CD38 antibody and ICAM1 antibody and their use

Abstract

We provide polyspecific antibodies. [Solution] Disclosed herein are anti-CD38 antibodies, anti-ICAM1 antibodies, pharmaceutical compositions comprising anti-CD38 antibodies and / or anti-ICAM1 antibodies, and methods of use for the treatment of proliferative disorders. In certain embodiments, also disclosed herein are polyspecific 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 polyspecific antibodies, and methods of use for the treatment of proliferative disorders.

Description

[Technical Field]

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

[0002] Sequence List This application includes a sequence listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The above ASCII copy, created on November 14, 2019, is named 55429-701_601_SL.txt and is 590,037 bytes in size. [Background technology]

[0003] Antibodies that bind to CD38 are useful in treating 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 effectiveness of anti-CD38 antibodies. Proposed solutions to overcome this limitation include treatment with antibodies that have a higher affinity for CD38, treatment with antibodies that bind to different epitopes on CD38, treatment with antibodies that more effectively inhibit the enzymatic activity of CD38, treatment with tetravalent anti-CD38 antibodies, and simultaneous treatment with all-trans retinoic acid to increase CD38 expression.

[0004] Embedding by citation All publications, patents, and patent applications herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application were explicitly and individually indicated to be incorporated by reference. In the event of any conflict between the terminology herein and the terminology of any cited document, the terminology herein shall prevail. [Overview of the project]

[0005] One embodiment provides a polyspecific protein comprising a first component that specifically binds to CD38 and a second component that specifically binds to ICAM1. In some embodiments, the polyspecific protein is divalent, trivalent, or tetravalent. In some embodiments, the first component comprises an antibody or its antigen-binding fragment that specifically binds to CD38. In some embodiments, the second component comprises an antibody or its antigen-binding fragment that specifically binds to ICAM1. In some embodiments, the antibody or its antigen-binding fragment that specifically binds to CD38 comprises a variable domain of the IgG heavy chain and a variable domain of the IgG light chain. In some embodiments, the antibody or its antigen-binding fragment that specifically binds to ICAM1 comprises a variable domain of the IgG heavy chain and a variable domain of the IgG light chain. In some embodiments, the polyspecific 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 polyspecific 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 the interaction with the Fc receptor.

[0006] In some embodiments, the multispecific protein of claim 11, wherein the Fc region comprises one or more mutations that increase the binding of the Fc region to the Fc receptor. In some embodiments, the Fc region comprises one or more mutations that decrease the glycosylation of the Fc region. In some embodiments, the one or more mutations that decrease the glycosylation of the Fc region comprises a mutation at a position corresponding to the N297 position of human IgG1, where 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 the activity of ADCC or CDC. In some embodiments, the Fc region comprises one or more mutations that increase ADCC, wherein the mutations that increase ADCC are at positions corresponding to the 239, 332, and 330 positions of human IgG1, where the mutations are S239D, I332E, and A330L, and where the amino acid numbering is according to the EU index of Kabat et al. In some embodiments, the heterodimer Fc region comprises a knob chain and a hole chain, forming a knob-in-hole (KIH) structure. In some embodiments, the knob chain comprises mutant T366W, and the hole chain comprises mutants T366S, L368A, and Y407V, where amino acid position numbering is according to the EU index of Kabat et al. In some embodiments, the antibody or antigen-binding fragment that specifically binds to CD38 comprises anti-CD38 IgG, and the antibody or antigen-binding fragment 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, each light chain fused to a single anti-ICAM1 scFv. In some embodiments, the C-terminus of each light chain of anti-CD38 IgG is fused to a single anti-ICAM1 scFv. In some embodiments, the N-terminus of each heavy chain of anti-CD38 IgG is fused to a single anti-ICAM1 scFv.In some embodiments, 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 anti-CD38 IgG, and the second component comprises two anti-ICAM1 variable heavy chain domains and two anti-ICAM-1 variable light chain domains, wherein each variable heavy chain domain of anti-CD38 IgG is fused to one of the anti-ICAM1 variable heavy chain domains, and each variable light chain domain of anti-CD38 IgG is fused to one of the anti-ICAM1 variable light chain domains. In some embodiments, the antibody or antigen-binding fragment that specifically binds to CD38 is a monovalent anti-CD38 antibody or antigen-binding fragment. In some embodiments, the antibody or antigen-binding fragment that specifically binds to ICAM1 is a monovalent anti-ICAM1 antibody or antigen-binding fragment. In some embodiments, the monovalent anti-CD38 antibody or antigen-binding fragment comprises anti-CD38 Fab. In some embodiments, the monovalent anti-ICAM1 antibody or antigen-binding fragment comprises anti-ICAM1 scFv. In some embodiments, the polyspecific 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 containing a KIH structure. In some embodiments, a monovalent anti-CD38 antibody or its antigen-binding fragment comprises one variable heavy chain domain (VH) and a variable light chain domain (VL), and a monovalent anti-ICAM1 antibody or its antigen-binding fragment comprises one variable heavy chain domain (VH).

[0008] In some embodiments, the polyspecific protein further comprises an Fc region. In some embodiments, the Fc region is a heterodimeric Fc region containing a KIH structure, and the polyspecific protein is of a general light chain bispecificity format. In some embodiments, the first component that specifically binds to CD38 comprises a heavy chain containing complementarity-determining regions CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 of the heavy chain are the following set of sequences: CDR1:CDR2:CDR3 (Sequence ID 1:Sequence ID 2:Sequence ID 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 (Sequence ID 1:Sequence ID 2:Sequence ID 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 (Sequence ID 6:Sequence ID 2:Sequence ID 3); CDR1:CDR2:CDR3 (Sequence ID 8:Sequence ID 5:Sequence ID 3); CDR1:CDR2:CDR3 (SEQ ID NO: 9:SEQ ID NO: 2:SEQ ID NO: 10); CDR1:CDR2:CDR3 (Sequence ID 11:Sequence ID 12:Sequence ID 13); CDR1:CDR2:CDR3 (Sequence ID 14:Sequence ID 15:Sequence ID 16); CDR1:CDR2:CDR3 (Sequence ID 17:Sequence ID 18:Sequence ID 19); CDR1:CDR2:CDR3 (Sequence ID 20:Sequence ID 21:Sequence ID 22); CDR1:CDR2:CDR3 (Sequence ID 23:Sequence ID 24:Sequence ID 25); CDR1:CDR2:CDR3 (Sequence ID 26:Sequence ID 27:Sequence ID 28); CDR1:CDR2:CDR3 (Sequence ID 29:Sequence ID 30:Sequence ID 31); CDR1:CDR2:CDR3 (Sequence ID 32:Sequence ID 33:Sequence ID 34); CDR1:CDR2:CDR3 (Sequence ID 35:Sequence ID 36:Sequence ID 37); CDR1:CDR2:CDR3 (Sequence ID 38:Sequence ID 39:Sequence ID 40); CDR1:CDR2:CDR3 (Sequence ID 41:Sequence ID 42:Sequence ID 43); CDR1:CDR2:CDR3 (Sequence ID 44:Sequence ID 45:Sequence ID 46); CDR1:CDR2:CDR3 (Sequence ID 47:Sequence ID 48:Sequence ID 49); CDR1:CDR2:CDR3 (Sequence ID 50:Sequence ID 51:Sequence ID 52); CDR1:CDR2:CDR3 (Sequence ID 53:Sequence ID 54:Sequence ID 55); CDR1:CDR2:CDR3 (Sequence ID 56:Sequence ID 57:Sequence ID 58); and, Includes a set of sequences selected from the group consisting of CDR1:CDR2:CDR3 (sequences 59:60:61).

[0009] In some embodiments, the heavy chain CDR1, CDR2, and CDR3 of the first component include the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID NO: 14:SEQ ID NO: 15:SEQ ID NO: 16). In some embodiments, the heavy chain CDR1, CDR2, and CDR3 of the first component include the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID NO: 17:SEQ ID NO: 18:SEQ ID NO: 19). In some embodiments, the heavy chain CDR1, CDR2, and CDR3 of the first component include the following sequence: CDR1:CDR2:CDR3 (SEQ ID NO: 1:SEQ ID NO: 2:SEQ ID NO: 7). In some embodiments, the first component that specifically binds to CD38 includes a light chain containing complementarity-determining regions CDR1, CDR2, and CDR3, where the CDR1, CDR2, and CDR3 of the light chain include the following set of sequences: CDR1:CDR2:CDR3 (Sequence ID 62:Sequence ID 63:Sequence ID 64); CDR1:CDR2:CDR3 (Sequence ID 65:Sequence ID 66:Sequence ID 67); CDR1:CDR2:CDR3 (Sequence ID 68:Sequence ID 69:Sequence ID 70); CDR1:CDR2:CDR3 (Sequence ID 71:Sequence ID 72:Sequence ID 73); CDR1:CDR2:CDR3 (Sequence ID 74:Sequence ID 75:Sequence ID 76); CDR1:CDR2:CDR3 (Sequence ID 77:Sequence ID 78:Sequence ID 79); CDR1:CDR2:CDR3 (Sequence ID 80:Sequence ID 81:Sequence ID 82); CDR1:CDR2:CDR3 (Sequence ID 83:Sequence ID 84:Sequence ID 85); CDR1:CDR2:CDR3 (Sequence ID 86:Sequence ID 78:Sequence ID 87); CDR1:CDR2:CDR3 (Sequence ID 86:Sequence ID 78:Sequence ID 88); CDR1:CDR2:CDR3 (Sequence ID 89:Sequence ID 90:Sequence ID 91); CDR1:CDR2:CDR3 (Sequence ID 92:Sequence ID 78:Sequence ID 93); CDR1:CDR2:CDR3 (SEQ ID NOs: 94:84:95); CDR1:CDR2:CDR3 (Sequence ID 96:Sequence ID 81:Sequence ID 97); CDR1:CDR2:CDR3 (SEQ ID NOs: 98:99:100); The sequence includes sequences selected from the group consisting of CDR1:CDR2:CDR3 (sequences 77:72:101) and CDR1:CDR2:CDR3 (sequences 102:84:103).

[0010] In some embodiments, the CDR1, CDR2, and CDR3 of the first component light chain include the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID NO: 68:SEQ ID NO: 69:SEQ ID NO: 70). In some embodiments, the CDR1, CDR2, and CDR3 of the first component light chain include the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID NO: 71:SEQ ID NO: 72:SEQ ID NO: 73). In some embodiments, the CDR1, CDR2, and CDR3 of the first component light chain include the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID NO: 62:SEQ ID NO: 63:SEQ ID NO: 64).

[0011] In some embodiments, the first component is the following set of sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NO: 1:SEQ ID NO: 2:SEQ ID NO: 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 ID NO: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 ID NO: 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 ID NO: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 ID NO: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 ID NO: 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 ID NO: 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 ID NO: 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 ID NO: 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 NOs. 23:SEQ ID NOs. 24:SEQ ID NOs. 25)-(SEQ ID NOs. 77:SEQ ID NOs. 78:SEQ ID NOs. 79); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NOs. 26:SEQ ID NOs. 27:SEQ ID NOs. 28)-(SEQ ID NOs. 80:SEQ ID NOs. 81:SEQ ID NOs. 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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, It contains six CDRs, each containing a sequence described by one of the following: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NOs. 56:SEQ ID NOs. 57:SEQ ID NOs. 58)-(SEQ ID NOs. 102:SEQ ID NOs. 84:SEQ ID NOs. 103).

[0012] In some embodiments, the first component includes six CDRs containing the following sequence set: 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 includes six CDRs containing the following sequence set: 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 includes six CDRs containing one of the following sequence sets: 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 containing complementarity-determining regions CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 of the heavy chain are the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID NOs: 208:209:210); CDR1:CDR2:CDR3 (Sequence ID 211:Sequence ID 212:Sequence ID 213); CDR1:CDR2:CDR3 (Sequence ID 214:Sequence ID 215:Sequence ID 216); CDR1:CDR2:CDR3 (Sequence IDs 217, 218, 219); CDR1:CDR2:CDR3 (Sequence ID 214:Sequence ID 220:Sequence ID 221); CDR1:CDR2:CDR3 (Sequence ID 222:Sequence ID 223:Sequence ID 224); CDR1:CDR2:CDR3 (Sequence ID 225:Sequence ID 223:Sequence ID 224); CDR1:CDR2:CDR3 (Sequence ID 222:Sequence ID 223:Sequence ID 226); CDR1:CDR2:CDR3 (Sequence ID 222:Sequence ID 227:Sequence ID 224); CDR1:CDR2:CDR3 (SEQ ID NOs: 228:229:230); CDR1:CDR2:CDR3 (Sequence ID 228:Sequence ID 220:Sequence ID 231); CDR1:CDR2:CDR3 (Sequence ID 232:Sequence ID 229:Sequence ID 233); CDR1:CDR2:CDR3 (Sequence ID 208:Sequence ID 234:Sequence ID 210); CDR1:CDR2:CDR3 (Sequence ID 235:Sequence ID 236:Sequence ID 237); CDR1:CDR2:CDR3 (SEQ ID NOs: 238:239:240); CDR1:CDR2:CDR3 (Sequence ID 241:Sequence ID 242:Sequence ID 243); CDR1:CDR2:CDR3 (Sequence ID 241:Sequence ID 244:Sequence ID 245); CDR1:CDR2:CDR3 (Sequence ID 241:Sequence ID 246:Sequence ID 245); CDR1:CDR2:CDR3 (Sequence ID 247:Sequence ID 248:Sequence ID 249); CDR1:CDR2:CDR3 (Sequence ID 250:Sequence ID 251:Sequence ID 252); and, It includes sequences selected from the group consisting of CDR1:CDR2:CDR3 (sequences 404:405:406).

[0014] In some embodiments, the CDR1, CDR2, and CDR3 of the second component heavy chain include the following sequence:(CDR1:CDR2:CDR3(SEQ ID NO: 228:SEQ ID NO: 229:SEQ ID NO: 230). In some embodiments, the CDR1, CDR2, and CDR3 of the second component heavy chain include the following sequence:CDR1:CDR2:CDR3(SEQ ID NO: 222:SEQ ID NO: 223:SEQ ID NO: 224). In some embodiments, the CDR1, CDR2, and CDR3 of the second component heavy chain include the following set of sequences:CDR1:CDR2:CDR3(SEQ ID NO: 232:SEQ ID NO: 229:SEQ ID NO: 233). In some embodiments, the CDR1, CDR2, and CDR3 of the second component heavy chain include the following set of sequences: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 includes a light chain comprising complementarity-determining regions CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 of the light chain are the following set of sequences: CDR1:CDR2:CDR3 (Sequence ID 253:Sequence ID 254:Sequence ID 255); CDR1:CDR2:CDR3 (Sequence ID 256:Sequence ID 257:Sequence ID 258); CDR1:CDR2:CDR3 (Sequence ID 259:Sequence ID 260:Sequence ID 261); CDR1:CDR2:CDR3 (Sequence ID 262:Sequence ID 263:Sequence ID 264); CDR1:CDR2:CDR3 (Sequence ID 265:Sequence ID 260:Sequence ID 266); CDR1:CDR2:CDR3 (Sequence ID 267:Sequence ID 263:Sequence ID 264); CDR1:CDR2:CDR3 (Sequence ID 268:Sequence ID 263:Sequence ID 264); CDR1:CDR2:CDR3 (Sequence ID 269:Sequence ID 263:Sequence ID 264); CDR1:CDR2:CDR3 (SEQ ID NOs: 270:260:271); CDR1:CDR2:CDR3 (Sequence ID 272:Sequence ID 260:Sequence ID 266); CDR1:CDR2:CDR3 (Sequence ID 259:Sequence ID 273:Sequence ID 266); CDR1:CDR2:CDR3 (Sequence ID 274:Sequence ID 275:Sequence ID 276); CDR1:CDR2:CDR3 (Sequence ID 277:Sequence ID 275:Sequence ID 278); CDR1:CDR2:CDR3 (Sequence ID 279:Sequence ID 280:Sequence ID 281); CDR1:CDR2:CDR3 (Sequence ID 282:Sequence ID 283:Sequence ID 284); Includes a set of sequences selected from the group consisting of CDR1:CDR2:CDR3 (sequences 62:63:64) and CDR1:CDR2:CDR3 (sequences 407:408:409).

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

[0017] In some embodiments, the second component includes six CDRs containing the following sequence: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NOs. 228:SEQ ID NOs. 229:SEQ ID NOs. 230)-(SEQ ID NOs. 270:SEQ ID NOs. 260:SEQ ID NOs. 271). In some embodiments, the second component includes six CDRs containing the following sequence: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NOs. 222:SEQ ID NOs. 223:SEQ ID NOs. 224)-(SEQ ID NOs. 267:SEQ ID NOs. 263:SEQ ID NOs. 264). In some embodiments, the second component includes six CDRs containing the following sequence: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NOs. 232:SEQ ID NOs. 229:SEQ ID NOs. 233)-(SEQ ID NOs. 259:SEQ ID NOs. 273:SEQ ID NOs. 266). In some embodiments, the second component includes six CDRs, including the following sequence set: 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 includes a variable heavy chain domain, and the variable heavy chain domain includes a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 104-129. In some embodiments, the first component includes a variable light chain domain, and the variable light chain domain is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 130-155. It includes sequences that are % identical. In some embodiments, the second component includes a variable heavy chain domain, and the variable heavy chain domain includes a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs. 288-309. In some embodiments, the second component includes a variable light chain domain, and the variable light chain domain includes a sequence that is at least about 90% identical 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 includes a full-length antibody comprising a light chain and a heavy chain, where the heavy chain includes a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs. 156-181.In some embodiments, the light chain contains a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 182-207. In some embodiments, the second component that specifically binds to ICAM1 contains a full-length antibody comprising a light chain and a heavy chain, wherein the heavy chain contains a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 328-349. In some embodiments, the light chain contains a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 183 and 350-366.

[0018] One embodiment provides a polyspecific protein comprising a heavy chain polypeptide (HC) containing VH and a light chain polypeptide (LC) containing VL, where the heavy chain polypeptide and the light chain polypeptide are the following sequence set: 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, The sequence selected from HC:LC (sequence ID 386:sequence ID 394) contains a sequence that is at least approximately 90% identical.

[0019] One embodiment provides a polyspecific protein comprising a first heavy chain polypeptide (HC1), a light chain polypeptide (LC), and a second heavy chain polypeptide (HC2), where HC1, LC, and HC2 are the following set of 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, The sequence selected from the group consisting of HC1:LC:HC2 (sequences 156:182:383) contains a sequence that is at least approximately 90% identical to it.

[0020] One embodiment provides a polyspecific 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), wherein HC1, LC1, HC2, and LC2 are the following set of sequences: HC1:LC1:HC2:HC3 (SEQ ID NO: 390:SEQ ID NO: 189:SEQ ID NO: 348:SEQ ID NO: 189); HC1:LC1:HC2:HC3(SEQ ID NO: 390:SEQ ID NO: 189:SEQ ID NO: 349:SEQ ID NO: 189); HC1:LC1:HC2:HC3 (SEQ ID NO: 391:SEQ ID NO: 186:SEQ ID NO: 348:SEQ ID NO: 186); and, The sequence selected from the group consisting of HC1:LC1:HC2:HC3 (sequence ID 391:sequence ID 186:sequence ID 349:sequence ID 186) contains a sequence that is at least approximately 90% identical to it.

[0021] One embodiment provides a polyspecific protein comprising a heavy chain sequence that is at least about 95% identical to the sequence described in SEQ ID NO: 410 and a light chain sequence that is at least about 95% identical to the sequence described in SEQ ID NO: 411.

