgG-HC & LC fusion antibody includes DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, or Zybody.

[0424] In some instances, Fc fusion antibodies include diabodies, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-Ig, or scFv2-Fcab.

[0425] In some cases, the CH3 fusion antibody comprises a diabody or scDb-CH3.

[0426] In some instances, the IgE / IgM CH2 fusion antibody comprises scFv-EHD2-scFv or scFv-MHD2-scFv.

[0427] In some instances, the F(ab')2 fusion antibody comprises F(ab')2-scFv2.

[0428] In some cases, the CH1 / CL fusion protein comprises scFv2-CH1-hinge / CL.

[0429] In some cases, modified IgG includes DAF (two-in-one-IgG), DutaMab or mAb 2 .

[0430] In some instances, the non-immunoglobulin fusion antibody comprises DNL-Fab4-IgG.

[0431] In some cases, anti-ICAM1 antibodies include, for example Figure 1A or Figure 1B The bispecific antibody or binding fragment thereof is shown.

[0432] In some embodiments, the anti-ICAM1 antibodies described herein comprise an IgG framework, an IgA framework, an IgE framework, or an IgM framework. In some cases, the anti-ICAM1 antibodies comprise an IgG framework (e.g., IgG1, IgG2, IgG3, or IgG4). In this case, the anti-ICAM1 antibodies comprise an IgG1, IgG2, IgG3, or IgG4 framework.

[0433] In some cases, the anti-ICAM1 antibody further comprises one or more mutations in the framework region (e.g., in the CH1 domain, CH2 domain, CH3 domain, hinge region, or a combination thereof). In some cases, the one or more mutations are used to stabilize the antibody and / or increase half-life. In some cases, the one or more mutations are used to modulate Fc receptor interactions to increase ADCC or CDC. In other cases, the one or more mutations are used to reduce or eliminate Fc effector functions, such as FcγR, ADCC, or CDC. In other cases, the one or more mutations are used to modulate glycosylation.

[0434] In some cases, the anti-ICAM1 antibody comprises an IgG1 framework. In some embodiments, the constant region of the anti-ICAM1 antibody is modified at one or more amino acid positions to alter Fc receptor interactions. Exemplary residues that regulate or alter Fc receptor interactions include, but are not limited to, G236, S239, T250, M252, S254, T256, K326, A330, I332, E333A, M428, H433, or N434 (Kabat numbering; EU index of Kabat et al. 1991 immunology target protein sequences). In some cases, mutations include G236A, S239D, T250Q, M252Y, S254T, T256E, K326W, A330L, I332E, E333A, E333S, M428L, H433K, or N434F.

[0435] In some embodiments, modifications at one or more amino acid positions in the IgG1 constant region that alter Fc receptor interactions result in increased half-life. In some cases, modifications at one or more amino acid positions include T250, M252, S254, T256, M428, H433, N434, or a combination thereof; for example, including T250Q / M428L or M252Y / S254T / T256E and H433K / N434F.

[0436] In some embodiments, the modification at one or more amino acid positions in the IgG1 constant region for changing Fc receptor interactions causes ADCC and / or CDC to increase. In some cases, the modification at one or more amino acid positions includes S239, K326, A330, I332, E333 or a combination thereof. In some cases, the modification at one or more amino acid positions for increasing ADCC and / or CDC includes, for example, E333A, S239D / A330L / I332E or K326W / E333S. In some cases, the modification at one or more amino acid positions for increasing ADCC includes S239D / A330L / I332E. In some cases, the modification at one or more amino acid positions for increasing CDC includes K326W / E333S.

[0437] In some embodiments, modifications at one or more amino acid positions in the IgG1 constant region that alter Fc receptor interactions result in increased macrophage phagocytosis. In some cases, modifications at one or more amino acid positions include G236, S239, I332, or a combination thereof. In some cases, modifications at one or more amino acid positions that increase macrophage phagocytosis include the combination S239D / I332I / G236A.

[0438] In some embodiments, the IgG1 constant region is modified at amino acid N297 (Kabat numbering), wherein residue N297 is afucosylated, wherein the oligosaccharide does not comprise a fucose unit.

[0439] In some embodiments, the anti-ICAM1 antibody comprises an IgG2 framework. In some cases, one or more amino acid positions in the IgG2 framework are modified to alter Fc receptor interactions, for example, to increase ADCC and / or CDC. In some cases, one or more amino acid positions in the IgG2 framework are modified to stabilize the antibody and / or increase half-life. In some cases, one or more amino acid positions in the IgG2 framework are modified to regulate glycosylation. In some cases, the IgG2 constant region is afucosylated at residue N297.

[0440] In some embodiments, the anti-ICAM1 antibody comprises an IgG3 framework. In some cases, one or more amino acid positions in the IgG3 framework are modified to alter Fc receptor interactions, e.g., to increase ADCC and / or CDC. In some cases, one or more amino acid positions in the IgG3 framework are modified to stabilize the antibody and / or increase half-life. In some cases, one or more amino acid positions in the IgG3 framework are modified to regulate glycosylation. In some cases, the constant region of the antibody is modified at amino acid R435 to extend half-life, e.g., R435H (Kabat numbering). In some cases, the constant region is non-fucosylated at residue N297.

[0441] In some embodiments, the anti-ICAM1 antibody comprises an IgG4 framework. In some cases, one or more amino acid positions in the IgG4 framework are modified to alter Fc receptor interactions, for example, to increase ADCC and / or CDC. In some cases, one or more amino acid positions in the IgG4 framework are modified to stabilize the antibody and / or increase half-life. In some cases, one or more amino acid positions in the IgG4 framework are modified to regulate glycosylation. In some cases, the constant region is modified in the hinge region to prevent or reduce chain exchange. In some cases, the modified amino acid is S228 (e.g., S228P).

[0442] In some embodiments, the human IgG constant region is modified to alter ADCC and / or CDC, e.g., with amino acid modifications as described in Natsume et al., 2008 Cancer Res, 68(10):3863-72; Idusogie et al., 2001 J Immunol, 166(4):2571-5; Moore et al., 2010 mAbs, 2(2):181-189; Lazar et al., 2006 PNAS, 103(11):4005-4010, Shields et al., 2001 JBC, 276(9):6591-6604; Stavenhagen et al., 2007 Cancer Res, 67(18):8882-8890; Stavenhagen et al., 2008 Advan. Enzyme Regul., 48:152-164; Alegre et al., 1992 J Immunol, 148: 3461-3468; reviewed in Kaneko and Niwa, 2011 Biodrugs, 25(1): 1-11.

