CD38 and ICAM1 antibodies and uses thereof

Abstract

The present application relates to CD38 and ICAM1 antibodies and uses thereof. 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. Also disclosed herein, in certain embodiments, 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

This application is a divisional application of the application with the filing date of November 15, 2019, application number 201980089423.6, and invention title "CD38 and ICAM1 Antibodies and Their Uses". Cross-reference

[0001] This application claims the benefit of U.S. Provisional Application No. 62 / 768,566, filed on November 16, 2018, which is hereby incorporated by reference in its entirety. Sequence Listing

[0002] This application contains a sequence listing that has been submitted electronically in ASCII format, which is hereby incorporated by reference in its entirety. The ASCII copy was created on November 14, 2019, named 55429-701_601_SL.txt, and is 590,037 bytes in size. BACKGROUND OF THE INVENTION

[0003] 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 adult multiple myeloma. Reduced CD38 expression can limit the efficacy of anti-CD38 antibodies. Suggestions for overcoming this limitation include treating with antibodies that have a higher affinity for CD38, treating with antibodies that bind to different epitopes on CD38, treating with antibodies that more effectively inhibit the enzymatic activity of CD38, treating with tetravalent anti-CD38 antibodies, and treating with all-trans retinoic acid simultaneously to increase CD38 expression. Incorporation by reference

[0004] All publications, patents, and patent applications herein are incorporated by reference to the extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. If a term in this application conflicts with a term in the incorporated reference, the term in this application shall control. SUMMARY OF THE INVENTION

[0005] One embodiment provides a multispecific protein that comprises a first moiety that specifically binds to CD38 and a second moiety that specifically binds to ICAM1. In some embodiments, the multispecific protein is bivalent, trivalent, or tetravalent. In some embodiments, the first moiety comprises an antibody or an antigen-binding fragment thereof that specifically binds to CD38. In some embodiments, the second moiety comprises an antibody or an 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 a variable domain of an IgG heavy chain and a variable domain of an IgG light chain. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to ICAM1 comprises a variable domain of an IgG heavy chain and a 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 Fc receptors.

[0006] In some embodiments, provided are multispecific proteins, 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 the position corresponding to position N297 of human IgG1, wherein the 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 the 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. In some embodiments, a heterodimeric Fc region, wherein the heterodimeric Fc region comprises a knob chain and a hole chain, and 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, an antibody or antigen-binding fragment thereof that specifically binds to CD38 comprises an anti-CD38 IgG, and an 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.

[0007] 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, 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. 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 one variable heavy chain domain (VH) and one variable light chain domain (VL), and wherein the monovalent anti-ICAM1 antibody or antigen-binding fragment thereof comprises one variable heavy chain domain (VH).

[0008] 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, the heavy chain comprising complementarity 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 the sequences of the following group: CDR1:CDR2:CDR3 (SEQ ID No.1:SEQ ID No:2:SEQ ID No.3); CDR1:CDR2:CDR3 (SEQ ID No.4:SEQ ID No.5:SEQ ID No.3); CDR1:CDR2:CDR3 (SEQ ID No.6:SEQ ID No.2:SEQ ID No.7); CDR1:CDR2:CDR3 (SEQ ID No.1:SEQ ID No.2:SEQ ID No.7); CDR1:CDR2:CDR3 (SEQ ID No.4:SEQ ID No.5:SEQ ID No.7); CDR1:CDR2:CDR3 (SEQ ID No.4:SEQ ID No.2:SEQ ID No.7); CDR1:CDR2:CDR3 (SEQ ID No.6:SEQ ID No.2:SEQ ID No.3); CDR1:CDR2:CDR3 (SEQ ID No.8:SEQ ID No.5:SEQ ID No.3); CDR1:CDR2:CDR3 (SEQ ID No.9:SEQ ID No.2:SEQ ID No.10); CDR1:CDR2:CDR3 (SEQ ID No.11:SEQ ID No.12:SEQ ID No.13); CDR1:CDR2:CDR3 (SEQ ID No.14:SEQ ID No.15:SEQ ID No.16); CDR1:CDR2:CDR3 (SEQ ID No.17:SEQ ID No.18:SEQ ID No.19); CDR1:CDR2:CDR3 (SEQ ID No.20:SEQ ID No.21:SEQ ID No.22); CDR1:CDR2:CDR3 (SEQ ID No.23:SEQ ID No.24:SEQ ID No.25); CDR1:CDR2:CDR3 (SEQ ID No.26:SEQ ID No.27:SEQ ID No.28); CDR1:CDR2:CDR3 (SEQ ID No.29:SEQ ID No.30:SEQ ID No.31); CDR1:CDR2:CDR3 (SEQ ID No.32:SEQ ID No.33:SEQ ID No.34); CDR1:CDR2:CDR3 (SEQ ID No.35:SEQ ID No.36:SEQ ID No.37); CDR1:CDR2:CDR3 (SEQ ID No.38:SEQ ID No.39:SEQ ID No.40); CDR1:CDR2:CDR3 (SEQ ID No.41:SEQ ID No.42:SEQ ID No.43); CDR1:CDR2:CDR3 (SEQ ID No.44:SEQ ID No.45:SEQ ID No.46); CDR1:CDR2:CDR3 (SEQ ID No.47:SEQ ID No.48:SEQ ID No.49); CDR1:CDR2:CDR3 (SEQ ID No.50:SEQ ID No.51:SEQ ID No.52); CDR1:CDR2:CDR3 (SEQ ID No.53:SEQ ID No.54:SEQ ID No.55); CDR1:CDR2:CDR3 (SEQ ID No.56:SEQ ID No.57:SEQ ID No.58); and CDR1:CDR2:CDR3 (SEQ ID No.59:SEQ ID No.60:SEQ ID No.61).

[0009] In some embodiments, CDR1, CDR2, and CDR3 of the heavy chain of the first component comprise sequences of the following sets: CDR1:CDR2:CDR3 (SEQ ID No.14:SEQ ID No.15:SEQ ID No.16). In some embodiments, CDR1, CDR2, and CDR3 of the heavy chain of the first component comprise sequences of the following sets: CDR1:CDR2:CDR3 (SEQ ID No.17:SEQ ID No.18:SEQ ID No.19). In some embodiments, CDR1, CDR2, and CDR3 of the heavy chain of the first component comprise the following sequences: 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, and the light chain comprises complementarity-determining regions CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 of the light chain comprise sequences selected from the group consisting of the sequences of the following sets: CDR1:CDR2:CDR3 (SEQ ID No.62:SEQ ID No:63:SEQ ID No.64); CDR1:CDR2:CDR3(SEQ ID No.65:SEQ ID No.66:SEQ ID No.67); CDR1:CDR2:CDR3(SEQ ID No.68:SEQ ID No.69:SEQ ID No.70); CDR1:CDR2:CDR3(SEQ ID No.71:SEQ ID No.72:SEQ ID No.73); CDR1:CDR2:CDR3(SEQ ID No.74:SEQ ID No.75:SEQ ID No.76); CDR1:CDR2:CDR3(SEQ ID No.77:SEQ ID No.78:SEQ ID No.79); CDR1:CDR2:CDR3(SEQ ID No.80:SEQ ID No.81:SEQ ID No.82); CDR1:CDR2:CDR3(SEQ ID No.83:SEQ ID No.84:SEQ ID No.85); CDR1:CDR2:CDR3(SEQ ID No.86:SEQ ID No.78:SEQ ID No.87); CDR1:CDR2:CDR3(SEQ ID No.86:SEQ ID No.78:SEQ ID No.88); CDR1:CDR2:CDR3(SEQ ID No.89:SEQ ID No.90:SEQ ID No.91); CDR1:CDR2:CDR3(SEQ ID No.92:SEQ ID No.78:SEQ ID No.93); CDR1:CDR2:CDR3(SEQ ID No.94:SEQ ID No.84:SEQ ID No.95); CDR1:CDR2:CDR3(SEQ ID No.96:SEQ ID No.81:SEQ ID No.97); CDR1:CDR2:CDR3(SEQ ID No.98:SEQ ID No.99:SEQ ID No.100); CDR1:CDR2:CDR3 (SEQ ID No.77:SEQ ID No.72:SEQ ID No.101); and CDR1:CDR2:CDR3 (SEQ ID No.102:SEQ ID No.84:SEQ ID No.103).

[0010] In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the first component comprise the sequences of any one of the following groups: 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 sequences of any one of the following groups: 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 sequences of any one of the following groups: CDR1:CDR2:CDR3 (SEQ ID No.62:SEQ ID No.63:SEQ ID No.64).

[0011] In some embodiments, the first component comprises six CDRs, and the six CDRs comprise the sequences shown in any one of the following groups of sequences: 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); 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); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID No.6:SEQ ID No:2:SEQ IDNo.7)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64); 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); 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); 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); 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); 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); 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); 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); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.11:SEQ ID No:12:SEQ ID No.13)-(SEQ ID No.65:SEQ ID No:66:SEQ ID No.67); 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); 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); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.20:SEQ ID No:21:SEQ ID No.22)-(SEQ ID No.74:SEQ ID No:75:SEQ ID No.76); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.23:SEQ ID No:24:SEQ ID No.25)-(SEQ ID No.77:SEQ ID No:78:SEQ ID No.79); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.26:SEQ ID No:27:SEQ ID No.28)-(SEQ ID No.80:SEQ ID No:81:SEQ ID No.82); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.29:SEQ ID No:30:SEQ ID No.31)-(SEQ ID No.83:SEQ ID No:84:SEQ ID No.85); 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); 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); 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); 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); 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); 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); 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); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.53:SEQ ID No:54:SEQ ID No.55)-(SEQ ID No.77:SEQ ID No:72:SEQ ID No.101); and HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.56:SEQ ID No:57:SEQ ID No.58)-(SEQ ID No.102:SEQ ID No:84:SEQ ID No.103).

[0012] In some embodiments, the first component comprises six CDRs, and the six CDRs comprise the sequences of the following group: 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, and the six CDRs comprise one of the sequences 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).

[0013] In some embodiments, the second component that specifically binds to ICAM1 comprises a heavy chain, and the heavy chain comprises complementarity determining regions CDR1, CDR2, and CDR3, wherein the CDR1, CDR2, and CDR3 of the heavy chain comprise sequences selected from the group consisting of the sequences of the following group: CDR1:CDR2:CDR3(SEQ ID No.208:SEQ ID No.209:SEQ ID No.210); CDR1:CDR2:CDR3 (SEQ ID No. 211:SEQ ID No. 212:SEQ ID No. 213); CDR1:CDR2:CDR3 (SEQ ID No. 214:SEQ ID No. 215:SEQ ID No. 216); CDR1:CDR2:CDR3 (SEQ ID No. 217:SEQ ID No. 218:SEQ ID No. 219); CDR1:CDR2:CDR3 (SEQ ID No. 214:SEQ ID No. 220:SEQ ID No. 221); CDR1:CDR2:CDR3 (SEQ ID No. 222:SEQ ID No. 223:SEQ ID No. 224); CDR1:CDR2:CDR3 (SEQ ID No. 225:SEQ ID No. 223:SEQ ID No. 224); CDR1:CDR2:CDR3 (SEQ ID No. 222:SEQ ID No. 223:SEQ ID No. 226); CDR1:CDR2:CDR3 (SEQ ID No. 222:SEQ ID No. 227:SEQ ID No. 224); CDR1:CDR2:CDR3 (SEQ ID No. 228:SEQ ID No. 229 SEQ ID No. 230); CDR1:CDR2:CDR3 (SEQ ID No. 228:SEQ ID No. 220:SEQ ID No. 231); CDR1:CDR2:CDR3 (SEQ ID No. 232:SEQ ID No. 229:SEQ ID No. 233); CDR1:CDR2:CDR3 (SEQ ID No. 208:SEQ ID No. 234:SEQ ID No. 210); CDR1:CDR2:CDR3 (SEQ ID No. 235:SEQ ID No. 236:SEQ ID No. 237); CDR1:CDR2:CDR3 (SEQ ID No. 238:SEQ ID No. 239 SEQ ID No. 240); CDR1:CDR2:CDR3 (SEQ ID No.241:SEQ ID No.242:SEQ ID No.243); CDR1:CDR2:CDR3 (SEQ ID No.241:SEQ ID No.244:SEQ ID No.245); CDR1:CDR2:CDR3 (SEQ ID No.241:SEQ ID No.246:SEQ ID No.245); CDR1:CDR2:CDR3 (SEQ ID No.247:SEQ ID No.248:SEQ ID No.249); CDR1:CDR2:CDR3 (SEQ ID No.250:SEQ ID No.251:SEQ ID No.252); and CDR1:CDR2:CDR3 (SEQ ID No.404:SEQ ID No.405:SEQ ID No.406).

[0014] In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the second component comprise the following sequences: (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 sequences: 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 a sequence from the following group: 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 a sequence from the following group: CDR1:CDR2:CDR3 (SEQ ID No.404:SEQ ID No.405:SEQ ID No.406).

[0015] In some embodiments, the second component that specifically binds to ICAM1 comprises a light chain, and the light chain comprises 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 the following groups: CDR1:CDR2:CDR3 (SEQ ID No.253:SEQ ID No.254:SEQ ID No.255); CDR1:CDR2:CDR3 (SEQ ID No.256:SEQ ID No.257:SEQ ID No.258); CDR1:CDR2:CDR3 (SEQ ID No.259:SEQ ID No.260:SEQ ID No.261); CDR1:CDR2:CDR3 (SEQ ID No.262:SEQ ID No.263:SEQ ID No.264); CDR1:CDR2:CDR3 (SEQ ID No.265:SEQ ID No.260:SEQ ID No.266); CDR1:CDR2:CDR3 (SEQ ID No.267:SEQ ID No.263:SEQ ID No.264); CDR1:CDR2:CDR3 (SEQ ID No.268:SEQ ID No.263:SEQ ID No.264); CDR1:CDR2:CDR3 (SEQ ID No.269:SEQ ID No.263:SEQ ID No.264); CDR1:CDR2:CDR3 (SEQ ID No.270:SEQ ID No.260:SEQ ID No.271); CDR1:CDR2:CDR3 (SEQ ID No.272:SEQ ID No.260:SEQ ID No.266); CDR1:CDR2:CDR3 (SEQ ID No.259:SEQ ID No.273:SEQ ID No.266); CDR1:CDR2:CDR3 (SEQ ID No.274:SEQ ID No.275:SEQ ID No.276); CDR1:CDR2:CDR3 (SEQ ID No.277:SEQ ID No.275:SEQ ID No.278); CDR1:CDR2:CDR3 (SEQ ID No.279:SEQ ID No.280:SEQ ID No.281); CDR1:CDR2:CDR3 (SEQ ID No.282:SEQ ID No.283:SEQ ID No.284); CDR1:CDR2:CDR3 (SEQ ID No.62:SEQ ID No.63:SEQ ID No.64); and CDR1:CDR2:CDR3 (SEQ ID No.407:SEQ ID No.408:SEQ ID No.409).

[0016] In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the second component comprise the sequences of the following groups: 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 sequences of the following groups: 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 sequences of the following groups: 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 the sequences of the following groups: (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, and the six CDRs comprise a set of sequences selected from the group consisting of: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID No.208:SEQ ID No:209:SEQ ID No.210)-(SEQ ID No.253:SEQ ID No:254:SEQ ID No.255); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID No.211:SEQ ID No:212:SEQ ID No.213)-(SEQ ID No.256:SEQ ID No:257:SEQ ID No.258); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.214:SEQ ID No:215:SEQID No.216)-(SEQ ID No.259:SEQ IDNo:260:SEQ ID No.261); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.217:SEQ ID No:218:SEQID No.219)-(SEQ ID No.262:SEQ IDNo:263:SEQ ID No.264); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.214:SEQ ID No:220:SEQID No.221)-(SEQ ID No.265:SEQ IDNo:260:SEQ ID No.266); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.222:SEQ ID No:223:SEQID No.224)-(SEQ ID No.267:SEQ IDNo:263:SEQ ID No.264); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.225:SEQ ID No:223:SEQID No.224)-(SEQ ID No.268:SEQ IDNo:263:SEQ ID No.264); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.222:SEQ ID No:223:SEQID No.226)-(SEQ ID No.268:SEQ IDNo:263:SEQ ID No.264); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.222:SEQ ID No:227:SEQID No.224)-(SEQ ID No.269:SEQ IDNo:263:SEQ ID No.264); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.228:SEQ ID No:229:SEQID No.230)-(SEQ ID No.270:SEQ IDNo:260:SEQ ID No.271); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.228:SEQ ID No:220:SEQID No.231)-(SEQ ID No.272:SEQ IDNo:260:SEQ ID No.266); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.232:SEQ ID No:229:SEQID No.233)-(SEQ ID No.259:SEQ IDNo:273:SEQ ID No.266); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.208:SEQ ID No:234:SEQID No.210)-(SEQ ID No.274:SEQ IDNo:275:SEQ ID No.276); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.208:SEQ ID No:234:SEQID No.210)-(SEQ ID No.277:SEQ IDNo:275:SEQ ID No.278); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.235:SEQ ID No:236:SEQID No.237)-(SEQ ID No.279:SEQ IDNo:280:SEQ ID No.281); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.238:SEQ ID No:239:SEQID No.240)-(SEQ ID No.282:SEQ IDNo:283:SEQ ID No.284); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.241:SEQ ID No:244:SEQID No.245)-(SEQ ID No.62:SEQ IDNo:63:SEQ ID No.64); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.241:SEQ ID No:246:SEQID No.245)-(SEQ ID No.62:SEQ IDNo:63:SEQ ID No.64); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.247:SEQ ID No:248:SEQID No.249)-(SEQ ID No.62:SEQ IDNo:63:SEQ ID No.64); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.250:SEQ ID No:251:SEQID No.252)-(SEQ ID No.62:SEQ IDNo:63:SEQ ID No.64); and HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.404:SEQ ID No.405:SEQID No.406)-(SEQ ID No.407:SEQ IDNo:408:SEQ ID No.409).

[0017] In some embodiments, the second component comprises six CDRs, and the six CDRs comprise 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, and the six CDRs comprise 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, and the six CDRs comprise the following sequences: 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, and the six CDRs comprise the sequences 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 having at least about 90% identity 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 having at least about 90% identity 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 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 its 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 that comprises a light chain and a heavy chain, wherein the heavy chain comprises a sequence having at least about 90% identity to a sequence selected from the group consisting of SEQ ID Nos. 156 - 181. In some embodiments, the light chain comprises a sequence having at least about 90% identity 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 that comprises a light chain and a heavy chain, wherein the heavy chain comprises a sequence having at least about 90% identity to a sequence selected from the group consisting of SEQ ID Nos. 328 - 349. In some embodiments, the light chain comprises a sequence having at least about 90% identity to a sequence selected from the group consisting of SEQ ID Nos. 183 and 350 - 366.

[0018] One embodiment provides a multispecific protein comprising a heavy chain polypeptide (HC) comprising VH and a light chain polypeptide (LC) comprising VL, wherein the heavy chain polypeptide and the light chain polypeptide comprise a sequence having at least about 90% identity to a sequence selected from the group consisting of: HC:LC (SEQ ID No. 160:SEQ ID No. 397); HC:LC (SEQ ID No. 389:SEQ ID No. 186); HC:LC (SEQ ID No. 163:SEQ ID No. 395); HC:LC (SEQ ID No. 387:SEQ ID No. 189); HC:LC (SEQ ID No. 164:SEQ ID No. 396); HC:LC (SEQ ID No. 388:SEQ ID No. 190); HC:LC (SEQ ID No. 156:SEQ ID No. 393); HC:LC (SEQ ID No. 384:SEQ ID No. 182); HC:LC (SEQ ID No. 385:SEQ ID No. 182); and HC:LC (SEQ ID No. 386:SEQ ID No. 394).

[0019] 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 having at least about 90% identity to sequences selected from the group consisting of the sequences: HC1:LC:HC2 (SEQ ID No.391:SEQ ID No.186:SEQ ID No.383); HC1:LC:HC2 (SEQ ID No.392:SEQ ID No.190:SEQ ID No.383); and HC1:LC:HC2 (SEQ ID No.156:SEQ ID No.182:SEQ ID No.383).

[0020] 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 having at least about 90% identity to sequences selected from the group consisting of the sequences: HC1:LC1:HC2:HC3 (SEQ ID No.390:SEQ I No.189:SEQ ID No.348:SEQ IDNo.189); HC1:LC1:HC2:HC3 (SEQ ID No.390:SEQ ID No.189:SEQ ID No.349:SEQ IDNo.189); HC1:LC1:HC2:HC3 (SEQ ID No.391:SEQ ID No.186:SEQ ID No.348:SEQ IDNo.186); and HC1:LC1:HC2:HC3 (SEQ ID No.391:SEQ ID No.186:SEQ ID No.349:SEQ IDNo.186).

[0021] One embodiment provides a multispecific protein comprising a heavy chain sequence having at least about 95% identity to the sequence shown in SEQ ID No.410 and a light chain sequence having at least about 95% identity to the sequence shown in SEQ ID No.411.

[0022] In some embodiments, the heavy chain comprises CDR1, CDR2, and CDR3, wherein CDR1 has the sequence of SEQ ID No. 412 (GFSLSZ1Z2AMG), CDR2 has the sequence of SEQ ID No. 413 (GIIGSSZ3Z4TYYAZ5WAKG), and CDR3 has the sequence of SEQ ID No. 414 (VRDPYDSZ6Z7Z8Z9YRL). In some embodiments, the light chain comprises CDR1, CDR2, and CDR3, wherein CDR1 has the sequence of SEQ ID No. 415 (QASZ 10 Z 11 IYZ 12 YZ 13 Z 14 ), CDR2 has the sequence of SEQ IDNo. 416 (DASKZ 15 AS), and CDR3 has the sequence of 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 glutamic acid; 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 is valine or alanine.