[0022] In some embodiments, the heavy chain comprises CDR1, CDR2, and CDR3, where CDR1 has the sequence of sequence number 412 (GFSLSZ1Z2AMG), CDR2 has the sequence of sequence number 413 (GIIGSSZ3Z4TYYAZ5WAKG), and CDR3 has the sequence of sequence number 414 (VRDPYDSZ6Z7Z8Z9YRL). In some embodiments, the light chain comprises CDR1, CDR2, and CDR3, where CDR1 has the sequence of sequence number 415 (QASZ 10 Z 11 IYZ12 YZ 13 Z 14 ) has an array, and CDR2 has an array of SEQ ID NO: 416 (DASKZ 15 AS), and CDR3 has an array of SEQ ID NO: 417 (QQAYSSZ 16 Z 17 Z 18 DNZ 19 ) has an array. 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 leucine or serine; 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 bispecific protein induces an enhanced ADCC effect on target cells as compared to antigen - dependent cellular cytotoxicity (ADCC) of antigen - dependent cells induced on target cells by the same bispecific protein that does not contain an afucosylated Fc region.

[0024] In some embodiments, the polyspecific protein induces an enhanced ADCC effect on target cells compared to ADCC induced on target cells by the same polyspecific protein that does not contain an Fc region with mutations at positions corresponding to human IgG1 239, 332, and 330, where the mutations are S239D, I332E, and A330L, and where amino acid numbering is according to the EU index by Kabat et al.

[0025] In some embodiments, the amount of a multispecific protein that binds to cells expressing CD38 and ICAM1 is higher than the amount of a monospecific protein containing a first component that binds to CD38, where cell binding is measured by flow cytometry. In some embodiments, the multispecific protein induces an enhanced ADCC effect on target cells compared to the ADCC effect induced on target cells by a monospecific protein containing a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, the multispecific protein induces an enhanced CDC effect on target cells compared to the CDC effect induced on target cells by a monospecific protein containing a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, the multispecific protein binds to target cells expressing CD38 and ICAM1 with enhanced affinity compared to a monospecific protein containing 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 cell surface 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 cell surface 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 in relation to CD38, compared to the ADCC effect induced on target cells by a monospecific protein containing a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, cells express at least 5,000, 10,000, 150,000, 20,000, 30,000, 50,000, 100,000, 150,000, 200,000, 250,000, 300,000, 400,000, or 500,000 ICAM1 proteins on their surface. In some embodiments, cells express at least 50,000 ICAM1 proteins on their surface.In some embodiments, cells express at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on their surface. In some embodiments, cells express at least 300 CD38 proteins on their surface. In some embodiments, cells express less than approximately 350,000, less than approximately 300,000, less than approximately 250,000, less than approximately 200,000, less than approximately 150,000, less than approximately 100,000, less than approximately 50,000, less than approximately 30,000, less than approximately 20,000, less than approximately 15,000, less than approximately 10,000, or less than approximately 5,000 CD38 proteins on their surface. In some embodiments, cells express less than approximately 350,000 CD38 proteins on their surface. In some embodiments, the ratio of ICAM1 to CD38 on the cell surface 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 cell surface is at least about 1. The ratio of ICAM1 to CD38 on the cell surface is at least about 10. In some embodiments, the cell expresses at least as much ICAM1 on its surface as NCI-H2291 cells. In some embodiments, the cell expresses at least as much CD38 on its surface as NCI-H2342 cells. In some embodiments, the cell expresses less CD38 on its surface than Daudi cells. In some embodiments, the ratio of ICAM1 to CD38 on the cell surface 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 induced on target cells by a monospecific protein containing 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 cell surface 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 cell surface 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 induced on target cells by a single-specific protein containing 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 cell surface 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 cell surface is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raji cells. In some embodiments, the multispecific protein exhibits reduced ability to kill NK (natural killer) cells in a population of fresh peripheral blood mononuclear cells compared to a single-specific protein containing either a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1, compared to the apoptotic effect induced on target cells. In some embodiments, the first component binds to human CD38 with a KD of approximately 0.15 nM to approximately 64 nM, as determined by surface plasmon resonance. In some embodiments, the first component binds to human CD38 with a KD of approximately 0.42 nM to approximately 13.14 nM, as determined by surface plasmon resonance. In some embodiments, the first component binds to human CD38 with a KD of approximately 0.15 nM to approximately 0.45 nM, as determined by surface plasmon resonance. In some embodiments, the second component binds to human ICAM1 with a KD of approximately 0.2 nM to approximately 24.4 nM, as determined by surface plasmon resonance. In some embodiments, the second component binds to human ICAM1 at a KD of about 0.2 nM to about 0.6 nM, as determined by surface plasmon resonance.

[0026] One embodiment provides a pharmaceutical composition comprising the polyspecific 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 for killing cells of a subject, comprising the step of administering the subject a multispecific protein of the Disclosure or a pharmaceutical composition of the Disclosure, wherein the cells express CD38 and ICAM1. In some embodiments, the cells are lysed. In some embodiments, the cells are tumor cells. One embodiment provides a method for treating cancer in a subject, comprising the step of administering the subject a multispecific protein of the Disclosure or a pharmaceutical composition of the Disclosure, wherein the cancer includes cells expressing CD38 and ICAM1. In some embodiments, the cancer includes solid tumors or hematological malignancies. In some embodiments, the cancer includes hematological malignancies. 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 cells express at least as much ICAM1 on their surface as NCI-H2291 cells. In some embodiments, the cells express at least as much CD38 on their surface as NCI-H2342 cells. In some embodiments, the cells express less CD38 on their surface than Daudi cells. In some embodiments, 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. In some embodiments, 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 Daudi cells.

[0028] In some embodiments, the ratio of ICAM1 to CD38 on the surface of a cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of a Raji cell. In some embodiments, a cell expresses at least 5000, 10000, 150000, 20000, 30000, 50000, 100000, 150000, 200000, 250000, 300000, 400000, or 500000 ICAM1 proteins on its surface. In some embodiments, a cell expresses at least 50,000 ICAM1 proteins on its surface. In some embodiments, a cell expresses at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on its surface. In some embodiments, cells express at least 300 CD38 proteins on their surface. In some embodiments, cells express less than approximately 350,000, less than approximately 300,000, less than approximately 250,000, less than approximately 200,000, less than approximately 150,000, less than approximately 100,000, less than approximately 50,000, less than approximately 30,000, less than approximately 20,000, less than approximately 15,000, less than approximately 10,000, or less than approximately 5,000 CD38 proteins on their surface. In some embodiments, cells express less than approximately 350,000 CD38 proteins on their surface. In some embodiments, the ratio of ICAM1 to CD38 on the cell surface is at least approximately 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 cell surface is at least about 1. The ratio of ICAM1 to CD38 on the cell surface is at least about 10. In some embodiments, the method further includes the step of administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent includes a chemotherapeutic agent, an immunotherapy agent, a targeted therapy agent, a hormone-based therapy agent, a stem cell-based therapy agent, or radiation. In some embodiments, the additional therapeutic agent includes 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, additional therapeutic agents and the multispecific protein are administered sequentially. In some embodiments, the subject is pre-treated. In some embodiments, the pre-treatment includes proteasome inhibitor (PI) therapy and immunomodulators. In some embodiments, the subject is double refractory to the therapy including proteasome inhibitor (PI) therapy and immunomodulators. In some embodiments, the subject is human. One embodiment provides a kit comprising the multispecific protein according to the Disclosure or a pharmaceutical composition comprising the above multispecific protein.

[0029] In certain embodiments, anti-CD38 antibodies, anti-ICAM1 antibodies, pharmaceutical compositions comprising anti-CD38 antibodies and / or anti-ICAM1 antibodies, and methods of use for the treatment of proliferative disorders are disclosed herein. In certain embodiments, polyspecific 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 polyspecific antibodies, and methods of use for the treatment of proliferative disorders 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 that exhibits an enhanced complement-dependent cytotoxicity (CDC) effect compared to the complement-dependent cytotoxicity (CDC) effect of a reference antibody, daratumumab. Similarly, as described herein, in certain embodiments, a bispecific antibody is disclosed herein that comprises a first targeting moiety that specifically binds to CD38 or ICAM1, and that exhibits an enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effect compared to the antibody-dependent cell-mediated cytotoxicity (ADCC) effect of a reference antibody, daratumumab. Similarly, as described herein, in certain embodiments, a bispecific antibody is disclosed herein that comprises a first targeting moiety that specifically binds to CD38 or ICAM1, and that exhibits a reduced cell-killing effect compared to the immune cell-killing effect of a reference antibody, daratumumab. In some embodiments, the bispecific antibody further comprises a second cell-targeting moiety that specifically binds to CD38 or ICAM1. In some embodiments, the enhanced CDC is at least 2, 3, 4, or more 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 more than the CDC effect of the reference antibody daratumumab. In some embodiments, the enhanced ADCC is at least 2, 3, 4, 5, or more than the ADCC effect of the reference antibody daratumumab. In some embodiments, the enhanced ADCC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more than the ADCC effect of the reference antibody daratumumab. In some embodiments, the immune cells are natural killer cells. In some embodiments, immune cell viability is improved by approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to immune cell viability in the presence of the reference antibody daratumumab. In some embodiments, the bispecific antibody is a bivalent antibody or its binding fragment.In some embodiments, the bivalent antibody or its binding fragment includes an IgG-scFv(LC) C-terminal fusion format, an IgG-HC-scFv C-terminal fusion format, an scFv-HCIgG N-terminal fusion format, or a DVD-Ig format. In some embodiments, the bispecific antibody is a monovalent antibody or its binding fragment. In some embodiments, the monovalent antibody or its binding fragment includes a Fab-scFv-Fc(KIH) format or a common LC format from Biclonics. In some embodiments, the scFv portion of the bispecific antibody specifically binds to ICAM1. In some embodiments, the first targeting portion specifically binds to CD38, and the second targeting portion specifically binds to ICAM1. In some embodiments, the first targeting portion includes a KD ranging from about 1 nM to about 100 nM. In some embodiments, the first targeted portion includes a KD of at least 1nM, 2nM, 3nM, 3.15nM, 3.2nM, 3.39nM, 3.5nM, 4nM, 4.5nM, 5nM, 5.32nM, 5.5nM, 6nM, 6.5nM, 7nM, 7.5nM, 8nM, 8.5nM, 9nM, 9.5nM, 10nM, 15nM, 18nM, 20nM, 25nM, 30nM, 35nM, 40nM, 45nM, 50nM, 60nM, 70nM, 80nM, 90nM, or 100nM. In some embodiments, the second targeted portion includes a KD ranging from about 0.1 to about 20nM. In some embodiments, the second targeting portion includes approximately 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. In some embodiments, the bispecific antibody induces apoptosis similar to that caused by the reference antibody daratumumab.In some embodiments, the first targeting region includes a variable heavy chain (VH) region and a variable light chain (VL) region, where the VH region is the CDR1 sequence X1GX2X3X4X5X6X7X8X9X. 10 X 11 X 12 Includes; where X1 is either 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It may or may not exist, and if it exists, it is C, and the VH region is 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 This includes, where X 13 is selected from A, G, or S; X 14 is selected from I, F, Y, V, S, or C; X 15 The following can be 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; X20 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 either present or absent, and if present, is selected from G or K, X 31 is either present or absent, and if present, is G, and the VH region has 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 includes; 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 39is 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 either present or absent, and if present, is currently selected from F, Y, V, D, A, N, G, E, or L; X 42 is either present or not present, and if present, is selected from P, L, Y, F, G, or T, X 43 is either present or not present, and if present, is selected from T, P, F, V, N, Y, or S, X 44 is either present or not present, and if present, is selected from G, L, S, T, or F, X 45 is either present or not present, and if present, is selected from F, L, E, N, or S, X 46 is either present or not present, and if present, is selected from D, S, L, or R, X 47 is either present or not present, and if present, is selected from Y or L, X 48 is either present or not present, and if present, is D; and, X 49 is either present or not present, 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 and includes; where X1 is either present or not present, 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 either present or not present, and if present, is selected from C or M, and, X 12It may or may not exist, and if it exists, it is C. In some embodiments, the VH region is the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 Includes; where X5 is selected from S or N; X6 is selected from R, S, or N; X7 is selected from Y, I, or N; X8 is selected from Y, D, G, or A; X9 is selected from V, M, or I; X 10 is selected from T, S, or M; and, X 11 It may or may not exist, and if it exists, it is C. In some embodiments, the VH region is the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 This includes; where 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 Selected; 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It may or may not exist, and if it exists, it is C. In some embodiments, the VH region is the CDR2 sequence AISGSGGSTX 22 Includes YADSVKG, where X 22 This is selected from F or Y. In some embodiments, the VH region is 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 Includes; where X 13is 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 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It may or may not exist, and if it exists, it is G. In some embodiments, the VH region is 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 Includes; where X 13 is selected from A or G; X 14 is selected from I, F, Y, V, S, or C; X 16is 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 It may or may not exist, and if it exists, it is G. In some embodiments, the VH region is 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 Includes; where 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; X23 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 A, W, N, or S; X 28 is selected from A or W; X 29 is selected from K or A; X 30 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It may or may not exist, and if it exists, it is G. In some embodiments, the VH region is the CDR3 sequence AKRGTYX 38 YSX 41 Includes PTGFDY, where X 38 is selected from A or G; and X 41 This is selected from F or Y. In some embodiments, the VH region is 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 Includes; where 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 40is selected from S, Y, G, R, W, N, L, D, or F; X 41 It may or may not exist, and if it exists, it is selected from V, D, Y, A, N, G, L, or E; X 42 It may or may not exist, and if it exists, it is selected from L, Y, F, T, or G, and X 43 It may or may not exist, and if it exists, it is selected from P, F, V, N, S, or Y, and X 44 It may or may not exist, and if it exists, it is selected from L, S, T, G, or F, and X 45 It may or may not exist, and if it exists, it is selected from L, F, E, S, or N, and X 46 It may or may not exist, and if it exists, it is selected from S, L, or R, and X 47 It either exists or does not exist, and if it exists, it is L, and X 48 It either exists or does not exist, and if it exists, it is D; and X 49 It may or may not exist, and if it exists, it is L. In some embodiments, the VH region is 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 Includes; where 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 40is 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 It may or may not exist, and if it exists, it is selected from P, F, V, or N; X 44 It may or may not exist, and if it exists, it is selected from L, S, or T; X 45 It may or may not exist, and if present, it is selected from L or F. In some embodiments, the VH region is 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 Includes; where 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 It may or may not exist, and if it exists, it is selected from V, Y, or E, and X 42 It either exists or does not exist, and if it exists, it is G; X 43 It either exists or does not exist, and if it exists, it is Y; X 44 It either exists or does not exist, and if it exists, it is F; X 45 It may or may not exist, and if it exists, it is selected from E or N; and X 46It may or may not exist, and if present, it is selected from S or L. In some embodiments, the VH region is the CDR1 sequence GFPFX5X6YAMS, the CDR2 sequence AISGSGGSTX 22 YADSVKG and CDR3 sequence AKRGTYX 38 YSX 41 Includes PTGFDY; where 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 is the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 , and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 This includes; where 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 V, M, or I Selected from; X 10 is selected from T, S, or M; X 11 It either exists or does not exist, and if it exists, it is C; X 13is 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 It either exists or does not exist, and if it exists, 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; 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 It may or may not exist, and if it exists, it is selected from P, F, V, or N; X 44 It may or may not exist, and if it exists, it is selected from L, S, or T; X 45It may or may not exist, and if it exists, it is selected from L or F. In some embodiments, the VH region is the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 , and CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 Includes; where 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 It may or may not exist, and if it exists, it is selected from C or M, X 12 It either exists or does not exist, and if it exists, it 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 20is 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 A, W, N, or S; X 28 is selected from A or W; X 29 is selected from K or A; X 30 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It either exists or does not exist, and if it exists, it is G, and 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 It may or may not exist, and if it exists, it is selected from V, Y, or E, and X 42 It either exists or does not exist, and if it exists, it is G; X 43 It either exists or does not exist, and if it exists, it is Y; X 44 It either exists or does not exist, and if it exists, it is F; X 45 It may or may not exist, and if it exists, it is selected from E or N; and X 46The region may or may not exist, and if present, it is selected from S or L. In some embodiments, the VH region consists of a CDR1 sequence selected from sequence numbers: 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 sequence numbers: 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 Includes; 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 If it exists or does not exist, then currently it is selected from F, Y, V, D, A, N, G, E, or L; X 42 It may or may not exist, and if it exists, it is selected from P, L, Y, F, G, or T, X 43It may or may not exist, and if it exists, it is selected from T, P, F, V, N, Y, or S, X 44 It may or may not exist, and if it exists, it is selected from G, L, S, T, or F, X 45 It may or may not exist, and if it exists, it is selected from F, L, E, N, or S, X 46 It may or may not exist, and if it exists, it is selected from D, S, L, or R, and X 47 It may or may not exist, and if it exists, it is selected from Y or L, X 48 It either exists or does not exist, and if it exists, it is D; and X 49It may or may not exist, and if it exists, it is L. In some embodiments, the VH region includes a CDR1 sequence selected from sequence numbers: 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 sequence numbers: 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 sequence numbers: 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 includes CDR1 sequences selected from sequence numbers 1, 4, 6, 8, and 9; CDR2 sequences selected from sequence numbers 2 and 5; and CDR3 sequences selected from sequence numbers 3, 7, and 10. In some embodiments, the VH region includes CDR1 sequences selected from sequence numbers 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; CDR2 sequences selected from sequence numbers 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and CDR3 sequences selected from sequence numbers 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region includes CDR1 sequences selected from sequence numbers 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequences selected from sequence numbers 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequences selected from sequence numbers 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, the VH region includes CDR1 sequences selected from sequence numbers 17, 23, 29, 44, and 56; CDR2 sequences selected from sequence numbers 18, 24, 30, 45, and 57; and CDR3 sequences selected from sequence numbers 19, 25, 31, 46, and 58.In some embodiments, the VL region includes a CDR1 sequence selected from sequence numbers 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from sequence numbers 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from sequence numbers 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103. In some embodiments, the VL region includes CDR1 sequences selected from sequence numbers 65, 68, 80, 86, 89, 92, and 98; CDR2 sequences selected from sequence numbers 66, 69, 81, 78, 90, and 99; and CDR3 sequences selected from sequence numbers 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, the VL region includes CDR1 sequences selected from sequence numbers 71, 77, 83, 94, and 102; CDR2 sequences selected from sequence numbers 72, 78, and 84; and CDR3 sequences selected from sequence numbers 73, 79, 85, 95, and 103. In some embodiments, the first targeted portion includes VH sequences selected from sequence numbers 104-128 and VL sequences selected from sequence numbers 130-154. In some embodiments, the second targeted region includes a variable heavy chain (VH) region and a variable light chain (VL) region, where the VH region is:CDR1 sequence X1X2X3X4X5X6X7X8X9X. 10 X 11 Includes; where X1 is selected from G or E; X2 is selected from F or Y; X3 is selected from S or T; X4 is selected from L, F, or S; X5 is selected from S or N; X6 is selected from S, N, T, or D; X7 is selected from Y, H, or G; X8 is selected from G, A, Y, W, or F; X9 is selected from M, W, Y, or I; X 10 is selected from S, G, N, M, or I; and X 11 It may or may not exist, and if it exists, it is C; the VH region is CDR2 sequence X 12 X 13 X 14X 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 This includes, 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 It may or may not exist, and if it exists, it is selected from K or G; and X 30 It may or may not exist, and if it exists, it is G; and the VH region is CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 This includes, where 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 It may or may not exist, and if it exists, it is selected from Y, A, G, I, or D; X 42 It may or may not exist, and if it exists, it is selected from I, Y, R, P, V, or G; X 43 It may or may not exist, and if it exists, it is selected from L, R, Y, G, or A; X 44 It may or may not exist, and if it exists, it is selected from N, L, S, Y, or W; X 45 It may or may not exist, and if it exists, it is selected from L, Y, F, or C; X 46 It may or may not exist, and if it exists, it is selected from D, A, or F; X 47 It may or may not exist, and if it exists, it is selected from M, P, Y, or N; X 48 It may or may not exist, and if it exists, it is selected from D or L, and X 49It may or may not exist, and if it exists, it is L. In some embodiments, the VH region is the CDR1 sequence GFSLX5X6X7X8MX 10 This includes, where X5 is selected from S or N; X6 is selected from S, N, T, or D; X7 is selected from Y or H; X8 is selected from G, A, or Y; and X 10 This is selected from S, G, or N. In some embodiments, the VH region is the CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 Includes WAKG, here 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 This is selected from S, T, or N. In some embodiments, the VH region is 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 This includes, 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 36is 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 It may or may not exist, and if it exists, it is selected from L, Y, or F; X 46 It either exists or does not exist, and if it exists, it is D; X 47 It may or may not exist, and if it exists, it is selected from M or P; X 48 It either exists or does not exist, and if it exists, it is D; and X 49It may or may not exist, and if present, it is L. In some embodiments, the VH region includes a CDR1 sequence selected from sequence numbers: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from sequence numbers: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence selected from sequence numbers: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252. In some embodiments, the VH region includes a CDR1 sequence selected from sequence numbers: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; a CDR2 sequence selected from sequence numbers: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and a CDR3 sequence selected from sequence numbers: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240. In some embodiments, the VH region includes a CDR1 sequence selected from sequence numbers 241, 247, and 250; a CDR2 sequence selected from sequence numbers 242, 244, 246, 248, and 251; and a CDR3 sequence selected from sequence numbers 243, 245, 249, and 252. In some embodiments, the VL region includes a CDR1 sequence selected from sequence numbers 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; a CDR2 sequence selected from sequence numbers 254, 257, 260, 263, 273, 275, 280, and 283; and a CDR3 sequence selected from sequence numbers 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284. In some embodiments, the second targeted portion includes a VH sequence selected from sequence numbers 289-309 and a VL sequence selected from sequence numbers 311-326 and 155.In some embodiments, the bispecific antibody comprises a humanized antibody or its conjugated fragment, or a chimeric antibody or its conjugated fragment. In some embodiments, the bispecific antibody comprises IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triplebody, miniantibody, 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 includes small molecules, peptides, or proteins.