[0443] In some embodiments, the human IgG constant region is modified to induce heterodimerization. For example, the CH3 domain has an amino acid modification at Thr366, which, when replaced by a bulkier amino acid (e.g., Trp (T366W)), can preferably pair with a second CH3 domain having amino acid modifications that produce smaller amino acids at Thr366, Leu368, and Tyr407, such as Ser, Ala, and Val (T366S / L368A / Y407V). In some cases, the heterodimerization performed by CH3 modification is further stabilized by introducing a disulfide bond, for example, by replacing Ser354 on the opposite CH3 domain with Cys (S354C) and Y349 with Cys (Y349C) (reviewed in Carter, 2001 Journal of Immunological Methods, 248: 7-15).

[0444] In some cases, the anti-ICAM1 antibodies described herein have reduced glycosylation or lack glycosylation but are unmodified at amino acid Asn297 (Kabat numbering). In these cases, glycosylation is eliminated, for example, by producing the antibody in a host cell that lacks post-translational glycosylation capabilities (e.g., a bacterial or yeast-derived system or a modified mammalian cell expression system). In certain aspects, such a system is a cell-free expression system.

[0445] In some embodiments, the anti-ICAM1 antibodies described herein are full-length antibodies comprising a heavy chain (HC) and a light chain (LC). In some cases, the heavy chain (HC) comprises a sequence selected from Table 11. In some cases, the light chain (LC) comprises a sequence selected from Table 12.

[0446] Table 11. Heavy chains of exemplary anti-ICAM1 antibodies

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453] Table 12. Light chains of exemplary anti-ICAM1 antibodies

[0454]

[0455]

[0456]

[0457] In some embodiments, ADCC activity is determined in an in vitro cytotoxicity assay, e.g., using cancer cells (e.g., human prostate cancer cells), and the anti-ICAM1 antibodies described herein have an EC of about 0.001 nM to about 2.5 nM (e.g., about 0.02 nM, 0.03 nM, about 0.04 nM, about 0.05 nM, about 0.06 nM, about 0.09 nM, about 0.1 nM, about 1.2 nM, about 1.7 nM, about 2.0 nM, about 2.5 nM). 50 .

[0458] In some instances, the serum half-life of an anti-ICAM1 antibody described herein is at least 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or longer. In some instances, the serum half-life of an anti-ICAM1 antibody described herein is about 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or longer.

[0459] Multispecific anti-CD38 and anti-ICAM1 antibodies

[0460] In certain embodiments, multispecific anti-CD38 antibodies or multispecific anti-ICAM1 antibodies are described herein. In some cases, the multispecific anti-CD38 antibodies or multispecific anti-ICAM1 antibodies comprise target binding portions that recognize two or more antigens. In some cases, the multispecific anti-CD38 antibodies comprise target binding portions that specifically bind to two or more antigens, e.g., three or more, four or more, or five or more antigens. In some cases, the multispecific anti-ICAM1 antibodies comprise target binding portions that specifically bind to two or more antigens, e.g., three or more, four or more, or five or more antigens.

[0461] In some embodiments, bispecific anti-CD38 antibodies are described herein. In some cases, the bispecific anti-CD38 antibodies comprise a first targeting moiety that specifically binds to CD38 and a second targeting moiety that specifically binds to a non-CD38 target. In some cases, the second target includes, but is not limited to, ICAM1, ephrin type A receptor 2 (EphA2), ephrin type A receptor 3 (EphA3), ephrin type A receptor 4 (EphA4), activated leukocyte adhesion molecule (ALCAM), BCMA (B cell maturation antigen or TNFRSF17), PDL1, CD30, CD33, PSMA, mesothelin, CD44, CD73, cell surface-associated mucin 1 (MUC1), oligomeric mucin gel-forming mucin 2 (MUC1), and TNFRSF17. C2), cell surface-associated mucin 16 (MUC16), carcinoembryonic antigen (CEA), cathepsin G, preferentially expressed antigen in melanoma (PRAME), CD52, EpCAM, tumor-associated glycoprotein 72 (TAG-72), carbonic anhydrase IX, PSMA, folate-binding protein, ganglioside, Lewis-Y, immature laminin receptor, BING-4, calcium-activated chloride channel 2 (CaCC), gp100, synovial sarcoma X breakpoint 2 (SSX-2), or SAP-1.

[0462] In some embodiments, bispecific anti-ICAM1 antibodies are described herein. In some cases, the bispecific anti-ICAM1 antibodies comprise a targeting moiety that specifically binds to ICAM1 and a targeting moiety that specifically binds to a non-ICAM1 target. In some cases, the non-ICAM1 targets include, but are not limited to, CD38, CD47, receptor tyrosine kinase-like orphan receptor 1 (ROR1), receptor tyrosine kinase-like orphan receptor 2 (ROR2), Erb3, IGF-IR, EGFR, PDL1, PDL2, PD1, CTLA4, or Tim3.

[0463] In some embodiments, described herein are bispecific antibodies comprising a first targeting moiety that specifically binds to CD38 or ICAM1.

[0464] In some embodiments, a bispecific antibody of the disclosure comprising a first component that binds CD38 and a second component that binds ICAM1 binds to a cell expressing the target antigen of the bispecific protein on its surface with at least 2-50 fold, 10-100 fold, 2 fold, 5 fold, 10 fold, 25 fold, 50 fold, or 100 fold greater affinity (e.g., preferentially binds) than the binding affinity of an antibody that is monospecific for only one of CD38 or ICAM1 to the cell.

[0465] In some cases, compared with the complement dependent cytotoxicity (CDC) effect of the reference antibody daratumumab, the bispecific antibody also has an enhanced CDC effect. In some cases, compared with the ADCC effect of the reference antibody daratumumab, the bispecific antibody also has an enhanced ADCC effect. In some cases, compared with the immune cell killing effect of the reference antibody daratumumab, the bispecific antibody also has a reduced immune cell killing effect. In some cases, the enhanced CDC is at least 2 times, 3 times, 4 times or more times the CDC effect of the reference antibody daratumumab. In some cases, the enhanced CDC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more high than the CDC effect of the reference antibody daratumumab. In some cases, the enhanced ADCC is at least 2 times, 3 times, 4 times, 5 times or more high than the ADCC effect of the reference antibody daratumumab. In some cases, the enhanced ADCC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more greater than the ADCC effect of a reference antibody, daratumumab. In some cases, the immune cells are natural killer cells. In some cases, the immune cell viability is increased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to the immune cell viability in the presence of a reference antibody, daratumumab.

[0466] In some embodiments, described herein are bispecific antibodies comprising a first targeting moiety that specifically binds to CD38 and a second targeting moiety that specifically binds to ICAM1. In some cases, the bispecific antibodies further have an enhanced CDC effect compared to the CDC effect of a reference antibody, daratumumab. In some cases, the bispecific antibodies further have an enhanced ADCC effect compared to the ADCC effect of a reference antibody, daratumumab.