[0023] In some embodiments, the multispecific protein induces an enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effect on target cells as compared to the ADCC effect on target cells induced by other multispecific proteins that are otherwise identical but do not comprise a fucose-free Fc region.

[0024] In some embodiments, the multispecific protein induces an enhanced ADCC effect on target cells compared to the ADCC effect on target cells induced by other otherwise identical multispecific proteins that do not contain an Fc region, the Fc region comprising mutations 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.

[0025] In some embodiments, the amount of the multispecific protein that binds to cells expressing CD38 and ICAM1 is higher than the amount of the monospecific protein comprising a first component that binds to CD38 that binds to the cells, wherein the binding to the cells is measured by flow cytometry. In some embodiments, the multispecific protein induces an enhanced ADCC effect on target cells 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 multispecific protein induces an enhanced CDC effect on target cells as 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 as 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 5000, 10000, 15000, 20000, 30000, 50000, 100000, 150000, 200000, 250000, 300000, 400000, or 500000 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 350000, 300000, 250000, 200000, 150000, 100000, 50000, 30000, 20000, 15000, 10000, or 5000 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 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 compared to 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 complement-dependent cytotoxicity (CDC) effect on target cells expressing CD38 and ICAM1 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 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 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. In some embodiments, the multispecific protein has a reduced ability to kill NK (natural killer) cells in a fresh peripheral blood mononuclear cell population 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. DBinds to human CD38. In some embodiments, the first component has a K of from about 0.42 nM to about 13.14 nM as determined by surface plasmon resonance D Binds to human CD38. In some embodiments, the first component has a K of from about 0.15 nM to about 0.45 nM as determined by surface plasmon resonance D Binds to human CD38. In some embodiments, the second component has a K of from about 0.2 nM to about 24.4 nM as determined by surface plasmon resonance D Binds to human ICAM1. In some embodiments, the second component has a K of from about 0.2 nM to about 0.6 nM as determined by surface plasmon resonance D Binds to human ICAM1.

[0026] One embodiment provides a pharmaceutical composition comprising the multispecific protein of the present disclosure. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or any combination thereof.

[0027] One embodiment provides a method of killing a cell of a subject, comprising administering to the subject the multispecific protein of the present disclosure or the pharmaceutical composition of the present disclosure, wherein the cell expresses CD38 and ICAM1. In some embodiments, the cell is lysed. In some embodiments, the cell is a tumor cell. One embodiment provides a method of treating cancer in a subject, comprising administering to the subject the multispecific protein of the present disclosure or the pharmaceutical composition of the present 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 lymphoma, or Hodgkin lymphoma. In some embodiments, the cancer is lung cancer or prostate cancer. 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 compared to Daudi cells. 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 Raji cells. 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 Daudi cells.

[0028] 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 5000, 10000, 15000, 20000, 30000, 50000, 100000, 150000, 200000, 250000, 300000, 400000, or 500000 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 350000, 300000, 250000, 200000, 150000, 100000, 50000, 30000, 20000, 15000, 10000, or 5000 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 prior treatment. In some embodiments, the prior treatment comprises proteasome inhibitor (PI) therapy and an immunomodulatory agent. In some embodiments, the subject is doubly refractory to a therapy comprising proteasome inhibitor (PI) therapy and an immunomodulatory agent. In some embodiments, the subject is a human. One embodiment provides a kit comprising the multispecific protein according to the present disclosure or a pharmaceutical composition comprising the same.

[0029] In certain embodiments, anti-CD38 antibodies, anti-ICAM1 antibodies, pharmaceutical compositions comprising anti-CD38 antibodies and / or anti-ICAM1 antibodies, and methods for treating proliferative diseases are disclosed herein. In certain embodiments, 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 are also disclosed herein.

[0030] In certain embodiments, a bispecific antibody is disclosed herein that comprises a first targeting moiety that specifically binds to CD38 or ICAM1 and has an enhanced complement-dependent cytotoxicity (CDC) effect compared to the CDC effect of the reference antibody daratumumab. In certain embodiments, a bispecific antibody is also described herein that comprises a first targeting moiety that specifically binds to CD38 or ICAM1 and has an enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effect compared to the ADCC effect of the reference antibody daratumumab. In certain embodiments, a bispecific antibody is additionally described herein that comprises a first targeting moiety 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 moiety that specifically binds to CD38 or ICAM1. In some embodiments, the enhanced CDC is at least 2-fold, 3-fold, 4-fold, or higher than 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 higher 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 higher 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 higher 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 higher 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 a 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 a binding fragment thereof. 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 D。In 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 from 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 apoptosis induced by the bispecific antibody is 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: 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 is 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 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 ; wherein X 13 is selected from A, G or S; X 14 is selected from I, F, Y, V, S or C; X 15 is selected from S, I, L, T or M; X 16 is selected from G, Y, S, T, L or V; X 17 is selected from S, I, K, Y, T, G or A; X 18 is selected from G, S, T, P, V or Y; X 19 is selected from G, A, D, S or T; X 20 is selected from S, T, I, N or G; X 21 is selected from T, I, D, N, S or A; X 22 is selected from F, Y, N, T, I or S; X 23 is selected from Y, D, K or I; X 24 is selected from A or Y; X 25 is selected from D, T, S, N, R, A or Y; X 26 is selected from S, W, T, A or N; X 27 is selected from V, A, W, N or S; X 28 is selected from K, R, Q, A or W; X 29 is selected from G, K or A; X 30 is present or absent, and if present, is selected from G or K; X 31 is present or absent, and if present, is G; and the 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 wherein X 32 is selected from A, G or V; X 33 is 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, and if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, and if present, selected from P, L, Y, F, G or T; X 43 Present or absent, and if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, and if present, selected from G, L, S, T or F; X 45 Present or absent, and if present, selected from F, L, E, N or S; X 46 Present or absent, and if present, selected from D, S, L or R; X 47 Present or absent, and if present, selected from Y or L; X 48 Present or absent, and if present, it is D; and X49 is present or absent, and if present, it is L. In some embodiments, the VH region comprises the CDR1 sequence GFPFX5X6YAMS, wherein X5 is selected from D or G; X6 is selected from V, A or T. In some embodiments, the VH region comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 ; wherein X1 is present or absent, and if present, it 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, and if present, selected from C or M; and X 12 Present or absent, and if present, it is 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 is present or absent, and if present, is 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 is 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. In some embodiments, the VH region comprises the CDR2 sequence AISGSGGSTX 22 YADSVKG, wherein X 22 is selected from F or Y. In some embodiments, the VH region comprises the 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 ; wherein X 13 is selected from A, G or S; X 14 is selected from I, F, Y, V, S or C; X 15 is selected from I, L, M or T; X 16 is selected from G, Y, S, T, L or V; X 17 is selected from S, I, K, Y, T, G or A; X 18 is selected from G, S, T, P or V; X 19 is selected from G, A, D, S or T; X 20 is selected from S, T, I, N or G; X 21 is selected from T, I, D, N, S or A; X 22 is selected from Y, N, T, I or S; X 23 is 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 Present or absent, if present, selected from G or K; and X 31 Present or absent, if present, it is G. In some embodiments, the VH region comprises the 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 ; wherein 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 Selected from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Selected from W or T; X 27 Selected from A or W; X 28 Selected from K, R, Q or A; X 29 Selected from G or K; and X 30 Present or absent, if present, it is G. In some embodiments, the VH region comprises the 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 ; wherein X 13 is selected from A or S; X 15 is selected from I, L or T; X 16 is selected from Y or V; X 17 is selected from S, T or A; X 18 is selected from G, P or V; X 19 is selected from D, S or T; X 20 is selected from S, T or G; X 21 is selected from D, N, S or A; X 22 is selected from T, I or S; X 23 is selected from Y, K or I; X 25 is selected from A or Y; X 26 is selected from S, T, A or N; X 27 is selected from W, N or S; X 28 is selected from A or W; X 29 is selected from 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 the CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY, wherein X 38 is selected from A or G; X 41 is selected from F or Y. In some embodiments, the VH region comprises the 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 ; wherein X 32 is selected from A, G or V; X 33 is selected from A, R, T, S or G; X 34 is selected from A, V, T, P, I, E, D or S; X 35 is 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, and if present, selected from V, D, Y, A, N, G, L or E; X 42 Present or absent, and if present, selected from L, Y, F, T or G; X 43 Present or absent, and if present, selected from P, F, V, N, S or Y; X 44 Present or absent, and if present, selected from L, S, T, G or F; X 45 Present or absent, and if present, selected from L, F, E, S or N; and X 46 Present or absent, and if present, selected from S, L or R; X 47 Present or absent, and if present, is L; X 48 Present or absent, and if present, is D; and X 49 Present or absent, and if present, is L. In some embodiments, the VH region comprises the 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 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 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, and if present, selected from P, F, V or N; X 44 Present or absent, and if present, selected from L, S or T; and X 45 Present or absent, and if present, 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 ; wherein X 33 is selected from R or G; X 34 is selected from E, D or S; X 35 is selected from G, L, P, S or A; X 36 is selected from D, S or R; X 37 is selected from Y, T, N or G; X 38 is selected from G, S, F or L; X 39 is selected from A, G, S or I; X 40 is selected from Y, N or L; X 41 Present or absent, and if present, selected from V, Y or E; X 42 Present or absent, and if present, is G; X 43 Present or absent, and if present, is Y; X 44 Present or absent, and if present, is F; X 45 Present or absent, and if present, selected from E or N; and X 46 Present or absent, and 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 the 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 is selected from F or Y; X 38 is selected from A or G; and X 41 is selected from F or Y. In some embodiments, the VH region comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 , the 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 the 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 is selected from T, S or M; X 11 is present or absent, and if present, it is C; X 13 is selected from A or G; X 14 is selected from I, F, Y, V, S or C; X 16 is selected from G, Y, S, T or L; X 17 is selected from S, I, K, Y, T or G; X 18 is selected from G, S or T; X 19 is selected from G, A, D or S; X 20 is selected from T, I, N or G; X 21 is selected from T, I or D; X 22 is selected from Y, N or T; X 23 is selected from Y or D; X 24 is selected from A or Y; X 25 is selected from T, S, N, R or A; X 26 is selected from W or T; X 27 is selected from A or W; X 28 is selected from K, R, Q or A; X 29 is selected from G or K; X 30 is present or absent, and if present, it is G; X 32 is selected from A or G; X 33 is selected from A, R or T; X 34 is selected from A, V, T, P, I, E or D; X 35 is selected from G, W, D, L, K or P; X 36Selected from P, A, Y, D, or G; X 37 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, and if present, selected from P, F, V, or N; X 44 Present or absent, and if present, selected from L, S, or T; and X 45 Present or absent, and if present, selected from L or F. In some embodiments, the VH region comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 、the 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 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 ; 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, and if present, selected from C or M; X 12 Present or absent, and if present, is C; X 13 Selected 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 Selected from A or W; X 29 Selected from K or A; X 30 Present or absent, and if present, selected from G or K; X 31 Present or absent, and if present, 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, and if present, selected from V, Y or E; X 42 Present or absent, and if present, is G; X 43 Present or absent, and if present, is Y; X 44 Present or absent, and if present, is F; X 45 Present or absent, and if present, selected from E or N; and X 46 Present or absent, and if present, selected from S or L. In some embodiments, 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 and 56; a CDR2 sequence selected from 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 is selected from A, G or V; X 33 is selected from K, A, R, T, G or S; X 34 is selected from R, A, V, T, P, I, E, D or S; X 35 is selected from G, W, D, L, K, P, S, A, T or R; X 36 is selected from T, P, A, Y, D, G, S, R, V or E; X 37 is selected from Y, V, T, S, N, A, G, Q, F or I; X 38 is selected from G, A, S, D, K, F, L or Y; X 39 is selected from Y, T, A, G, S or I; X 40 is selected from S, Y, G, R, W, N, L, D or F; X 41 is present or absent, and if present, is selected from F, Y, V, D, A, N, G, E or L; X 42 is present or absent, and if present, is selected from P, L, Y, F, G or T; X 43 is present or absent, and if present, is selected from T, P, F, V, N, Y or S; X 44 is present or absent, and if present, is selected from G, L, S, T or F; X 45 is present or absent, and if present, is selected from F, L, E, N or S; X 46 is present or absent, and if present, is selected from D, S, L or R; X 47 is present or absent, and if present, is selected from Y or L; X 48 is present or absent, and if present, is D; and X 49Present or absent, and if present, is L. In some embodiments, 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, and 56; a CDR2 sequence selected from 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 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 SEQ ID NO: 1, 4, 6, 8, and 9; a CDR2 sequence selected from SEQ ID NO: 2 and 5; and a CDR3 sequence selected from SEQ ID NO: 3, 7, and 10. In some embodiments, 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; a CDR2 sequence selected from 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 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 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 selected from SEQ ID NO: 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NO: 17, 23, 29, 44, and 56; a CDR2 sequence selected from SEQ ID NO: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from SEQ ID NO: 19, 25, 31, 46, and 58.In some embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID 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. In some embodiments, 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, 81, 78, 90, and 99; and a CDR3 sequence selected from SEQ ID NO: 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, 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 SEQ ID NO: 73, 79, 85, 95, and 103. In some embodiments, the first targeting moiety comprises a VH sequence selected from SEQ ID NO: 104 - 128 and a VL sequence selected from SEQ ID NO: 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: 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 ; wherein X 1 is selected from G or E; X 2 is selected from F or Y; X 3 is selected from S or T; X 4 is selected from L, F or S; X 5 is selected from S or N; X 6 is selected from S, N, T or D; X 7 is selected from Y, H or G; X 8 is selected from G, A, Y, W or F; X 9 is selected from M, W, Y or I; X 10 is selected from S, G, N, M or I; and X 11Present or absent, and if present, it is 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 is selected from G, T, A, I or Y; X 13 is selected from W, I, Y or C; X 14 is selected from I, S or Y; X 15 is selected from S, G, T, D or P; X 16 is selected from F, S, D, T or A; X 17 is selected from S, R, G or D; X 18 is selected from G, D or S; X 19 is selected from S, R, T, N, Y, A, D or P; X 20 is selected from T, A, G or Y; X 21 is selected from Y, H, A, S or T; X 22 is selected from Y or N; X 23 is selected from A, P, Y or S; X 24 is selected from S, T, N, D, Y, A or P; X 25 is selected from W, S, A or D; X 26 is selected from A, V, T, W, F or S; X 27 is selected from K, W, A, Q or V; X 28 is selected from G, A or K; X 29 Present or absent, and if present, it is selected from K or G; and X 30 Present or absent, and if present, it is 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 ; wherein X 31 is selected from A or V; X 32 is selected from R or I; X 33 is selected from G, D, P, A or V; X 34 is selected from G, P, W, D, N or R; X 35 is selected from D, Y, S, L, G, F or W; X 36 is selected from Y, D, V, L, S, G or P; X 37 is selected from G, S, D, V or E; X 38 is selected from G, Y, F, S or D; X 39 is selected from S, D, G, T, N, A or V; X 40 is selected from T, A, D, S, Y, L or F; X 41 is present or absent, and if present, is selected from Y, A, G, I or D; X 42 is present or absent, and if present, is selected from I, Y, R, P, V or G; X 43 is present or absent, and if present, is selected from L, R, Y, G or A; X 44 is present or absent, and if present, is selected from N, L, Y, S or W; X 45 is present or absent, and if present, is selected from L, Y, F or C; X 46 is present or absent, and if present, is selected from D, A or F; X 47 is present or absent, and if present, is 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. In some embodiments, the VH region comprises the CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 wherein X 5 is selected from S or N; X 6 is selected from S, N, T or D; X 7 is selected from Y or H; X 8 is selected from G, A or Y; and X 10 is 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, wherein X 13 is selected from W, I or Y; X 15 is selected from S or G; X 16 is selected from F, S, D or T; X 17 is selected from S or R; X 18 is selected from G or D; X 19 is 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 the 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 , wherein X 31 is selected from A or V; X 33 is selected from G or D; X 34 is selected from G, P, W or D; X 35 is selected from D, Y, S or L; X 36 is selected from Y, D, V or L; X 37 is selected from G, S or D; X 38 is selected from G, Y, F or S; X 39 is selected from S, D, G or T; X 40 is selected from T, A, D, S or Y; X 41 is selected from Y, A, G or I; X 42 is selected from I, Y or R; X 43 is selected from L, R, Y or G; X 44 is selected from N, L, Y or S; X 45 is present or absent, and if present, is selected from L, Y or F; X 46 is present or absent, and if present, is D; X 47 is present or absent, and if present, is selected from M or P; X 48 is present or absent, and if present, is D; and X 49Present or absent, and if present, is L. In some embodiments, 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; a CDR2 sequence selected from 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 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 SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; 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. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NO: 241, 247, and 250; a CDR2 sequence selected from SEQ ID NO: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from SEQ ID NO: 243, 245, 249, and 252. In some embodiments, 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. In some embodiments, the second targeting moiety comprises a VH sequence selected from SEQ ID NO: 289 - 309 and a VL sequence selected from SEQ ID NO: 311 - 326 and 155. In some embodiments, the bispecific antibody comprises a humanized antibody or a binding fragment thereof or a chimeric antibody or a binding fragment thereof.In some embodiments, the bispecific antibody comprises IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triple body, mini-antibody, minibody, 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, tetravalent HCAb, scDiabody-Fc, diabody-Fc, tandem scFv-Fc or 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.