[0031] In certain embodiments, an anti-CD38 antibody comprising a variable heavy chain (VH) region and a variable light chain (VL) region is disclosed herein, where the VH region comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 Includes; where X1 is either 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12It may or may not exist, and if it exists, it is C, and the VH region is 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 This includes, where X 13 is selected from A, G, or S; X 14 is selected from I, F, Y, V, S, or C; X 15 The following can be 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 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It may or may not exist, and if it exists, it is G, as well as the CDR3 sequence X32 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 Includes; 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 If it exists or does not exist, then currently it is selected from F, Y, V, D, A, N, G, E, or L; X 42 It may or may not exist, and if it exists, it is selected from P, L, Y, F, G, or T, X 43 It may or may not exist, and if it exists, it is selected from T, P, F, V, N, Y, or S, X 44 It may or may not exist, and if it exists, it is selected from G, L, S, T, or F, X 45 It may or may not exist, and if it exists, it is selected from F, L, E, N, or S, X 46 It may or may not exist, and if it exists, it is selected from D, S, L, or R, and X 47 It may or may not exist, and if it exists, it is selected from Y or L, X48 It either exists or does not exist, and if it exists, it is D; and X 49 It may or may not exist, and if present, it is L. In some embodiments, the VH region includes 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 includes the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 Includes; 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It may or may not exist, and if it exists, it is C. In some embodiments, the VH region is the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 Includes; where X5 is selected from S or N; X6 is selected from R, S, or N; X7 is selected from Y, I, or N; X8 is selected from Y, D, G, or A; X9 is selected from V, M, or I; X 10 is selected from T, S, or M; and, X 11 It may or may not exist, and if it exists, it is C. In some embodiments, the VH region is the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12Includes; where 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It may or may not exist, and if it exists, it is C. In some embodiments, the VH region is the CDR2 sequence AISGSGGSTX 22 Includes YADSVKG, where X 22 This is selected from F or Y. In some embodiments, the VH region is 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 Includes; where 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 23is 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 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It may or may not exist, and if it exists, it is G. In some embodiments, the VH region is 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 Includes; where 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 27is 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 It may or may not exist, and if it exists, it is G. In some embodiments, the VH region is 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 Includes; where 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 G, P, ma or is selected from 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 A, W, N, or S; X 28 is selected from A or W; X 29 is selected from K or A; X 30 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It may or may not exist, and if it exists, it is G. In some embodiments, the VH region is the CDR3 sequence AKRGTYX 38 YSX 41Includes PTGFDY, where X 38 is selected from A or G; and X 41 This is selected from F or Y. In some embodiments, the VH region is 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 Includes; where 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 It may or may not exist, and if it exists, it is selected from V, D, Y, A, N, G, L, or E; X 42 It may or may not exist, and if it exists, it is selected from L, Y, F, T, or G, and X 43 It may or may not exist, and if it exists, it is selected from P, F, V, N, S, or Y, and X 44 It may or may not exist, and if it exists, it is selected from L, S, T, G, F, and X 45 It may or may not exist, and if it exists, it is selected from L, F, E, S, or N, and X 46either exists or does not exist, and if it exists, is selected from S, L, or R, X 47 either exists or does not exist, and if it exists, is L, X 48 either exists or does not exist, and if it exists, is D; and, X 49 either exists or does not exist, and if it exists, is L. In some embodiments, the VH region is 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 including; where 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 either exists or does not exist, and if it exists, is selected from P, F, V, or N; X 44 either exists or does not exist, and if it exists, is selected from L, S, or T; X 45 either exists or does not exist, and if it exists, is selected from L or F. In some embodiments, the VH region is the CDR3 sequence AX 33 X 34 X 35 X 36 X 37X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 Includes; where 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 It may or may not exist, and if it exists, it is selected from V, Y, or E, and X 42 It either exists or does not exist, and if it exists, it is G; X 43 It either exists or does not exist, and if it exists, it is Y; X 44 It either exists or does not exist, and if it exists, it is F; X 45 It may or may not exist, and if it exists, it is selected from E or N; and X 46 It may or may not exist, and if present, it is selected from S or L. In some embodiments, the VH region is the CDR1 sequence GFPFX5X6YAMS, the CDR2 sequence AISGSGGSTX 22 YADSVKG and CDR3 sequence AKRGTYX 38 YSX 41 Includes PTGFDY; where 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 is the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 CDR2 sequence X 13 X 14IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 comprising; 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, 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 27is 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 It either exists or does not exist, and if it exists, 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; 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 It may or may not exist, and if it exists, it is selected from P, F, V, or N; X 44 It may or may not exist, and if it exists, it is selected from L, S, or T; X 45 It may or may not exist, and if it exists, it is selected from L or F. In some embodiments, the VH region is the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 , and CDR3 sequence AX 33 X 34 X35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 Includes; where 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 It may or may not exist, and if it exists, it is selected from C or M, X 12 It either exists or does not exist, and if it exists, it 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 Choose from A, W, N, or S. X 28 is selected from A or W; X 29 is selected from K or A; X 30 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It either exists or does not exist, and if it exists, it is G, and X 33 is selected from R or G; X 34 is selected from E, D, or S; X35 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 It may or may not exist, and if it exists, it is selected from V, Y, or E, and X 42 It either exists or does not exist, and if it exists, it is G; X 43 It either exists or does not exist, and if it exists, it is Y; X 44 It either exists or does not exist, and if it exists, it is F; X 45 It may or may not exist, and if it exists, it is selected from E or N; and X 46 The region may or may not exist, and if present, it is selected from S or L. In some embodiments, the VH region consists of a CDR1 sequence selected from sequence numbers: 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 sequence numbers: 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 Includes; where X 32 is selected from A, G, or V; X 33 is selected from K, A, R, T, G, or S; X 34is 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 If it exists or does not exist, then currently it is selected from F, Y, V, D, A, N, G, E, or L; X 42 It may or may not exist, and if it exists, it is selected from P, L, Y, F, G, or T, X 43 It may or may not exist, and if it exists, it is selected from T, P, F, V, N, Y, or S, X 44 It may or may not exist, and if it exists, it is selected from G, L, S, T, or F, X 45 It may or may not exist, and if it exists, it is selected from F, L, E, N, or S, X 46 It may or may not exist, and if it exists, it is selected from D, S, L, or R, and X 47 It may or may not exist, and if it exists, it is selected from Y or L, X 48 It either exists or does not exist, and if it exists, it is D; and X 49It may or may not exist, and if it exists, it is L. In some embodiments, the VH region includes a CDR1 sequence selected from sequence numbers: 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 sequence numbers: 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 sequence numbers: 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 includes CDR1 sequences selected from sequence numbers 1, 4, 6, 8, and 9; CDR2 sequences selected from sequence numbers 2 and 5; and CDR3 sequences selected from sequence numbers 3, 7, and 10. In some embodiments, the VH region includes CDR1 sequences selected from sequence numbers 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; CDR2 sequences selected from sequence numbers 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and CDR3 sequences selected from sequence numbers 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region includes CDR1 sequences selected from sequence numbers 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequences selected from sequence numbers 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequences selected from sequence numbers 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, the VH region includes CDR1 sequences selected from sequence numbers 17, 23, 29, 44, and 56; CDR2 sequences selected from sequence numbers 18, 24, 30, 45, and 57; and CDR3 sequences selected from sequence numbers 19, 25, 31, 46, and 58.In some embodiments, the VL region includes a CDR1 sequence selected from sequence numbers 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from sequence numbers 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from sequence numbers 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103. In some embodiments, the VL region includes CDR1 sequences selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; CDR2 sequences selected from SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and CDR3 sequences selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, the VL region includes CDR1 sequences selected from SEQ ID NOs: 71, 77, 83, 94, and 102; CDR2 sequences selected from SEQ ID NOs: 72, 78, and 84; and CDR3 sequences selected from SEQ ID NOs: 73, 79, 85, 95, and 103. In some embodiments, the anti-CD38 antibody includes a VH sequence selected from SEQ ID NOs: 104-128 and a VL sequence selected from SEQ ID NOs: 130-154. In some embodiments, the anti-CD38 antibody is a polyspecific antibody containing a second targeting moiety. In some embodiments, the second targeting region specifically binds to ICAM1. In some embodiments, the second targeting region includes a variable heavy chain (VH) region and a variable light chain (VL) region, where the VH region is the CDR1 sequence X1X2X3X4X5X6X7X8X9X. 10 X 11 Includes; where X1 is selected from G or E; X2 is selected from F or Y; X3 is selected from S or T; X4 is selected from L, F, or S; X5 is selected from S or N; X6 is selected from S, N, T, or D; X7 is selected from Y, H, or G; X8 is selected from G, A, Y, W, or F; X9 is selected from M, W, Y, or I; X 10 is selected from S, G, N, M, or I; and X 11It may or may not exist, and if it exists, it is C; the VH region is 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 This includes, 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 It may or may not exist, and if it exists, it is selected from K or G; and X 30 It may or may not exist, and if it exists, it is G; and the VH region is CDR3 sequence X 31 X32 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 This includes, where 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 It may or may not exist, and if it exists, it is selected from Y, A, G, I, or D; X 42 It may or may not exist, and if it exists, it is selected from I, Y, R, P, V, or G; X 43 It may or may not exist, and if it exists, it is selected from L, R, Y, G, or A; X 44 It may or may not exist, and if it exists, it is selected from N, L, S, Y, or W; X 45 It may or may not exist, and if it exists, it is selected from L, Y, F, or C; X 46 It may or may not exist, and if it exists, it is selected from D, A, or F; X 47 It may or may not exist, and if it exists, it is selected from M, P, Y, or N; X48 It may or may not exist, and if it exists, it is selected from D or L, and X 49 It may or may not exist, and if it exists, it is L. In some embodiments, the VH region is the CDR1 sequence GFSLX5X6X7X8MX 10 This includes, where X5 is selected from S or N; X6 is selected from S, N, T, or D; X7 is selected from Y or H; X8 is selected from G, A, or Y; and X 10 This is selected from S, G, or N. In some embodiments, the VH region is the CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 Includes WAKG, here 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 This is selected from S, T, or N. In some embodiments, the VH region is 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 This includes, where X 31 is selected from A or V; X 33 is selected from G or D; X 34is 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 It may or may not exist, and if it exists, it is selected from L, Y, or F; X 46 It either exists or does not exist, and if it exists, it is D; X 47 It may or may not exist, and if it exists, it is selected from M or P; X 48 It either exists or does not exist, and if it exists, it is D; and X 49It may or may not exist, and if present, it is L. In some embodiments, the VH region includes a CDR1 sequence selected from sequence numbers: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from sequence numbers: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence selected from sequence numbers: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252. In some embodiments, the VH region includes a CDR1 sequence selected from sequence numbers: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; a CDR2 sequence selected from sequence numbers: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and a CDR3 sequence selected from sequence numbers: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240. In some embodiments, the VH region includes a CDR1 sequence selected from sequence numbers 241, 247, and 250; a CDR2 sequence selected from sequence numbers 242, 244, 246, 248, and 251; and a CDR3 sequence selected from sequence numbers 243, 245, 249, and 252. In some embodiments, the VL region includes a CDR1 sequence selected from sequence numbers 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; a CDR2 sequence selected from sequence numbers 254, 257, 260, 263, 273, 275, 280, and 283; and a CDR3 sequence selected from sequence numbers 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284. In some embodiments, the second targeted portion includes a VH sequence selected from sequence numbers 289-309 and a VL sequence selected from sequence numbers 311-326 and 155.In some embodiments, the anti-CD38 antibody comprises a humanized antibody or its conjugated fragment, or a chimeric antibody or its conjugated fragment. In some embodiments, the anti-CD38 antibody comprises a bispecific antibody or its conjugated fragment. In some embodiments, the bispecific antibody or its conjugated fragment comprises IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triplebody, miniantibody, 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 anti-CD38 antibody comprises an IgG1 framework sequence. In some embodiments, the anti-CD38 antibody includes an IgG2 framework sequence. In some embodiments, the anti-CD38 antibody includes an IgG4 framework sequence. In some embodiments, the anti-CD38 antibody includes an HC sequence selected from SEQ ID NOs: 157-181 and an LC sequence selected from SEQ ID NOs: 183-207. In some embodiments, the anti-CD38 antibody further includes a payload. In some embodiments, the payload includes a small molecule, a peptide, or a protein.