[0467] In some cases, the enhanced CDC is at least 2-fold, 3-fold, 4-fold, or more times greater than the CDC effect of a reference antibody, daratumumab. In some cases, the enhanced CDC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more greater than the CDC effect of a reference antibody, daratumumab. In some cases, the enhanced ADCC is at least 2-fold, 3-fold, 4-fold, 5-fold, or more greater than the ADCC effect of a reference antibody, daratumumab. In some cases, the enhanced ADCC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more greater than the ADCC effect of a reference antibody, daratumumab.

[0468] In some embodiments, described herein are bispecific antibodies comprising a first component that specifically binds to CD38 and a second component that specifically binds to ICAM1, wherein the bispecific antibody mediates ADCC more effectively than a monospecific antibody comprising either the first component or the second component, wherein ADCC activity is determined using an in vitro cytotoxicity assay. In some embodiments, the bispecific antibody mediates at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 75%, or at least about 100% greater maximal cytotoxicity in an in vitro ADCC assay than a monospecific antibody comprising either the first component or the second component. In some embodiments, the maximal cytotoxicity mediated by the bispecific antibody in an in vitro ADCC assay is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 10-fold greater than that of a monospecific antibody comprising either the first component or the second component.

[0469] In some embodiments, described herein are bispecific antibodies comprising a first component that specifically binds to CD38 and a second component that specifically binds to ICAM1, wherein the bispecific antibody mediates complement dependent cytotoxicity (CDC) more efficiently than a monospecific antibody comprising the first component or the second component, wherein ADCC activity is determined using an in vitro cytotoxicity assay, wherein CDC activity is determined using an in vitro cytotoxicity assay. In some embodiments, the bispecific antibody mediates at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 75%, or at least about 100% greater maximal cytotoxicity in an in vitro CDC assay than a monospecific antibody comprising the first component or the second component.

[0470] In some cases, the bispecific antibody also has a reduced immune cell killing effect compared to the immune cell killing effect of the reference antibody daratumumab. In some cases, the immune cell viability is increased by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to the immune cell viability in the presence of the reference antibody daratumumab. In some cases, the immune cell is a natural killer cell.

[0471] In some embodiments, bispecific antibodies comprising a CD38 targeting moiety and an ICAM1 targeting moiety include bispecific antibody conjugates, hybrid bispecific IgG, variable domain only bispecific antibodies, CH1 / CL fusion proteins, Fab fusion proteins, non-immunoglobulin fusion proteins, Fc-modified IgG, appended and Fc-modified IgG, modified Fc and CH3 fusion proteins, appended IgG-HC fusions, Fc fusions, CH3 fusions, IgE / IgM CH2 fusions, or F(ab')2 fusions.

[0472] In some embodiments, the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety comprises a knob-in-hole structure (KIH), an asymmetric reengineered technology-immunoglobulin (ART-Ig), a Triomab tetravalent tumor, a bispecific monoclonal antibody (BiMAb, BsmAb, BsAb, bsMab, BS-Mab or Bi-MAb), FcΔAdp, XmAb, Azymetric, Bispecific engagement of T cell receptor-based antibodies (BEAT), bispecific T cell engager (BiTE), Biclonics, Fab-scFv-Fc, two-in-one / bifunctional Fab (DAF), Finomab, scFv-Fc-(Fab)-fusion, docking and locking (DNL), Adaptir (formerly SCORPION), tandem diabodies (TandAb), dual affinity retargeting (DART) or nanobody.

[0473] In some embodiments, the variable domain-only bispecific antibodies include tandem scFv (taFv), triabodies, diabodies (Db), dsDb, Db(KIH), scDb, dsFv-dsFv', tandAbs, triple heads, tandem dAb / VHH, triple dAb / VHH, or tetravalent dAb / VHH.

[0474] In some embodiments, the CH1 / CL fusion protein comprises scFv2-CH1 / CL or VHH2-CH1 / CL.

[0475] In some cases, the Fab fusion protein comprises Fab-scFv (diabody), Fab-scFv2 (triabody), Fab-Fv, Fab-dsFv, Fab-VHH, or orthogonal Fab-Fab.

[0476] In some instances, the non-immunoglobulin fusion protein comprises scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, minibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine 2, or ImmTAC (TCR-scFv).

[0477] In some cases, the Fc-modified IgG includes IgG(KIH), IgG(KIH) common LC, ZW1 IgG common LC, Biclonics common LC, CrossMAb, scFab-IgG(KIH), Fab-scFab-IgG(KIH), orthogonal Fab IgG(KIH), DuetMab, CH3 charge pair + CH1 / CL charge pair, hinge / CH3 charge pair, DuoBody, four-in-one-CrossMab(KIH), LUZ-Y common LC, LUZ-Y scFab-IgG or FcFc*.

[0478] In some cases, the appended and Fc-modified IgG includes IgG(KIH)-Fv, IgG(HA-TF-FV), IgG(KIH)-scFab, scFab-Fc(KIH)-scFv2, scFab-Fc(KIH)-scFv, half DVD-Ig, dual variable domain-immunoglobulin (DVD-Ig) or CrossMab-Fab.

[0479] In some cases, the modified Fc and CH3 fusion proteins include scFv-Fc (KIH), scFv-Fc (CH3 charge pair), scFv-FC (EW-RVT), scFv-Fc (HA-TF), scFv-Fc (SEEDbody), taFv-Fc (KIH), scFv-Fc (KIH)-Fv, Fab-Fc (KIH)-scFv, Fab-scFv-Fc (KIH), Fab-scFv-Fc (BEAT), DART-Fc, scFv-CH3 (KIH) or TriFabs.

[0480] In some cases, the additional IgG-HC fusion antibody includes IgG-HC-scFv, IgG-dAb, IgG-taFv, IgG-CrossFab, IgG-orthogonal Fab, IgG-(CαCβ)Fab, scFv-HC-IgG, tandem Fab-IgG, Fab-IgG(CαCβFab), Fab-IgG(CR3) or Fab-hinge-IgG(CR3).

[0481] In some cases, the additional IgG-LC fusion antibody comprises IgG-scFv(LC), scFv(LC)-IgG, or dAb-IgG.

[0482] In some cases, the additional IgG-HC & LC fusion antibody includes DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, or Zybody.

[0483] In some instances, Fc fusion antibodies include diabodies, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-Ig, or scFv2-Fcab.

[0484] In some cases, the CH3 fusion antibody comprises a diabody or scDb-CH3.

[0485] In some instances, the IgE / IgM CH2 fusion antibody comprises scFv-EHD2-scFv or scFv-MHD2-scFv.

[0486] In some instances, the F(ab')2 fusion antibody comprises F(ab')2-scFv2.

[0487] In some cases, the CH1 / CL fusion protein comprises scFv2-CH1-hinge / CL.

[0488] In some cases, modified IgG includes DAF (two-in-one-IgG), DutaMab or mAb 2 .

[0489] In some instances, the non-immunoglobulin fusion antibody comprises DNL-Fab4-IgG.