[0031] In certain embodiments, anti-CD38 antibodies are disclosed herein that comprise 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 is 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 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 ; wherein X 13 is selected from A, G or S; X 14 is selected from I, F, Y, V, S or C; X 15 is selected from S, I, L, T or M; X 16 is selected from G, Y, S, T, L or V; X 17 is selected from S, I, K, Y, T, G or A; X 18 is selected from G, S, T, P, V or Y; X 19 is selected from G, A, D, S or T; X 20 is selected from S, T, I, N or G; X 21 is selected from T, I, D, N, S or A; X 22 is 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 is selected from D, T, S, N, R, A or Y; X 26 is selected from S, W, T, A or N; X 27 is selected from V, A, W, N or S; X 28 is selected from K, R, Q, A or W; X 29 is selected from G, K or A; X 30 is present or absent, and if present, is selected from G or K; X 31 is present or absent, and if present, is G; and the 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 ; wherein X 32 is selected from A, G or V; X 33 is selected from K, A, R, T, G or S; X 34 is selected from R, A, V, T, P, I, E, D or S; X 35 is selected from G, W, D, L, K, P, S, A, T or R; X 36 is 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, and if present, selected from F, Y, V, D, A, N, G, E or L; X 42 present or absent, and if present, selected from P, L, Y, F, G or T; X 43 present or absent, and if present, selected from T, P, F, V, N, Y or S; X 44 present or absent, and if present, selected from G, L, S, T or F; X 45 present or absent, and if present, selected from F, L, E, N or S; X 46 present or absent, and if present, selected from D, S, L or R; X 47 present or absent, and if present, selected from Y or L; X 48 present or absent, and if present, is D; and X 49 present or absent, and if present, is L. In some embodiments, the VH region comprises the 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 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, and if present, selected from C or M; and X 12 present or absent, and if present, is 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 selected from T, S or M; and X 11Present or absent, and if present, is 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 is 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. In some embodiments, the VH region comprises the CDR2 sequence AISGSGGSTX 22 YADSVKG, wherein X 22 is selected from F or Y. In some embodiments, the VH region comprises the 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 ; wherein X 13 is selected from A, G or S; X14 is selected from I, F, Y, V, S or C; X 15 is selected from I, L, M or T; X 16 is selected from G, Y, S, T, L or V; X 17 is selected from S, I, K, Y, T, G or A; X 18 is selected from G, S, T, P or V; X 19 is selected from G, A, D, S or T; X 20 is selected from S, T, I, N or G; X 21 is selected from T, I, D, N, S or A; X 22 is selected from Y, N, T, I or S; X 23 is selected from Y, D, K or I; X 24 is selected from A or Y; X 25 is selected from T, S, N, R, A or Y; X 26 is selected from S, W, T, A or N; X 27 is 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 Present or absent, and if present, selected from G or K; and X 31 Present or absent, and if present, is G. In some embodiments, the VH region comprises the 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 ; wherein 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 Selected from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Selected from W or T; X 27 Selected from A or W; X 28 Selected from K, R, Q or A; X 29 Selected from G or K; and X 30 Present or absent, and if present, is G. In some embodiments, the VH region comprises the 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 ; wherein X 13 is selected from A or S; X 15 is selected from I, L or T; X 16 is selected from Y or V; X 17 is selected from S, T or A; X 18 is selected from G, P or V; X 19 is selected from D, S or T; X 20 is selected from S, T or G; X 21 is selected from D, N, S or A; X 22 is selected from T, I or S; X 23 is selected from Y, K or I; X 25 is selected from A or Y; X 26 is selected from S, T, A or N; X 27 is selected from W, N or S; X 28 is selected from A or W; X 29 is selected from 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 the CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY, wherein X 38 is selected from A or G; and X 41 is selected from F or Y. In some embodiments, the VH region comprises the 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 ; wherein X 32 is selected from A, G or V; X 33 is selected from A, R, T, S or G; X 34 is selected from A, V, T, P, I, E, D or S; X 35 is selected from G, W, D, L, K, P, S, R or A; X 36 is selected from P, A, Y, D, G, S, R, V, E or T; X 37 is 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, and if present, selected from V, D, Y, A, N, G, L or E; X 42 Present or absent, and if present, selected from L, Y, F, T or G; X 43 Present or absent, and if present, selected from P, F, V, N, S or Y; X 44 Present or absent, and if present, selected from L, S, T, G, F; X 45 Present or absent, and if present, selected from L, F, E, S or N; X 46 Present or absent, and if present, selected from S, L or R; X 47 Present or absent, and if present, is L; X 48 Present or absent, and if present, is D; and X 49 Present or absent, and if present, is L. In some embodiments, the VH region comprises the 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 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 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, and if present, selected from P, F, V or N; X 44 Present or absent, and if present, selected from L, S or T; and X 45Present or absent, and if present, 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 ; wherein X 33 is selected from R or G; X 34 is selected from E, D or S; X 35 is selected from G, L, P, S or A; X 36 is selected from D, S or R; X 37 is selected from Y, T, N or G; X 38 is selected from G, S, F or L; X 39 is selected from A, G, S or I; X 40 is selected from Y, N or L; X 41 Present or absent, and if present, selected from V, Y or E; X 42 Present or absent, and if present, is G; X 43 Present or absent, and if present, is Y; X 44 Present or absent, and if present, is F; X 45 Present or absent, and if present, selected from E or N; and X 46 Present or absent, and 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 the 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 is selected from F or Y; X 38 is selected from A or G; and X 41 is selected from F or Y. In some embodiments, the VH region comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 、the 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 the 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 is selected from T, S or M; X 11 is present or absent, and if present, it is C; X 13 is selected from A or G; X 14 is selected from I, F, Y, V, S or C; X 16 is selected from G, Y, S, T or L; X 17 is selected from S, I, K, Y, T or G; X 18 is selected from G, S or T; X 19 is selected from G, A, D or S; X 20 is selected from T, I, N or G; X 21 is selected from T, I or D; X 22 is selected from Y, N or T; X 23 is selected from Y or D; X 24 is selected from A or Y; X 25 is selected from T, S, N, R or A; X 26 is selected from W or T; X 27 is selected from A or W; X 28 is selected from K, R, Q or A; X 29 is selected from G or K; X 30 is present or absent, and if present, it is G; X 32 is selected from A or G; X 33 is selected from A, R or T; X 34 is selected from A, V, T, P, I, E or D; X 35 is selected from G, W, D, L, K or P; X 36 is selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X 38 is 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, and if present, selected from P, F, V or N; X 44 Present or absent, and if present, selected from L, S or T; and X 45 Present or absent, and if present, selected from L or F. In some embodiments, the VH region comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 , the 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 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 ; 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, and if present, selected from C or M; X 12 Present or absent, and if present, is 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 Selected from A or W; X 29 Selected from K or A; X 30 Present or absent, and if present, selected from G or K; X 31 Present or absent, and if present, 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, and if present, selected from V, Y or E; X 42 Present or absent, and if present, is G; X 43 Present or absent, and if present, is Y; X 44 Present or absent, and if present, is F; X 45 Present or absent, and if present, selected from E or N; and X 46 Present or absent, and if present, selected from S or L. In some embodiments, 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 and 56; a CDR2 sequence selected from 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 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 ; wherein X 32 is selected from A, G or V; X 33 is selected from K, A, R, T, G or S; X 34 is selected from R, A, V, T, P, I, E, D or S; X 35 is selected from G, W, D, L, K, P, S, A, T or R; X 36 is selected from T, P, A, Y, D, G, S, R, V or E; X 37 is selected from Y, V, T, S, N, A, G, Q, F or I; X 38 is selected from G, A, S, D, K, F, L or Y; X 39 is selected from Y, T, A, G, S or I; X 40 is selected from S, Y, G, R, W, N, L, D or F; X 41 is present or absent, and if present, is selected from F, Y, V, D, A, N, G, E or L; X 42 is present or absent, and if present, is selected from P, L, Y, F, G or T; X 43 is present or absent, and if present, is selected from T, P, F, V, N, Y or S; X 44 is present or absent, and if present, is selected from G, L, S, T or F; X 45 is present or absent, and if present, is selected from F, L, E, N or S; X 46 is present or absent, and if present, is selected from D, S, L or R; X 47 is present or absent, and if present, is selected from Y or L; X 48 is present or absent, and if present, is D; and X 49Present or absent, and if present, is L. In some embodiments, 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, and 56; a CDR2 sequence selected from 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 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 SEQ ID NO: 1, 4, 6, 8, and 9; a CDR2 sequence selected from SEQ ID NO: 2 and 5; and a CDR3 sequence selected from SEQ ID NO: 3, 7, and 10. In some embodiments, 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; a CDR2 sequence selected from 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 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 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 selected from SEQ ID NO: 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NO: 17, 23, 29, 44, and 56; a CDR2 sequence selected from SEQ ID NO: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from SEQ ID NO: 19, 25, 31, 46, and 58.In some embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID 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. In some embodiments, 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, 81, 78, 90, and 99; and a CDR3 sequence selected from SEQ ID NO: 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, 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 SEQ ID NO: 73, 79, 85, 95, and 103. In some embodiments, the anti-CD38 antibody comprises a VH sequence selected from SEQ ID NO: 104 - 128 and a VL sequence selected from SEQ ID NO: 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: 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 ; wherein X 1 is selected from G or E; X 2 is selected from F or Y; X 3 is selected from S or T; X 4 is selected from L, F, or S; X 5 is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y, H, or G; X 8 is selected from G, A, Y, W, or F; X 9 is selected from M, W, Y, or I; X10 selected from S, G, N, M or I; and X 11 is present or absent, and if present, is 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 is selected from G, T, A, I or Y; X 13 is selected from W, I, Y or C; X 14 is selected from I, S or Y; X 15 is selected from S, G, T, D or P; X 16 is selected from F, S, D, T or A; X 17 is selected from S, R, G or D; X 18 is selected from G, D or S; X 19 is selected from S, R, T, N, Y, A, D or P; X 20 is selected from T, A, G or Y; X 21 is selected from Y, H, A, S or T; X 22 is selected from Y or N; X 23 is selected from A, P, Y or S; X 24 is selected from S, T, N, D, Y, A or P; X 25 is selected from W, S, A or D; X 26 is selected from A, V, T, W, F or S; X 27 is selected from K, W, A, Q or V; X 28 is selected from G, A or K; X 29 is present or absent, and if present, is selected from K or G; and X 30 is present or absent, and if present, is 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 ; wherein X 31 is selected from A or V; X 32 is selected from R or I; X 33 is selected from G, D, P, A or V; X 34 is selected from G, P, W, D, N or R; X 35 is selected from D, Y, S, L, G, F or W; X 36 is selected from Y, D, V, L, S, G or P; X 37 is selected from G, S, D, V or E; X 38 is selected from G, Y, F, S or D; X 39 is selected from S, D, G, T, N, A or V; X 40 is selected from T, A, D, S, Y, L or F; X 41 is present or absent, and if present, is selected from Y, A, G, I or D; X 42 is present or absent, and if present, is selected from I, Y, R, P, V or G; X 43 is present or absent, and if present, is selected from L, R, Y, G or A; X 44 is present or absent, and if present, is selected from N, L, Y, S or W; X 45 is present or absent, and if present, is selected from L, Y, F or C; X 46 is present or absent, and if present, is selected from D, A or F; X 47 is present or absent, and if present, is 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. In some embodiments, the VH region comprises the CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 , wherein X 5 is selected from S or N; X 6 is selected from S, N, T or D; X 7 is selected from Y or H; X 8 is selected from G, A or Y; and X 10 is 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 is selected from W, I or Y; X 15 is selected from S or G; X 16 is selected from F, S, D or T; X 17 is selected from S or R; X 18 is selected from G or D; X 19 is 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 the 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 is selected from A or V; X 33 is selected from G or D; X 34 is selected from G, P, W or D; X 35 is selected from D, Y, S or L; X 36 is selected from Y, D, V or L; X 37 is selected from G, S or D; X 38 is selected from G, Y, F or S; X 39 is selected from S, D, G or T; X 40 is selected from T, A, D, S or Y; X 41 is selected from Y, A, G or I; X 42 is selected from I, Y or R; X 43 is selected from L, R, Y or G; X 44 is selected from N, L, Y or S; X 45 is present or absent, and if present, is selected from L, Y or F; X 46 is present or absent, and if present, is D; X 47 is present or absent, and if present, is selected from M or P; X 48 is present or absent, and if present, is D; and X 49Present or absent, and if present, is L. In some embodiments, 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; a CDR2 sequence selected from 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 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 SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; 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. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NO: 241, 247, and 250; a CDR2 sequence selected from SEQ ID NO: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from SEQ ID NO: 243, 245, 249, and 252. In some embodiments, 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. In some embodiments, the second targeting moiety comprises a VH sequence selected from SEQ ID NO: 289 - 309 and a VL sequence selected from SEQ ID NO: 311 - 326 and 155. In some embodiments, the anti - CD38 antibody comprises a humanized antibody or a binding fragment thereof or a chimeric antibody or a 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 its binding fragment comprises IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triabody, minibody, microbody, TriBi microbody, 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, tetravalent HCAb, scDiabody-Fc, diabody-Fc, tandem scFv-Fc or intracellular antibody. In some embodiments, the anti-CD38 antibody comprises an IgGl 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 NO: 157-181 and an LC sequence selected from SEQ ID NO: 183-207. In some embodiments, the anti-CD38 antibody further comprises a payload. In some embodiments, the payload includes a small molecule, a peptide or a protein.

[0032] In certain embodiments, provided herein is an anti-ICAM1 antibody 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 ; wherein X 1 is selected from G or E; X 2 is selected from F or Y; X 3 is selected from S or T; X 4 is selected from L, F or S; X 5 is selected from S or N; X 6 is selected from S, N, T or D; X 7 is selected from Y, H or G; X 8 is selected from G, A, Y, W or F; X 9 is 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; 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 ; wherein X 12 is selected from G, T, A, I or Y; X 13 is selected from W, I, Y or C; X 14 is selected from I, S or Y; X 15 is selected from S, G, T, D or P; X 16 is selected from F, S, D, T or A; X 17 is selected from S, R, G or D; X 18 is selected from G, D or S; X 19 is selected from S, R, T, N, Y, A, D or P; X 20 is selected from T, A, G or Y; X 21 is selected from Y, H, A, S or T; X 22 is selected from Y or N; X 23 is selected from A, P, Y or S; X 24 is selected from S, T, N, D, Y, A or P; X 25 is selected from W, S, A or D; X 26 is selected from A, V, T, W, F or S; X 27 is selected from K, W, A, Q or V; X 28 is selected from G, A or K; X 29 is present or absent, and if present, is selected from K or G; and X 30 is present or absent, and if present, is G; and the 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 ; wherein 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, and if present, selected from Y, A, G, I or D; X 42 Present or absent, and if present, selected from I, Y, R, P, V or G; X 43 Present or absent, and if present, selected from L, R, Y, G or A; X 44 Present or absent, and if present, selected from N, L, Y, S or W; X 45 Present or absent, and if present, selected from L, Y, F or C; X 46 Present or absent, and if present, selected from D, A or F; X 47 Present or absent, and if present, selected from M, P, Y or N; X 48 Present or absent, and if present, selected from D or L; and X 49 Present or absent, and if present, is L. In some embodiments, the VH region comprises the CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 , 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; 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, wherein 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 Selected from G or D; X 19 Selected from S, R, T or N; X 20 Selected from T or A; and X 24 Selected from S, T or N. In some embodiments, the VH region 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 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , wherein X 31 Selected from A or V; X 33 Selected 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, and if present, selected from L, Y or F; X 46 Present or absent, and if present, is D; X 47 Present or absent, and if present, selected from M or P; X 48 Present or absent, and if present, is D; and X 49Present or absent, and if present, is L. In some embodiments, 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; a CDR2 sequence selected from SEQ ID NO: 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 wherein X 31 is selected from A or V; X 32 is selected from R or I; X 33 is selected from G, D, P, A or V; X 34 is selected from G, P, W, D, N or R; X 35 is selected from D, Y, S, L, G, F or W; X 36 is selected from Y, D, V, L, S, G or P; X 37 is selected from G, S, D, V or E; X 38 is selected from G, Y, F, S or D; X 39 is selected from S, D, G, T, N, A or V; X 40 is selected from T, A, D, S, Y, L or F; X 41 Present or absent, and if present, is selected from Y, A, G, I or D; X 42 Present or absent, and if present, is selected from I, Y, R, P, V or G; X 43 Present or absent, and if present, is selected from L, R, Y, G or A; X 44 Present or absent, and if present, is selected from N, L, Y, S or W; X 45 Present or absent, and if present, is selected from L, Y, F or C; X 46 Present or absent, and if present, is selected from D, A or F; X 47 Present or absent, and if present, is selected from M, P, Y or N; X48 Present or absent, and if present, selected from D or L; and X 49Present or absent, and if present, it is L. In some embodiments, 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; a CDR2 sequence selected from 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 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 SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; 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. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NO: 241, 247, and 250; a CDR2 sequence selected from SEQ ID NO: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from SEQ ID NO: 243, 245, 249, and 252. In some embodiments, 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. In some embodiments, the second targeting moiety comprises a VH sequence selected from SEQ ID NO: 289 - 309 and a VL sequence selected from SEQ ID NO: 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: 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 is 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; X 12 is present or absent, and if present, is C; a 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 ; wherein X 13 is selected from A, G or S; X 14 is selected from I, F, Y, V, S or C; X 15 is selected from S, I, L, T or M; X 16 is selected from G, Y, S, T, L or V; X 17 is selected from S, I, K, Y, T, G or A; X 18 is selected from G, S, T, P, V or Y; X 19 is selected from G, A, D, S or T; X 20 is selected from S, T, I, N or G; X 21 is selected from T, I, D, N, S or A; X 22 is selected from F, Y, N, T, I or S; X 23 is selected from Y, D, K or I; X 24 is selected from A or Y; X 25 is selected from D, T, S, N, R, A or Y; X 26 is 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, and if present, selected from G or K; X 31 Present or absent, and if present, is 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 wherein 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, and if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, and if present, selected from P, L, Y, F, G or T; X 43 Present or absent, and if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, and if present, selected from G, L, S, T or F; X 45 Present or absent, and if present, selected from F, L, E, N or S; X 46 Present or absent, and if present, selected from D, S, L or R; X 47 Present or absent, and if present, selected from Y or L; X 48 Present or absent, and if present, is D; and X 49Present or absent, and if present, is L. In some embodiments, the VH region comprises the CDR1 sequence GFPFX5X6YAMS, where X5 is selected from D or G; and X6 is selected from V, A or T. In some embodiments, 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 is 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. 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 is present or absent, and if present, is 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 is 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. 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 the 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 ; wherein X 13 is selected from A, G, or S; X 14 is selected from I, F, Y, V, S, or C; X 15 is selected from I, L, M, or T; X 16 is selected from G, Y, S, T, L, or V; X 17 is selected from S, I, K, Y, T, G, or A; X 18 is selected from G, S, T, P, or V; X 19 is selected from G, A, D, S, or T; X 20 is selected from S, T, I, N, or G; X 21 is selected from T, I, D, N, S, or A; X 22 is selected from Y, N, T, I, or S; X 23 is selected from Y, D, K, or I; X 24 is selected from A or Y; X 25 is selected from T, S, N, R, A, or Y; X 26 is selected from S, W, T, A, or N; X 27 is selected from A, W, N, or S; X 28 is selected from K, R, Q, A, or W; X 29 is 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 the 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 ; wherein X 13 is selected from A or G; X 14 is selected from I, F, Y, V, S, or C; X 16 is selected from G, Y, S, T, or L; X 17 is 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 Selected from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Selected from W or T; X 27 Selected from A or W; X 28 Selected from K, R, Q or A; X 29 Selected from G or K; and X 30 Present or absent, and if present, is G. In some embodiments, the VH region comprises the 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 ; wherein 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 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 Selected from A or W; X 29 Selected from K or A; X 30 Present or absent, and if present, selected from G or K; and X 31 Present or absent, and if present, is G. In some embodiments, the VH region comprises the CDR3 sequence AKRGTYX 38 YSX 41PTGFDY, wherein X 38 is selected from A or G; and X 41 is selected from F or Y. In some embodiments, the VH region comprises the 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 ; wherein X 32 is selected from A, G or V; X 33 is selected from A, R, T, S or G; X 34 is selected from A, V, T, P, I, E, D or S; X 35 is selected from G, W, D, L, K, P, S, R or A; X 36 is selected from P, A, Y, D, G, S, R, V, E or T; X 37 is selected from Y, V, T, S, N, A, G, Q, F or I; X 38 is selected from G, S, D, K, F, L or Y; X 39 is selected from T, A, G, S, I or Y; X 40 is selected from S, Y, G, R, W, N, L, D or F; X 41 is present or absent, and if present, is selected from V, D, Y, A, N, G, L or E; X 42 is present or absent, and if present, is selected from L, Y, F, T or G; X 43 is present or absent, and if present, is selected from P, F, V, N, S or Y; X 44 is present or absent, and if present, is 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; X 46 is present or absent, and if present, is selected from S, L or R; X 47 is present or absent, and if present, is L; X 48 is present or absent, and if present, is D; and X 49 is present or absent, and if present, is L. In some embodiments, the VH region comprises the 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 ; wherein X 32 is selected from A or G; X 33 is selected from A, R or T; X 34 is selected from A, V, T, P, I, E or D; X 35 is selected from G, W, D, L, K or P; X 36 is selected from P, A, Y, D or G; X 37 is selected from Y, V, T, S, N, A or G; X 38 is selected from G, S, D or K; X 39 is selected from T, A, G, S or I; X 40 is selected from S, Y, G, R or W; X 41 is selected from V, D, Y, A, N or G; X 42 is selected from L, Y or F; X 43 is present or absent, and if present, is selected from P, F, V or N; X 44 is present or absent, and if present, is selected from L, S or T; and 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 ; wherein X 33 is selected from R or G; X 34 is selected from E, D or S; X 35 is selected from G, L, P, S or A; X 36 is selected from D, S or R; X 37 is selected from Y, T, N or G; X 38 is selected from G, S, F or L; X 39 is selected from A, G, S or I; X 40 is selected from Y, N or L; X 41 is present or absent, and if present, is selected from V, Y or E; X 42Present or absent, and if present, then G; X 43 Present or absent, and if present, then Y; X 44 Present or absent, and if present, then F; X 45 Present or absent, and if present, then selected from E or N; and X 46 Present or absent, and if present, then selected from S or L. In some embodiments, the VH region comprises the CDR1 sequence GFPFX5X6YAMS, the CDR2 sequence AISGSGGSTX 22 YADSVKG, and the 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 is selected from F or Y; X 38 is selected from A or G; and X 41 is selected from F or Y. In some embodiments, the VH region comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 the 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 the 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 is selected from T, S or M; X 11 Present or absent, and if present, then C; X 13 is 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 Selected from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Selected from W or T; X 27 Selected from A or W; X 28 Selected from K, R, Q or A; X 29 Selected from G or K; X 30 Present or absent, if present, then 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 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 [[ID=A]]Present or absent, if present, then selected from P, F, V or N; X 44 Present or absent, if present, then selected from L, S or T; and X 45 " Present or absent, if present, then selected from L or F. In some embodiments, the VH region comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 , the 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 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 ; 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 is selected from C, I, Y or M; X 11 is present or absent, and if present, is selected from C or M; X 12 is present or absent, and if present, is C; X 13 is selected from A or S; X 15 is selected from I, L or T; X 16 is selected from Y or V; X 17 is selected from S, T or A; X 18 is selected from G, P or V; X 19 is selected from D, S or T; X 20 is selected from S, T or G; X 21 is selected from D, N, S or A; X 22 is selected from T, I or S; X 23 is selected from Y, K or I; X 25 is selected from A or Y; X 26 is selected from S, T, A or N; X 27 is selected from W, N or S; X 28 is selected from A or W; X 29 is selected from K or A; X 30 is present or absent, and if present, is selected from G or K; X 31 is present or absent, and if present, is G; X 33 is selected from R or G; X 34 is selected from E, D or S; X 35 is selected from G, L, P, S or A; X 36 is selected from D, S or R; X 37 is selected from Y, T, N or G; X 38 is selected from G, S, F or L; X 39 is selected from A, G, S or I; X 40 is selected from Y, N or L; X41 Present or absent, and if present, selected from V, Y, or E; X 42 Present or absent, and if present, is G; X 43 Present or absent, and if present, is Y; X 44 Present or absent, and if present, is F; X 45 Present or absent, and if present, selected from E or N; and X 46 Present or absent, and if present, selected from S or L. In some embodiments, 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, and 56; a CDR2 sequence selected from 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 ; wherein 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, and if present, selected from F, Y, V, D, A, N, G, E, or L; X 42 Present or absent, and if present, selected from P, L, Y, F, G, or T; X43 Present or absent, and if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, and if present, selected from G, L, S, T or F; X 45 Present or absent, and if present, selected from F, L, E, N or S; X 46 Present or absent, and if present, selected from D, S, L or R; X 47 Present or absent, and if present, selected from Y or L; X 48 Present or absent, and if present, is D; and X 49Present or absent, and if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from 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 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 SEQ ID NOs: 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 SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10. In some embodiments, the VH region comprises a CDR1 sequence selected from 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 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 SEQ ID NOs: 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 SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, 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 selected from SEQ ID NOs: 19, 25, 31, 46, and 58.In some embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID 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. In some embodiments, 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, 81, 78, 90, and 99; and a CDR3 sequence selected from SEQ ID NO: 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, 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 SEQ ID NO: 73, 79, 85, 95, and 103. In some embodiments, the anti-CD38 antibody comprises a VH sequence selected from SEQ ID NO: 104 - 128 and a VL sequence selected from SEQ ID NO: 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 a binding fragment thereof comprises IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triabody, minibody, microbody, TriBi microbody, scFv-CH3KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, F(ab’)2, F(ab’)2-scFv2, scFv-KIH, Fab-scFv-Fc, tetravalent HCAb, scDiabody-Fc, diabody-Fc, tandem scFv-Fc, or an intracellular antibody. 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 NO: 329-349 and an LC sequence selected from SEQ ID NO: 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.