[0032] In certain embodiments, an anti-ICAM1 antibody comprising a variable heavy chain (VH) region and a variable light chain (VL) region is disclosed herein, where the VH region is: CDR1 sequence X1X2X3X4X5X6X7X8X9X 10 X 11 Includes; where X1 is selected from G or E; X2 is selected from F or Y; X3 is selected from S or T; X4 is selected from L, F, or S; X5 is selected from S or N; X6 is selected from S, N, T, or D; X7 is selected from Y, H, or G; X8 is selected from G, A, Y, W, or F; X9 is selected from M, W, Y, or I; X 10is selected from S, G, N, M, or I; and X 11 It may or may not exist, and if it exists, it is C; the VH region is 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 This includes, 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 It may or may not exist, and if it exists, it is selected from K or G; and X 30It may or may not exist, and if it exists, it is G; and the VH region is 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 This includes, where 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 It may or may not exist, and if it exists, it is selected from Y, A, G, I, or D; X 42 It may or may not exist, and if it exists, it is selected from I, Y, R, P, V, or G; X 43 It may or may not exist, and if it exists, it is selected from L, R, Y, G, or A; X 44 It may or may not exist, and if it exists, it is selected from N, L, S, Y, or W; X 45 It may or may not exist, and if it exists, it is selected from L, Y, F, or C; X 46 It may or may not exist, and if it exists, it is selected from D, A, or F; X 47It may or may not exist, and if it exists, it is selected from M, P, Y, or N; X 48 It may or may not exist, and if it exists, it is selected from D or L, and X 49 It may or may not exist, and if it exists, it is L. In some embodiments, the VH region is the CDR1 sequence GFSLX5X6X7X8MX 10 This includes, where X5 is selected from S or N; X6 is selected from S, N, T, or D; X7 is selected from Y or H; X8 is selected from G, A, or Y; and X 10 This is selected from S, G, or N. In some embodiments, the VH region is the CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 Includes WAKG, here 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 This is selected from S, T, or N. In some embodiments, the VH region is 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 This includes, where X 31 is selected from A or V; X33 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 It may or may not exist, and if it exists, it is selected from L, Y, or F; X 46 It either exists or does not exist, and if it exists, it is D; X 47 It may or may not exist, and if it exists, it is selected from M or P; X 48 It either exists or does not exist, and if it exists, it is D; and X 49 It may or may not exist, and if it exists, it is L. In some embodiments, the VH region is a CDR1 sequence selected from sequence numbers: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from sequence numbers: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and the VH region is 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 X46 X 47 X 48 X 49 This includes, where 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 It may or may not exist, and if it exists, it is selected from Y, A, G, I, or D; X 42 It may or may not exist, and if it exists, it is selected from I, Y, R, P, V, or G; X 43 It may or may not exist, and if it exists, it is selected from L, R, Y, G, or A; X 44 It may or may not exist, and if it exists, it is selected from N, L, S, Y, or W; X 45 It may or may not exist, and if it exists, it is selected from L, Y, F, or C; X 46 It may or may not exist, and if it exists, it is selected from D, A, or F; X 47 It may or may not exist, and if it exists, it is selected from M, P, Y, or N; X 48 It may or may not exist, and if it exists, it is selected from D or L, and X 49It may or may not exist, and if present, it is L. In some embodiments, the VH region includes a CDR1 sequence selected from sequence numbers: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from sequence numbers: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence selected from sequence numbers: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252. In some embodiments, the VH region includes a CDR1 sequence selected from sequence numbers: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; a CDR2 sequence selected from sequence numbers: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and a CDR3 sequence selected from sequence numbers: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240. In some embodiments, the VH region includes CDR1 sequences selected from sequence numbers 241, 247, and 250; CDR2 sequences selected from sequence numbers 242, 244, 246, 248, and 251; and CDR3 sequences selected from sequence numbers 243, 245, 249, and 252. In some embodiments, the VL region includes CDR1 sequences selected from sequence numbers 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; CDR2 sequences selected from sequence numbers 254, 257, 260, 263, 273, 275, 280, and 283; sequence number 255, The antibody includes a CDR3 sequence selected from 258, 261, 264, 266, 271, 276, 278, 281, and 284. In some embodiments, the second targeting moiety includes a VH sequence selected from SEQ ID NOs: 289-309 and a VL sequence selected from SEQ ID NOs: 311-326 and 155. In some embodiments, the anti-ICAM1 antibody is a polyspecific antibody containing an additional targeting moiety. In some embodiments, the additional targeting moiety specifically binds to CD38. In some embodiments, the additional targeting moiety includes a variable heavy chain (VH) region and a variable light chain (VL) region, where the VH region is the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 Includes; where X1 is either 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It may or may not exist, and if it exists, it is C, and the VH region is 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 This includes, where X 13 is selected from A, G, or S; X14 is selected from I, F, Y, V, S, or C; X 15 The following can be 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 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It may or may not exist, and if it exists, it is G, as well as 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 Includes; where X 32 is selected from A, G, or V; X 33 is selected from K, A, R, T, G, or S; X 34is 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 If it exists or does not exist, then currently it is selected from F, Y, V, D, A, N, G, E, or L; X 42 It may or may not exist, and if it exists, it is selected from P, L, Y, F, G, or T, X 43 It may or may not exist, and if it exists, it is selected from T, P, F, V, N, Y, or S, X 44 It may or may not exist, and if it exists, it is selected from G, L, S, T, or F, X 45 It may or may not exist, and if it exists, it is selected from F, L, E, N, or S, X 46 It may or may not exist, and if it exists, it is selected from D, S, L, or R, and X 47 It may or may not exist, and if it exists, it is selected from Y or L, X 48 It either exists or does not exist, and if it exists, it is D; and X 49 It may or may not exist, and if present, it is L. In some embodiments, the VH region includes 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 includes the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12Includes; 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It may or may not exist, and if it exists, it is C. In some embodiments, the VH region is the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 Includes; where X5 is selected from S or N; X6 is selected from R, S, or N; X7 is selected from Y, I, or N; X8 is selected from Y, D, G, or A; X9 is selected from V, M, or I; X 10 is selected from T, S, or M; and, X 11 It may or may not exist, and if it exists, it is C. In some embodiments, the VH region is the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 Includes; where 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It may or may not exist, and if it exists, it is C. In some embodiments, the VH region is the CDR2 sequence AISGSGGSTX 22 Includes YADSVKG, where X 22 This is selected from F or Y. In some embodiments, the VH region is the CDR2 sequence X13 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 Includes; where 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 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It may or may not exist, and if it exists, it is G. In some embodiments, the VH region is the CDR2 sequence X 13 X 14 IX 16 X17 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 Includes; where 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 It may or may not exist, and if it exists, it is G. In some embodiments, the VH region is 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 Includes; where 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 A, W, N, or S; X 28 is selected from A or W; X 29 is selected from K or A; X 30 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It may or may not exist, and if it exists, it is G. In some embodiments, the VH region is the CDR3 sequence AKRGTYX 38 YSX 41 Includes PTGFDY, where X 38 is selected from A or G; and X 41 This is selected from F or Y. In some embodiments, the VH region is 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 Includes; where X 32 is selected from A, G, or V; X33 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 It may or may not exist, and if it exists, it is selected from V, D, Y, A, N, G, L, or E; X 42 It may or may not exist, and if it exists, it is selected from L, Y, F, T, or G, and X 43 It may or may not exist, and if it exists, it is selected from P, F, V, N, S, or Y, and X 44 It may or may not exist, and if it exists, it is selected from L, S, T, G, or F, and X 45 It may or may not exist, and if it exists, it is selected from L, F, E, S, or N, and X 46 It may or may not exist, and if it exists, it is selected from S, L, or R, and X 47 It either exists or does not exist, and if it exists, it is L, and X 48 It either exists or does not exist, and if it exists, it is D; and X 49 It may or may not exist, and if it exists, it is L. In some embodiments, the VH region is 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 45Includes; where 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 It may or may not exist, and if it exists, it is selected from P, F, V, or N; X 44 It may or may not exist, and if it exists, it is selected from L, S, or T; X 45 It may or may not exist, and if present, it is selected from L or F. In some embodiments, the VH region is 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 Includes; where 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 40is selected from Y, N, or L; X 41 It may or may not exist, and if it exists, it is selected from V, Y, or E, and X 42 It either exists or does not exist, and if it exists, it is G; X 43 It either exists or does not exist, and if it exists, it is Y; X 44 It either exists or does not exist, and if it exists, it is F; X 45 It may or may not exist, and if it exists, it is selected from E or N; and X 46 It may or may not exist, and if present, it is selected from S or L. In some embodiments, the VH region is the CDR1 sequence GFPFX5X6YAMS, the CDR2 sequence AISGSGGSTX 22 YADSVKG and CDR3 sequence AKRGTYX 38 YSX 41 Includes PTGFDY; where 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 is the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 , and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X42 X 43 X 44 X 45 Includes; where 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 It either exists or does not exist, and if it exists, 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 It either exists or does not exist, and if it exists, 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; X 39is 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 It may or may not exist, and if it exists, it is selected from P, F, V, or N; X 44 It may or may not exist, and if it exists, it is selected from L, S, or T; X 45 It may or may not exist, and if it exists, it is selected from L or F. In some embodiments, the VH region is the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 , and CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 Includes; where 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 It may or may not exist, and if it exists, it is selected from C or M, X12 It either exists or does not exist, and if it exists, it 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 G, P, or selected from 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 A, W, N, or S; X 28 is selected from A or W; X 29 is selected from K or A; X 30 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It either exists or does not exist, and if it exists, it is G, and 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 It may or may not exist, and if it exists, it is selected from V, Y, or E, and X 42 It either exists or does not exist, and if it exists, it is G; X 43 It either exists or does not exist, and if it exists, it is Y; X 44 It either exists or does not exist, and if it exists, it is F; X45 It may or may not exist, and if it exists, it is selected from E or N; and X 46 The region may or may not exist, and if present, it is selected from S or L. In some embodiments, the VH region consists of a CDR1 sequence selected from sequence numbers: 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 sequence numbers: 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 Includes; 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 If it exists or does not exist, then currently it is selected from F, Y, V, D, A, N, G, E, or L; X 42It may or may not exist, and if it exists, it is selected from P, L, Y, F, G, or T, X 43 It may or may not exist, and if it exists, it is selected from T, P, F, V, N, Y, or S, X 44 It may or may not exist, and if it exists, it is selected from G, L, S, T, or F, X 45 It may or may not exist, and if it exists, it is selected from F, L, E, N, or S, X 46 It may or may not exist, and if it exists, it is selected from D, S, L, or R, and X 47 It may or may not exist, and if it exists, it is selected from Y or L, X 48 It either exists or does not exist, and if it exists, it is D; and X 49It may or may not exist, and if it exists, it is L. In some embodiments, the VH region includes a CDR1 sequence selected from sequence numbers: 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 sequence numbers: 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 sequence numbers: 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 includes CDR1 sequences selected from sequence numbers 1, 4, 6, 8, and 9; CDR2 sequences selected from sequence numbers 2 and 5; and CDR3 sequences selected from sequence numbers 3, 7, and 10. In some embodiments, the VH region includes CDR1 sequences selected from sequence numbers 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; CDR2 sequences selected from sequence numbers 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and CDR3 sequences selected from sequence numbers 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region includes CDR1 sequences selected from sequence numbers 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequences selected from sequence numbers 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequences selected from sequence numbers 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, the VH region includes CDR1 sequences selected from sequence numbers 17, 23, 29, 44, and 56; CDR2 sequences selected from sequence numbers 18, 24, 30, 45, and 57; and CDR3 sequences selected from sequence numbers 19, 25, 31, 46, and 58.In some embodiments, the VL region includes a CDR1 sequence selected from sequence numbers 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from sequence numbers 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from sequence numbers 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103. In some embodiments, the VL region includes CDR1 sequences selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; CDR2 sequences selected from SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and CDR3 sequences selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, the VL region includes CDR1 sequences selected from SEQ ID NOs: 71, 77, 83, 94, and 102; CDR2 sequences selected from SEQ ID NOs: 72, 78, and 84; and CDR3 sequences selected from SEQ ID NOs: 73, 79, 85, 95, and 103. In some embodiments, the anti-CD38 antibody includes a VH sequence selected from SEQ ID NOs: 104-128 and a VL sequence selected from SEQ ID NOs: 130-154. In some embodiments, the anti-ICAM1 antibody comprises a humanized antibody or its conjugated fragment, or a chimeric antibody or its conjugated fragment. In some embodiments, the anti-ICAM1 antibody comprises a bispecific antibody or its conjugated fragment. In some embodiments, the bispecific antibody or its conjugated fragment comprises IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triplebody, miniantibody, 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 anti-ICAM1 antibody includes an IgG1 framework sequence. In some embodiments, the anti-ICAM1 antibody includes an IgG2 framework sequence. In some embodiments, the anti-ICAM1 antibody includes an IgG4 framework sequence. In some embodiments, the anti-ICAM1 antibody includes an HC sequence selected from SEQ ID NOs: 157-181 and an LC sequence selected from SEQ ID NOs: 183-207. In some embodiments, the anti-ICAM1 antibody further includes a payload. In some embodiments, the payload includes 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 herein.

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

[0035] In certain embodiments, pharmaceutical compositions comprising a bispecific antibody described herein, an anti-CD38 antibody described herein, or an anti-ICAM1 antibody described herein, and a pharmaceutically acceptable excipient are disclosed herein. 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 for treating a subject's cancer is disclosed herein, the method comprising the step of administering to a subject a bispecific antibody, an anti-CD38 antibody, an anti-ICAM1 antibody, or a pharmaceutical composition described herein, thereby treating the subject's cancer. In some embodiments, the subject has a solid tumor. In some embodiments, the solid tumor is bladder cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, eye cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer. In some embodiments, the cancer is a hematological malignancy. In some embodiments, the hematological malignancy is a B-cell lymphoma or a T-cell lymphoma. In some embodiments, the hematological malignancy is a Hodgkin lymphoma or a non-Hodgkin lymphoma. In some embodiments, hematological malignancies include chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenström macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt lymphoma, and non-Burkitt lymphoma. The cancers include high-grade trimymphoid lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B-cell pre-lymphoblastic leukemia, lymphoplasmacytic lymphoma, perisplenic zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary coeloplasmosis, 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 includes the step of administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent includes a chemotherapeutic agent, an immunotherapy agent, a targeted therapy agent, a hormone-based therapy agent, a stem cell-based therapy agent, or radiation. In some embodiments, the additional therapeutic agent is a first-line therapy agent. In some embodiments, the additional therapeutic agent and the antibody are administered simultaneously. In some embodiments, the additional therapeutic agent and the antibody are administered sequentially.In some embodiments, the additional therapeutic agent is administered before the antibody. In some embodiments, the additional therapeutic agent is administered after the antibody. In some embodiments, the additional therapeutic agent and the antibody are administered in separate doses. In some embodiments, the subject undergoes surgery. In some embodiments, the subject is human.

[0037] In certain embodiments, kits comprising a bispecific antibody described herein, an anti-CD38 antibody described herein, an anti-ICAM1 antibody described herein, or a pharmaceutical composition described herein are disclosed herein. [Brief explanation of the drawing]

[0038] Novel features of the present invention are described in particular in the appended claims. For a better understanding of the features and advantages of the present invention, please refer to the following detailed description and accompanying drawings illustrating exemplary embodiments in which the principles of the present invention are used. [Figure 1A] This illustrates the exemplary bispecific antibody format intended herein. Figures 1A and 1B are taken from Figure 2 of Brinkmann and Kontermann, “The making of bispecific antibodies,” MABS 9(2):182-212 (2017). [Figure 1B] This illustrates the exemplary bispecific antibody format intended herein. Figures 1A and 1B are taken from Figure 2 of Brinkmann and Kontermann, “The making of bispecific antibodies,” MABS 9(2):182-212 (2017). [Figure 2] This specification illustrates exemplary bispecificity formats: A: light chain C-terminal fusion; B: heavy chain C-terminal fusion; C: heavy chain N-terminal fusion; D: DVD format; E: triple chain knob-into-hole (KIH); and F in Figure 2: general light chain bispecificity. [Figure 3]AB represents the levels of CD38 (3A) and ICAM1 (3B) on the surface of various cell lines, as measured by flow cytometry using PE-labeled anti-hCD38 (Biolegend) or AlexaFluor488-labeled anti-hCD54 (Biolegend). [Figure 4] AB shows complement-dependent cytotoxicity (CDC)-mediated lysis of Daudi cells (A) and Raji cells (B) by selected monoclonal antibodies and bispecific antibodies. [Figure 5A] This study illustrates antibody-dependent cell-mediated lysis of 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 cells (Figure 5F) using NK92 / CD16A as effector cells. [Figure 5B] This study illustrates antibody-dependent cell-mediated lysis of 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 cells (Figure 5F) using NK92 / CD16A as effector cells. [Figure 5C] This study illustrates antibody-dependent cell-mediated lysis of 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 cells (Figure 5F) using NK92 / CD16A as effector cells. [Figure 5D] This study illustrates antibody-dependent cell-mediated lysis of 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 cells (Figure 5F) using NK92 / CD16A as effector cells. [Figure 5E]This study illustrates antibody-dependent cell-mediated lysis of 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 cells (Figure 5F) using NK92 / CD16A as effector cells. [Figure 5F] This study illustrates antibody-dependent cell-mediated lysis of 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 cells (Figure 5F) using NK92 / CD16A as effector cells. [Figure 6A] This shows ADCC-mediated lysis of Daudi cells (Figure 6A), DU145 cells (Figure 6B), HCC44 cells (Figure 6C), and NCI-H2444 cells (Figure 6D) using fresh PBMCs as effector cells. [Figure 6B] This shows ADCC-mediated lysis of Daudi cells (Figure 6A), DU145 cells (Figure 6B), HCC44 cells (Figure 6C), and NCI-H2444 cells (Figure 6D) using fresh PBMCs as effector cells. [Figure 6C] This shows ADCC-mediated lysis of Daudi cells (Figure 6A), DU145 cells (Figure 6B), HCC44 cells (Figure 6C), and NCI-H2444 cells (Figure 6D) using fresh PBMCs as effector cells. [Figure 6D] This shows ADCC-mediated lysis of Daudi cells (Figure 6A), DU145 cells (Figure 6B), HCC44 cells (Figure 6C), and NCI-H2444 cells (Figure 6D) using fresh PBMCs as effector cells. [Figure 7] This illustrates the induction of cell death and apoptosis in Daudi cells with and without cross-linking by selected monoclonal and bispecific antibodies. [Figure 8A]Figure 8B shows antibody-induced cell death of NK cells from NK92 / CD16a cells (Figure 8A) and fresh PBMCs. HC N-fusion and triple-chain KIH antibodies showed reduced NK cell death compared to anti-CD38 BMK clones (or the reference antibody daratumumab). [Figure 8B] Figure 8B shows antibody-induced cell death of NK cells from NK92 / CD16a cells (Figure 8A) and fresh PBMCs. HC N-fusion and triple-chain KIH antibodies showed reduced NK cell death compared to anti-CD38 BMK clones (or the reference antibody daratumumab). [Figure 9A] Exemplary ELISA conjugation of anti-CD38 rabbit-human chimeric clones against recombinant human CD38 ECD (Figure 9A) and cynomolgus monkey CD38 ECD (Figure 9B) is shown. [Figure 9B] Exemplary ELISA conjugation of anti-CD38 rabbit-human chimeric clones against recombinant human CD38 ECD (Figure 9A) and cynomolgus monkey CD38 ECD (Figure 9B) is shown. [Figure 10A] This shows exemplary ELISA conjugation of anti-ICAM1 rabbit-human chimeric clones against recombinant human ICAM1 ECD (Figure 10A) and rhesus monkey ICAM1 ECD (Figure 10B). [Figure 10B] This shows exemplary ELISA conjugation of anti-ICAM1 rabbit-human chimeric clones against recombinant human ICAM1 ECD (Figure 10A) and rhesus monkey ICAM1 ECD (Figure 10B). [Figure 11] This shows the binding of exemplary anti-CD38 rabbit-human chimeric clones to Daudi cells, as determined by flow cytometry. [Figure 12] This shows the binding of anti-ICAM1 rabbit-human chimeric clones to DU145 cells as determined by flow cytometry. [Figure 13] This shows benchmark and exemplary CDC-mediated lysis of Daudi cells by rabbit-human-chimeric anti-CD38 antibodies. [Figure 14A]Using NK92 / CD16A as effector cells, we demonstrate ADCC-mediated lysis of Daudi cells (Figure 14A) and HuNS1 cells (Figure 14B) by anti-CD38 antibody. [Figure 14B] Using NK92 / CD16A as effector cells, we demonstrate ADCC-mediated lysis of Daudi cells (Figure 14A) and HuNS1 cells (Figure 14B) by anti-CD38 antibody. [Figure 15A] Using NK92 / CD16A as effector cells, we demonstrate ADCC-mediated lysis of Daudi cells (Figure 15A) and HuNS1 cells (Figure 15B) with an exemplary rabbit-human-chimeric anti-CD38 antibody. [Figure 15B] Using NK92 / CD16A as effector cells, we demonstrate ADCC-mediated lysis of Daudi cells (Figure 15A) and HuNS1 cells (Figure 15B) with an exemplary rabbit-human-chimeric anti-CD38 antibody. [Figure 16A] Using NK92 / CD16A as effector cells, we demonstrate ADCC-mediated lysis of DU145 (Figure 16A), Daudi cells (Figure 16B), and HuNS1 cells (Figure 16C) with anti-ICAM1 clone G12 and exemplary rabbit-human-chimeric anti-ICAM1 antibodies. [Figure 16B] Using NK92 / CD16A as effector cells, we demonstrate ADCC-mediated lysis of DU145 (Figure 16A), Daudi cells (Figure 16B), and HuNS1 cells (Figure 16C) with anti-ICAM1 clone G12 and exemplary rabbit-human-chimeric anti-ICAM1 antibodies. [Figure 16C] Using NK92 / CD16A as effector cells, we demonstrate ADCC-mediated lysis of DU145 (Figure 16A), Daudi cells (Figure 16B), and HuNS1 cells (Figure 16C) with anti-ICAM1 clone G12 and exemplary rabbit-human-chimeric anti-ICAM1 antibodies. [Figure 17A]Using fresh PBMCs as effector cells, we demonstrate ADCC-mediated lysis of DU145 cells with exemplary high-affinity anti-CD38 4618_1_12 bispecific antibody (Figure 17A), exemplary moderate-affinity anti-CD38 32218_1 bispecific antibody (Figure 17B), and exemplary low-affinity anti-CD38 33218_2 bispecific antibody (Figure 17C). [Figure 17B] Using fresh PBMCs as effector cells, we demonstrate ADCC-mediated lysis of DU145 cells with exemplary high-affinity anti-CD38 4618_1_12 bispecific antibody (Figure 17A), exemplary moderate-affinity anti-CD38 32218_1 bispecific antibody (Figure 17B), and exemplary low-affinity anti-CD38 33218_2 bispecific antibody (Figure 17C). [Figure 17C] Using fresh PBMCs as effector cells, we demonstrate ADCC-mediated lysis of DU145 cells with exemplary high-affinity anti-CD38 4618_1_12 bispecific antibody (Figure 17A), exemplary moderate-affinity anti-CD38 32218_1 bispecific antibody (Figure 17B), and exemplary low-affinity anti-CD38 33218_2 bispecific antibody (Figure 17C). [Figure 18A] Exemplary monovalent anti-CD38 (culture affinity, 32218_1), monovalent anti-ICAM1, and anti-CD38 / ICAM1 bispecific antibodies are used to demonstrate ADCC-mediated lysis of Raji (Figure 18A), DU145 (Figure 18B), and HCC44 (Figure 18C). [Figure 18B] Exemplary monovalent anti-CD38 (culture affinity, 32218_1), monovalent anti-ICAM1, and anti-CD38 / ICAM1 bispecific antibodies are used to demonstrate ADCC-mediated lysis of Raji (Figure 18A), DU145 (Figure 18B), and HCC44 (Figure 18C). [Figure 18C] Exemplary monovalent anti-CD38 (culture affinity, 32218_1), monovalent anti-ICAM1, and anti-CD38 / ICAM1 bispecific antibodies are used to demonstrate ADCC-mediated lysis of Raji (Figure 18A), DU145 (Figure 18B), and HCC44 (Figure 18C). [Figure 19A]This shows increased ADCC-mediated lysis of Raji (Figure 19A) cells and KMS26 (Figure 19B) cells using a CD38 / ICAM1 KIH bispecific antibody with Fc mutations (high ADCC). [Figure 19B] This shows increased ADCC-mediated lysis of Raji (Figure 19A) cells and KMS26 (Figure 19B) cells using a CD38 / ICAM1 KIH bispecific antibody with Fc mutations (high ADCC). [Figure 20A] This shows increased ADCC-mediated lysis of Raji (Figure 20A) cells and KMS26 (Figure 20B) cells using afucosylated CD38 / ICAM1 KIH bispecific antibodies. [Figure 20B] This shows increased ADCC-mediated lysis of Raji (Figure 20A) cells and KMS26 (Figure 20B) cells using afucosylated CD38 / ICAM1 KIH bispecific antibodies. [Figure 21] This shows the mean volume of xenograft tumors derived from Raji cells treated with a single-specific CD38 or ICAM1 antibody, or a triple-chain KIH CD38 / ICAM1 bispecific antibody. [Figure 22] The mean volume of xenograft tumors derived from Raji cells treated with a single-specific CD38 antibody, a tri-chain KIH CD38 / ICAM1 bispecific antibody having an anti-CD38 binding domain from anti-CD38 BMK, or a tri-chain KIH CD38 / ICAM1 bispecific antibody having a CD38 binding domain from 32218_1 (tri-chain KIH(Med)) is shown. [Figure 23] This shows the mean volume of xenograft tumors derived from HuNS1 cells treated with a single-specific CD38 or ICAM1 antibody, or a triple-chain KIH CD38 / ICAM1 bispecific antibody. [Figure 24]The mean volume of xenograft tumors derived from HCC44 cells treated with a bispecific antibody having a CD38-binding domain derived from 18E4 and an ICAM1-binding domain derived from 11F2, a monospecific antibody having the same binding domain, and fucosylated and afucosylated forms of a monospecific anti-CD38 reference antibody (anti-CD38 BMK). [Modes for carrying out the invention]

[0039] Antibody-based therapies are emerging as an effective cancer treatment option due to the specificity and affinity of antibody-target binding, as well as the ease of chemical and molecular modification. Examples of approved antibody-based therapies include monoclonal antibodies such as rituximab, tocitumomab, and trastuzumab; and bispecific T-cell activators such as blinatumomab.