[0490] In some cases, a bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety includes, for example Figure 1A or Figure 1B Antibody formats indicated.

[0491] In some cases, the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety is a bivalent antibody or a binding fragment thereof. In some cases, the bivalent antibody or binding fragment thereof comprises an IgG-scFv (LC) C-terminal fusion form ( Figure 2A ), IgG-HC-scFv C-terminal fusion form ( Figure 2B ), scFv-HC-IgG N-terminal fusion form ( Figure 2C ) or DVD-Ig format ( Figure 2D ).

[0492] In some cases, the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety is a monovalent antibody or a binding fragment thereof. In some cases, the monovalent antibody or binding fragment thereof comprises a Fab-scFv-Fc (KIH) format (also referred to herein as a three-chain knob-in-hole structure) ( Figure 2E ) or Biclonics common LC format (also referred to herein as common light chain bispecific) ( Figure 2F ).

[0493] In some embodiments, the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety has a K for CD38 of about 1 nM to about 100 nM. D In some cases, K D is at least 1 nM, 2nM, 3nM, 3.15nM, 3.2nM, 3.39nM, 3.5nM, 4nM, 4.5nM, 5nM, 5.32nM, 5.5nM, 6nM, 6.5nM, 7nM, 7.5nM, 8nM, 8.5nM, 9nM, 9.5nM, 10nM, 15nM, 18nM, 20nM, 25nM, 30nM, 35nM, 40nM, 45nM, 50nM, 60nM, 70nM, 80nM, 90nM or 100nM.

[0494] In some embodiments, the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety has a K for ICAM1 of about 0.1 nM to about 20 nM. D In some cases, K D is about 0.15nM, 0.2nM, 0.24nM, 0.25nM, 0.29nM, 0.3nM, 0.4nM, 0.5nM, 0.6nM, 0.7nM, 0.8nM, 0.9nM, 1nM, 1.5nM, 1.72nM, 2nM, 2.28nM, 2.5nM, 3nM, 3.5nM, 4nM, 4.5nM, 5nM, 6nM, 7nM, 8nM, 9nM, 10nM, 11nM, 12nM, 13nM, 14nM, 15nM, 16nM, 17nM, 18nM, 19nM or 20nM.

[0495] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X43 X 44 X 45 X 46 X 47 X 48 X 49 ; where X 32 Selected from A, G or V; X 33 Selected from K, A, R, T, G or S; X 34 Selected from R, A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, A, T or R; X 36 Selected from T, P, A, Y, D, G, S, R, V or E; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, A, S, D, K, F, L or Y; X 39 Selected from Y, T, A, G, S or I; X 40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, if present, selected from P, L, Y, F, G or T; X 43 Present or absent, if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, if present, selected from G, L, S, T or F; X 45 Present or absent, if present, selected from F, L, E, N or S; X 46 Present or absent, if present, selected from D, S, L or R; X 47 Present or absent, if present, selected from Y or L; X 48 exists or does not exist, if it exists, it is D; and X 49 is present or absent, and if present, is L; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NO: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0496] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from SEQ ID NOs: 2 and 5; and a CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY (SEQ ID No. 421), wherein X 38 Select from A or G, X 41 Selected from F or Y; and wherein the VL region comprises a CDR1 sequence consisting of SEQ ID NO: 62, a CDR2 sequence consisting of SEQ ID NO: 63, and a CDR3 sequence consisting of SEQ ID NO: 64.

[0497] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , where X 32 Selected from A, G or V; X 33 Selected from A, R, T, S or G; X 34 Selected from A, V, T, P, I, E, D or S; X 35 Selected from G, W, D, L, K, P, S, R or A; X 36 Selected from P, A, Y, D, G, S, R, V, E or T; X 37 selected from Y, V, T, S, N, A, G, Q, F or I; X 38 Selected from G, S, D, K, F, L or Y; X 39 Selected from T, A, G, S, I or Y; X40 Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, if present, selected from V, D, Y, A, N, G, L or E; X 42 Present or absent, if present, selected from L, Y, F, T or G; X 43 Present or absent, if present, selected from P, F, V, N, S or Y; X 44 Present or absent, if present, selected from L, S, T, G or F; X 45 Present or absent, if present, selected from L, F, E, S or N; X 46 Present or absent, if present, selected from S, L or R; X 47 Exist or not, if it exists, it is L; X 48 exists or does not exist, if it exists, it is D; and X 49 is present or absent, and if present, is L; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NO: 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0498] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 , where X 32 Selected from A or G; X 33 Selected from A, R or T; X 34 Selected from A, V, T, P, I, E or D; X 35Selected from G, W, D, L, K or P; X 36 Selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X 38 Selected from G, S, D or K; X 39 Selected from T, A, G, S or I; X 40 Selected from S, Y, G, R or W; X 41 Selected from V, D, Y, A, N or G; X 42 Selected from L, Y or F; X 43 Present or absent, if present, selected from P, F, V or N; X 44 is present or absent, and if present is selected from L, S or T; and X 45 is present or absent, and if present is selected from L or F, and wherein the VL region comprises a CDR1 sequence selected from SEQ ID NO: 65, 68, 80, 86, 89, 92 and 98; a CDR2 sequence selected from SEQ ID NO: 66, 69, 78, 81, 90 and 99; and a CDR3 sequence selected from SEQ ID NO: 67, 70, 82, 87, 88, 91, 93 and 100.

[0499] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence AX. 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 (SEQ ID No. 422), wherein X 33 Selected from R or G; X 34 Selected from E, D or S; X 35 Selected from G, L, P, S or A; X 36 Selected from D, S or R; X 37 Selected from Y, T, N or G; X 38 Selected from G, S, F or L; X 39 Selected from A, G, S or I; X 40 Selected from Y, N or L; X 41Present or absent, if present, selected from V, Y or E; X 42 Exist or not, if it exists, it is G; X 43 Exists or does not exist, if exists, then it is Y; X 44 Exist or not, if it exists, then F; X 45 is present or absent, and if present, is selected from E or N; and X 46 is present or absent, and if present is selected from S or L, and wherein the VL region comprises a CDR1 sequence selected from SEQ ID NO: 71, 77, 83, 94 and 102; a CDR2 sequence selected from SEQ ID NO: 72, 78 and 84; and a CDR3 sequence selected from 73, 79, 85, 95 and 103.

[0500] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 , wherein X1 is present or absent, and if present, is S; X2 is selected from F or I; X3 is selected from P, S or D; X4 is selected from F, L or A; X5 is selected from D, G, S, N or T; X6 is selected from V, A, T, R, S, I or N; X7 is selected from Y, I, N, R, A, G or D; X8 is selected from A, Y, D, G, W, C or T; X9 is selected from M, V, I, W, D or Y; X 10 Selected from S, T, M, C, I, Y, A or G; X 11 is present or absent, and if present, is selected from C or M; and X 12 is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58, and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: NO:63, 66, 69, 72, 75, 78, 81, 84, 90 and 99; and a CDR3 sequence selected from SEQ ID NO:64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101 and 103.