[0033] In certain embodiments, nucleic acid polymers encoding the bispecific antibodies, anti-CD38 antibodies, or anti-ICAM1 antibodies described herein are disclosed.

[0034] In certain embodiments, vectors comprising nucleic acid polymers encoding the bispecific antibodies, anti-CD38 antibodies, or anti-ICAM1 antibodies described herein are disclosed.

[0035] In certain embodiments, a pharmaceutical composition is disclosed that comprises: a bispecific antibody, an anti-CD38 antibody, 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.

[0036] In certain embodiments, a method of treating cancer in a subject in need thereof is disclosed herein, comprising: administering to the subject the bispecific antibody described herein, the anti-CD38 antibody described herein, the anti-ICAM1 antibody described herein, or the pharmaceutical composition described herein, thereby treating the cancer in the subject. 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 hematologic malignancy. In some embodiments, the hematologic malignancy is B-cell lymphoma or T-cell lymphoma. In some embodiments, the hematologic malignancy is Hodgkin lymphoma or non-Hodgkin lymphoma. In some embodiments, the hematologic 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, plasmacytoma, plasmacytosis, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is 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 therapeutic agent, a hormone-based therapeutic agent, a stem cell-based therapeutic agent, or radiation. In some embodiments, the additional therapeutic agent comprises a first-line therapeutic 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 a human.

[0037] In certain embodiments, a kit is disclosed herein that comprises the bispecific antibody described herein, the anti-CD38 antibody described herein, the anti-ICAM1 antibody described herein, or the pharmaceutical composition described herein. The present application provides the following: 1. A multispecific protein comprising a first component that specifically binds to CD38 and a second component that specifically binds to ICAM1. 2. The multispecific protein according to item 1, wherein the multispecific protein is bivalent, trivalent or tetravalent. 3. The multispecific protein according to item 1 or 2, wherein the first component comprises an antibody or an antigen-binding fragment thereof that specifically binds to CD38. 4. The multispecific protein according to any one of items 1-3, wherein the second component comprises an antibody or an antigen-binding fragment thereof that specifically binds to ICAM1. 5. The multispecific protein according to item 3 or 4, wherein the antibody or antigen-binding fragment thereof that specifically binds to CD38 comprises a variable domain of an IgG heavy chain and a variable domain of an IgG light chain. 6. The multispecific protein according to item 4 or 5, wherein the antibody or antigen-binding fragment thereof that specifically binds to ICAM1 comprises a variable domain of an IgG heavy chain and a variable domain of an IgG light chain. 7. The multispecific protein according to any one of items 1-6, further comprising an Fc region. 8. The multispecific protein according to item 7, wherein the Fc region comprises a heterodimeric Fc region. 9. The multispecific protein according to item 7 or 8, wherein the Fc region comprises one or more mutations that increase the half-life of the multispecific protein. 10. The multispecific protein according to any one of items 7-9, wherein the Fc region comprises one or more stabilizing mutations. 11. The multispecific protein according to any one of items 7-10, wherein the Fc region comprises one or more mutations that modulate the interaction of the Fc region with Fc receptors. 12. The multispecific protein according to item 11, wherein the Fc region comprises one or more mutations that increase the binding of the Fc region to Fc receptors. 13. The multispecific protein according to any one of items 7-12, wherein the Fc region comprises one or more mutations that reduce the glycosylation of the Fc region. 14. The multispecific protein according to item 13, wherein the one or more mutations that reduce the glycosylation of the Fc region comprise a mutation at the position corresponding to position N297 of human IgG1, wherein the numbering is according to the EU index of Kabat et al. 15. The multispecific protein according to any one of items 7-14, wherein the Fc region is afucosylated. 16. The multispecific protein according to any one of items 7-15, wherein the Fc region comprises one or more mutations that increase ADCC or CDC activity. 17. The multispecific protein according to item 16, 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. 18. The multispecific protein according to any one of items 8-17, comprising the heterodimeric Fc region, wherein the heterodimeric Fc region comprises a staphylococcal protein A chain and a streptococcal protein G chain, forming a staphylococcal protein A-streptococcal protein G (KIH) structure. 19. The multispecific protein according to item 18, wherein the staphylococcal protein A chain comprises the mutation T366W, and the streptococcal protein G chain comprises the mutations T366S, L368A, and Y407V, wherein the amino acid position numbering is according to the EU index of Kabat et al. 20. The multispecific protein according to any one of items 4-19, wherein the antibody or antigen-binding fragment thereof that specifically binds to CD38 comprises 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). 21. The multispecific protein according to item 20, wherein the anti-CD38 IgG comprises two light chains and each light chain is fused to a single anti-ICAM1 scFv. 22. The multispecific protein according to item 21, wherein the C-terminus of each light chain of the anti-CD38 IgG is fused to a single anti-ICAM1 scFv. 23. The multispecific protein according to item 21, wherein the N-terminus of each heavy chain of the anti-CD38 IgG is fused to a single anti-ICAM1 scFv. 24. The multispecific protein according to item 21, 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. 25. The multispecific protein according to any one of items 4-20, wherein the first component comprises 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. 26. The multispecific protein according to any one of items 3-20, wherein the antibody or antigen-binding fragment thereof that specifically binds to CD38 is a monovalent anti-CD38 antibody or antigen-binding fragment thereof. 27. The multispecific protein according to any one of items 4-20 and 26, wherein the antibody or antigen-binding fragment thereof that specifically binds to ICAM1 is a monovalent anti-ICAM1 antibody or antigen-binding fragment thereof. 28. The multispecific protein according to item 26 or 27, wherein the monovalent anti-CD38 antibody or antigen-binding fragment thereof comprises an anti-CD38 Fab. 29. The multispecific protein according to any one of items 26-28, wherein the monovalent anti-ICAM1 antibody or antigen-binding fragment thereof comprises an anti-ICAM1 scFv. 30. The multispecific protein according to item 29, wherein the multispecific protein comprises an anti-CD38 Fab, an anti-ICAM1 scFv, and an Fc region. 31. The multispecific protein according to item 30, wherein the Fc region is a heterodimeric Fc region comprising a KIH structure. 32. The multispecific protein according to item 27, wherein 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). 33. The multispecific protein according to item 32, further comprising an Fc region. 34. The multispecific protein according to item 33, wherein the Fc region is a heterodimeric Fc region comprising a KIH structure, and wherein the multispecific protein has a common light chain bispecific form. 35. The multispecific protein according to any one of items 1-34, wherein the first component that specifically binds to CD38 comprises a heavy chain, the heavy chain comprising complementarity 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 the sequences of the following group: CDR1:CDR2:CDR3 (SEQ ID No.1:SEQ ID No:2:SEQ ID No.3); CDR1:CDR2:CDR3 (SEQ ID No.4:SEQ ID No.5:SEQ ID No.3); CDR1:CDR2:CDR3(SEQ ID No.6:SEQ ID No.2:SEQ ID No.7); CDR1:CDR2:CDR3(SEQ ID No.1:SEQ ID No.2:SEQ ID No.7); CDR1:CDR2:CDR3(SEQ ID No.4:SEQ ID No.5:SEQ ID No.7); CDR1:CDR2:CDR3(SEQ ID No.4:SEQ ID No.2:SEQ ID No.7); CDR1:CDR2:CDR3(SEQ ID No.6:SEQ ID No.2:SEQ ID No.3); CDR1:CDR2:CDR3(SEQ ID No.8:SEQ ID No.5:SEQ ID No.3); CDR1:CDR2:CDR3(SEQ ID No.9:SEQ ID No.2:SEQ ID No.10); CDR1:CDR2:CDR3(SEQ ID No.11:SEQ ID No.12:SEQ ID No.13); CDR1:CDR2:CDR3(SEQ ID No.14:SEQ ID No.15:SEQ ID No.16); CDR1:CDR2:CDR3(SEQ ID No.17:SEQ ID No.18:SEQ ID No.19); CDR1:CDR2:CDR3(SEQ ID No.20:SEQ ID No.21:SEQ ID No.22); CDR1:CDR2:CDR3(SEQ ID No.23:SEQ ID No.24:SEQ ID No.25); CDR1:CDR2:CDR3(SEQ ID No.26:SEQ ID No.27:SEQ ID No.28); CDR1:CDR2:CDR3(SEQ ID No.29:SEQ ID No.30:SEQ ID No.31); CDR1:CDR2:CDR3(SEQ ID No.32:SEQ ID No.33:SEQ ID No.34); CDR1:CDR2:CDR3 (SEQ ID No.35:SEQ ID No.36:SEQ ID No.37); CDR1:CDR2:CDR3 (SEQ ID No.38:SEQ ID No.39:SEQ ID No.40); CDR1:CDR2:CDR3 (SEQ ID No.41:SEQ ID No.42:SEQ ID No.43); CDR1:CDR2:CDR3 (SEQ ID No.44:SEQ ID No.45:SEQ ID No.46); CDR1:CDR2:CDR3 (SEQ ID No.47:SEQ ID No.48:SEQ ID No.49); CDR1:CDR2:CDR3 (SEQ ID No.50:SEQ ID No.51:SEQ ID No.52); CDR1:CDR2:CDR3 (SEQ ID No.53:SEQ ID No.54:SEQ ID No.55); CDR1:CDR2:CDR3 (SEQ ID No.56:SEQ ID No.57:SEQ ID No.58); and CDR1:CDR2:CDR3 (SEQ ID No.59:SEQ ID No.60:SEQ ID No.61). 36. The multispecific protein according to item 35, wherein the CDR1, CDR2, and CDR3 of the heavy chain comprise the sequences of the following group: CDR1:CDR2:CDR3 (SEQ ID No.14:SEQ ID No.15:SEQ ID No.16). 37. The multispecific protein according to item 35, wherein the CDR1, CDR2, and CDR3 of the heavy chain comprise the sequences of the following group: CDR1:CDR2:CDR3 (SEQ ID No.17:SEQ ID No.18:SEQ ID No.19). 38. The multispecific protein according to item 35, wherein the CDR1, CDR2, and CDR3 of the heavy chain comprise the following sequences: CDR1:CDR2:CDR3 (SEQ ID No.1:SEQ IDNo.2:SEQ ID No.7). 39. The multispecific protein according to any one of items 1-38, wherein the first component that specifically binds to CD38 comprises a light chain, and the light chain comprises complementarity determining regions CDR1, CDR2, and CDR3, and the CDR1, CDR2, and CDR3 of the light chain comprise sequences selected from the group consisting of the sequences of the following groups: CDR1:CDR2:CDR3 (SEQ ID No.62:SEQ ID No:63:SEQ ID No.64); CDR1:CDR2:CDR3 (SEQ ID No.65:SEQ ID No.66:SEQ ID No.67); CDR1:CDR2:CDR3 (SEQ ID No.68:SEQ ID No.69:SEQ ID No.70); CDR1:CDR2:CDR3 (SEQ ID No.71:SEQ ID No.72:SEQ ID No.73); CDR1:CDR2:CDR3 (SEQ ID No.74:SEQ ID No.75:SEQ ID No.76); CDR1:CDR2:CDR3 (SEQ ID No.77:SEQ ID No.78:SEQ ID No.79); CDR1:CDR2:CDR3 (SEQ ID No.80:SEQ ID No.81:SEQ ID No.82); CDR1:CDR2:CDR3 (SEQ ID No.83:SEQ ID No.84:SEQ ID No.85); CDR1:CDR2:CDR3 (SEQ ID No.86:SEQ ID No.78:SEQ ID No.87); CDR1:CDR2:CDR3 (SEQ ID No.86:SEQ ID No.78:SEQ ID No.88); CDR1:CDR2:CDR3 (SEQ ID No.89:SEQ ID No.90:SEQ ID No.91); CDR1:CDR2:CDR3 (SEQ ID No.92:SEQ ID No.78:SEQ ID No.93); CDR1:CDR2:CDR3 (SEQ ID No.94:SEQ ID No.84:SEQ ID No.95); CDR1:CDR2:CDR3 (SEQ ID No.96:SEQ ID No.81:SEQ ID No.97); CDR1:CDR2:CDR3 (SEQ ID No.98:SEQ ID No.99:SEQ ID No.100); CDR1:CDR2:CDR3 (SEQ ID No.77:SEQ ID No.72:SEQ ID No.101); and CDR1:CDR2:CDR3 (SEQ ID No.102:SEQ ID No.84:SEQ ID No.103). 40. The multispecific protein according to item 39, wherein the CDR1, CDR2 and CDR3 of the light chain comprise the sequences of the following group: CDR1:CDR2:CDR3 (SEQ ID No.68:SEQ ID No.69:SEQ ID No.70). 41. The multispecific protein according to item 39, wherein the CDR1, CDR2 and CDR3 of the light chain comprise the sequences of the following group: CDR1:CDR2:CDR3 (SEQ ID No.71:SEQ ID No.72:SEQ ID No.73). 42. The multispecific protein according to item 39, wherein the CDR1, CDR2 and CDR3 of the light chain comprise the sequences of the following group: CDR1:CDR2:CDR3 (SEQ ID No.62:SEQ ID No.63:SEQ ID No.64). 43. The multispecific protein according to item 39, wherein the first component comprises six CDRs, and the six CDRs comprise the sequences shown in any one of the following groups of sequences: 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); 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); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.6:SEQ ID No:2:SEQ IDNo.7)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64); 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); 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); 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); 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); 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); 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); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.59:SEQ ID No:60:SEQ ID No.61)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.11:SEQ ID No:12:SEQ ID No.13)-(SEQ ID No.65:SEQ ID No:66:SEQ ID No.67); 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); 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); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.20:SEQ ID No:21:SEQ ID No.22)-(SEQ ID No.74:SEQ ID No:75:SEQ ID No.76); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.23:SEQ ID No:24:SEQ ID No.25)-(SEQ ID No.77:SEQ ID No:78:SEQ ID No.79); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.26:SEQ ID No:27:SEQ ID No.28)-(SEQ ID No.80:SEQ ID No:81:SEQ ID No.82); 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); 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); 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); 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); 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); 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); 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); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.50:SEQ ID No:51:SEQ ID No.52)-(SEQ ID No.98:SEQ ID No:99:SEQ ID No.100); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.53:SEQ ID No:54:SEQ ID No.55)-(SEQ ID No.77:SEQ ID No:72:SEQ ID No.101); and HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.56:SEQ ID No:57:SEQ ID No.58)-(SEQ ID No.102:SEQ ID No:84:SEQ ID No.103). 44. The multispecific protein according to item 43, wherein the first component comprises six CDRs, and the six CDRs comprise a sequence of the following group: 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). 45. The multispecific protein according to any one of items 39-44, wherein the first component comprises six CDRs having the following sequence: 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). 46. The multispecific protein according to item 43, wherein the first component comprises six CDRs, and the six CDRs comprise one sequence of the following groups 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). 47. The multispecific protein according to any one of items 1-46, wherein the second component specifically binding to ICAM1 comprises a heavy chain, and the heavy chain comprises complementarity determining regions CDR1, CDR2 and CDR3, wherein the CDR1, CDR2 and CDR3 of the heavy chain comprise sequences selected from the group consisting of the sequences of the following group: CDR1:CDR2:CDR3 (SEQ ID No.208:SEQ ID No.209:SEQ ID No.210); CDR1:CDR2:CDR3 (SEQ ID No.211:SEQ ID No.212:SEQ ID No.213); CDR1:CDR2:CDR3 (SEQ ID No.214:SEQ ID No.215:SEQ ID No.216); CDR1:CDR2:CDR3 (SEQ ID No.217:SEQ ID No.218:SEQ ID No.219); CDR1:CDR2:CDR3 (SEQ ID No.214:SEQ ID No.220:SEQ ID No.221); CDR1:CDR2:CDR3 (SEQ ID No.222:SEQ ID No.223:SEQ ID No.224); CDR1:CDR2:CDR3 (SEQ ID No.225:SEQ ID No.223:SEQ ID No.224); CDR1:CDR2:CDR3 (SEQ ID No.222:SEQ ID No.223:SEQ ID No.226); CDR1:CDR2:CDR3 (SEQ ID No.222:SEQ ID No.227:SEQ ID No.224); CDR1:CDR2:CDR3 (SEQ ID No.228:SEQ ID No.229 SEQ ID No.230); CDR1:CDR2:CDR3 (SEQ ID No.228:SEQ ID No.220:SEQ ID No.231); CDR1:CDR2:CDR3 (SEQ ID No.232:SEQ ID No.229:SEQ ID No.233); CDR1:CDR2:CDR3(SEQ ID No.208:SEQ ID No.234:SEQ ID No.210); CDR1:CDR2:CDR3(SEQ ID No.235:SEQ ID No.236:SEQ ID No.237); CDR1:CDR2:CDR3(SEQ ID No.238:SEQ ID No.239 SEQ ID No.240); CDR1:CDR2:CDR3(SEQ ID No.241:SEQ ID No.242:SEQ ID No.243); CDR1:CDR2:CDR3(SEQ ID No.241:SEQ ID No.244:SEQ ID No.245); CDR1:CDR2:CDR3(SEQ ID No.241:SEQ ID No.246:SEQ ID No.245); CDR1:CDR2:CDR3(SEQ ID No.247:SEQ ID No.248:SEQ ID No.249); CDR1:CDR2:CDR3(SEQ ID No.250:SEQ ID No.251:SEQ ID No.252); and CDR1:CDR2:CDR3(SEQ ID No.404:SEQ ID No.405:SEQ ID No.406). 48. The multispecific protein according to item 47, wherein the CDR1, CDR2, and CDR3 of the heavy chain comprise the following sequences: (CDR1:CDR2:CDR3(SEQ ID No.228:SEQ ID No.229:SEQ ID No.230). 49. The multispecific protein according to item 47, wherein the CDR1, CDR2, and CDR3 of the heavy chain comprise the following sequences: CDR1:CDR2:CDR3(SEQ ID No.222:SEQ ID No.223:SEQ ID No.224). 50. The multispecific protein according to item 47, wherein the CDR1, CDR2, and CDR3 of the heavy chain comprise the sequences of the following group: CDR1:CDR2:CDR3(SEQ ID No.232:SEQ ID No.229:SEQ ID No.233). 51. The multispecific protein according to item 45, wherein the CDR1, CDR2, and CDR3 of the heavy chain comprise sequences from the following group: CDR1:CDR2:CDR3 (SEQ ID No. 404:SEQ ID No. 405:SEQ ID No. 406). 52. The multispecific protein according to any one of items 1 - 51, wherein the second component that specifically binds to ICAM1 comprises a light chain, and the light chain comprises complementarity determining regions CDR1, CDR2, and CDR3, and the CDR1, CDR2, and CDR3 of the light chain comprise a set of sequences selected from the group consisting of the following groups of sequences: CDR1:CDR2:CDR3 (SEQ ID No. 253:SEQ ID No. 254:SEQ ID No. 255); CDR1:CDR2:CDR3 (SEQ ID No. 256:SEQ ID No. 257:SEQ ID No. 258); CDR1:CDR2:CDR3 (SEQ ID No. 259:SEQ ID No. 260:SEQ ID No. 261); CDR1:CDR2:CDR3 (SEQ ID No. 262:SEQ ID No. 263:SEQ ID No. 264); CDR1:CDR2:CDR3 (SEQ ID No. 265:SEQ ID No. 260:SEQ ID No. 266); CDR1:CDR2:CDR3 (SEQ ID No. 267:SEQ ID No. 263:SEQ ID No. 264); CDR1:CDR2:CDR3 (SEQ ID No. 268:SEQ ID No. 263:SEQ ID No. 264); CDR1:CDR2:CDR3 (SEQ ID No. 269:SEQ ID No. 263:SEQ ID No. 264); CDR1:CDR2:CDR3 (SEQ ID No. 270:SEQ ID No. 260:SEQ ID No. 271); CDR1:CDR2:CDR3 (SEQ ID No. 272:SEQ ID No. 260:SEQ ID No. 266); CDR1:CDR2:CDR3 (SEQ ID No.259:SEQ ID No.273:SEQ ID No.266); CDR1:CDR2:CDR3 (SEQ ID No.274:SEQ ID No.275:SEQ ID No.276); CDR1:CDR2:CDR3 (SEQ ID No.277:SEQ ID No.275:SEQ ID No.278); CDR1:CDR2:CDR3 (SEQ ID No.279:SEQ ID No.280:SEQ ID No.281); CDR1:CDR2:CDR3 (SEQ ID No.282:SEQ ID No.283:SEQ ID No.284); CDR1:CDR2:CDR3 (SEQ ID No.62:SEQ ID No.63:SEQ ID No.64); and CDR1:CDR2:CDR3 (SEQ ID No.407:SEQ ID No.408:SEQ ID No.409). 53. The multispecific protein according to item 51, wherein the CDR1, CDR2 and CDR3 of the light chain comprise the sequences of the following group: CDR1:CDR2:CDR3 (SEQ ID No.270:SEQ ID No.260:SEQ ID No.271). 54. The multispecific protein according to item 51, wherein the CDR1, CDR2 and CDR3 of the light chain comprise the sequences of the following group: CDR1:CDR2:CDR3 (SEQ ID No.267:SEQ ID No.263:SEQ ID No.264). 55. The multispecific protein according to item 51, wherein the CDR1, CDR2 and CDR3 of the light chain comprise the sequences of the following group: CDR1:CDR2:CDR3 (SEQ ID No.259:SEQ ID No.273:SEQ ID No.266). 56. The multispecific protein according to item 51, wherein the CDR1, CDR2 and CDR3 of the light chain comprise the sequences of the following group: (i) CDR1:CDR2:CDR3 (SEQ IDNo.407:SEQ ID No.408:SEQ ID No.409). 57. The multispecific protein according to item 47 - 56, wherein the second component comprises six CDRs, and the six CDRs comprise a set of sequences selected from the group consisting of the following sequences: 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); 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); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.241:SEQ ID No:244:SEQID No.245)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.241:SEQ ID No:246:SEQID No.245)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.247:SEQ ID No:248:SEQID No.249)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.250:SEQ ID No:251:SEQID No.252)-(SEQ ID No.62:SEQ ID No:63:SEQ ID No.64); and HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.404:SEQ ID No.405:SEQID No.406)-(SEQ ID No.407:SEQ ID No:408:SEQ ID No.409). 58. The multispecific protein according to item 57, wherein the second component comprises six CDRs, and the six CDRs comprise the following sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.228:SEQ IDNo.229:SEQ ID No.230)-(SEQ ID No.270:SEQ ID No.260:SEQ ID No.271). 59. The multispecific protein according to item 57, wherein the second component comprises six CDRs, and the six CDRs comprise the following sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.222:SEQ IDNo:223:SEQ ID No.224)-(SEQ ID No.267:SEQ ID No:263:SEQ ID No.264). 60. The multispecific protein according to item 57, wherein the second component comprises six CDRs, and the six CDRs comprise the following sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.232:SEQ IDNo:229:SEQ ID No.233)-(SEQ ID No.259:SEQ ID No:273:SEQ ID No.266). 61. The multispecific protein according to item 57, wherein the second component comprises six CDRs, and the six CDRs comprise the following sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID No.404:SEQ IDNo.405:SEQ ID No.406)-(SEQ ID No.407:SEQ ID No.408:SEQ ID No.409. 62. The multispecific protein according to any one of items 35 - 61, wherein the first component comprises a variable heavy chain domain and wherein the variable heavy chain domain comprises a sequence having at least 90% identity with a sequence selected from the group consisting of SEQ ID Nos. 104 - 129. 63. The multispecific protein according to any one of items 35 - 62, wherein the first component comprises a variable light chain domain and wherein the variable light chain domain comprises a sequence having at least 90% identity with a sequence selected from the group consisting of SEQ ID No. 130 - 155. 64. The multispecific protein according to any one of items 47 - 63, wherein the second component comprises a variable heavy chain domain and wherein the variable heavy chain domain comprises a sequence having at least 90% identity with a sequence selected from the group consisting of SEQ ID No. 288 - 309. 65. The multispecific protein according to any one of items 47 - 64, wherein the second component comprises a variable light chain domain, wherein the variable light chain domain comprises a sequence having at least 90% identity with a sequence selected from the group consisting of SEQ ID No. 310 - 326. 66. The multispecific protein according to any one of items 1 - 65, wherein the first component that specifically binds to CD38 comprises a full - length antibody, the full - length antibody comprising a light chain and a heavy chain, wherein the heavy chain comprises a sequence having at least 90% identity with a sequence selected from the group consisting of SEQ ID No. 156 - 181. 67. The multispecific protein according to item 66, wherein the light chain comprises a sequence having at least 90% identity with a sequence selected from the group consisting of SEQ ID No. 182 - 207. 68. The multispecific protein according to any one of items 1 - 67, wherein the second component that specifically binds to ICAM1 comprises a full - length antibody, the full - length antibody comprising a light chain and a heavy chain, wherein the heavy chain comprises a sequence having at least 90% identity with a sequence selected from the group consisting of SEQ ID No. 328 - 349. 69. The multispecific protein according to item 68, wherein the light chain comprises a sequence having at least 90% identity with a sequence selected from the group consisting of SEQ ID No. 183 and 350 - 366. 70. A multispecific protein comprising a heavy - chain polypeptide (HC) comprising VH and a light - chain polypeptide (LC) comprising VL, wherein the heavy - chain polypeptide and the light - chain polypeptide comprise sequences having at least 90% identity with sequences selected from the following groups: HC:LC (SEQ ID No. 160:SEQ ID No. 397); HC:LC (SEQ ID No. 389:SEQ ID No. 186); HC:LC (SEQ ID No. 163:SEQ ID No. 395); HC:LC(SEQ ID No.387:SEQ ID No.189); HC:LC(SEQ ID No.164:SEQ ID No.396); HC:LC(SEQ ID No.388:SEQ ID No.190); HC:LC(SEQ ID No.156:SEQ ID No.393); HC:LC(SEQ ID No.384:SEQ ID No.182); HC:LC(SEQ ID No.385:SEQ ID No.182); and HC:LC(SEQ ID No.386:SEQ ID No.394). 71. 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 having at least 90% identity to sequences selected from the group consisting of the sequences: HC1:LC:HC2(SEQ ID No.391:SEQ ID No.186:SEQ ID No.383); HC1:LC:HC2(SEQ ID No.392:SEQ ID No.190:SEQ ID No.383); and HC1:LC:HC2(SEQ ID No.156:SEQ ID No.182:SEQ ID No.383). 72. 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 having at least 90% identity to sequences selected from the group consisting of the sequences: HC1:LC1:HC2:HC3(SEQ ID No.390:SEQ INo.189:SEQ ID No.348:SEQ IDNo.189); HC1:LC1:HC2:HC3(SEQ ID No.390:SEQ ID No.189:SEQ ID No.349:SEQ IDNo.189); HC1:LC1:HC2:HC3 (SEQ ID No.391:SEQ ID No.186:SEQ ID No.348:SEQ ID No.186); and HC1:LC1:HC2:HC3 (SEQ ID No.391:SEQ ID No.186:SEQ ID No.349:SEQ ID No.186). 73. A multispecific protein comprising a heavy chain sequence having at least 95% identity to the sequence shown in SEQ ID No.410 and a light chain sequence having at least 95% identity to the sequence shown in SEQ ID No.411. 74. The multispecific protein according to item 73, wherein the heavy chain comprises CDR1, CDR2 and CDR3, wherein CDR1 has the sequence of SEQ ID No.412 (GFSLSZ1Z2AMG), CDR2 has the sequence of SEQ ID No.413 (GIIGSSZ3Z4TYYAZ5WAKG), and CDR3 has the sequence of SEQ ID No.414 (VRDPYDSZ6Z7Z8Z9YRL). 75. The multispecific protein according to item 73 or 74, wherein the light chain comprises CDR1, CDR2 and CDR3, wherein CDR1 has the sequence of SEQ ID No.415 (QASZ 10 Z 11 IYZ 12 YZ 13 Z 14 ), CDR2 has the sequence of SEQ ID No.416 (DASKZ 15 AS), and CDR3 has the sequence of SEQ ID No.417 (QQAYSSZ 16 Z 17 Z 18 DNZ 19 ). 76. The multispecific protein according to item 74 or 75, wherein:[[]] 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 glutamic acid; 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 is valine or alanine. 77. The multispecific protein according to any one of items 15 - 76, wherein the multispecific protein induces an enhanced antibody - dependent cellular cytotoxicity (ADCC) effect on the target cells as compared to the ADCC effect on the target cells induced by a multispecific protein that is otherwise identical but does not comprise a fucosylation - free Fc region. 78. The multispecific protein according to any one of items 17 - 77, wherein the multispecific protein induces an enhanced ADCC effect on the target cells as compared to the ADCC effect on the target cells induced by a multispecific protein that is otherwise identical but does not comprise an Fc region, the Fc region comprising mutations 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. 79. The multispecific protein according to any one of items 1 - 78, wherein the amount of the multispecific protein that binds to cells expressing CD38 and ICAM1 is higher than the amount of a monospecific protein comprising the first component that binds to CD38 and binds to the cells, wherein the binding to the cells is measured by flow cytometry. 80. The multispecific protein according to any one of items 1 - 79, wherein the multispecific protein induces an enhanced ADCC effect on the target cells as compared to the ADCC 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. 81. The multispecific protein according to any one of Items 1 - 80, wherein compared with the CDC effect on target cells induced by a monospecific protein comprising the first component specifically binding to CD38 or the second component specifically binding to ICAM1, the multispecific protein induces an enhanced CDC effect on the target cells. 82. The multispecific protein according to any one of Items 1 - 81, wherein compared with a monospecific protein comprising the first component specifically binding to CD38 or the second component specifically binding to ICAM1, the multispecific protein binds to target cells expressing CD38 and ICAM1 with enhanced affinity. 83. The multispecific protein according to Item 82, 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. 84. The multispecific protein according to Item 82, 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. 85. The multispecific protein according to any one of Items 1 - 84, wherein compared with the ADCC effect on target cells induced by a monospecific protein comprising the first component specifically binding to CD38 or the second component specifically binding to ICAM1, the multispecific protein induces an enhanced ADCC effect on the target cells expressing ICAM1 or CD38. 86. The multispecific protein according to Item 85, wherein the cells express at least 5000, 10000, 15000, 20000, 30000, 50000, 100000, 150000, 200000, 250000, 300000, 400000, or 500000 ICAM1 proteins on their surface. 87. The multispecific protein according to Item 86, wherein the cells express at least 50,000 ICAM1 proteins on their surface. 88. The multispecific protein according to any one of Items 85 - 87, wherein the cells express at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on their surface. 89. The multispecific protein according to Item 88, wherein the cells express at least 300 CD38 proteins on their surface. 90. The multispecific protein according to any one of items 88 - 89, wherein the cell expresses fewer 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. 91. The multispecific protein according to item 90, wherein the cell expresses fewer than 350,000 CD38 proteins on its surface. 92. The multispecific protein according to any one of items 85 - 91, 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. 93. The multispecific protein according to item 92, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least 1. 94. The multispecific protein according to item 92, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least 10. 95. The multispecific protein according to any one of items 85 - 94, wherein the cell expresses at least as much ICAM1 on its surface as NCI - H2291 cells. 96. The multispecific protein according to any one of items 85 - 95, wherein the cell expresses at least as much CD38 on its surface as NCI - H2342 cells. 97. The multispecific protein according to any one of items 85 - 96, wherein the cell expresses less CD38 on its surface compared to Daudi cells. 98. The multispecific protein according to any one of items 85 - 97, 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. 99. The multispecific protein according to any one of items 1 - 98, wherein compared to the complement - dependent cytotoxicity (CDC) 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, the multispecific protein induces an enhanced CDC effect on the target cells expressing CD38 and ICAM1. 100. The multispecific protein according to item 99, 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. 101. The multispecific protein according to item 99, 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. 102. The multispecific protein according to any one of items 1 - 101, wherein the multispecific protein induces an enhanced apoptotic effect on the target cells expressing CD38 and ICAM1 as compared to the apoptotic effect on the target cells induced by a monospecific protein comprising the first component specifically binding to CD38 or the second component specifically binding to ICAM1. 103. The multispecific protein according to item 102, 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. 104. The multispecific protein according to item 102, 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. 105. The multispecific protein according to any one of items 1 - 104, wherein the multispecific protein has a reduced ability to kill natural killer (NK) cells in a fresh peripheral blood mononuclear cell population as compared to a monospecific protein comprising the first component specifically binding to CD38 or the second component specifically binding to ICAM1. 106. The multispecific protein according to any one of items 1 - 105, wherein the first component binds to human CD38 with a K as determined by surface plasmon resonance of 0.15 nM to 64 nM. D binds to human CD38. 107. The multispecific protein according to item 106, wherein the first component binds to human CD38 with a K as determined by surface plasmon resonance of 0.42 nM to 13.14 nM. D binds to human CD38. 108. The multispecific protein according to item 106, wherein the first component binds to human CD38 with a K as determined by surface plasmon resonance of 0.15 nM to 0.45 nM. D binds to human CD38. 109. The multispecific protein according to any one of items 1 - 108, wherein the second component binds to human ICAM1 with a K as determined by surface plasmon resonance of 0.2 nM to 24.4 nM. D binds to human ICAM1. 110. The multispecific protein according to item 109, wherein the second component binds to human ICAM1 with a K as determined by surface plasmon resonance of 0.2 nM to 0.6 nM. D binds to human ICAM1. 111. A pharmaceutical composition comprising a multispecific protein according to any one of items 1-110. 112. The pharmaceutical composition according to item 111, further comprising a pharmaceutically acceptable carrier, excipient, or any combination thereof. 113. A method of killing cells of a subject, comprising administering to the subject a multispecific protein according to any one of items 1-110 or a pharmaceutical composition according to item 111 or 112, wherein the cells express CD38 and ICAM1. 114. The method according to item 113, wherein the cells are lysed. 115. The method according to item 113 or 114, wherein the cells are tumor cells. 116. A method of treating cancer in a subject, comprising administering to the subject a multispecific protein according to any one of items 1-110 or a pharmaceutical composition according to item 111 or 112, wherein the cancer comprises cells expressing CD38 and ICAM1. 117. The method according to item 116, wherein the cancer comprises a solid tumor or a hematological malignancy. 118. The method according to item 117, wherein the cancer comprises a hematological malignancy. 119. The method according to item 118, wherein the hematological malignancy is multiple myeloma, leukemia, non-Hodgkin lymphoma, or Hodgkin lymphoma. 120. The method according to item 116, wherein the cancer is lung cancer or prostate cancer. 121. The method according to any one of items 113-120, wherein the cells express at least as much ICAM1 on their surface as NCI-H2291 cells. 122. The method according to item 121, wherein the cells express at least as much CD38 on their surface as NCI-H2342 cells. 123. The method according to any one of items 113-122, wherein the cells express less CD38 on their surface compared to Daudi cells. 124. The method according to item 123, 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. 125. The method according to any one of items 113-124, wherein the ratio of ICAM1 to CD38 on the surface of the cells is greater than the ratio of ICAM1 to CD38 on the surface of Daudi cells. 126. The method according to item 125, 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. 127. The method according to any one of items 113-126, 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. 128. The method according to item 127, wherein the cell expresses at least 50,000 ICAM1 proteins on its surface. 129. The method according to any one of items 113-128, wherein the cell expresses at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000 or 5000 CD38 proteins on its surface. 130. The method according to item 129, wherein the cell expresses at least 300 CD38 proteins on its surface. 131. The method according to item 129 or 130, wherein the cell expresses less than 350000, 300000, 250000, 200000, 150000, 100000, 50000, 30000, 20000, 15000, 10000 or 5000 CD38 proteins on its surface. 132. The method according to item 131, wherein the cell expresses less than 350,000 CD38 proteins on its surface. 133. The method according to any one of items 113-132, 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. 134. The method according to item 133, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least 1. 135. The method according to item 133, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least 10. 136. The method according to any one of items 113-135, wherein the method further comprises administering an additional therapeutic agent. 137. The method according to item 136, 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 a radiological agent. 138. The method according to item 137, wherein the additional therapeutic agent comprises at least one of lenalidomide, dexamethasone, bortezomib, or any combination thereof. 139. The method according to any one of items 136 - 138, wherein the additional therapeutic agent and the multispecific protein are administered simultaneously. 140. The method according to any one of items 136 - 138, wherein the additional therapeutic agent and the multispecific protein are administered sequentially. 141. The method according to any one of items 136 - 140, wherein the subject has received prior treatment. 142. The method according to item 141, wherein the prior treatment comprises proteasome inhibitor (PI) therapy and an immunomodulator. 143. The method according to any one of items 136 - 142, wherein the subject is doubly refractory to a therapy comprising proteasome inhibitor (PI) therapy and an immunomodulator. 144. The method according to any one of items 136 - 143, wherein the subject is a human. 145. A kit comprising the multispecific protein according to any one of items 1 - 110 or the pharmaceutical composition according to item 111 or 112. Description of the Drawings