[0040] In some cases, a low copy number of receptors on target cells or low affinity for the antigen hindered the therapeutic effect of antibody-based therapies. In other cases, the nonspecificity of antibodies against the target antigen, or the presence of the target antigen in both cancer and non-cancerous cells, further limited the use of antibody-based therapies.

[0041] 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 lymphocyte activation and proliferation (Funaro et al, J Immunology 145:2390-6, 1990; Guse et al, Nature 398:70-3, 1999), and regulates extracellular NAD+ levels involved in regulatory T cell compartmentalization through its NAD glycohydrolase activity (Adriouch et al., 14:1284-92, 2012; Chiarugi et al., Nature Reviews 12:741-52, 2012). In some cases, CD38 is upregulated in various types of cancer, particularly hematological malignancies such as multiple myeloma.

[0042] ICAM1, also known as CD54, is an Ig-like cell adhesion molecule. ICAM1 is a transmembrane protein associated with endothelial cells and leukocytes, and is involved in stabilizing intercellular interactions and promoting leukocyte endothelial migration. ICAM1 is expressed in various cell types, including endothelial cells and leukocytes, and may be expressed and / or overexpressed in various cancer cells, such as myeloma, pancreatic cancer, glioma, lung cancer, melanoma, colorectal cancer, and lymphoma.

[0043] In some embodiments, anti-CD38 antibodies, anti-ICAM1 antibodies, and polyspecific antibodies are disclosed herein, including anti-CD38 antibodies, anti-ICAM1 antibodies, or combinations thereof, comprising a targeting moiety for CD38, an anti-ICAM1 moiety, or a combination thereof. In some embodiments, bispecific antibodies comprising a first targeting moiety for CD38 and a second targeting moiety for ICAM1 are also described herein. In additional embodiments, methods for treating cancer using anti-CD38 antibodies, anti-ICAM1 antibodies, or polyspecific antibodies (e.g., bispecific CD38 / ICAM1 antibodies) are also described herein.

[0044] multispecific proteins In certain embodiments, a polyspecific protein comprising a first component that binds to CD38 and a second component that binds to ICAM1 is disclosed herein. The first component is, in some examples, a CD38-binding protein such as an anti-CD38 antibody or an anti-CD38 antibody mimetic. The second component is, in some examples, a CD38-binding protein such as an anti-ICAM1 antibody or an anti-ICAM1 antibody mimetic. See, for example, Yu et al., Annu Rev Anal Chem (Palo Alto Calif). 2017 June 12; 10(1):293-320.

[0045] In some cases, multispecific proteins are bispecific, triplicate, or quadruplicate. In some cases, multispecific proteins are divalent, trivalent, tetravalent, or greater than tetravalent. In some cases, multispecific proteins have more than one binding site to CD38. In some cases, multispecific proteins have more than one binding site to ICAM1. In some cases, multispecific proteins have more than one binding site to each of one, two, three, or four different target proteins. In some cases, multispecific proteins bind to more than one epitope on CD38 and / or ICAM1. In some cases, multispecific proteins are divalent to CD38 and monovalent to ICAM1. In some cases, multispecific proteins are divalent to ICAM1 and monovalent to CD38.

[0046] In some embodiments, the first component comprises an antibody mimetic containing a CD38-specific binding site, and is an affibody, adonectin (also called a monobody), affimer, afitin (also called nanophytin), antikalin, atrimer, avimer, fyonmer, an antibody mimetic containing an armadillo repeat domain, a Kuntiz domain, Nottin, 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, adonectin (also called a monobody), affimer, afitin (also called nanophytin), antikalin, atrimer, avimer, fyonmer, an armadillo repeat domain, a Kuntiz domain, Nottin, DARpin, or any combination thereof.

[0047] 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 main antibody (sdAb); a VHH domain (or camelized antibody); a variable heavy chain domain (VH); a variable light chain domain (VL); Fab, F(ab')2; a single-stranded variable fragment (scFv); scFv (scFv Fc) comprising an Fc region; monovalent IgG; V-NAR; IgGNAR; camel heavy chain IgG (hcIgG); and scFv (scFv-CH3) fused to a CH3 domain.

[0048] 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 main antibody (sdAb); a VHH domain (or camelized antibody); a variable heavy chain domain (VH); a variable light chain domain (VL); Fab, F(ab')2; a single-stranded variable fragment (scFv); scFv (scFv Fc) comprising an Fc region; monovalent IgG; V-NAR; IgGNAR; camel heavy chain IgG (hcIgG); and scFv (scFv-CH3) fused to a CH3 domain.

[0049] In some embodiments, a polyspecific protein comprising a first component that binds to CD38 and a second component that binds to ICAM1 has varying affinity (KD) to each target antigen, as measured by surface plasmon resonance. In some cases, the first component has affinity ranges of approximately 0.1 nM to 100 nM, 0.15 nM to 95 nM, 0.2 nM to 90 nM, 0.25 nM to 85 nM, 0.3 nM to 80 nM, 0.35 nM to 75 nM, 0.4 nM to 70 nM, 0.5 nM to 70 nM, 0.6 nM to 60 nM, 0.7 nM to 50 nM, 0.8 nM to 40 nM, and 0.9 nM to 3 It binds to human CD38 at KD values ​​of 0 nM, approximately 1 nM to 20 nM, approximately 1.5 nM to 10 nM, approximately 0.01 nM to 25 nM, approximately 0.01 nM to 20 nM, approximately 0.01 nM to 10 nM, approximately 0.01 nM to 5 nM, approximately 0.02 nM to 20 nM, approximately 0.04 nM to 20 nM, approximately 0.06 nM to 20 nM, approximately 0.08 nM to 20 nM, or approximately 0.1 nM to 20 nM.

[0050] In some cases, the second component is approximately 0.1nM to 100nM, 0.15nM to 95nM, 0.2nM to 90nM, 0.25nM to 85nM, 0.3nM to 80nM, 0.35nM to 75nM, 0.4nM to 70nM, 0.5nM to 70nM, 0.6nM to 60nM, 0.7nM to 50nM, 0.8nM to 40nM, 0.9nM to 30nM, 1nM to 20nM, 1.5nM to 10nM, and approximately 0. It binds to human ICAM1 with KD values ​​of 15nM to approximately 30nM, approximately 0.16nM to approximately 25nM, approximately 0.17nM to approximately 20nM, approximately 0.18nM to approximately 15nM, approximately 0.19nM to approximately 10nM, approximately 0.1nM to approximately 6nM, approximately 0.2nM to approximately 6nM, approximately 0.2nM to approximately 4nM, approximately 0.2nM to approximately 2nM, approximately 0.2nM to approximately 1.5nM, approximately 0.2nM to approximately 1nM, approximately 0.2nM to approximately 0.8nM, approximately 0.2nM to approximately 0.6nM, or approximately 0.2nM to approximately 0.4nM.

[0051] In some embodiments, the polyspecific proteins provided herein bind to target cells that express ICAM1 at higher levels than CD38 on their surface. For example, the ratio of ICAM1 protein expression to CD38 on the target cell surface is about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200, as measured by flow cytometry. For example, the ratio of ICAM1 protein expression to CD38 on the target cell surface is about 1.1 to 700, for example, about 2.5, 14.2, 29.1, 64.5, 34.0, 50.3, 357.1, or 666.7, based on the quantification of protein surface expression.

[0052] In some cases, target cells express at least 500, 1000, 2000, 3000, 5000, 10000, 150000, 20000, 30000, 50000, 100000, 150000, 200000, 250000, 300000, 400000, or 500000 ICAM1 protein on their surface, as measured by flow cytometry.

[0053] In some embodiments, 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 examples, target cells express fewer than 350,000, 300,000, 250,000, 200,000, 150,000, 100,000, 50,000, or 25,000 CD38 proteins on their surface, as measured by flow cytometry. In some examples, the number of CD38 proteins on the surface of target cells is 100-350,000, 100-300,000, 100-250,000, 100-200,000, 100-150,000, 100-100,000, 100-80,000, 100-60,000, 100-50,000, 100-40,000, 100-30,000, and 100-20,000. The values ​​are 0, 100-10,000, 300-350,000, 300-300,000, 300-250,000, 300-200,000, 300-150,000, 300-100,000, 300-80,000, 300-60,000, 300-50,000, 300-40,000, 300-30,000, 300-20,000, or 300-10,000. In some examples, target cells have less CD38 protein on their surface than Daudi cells, Raji cells, KMS-26 cells, HuNS1 cells, HCC44 cells, NCI-H2444 cells, or DU145 cells. In some cases, target cells have at least 200 CD38 proteins on their surface, but fewer than Daudi cells, Raji cells, KMS-26 cells, HuNS1 cells, HCC44 cells, NCI-H2444 cells, or DU145 cells.

[0054] In some embodiments, the target cells are transformed cells, where the ratio of ICAM1 protein to CD38 is at least 1, 2, 5, 10, 15, 20, 35, 40, 50, or 200. In some cases, the transformed cells express at least 100, 200, 300, 400, 500, 750, 1000, 1250, 1500, 2000, or 3000 CD38 cells on their surface. In some cases, the target cells are myeloid cells, lymphoma cells, pancreatic cancer cells, lung adenocarcinoma cells, or prostate cancer cells, where the ratio of ICAM1 protein to CD38 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 cells originate from lung adenocarcinoma, where the ratio of ICAM1 protein to CD38 is at least 1, 2, 5, 10, 15, 20, 35, 40, 50, or 200. In some cases, bone marrow 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, or 3000 CD38 cells on their surface.

[0055] In some embodiments, multispecific proteins having CD38-binding domains and ICAM1-binding domains exhibit enhanced affinity to cells expressing CD38 and ICAM1 compared to monospecific proteins having a CD38-binding domain and / or monospecific proteins having an ICAM1-binding domain. In some examples, multispecific proteins have 1.5, 2, 3, 4, 5, or 10-fold higher affinity to cells expressing CD38 than monospecific proteins that bind to CD38 or monospecific proteins that bind to ICAM1. In some embodiments, multispecific proteins having CD38-binding domains and ICAM1-binding domains exhibit enhanced affinity to cells expressing higher levels of CD38 than ICAM1 compared to monospecific proteins having a CD38-binding domain. In some embodiments, multispecific proteins have 1.5, 2, 3, 4, 5, or 10-fold higher affinity to cells expressing higher levels of ICAM1 than CD38 compared to monospecific proteins that bind to CD38.

[0056] In some embodiments, a large amount of polyspecific protein having CD38-binding domains and ICAM1-binding domains binds to the surface of cells expressing CD38 and ICAM1 compared to monospecific proteins having CD38-binding domains and / or monospecific proteins having ICAM1-binding domains. In some examples, 1.5, 2, 3, 4, 5, or more than 10 times the amount of polyspecific protein binds to CD38-expressing cells compared to monospecific proteins that bind to CD38 or monospecific proteins that bind to ICAM1. In some embodiments, a large amount of polyspecific protein having CD38-binding domains and ICAM1-binding domains binds to the surface of cells where ICAM1 expression is higher than CD38 expression compared to monospecific proteins having CD38-binding domains. In some examples, 1.5, 2, 3, 4, 5, or more than 10 times the amount of polyspecific protein binds to cells expressing ICAM1 more than CD38 compared to monospecific proteins that bind to CD38.

[0057] In some embodiments, multispecific proteins having both a CD38-binding domain and an ICAM1-binding domain exhibit higher immunoactivity against CD38-expressing cells compared to monospecific proteins having a CD38-binding domain and / or monospecific proteins having an ICAM1-binding domain. In some examples, multispecific proteins exhibit 1.5, 2, 3, 4, 5, or 10-fold higher immunoactivity than monospecific proteins having a CD38-binding domain and / or monospecific proteins having an ICAM1-binding domain. The various immunoactivities of multispecific proteins can be measured in in vitro assays such as ADCC assays and CDC assays. In some examples, multispecific proteins exhibit 1.5, 2, 3, 4, 5, or 10-fold higher ADCC activity than monospecific proteins having a CD38-binding domain and / or monospecific proteins having an ICAM1-binding domain. In some examples, multispecific proteins exhibit 1.5, 2, 3, 4, 5, or 10-fold higher CDC activity than monospecific proteins having a CD38-binding domain and / or monospecific proteins having an ICAM1-binding domain.

[0058] Immune activity can be measured by cell line-derived xenograft assays, where transformed cells are injected into mice to form tumors. In some cases, multispecific proteins with CD38-binding domains and ICAM1-binding domains inhibit tumor growth, including CD38-expressing cells, more significantly than monospecific proteins with CD38-binding domains and / or monospecific proteins with ICAM1-binding domains. In some cases, multispecific proteins show 1.5, 2, 3, 4, 5, or 10-fold higher inhibition of xenograft growth compared to monospecific proteins with CD38-binding domains and / or monospecific proteins with ICAM1-binding domains.

[0059] As used herein, “antibody-dependent cell-mediated cytotoxicity” and “ADCC” refer to a cell-mediated reaction in which nonspecific cytotoxic cells (e.g., natural killer (NK) cells, neutrophils, and macrophages) recognize bound antibodies on target cells, subsequently causing lysis of the target cells. In one embodiment, the target cells are human cells such as tumor cells (e.g., myeloma cells). While not wishing to be constrained to any particular mechanism of action, cytotoxic cells that mediate ADCC generally express Fc receptors (FcRs). NK cells, which are ADCC-mediating 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).

[0060] In some embodiments, in vitro ADCC assays, such as cytotoxicity assays using cancer cell lines, are performed to evaluate the ADCC activity of multispecific proteins as described herein. Useful effector cells for such assays include, but are not limited to, peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. Alternatively or additionally, the ADCC activity of the multispecific protein of interest is evaluated in vivo, for example, in animals, in some embodiments.

[0061] "Complement-dependent cytotoxicity" or "CDC" refers to a molecule's ability to initiate complement activation and lyse its target in the presence of complement. The complement activation pathway is initiated by the binding of a first component of the complement system (C1q) to a molecule (e.g., an antibody) compounded with a congener antigen. To assess complement activation, CDC assays, such as those described in "Gazzano-Santaro et al., J.Immunol. Methods, 202:163 (1996)," are performed in several embodiments.

[0062] In some embodiments, a polyspecific protein, such as those described herein, that binds to CD38 and ICAM1 mediates complement-dependent lysis in at least 50% of cells in an exponentially growing Raji cell population at a concentration of about 2 nM. In some embodiments, a polyspecific protein, such as those described herein, that binds to CD38 and ICAM1 mediates ADCC by PBMCs in 40% of cells in an exponentially growing NCI-H2444 cell population at a concentration of about 1 nM. In some embodiments, a polyspecific (such as bispecific) and polyvalent (such as divalent, trivalent, tetravalent) protein, such as those described herein, that binds to CD38 and ICAM1 does not induce apoptosis without crosslinking.

[0063] Anti-CD38 antibody In some embodiments, an anti-CD38 antibody is disclosed herein. In some examples, the anti-CD38 antibody comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region is the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 This includes, where X1 is either present or absent, if present it 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It may or may not exist, and if it exists, it is C, and the VH region is CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 This includes, where X 13 is selected from A, G, or S, X 14 is selected from I, F, Y, V, S, or C, X 15 The letter is selected from S, I, L, T, or M, and X 16 The first letter is selected from G, Y, S, T, L, or V, and 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, and X 24 The choice is between A and Y, and X 25 The first letter is selected from D, T, S, N, R, A, or Y, and 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 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It may or may not exist, and if it exists, it is G, and the VH region is 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 X44 X 45 X 46 X 47 X 48 X 49 This includes, 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 The letter is selected from G, W, D, L, K, P, S, A, T, or R, and 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 It may or may not exist, and if it exists, it is selected from F, Y, V, D, A, N, G, E, or L, and X 42 It may or may not exist, and if it exists, it is selected from P, L, Y, F, G, or T, X 43 It may or may not exist, and if it exists, it is selected from T, P, F, V, N, Y, or S, X 44 It may or may not exist, and if it exists, it is selected from G, L, S, T, or F, X 45 It may or may not exist, and if it exists, it is selected from F, L, E, N, or S, X 46 It may or may not exist, and if it exists, it is selected from D, S, L, or R, and X 47 It may or may not exist, and if it exists, it is selected from Y or L, X 48 It either exists or does not exist, and if it exists, it is D, and X 49 It either exists or does not exist, and if it exists, it is L.

[0064] In some examples, the VH region of the anti-CD38 antibody contains the CDR1 sequence GFPFX5X6YAMS (SEQ ID NO: 423), where X5 is selected from D or G, and X6 is selected from V, A, or T.

[0065] In some cases, the VH region of the anti-CD38 antibody is the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 This includes, where X1 is either present or absent, 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 is selected from T, S, M, C, I, Y, A, or G, X 11 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It either exists or does not exist, and if it exists, it is C.

[0066] In some cases, the VH region of the anti-CD38 antibody is the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (Sequence ID 426) includes, where X5 is selected from S or N, X6 is selected from R, S, or N, X7 is selected from Y, I, or N, X8 is selected from Y, D, G, or A, X9 is selected from V, M, or I, X 10 is selected from T, S, or M, and X 11 It either exists or does not exist, and if it exists, it is C.

[0067] In some cases, the VH region of the anti-CD38 antibody is the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12(Sequence ID 419) includes, where 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It either exists or does not exist, and if it exists, it is C.

[0068] In some cases, the VH region of the anti-CD38 antibody is the CDR2 sequence AISGSGGSTX 22 Includes YADSVKG (SEQ ID NO: 418), where X 22 It is selected from F or Y.

[0069] In some cases, the VH region of the anti-CD38 antibody is 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 This includes, where 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 The first letter is selected from G, Y, S, T, L, or V, and 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, X21 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, and X 24 The choice is between A and Y, and 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 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It either exists or does not exist, and if it exists, it is G.