[0501] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence GFPFX5X6YAMS (SEQ ID NO:423), wherein X5 is selected from D or G and X6 is selected from V, A or T; a CDR2 sequence selected from SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from SEQ ID NOs: 3, 7 and 10; and wherein the VL region comprises a CDR1 sequence consisting of SEQ ID NO: 62, a CDR2 sequence consisting of SEQ ID NO: 63, and a CDR3 sequence consisting of SEQ ID NO: 64.

[0502] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 , wherein X1 is present or absent, and if present, is S; X2 is selected from F or I; X3 is selected from S or D; X4 is selected from L, F or A; X5 is selected from S, N or T; X6 is selected from R, S, N, I or T; X7 is selected from Y, I, N, R, A, D or G; X8 is selected from Y, D, G, A, W, T or C; X9 is selected from V, M, I, W, Y or D; X 10 Selected from T, S, M, C, I, Y, A or G; X 11 is present or absent, and if present, is selected from C or M; and X 12 is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: NO: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101 and 103.

[0503] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (SEQ ID NO: 426), wherein X5 is selected from S or N; X6 is selected from R, S or N; X7 is selected from Y, I or N; X8 is selected from Y, D, G or A; X9 is selected from V, M or I; X 10 is selected from T, S or M; and X 11 is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 78, 81, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.

[0504] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (SEQ ID NO: 419), wherein X4 is selected from F or A; X5 is selected from S, T or N; X6 is selected from S, T or N; X7 is selected from Y, R, A or G; X8 is selected from W, Y or C; X9 is selected from I, W, Y or D; X 10 Selected from C, I, Y or M; X 11 Present or absent, if present, selected from C or M; X 12 is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 71, 77, 83, 94, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 72, 78, and 84; and a CDR3 sequence selected from the group consisting of 73, 79, 85, 95, and 103.

[0505] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 56, and 59; and a CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 , where X 13 Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from S, I, L, T or M; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P, V or Y; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from F, Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25 Selected from D, T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from V, A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 Present or absent, if present, selected from G or K; X 31is present or absent, and if present, is G; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: NO: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101 and 103.

[0506] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; and a CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID NO: 418), wherein X 22 selected from F or Y; and a CDR3 sequence selected from SEQ ID NO: 3, 7 and 10; and wherein the VL region comprises a CDR1 sequence consisting of SEQ ID NO: 62, a CDR2 sequence consisting of SEQ ID NO: 63, and a CDR3 sequence consisting of SEQ ID NO: 64.

[0507] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; and a CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 , where X 13Selected from A, G or S; X 14 selected from I, F, Y, V, S or C; X 15 Selected from I, L, M or T; X 16 Selected from G, Y, S, T, L or V; X 17 Selected from S, I, K, Y, T, G or A; X 18 Selected from G, S, T, P or V; X 19 Selected from G, A, D, S or T; X 20 Selected from S, T, I, N or G; X 21 Selected from T, I, D, N, S or A; X 22 Selected from Y, N, T, I or S; X 23 Selected from Y, D, K or I; X 24 Selected from A or Y; X 25 Selected from T, S, N, R, A or Y; X 26 Selected from S, W, T, A or N; X 27 Selected from A, W, N or S; X 28 Selected from K, R, Q, A or W; X 29 Selected from G, K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 is present or absent, and if present, is G; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0508] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 11, 14, 26, 32, 35, 38, 41, and 50; and a CDR2 sequence X 13 X 14 IX 16 X 17 X18X 19 X 20 X 21 X 22 X 23 X24 X 25 X 26 X 27 X 28 X 29 X 30 , where X 13 Selected from A or G; X 14 selected from I, F, Y, V, S or C; X 16 Selected from G, Y, S, T or L; X 17 Selected from S, I, K, Y, T or G; X 18 Selected from G, S or T; X 19 Selected from G, A, D or S; X 20 Selected from T, I, N or G; X 21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Select from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Select from W or T; X 27 Select from A or W; X 28 Selected from K, R, Q or A; X 29 is selected from G or K; and X 30 is present or absent, and if present, is G; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 78, 81, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.

[0509] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NO: 17, 23, 29, 44, and 56; and a CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X22X 23 YX 25 X 26 X 27 X 28 X 29 X 30X 31 , where X 13 Select from A or S; X 15 Selected from I, L or T; X 16 Selected from Y or V; X 17 Selected from S, T or A; X 18 Selected from G, P or V; X 19 Selected from D, S or T; X 20 Selected from S, T or G; X 21 Selected from D, N, S or A; X 22 Selected from T, I or S; X 23 Selected from Y, K or I; X 25 Selected from A or Y; X 26 Selected from S, T, A or N; X 27 Selected from W, N or S; X 28 Select from A or W; X 29 Select K or A; X 30 is present or absent, and if present, is selected from G or K; and X 31 is present or absent, and if present, is G; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 71, 77, 83, 94, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 72, 78, and 84; and a CDR3 sequence selected from the group consisting of 73, 79, 85, 95, and 103.

[0510] In some instances, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: NO: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98 and 102; a CDR2 sequence selected from SEQ ID NO: 63, 66, 69, 72, 75, 78, 81, 84, 90 and 99; and a CDR3 sequence selected from SEQ ID NO: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101 and 103.

[0511] In some cases, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 3, 7, and 10; and wherein the VL region comprises a CDR1 sequence consisting of SEQ ID NO: 62, a CDR2 sequence consisting of SEQ ID NO: 63, and a CDR3 sequence consisting of SEQ ID NO: 64.

[0512] In some instances, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: NO: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98 and 102; a CDR2 sequence selected from SEQ ID NO: 66, 69, 72, 75, 78, 81, 84, 90 and 99; and a CDR3 sequence selected from SEQ ID NO: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101 and 103.

[0513] In some cases, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 66, 69, 78, 81, 90, and 99; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.

[0514] In some cases, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 19, 25, 31, 46, and 58; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 71, 77, 83, 94, and 102; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 72, 78, and 84; and a CDR3 sequence selected from the group consisting of 73, 79, 85, 95, and 103.