[0038] The novel features of the present invention are particularly set forth in the appended claims. The features and advantages of the present invention will be better understood from the following detailed description, which sets forth illustrative embodiments that utilize the principles of the present invention, wherein:

[0039] Figures 1A - 1B Exemplary bispecific antibody forms contemplated herein are shown. Figure 1A and Figure 1B Figure 2, adapted from Brinkmann and Kontermann, “The making of bispecific antibodies,” MABS 9(2):182 - 212 (2017).

[0040] Figures 2A - 2F Exemplary bispecific forms described herein are shown. Figure 2A : Light chain C - terminal fusion; Figure 2B : Heavy chain C - terminal fusion; Figure 2C : Heavy chain N - terminal fusion; Figure 2D : DVD form; Figure 2E : Three - chain knobs - into - holes structure (KIH); and Figure 2F : Common light chain bispecific.

[0041] Figures 3A - 3BShows the levels of CD38 ( Figure 3A ) and ICAM1 ( Figure 3B ) on the surface of various cell lines measured by flow cytometry with anti-hCD38 labeled with PE (Biolegend) or anti-hCD54 labeled with AlexaFluor488 (Biolegend).

[0042] Figures 4A - 4B Shows complement-dependent cytotoxicity (CDC)-mediated lysis of selected monoclonal and bispecific antibodies against Daudi cells ( Figure 4A ) and Raji cells ( Figure 4B ).

[0043] Figures 5A - 5F Shows antibody-dependent cell-mediated cytotoxicity (ADCC)-mediated lysis using NK92 / CD16A as effector cells against 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.

[0044] Figures 6A - 6D Shows ADCC-mediated lysis using fresh PBMC as effector cells against Daudi cells ( Figure 6A ), DU145 cells ( Figure 6B ), HCC44 cells ( Figure 6C ) and NCI-H2444 cells ( Figure 6D ).

[0045] Figure 7 Shows induction of cell death and apoptosis by selected monoclonal and bispecific antibodies in the presence (gray bars) or absence (black bars) of a crosslinker in Daudi cells.

[0046] Figures 8A - 8B Shows antibody-induced cell death in NK92 / CD16a cells ( Figure 8A ) and NK cells in fresh PBMC ( Figure 8B ). Compared to the anti-CD38 BMK clone (or the reference antibody daratumumab), the HC N-fusion and trispecific KIH antibodies showed reduced NK killing.

[0047] Figures 9A - 9B Shows an exemplary anti-CD38 rabbit-human chimeric clone with recombinant human CD38 ECD ( Figure 9A ) and cynomolgus monkey CD38 ECD (Figure 9B ) ELISA binding.

[0048] Figures 10A - 10B Shows the ELISA binding of exemplary anti-ICAM1 rabbit-human chimeric clones to recombinant human ICAM1 ECD ( Figure 10A ) and rhesus monkey ICAM1 ECD ( Figure 10B ) ELISA binding.

[0049] Figure 11 Shows the binding of an exemplary anti-CD38 rabbit-human chimeric clone to Daudi cells as determined by flow cytometry.

[0050] Figure 12 Shows the binding of an anti-ICAM1 rabbit-human chimeric clone to DU145 cells as determined by flow cytometry.

[0051] Figure 13 Shows CDC-mediated lysis of Daudi cells by benchmark and exemplary rabbit-human chimeric anti-CD38 antibodies.

[0052] Figures 14A - 14B Shows ADCC-mediated lysis of Daudi cells ( Figure 14A ) and HuNS1 cells ( Figure 14B ) by anti-CD38 antibodies using NK92 / CD16A as effector cells.

[0053] Figures 15A - 15B Shows ADCC-mediated lysis of Daudi cells ( Figure 15A ) and HuNS1 cells ( Figure 15B ) by benchmark and exemplary rabbit-human chimeric anti-CD38 antibodies using NK92 / CD16A as effector cells.

[0054] Figures 16A - 16C Shows ADCC-mediated lysis of DU145 ( Figure 16A ), Daudi cells ( Figure 16B ), and HuNS1 cells ( Figure 16C ) by anti-ICAM1 clone G12 and an exemplary rabbit-human chimeric anti-ICAM1 antibody using NK92 / CD16A as effector cells.

[0055] Figures 17A - 17C Shows ADCC-mediated lysis of exemplary high-affinity anti-CD38 4618_1_12 bispecific antibody ( Figure 17A ), exemplary medium-affinity anti-CD38 32218_1 bispecific antibody ( Figure 17B ), and exemplary low-affinity anti-CD38 33218_2 bispecific antibody ( Figure 17C)ADCC-mediated lysis of DU145 cells.

[0056] Figures 18A - 18C Shows ADCC-mediated lysis of Raji ( Figure 18A ), DU145 ( Figure 18B ), and HCC44 ( Figure 18C ) using exemplary monovalent anti-CD38 (medium affinity, 32218_1), monovalent anti-ICAM1, and anti-CD38 / ICAM1 bispecific antibodies.

[0057] Figures 19A - 19B Shows increased ADCC-mediated lysis of Raji ( Figure 19A ) and KMS26 ( Figure 19B ) cells using a CD38 / ICAM1 KIH bispecific antibody with an Fc mutation (ADCC-high).

[0058] Figures 20A - 20B Shows increased ADCC-mediated lysis of Raji ( Figure 20A ) and KMS26 ( Figure 20B ) cells using an afucosylated CD38 / ICAM1 KIH bispecific antibody.

[0059] Figure 21 Shows the average volume of Raji cell-derived xenograft tumors treated with monospecific CD38 or ICAM1 antibodies or a trispecific KIH CD38 / ICAM1 bispecific antibody.

[0060] Figure 22 Shows the average volume of Raji cell-derived xenograft tumors treated with a monospecific CD38 antibody, a trispecific KIH CD38 / ICAM1 bispecific antibody with a CD38 binding domain from anti-CD38 BMK, or a trispecific KIH CD38 / ICAM1 bispecific antibody with a CD38 binding domain from 32218_1 (trispecific KIH (medium)).

[0061] Figure 23 Shows the average volume of HuNS1 cell-derived xenograft tumors treated with monospecific CD38 or ICAM1 antibodies or a trispecific KIH CD38 / ICAM1 bispecific antibody.

[0062] Figure 24Shows the mean volumes of xenograft tumors derived from HCC44 cells treated with fucosylated and afucosylated forms of bispecific antibodies having a CD38 binding domain derived from 18E4 and an ICAM1 binding domain derived from 11F2, monospecific antibodies having the same binding domains, and a monospecific anti-CD38 reference antibody (anti-CD38 BMK). Detailed Description

[0063] Due to the specificity and affinity of antibody binding to targets and the ease of chemical and molecular modification, antibody-based therapies have become effective cancer treatment options. For example, approved antibody-based therapies include monoclonal antibodies such as rituximab, tositumomab, and trastuzumab; and bispecific T cell engagers such as blinatumomab.