[0070] In some cases, the VH region of the anti-CD38 antibody is 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 This includes, where X 13 is selected from A or G, X 14 is selected from I, F, Y, V, S, or C, X 16 The letter is selected from G, Y, S, T, or L, and X 17 The letter is selected from S, I, K, Y, T, or G, and 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 23The choice is between Y and D, and X 24 The choice is between A and Y, and X 25 is selected from T, S, N, R, or A, X 26 is selected from W or T, X 27 The choice is between A and W, and X 28 is selected from K, R, Q, or A, X 29 is selected from G or K, and X 30 It either exists or does not exist, and if it exists, it is G.

[0071] In some cases, the VH region of the anti-CD38 antibody is 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 This includes, where X 13 It 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 The first letter is selected from S, T, or G, and 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 The choice is between A and Y, and X 26 is selected from S, T, A, or N, X 27 is selected from W, N, or S, X 28 The choice is between A and W, and X 29 is selected from K or A, X 30It may or may not exist, and if it exists, it is selected from G or K, and X 31 It either exists or does not exist, and if it exists, it is G.

[0072] In some cases, the VH region of the anti-CD38 antibody is the CDR3 sequence AKRGTYX 38 YSX 41 Includes PTGFDY (sequence number 421), where X 38 is selected from A or G, and X 41 It is selected from F or Y.

[0073] In some cases, the VH region of an anti-CD38 antibody is 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 This includes, where 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 The letter is selected from G, W, D, L, K, P, S, R, or A, and 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 It may or may not exist, and if it exists, it is selected from V, D, A, N, G, L, or E, X 42It may or may not exist, and if it exists, it is selected from L, Y, F, T, or G, and X 43 It may or may not exist, and if it exists, it is selected from P, F, V, N, S, or Y, X 44 It may or may not exist, and if it exists, it is selected from L, S, T, G, F, and X 45 It may or may not exist, and if it exists, it is selected from L, F, E, S, or N, and X 46 It may or may not exist, and if it exists, it is selected from S, L, or R, and X 47 It either exists or does not exist, and if it exists, it is L, and X 48 It either exists or does not exist, and if it exists, it is D, and X 49 It either exists or does not exist, and if it exists, it is L.

[0074] In some cases, the VH region of an anti-CD38 antibody is 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 This includes, where 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 The letter is selected from G, W, D, L, K, or P, and 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 The value is selected from S, Y, G, R, or W, and X 41 is selected from V, D, Y, A, N, or G, X 42is selected from L, Y, or F, X 43 It may or may not exist, and if it exists, it is selected from P, F, V, or N, X 44 It may or may not exist, and if it exists, it is selected from L, S, or T, and X 45 It may or may not exist, and if it exists, it is selected from L or F.

[0075] In some cases, the VH region of an anti-CD38 antibody is 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 (Sequence code 422) is included, where X 33 is selected from R or G, X 34 is selected from E, D, or S, X 35 The first letter is selected from G, L, P, S, or A, and X 36 is selected from D, S, or R, X 37 is selected from Y, T, N, or G, X 38 It is selected from G, S, F, or L, X 39 is selected from A, G, S, or I, X 40 The value is selected from Y, N, or L, and X 41 It may or may not exist, and if it exists, it is selected from V, Y, or E, and X 42 It either exists or does not exist, and if it exists, it is G, and X 43 It either exists or does not exist, and if it exists, it is Y, and X 44 It either exists or does not exist, and if it exists, it is F, and X 45 It may or may not exist, and if it exists, it is selected from E or N, and X 46 It may or may not exist, and if it exists, it is selected from S or L.

[0076] In some examples, the VH region of anti-CD38 antibodies consists of the CDR1 sequence GFPFX5X6YAMS (SEQ ID NO: 423) and the CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID NO: 418) and CDR3 sequence AKRGTYX 38 YSX 41 Includes PTGFDY (Sequence ID 421), where X5 is selected from D or G, X6 is selected from V, A or T, and X 22 is selected from F or Y, X 38 is selected from A or G, and X 41 It is selected from F or Y.

[0077] In some cases, the VH region of the anti-CD38 antibody is the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (Sequence ID 426), CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 , and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 This includes, where 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 It is selected from T, S, or M, X 11It either exists or does not exist, and if it exists, it is C, and X 13 is selected from A or G, X 14 is selected from I, F, Y, V, S, or C, X 16 The letter is selected from G, Y, S, T, or L, and X 17 The letter is selected from S, I, K, Y, T, or G, and 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 The choice is between Y and D, and X 24 The choice is between A and Y, and X 25 is selected from T, S, N, R, or A, X 26 is selected from W or T, X 27 The choice is between A and W, and X 28 is selected from K, R, Q, or A, X 29 is selected from G or K, X 30 It either exists or does not exist, and if it exists, it is G, and 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 The letter is selected from G, W, D, L, K, or P, and 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 The value is selected from S, Y, G, R, or W, and X 41 is selected from V, D, Y, A, N, or G, X 42 is selected from L, Y, or F, X 43 It may or may not exist, and if it exists, it is selected from P, F, V, or N, X 44It may or may not exist, and if it exists, it is selected from L, S, or T, and X 45 It may or may not exist, and if it exists, it is selected from L or F.

[0078] In some cases, the VH region of the anti-CD38 antibody is the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (Sequence ID 419), CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 , and CDR3 sequence AX 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 (Sequence ID 422) includes, where 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 It may or may not exist, and if it exists, it is selected from C or M, X 12 It either exists or does not exist, and if it exists, it is C, and X 13 It is selected from A or S, X 15 is selected from I, L, or T, X 16is 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 The first letter is selected from S, T, or G, and 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 The choice is between A and Y, and X 26 is selected from S, T, A, or N, X 27 is selected from W, N, or S, X 28 The choice is between A and W, and X 29 is selected from K or A, X 30 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It either exists or does not exist, and if it exists, it is G, and X 33 is selected from R or G, X 34 is selected from E, D, or S, X 35 The first letter is selected from G, L, P, S, or A, and X 36 is selected from D, S, or R, X 37 is selected from Y, T, N, or G, X 38 It is selected from G, S, F, or L, X 39 is selected from A, G, S, or I, X 40 The value is selected from Y, N, or L, and X 41 It may or may not exist, and if it exists, it is selected from V, Y, or E, and X 42 It either exists or does not exist, and if it exists, it is G, and X 43 It either exists or does not exist, and if it exists, it is Y, and X 44 It either exists or does not exist, and if it exists, it is F, and X 45 It may or may not exist, and if it exists, it is selected from E or N, and X 46 It may or may not exist, and if it exists, it is selected from S or L.

[0079] In some embodiments, the VH region of the anti-CD38 antibody includes CDR1, CDR2, and CDR3 sequences selected from Table 1.

[0080] [Table 1]

[0081] In some embodiments, the VH region of the anti-CD38 antibody 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 This includes, 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 The letter is selected from G, W, D, L, K, P, S, A, T, or R, and 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 40is selected from S, Y, G, R, W, N, L, D, or F, X 41 It may or may not exist, and if it exists, it is selected from F, Y, V, D, A, N, G, E, or L, and X 42 It may or may not exist, and if it exists, it is selected from P, L, Y, F, G, or T, X 43 It may or may not exist, and if it exists, it is selected from T, P, F, V, N, Y, or S, X 44 It may or may not exist, and if it exists, it is selected from G, L, S, T, or F, X 45 It may or may not exist, and if it exists, it is selected from F, L, E, N, or S, X 46 It may or may not exist, and if it exists, it is selected from D, S, L, or R, and X 47 It may or may not exist, and if it exists, it is selected from Y or L, X 48 It either exists or does not exist, and if it exists, it is D, and X 49 It either exists or does not exist, and if it exists, it is L.

[0082] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9, a CDR2 sequence selected from SEQ ID NOs: 2 and 5, and a CDR3 sequence AKRGTYX 38 YSX 41 Includes PTGFDY (sequence number 421), where X 38 is selected from A or G, X 41 It is selected from F or Y.

[0083] In some embodiments, the VH region of the anti-CD38 antibody 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 X 32 X 33 X 34 X 35 X36 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 This includes, where 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 The letter is selected from G, W, D, L, K, P, S, R, or A, and 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 It may or may not exist, and if it exists, it is selected from V, D, A, N, G, L, or E, X 42 It may or may not exist, and if it exists, it is selected from L, Y, F, T, or G, and X 43 It may or may not exist, and if it exists, it is selected from P, F, V, N, S, or Y, X 44 It may or may not exist, and if it exists, it is selected from L, S, T, G, or F, and X 45 It may or may not exist, and if it exists, it is selected from L, F, E, S, or N, and X 46 It may or may not exist, and if it exists, it is selected from S, L, or R, and X 47 It either exists or does not exist, and if it exists, it is L, and X 48 It either exists or does not exist, and if it exists, it is D, and X 49 It either exists or does not exist, and if it exists, it is L.

[0084] In some embodiments, the VH region of the anti-CD38 antibody 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 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 This includes, where 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 The letter is selected from G, W, D, L, K, or P, and 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 The value is selected from S, Y, G, R, or W, and X 41 is selected from V, D, Y, A, N, or G, X 42 is selected from L, Y, or F, X 43 It may or may not exist, and if it exists, it is selected from P, F, V, or N, X 44 It may or may not exist, and if it exists, it is selected from L, S, or T, and X 45 It may or may not exist, and if it exists, it is selected from L or F.

[0085] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56, a CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57, and a CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 (Sequence ID 422) is included, where X 33 is selected from R or G, X 34 is selected from E, D, or S, X 35 The first letter is selected from G, L, P, S, or A, and X 36 is selected from D, S, or R, X 37 is selected from Y, T, N, or G, X 38 It is selected from G, S, F, or L, X 39 is selected from A, G, S, or I, X 40 The value is selected from Y, N, or L, and X 41 It may or may not exist, and if it exists, it is selected from V, Y, or E, and X 42 It either exists or does not exist, and if it exists, it is G, and X 43 It either exists or does not exist, and if it exists, it is Y, and X 44 It either exists or does not exist, and if it exists, it is F, and X 45 It may or may not exist, and if it exists, it is selected from E or N, and X 46 It may or may not exist, and if it exists, it is selected from S or L.

[0086] In some embodiments, the VH region of the anti-CD38 antibody is the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12This includes, where X1 is either present or absent, and if present it 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12 The VH region may or may not exist, and if present, it is C, and the VH region further includes a CDR2 sequence selected from sequence numbers 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 sequence numbers 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.

[0087] In some embodiments, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFPFX5X6YAMS (SEQ ID NO: 423), where X5 is selected from D or G, and X6 is selected from V, A, or T, and the VH region further comprises the CDR2 sequence selected from SEQ ID NOs: 2 and 5, and the CDR3 sequence selected from SEQ ID NOs: 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 This includes, where X1 is either present or absent, 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, X10 is selected from T, S, M, C, I, Y, A, or G, X 11 It may or may not exist, and if it exists, it is selected from C or M, and X 12 The function may or may not exist, and if present, it is C, and the VH region further includes a CDR2 sequence selected from sequence numbers 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57, and a CDR3 sequence selected from sequence numbers 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.

[0088] In some embodiments, the VH region of the anti-CD38 antibody is the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (Sequence ID 426) includes, where 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 The function may or may not exist, and if present, it is C, and the VH region further includes a CDR2 sequence selected from sequence numbers 12, 15, 27, 33, 36, 39, 42, and 51, and a CDR3 sequence selected from sequence numbers 13, 16, 28, 34, 37, 40, 43, and 52.

[0089] In some embodiments, the VH region of the anti-CD38 antibody is the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (Sequence ID 419) includes, where 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 11It may or may not exist, and if it exists, it is selected from C or M, and X 12 The function may or may not exist, and if present, it is C, and the VH region further includes a CDR2 sequence selected from sequence numbers 18, 24, 30, 45, and 57, and a CDR3 sequence selected from sequence numbers 19, 25, 31, 46, and 58.

[0090] In some embodiments, the VH region of the anti-CD38 antibody 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, 56, and 59, and a CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 This includes, where X 13 is selected from A, G, or S, X 14 is selected from I, F, Y, V, S, or C, X 15 The letter is selected from S, I, L, T, or M, and X 16 The first letter is selected from G, Y, S, T, L, or V, and 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, and X 24 The choice is between A and Y, and X25 The first letter is selected from D, T, S, N, R, A, or Y, and 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 It may or may not exist, and if it exists, it is selected from G or K, and X 31 The VH region may or may not exist, and if present, it is G, and the VH region further includes a CDR3 sequence selected from sequence numbers 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.

[0091] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9, and a CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID NO: 418) is included, where X 22 The VH region is selected from F or Y, and the VH region further includes a CDR3 sequence selected from sequence numbers 3, 7, and 10.

[0092] In some embodiments, the VH region of the anti-CD38 antibody consists of a CDR1 sequence and a CDR2 sequence X selected from SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56. 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 This includes, where X 13is 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 The first letter is selected from G, Y, S, T, L, or V, and 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, and X 24 The choice is between A and Y, and 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 It may or may not exist, and if it exists, it is selected from G or K, and X 31 The VH region may or may not exist, and if present, it is G, and the VH region further includes a CDR3 sequence selected from sequence numbers 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.

[0093] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50, and a CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X25 X 26 X 27 X 28 X 29 X 30 This includes, where X 13 is selected from A or G, X 14 is selected from I, F, Y, V, S, or C, X 16 The letter is selected from G, Y, S, T, or L, and X 17 The letter is selected from S, I, K, Y, T, or G, and 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 The choice is between Y and D, and X 24 The choice is between A and Y, and X 25 is selected from T, S, N, R, or A, X 26 is selected from W or T, X 27 The choice is between A and W, and X 28 is selected from K, R, Q, or A, X 29 is selected from G or K, and X 30 The VH region may or may not exist, and if present, it is G, and the VH region further includes a CDR3 sequence selected from sequence numbers 13, 16, 28, 34, 37, 40, 43, and 52.

[0094] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56, and a CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X30 X 31 This includes, where X 13 It 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 The first letter is selected from S, T, or G, and 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 The choice is between A and Y, and X 26 is selected from S, T, A, or N, X 27 is selected from W, N, or S, X 28 The choice is between A and W, and X 29 is selected from K or A, X 30 It may or may not exist, and if it exists, it is selected from G or K, and X 31 The VH region may or may not exist, and if present, it is G, and the VH region further includes a CDR3 sequence selected from sequence numbers 19, 25, 31, 46, and 58.

[0095] In some examples, the VH region of an anti-CD38 antibody contains 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.

[0096] In some examples, the VH region of an anti-CD38 antibody includes 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.

[0097] In some examples, the VH region of an anti-CD38 antibody contains 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.

[0098] In some examples, the VH region of an anti-CD38 antibody includes 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.

[0099] In some examples, the VH region of an anti-CD38 antibody includes 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.

[0100] In some embodiments, the VL region of the anti-CD38 antibody includes CDR1, CDR2, and CDR3 sequences selected from Table 2.

[0101] [Table 2]

[0102] In some embodiments, the VL region of the anti-CD38 antibody includes 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 examples, the VL region includes a CDR1 sequence selected from sequence numbers 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from sequence numbers 66, 69, 81, 78, 90, and 99, and a CDR3 sequence selected from sequence numbers 67, 70, 82, 87, 88, 91, 93, and 100. In some examples, the VL region includes a CDR1 sequence selected from sequence numbers 71, 77, 83, 94, and 102, a CDR2 sequence selected from sequence numbers 72, 78, and 84, and a CDR3 sequence selected from sequence numbers 73, 79, 85, 95, and 103.

[0103] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising 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 This includes, where X32 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 The letter is selected from G, W, D, L, K, P, S, A, T, or R, and 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 It may or may not exist, and if it exists, it is selected from F, Y, V, D, A, N, G, E, or L, and X 42 It may or may not exist, and if it exists, it is selected from P, L, Y, F, G, or T, X 43 It may or may not exist, and if it exists, it is selected from T, P, F, V, N, Y, or S, X 44 It may or may not exist, and if it exists, it is selected from G, L, S, T, or F, X 45 It may or may not exist, and if it exists, it is selected from F, L, E, N, or S, X 46 It may or may not exist, and if it exists, it is selected from D, S, L, or R, and X 47 It may or may not exist, and if it exists, it is selected from Y or L, X 48 It either exists or does not exist, and if it exists, it is D, and X 49The VL region may or may not exist, and if it exists, it is L, and the VL region includes a CDR1 sequence selected from sequence numbers 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102, a CDR2 sequence selected from sequence numbers 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from sequence numbers 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0104] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9, a CDR2 sequence selected from SEQ ID NOs: 2 and 5, and a CDR3 sequence AKRGTYX 38 YSX 41 Includes PTGFDY (sequence number 421), where X 38 is selected from A or G, X 41 The VL region is selected from F or Y, and the VL region includes a CDR1 sequence consisting of sequence number 62, a CDR2 sequence consisting of sequence number 63, and a CDR3 sequence consisting of sequence number 64.

[0105] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising 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 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 X48 X 49 This includes, where 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 The letter is selected from G, W, D, L, K, P, S, R, or A, and 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 It may or may not exist, and if it exists, it is selected from V, D, A, N, G, L, or E, X 42 It may or may not exist, and if it exists, it is selected from L, Y, F, T, or G, and X 43 It may or may not exist, and if it exists, it is selected from P, F, V, N, S, or Y, X 44 It may or may not exist, and if it exists, it is selected from L, S, T, G, or F, and X 45 It may or may not exist, and if it exists, it is selected from L, F, E, S, or N, and X 46 It may or may not exist, and if it exists, it is selected from S, L, or R, and X 47 It either exists or does not exist, and if it exists, it is L, and X 48 It either exists or does not exist, and if it exists, it is D, and X 49The VL region may or may not exist, and if it exists, it is L, and the VL region includes a CDR1 sequence selected from sequence numbers 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102, a CDR2 sequence selected from sequence numbers 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from sequence numbers 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0106] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising 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 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 This includes, where 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 The letter is selected from G, W, D, L, K, or P, and 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 The value is selected from S, Y, G, R, or W, and X 41 is selected from V, D, Y, A, N, or G, X 42 is selected from L, Y, or F, X 43It may or may not exist, and if it exists, it is selected from P, F, V, or N, X 44 It may or may not exist, and if it exists, it is selected from L, S, or T, and X 45 The VL region may or may not exist, and if present, it is selected from L or F, and the VL region includes a CDR1 sequence selected from sequence numbers 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from sequence numbers 66, 69, 78, 81, 90, and 99, and a CDR3 sequence selected from sequence numbers 67, 70, 82, 87, 88, 91, 93, and 100.

[0107] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56, a CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57, and a CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 (Sequence ID 422) is included, where X 33 is selected from R or G, X 34 is selected from E, D, or S, X 35 The first letter is selected from G, L, P, S, or A, and X 36 is selected from D, S, or R, X 37 is selected from Y, T, N, or G, X 38 It is selected from G, S, F, or L, X 39 is selected from A, G, S, or I, X 40 The value is selected from Y, N, or L, and X 41 It may or may not exist, and if it exists, it is selected from V, Y, or E, and X 42 It either exists or does not exist, and if it exists, it is G, and X 43It either exists or does not exist, and if it exists, it is Y, and X 44 It either exists or does not exist, and if it exists, it is F, and X 45 It may or may not exist, and if it exists, it is selected from E or N, and X 46 The VL region may or may not exist, and if present, it is selected from S or L, and the VL region includes a CDR1 sequence selected from sequence numbers 71, 77, 83, 94, and 102, a CDR2 sequence selected from sequence numbers 72, 78, and 84, and a CDR3 sequence selected from sequence numbers 73, 79, 85, 95, and 103.