[0515] In some embodiments, the second targeting moiety that specifically binds to ICAM1 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , where X 31 Selected from A or V; X 32 Selected from R or I; X 33 Selected from G, D, P, A or V; X 34 Selected from G, P, W, D, N or R; X 35 Selected from D, Y, S, L, G, F or W; X 36 Selected from Y, D, V, L, S, G or P; X 37 Selected from G, S, D, V or E; X 38 Selected from G, Y, F, S or D; X 39 Selected from S, D, G, T, N, A or V; X 40Selected from T, A, D, S, Y, L or F; X 41 Present or absent, if present, selected from Y, A, G, I or D; X 42 Present or absent, if present, selected from I, Y, R, P, V or G; X 43 Present or absent, if present, selected from L, R, Y, G or A; X 44 Present or absent, if present, selected from N, L, Y, S or W; X 45 Present or absent, if present, selected from L, Y, F or C; X 46 Present or absent, if present, selected from D, A or F; X 47 Present or absent, if present, selected from M, P, Y or N; X 48 is present or absent, and if present, is selected from D or L; and X 49 is present or absent, and if present, is L; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62; a CDR2 sequence selected from the group consisting of SEQ ID NO: 254, 257, 260, 263, 273, 275, 280, 283, and 63; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 64.

[0516] In some embodiments, the second targeting moiety that specifically binds to ICAM1 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and a CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X49 (SEQ ID NO: 424), wherein X 31 Selected from A or V; X 33 Select from G or D; X 34 Selected from G, P, W or D; X 35 Selected from D, Y, S or L; X 36 Selected from Y, D, V or L; X 37 Selected from G, S or D; X 38 Selected from G, Y, F or S; X 39 Selected from S, D, G or T; X 40 Selected from T, A, D, S or Y; X 41 Selected from Y, A, G or I; X 42 selected from I, Y or R; X 43 Selected from L, R, Y or G; X 44 Selected from N, L, Y or S; X 45 Present or absent, if present, selected from L, Y or F; X 46 Exist or not, if it exists, then D; X 47 Present or absent, if present, selected from M or P; X 48 exists or does not exist, if it exists, it is D; and X 49 is present or absent, and if present, is L; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NO: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279 and 282; a CDR2 sequence selected from the group consisting of SEQ ID NO: 254, 257, 260, 263, 273, 275, 280 and 283; and a CDR3 sequence selected from the group consisting of SEQ ID NO: 255, 258, 261, 264, 266, 271, 276, 278, 281 and 284.

[0517] In some embodiments, the second targeting moiety that specifically binds to ICAM1 comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 , where X 1 Selected from G or E; X 2 Selected from F or Y; X 3 Select from S or T; X 4Selected from L, F or S; X 5 Selected from S or N; X 6 Selected from S, N, T or D; X 7 Selected from Y, H or G; X 8 Selected from G, A, Y, W or F; X 9 Selected from M, W, Y or I; X 10 is selected from S, G, N, M or I; and X 11 is present or absent, and if present, is C; a CDR2 sequence selected from the group consisting of SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence selected from the group consisting of SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252; and wherein the VL region comprises a CDR1 sequence selected from the group consisting of SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62; a CDR2 sequence selected from the group consisting of SEQ ID NOs: NO:254, 257, 260, 263, 273, 275, 280, 283 and 63; and a CDR3 sequence selected from SEQ ID NO:255, 258, 261, 264, 266, 271, 276, 278, 281, 284 and 64.

[0518] In some embodiments, the second targetin...

Claims

1. A bispecific protein comprising a first component that specifically binds to CD38 and a second component that specifically binds to ICAM1, wherein the bispecific protein comprises the following structure: (a) the first component comprises a complete anti-CD38 immunoglobulin (IgG) molecule, and the second component comprises an anti-ICAM1 single chain variable fragment (scFv); or (b) the first component comprises a Fab fragment of anti-CD38 IgG, and the second component comprises an anti-ICAM1 scFv; wherein the first component that specifically binds to CD38 comprises a heavy chain and a light chain, the heavy chain comprises complementary determining regions HCDR1, HCDR2 and HCDR3, and the HCDR1, HCDR2 and HCDR3 consist of sequences of SEQ ID NOs: 1, 2 and 7, respectively, and the light chain comprises complementary determining regions LCDR1, LCDR2 and LCDR3, and the LCDR1, LCDR2 and LCDR3 consist of sequences of SEQ ID NOs: 62, 63 and 64, respectively; and The second component that specifically binds to ICAM1 comprises a heavy chain and a light chain, wherein the heavy chain comprises complementary determining regions HCDR1, HCDR2 and HCDR3, and the HCDR1, HCDR2 and HCDR3 are composed of sequences of SEQ ID NOs: 228, 229 and 230, respectively; and the light chain comprises complementary determining regions LCDR1, LCDR2 and LCDR3, and the LCDR1, LCDR2 and LCDR3 are composed of sequences of SEQ ID NOs: 270, 260 and 271, respectively.

2. The bispecific protein of claim 1, wherein the bispecific protein is bivalent, trivalent or tetravalent.

3. The bispecific protein according to any one of claims 1-2, further comprising an Fc region.

4. The bispecific protein of claim 3, wherein the Fc region comprises a heterodimeric Fc region.

5. The bispecific protein of claim 3 or 4, wherein the Fc region comprises one or more mutations that increase the half-life of the bispecific protein.

6. The bispecific protein of any one of claims 3-5, wherein the Fc region comprises one or more stabilizing mutations.

7. The bispecific protein of any one of claims 3-6, wherein the Fc region comprises one or more mutations that modulate the interaction of the Fc region with an Fc receptor.

8. The bispecific protein of claim 7, wherein the Fc region comprises one or more mutations that increase binding of the Fc region to an Fc receptor.

9. The bispecific protein of any one of claims 3-8, wherein the Fc region comprises one or more mutations that reduce glycosylation of the Fc region.

10. The bispecific protein of claim 9, wherein the one or more mutations that reduce glycosylation of the Fc region comprise a mutation at a position corresponding to position N297 of human IgG1, wherein numbering is according to the EU index of Kabat et al.

11. The bispecific protein of any one of claims 3-10, wherein the Fc region is afucosylated.

12. The bispecific protein of any one of claims 3-11, wherein the Fc region comprises one or more mutations that increase ADCC or CDC activity.

13. The bispecific protein of claim 12, wherein the Fc region comprises one or more mutations that increase ADCC, wherein the mutations that increase ADCC are at positions corresponding to positions 239, 332, and 330 of human IgG1, wherein the mutations are S239D, I332E, and A330L, and wherein the amino acid numbering is according to the EU index of Kabat et al. 14 . The bispecific protein according to any one of claims 4 to 13 , comprising the heterodimeric Fc region, wherein the heterodimeric Fc region comprises a knob chain and a hole chain, forming a knob-in-hole (KIH) structure.

15. The bispecific protein of claim 14, wherein the knob chain comprises the mutation T366W and the hole chain comprises the mutations T366S, L368A and Y407V, wherein the amino acid positions are numbered according to the EU index of Kabat et al.

16. The bispecific protein of claim 1, wherein the anti-CD38 IgG comprises two light chains and each light chain is fused to a single anti-ICAM1 scFv.

17. The bispecific protein of claim 16, wherein the C-terminus of each light chain of the anti-CD38 IgG is fused to a single anti-ICAM1 scFv.