[0064] In some cases, low receptor copy numbers on target cells or low affinity for antigens have hindered the efficacy of antibody-based therapies. In some cases, antibodies are non-specific for target antigens, or the presence of targets in both cancer and non-cancer cells further limits the use of antibody-based therapies.

[0065] 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 the 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 associated with the regulation of the regulatory T cell compartment (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.

[0066] ICAM1, also known as CD54, is an Ig-like cell adhesion molecule. ICAM1 is an endothelial and leukocyte-associated transmembrane protein that participates 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 (e.g., myeloma, pancreatic cancer, glioma, lung cancer, melanoma, colorectal cancer, and lymphoma).

[0067] In some embodiments, anti-CD38 antibodies, anti-ICAM1 antibodies, and multispecific antibodies are disclosed herein that comprise a CD38-targeting moiety, an ICAM1-targeting moiety, or a combination thereof. In some embodiments, bispecific antibodies are also described herein that comprise a first CD38-targeting moiety and a second ICAM1-targeting moiety. In additional embodiments, methods of treating cancer using an anti-CD38 antibody, an anti-ICAM1 antibody, or a multispecific antibody (e.g., a bispecific CD38 / ICAM1 antibody) are also described herein. Multispecific protein

[0068] In certain embodiments, multispecific proteins are disclosed herein that comprise a first component that binds to CD38 and a second component that binds to ICAM1. In some instances, the first component is a CD38-binding protein such as an anti-CD38 antibody or an anti-CD38 antibody mimetic. In some instances, 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). Jun 12, 2017;10(1):293-320.

[0069] In some instances, the multispecific protein is bispecific, trispecific, or tetra-specific. In some instances, the multispecific protein is bivalent, trivalent, tetravalent, or more than tetravalent. In some instances, the multispecific protein has more than one binding site that binds to CD38. In some instances, the multispecific protein has more than one binding site that binds to ICAM1. In some instances, the multispecific protein has more than one binding site for each of 1, 2, 3, or 4 different target proteins. In some instances, the multispecific protein binds to more than one epitope on CD38 and / or ICAM1. In some instances, the multispecific protein is bivalent for CD38 and monovalent for ICAM1. In some instances, the multispecific protein is bivalent for ICAM1 and monovalent for CD38.

[0070] In some embodiments, the first component comprises an antibody mimetic containing a CD38-specific binding site and is an affibody, adnectin (also known as monobody), affimer, affitin (also known as nanofitin), anticalin, atrimer, avimer, fyonmer, an antibody mimetic containing an armadillo repeat domain, a kunitz domain, a knottin, a DARpin, or any combination thereof. In some embodiments, the second component comprises an antibody mimetic containing an ICAM1-specific binding site and is an affibody, adnectin (also known as monobody), affimer, adnectin (also known as monobody), affimer, affitin (also known as nanofitin), anticalin, atrimer, avimer, fyonmer, an antibody mimetic containing an armadillo repeat domain, a kunitz domain, a knottin, a DARpin, or any combination thereof.

[0071] 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), a Fab, an F(ab’)2, a single-chain variable fragment (scFv), an scFv comprising an Fc region (scFv Fc), a monovalent IgG, a V-NAR, an IgGNAR, a camel heavy chain IgG (hcIgG), an scFv fused to a CH3 domain (scFv-CH3).

[0072] 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), a Fab, an F(ab’)2, a single-chain variable fragment (scFv), an scFv comprising an Fc region (scFv Fc), a monovalent IgG, a V-NAR, an IgGNAR, a camel heavy chain IgG (hcIgG), an scFv fused to a CH3 domain (scFv-CH3).

[0073] In some embodiments, the multispecific protein comprising a first CD38-binding moiety and a second ICAM1-binding moiety has different affinities (K D ) for their respective target antigens, as measured by surface plasmon resonance. In some cases, the first moiety binds to human CD38 with a K D of from about 0.1 nM to about 100 nM, about 0.15 nM to about 95 nM, about 0.2 nM to about 90 nM, from 0.25 nM to about 85 nM, about 0.3 nM to about 80 nM, about 0.35 nM to about 75 nM, about 0.4 nM to about 70 nM, about 0.5 nM to about 70 nM, about 0.6 nM to about 60 nM, about 0.7 nM to about 50 nM, about 0.8 nM to about 40 nM, about 0.9 nM to about 30 nM, about 1 nM to about 20 nM, 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.

[0074] In some cases, the second moiety binds to human ICAM1 with a K D of from about 0.1 nM to about 100 nM, about 0.15 nM to about 95 nM, about 0.2 nM to about 90 nM, from 0.25 nM to about 85 nM, about 0.3 nM to about 80 nM, about 0.35 nM to about 75 nM, about 0.4 nM to about 70 nM, about 0.5 nM to about 70 nM, about 0.6 nM to about 60 nM, about 0.7 nM to about 50 nM, about 0.8 nM to about 40 nM, about 0.9 nM to about 30 nM, about 1 nM to about 20 nM, about 1.5 nM to about 10 nM, about 0.15 nM to about 30 nM, about 0.16 nM to about 25 nM, about 0.17 nM to about 20 nM, 0.18 nM to about 15 nM, about 0.19 nM to about 10 nM, about 0.1 nM to about 6 nM, about 0.2 nM to about 6 nM, about 0.2 nM to about 4 nM, about 0.2 nM to about 2 nM, about 0.2 nM to about 1.5 nM, about 0.2 nM to about 1 nM, about 0.2 nM to about 0.8 nM, about 0.2 nM to about 0.6 nM, or about 0.2 nM to about 0.4 nM.

[0075] 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 the quantification of protein surface expression, the ratio of ICAM1 to CD38 protein expression on the surface of the target cells is about 1.1 to 700, such as about 2.5, 14.2, 29.1, 64.5, 34.0, 50.3, 357.1, 666.7.

[0076] In some cases, the target cells express at least 500, 1000, 2000, 3000, 5000, 10000, 15000, 20000, 30000, 50000, 100000, 150000, 200000, 250000, 300000, 400000, or 500000 ICAM1 proteins on their surface, as measured by flow cytometry.

[0077] In some cases, the target cells express at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000 or 5000 CD38 proteins on their surface, as measured by flow cytometry. In some cases, the target cells express less than 350,000, 300,000, 250,000, 200,000, 150,000, 100,000, 50,000, 25,000 CD38 proteins on their surface, as measured by flow cytometry. In some cases, the number of CD38 proteins on the surface of the target cells 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, 100 to 10,000, 300 to 350,000, 300 to 300,000, 300 to 250,000, 300 to 200,000, 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, compared to Daudi cells, Raji cells, KMS-26 cells, HuNS1 cells, HCC44 cells, NCI-H2444 cells or DU145 cells, the target cells have fewer CD38 proteins on their surface. In some cases, the target cells have at least 200 CD38 proteins on their surface, but have fewer CD38 proteins on their surface compared to Daudi cells, Raji cells, KMS-26 cells, HuNS1 cells, HCC44 cells, NCI-H2444 cells or DU145 cells.

[0078] 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, lymphoma cell, pancreatic cancer cell, lung adenocarcinoma cell, or 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 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, myeloma cells, lymphoma cells, pancreatic cancer cells, lung adenocarcinoma cells, or prostate cancer cells express at least 100, 200, 300, 400, 500, 750, 1000, 1250, 1500, 2000, 3000 CD38 cells on their surface.

[0079] In some embodiments, a multispecific protein having a CD38 binding domain and an ICAM1 binding domain has enhanced affinity for cells expressing CD38 and ICAM1 as 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 1.5, 2, 3, 4, 5, or 10-fold higher affinity for cells expressing CD38 as compared to a monospecific protein that binds CD38 or a monospecific protein that binds ICAM1. In some embodiments, a multispecific protein having a CD38 binding domain and an ICAM1 binding domain has enhanced affinity for cells expressing a higher level of CD38 than ICAM1 as compared to a monospecific protein having a CD38 binding domain. In some cases, the multispecific protein has 1.5, 2, 3, 4, 5, or 10-fold higher affinity for cells having a higher expression of ICAM1 than CD38 as compared to a monospecific protein that binds CD38.

[0080] In some embodiments, compared to a monospecific protein having a CD38 binding domain and / or a monospecific protein having an ICAM1 binding domain, a greater amount of a multispecific protein having a CD38 binding domain and an ICAM1 binding domain binds to the cell surface expressing CD38 and ICAM. In some cases, the multispecific protein that binds to cells expressing CD38 is 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, compared to a monospecific protein having a CD38 binding domain, a greater amount of a multispecific protein having a CD38 binding domain and an ICAM1 binding domain binds to the cell surface having an ICAM1 expression higher than the CD38 expression. In some cases, the multispecific protein that binds to cells expressing more ICAM1 than CD38 is 1.5, 2, 3, 4, 5, or 10 times more than the monospecific protein that binds to CD38.

[0081] In some embodiments, compared to a monospecific protein having a CD38 binding domain and / or a monospecific protein having an ICAM1 binding domain, a multispecific protein having a CD38 binding domain and an ICAM1 binding domain has higher immune activity against cells expressing CD38. In some cases, the immune activity of the multispecific protein is 1.5, 2, 3, 4, 5, or 10 times higher than that of the monospecific protein having a CD38 binding domain and / or the monospecific protein having an ICAM1 binding domain. Various immunological activities of the multispecific protein can be measured by in vitro assays (such as ADCC assay and CDC assay). In some cases, the ADCC activity of the multispecific protein is 1.5, 2, 3, 4, 5, or 10 times higher than that of the monospecific protein having a CD38 binding domain and / or the monospecific protein having an ICAM1 binding domain. In some cases, the CDC activity of the multispecific protein is 1.5, 2, 3, 4, 5, or 10 times higher than that of the monospecific protein having a CD38 binding domain and / or the monospecific protein having an ICAM1 binding domain.

[0082] Immunoreactivity can also be measured in a cell line-derived xenograft assay, where transformed cells are injected into a mouse and tumors form. In some cases, a multispecific protein having a CD38-binding domain and an ICAM1-binding domain inhibits the growth of tumors comprising 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 higher xenograft tumor growth inhibition compared to a monospecific protein having a CD38-binding domain and / or a monospecific protein having an ICAM1-binding domain.

[0083] As used herein, “antibody-dependent cell-mediated cytotoxicity” and “ADCC” refer to a cell-mediated reaction in which non-specific cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages) recognize an antibody bound to a target cell, subsequently resulting in lysis of the target cell. In one embodiment, the target cell is a human cell, such as a tumor cell (e.g., a myeloma cell). While not wishing to be bound by any particular mechanism of action, cytotoxic cells mediating ADCC generally express Fc receptors (FcR). Cytotoxic cells mediating ADCC, NK cells, 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).

[0084] 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 (PBMC) and natural killer (NK) cells. Optionally, or additionally, in some embodiments, the ADCC activity of the target multispecific protein is assessed in vivo (e.g., in an animal).

[0085] “Complement-dependent cytotoxicity” or “CDC” refers to the ability of a molecule to initiate complement activation and lysis of 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 complexed with a cognate antigen (e.g., an antibody). To assess complement activation, in some embodiments a CDC assay is performed, e.g., as described by Gazzano-Santaro et al., J. Immunol. Methods, 202:163 (1996).

[0086] In some embodiments, a multispecific protein as described herein that binds CD38 and ICAM1 mediates complement-dependent lysis of at least 50% of 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 40% of cells by PBMC 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 without crosslinking. Anti-CD38 antibody

[0087] 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 is 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; 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 ; wherein X 13 is selected from A, G or S; X 14 is selected from I, F, Y, V, S or C; X 15 is selected from S, I, L, T or M; X 16Selected 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, it is 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 ; wherein 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, and if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, and if present, selected from P, L, Y, F, G or T; X 43 Present or absent, and if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, and if present, selected from G, L, S, T or F; X 45 Present or absent, and if present, selected from F, L, E, N or S; X 46 Present or absent, and if present, selected from D, S, L or R; X 47 Present or absent, and if present, selected from Y or L; X 48 Present or absent, and if present, is D; and X 49 Present or absent, and if present, is L

[0088] In some cases, 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.

[0089] 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 is selected from T, S, M, C, I, Y, A or G; X 11 Present or absent, and if present, selected from C or M; and X 12 Present or absent, and if present, is C.

[0090] 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 Present or absent, and if present, is C.

[0091] 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 is 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.

[0092] In some cases, the VH region of the anti-CD38 antibody comprises the CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID No. 418), wherein X 22 is selected from F or Y.

[0093] In some cases, the VH region of the anti-CD38 antibody comprises the 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 ; wherein X 13 is selected from A, G or S; X 14 is selected from I, F, Y, V, S or C; X 15 is selected from I, L, M or T; X 16 is selected from G, Y, S, T, L or V; X 17 is selected from S, I, K, Y, T, G or A; X 18 is selected from G, S, T, P or V; X 19 is selected from G, A, D, S or T; X 20 is selected from S, T, I, N or G; X 21 is selected from T, I, D, N, S or A; X 22 is selected from Y, N, T, I or S; X 23 is selected from Y, D, K or I; X 24 is 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 Present or absent, if present, selected from G or K; and X 31 Present or absent, if present, it is G.

[0094] In some cases, the VH region of the anti-CD38 antibody contains the 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 ; wherein 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 Selected from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Selected from W or T; X 27 Selected from A or W; X 28 Selected from K, R, Q or A; X 29 Selected from G or K; and X 30 Present or absent, if present, it is G.

[0095] In some cases, the VH region of the anti-CD38 antibody contains the 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 ; wherein X 13 is selected from A or S; X 15 is selected from I, L or T; X 16 is selected from Y or V; X 17 is selected from S, T or A; X 18 is selected from G, P or V; X 19 is selected from D, S or T; X 20 is selected from S, T or G; X 21 is selected from D, N, S or A; X 22 is selected from T, I or S; X 23 is selected from Y, K or I; X 25 is selected from A or Y; X 26 is selected from S, T, A or N; X 27 is selected from W, N or S; X 28 is selected from A or W; X 29 is selected from 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.

[0096] In some cases, 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 is selected from F or Y.

[0097] In some cases, the VH region of the anti-CD38 antibody comprises the 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 ; wherein 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, and if present, selected from V, D, Y, A, N, G, L or E; X 42 Present or absent, and if present, selected from L, Y, F, T or G; X 43 Present or absent, and if present, selected from P, F, V, N, S or Y; X 44 Present or absent, and if present, selected from L, S, T, G, F; X 45 Present or absent, and if present, selected from L, F, E, S or N; X 46 Present or absent, and if present, selected from S, L or R; X 47 Present or absent, and if present, is L; X 48 Present or absent, and if present, is D; and X 49 Present or absent, and if present, is L.

[0098] In some cases, the VH region of the anti-CD38 antibody comprises the 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 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 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, and if present, selected from P, F, V or N; X 44 Present or absent, and if present, selected from L, S or T; and X 45 Present or absent, and if present, selected from L or F.

[0099] In some cases, the VH region of the anti-CD38 antibody contains 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, and if present, selected from V, Y or E; X 42 Present or absent, and if present, is G; X 43 Present or absent, and if present, is Y; X 44 Present or absent, and if present, is F; X 45 Present or absent, and if present, selected from E or N; and X 46 Present or absent, and if present, selected from S or L.

[0100] In some cases, the VH region of the anti-CD38 antibody contains the CDRl sequence GFPFX5X6YAMS (SEQ ID NO:423), the CDR2 sequence AISGSGGSTX 22YADSVKG (SEQ ID NO:418) and the CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY (SEQID NO:421); wherein X5 is selected from D or G; X6 is selected from V, A or T; X 22 is selected from F or Y; X 38 is selected from A or G; and X 41 is selected from F or Y.

[0101] In some cases, the VH region of the anti-CD38 antibody comprises the CDRl sequence GFSLX5X6X7X8X9X 10 X 11 (SEQ ID NO:426), the 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 the 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 is selected from T, S or M; X 11 is present or absent, and if present, it is C; X 13 is selected from A or G; X 14 is selected from I, F, Y, V, S or C; X 16 is selected from G, Y, S, T or L; X 17 is selected from S, I, K, Y, T or G; X 18 is selected from G, S or T; X 19 is selected from G, A, D or S; X 20 is selected from T, I, N or G; X21 Selected from T, I or D; X 22 Selected from Y, N or T; X 23 Selected from Y or D; X 24 Selected from A or Y; X 25 Selected from T, S, N, R or A; X 26 Selected from W or T; X 27 Selected from A or W; X 28 Selected from K, R, Q or A; X 29 Selected from G or K; X 30 Present or absent, if present, then 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 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, then selected from P, F, V or N; X 44 Present or absent, if present, then selected from L, S or T; and X 45 Present or absent, if present, then selected from L or F.

[0102] In some cases, the VH region of the anti-CD38 antibody comprises the CDRl sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (SEQ IDNO:419), the 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 the 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 is selected from C, I, Y or M; X 11 is present or absent, and if present, is selected from C or M; X 12 is present or absent, and if present, is C; X 13 is selected from A or S; X 15 is selected from I, L or T; X 16 is selected from Y or V; X 17 is selected from S, T or A; X 18 is selected from G, P or V; X 19 is selected from D, S or T; X 20 is selected from S, T or G; X 21 is selected from D, N, S or A; X 22 is selected from T, I or S; X 23 is selected from Y, K or I; X 25 is selected from A or Y; X 26 is selected from S, T, A or N; X 27 is selected from W, N or S; X 28 is selected from A or W; X 29 is selected from K or A; X 30 is present or absent, and if present, is selected from G or K; X 31 is present or absent, and if present, is G; X 33 is selected from R or G; X 34 is selected from E, D or S; X 35 is selected from G, L, P, S or A; X 36 is selected from D, S or R; X 37 is selected from Y, T, N or G; X 38 is selected from G, S, F or L; X 39 is selected from A, G, S or I; X 40 is selected from Y, N or L; X 41 is present or absent, and if present, is selected from V, Y or E; X 42 is present or absent, and if present, is G; X 43Present or absent, and if present, then Y; X 44 Present or absent, and if present, then F; X 45 Present or absent, and if present, then selected from E or N; and X 46 Present or absent, and if present, then selected from S or L.

[0103] In some embodiments, the VH region of the anti-CD38 antibody comprises CDR1, CDR2, and CDR3 sequences selected from Table 1. Table 1. Heavy chain complementarity determining regions of exemplary anti-CD38 antibodies

[0104] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDRl 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, and 56; a CDR2 sequence selected from 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 ; wherein X 32 is selected from A, G, or V; X 33 is selected from K, A, R, T, G, or S; X 34 is selected from R, A, V, T, P, I, E, D, or S; X 35 is selected from G, W, D, L, K, P, S, A, T, or R; X 36 is selected from T, P, A, Y, D, G, S, R, V, or E; X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I; X 38 is selected from G, A, S, D, K, F, L, or Y; X 39 is selected from Y, T, A, G, S, or I; X 40Selected from S, Y, G, R, W, N, L, D or F; X 41 Present or absent, and if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, and if present, selected from P, L, Y, F, G or T; X 43 Present or absent, and if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, and if present, selected from G, L, S, T or F; X 45 Present or absent, and if present, selected from F, L, E, N or S; X 46 Present or absent, and if present, selected from D, S, L or R; X 47 Present or absent, and if present, selected from Y or L; X 48 Present or absent, and if present, is D; and X 49 Present or absent, and if present, is L.

[0105] 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 selected from SEQ ID NO: 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 Selected from F or Y.

[0106] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDRl sequence selected from 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 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 X 47 X 48 X49 , wherein X 32 is selected from A, G or V; X 33 is selected from A, R, T, S or G; X 34 is selected from A, V, T, P, I, E, D or S; X 35 is selected from G, W, D, L, K, P, S, R or A; X 36 is selected from P, A, Y, D, G, S, R, V, E or T; X 37 is selected from Y, V, T, S, N, A, G, Q, F or I; X 38 is selected from G, S, D, K, F, L or Y; X 39 is selected from T, A, G, S, I or Y; X 40 is selected from S, Y, G, R, W, N, L, D or F; X 41 is present or absent, and if present, is selected from V, D, Y, A, N, G, L or E; X 42 is present or absent, and if present, is selected from L, Y, F, T or G; X 43 is present or absent, and if present, is selected from P, F, V, N, S or Y; X 44 is present or absent, and if present, is 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; X 46 is present or absent, and if present, is selected from S, L or R; X 47 is present or absent, and if present, is L; X 48 is present or absent, and if present, is D; and X 49 is present or absent, and if present, is L.

[0107] In some embodiments, the VH region of the anti-CD38 antibody 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 , wherein X 32 is selected from A or G; X 33Selected 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 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, and if present, selected from P, F, V or N; X 44 Present or absent, and if present, selected from L, S or T; and X 45 Present or absent, and if present, selected from L or F.

[0108] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NO:17, 23, 29, 44 and 56; a CDR2 sequence selected from SEQ ID NO: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, and if present, selected from V, Y or E; X 42 Present or absent, and if present, is G; X 43 Present or absent, and if present, is Y; X 44 Present or absent, and if present, is F; X45 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.

[0109] 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 is 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; X 12 is present or absent, and if present, is C; the CDR2 sequence, which is selected from SEQ ID NO: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54 and 57; and the CDR3 sequence, which is 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.

[0110] 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; the CDR2 sequence, which is selected from SEQ ID NO: 2 and 5; and the CDR3 sequence, which is selected from SEQ ID NO: 3, 7 and 10. 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 10 is selected from T, S, M, C, I, Y, A or G; X 11Present or absent, and if present, selected from C or M; X 12 Present or absent, and if present, is C; a CDR2 sequence selected from 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 SEQ ID NO: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55 and 58.