[0108] In some embodiments, the anti-CD38 antibody includes a VH region and a VL region, wherein the VH region is the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 This includes, where X1 is either present or absent, and if present it 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12is present or absent, and if present, is C, and the VH region further includes a CDR2 sequence selected from sequence numbers 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 sequence numbers 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58, and the VL region is It includes a CDR1 sequence selected from sequence numbers 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from sequence numbers 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from sequence numbers 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0109] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising the CDR1 sequence GFPFX5X6YAMS (SEQ ID NO: 423), where X5 is selected from D or G, and X6 is selected from V, A, or T; the VH region further comprises a CDR2 sequence selected from SEQ ID NOs: 2 and 5, and a CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10; and 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.

[0110] In some embodiments, the anti-CD38 antibody includes a VH region and a VL region, wherein the VH region is the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12This includes, where X1 is either present or absent, 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 is selected from T, S, M, C, I, Y, A, or G, X 11 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It may or may not exist, and if it exists, it is C, and the VH region further includes a CDR2 sequence selected from sequence numbers 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57, and a CDR3 sequence selected from sequence numbers 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58, and the VL region is It includes a CDR1 sequence selected from sequence numbers 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from sequence numbers 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from sequence numbers 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0111] In some embodiments, the anti-CD38 antibody includes a VH region and a VL region, wherein the VH region is the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (Sequence ID 426) includes, where 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 11The function may or may not exist, and if present, it is C, and the VH region further includes a CDR2 sequence selected from sequence numbers 12, 15, 27, 33, 36, 39, 42, and 51, and a CDR3 sequence selected from sequence numbers 13, 16, 28, 34, 37, 40, 43, and 52, and the VL region includes a CDR1 sequence selected from sequence numbers 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from sequence numbers 66, 69, 78, 81, 90, and 99, and a CDR3 sequence selected from sequence numbers 67, 70, 82, 87, 88, 91, 93, and 100.

[0112] In some embodiments, the anti-CD38 antibody includes a VH region and a VL region, wherein the VH region is the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (Sequence ID 419) includes, where X4 is selected from F or O, 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 It may or may not exist, and if it exists, it is selected from C or M, and X 12 The function may or may not exist, and if present, it is C, and the VH region further includes a CDR2 sequence selected from sequence numbers 18, 24, 30, 45, and 57 and a CDR3 sequence selected from sequence numbers 19, 25, 31, 46, and 58, and the VL region includes a CDR1 sequence selected from sequence numbers 71, 77, 83, 94, and 102, a CDR2 sequence selected from sequence numbers 72, 78, and 84 and a CDR3 sequence selected from sequence numbers 73, 79, 85, 95, and 103.

[0113] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising 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, 56, and 59, and a CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 This includes, where X 13 is selected from A, G, or S, X 14 is selected from I, F, Y, V, S, or C, X 15 The letter is selected from S, I, L, T, or M, and X 16 The first letter is selected from G, Y, S, T, L, or V, and 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, and X 24 The choice is between A and Y, and X 25 The first letter is selected from D, T, S, N, R, A, or Y, and 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 30It may or may not exist, and if it exists, it is selected from G or K, and X 31 It may or may not exist, and if it exists, it is G, and the VH region further includes a CDR3 sequence selected from sequence numbers 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58, and the VL region includes sequence numbers 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92 It includes a CDR1 sequence selected from 94, 96, 98, and 102, a CDR2 sequence selected from sequence numbers 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from sequence numbers 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0114] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9, and a CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID NO: 418) is included, where X 22 The VH region is selected from F or Y, and the VL region further includes a CDR3 sequence selected from sequence numbers 3, 7, and 10, and the VL region includes a CDR1 sequence consisting of sequence number 62, a CDR2 sequence consisting of sequence number 63, and a CDR3 sequence consisting of sequence number 64.

[0115] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising 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, and a CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25X 26 X 27 X 28 X 29 X 30 X 31 This includes, where 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 The first letter is selected from G, Y, S, T, L, or V, and 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, and X 24 The choice is between A and Y, and 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 It may or may not exist, and if it exists, it is selected from G or K, and X 31It may or may not exist, and if it exists, it is G, and the VH region further includes a CDR3 sequence selected from sequence numbers 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58, and the VL region includes a CDR1 sequence selected from sequence numbers 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102, a CDR2 sequence selected from sequence numbers 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from sequence numbers 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0116] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50, and a CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 This includes, where X 13 is selected from A or G, X 14 is selected from I, F, Y, V, S, or C, X 16 The letter is selected from G, Y, S, T, or L, and X 17 The letter is selected from S, I, K, Y, T, or G, and 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 The choice is between Y and D, and X24 The choice is between A and Y, and X 25 is selected from T, S, N, R, or A, X 26 is selected from W or T, X 27 The choice is between A and W, and X 28 is selected from K, R, Q, or A, X 29 is selected from G or K, and X 30 It may or may not exist, and if it exists, it is G, and the VH region further includes a CDR3 sequence selected from sequence numbers 13, 16, 28, 34, 37, 40, 43, and 52, and the VL region includes a CDR1 sequence selected from sequence numbers 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from sequence numbers 66, 69, 78, 81, 90, and 99, and a CDR3 sequence selected from sequence numbers 67, 70, 82, 87, 88, 91, 93, and 100.

[0117] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56, and a CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 This includes, where X 13 It 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 The first letter is selected from S, T, or G, and X 21is 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 The choice is between A and Y, and X 26 is selected from S, T, A, or N, X 27 is selected from W, N, or S, X 28 The choice is between A and W, and X 29 is selected from K or A, X 30 It may or may not exist, and if it exists, it is selected from G or K, and X 31 It may or may not exist, and if it exists, it is G, and the VH region further includes a CDR3 sequence selected from sequence numbers 19, 25, 31, 46, and 58, and the VL region includes a CDR1 sequence selected from sequence numbers 71, 77, 83, 94, and 102, a CDR2 sequence selected from sequence numbers 72, 78, and 84, and a CDR3 sequence selected from sequence numbers 73, 79, 85, 95, and 103.

[0118] In some examples, the anti-CD38 antibody includes 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 SEQ ID NOs: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, and 46 The VL region includes a CDR1 sequence selected from sequence numbers 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102, a CDR2 sequence selected from sequence numbers 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from sequence numbers 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0119] In some examples, an anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9, a CDR2 sequence selected from SEQ ID NOs: 2 and 5, and a CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10, and 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.

[0120] In some examples, the anti-CD38 antibody includes a VH region and a VL region, wherein 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 SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52 The VL region includes a CDR1 sequence selected from sequence numbers 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102, a CDR2 sequence selected from sequence numbers 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from sequence numbers 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0121] In some examples, an anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising 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, the VL region comprising 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, 78, 81, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.

[0122] In some examples, an anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56, a CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57, and a CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58; and 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.

[0123] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the sequence of the VH region contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NOs. 104-128, and the sequence of the VL region contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NOs. 130-154.

[0124] In some embodiments, the VH region includes an array selected from Table 3, and the VL region includes an array selected from Table 4.

[0125] [Table 3-1]

[0126] [Table 3-2]

[0127] [Table 4-1]

[0128] [Table 4-2]

[0129] In some embodiments, the anti-CD38 antibody described above is a full-length antibody. In other embodiments, the anti-CD38 antibody is a binding fragment. In some examples, the anti-CD38 antibody includes 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. Depending on the case, the anti-CD38 antibody may include 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 camel antibody or its binding fragment.

[0130] In some embodiments, the anti-CD38 antibody comprises a bispecific antibody or its conjugated fragment. In some examples, the bispecific antibody or its conjugated fragment is a bispecific antibody conjugate, a hybrid bispecific IgG, a bispecific antibody with only a variable domain, a CH1 / CL fusion protein, a Fab fusion protein, a non-immunoglobulin fusion protein, an Fc-modified IgG, an appended & Fc-modified IgG, a modified Fc and CH3 fusion protein, an appended IgG-HC fusion, an Fc fusion, a CH3 fusion, an IgE / IgM CH2 fusion, or an F(ab')2 fusion.

[0131] In some embodiments, bispecific antibodies or binding fragments include Knobs-into-Hole (KIH), Asymmetric Re-engineering Technology-immunoglobulin (ART-Ig), Triomab quadroma, bispecific monoclonal antibodies (BiMAb, BsmAb, BsAb, bsMab, BS-Mab, or Bi-MAb), FcΔAdp, XmAb, Azymetric, bispecific involvement by antibodies based on T cell receptors (BEAT), Bispecific T-cell Engager (BiTE), Biclonics, Fab-scFv-Fc, Two-in-one / Dual Action Fab (DAF), FinomAb, scFv-Fc-(Fab)-lysis, Dock-aNd-Lock (DNL), Adaptir (formerly SCORPION), Tandem diAbody (TandAb), Dual-affinity-ReTargeting (DART), or nanobodies.

[0132] In some embodiments, bispecific antibodies containing only the variable domain include tandem scFv (taFv), triplebody, diabody (Db), dsDb, Db (KIH), scDb, dsFv-dsFv', tandAbs, triple heads, tandem dAb / VHH, triple dAb / VHH, or tetravalent dAb / VHH.

[0133] In some embodiments, the CH1 / CL fusion protein includes scFv2-CH1 / CL or VHH2-CH1 / CL.

[0134] In some examples, Fab fusion proteins include Fab-scFv (bibody), Fab-scFv2 (tribody), Fab-Fv, Fab-dsFv, Fab-VHH, or orthogonal Fab-Fab.

[0135] In some examples, non-immunoglobulin fusion proteins include scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, mini-antibodies, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, or ImmTAC(TCR-scFv).

[0136] In some examples, Fc-modified IgG includes IgG(KIH), IgG(KIH)common LC, ZW1 IgG common LC, Biclonics common LC, CrossMAb, scFab-IgG(KIH), Fab-scFab-IgG(KIH), orthogonal Fab IgG(KIH), DuetMab, CH3 charge pair + CH1 / CL charge pair, hinge / CH3 charge pair, DuoBody, four-in-one-CrossMab(KIH), LUZ-Y Common LC, LUZ-Y scFab-IgG, or FcFc.

[0137] In some examples, associated &Fc modified IgG includes IgG(KIH)-Fv, IgG(HA-TF-FV), IgG(KIH)-scFab, scFab-Fc(KIH)-scFv2, scFab-Fc(KIH)-scFv, half-DVD-Ig, Dual Variable Domain-immunoglobulin (DVD-Ig), or CrossMab-Fab.

[0138] Depending on the case, modified Fc-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 TriFab.

[0139] Depending on the case, the accompanying IgG-HC fusion antibody may include IgG-HC-scFv, IgG-dAb, IgG-taFv, IgG-CrossFab, IgG-(CαCβ)Fab, scFv-HC-IgG, tandem Fab-IgG, Fab-IgG(CαCβFab), Fab-IgG(CR3), or Fab-Hinge-IgG(CR3).

[0140] Depending on the case, the accompanying IgG-LC fusion antibody may include IgG-scFv(LC), scFv(LC)-IgG, or dAb-IgG.

[0141] Depending on the case, the accompanying IgG-HC&LC fusion antibody may include DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, or Zybody.

[0142] In some examples, Fc fusion antibodies include Di-diabody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-Ig, or scFv2-Fcab.

[0143] In some cases, CH3 fusion antibodies include Di-diabody or scDb-CH3.

[0144] In some cases, IgE / IgM CH2 fusion antibodies include scFv-EHD2-scFv or scFv-MHD2-scFv.

[0145] In some cases, the F(ab')2 fusion antibody contains F(ab')2-scFv2.

[0146] In some examples, the CH1 / CL fusion protein contains scFv2-CH1-hinge / CL.

[0147] In some cases, modified IgG is called DAF (two-in-one-IgG), DutaMab, or mAb. 2 Includes.

[0148] In some cases, the non-immunoglobulin fusion antibody includes DNL-Fab4-IgG.

[0149] In some examples, the anti-CD38 antibody includes a bispecific antibody or its conjugated fragment, as illustrated in Figure 1A or Figure 1B.

[0150] In some embodiments, the anti-CD38 antibodies described herein include an IgG framework, an IgA framework, an IgE framework, or an IgM framework. In some examples, the anti-CD38 antibody includes an IgG framework (e.g., IgG1, IgG2, IgG3, or IgG4). In such cases, the anti-CD38 antibody includes a framework of IgG1, IgG2, IgG3, or IgG4.

[0151] In some cases, anti-CD38 antibodies further contain one or more mutations in the framework region, e.g., the CH1 domain, CH2 domain, CH3 domain, hinge region, or combination thereof. In some cases, the one or more mutations stabilize the antibody and / or extend its half-life. In some cases, the one or more mutations modulate Fc receptor interactions and increase ADCC or complement-dependent cytotoxicity (CDC). In other cases, the one or more mutations reduce or eliminate Fc effector functions such as FcγR binding, ADCC, or CDC. In additional cases, the one or more mutations modulate glycosylation.

[0152] In some cases, the anti-CD38 antibody includes an IgG1 framework. In some embodiments, the constant region of the anti-CD38 antibody is modified at one or more amino acid positions to modify the Fc receptor interaction. Typical residues that modulate or modify the 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 1991 Sequences of Proteins of Immunological Interest). In some examples, the mutations include G236A, S239D, T250Q, M252Y, S254T, T256E, K326W, A330L, I332E, E333A, E333S, M428L, H433K, or N434F.

[0153] In some embodiments, modifications at one or more amino acid positions in the constant region of IgG1 aimed at modifying Fc receptor interactions extend the half-life. In some examples, modifications at one or more amino acid positions include T250, M252, S254, T256, M428, H433, N434, or combinations thereof, such as T250Q / M428L or M252Y / S254T / T256E and H433K / N434F.

[0154] In some embodiments, modifications at one or more amino acid positions in the IgG1 constant region aimed at modifying Fc receptor interactions increase ADCC and / or CDC. In some examples, modifications at one or more amino acid positions include S239, K326, A330, I332, E333, or combinations thereof. In some examples, modifications at one or more amino acid positions aimed at increasing ADCC and / or CDC include, for example, E333A, S239D / A330L / I332E, or K326W / E333S. In some cases, modifications at one or more amino acid positions aimed at increasing ADCC include S239D / A330L / I332E. In some cases, modifications at one or more amino acid positions aimed at increasing CDC include K326W / E333S.

[0155] In some embodiments, modifications at one or more amino acid positions in the constant region of IgG1 aimed at modifying Fc receptor interactions increase macrophage phagocytosis. In some examples, 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 aimed at increasing macrophage phagocytosis include the combination of S239D / I332I / G236A.

[0156] In some embodiments, the constant region of IgG1 is modified with amino acid N297 (Kabat numbered), for example, N297C.

[0157] In some embodiments, the anti-CD38 antibody includes an IgG2 framework. In some examples, one or more amino acid positions in the IgG2 framework are modified to alter Fc receptor interactions, e.g., to increase ADCC and / or CDC. In some cases, one or more amino acid positions in the IgG2 framework are modified to stabilize the antibody and / or extend its half-life. In some examples, one or more amino acid positions in the IgG2 framework are modified to regulate glycosylation. In some cases, the constant region of IgG2 is afucosylated.

[0158] In some embodiments, the anti-CD38 antibody comprises an IgG3 framework. In some examples, one or more amino acid positions in the IgG3 framework are modified to alter Fc receptor interactions, e.g., to increase ADCC and / or CDC. In some cases, one or more amino acid positions in the IgG3 framework are modified to stabilize the antibody and / or extend its half-life. In some examples, 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 with amino acid R435, e.g., R435H (Kabat numbered), to extend its half-life. In some examples, the constant region is afucosylated.

[0159] In some embodiments, the anti-CD38 antibody comprises an IgG4 framework. In some examples, one or more amino acid positions in the IgG4 framework are modified to alter Fc receptor interactions, e.g., to increase ADCC and / or CDC. For example, mutations that increase ADCC include, in some embodiments, S239D, I332E, and A330L, such as those described in U.S. Patent No. 8,093,359 (amino acid numbering follows the EU index of Kabat et al). Optionally, one or more amino acid positions in the IgG4 framework are modified to stabilize the antibody and / or extend its half-life. In some examples, one or more amino acid positions in the IgG4 framework are modified to regulate glycosylation. Optionally, the constant region is modified in the hinge region to prevent or reduce chain exchange. In some examples, the amino acid modified is S228 (e.g., S228P).

[0160] In some embodiments, the human IgG constant region is modified to ADCC and / or CDC, for example, "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 The amino acid modifications described in "Immunol, 148:3461-3468" and "Reviewed in Kaneko and Niwa, 2011 Biodrugs, 25(1):1-11" are used.

[0161] In some embodiments, the constant region of human IgG is modified to induce heterodimerization. For example, if there is an amino acid modification within the CH3 domain at Thr366, which is substituted with a more bulky amino acid, such as Trp(T366W), it can preferentially pair with a second CH3 domain having amino acid modifications to less bulky amino acids at the positions of Thr366, Leu368, and Tyr407, e.g., Ser, Ala, and Val, respectively. In some cases, heterodimerization via CH3 modification is further stabilized by the introduction of disulfide bonds, for example, by changes from Ser354 to Cys(S354C) and Y349 to Cys(Y349C) in the opposite CH3 domain (Reviewed in Carter, 2001 Journal of Immunological Methods, 248:7-15).

[0162] In some cases, the anti-CD38 antibodies described herein have reduced or absent glycosylation but are not modified with amino acid Asn297 (Kabat numbering). In these cases, glycosylation is eliminated, for example, by antibody production in host cells lacking posttranslational glycosylation ability, such as bacterial or yeast-derived systems, or in modified mammalian cell expression systems. In some embodiments, such systems are cell-free expression systems.

[0163] In some embodiments, the anti-CD38 antibody described herein is a full-length antibody comprising a heavy chain (HC) and a light chain (LC). Optionally, the heavy chain (HC) comprises a sequence selected from Table 5. Optionally, the light chain (LC) comprises a sequence selected from Table 6.

[0164] [Table 5-1]

[0165] [Table 5-2]

[0166] [Table 5-3]

[0167] [Table 5-4]

[0168] [Table 5-5]

[0169] [Table 6-1]

[0170] [Table 6-2]

[0171] [Table 6-3]

[0172] In some embodiments, the anti-CD38 antibodies described herein are enhanced with ADCC and / or CDC compared to daratumumab as the reference antibody. In some cases, the enhancement of ADCC and / or CDC is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, or more compared to daratumumab. In some cases, the enhancement of ADCC and / or CDC is about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, or more compared to daratumumab.

[0173] In some cases, the enhancement of ADCC and / or CDC is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or more compared to the reference antibody, daratumumab. In some cases, the enhancement of ADCC and / or CDC is approximately 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or more compared to the reference antibody, daratumumab.

[0174] In some embodiments, the anti-CD38 antibodies described herein are used to determine ADCC activity in in vitro cytotoxicity tests using target cancer cells such as PBMC effector cells and lymphoma-derived B lymphoblast cells (e.g., Daudi cells) at a rate of approximately 1 x 10⁻¹⁶. -6 nM ~ approximately 2nM, for example, approximately 4 x 10⁻¹⁰ -6nM, approximately 0.000014nM, 0.00007nM, 0.00006nM, approximately 0.00010nM, approximately 0.0002nM, approximately 0.0003nM, 0.1nM, approximately 0.2nM, approximately 0.3nM, approximately 0.4nM, approximately 0.5nM, approximately 0.6nM, approximately 0.7nM, approximately 0.8nM, approximately 0.9nM, approximately 1.0nM, or EC of approximately 0.00001 to approximately 0.00003nM 50 It has.

[0175] In some embodiments, the anti-CD38 antibodies described herein exhibit improved cell-killing efficacy compared to the reference antibody, daratumumab. In some cases, the improvement in cell-killing efficacy is an increase of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, or more compared to the reference antibody, daratumumab. In some cases, the improvement in cell-killing efficacy is an increase of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, or more compared to the reference antibody, daratumumab.