18. The bispecific protein of claim 1, wherein the anti-CD38 IgG comprises two heavy chains and the N-terminus of each heavy chain is fused to a single anti-ICAM1 scFv.

19. The bispecific protein of claim 1, wherein the anti-CD38 IgG comprises two heavy chains and the C-terminus of each heavy chain is conjugated to a single anti-ICAM1 scFv.

20. The bispecific protein of any one of claims 1-15, wherein the first component comprises an anti-CD38 IgG and the second component comprises two anti-ICAM1 variable heavy chain domains and two anti-ICAM1 variable light chain domains, and wherein each variable heavy chain domain of the anti-CD38 IgG is fused to one of the anti-ICAM1 variable heavy chain domains, and each variable light chain domain of the anti-CD38 IgG is fused to one of the anti-ICAM1 variable light chain domains.

21. The bispecific protein of any one of claims 1-20, wherein the first component comprises a variable heavy chain domain and wherein the variable heavy chain domain comprises a sequence that is at least 90% identical to SEQ ID No:

107.

22. The bispecific protein of claim 21, wherein the first component comprises a variable light chain domain and wherein the variable light chain domain comprises a sequence that is at least 90% identical to SEQ ID No:

133.

23. The bispecific protein of any one of claims 1-22, wherein the second component comprises a variable heavy chain domain and wherein the variable heavy chain domain comprises a sequence that is at least 90% identical to SEQ ID No:

298.

24. The bispecific protein of claim 23, wherein the second component comprises a variable light chain domain, wherein the variable light chain domain comprises a sequence having at least 90% identity to SEQ ID No:

320.

25. The bispecific protein of any one of claims 1-24, wherein the first component that specifically binds to CD38 comprises a full-length antibody comprising a light chain and a heavy chain, wherein the heavy chain comprises a sequence that is at least 90% identical to SEQ ID No:

160.

26. The bispecific protein of claim 25, wherein the light chain comprises a sequence that is at least 90% identical to SEQ ID No:

186.

27. A bispecific protein, comprising a first component that specifically binds to CD38 and a second component that specifically binds to ICAM1, wherein the first component that specifically binds to CD38 comprises a heavy chain and a light chain, the heavy chain comprises complementary determining regions HCDR1, HCDR2 and HCDR3, wherein the HCDR1, HCDR2 and HCDR3 consist of the sequences of SEQ ID NOs: 1, 2 and 7, respectively, and the light chain comprises complementary determining regions LCDR1, LCDR2 and LCDR3, wherein the LCDR1, LCDR2 and LCDR3 consist of the sequences of SEQ ID NOs: 62, 63 and 64, respectively; and The second component that specifically binds to ICAM1 comprises a full-length antibody, which comprises a light chain and a heavy chain, wherein the light chain comprises complementary determining regions LCDR1, LCDR2 and LCDR3, and the LCDR1, LCDR2 and LCDR3 are composed of sequences of SEQ ID NOs: 270, 260 and 271, respectively, and the heavy chain comprises complementary determining regions HCDR1, HCDR2 and HCDR3, and the HCDR1, HCDR2 and HCDR3 are composed of sequences of SEQ ID NOs: 228, 229 and 230, respectively.

28. The bispecific protein of claim 27, wherein the heavy chain of the second component that specifically binds to ICAM1 comprises a sequence that is at least 90% identical to SEQ ID No: 338, or wherein the light chain of the second component that specifically binds to ICAM1 comprises a sequence that is at least 90% identical to SEQ ID No:

360.

29. The bispecific protein of any one of claims 1-28, wherein the bispecific protein induces an enhanced antibody-dependent cellular cytotoxicity (ADCC) effect on target cells compared to an ADCC effect on target cells induced by an otherwise identical bispecific protein not comprising an afucosylated Fc region.

30. The bispecific protein of any one of claims 1-29, wherein the bispecific protein induces an enhanced ADCC effect on the target cells compared to the ADCC effect on the target cells induced by an otherwise identical bispecific protein not comprising an Fc region, the Fc region comprising mutations at positions 239, 332, and 330 corresponding to human IgG1, wherein the mutations are S239D, I332E, and A330L, and wherein the amino acid numbering is according to the EU index of Kabat et al.

31. The bispecific protein of any one of claims 1-30, wherein the amount of said bispecific protein that binds to cells expressing CD38 and ICAM1 is greater than the amount of said monospecific protein that binds to said cells comprising said first component that binds to CD38, wherein binding to said cells is measured by flow cytometry.

32. The bispecific protein of any one of claims 1-31, wherein the bispecific protein induces an enhanced ADCC effect on the target cell compared to the ADCC effect on the target cell induced by a monospecific protein comprising the first component that specifically binds to CD38 or the second component that specifically binds to ICAM1.

33. The bispecific protein of any one of claims 1-32, wherein the bispecific protein induces an enhanced CDC effect on the target cell compared to the CDC effect on the target cell induced by a monospecific protein comprising the first component that specifically binds to CD38 or the second component that specifically binds to ICAM1.

34. The bispecific protein of any one of claims 1-33, wherein the bispecific protein binds to a target cell expressing CD38 and ICAM1 with enhanced affinity compared to a monospecific protein comprising the first component that specifically binds to CD38 or the second component that specifically binds to ICAM1.

35. The bispecific protein of claim 34, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200.

36. The bispecific protein of claim 34, wherein the ratio of ICAM1 to CD38 on the surface of the cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raji cells.

37. The bispecific protein of any one of claims 1-36, wherein the bispecific protein induces an enhanced ADCC effect on the target cells expressing ICAM1 or CD38 compared to the ADCC effect on target cells induced by a monospecific protein comprising the first component that specifically binds to CD38 or the second component that specifically binds to ICAM1.

38. The bispecific protein of claim 37, wherein the cell expresses at least 5,000, 10,000, 15,000, 20,000, 30,000, 50,000, 100,000, 150,000, 200,000, 250,000, 300,000, 400,000, or 500,000 ICAM1 proteins on its surface.

39. The bispecific protein of claim 38, wherein the cell expresses at least 50,000 ICAM1 proteins on its surface.

40. The bispecific protein of any one of claims 37-39, wherein the cell expresses at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on its surface.

41. The bispecific protein of claim 40, wherein the cell expresses at least 300 CD38 proteins on its surface.

42. The bispecific protein of any one of claims 40-41, wherein the cell expresses less than 350,000, 300,000, 250,000, 200,000, 150,000, 100,000, 50,000, 30,000, 20,000, 15,000, 10,000, or 5,000 CD38 proteins on its surface.

43. The bispecific protein of claim 42, wherein the cell expresses fewer than 350,000 CD38 proteins on its surface.

44. The bispecific protein of any one of claims 37-43, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200.

45. The bispecific protein of claim 44, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least 1.

46. ​​The bispecific protein of claim 44, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least 10.