[0111] 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 Selected from T, S or M; X 11 Present or absent, and if present, is C; a CDR2 sequence selected from SEQ ID NO: 12, 15, 27, 33, 36, 39, 42 and 51; and a CDR3 sequence selected from SEQ ID NO: 13, 16, 28, 34, 37, 40, 43 and 52.

[0112] 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, and if present, selected from C or M; X 12 Present or absent, and if present, is C; a CDR2 sequence selected from SEQ ID NO: 18, 24, 30, 45 and 57; and a CDR3 sequence selected from SEQ ID NO: 19, 25, 31, 46 and 58.

[0113] In some embodiments, the VH region of the anti-CD38 antibody 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; a CDR2 sequence X 13 X14 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 , wherein X 13 is selected from A, G or S; X 14 is selected from I, F, Y, V, S or C; X 15 is selected from S, I, L, T or M; X 16 is selected from G, Y, S, T, L or V; X 17 is selected from S, I, K, Y, T, G or A; X 18 is selected from G, S, T, P, V or Y; X 19 is selected from G, A, D, S or T; X 20 is selected from S, T, I, N or G; X 21 is selected from T, I, D, N, S or A; X 22 is selected from F, Y, N, T, I or S; X 23 is selected from Y, D, K or I; X 24 is selected from A or Y; X 25 is selected from D, T, S, N, R, A or Y; X 26 is selected from S, W, T, A or N; X 27 is selected from V, A, W, N or S; X 28 is selected from K, R, Q, A or W; X 29 is selected from G, K or A; X 30 is present or absent, and if present, is selected from G or K; X 31 is present or absent, and if present, is G; and a CDR3 sequence, which is 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.

[0114] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence, which is selected from SEQ ID NO: 1, 4, 6, 8 and 9; a CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID No. 418), wherein X 22selected from F or Y; and a CDR3 sequence selected from SEQ ID NO: 3, 7, and 10.

[0115] In some embodiments, the VH region of the anti-CD38 antibody 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; 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 , wherein X 13 is selected from A, G, or S; X 14 is selected from I, F, Y, V, S, or C; X 15 is selected from I, L, M, or T; X 16 is selected from G, Y, S, T, L, or V; X 17 is selected from S, I, K, Y, T, G, or A; X 18 is selected from G, S, T, P, or V; X 19 is selected from G, A, D, S, or T; X 20 is selected from S, T, I, N, or G; X 21 is selected from T, I, D, N, S, or A; X 22 is selected from Y, N, T, I, or S; X 23 is selected from Y, D, K, or I; X 24 is selected from A or Y; X 25 is selected from T, S, N, R, A, or Y; X 26 is selected from S, W, T, A, or N; X 27 is selected from A, W, N, or S; X 28 is selected from K, R, Q, A, or W; X 29 is 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 SEQ ID NO: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.

[0116] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NO: 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 , wherein X 13 is selected from A or G; X 14 is selected from I, F, Y, V, S, or C; X 16 is selected from G, Y, S, T, or L; X 17 is selected from S, I, K, Y, T, or G; X 18 is selected from G, S, or T; X 19 is selected from G, A, D, or S; X 20 is selected from T, I, N, or G; X 21 is selected from T, I, or D; X 22 is selected from Y, N, or T; X 23 is selected from Y or D; X 24 is selected from A or Y; X 25 is selected from T, S, N, R, or A; X 26 is selected from W or T; X 27 is selected from A or W; X 28 is 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 SEQ ID NO: 13, 16, 28, 34, 37, 40, 43, and 52.

[0117] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NO: 17, 23, 29, 44, and 56; a CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX25 X 26 X 27 X 28 X 29 X 30 X 31 , wherein X 13 is selected from A or S; X 15 is selected from I, L or T; X 16 is selected from Y or V; X 17 is selected from S, T or A; X 18 is selected from G, P or V; X 19 is selected from D, S or T; X 20 is selected from S, T or G; X 21 is selected from D, N, S or A; X 22 is selected from T, I or S; X 23 is selected from Y, K or I; X 25 is selected from A or Y; X 26 is selected from S, T, A or N; X 27 is selected from W, N or S; X 28 is selected from A or W; X 29 is selected from 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, which is selected from SEQ ID NO: 19, 25, 31, 46 and 58.

[0118] In some cases, the VH region of the anti-CD_{38} antibody comprises a CDR1 sequence, which is 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 and 56; a CDR2 sequence, which is selected from 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, which is 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.

[0119] In some cases, the VH region of the anti-CD_{38} antibody comprises a CDR1 sequence, which is selected from SEQ ID NO: 1, 4, 6, 8 and 9; a CDR2 sequence, which is selected from SEQ ID NO: 2 and 5; and a CDR3 sequence, which is selected from SEQ ID NO: 3, 7 and 10.

[0120] In some cases, the VH region of the anti-CD38 antibody 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; a CDR2 sequence selected from 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 SEQ ID NO: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55 and 58.

[0121] In some cases, the VH region of the anti-CD38 antibody 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 selected from SEQ ID NO: 13, 16, 28, 34, 37, 40, 43 and 52.

[0122] In some cases, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NO: 17, 23, 29, 44 and 56; a CDR2 sequence selected from SEQ ID NO: 18, 24, 30, 45 and 57; and a CDR3 sequence selected from SEQ ID NO: 19, 25, 31, 46 and 58.

[0123] In some embodiments, the VL region of the anti-CD38 antibody comprises CDR1, CDR2 and CDR3 sequences selected from Table 2. Table 2. Light chain complementarity determining regions of exemplary anti-CD38 antibodies 1 4618_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.

[0124] In some embodiments, the VL region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from SEQ ID NOs: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103. In some cases, the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100. In some cases, the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 71, 77, 83, 94, and 102; a CDR2 sequence selected from SEQ ID NOs: 72, 78, and 84; and a CDR3 sequence selected from SEQ ID NOs: 73, 79, 85, 95, and 103.

[0125] 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, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from 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 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 ; wherein X 32 is selected from A, G, or V; X 33 is 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, and if present, selected from F, Y, V, D, A, N, G, E or L; X 42 Present or absent, and if present, selected from P, L, Y, F, G or T; X 43 Present or absent, and if present, selected from T, P, F, V, N, Y or S; X 44 Present or absent, and if present, selected from G, L, S, T or F; X 45 Present or absent, and if present, selected from F, L, E, N or S; X 46 Present or absent, and if present, selected from D, S, L or R; X 47 Present or absent, and if present, selected from Y or L; X 48 Present or absent, and if present, is D; and X 49 Present or absent, and if present, is L; and wherein the VL region comprises a CDR1 sequence selected from SEQ ID 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.

[0126] 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; a CDR2 sequence selected from SEQ ID NO: 2 and 5; and a CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY (SEQ ID No. 421), wherein X 38 Selected from A or G, X 41selected 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.

[0127] 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; a CDR2 sequence selected from 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 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 , wherein X 32 is selected from A, G, or V; X 33 is selected from A, R, T, S, or G; X 34 is selected from A, V, T, P, I, E, D, or S; X 35 is selected from G, W, D, L, K, P, S, R, or A; X 36 is selected from P, A, Y, D, G, S, R, V, E, or T; X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I; X 38 is selected from G, S, D, K, F, L, or Y; X 39 is selected from T, A, G, S, I, or Y; X 40 is selected from S, Y, G, R, W, N, L, D, or F; X 41 is present or absent, and if present, is selected from V, D, Y, A, N, G, L, or E; X 42 is present or absent, and if present, is selected from L, Y, F, T, or G; X 43 is present or absent, and if present, is selected from P, F, V, N, S, or Y; X 44 is present or absent, and if present, is selected from L, S, T, G, or F; X 45Present or absent, and if present, selected from L, F, E, S or N; X 46 Present or absent, and if present, selected from S, L or R; X 47 Present or absent, and if present, is L; X 48 Present or absent, and if present, is D; and X 49 Present or absent, and if present, is L; and wherein the VL region comprises a CDR1 sequence selected from SEQ ID 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.

[0128] 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 , wherein 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 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, and if present, selected from P, F, V or N; X 44 Present or absent, and if present, selected from L, S or T; and X 45 Present or absent, and if present, 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.

[0129] 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; a CDR2 sequence selected from SEQ ID NO: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, and if present, selected from V, Y or E; X 42 Present or absent, and if present, is G; X 43 Present or absent, and if present, is Y; X 44 Present or absent, and if present, is F; X 45 Present or absent, and if present, selected from E or N; X 46Present or absent, and 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.

[0130] In some embodiments, the anti-CD38 antibody comprises a VH region and a 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 is 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 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 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 SEQ ID 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.

[0131] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence of GFPFX5X6YAMS (SEQ ID No. 423), where X5 is selected from D or G and X6 is selected from V, A or T; a CDR2 sequence selected from SEQ ID NO: 2 and 5; 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.

[0132] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence of X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 , where 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 is 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; X 12 is present or absent, and if present, is C; a CDR2 sequence selected from 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 SEQ ID NO: 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 SEQ ID 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.

[0133] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDRl sequence of 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 SEQ ID NO: 12, 15, 27, 33, 36, 39, 42 and 51; and a CDR3 sequence selected from SEQ ID NO: 13, 16, 28, 34, 37, 40, 43 and 52; 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.

[0134] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a 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 is 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 SEQ ID NO: 18, 24, 30, 45 and 57; and a CDR3 sequence selected from SEQ ID NO: 19, 25, 31, 46 and 58; 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.

[0135] 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; 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 , wherein X 13 is selected from A, G or S; X 14 is selected from I, F, Y, V, S or C; X 15 is selected from S, I, L, T or M; X 16 is selected from G, Y, S, T, L or V; X 17 is selected from S, I, K, Y, T, G or A; X 18 is selected from G, S, T, P, V or Y; X 19 is selected from G, A, D, S or T; X 20 is selected from S, T, I, N or G; X 21 is selected from T, I, D, N, S or A; X 22 is selected from F, Y, N, T, I or S; X 23 is selected from Y, D, K or I; X 24 is selected from A or Y; X 25 is selected from D, T, S, N, R, A or Y; X 26 is selected from S, W, T, A or N; X 27 is selected from V, A, W, N or S; X 28 is selected from K, R, Q, A or W; X 29 is selected from G, K or A; X 30 is present or absent, and if present, is selected from G or K; X 31Present or absent, and if present, it 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; and wherein the VL region contains a CDR1 sequence selected from SEQ ID 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.

[0136] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region contains 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; and wherein the VL region contains 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.

[0137] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region contains 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; 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 , wherein X 13 is 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 Present or absent, and if present, selected from G or K; and X 31 Present or absent, and if present, is G; and a CDR3 sequence selected from SEQ ID NO: 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 SEQ ID 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.

[0138] 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 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 , wherein X 13 is selected from A or G; X 14 is selected from I, F, Y, V, S or C; X 16 is selected from G, Y, S, T or L; X 17 is selected from S, I, K, Y, T or G; X 18 is selected from G, S or T; X 19 is selected from G, A, D or S; X 20 is selected from T, I, N or G; X 21 is selected from T, I or D; X 22 is selected from Y, N or T; X 23 is selected from Y or D; X 24 is selected from A or Y; X 25 is selected from T, S, N, R or A; X 26 is selected from W or T; X 27 is selected from A or W; X 28 is 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 SEQ ID NO: 13, 16, 28, 34, 37, 40, 43 and 52; 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.

[0139] 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; 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 , wherein X 13Selected 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 Selected from A or W; X 29 Selected from K or A; X 30 Present or absent, and if present, selected from G or K; and X 31 Present or absent, and if present, is G; and a CDR3 sequence selected from SEQ ID NO: 19, 25, 31, 46 and 58; 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.

[0140] In some cases, 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 and 56; a CDR2 sequence selected from 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 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 SEQ ID 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.

[0141] In some cases, 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; a CDR2 sequence selected from SEQ ID NO: 2 and 5; 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.

[0142] In some cases, 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; a CDR2 sequence selected from 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 SEQ ID NO: 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 SEQ ID 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.

[0143] In some cases, 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 selected from SEQ ID NO: 13, 16, 28, 34, 37, 40, 43, and 52; 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.

[0144] In some cases, 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; a CDR2 sequence selected from SEQ ID NO: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from SEQ ID NO: 19, 25, 31, 46, and 58; 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.

[0145] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the sequence of the VH region has about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 104 - 128, and the sequence of the VL region has about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 130 - 154.

[0146] In some embodiments, the VH region comprises a sequence selected from Table 3 and the VL region comprises a sequence selected from Table 4. Table 3. Heavy chain variable domains of exemplary anti-CD38 antibodies. Underlined regions indicate the respective CDR1, CDR2, or CDR3 sequences. Table 4. Light chain variable domains of exemplary anti-CD38 antibodies. Underlined regions indicate the respective CDR1, CDR2, or CDR3 sequences.

[0147] In some embodiments, the anti-CD38 antibody is a full-length antibody. In other embodiments, the anti-CD38 antibody is a binding fragment. In some cases, the anti-CD38 antibody comprises an antibody or its binding fragment, a chimeric antibody or its binding fragment, a monoclonal antibody or its binding fragment, or a bispecific antibody or its binding fragment. 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 its binding fragment.

[0148] In some embodiments, the anti-CD38 antibody comprises a bispecific antibody or its binding fragment. In some cases, the bispecific antibody or its binding fragment 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 additional and Fc-modified IgG, a modified Fc and CH3 fusion protein, an additional IgG-HC fusion, an Fc fusion, a CH3 fusion, an IgE / IgM CH2 fusion, or an F(ab’)2 fusion.

[0149] In some embodiments, the bispecific antibody or binding fragment includes a knobs-into-holes (KIH), an asymmetric re-engineering technology-immunoglobulin (ART-Ig), a Triomab quadroma, a bispecific monoclonal antibody (BiMAb, BsmAb, BsAb, bsMab, BS-Mab, or Bi-MAb), an FcΔAdp, an XmAb, an Azymetric, a bispecific engagement of a T cell receptor-based antibody (BEAT), a bispecific T cell engager (BiTE), a Biclonics, a Fab-scFv-Fc, a two-in-one / dual-affinity Fab (DAF), a FinomAb, a scFv-Fc-(Fab)-fusion, a dock-and-lock (DNL), an Adaptir (previously SCORPION), a tandem diabody (TandAb), a dual-affinity retargeting (DART), or a nanobody.

[0150] In some embodiments, the variable domain-only bispecific antibody includes a tandem scFv (taFv), a trisbody, a diabody (Db), a dsDb, a Db(KIH), a scDb, a dsFv-dsFv', a tandAbs, triple heads, a tandem dAb / VHH, a triple dAb / VHH, or a tetravalent dAb / VHH.

[0151] In some embodiments, the CH1 / CL fusion protein comprises scFv2-CH1 / CL or VHH2-CH1 / CL.

[0152] In some cases, the Fab fusion protein comprises Fab-scFv (diabody), Fab-scFv2 (tribody), Fab-Fv, Fab-dsFv, Fab-VHH, or orthogonal Fab-Fab.

[0153] In some cases, the non-immunoglobulin fusion protein comprises scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, minibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, or ImmTAC (TCR-scFv).

[0154] In some cases, the Fc-modified IgG comprises 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.

[0155] In some cases, the additional and Fc-modified IgG comprises 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.

[0156] In some cases, the modified Fc and CH3 fusion protein comprises 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.

[0157] 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).

[0158] In some cases, the additional IgG-LC fusion antibody comprises IgG-scFv(LC), scFv(LC)-IgG, or dAb-IgG.

[0159] In some cases, the additional IgG-HC & LC fusion antibody includes DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, or Zybody.

[0160] 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.

[0161] In some cases, the CH3 fusion antibody comprises a diabody or scDb-CH3.

[0162] In some instances, the IgE / IgM CH2 fusion antibody comprises scFv-EHD2-scFv or scFv-MHD2-scFv.

[0163] In some instances, the F(ab')2 fusion antibody comprises F(ab')2-scFv2.

[0164] In some cases, the CH1 / CL fusion protein comprises scFv2-CH1-hinge / CL.

[0165] In some cases, modified IgG includes DAF (two-in-one-IgG), DutaMab or mAb 2 .

[0166] In some instances, the non-immunoglobulin fusion antibody comprises DNL-Fab4-IgG.

[0167] In some cases, anti-CD38 antibodies include, for example Figure 1A or Figure 1B The bispecific antibody or binding fragment thereof is shown.

[0168] 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 antibody comprises an IgG framework (e.g., IgG1, IgG2, IgG3, or IgG4). In such cases, the anti-CD38 antibody comprises an IgG1, IgG2, IgG3, or IgG4 framework.

[0169] 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 the half-life. In some cases, the one or more mutations are used to modulate Fc receptor interaction for increasing antibody-dependent cell-mediated cytotoxicity (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 additional examples, the one or more mutations are used to modulate glycosylation.

[0170] In some cases, the anti-CD38 antibody comprises an IgG1 framework. In some embodiments, the constant region of the anti-CD38 antibody is modified at one or more amino acid positions to alter Fc receptor interaction. Exemplary residues for modulating or altering Fc receptor interaction 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., Sequences of Proteins of Immunological Interest, 1991). In some cases, the mutations include G236A, S239D, T250Q, M252Y, S254T, T256E, K326W, A330L, I332E, E333A, E333S, M428L, H433K, or N434F.

[0171] In some embodiments, the modification for altering Fc receptor interaction at one or more amino acid positions in the IgG1 constant region results in an increased half-life. In some cases, the modification at one or more amino acid positions includes T250, M252, S254, T256, M428, H433, N434, or a combination thereof; e.g., including T250Q / M428L or M252Y / S254T / T256E and H433K / N434F.

[0172] In some embodiments, modifications at one or more amino acid positions in the IgGl constant region for altering Fc receptor interaction result in increased ADCC and / or CDC. In some cases, the modifications at one or more amino acid positions include S239, K326, A330, I332, E333, or combinations thereof. In some cases, the modifications at one or more amino acid positions for increasing ADCC and / or CDC include, for example, E333A, S239D / A330L / I332E, or K326W / E333S. In some cases, the modifications at one or more amino acid positions for increasing ADCC include S239D / A330L / I332E. In some cases, the modifications at one or more amino acid positions for increasing CDC include K326W / E333S.

[0173] In some embodiments, modifications at one or more amino acid positions in the IgGl constant region for altering Fc receptor interaction result in increased macrophage phagocytosis. In some cases, the modifications at one or more amino acid positions include G236, S239, I332, or combinations thereof. In some cases, the modifications at one or more amino acid positions for increasing macrophage phagocytosis include the combination S239D / I332I / G236A.

[0174] In some embodiments, the IgGl constant region is modified at amino acid N297 (Kabat number), for example, modified to N297C.

[0175] 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 interaction, for example, for increasing 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 the 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.

[0176] 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, e.g., for increasing 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 the 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 the half-life, e.g., R435H (Kabat numbering). In some cases, the constant region is afucosylated.

[0177] In some embodiments, the anti-CD38 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, e.g., 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.), as described, for example, 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 the 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).

[0178] In some embodiments, the human IgG constant region is modified for ADCC and / or CDC, e.g., having 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.

[0179] 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 with a larger amino acid (e.g., Trp (T366W)), is capable of preferentially pairing with a second CH3 domain that has amino acid modifications at positions Thr366, Leu368, and Tyr407 that result in a smaller volume, such as Ser, Ala, and Val (T366S / L368A / Y407V). In some cases, heterodimerization by CH3 modification is further stabilized by introducing disulfide bonds, for example, by replacing Ser354 with Cys (S354C) and Y349 with Cys (Y349C) on opposite CH3 domains (reviewed in Carter, 2001 Journal of Immunological Methods, 248:7-15).

[0180] In some cases, the anti-CD38 antibodies described herein have reduced glycosylation or lack glycosylation and are unmodified at amino acid Asn297 (Kabat numbering). In these cases, glycosylation is eliminated, for example, by producing the antibody in a host cell lacking the ability for post-translational glycosylation (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.

[0181] 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. Table 5. Heavy Chains of Exemplary Anti-CD38 Antibodies Table 6. Light Chains of Exemplary Anti-CD38 Antibodies

[0182] In some embodiments, the anti-CD38 antibodies described herein have enhanced ADCC and / or CDC compared to daratumumab, which is used as a reference antibody. In some cases, compared to daratumumab, 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. In some cases, compared to daratumumab, 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.

[0183] In some cases, compared to the reference antibody daratumumab, the enhanced ADCC and / or CDC is an increase of 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. In some cases, compared to the reference antibody daratumumab, the enhanced ADCC and / or CDC is an increase of 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.

[0184] In some embodiments, ADCC activity is determined by an in vitro cytotoxicity assay, for example, using PBMC effector cells and targeting cancer cells, such as B lymphoblasts from lymphoma, such as Daudi cells. The anti-CD38 antibodies described herein have an EC -6 of about 1×10 -6 nM to about 2 nM (such as about 4×10 50 nM, about 0.000014 nM, 0.00007 nM, 0.00006 nM, about 0.00010 nM, about 0.0002 nM, about 0.0003 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 about 0.00001 to about 0.00003 nM.

[0185] In some embodiments, the anti-CD38 antibodies described herein have improved cell killing effects compared to the reference antibody daratumumab. In some cases, compared to the reference antibody daratumumab, 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. In some cases, compared to the reference antibody daratumumab, 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.

[0186] In some cases, compared to the reference antibody daratumumab, the improved cell killing effect is an increase of 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. In some cases, compared to the reference antibody daratumumab, the improved cell killing effect is an increase of 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.

[0187] In some embodiments, the anti-CD38 antibodies described herein have an 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.

[0188] In some cases, the serum half-life of the anti-CD38 antibodies 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 cases, the serum half-life of the anti-CD38 antibodies 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. Anti-ICAM1 antibody

[0189] 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 ; wherein X 1 is selected from G or E; X 2 is selected from F or Y; X 3 is selected from S or T; X 4 is selected from L, F or S; X 5 is selected from S or N; X 6 is selected from S, N, T or D; X 7 is selected from Y, H or G; X 8 is selected from G, A, Y, W or F; X 9 is 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; the 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 ; wherein X 12 is selected from G, T, A, I or Y; X 13 is selected from W, I, Y or C; X 14 is selected from I, S or Y; X 15 is selected from S, G, T, D or P; X 16 is selected from F, S, D, T or A; X 17 is selected from S, R, G or D; X 18 is selected from G, D or S; X 19 is selected from S, R, T, N, Y, A, D or P; X 20 is selected from T, A, G or Y; X 21Selected from Y, H, A, S or T; X 22 Selected 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 Present or absent, if present, selected from K or G; and X 30 Present or absent, if present, is 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 ; wherein 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 45Present or absent, and if present, selected from L, Y, F or C; X 46 Present or absent, and if present, selected from D, A or F; X 47 Present or absent, and if present, selected from M, P, Y or N; X 48 Present or absent, and if present, selected from D or L; and X 49 Present or absent, and if present, is L.

[0190] 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 is selected from S or N; X 6 is selected from S, N, T or D; X 7 is selected from Y or H; X 8 is selected from G, A or Y; and X 10 is selected from S, G or N.

[0191] In some cases, the VH region of the anti-ICAMl 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 is selected from W, I or Y; X 15 is selected from S or G; X 16 is selected from F, S, D or T; X 17 is selected from S or R; X 18 is selected from G or D; X 19 is 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.

[0192] In some cases, the VH region of the anti-ICAMl 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 selected from A or V; X 33 selected 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, and if present, selected from L, Y or F; X 46 present or absent, and if present, is D; X 47 present or absent, and if present, selected from M or P; X 48 present or absent, and if present, is D; and X 49 present or absent, and if present, is L.

[0193] 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), the CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG(SEQ ID NO:420) and the 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 is selected from S or N; X 6 is selected from S, N, T or D; X 7 is selected from Y or H; X 8 is selected from G, A or Y; X 10 is selected from S, G or N; X 13 is selected from W, I or Y; X 15 is selected from S or G; X 16 is selected from F, S, D or T; X 17 is selected from S or R; X 18 is selected from G or D; X 19 is selected from S, R, T or N; X 20 is selected from T or A; X 24 is selected from S, T or N; X 31 is selected from A or V; X 33 is selected from G or D; X 34 is selected from G, P, W or D; X 35 is selected from D, Y, S or L; X 36 is selected from Y, D, V or L; X 37 is selected from G, S or D; X 38 is selected from G, Y, F or S; X 39 is selected from S, D, G or T; X 40 is selected from T, A, D, S or Y; X 41 is selected from Y, A, G or I; X 42 is selected from I, Y or R; X 43 is selected from L, R, Y or G; X 44 is selected from N, L, Y or S; X 45 is present or absent, and if present, is selected from L, Y or F; X 46 is present or absent, and if present, is D; X 47 is present or absent, and if present, is selected from M or P; X 48 is present or absent, and if present, is D; and X 49 is present or absent, and if present, is L.

[0194] In some embodiments, the VH region of the anti-ICAM1 antibody comprises CDR1, CDR2, and CDR3 sequences selected from Table 7. Table 7. Heavy Chain Complementary Determining Regions of Exemplary Anti-ICAM1 Antibodies

[0195] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from SEQ ID NO: 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 , wherein X 31 is selected from A or V; X 32 is selected from R or I; X 33 is selected from G, D, P, A, or V; X 34 is selected from G, P, W, D, N, or R; X 35 is selected from D, Y, S, L, G, F, or W; X 36 is selected from Y, D, V, L, S, G, or P; X 37 is selected from G, S, D, V, or E; X 38 is selected from G, Y, F, S, or D; X 39 is selected from S, D, G, T, N, A, or V; X 40 is selected from T, A, D, S, Y, L, or F; X 41 is present or absent, and if present, is selected from Y, A, G, I, or D; X 42 is present or absent, and if present, is selected from I, Y, R, P, V, or G; X 43 is present or absent, and if present, is selected from L, R, Y, G, or A; X 44 is present or absent, and if present, is selected from N, L, Y, S, or W; X 45 is present or absent, and if present, is selected from L, Y, F, or C; X 46Present or absent, and if present, selected from D, A or F; X 47 Present or absent, and if present, selected from M, P, Y or N; X 48 Present or absent, and if present, selected from D or L; and X 49 Present or absent, and if present, is L.

[0196] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235 and 238; a CDR2 sequence selected from SEQ ID NO: 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 selected 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, and if present, selected from L, Y or F; X 46 Present or absent, and if present, is D; X 47 Present or absent, and if present, selected from M or P; X 48Present or absent, and if present, is D; and X 49 Present or absent, and if present, is L.

[0197] 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 , wherein X 1 is selected from G or E; X 2 is selected from F or Y; X 3 is selected from S or T; X 4 is selected from L, F or S; X 5 is selected from S or N; X 6 is selected from S, N, T or D; X 7 is selected from Y, H or G; X 8 is selected from G, A, Y, W or F; X 9 is selected from M, W, Y or I; X 10 is selected from S, G, N, M or I; X 11 Present or absent, and if present, is C; a CDR2 sequence selected from 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 SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249 and 252.

[0198] 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 IDNO:425), wherein X 5 is selected from S or N; X 6 is selected from S, N, T or D; X 7 is 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.

[0199] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from SEQ ID NO: 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 selected 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 present or absent, and if present, selected from K or G; and X30 Present or absent, and if present, it 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.

[0200] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from SEQ ID NO: 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 is selected from W, I, or Y; X 15 is selected from S or G; X 16 is selected from F, S, D, or T; X 17 is selected from S or R; X 18 is selected from G or D; X 19 is 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.

[0201] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from 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 SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252.

[0202] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from SEQ ID NO: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, and 412; a CDR2 sequence selected from SEQ ID NO: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, and 413; and a CDR3 sequence selected from SEQ ID NO: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, and 414.

[0203] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from SEQ ID NO: 241, 247, and 250; a CDR2 sequence selected from SEQ ID NO: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from SEQ ID NO: 243, 245, 249, and 252.

[0204] In some embodiments, the VL region of the anti-ICAM1 antibody comprises CDR1, CDR2, and CDR3 sequences selected from Table 8. Table 8. Light chain complementarity determining regions of exemplary anti-ICAM1 antibodies

[0205] In some embodiments, the VL region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from SEQ ID NO: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 415; a CDR2 sequence selected from SEQ ID NO: 254, 257, 260, 263, 273, 275, 280, 283, and 416; and a CDR3 sequence selected from SEQ ID NO: 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 417.

[0206] In some embodiments, the VL region of the anti-ICAM1 antibody comprises CDR1, CDR2, and CDR3 sequences SEQ ID NO: 62 - 64, respectively.

[0207] 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; a CDR2 sequence selected from SEQ ID NO: 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 , wherein X 31 is selected from A or V; X 32 is selected from R or I; X 33 is selected from G, D, P, A or V; X 34 is selected from G, P, W, D, N or R; X 35 is selected from D, Y, S, L, G, F or W; X 36 is selected from Y, D, V, L, S, G or P; X 37 is selected from G, S, D, V or E; X 38 is selected from G, Y, F, S or D; X 39 is selected from S, D, G, T, N, A or V; X 40 is selected from T, A, D, S, Y, L or F; X 41 is present or absent, and if present, is selected from Y, A, G, I or D; X 42 is present or absent, and if present, is selected from I, Y, R, P, V or G; X 43 is present or absent, and if present, is selected from L, R, Y, G or A; X 44 is present or absent, and if present, is selected from N, L, Y, S or W; X 45 is present or absent, and if present, is selected from L, Y, F or C; X 46 is present or absent, and if present, is selected from D, A or F; X 47 is present or absent, and if present, is 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 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.

[0208] 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; a CDR2 sequence selected from SEQ ID NO: 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 is selected from A or V; X 33 is selected from G or D; X 34 is selected from G, P, W, or D; X 35 is selected from D, Y, S, or L; X 36 is selected from Y, D, V, or L; X 37 is selected from G, S, or D; X 38 is selected from G, Y, F, or S; X 39 is selected from S, D, G, or T; X 40 is selected from T, A, D, S, or Y; X 41 is selected from Y, A, G, or I; X 42 is 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, and if present, selected from L, Y or F; X 46 Present or absent, and if present, is D; X 47 Present or absent, and if present, selected from M or P; X 48 Present or absent, and if present, is D; and X 49 Present or absent, and if present, is L; 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.

[0209] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a 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 , wherein X 1 Selected from G or E; X 2 Selected from F or Y; X 3 Selected 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 11Present or absent, and if present, is C; a CDR2 sequence selected from 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 SEQ ID 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.

[0210] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 (SEQ ID NO: 425), wherein X 5 is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y or H; X 8 is selected from G, A, or Y; and X 10 is selected 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; 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.

[0211] 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; 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 , wherein X 12 is selected from G, T, A, I, or Y; X 13 is selected from W, I, Y, or C; X 14 is selected from I, S, or Y; X 15 is selected from S, G, T, D, or P; X 16 is selected from F, S, D, T, or A; X 17 is selected from S, R, G, or D; X 18 is selected from G, D, or S; X 19 is selected from S, R, T, N, Y, A, D, or P; X 20 is selected from T, A, G, or Y; X 21 is selected from Y, H, A, S, or T; X 22 is selected from Y or N; X 23 is selected from A, P, Y, or S; X 24 is selected from S, T, N, D, Y, A, or P; X 25 is selected from W, S, A, or D; X 26 is selected from A, V, T, W, F, or S; X 27 is selected from K, W, A, Q, or V; X 28 is selected from G, A, or K; X 29 is present or absent, and if present, is selected from K or G; and X 30Present 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; 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.

[0212] 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; 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 is selected from W, I or Y; X 15 is selected from S or G; X 16 is selected from F, S, D or T; X 17 is selected from S or R; X 18 is selected from G or D; X 19 is 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.

[0213] 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; a CDR2 sequence selected from SEQ ID NO: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248 or 251; 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; 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.

[0214] 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; 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; 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.

[0215] 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: 241, 247, and 250; a CDR2 sequence selected from SEQ ID NO: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from SEQ ID NO: 243, 245, 249, and 252; and wherein the VL region comprises CDR1, CDR2, and CDR3 sequences SEQ ID NO: 62 - 64, respectively.

[0216] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the sequence of the VH region has about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 289 - 309, and the sequence of the VL region has about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NO: 311 - 326 and 155.

[0217] In some embodiments, the VH region comprises a sequence selected from Table 9 and the VL region comprises a sequence selected from Table 10. Table 9. Heavy chain variable domains of exemplary anti-ICAM1 antibodies. Underlined regions indicate the respective CDR1, CDR2, or CDR3 sequences. Table 10. Light chain variable domains of exemplary anti-ICAM1 antibodies. Underlined regions indicate the respective CDR1, CDR2, or CDR3 sequences.

[0218] In some embodiments, the anti-ICAM1 antibody described above 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 its binding fragment, a chimeric antibody or its binding fragment, a monoclonal antibody or its binding fragment, or a bispecific antibody or its binding fragment. In some cases, the anti-CD38 antibody comprises a monovalent Fab, bivalent Fab'2, single-chain variable fragment (scFv), diabody, minibody, nanobody, single-domain antibody (sdAb), or a camelid antibody or its binding fragment.

[0219] In some embodiments, the anti-ICAM1 antibody includes a bispecific antibody or its binding fragment. In some cases, the bispecific antibody or its binding fragment is a bispecific antibody conjugate, a heterodimeric 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 additional and Fc-modified IgG, a modified Fc and CH3 fusion protein, an additional IgG-HC fusion, an Fc fusion, a CH3 fusion, an IgE / IgM CH2 fusion, or an F(ab’)2 fusion.

[0220] In some embodiments, the bispecific antibody or binding fragment includes a knobs-into-holes (KIH), an asymmetric re-engineering technology-immunoglobulin (ART-Ig), a Triomab tetrabody, a bispecific monoclonal antibody (BiMAb, BsmAb, BsAb, bsMab, BS-Mab, or Bi-MAb), an FcΔAdp, an XmAb, an Azymetric, a bispecific engagement of a T cell receptor-based antibody (BEAT), a bispecific T cell engager (BiTE), a Biclonics, a Fab-scFv-Fc, a dual action / dual function Fab (DAF), a FinomAb, a scFv-Fc-(Fab)-fusion, a docking and locking (DNL), an Adaptir (previously SCORPION), a tandem diabody (TandAb), a bispecific affinity retargeting (DART), or a nanobody.

[0221] In some embodiments, the variable domain only bispecific antibodies include tandem scFv (taFv), trisomab, diabody (Db), dsDb, Db(KIH), scDb, dsFv-dsFv', tandAbs, triple head, tandem dAb / VHH, triple dAb / VHH or tetravalent dAb / VHH.

[0222] In some embodiments, the CH1 / CL fusion proteins include scFv2-CH1 / CL or VHH2-CH1 / CL.

[0223] In some cases, the Fab fusion proteins include Fab-scFv (diabody), Fab-scFv2 (trisomab), Fab-Fv, Fab-dsFv, Fab-VHH or orthogonal Fab-Fab.

[0224] In some cases, the non-immunoglobulin fusion proteins include scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, minibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2 or ImmTAC (TCR-scFv).

[0225] In some cases, the Fc-modified IgG include 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, quadroma-CrossMab(KIH), LUZ-Y common LC, LUZ-Y scFab-IgG or FcFc*.

[0226] In some cases, the additional and Fc-modified IgG include IgG(KIH)-Fv, IgG(HA-TF-FV), IgG(KIH)-scFab, scFab-Fc(KIH)-scFv2, scFab-Fc(KIH)-scFv, semi-DVD-Ig, dual variable domain-immunoglobulin (DVD-Ig) or CrossMab-Fab.

[0227] 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.

[0228] In some cases, the additional IgG-HC fusion antibodies include 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).

[0229] In some cases, the additional IgG-LC fusion antibodies include IgG-scFv(LC), scFv(LC)-IgG or dAb-IgG.

[0230] In some cases, the additional IgG-HC&LC fusion antibodies include DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG or Zybody.

[0231] In some cases, the Fc fusion antibodies include bis-bispecific antibodies, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-Ig or scFv2-Fcab.

[0232] In some cases, the CH3 fusion antibodies include bis-bispecific antibodies or scDb-CH3.

[0233] In some cases, the IgE / IgM CH2 fusion antibodies include scFv-EHD2-scFv or scFv-MHD2-scFv.

[0234] In some cases, the F(ab’)2 fusion antibodies include F(ab’)2-scFv2.

[0235] In some cases, the CH1 / CL fusion proteins include scFv2-CH1-hinge / CL.

[0236] In some cases, the modified IgG includes DAF (diabody-IgG), DutaMab, or mAb 2 .

[0237] In some cases, the non-immunoglobulin fusion antibody includes DNL-Fab4-IgG.

[0238] In some cases, the anti-ICAM1 antibody includes a bispecific antibody or a binding fragment thereof as shown in Figure 1A or Figure 1B .

[0239] In some embodiments, the anti-ICAM1 antibody described herein comprises an IgG framework, an IgA framework, an IgE framework, or an IgM framework. In some cases, the anti-ICAM1 antibody comprises an IgG framework (e.g., IgG1, IgG2, IgG3, or IgG4). In such cases, the anti-ICAM1 antibody comprises an IgG1, IgG2, IgG3, or IgG4 framework.

[0240] 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 the half-life. In some cases, the one or more mutations are used to modulate Fc receptor interaction 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 additional cases, the one or more mutations are used to modulate glycosylation.

[0241] 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 interaction. Exemplary residues that regulate or alter Fc receptor interaction include, but are not limited to, G236, S239, T250, M252, S254, T256, K326, A330, I332, E333A, M428, H433, or N434 (Kabat numbering; Kabat et al., Sequences of Proteins of Immunological Interest, EU index, 1991). In some cases, the mutations include G236A, S239D, T250Q, M252Y, S254T, T256E, K326W, A330L, I332E, E333A, E333S, M428L, H433K, or N434F.

[0242] In some embodiments, modifications at one or more amino acid positions in the IgGl constant region for altering Fc receptor interaction result in an increased half-life. In some cases, the modification at one or more amino acid positions includes T250, M252, S254, T256, M428, H433, N434, or a combination thereof; for example, including T250Q / M428L or M252Y / S254T / T256E and H433K / N434F.

[0243] In some embodiments, modifications at one or more amino acid positions in the IgGl constant region for altering Fc receptor interaction result in an increase in ADCC and / or CDC. 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.

[0244] In some embodiments, modifications at one or more amino acid positions in the IgGl constant region for altering Fc receptor interaction result in an increase in macrophage phagocytosis. In some cases, the modification at one or more amino acid positions includes G236, S239, I332, or a combination thereof. In some cases, the modification at one or more amino acid positions for increasing macrophage phagocytosis includes the combination S239D / I332I / G236A.

[0245] In some embodiments, the IgGl constant region is modified at amino acid N297 (Kabat number), where the residue N297 is afucosylated and the oligosaccharide does not contain a fucose unit.

[0246] 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 interaction, for example, for increasing 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 the 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.

[0247] 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 interaction, e.g., for increasing 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 the 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 the half-life, e.g., R435H (Kabat numbering). In some cases, the constant region is afucosylated at residue N297.

[0248] 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 interaction, e.g., for increasing 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 the 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).

[0249] In some embodiments, the human IgG constant region is modified to alter ADCC and / or CDC, e.g., having 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.

[0250] 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 with a larger amino acid (e.g., Trp (T366W)), is capable of preferably pairing with a second CH3 domain that has amino acid modifications at the Thr366, Leu368, and Tyr407 positions to produce smaller amino acids, such as Ser, Ala, and Val (T366S / L368A / Y407V). In some cases, heterodimerization by CH3 modification is further stabilized by introducing disulfide bonds, such as by replacing Ser354 with Cys (S354C) and Y349 with Cys (Y349C) on opposite CH3 domains (reviewed in Carter, 2001 Journal of Immunological Methods, 248:7-15).

[0251] 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 lacking the ability for post-translational glycosylation (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.

[0252] 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. Table 11. Heavy Chains of Exemplary Anti-ICAM1 Antibodies Table 12. Light Chains of Exemplary Anti-ICAM1 Antibodies

[0253] 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 from 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 。

[0254] In some cases, the serum half-life of the anti-ICAM1 antibodies 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 cases, the serum half-life of the anti-ICAM1 antibodies 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. Bispecific anti-CD38 and anti-ICAM1 antibodies

[0255] In certain embodiments, bispecific anti-CD38 antibodies or bispecific anti-ICAM1 antibodies are described herein. In some cases, the bispecific anti-CD38 antibodies or bispecific anti-ICAM1 antibodies comprise target-binding portions that recognize two or more antigens. In some cases, the bispecific 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 bispecific 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.

[0256] In some embodiments, bispecific anti-CD38 antibodies are described herein. In some cases, the bispecific anti-CD38 antibody comprises 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 Cell 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 (MUC2), 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.

[0257] In some embodiments, bispecific anti-ICAM1 antibodies are described herein. In some cases, the bispecific anti-ICAM1 antibody comprises 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 target includes, but is not limited to, CD38, CD47, Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1), Receptor Tyrosine Kinase-Like Orphan Receptor 2 (ROR2), Erb3, IGFR1R, EGFR, PDL1, PDL2, PD1, CTLA4, or Tim3.

[0258] In some embodiments, bispecific antibodies are described herein that comprise a first targeting moiety that specifically binds to CD38 or ICAM1.

[0259] In some embodiments, the bispecific antibodies of the present disclosure that comprise a first component that binds CD38 and a second component that binds ICAM1 bind to cells with a target antigen that expresses 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, or 20 - 50%, 50 - 100%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or higher affinity (e.g., preferential binding) compared to the binding affinity of an antibody that is monospecific for only one of CD38 or ICAM1 to the cells.

[0260] 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 antibody-dependent cell-mediated cytotoxicity (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 has a reduced immune cell killing effect. In some cases, the enhanced CDC is at least 2-fold, 3-fold, 4-fold or higher than 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 higher than the CDC effect of the reference antibody daratumumab. In...

Claims

1. A multispecific protein comprising a first component that specifically binds to CD38 and a second component that specifically binds to ICAM1.

2. The multispecific protein according to claim 1, wherein the multispecific protein is bivalent, trivalent or tetravalent.

3. The multispecific protein according to claim 1 or 2, wherein the first component comprises an antibody or an antigen-binding fragment thereof that specifically binds to CD38.

4. The multispecific protein according to any one of claims 1-3, wherein the second component comprises an antibody or an antigen-binding fragment thereof that specifically binds to ICAM1.

5. The multispecific protein according to claim 3 or 4, wherein the antibody or antigen-binding fragment thereof that specifically binds to CD38 comprises a variable domain of an IgG heavy chain and a variable domain of an IgG light chain.

6. The multispecific protein according to claim 4 or 5, wherein the antibody or antigen-binding fragment thereof that specifically binds to ICAM1 comprises a variable domain of an IgG heavy chain and a variable domain of an IgG light chain.

7. The multispecific protein according to any one of claims 1-6, further comprising an Fc region.

8. The multispecific protein according to claim 7, wherein the Fc region comprises a heterodimeric Fc region.

9. The multispecific protein according to claim 7 or 8, wherein the Fc region comprises one or more mutations that increase the half-life of the multispecific protein.

10. The multispecific protein according to any one of claims 7-9, wherein the Fc region comprises one or more stabilizing mutations.

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