47. The bispecific protein of any one of claims 37-46, wherein the cells express at least as much ICAM1 on their surface as NCI-H2291 cells.

48. The bispecific protein of any one of claims 37-47, wherein the cells express at least as much CD38 on their surface as NCI-H2342 cells.

49. The bispecific protein of any one of claims 37-48, wherein the cells express less CD38 on their surface than Daudi cells.

50. The bispecific protein of any one of claims 37-49, wherein the ratio of ICAM1 to CD38 on the surface of the cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raji cells.

51. The bispecific protein of any one of claims 1-50, wherein the bispecific protein induces an enhanced CDC effect on the target cells expressing CD38 and ICAM1 compared to the complement dependent cytotoxicity (CDC) effect on the target cells induced by a monospecific protein comprising the first component that specifically binds to CD38 or the second component that specifically binds to ICAM1.

52. The bispecific protein of claim 51, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200.

53. The bispecific protein of claim 51, wherein the ratio of ICAM1 to CD38 on the surface of the cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raji cells.

54. The bispecific protein of any one of claims 1-53, wherein the bispecific protein induces an enhanced apoptotic effect on the target cells expressing CD38 and ICAM1 compared to the apoptotic effect on the target cells induced by a monospecific protein comprising the first component that specifically binds to CD38 or the second component that specifically binds to ICAM1.

55. The bispecific protein of claim 54, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200.

56. The bispecific protein of claim 54, wherein the ratio of ICAM to CD38 on the surface of the cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raji cells.

57. The bispecific protein of any one of claims 1-56, wherein the bispecific protein has reduced ability to kill natural killer (NK) cells in a fresh peripheral blood mononuclear cell population compared to a monospecific protein comprising the first component that specifically binds to CD38 or the second component that specifically binds to ICAM1.

58. The bispecific protein of any one of claims 1-57, wherein the first component has a K of 0.15 nM to 64 nM as determined by surface plasmon resonance. D Binds to human CD38.

59. The bispecific protein of claim 58, wherein the first component has a K of 0.42 nM to 13.14 nM as determined by surface plasmon resonance. D Binds to human CD38.

60. The bispecific protein of claim 58, wherein the first component has a K of 0.15 nM to 0.45 nM as determined by surface plasmon resonance. D Binds to human CD38.

61. The bispecific protein of any one of claims 1-60, wherein the second component has a K of 0.2 nM to 24.4 nM as determined by surface plasmon resonance. D Binds to human ICAM1.

62. The bispecific protein of claim 61, wherein the second component has a K of 0.2 nM to 0.6 nM as determined by surface plasmon resonance. D Binds to human ICAM1.

63. A pharmaceutical composition comprising the bispecific protein according to any one of claims 1-62.

64. The pharmaceutical composition of claim 63, further comprising a pharmaceutically acceptable carrier, excipient or any combination thereof.

65. Use of a bispecific protein or a pharmaceutical composition in the preparation of a medicament for killing cells of a subject in need thereof, wherein the bispecific protein is a bispecific protein according to any one of claims 1-62, and the pharmaceutical composition is a pharmaceutical composition according to claim 63 or 64, wherein the cells express CD38 and ICAM1, wherein the cells are cells from multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer or prostate cancer.

66. The use according to claim 65, wherein the cells are lysed.

67. Use of a bispecific protein or a pharmaceutical composition in the preparation of a medicament for treating cancer in a subject in need thereof, wherein the bispecific protein is the bispecific protein according to any one of claims 1-62, and the pharmaceutical composition is the pharmaceutical composition according to claim 63 or 64, wherein the cancer comprises cells expressing CD38 and ICAM1, wherein the cancer is selected from the group consisting of: multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, lung cancer and prostate cancer.

68. The use according to any one of claims 65-67, wherein the cells express at least as much ICAM1 on their surface as NCI-H2291 cells.

69. The use of claim 68, wherein the cells express at least as much CD38 on their surface as NCI-H2342 cells.

70. The use according to any one of claims 65-69, wherein the cells express less CD38 on their surface compared to Daudi cells.

71. The use according to claim 70, wherein the amount of CD38 on the surface of the cells is less than or equal to the amount of CD38 on the surface of Raji cells.

72. The use according to any one of claims 65-71, wherein the ratio of ICAM1 to CD38 on the surface of the cell is greater than the ratio of ICAM1 to CD38 on the surface of a Daudi cell.

73. The use according to claim 72, wherein the ratio of ICAM1 to CD38 on the surface of the cells is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raji cells.

74. The use according to any one of claims 65-73, wherein the cell expresses at least 5000, 10000, 15000, 20000, 30000, 50000, 100000, 150000, 200000, 250000, 300000, 400000 or 500000 ICAM1 proteins on its surface.

75. The use according to claim 74, wherein the cell expresses at least 50,000 ICAM1 proteins on its surface.

76. The use of any one of claims 65-75, wherein the cell expresses at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000 or 5000 CD38 proteins on its surface.

77. The use according to claim 76, wherein the cell expresses at least 300 CD38 proteins on its surface.

78. The use of claim 76 or 77, wherein the cell expresses less than 350,000, 300,000, 250,000, 200,000, 150,000, 100,000, 50,000, 30,000, 20,000, 15,000, 10,000 or 5,000 CD38 proteins on its surface.

79. The use of claim 78, wherein the cell expresses less than 350,000 CD38 proteins on its surface.

80. The use of any one of claims 65-79, wherein the ratio of ICAM1 to CD38 on the surface of the cells is at least 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100 or 200.

81. The use according to claim 80, wherein the ratio of ICAM1 to CD38 on the surface of the cells is at least 1.

82. The use according to claim 80, wherein the ratio of ICAM1 to CD38 on the surface of the cells is at least 10.

83. The use according to any one of claims 65-82, wherein an additional therapeutic agent is administered.

84. The use of claim 83, wherein the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapeutic agent, a hormone-based therapeutic agent, a stem cell-based therapeutic agent, or radiation.

85. The use according to claim 84, wherein the additional therapeutic agent comprises at least one of lenalidomide, dexamethasone, bortezomib, or any combination thereof.

86. The use of any one of claims 83-85, wherein the additional therapeutic agent and the bispecific protein are administered simultaneously.

87. The use of any one of claims 83-85, wherein the additional therapeutic agent and the bispecific protein are administered sequentially.

88. The use according to any one of claims 83-87, wherein the subject has received previous treatment.

89. The use of claim 88, wherein the previous treatment comprises proteasome inhibitor (PI) therapy and an immunomodulator.

90. The use of any one of claims 83-89, wherein the subject is doubly refractory to a therapy comprising a proteasome inhibitor (PI) therapy and an immunomodulatory agent.

91. The use according to any one of claims 83-90, wherein the subject is a human.

92. A kit comprising the bispecific protein of any one of claims 1-62 or the pharmaceutical composition of claim 63 or 64.

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