[0176] In some cases, the improvement in cell death efficacy is at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or more compared to the reference antibody, daratumumab. In some cases, the improvement in cell death efficacy is approximately 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or more compared to the reference antibody, daratumumab.

[0177] In some embodiments, the anti-CD38 antibodies described herein exhibit an improved serum half-life compared to the reference antibody, daratumumab. In some examples, the improvement in 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 compared to the reference antibody, daratumumab.

[0178] In some cases, the serum half-life of the anti-CD38 antibody described herein is at least 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or longer. In some cases, the serum half-life of the anti-CD38 antibody described herein is about 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or longer.

[0179] Anti-ICAM1 antibody In some embodiments, an anti-ICAM1 antibody is disclosed herein. In some examples, the anti-ICAM1 antibody comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region is a CDR1 sequence X1X2X3X4X5X6X7X8X9X 10 X 11 This includes, where X1 is selected from G or E, X2 is selected from F or Y, X3 is selected from S or T, X4 is selected from L, F, or S, X5 is selected from S or N, X6 is selected from S, N, T, or D, X7 is selected from Y, H, or G, X8 is selected from G, A, Y, W, or F, X9 is selected from M, W, Y, or I, X 10 is selected from S, G, N, M, or I, and X 11 It may or may not exist, and if it exists, it is C, and the VH region is 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 28X 29 X 30 This includes, where X 12 The first letter is selected from G, T, A, I, or Y, and X 13 is selected from W, I, Y, or C, and 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 The first letter is selected from S, R, G, or D, and X 18 is selected from G, D, or S, X 19 The letter is selected from S, R, T, N, Y, A, D, or P, and X 20 is selected from T, A, G, or Y, X 21 is selected from Y, H, A, S, or T, X 22 The value is selected from Y or N, and 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 It may or may not exist, and if it exists, it is selected from K or G, and X 30 It may or may not exist, and if it exists, it is G, and the VH region is 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 This includes, where X 31is 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 The first letter is selected from D, Y, S, L, G, F, or W, and 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 It may or may not exist, and if it exists, it is selected from Y, A, G, I, or D, X 42 It may or may not exist, and if it exists, it is selected from I, Y, R, P, V, or G, and X 43 It may or may not exist, and if it exists, it is selected from L, R, Y, G, or A, and X 44 It may or may not exist, and if it exists, it is selected from N, L, S, Y, S, or W, X 45 It may or may not exist, and if it exists, it is selected from L, Y, F, or C, and X 46 It may or may not exist, and if it exists, it is selected from D, A, or F, X 47 It may or may not exist, and if it exists, it is selected from M, P, Y, or N, X 48 It may or may not exist, and if it exists, it is selected from D or L, and X 49 It either exists or does not exist, and if it exists, it is L.

[0180] In some cases, the VH region of anti-ICAM1 antibodies is the CDR1 sequence GFSLX5X6X7X8MX 10 (Sequence ID 425) includes, where X5 is selected from S or N, X6 is selected from S, N, T, or D, X7 is selected from Y or H, X8 is selected from G, A, or Y, and X 10It is selected from S, G, or N.

[0181] In some cases, the VH region of anti-ICAM1 antibodies is the CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 Includes WAKG (sequence number 420), where X 13 is selected from W, I, or Y, X 15 It is selected from S or G, X 16 is selected from F, S, D, or T, X 17 The option is selected from S or R, X 18 It 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 It is selected from S, T, or N.

[0182] In some cases, the VH region of anti-ICAM1 antibodies is 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 (Sequence code 424) is included, where X 31 is selected from A or V, X 33 It is selected from G or D, X 34 is selected from G, P, W, or D, X 35 The value is selected from D, Y, S, or L, and X 36 is selected from Y, D, V, or L, X 37 is selected from G, S, or D, X 38is 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 The can be selected from L, R, Y, or G, and X 44 is selected from N, L, Y, or S, X 45 It may or may not exist, and if it exists, it is selected from L, Y, or F, and X 46 It either exists or does not exist, and if it exists, it is D, and X 47 It may or may not exist, and if it exists, it is selected from M or P, X 48 It either exists or does not exist, and if it exists, it is D, and X 49 It either exists or does not exist, and if it exists, it is L.

[0183] In some cases, the VH region of the anti-ICAM1 antibody is the CDR1 sequence GFSLX5X6X7X8MX 10 (Sequence number 425) and CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG (sequence number 420) and 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(Sequence ID 424) includes, where X5 is selected from S or N, X6 is selected from S, N, T, or D, X7 is selected from Y or H, X8 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 It is selected from S or G, X 16 is selected from F, S, D, or T, X 17 The option is selected from S or R, X 18 It 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 It is selected from G or D, X 34 is selected from G, P, W, or D, X 35 The value is selected from D, Y, S, or L, and 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 The can be selected from L, R, Y, or G, and X 44 is selected from N, L, Y, or S, X 45 It may or may not exist, and if it exists, it is selected from L, Y, or F, and X 46 It either exists or does not exist, and if it exists, it is D, and X 47 It may or may not exist, and if it exists, it is selected from M or P, X 48 It either exists or does not exist, and if it exists, it is D, and X 49 It either exists or does not exist, and if it exists, it is L.

[0184] In some embodiments, the VH region of the anti-ICAM1 antibody includes CDR1, CDR2, and CDR3 sequences selected from Table 7.

[0185] [Table 7]

[0186] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250, a CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251, and a CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 This includes, where 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 The first letter is selected from D, Y, S, L, G, F, or W, and 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 40is selected from T, A, D, S, Y, L, or F, X 41 It may or may not exist, and if it exists, it is selected from Y, A, G, I, or D, X 42 It may or may not exist, and if it exists, it is selected from I, Y, R, P, V, or G, and X 43 It may or may not exist, and if it exists, it is selected from L, R, Y, G, or A, and X 44 It may or may not exist, and if it exists, it is selected from N, L, S, Y, S, or W, X 45 It may or may not exist, and if it exists, it is selected from L, Y, F, or C, and X 46 It may or may not exist, and if it exists, it is selected from D, A, or F, X 47 It may or may not exist, and if it exists, it is selected from M, P, Y, or N, X 48 It may or may not exist, and if it exists, it is selected from D or L, and X 49 It either exists or does not exist, and if it exists, it is L.

[0187] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from SEQ ID NOs. 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238, a CDR2 sequence selected from SEQ ID NOs. 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239, and a CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 (Sequence code 424) is included, where X 31 is selected from A or V, X 33It is selected from G or D, X 34 is selected from G, P, W, or D, X 35 The value is selected from D, Y, S, or L, and 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 The can be selected from L, R, Y, or G, and X 44 is selected from N, L, Y, or S, X 45 It may or may not exist, and if it exists, it is selected from L, Y, or F, and X 46 It either exists or does not exist, and if it exists, it is D, and X 47 It may or may not exist, and if it exists, it is selected from M or P, X 48 It either exists or does not exist, and if it exists, it is D, and X 49 It either exists or does not exist, and if it exists, it is L.

[0188] In some embodiments, the VH region of the anti-ICAM1 antibody is the CDR1 sequence X1X2X3X4X5X6X7X8X9X 10 X 11 This includes, where X1 is selected from G or E, X2 is selected from F or Y, X3 is selected from S or T, X4 is selected from L, F, or S, X5 is selected from S or N, X6 is selected from S, N, T, or D, X7 is selected from Y, H, or G, X8 is selected from G, A, Y, W, or F, X9 is selected from M, W, Y, or I, X 10 is selected from S, G, N, M, or I, and X 11The VH region may or may not exist, and if present, it is C, and the VH region further includes a CDR2 sequence selected from sequence numbers 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251, and a CDR3 sequence selected from sequence numbers 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252.

[0189] In some embodiments, the VH region of the anti-ICAM1 antibody is the CDR1 sequence GFSLX5X6X7X8MX 10 (Sequence ID 425) includes, where X5 is selected from S or N, X6 is selected from S, N, T, or D, X7 is selected from Y or H, X8 is selected from G, A, or Y, and X 10 The VH region is selected from S, G, or N, and the VH region further includes a CDR2 sequence selected from sequence numbers 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239, and a CDR3 sequence selected from sequence numbers 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240.

[0190] In some embodiments, the VH region of the anti-ICAM1 antibody consists of a CDR1 sequence and a CDR2 sequence X selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250. 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 This includes, where X 12The first letter is selected from G, T, A, I, or Y, and X 13 is selected from W, I, Y, or C, and 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 The first letter is selected from S, R, G, or D, and X 18 is selected from G, D, or S, X 19 The letter is selected from S, R, T, N, Y, A, D, or P, and X 20 is selected from T, A, G, or Y, X 21 is selected from Y, H, A, S, or T, X 22 The value is selected from Y or N, and 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 It may or may not exist, and if it exists, it is selected from K or G, and X 30 The VH region may or may not exist, and if present, it is G, and the VH region further includes a CDR3 sequence selected from sequence numbers 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252.

[0191] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1 sequence selected from SEQ ID NOs. 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238, and a CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24Includes WAKG (sequence number 420), where X 13 is selected from W, I, or Y, X 15 It is selected from S or G, X 16 is selected from F, S, D, or T, X 17 The option is selected from S or R, X 18 It 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 The VH region is selected from S, T, or N, and the VH region further includes a CDR3 sequence selected from sequence numbers 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240.

[0192] In some embodiments, the VH region of the anti-ICAM1 antibody includes a CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; a CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and a CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252.

[0193] In some embodiments, the VH region of the anti-ICAM1 antibody includes a CDR1 sequence selected from SEQ ID NOs. 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, and 412; a CDR2 sequence selected from SEQ ID NOs. 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, and 413; and a CDR3 sequence selected from SEQ ID NOs. 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, and 414.

[0194] In some embodiments, the VH region of the anti-ICAM1 antibody includes a CDR1 sequence selected from SEQ ID NOs: 241, 247, and 250, a CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251, and a CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252.

[0195] In some embodiments, the VL region of the anti-ICAM1 antibody includes CDR1, CDR2, and CDR3 sequences selected from Table 8.

[0196] [Table 8]

[0197] In some embodiments, the VL region of the anti-ICAM1 antibody includes a CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 415; a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, 283, and 416; and a CDR3 sequence selected from SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 417.

[0198] In some embodiments, the VL region of the anti-ICAM1 antibody includes CDR1, CDR2, and CDR3 sequences selected from SEQ ID NOs. 62-64, respectively.

[0199] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250, a CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251, and a CDR3 sequence X 31 X 32 X33 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 This includes, where 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 The first letter is selected from D, Y, S, L, G, F, or W, and 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 It may or may not exist, and if it exists, it is selected from Y, A, G, I, or D, X 42 It may or may not exist, and if it exists, it is selected from I, Y, R, P, V, or G, and X 43 It may or may not exist, and if it exists, it is selected from L, R, Y, G, or A, and X 44 It may or may not exist, and if it exists, it is selected from N, L, S, Y, S, or W, X 45 It may or may not exist, and if it exists, it is selected from L, Y, F, or C, and X 46 It may or may not exist, and if it exists, it is selected from D, A, or F, X 47 It may or may not exist, and if it exists, it is selected from M, P, Y, or N, X 48It may or may not exist, and if it exists, it is selected from D or L, and X 49 The VL region may or may not exist, and if it exists, it is L, and the VL region includes a CDR1 sequence selected from sequence numbers 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62; a CDR2 sequence selected from sequence numbers 254, 257, 260, 263, 273, 275, 280, 283, and 63; and a CDR3 sequence selected from sequence numbers 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 64.

[0200] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs. 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238, a CDR2 sequence selected from SEQ ID NOs. 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239, and a CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 (Sequence code 424) is included, where X 31 is selected from A or V, X 33 It is selected from G or D, X 34 is selected from G, P, W, or D, X 35 The value is selected from D, Y, S, or L, and 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 39is 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 The can be selected from L, R, Y, or G, and X 44 is selected from N, L, Y, or S, X 45 It may or may not exist, and if it exists, it is selected from L, Y, or F, and X 46 It either exists or does not exist, and if it exists, it is D, and X 47 It may or may not exist, and if it exists, it is selected from M or P, X 48 It either exists or does not exist, and if it exists, it is D, and X 49 The VL region may or may not exist, and if it exists, it is L, and the VL region includes a CDR1 sequence selected from sequence numbers 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282, a CDR2 sequence selected from sequence numbers 254, 257, 260, 263, 273, 275, 280, and 283, and a CDR3 sequence selected from sequence numbers 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284.

[0201] In some embodiments, the anti-ICAM1 antibody includes a VH region and a VL region, wherein the VH region is the CDR1 sequence X1X2X3X4X5X6X7X8X9X 10 X 11 This includes, where X1 is selected from G or E, X2 is selected from F or Y, X3 is selected from S or T, X4 is selected from L, F, or S, X5 is selected from S or N, X6 is selected from S, N, T, or D, X7 is selected from Y, H, or G, X8 is selected from G, A, Y, W, or F, X9 is selected from M, W, Y, or I, X 10 is selected from S, G, N, M, or I, and X 11The VH region further includes a CDR2 sequence selected from sequence numbers 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251, and a CDR3 sequence selected from sequence numbers 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252, and the The VL region includes a CDR1 sequence selected from sequence numbers 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62; a CDR2 sequence selected from sequence numbers 254, 257, 260, 263, 273, 275, 280, 283, and 63; and a CDR3 sequence selected from sequence numbers 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 64.

[0202] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the VH region is the CDR1 sequence GFSLX5X6X7X8MX 10 (Sequence ID 425) includes, where X5 is selected from S or N, X6 is selected from S, N, T, or D, X7 is selected from Y or H, X8 is selected from G, A, or Y, and X 10 The VH region is selected from S, G, or N, and the VH region further includes a CDR2 sequence selected from sequence numbers 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239, and a CDR3 sequence selected from sequence numbers 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240, and the VL region includes sequence numbers 253, 256, 2 It includes a CDR1 sequence selected from sequence numbers 59, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; a CDR2 sequence selected from sequence numbers 254, 257, 260, 263, 273, 275, 280, and 283; and a CDR3 sequence selected from sequence numbers 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284.

[0203] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs. 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250, and a CDR2 sequence X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 This includes, where X 12 The first letter is selected from G, T, A, I, or Y, and X 13 is selected from W, I, Y, or C, and 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 The first letter is selected from S, R, G, or D, and X 18 is selected from G, D, or S, X 19 The letter is selected from S, R, T, N, Y, A, D, or P, and X 20 is selected from T, A, G, or Y, X 21 is selected from Y, H, A, S, or T, X 22 The value is selected from Y or N, and 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, X29 It may or may not exist, and if it exists, it is selected from K or G, and X 30 The VH region may or may not exist, and if present, it is G, and the VL region further includes a CDR3 sequence selected from sequence numbers 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252, and the VL region includes sequence numbers 253, 256, 259, 262, 265, 267, 268, 269 It includes a CDR1 sequence selected from sequence numbers 270, 272, 274, 277, 279, 282, and 62; a CDR2 sequence selected from sequence numbers 254, 257, 260, 263, 273, 275, 280, 283, and 63; and a CDR3 sequence selected from sequence numbers 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 64.

[0204] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs. 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238, and a CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 Includes WAKG (sequence number 420), where X 13 is selected from W, I, or Y, X 15 It is selected from S or G, X 16 is selected from F, S, D, or T, X 17 The option is selected from S or R, X 18 It 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 24The VH region is selected from S, T, or N, and the VL region further includes a CDR3 sequence selected from sequence numbers 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240, and the VL region includes a CDR1 sequence selected from sequence numbers 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282, a CDR2 sequence selected from sequence numbers 254, 257, 260, 263, 273, 275, 280, and 283, and a CDR3 sequence selected from sequence numbers 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284.

[0205] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs. 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250, a CDR2 sequence selected from SEQ ID NOs. 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251, and SEQ ID NOs. 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240 The VL region includes a CDR1 sequence selected from sequence numbers 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62, a CDR2 sequence selected from sequence numbers 254, 257, 260, 263, 273, 275, 280, 283, and 63, and a CDR3 sequence selected from sequence numbers 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 64.

[0206] 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 NOs. 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238, a CDR2 sequence selected from SEQ ID NOs. 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239, and SEQ ID NOs. 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240. The VL region includes a CDR1 sequence selected from sequence numbers 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282, a CDR2 sequence selected from sequence numbers 254, 257, 260, 263, 273, 275, 280, and 283, and a CDR3 sequence selected from sequence numbers 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284.

[0207] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs: 241, 247, and 250, a CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251, and a CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252, and the VL region comprising a CDR1 sequence, a CDR2 sequence, and a CDR3 sequence selected from SEQ ID NOs: 62 to 64, respectively.

[0208] In some embodiments, the anti-ICAM1 antibody comprises a VH region and a VL region, wherein the sequence of the VH region contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NOs. 289-309, and the sequence of the VL region contains approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity with SEQ ID NOs. 311-326 and 155.

[0209] In some embodiments, the VH region includes an array selected from Table 9, and the VL region includes an array selected from Table 10.

[0210] [Table 9-1]

[0211] [Table 9-2]

[0212] [Table 10-1]

[0213] [Table 10-2]

[0214] 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 examples, the anti-ICAM1 antibody includes 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 includes 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 camel antibody or its binding fragment.

[0215] In some embodiments, the anti-ICAM1 antibody comprises a bispecific antibody or its conjugated fragment. In some examples, the bispecific antibody or its conjugated fragment is a bispecific antibody conjugate, a hybrid bispecific IgG, a bispecific antibody with only a variable domain, a CH1 / CL fusion protein, a Fab fusion protein, a non-immunoglobulin fusion protein, an Fc-modified IgG, an associated &Fc-modified IgG, a modified Fc and CH3 fusion protein, an associated IgG-HC fusion, an Fc fusion, a CH3 fusion, an IgE / IgM CH2 fusion, or an F(ab')2 fusion.

[0216] In some embodiments, bispecific antibodies or binding fragments include Knobs-into-Hole (KIH), Asymmetric Re-engineering Technology-immunoglobulin (ART-Ig), Triomab quadroma, bispecific monoclonal antibodies (BiMAb, BsmAb, BsAb, bsMab, BS-Mab, or Bi-MAb), FcΔAdp, XmAb, Azymetric, bispecific involvement by antibodies based on T cell receptors (BEAT), Bispecific T-cell Engager (BiTE), Biclonics, Fab-scFv-Fc, Two-in-one / Dual Action Fab (DAF), FinomAb, scFv-Fc-(Fab)-lysis, Dock-aNd-Lock (DNL), Adaptir (formerly SCORPION), Tandem diAbody (TandAb), Dual-affinity-ReTargeting (DART), or nanobodies.

[0217] In some embodiments, bispecific antibodies containing only the variable domain include tandem scFv(taFv), triple-body, diabody(Db), dsDb, Db(KIH), scDb, dsFv-dsFv', tandAbs, triple-head, tandem dAb / VHH, triple dAb / VHH, or tetravalent dAb / VHH.

[0218] In some embodiments, the CH1 / CL fusion protein includes scFv2-CH1 / CL or VHH2-CH1 / CL.

[0219] In some examples, Fab fusion proteins include Fab-scFv (vibody), Fab-scFv2 (tribody), Fab-Fv, Fab-dsFv, Fab-VHH, or orthogonal Fab-Fab.

[0220] In some examples, non-immunoglobulin fusion proteins include scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, mini-antibodies, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, or ImmTAC(TCR-scFv).

[0221] In some examples, Fc-modified IgG is called 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 * Includes.

[0222] In some examples, associated &Fc modified IgG includes IgG(KIH)-Fv, IgG(HA-TF-FV), IgG(KIH)-scFab, scFab-Fc(KIH)-scFv2, scFab-Fc(KIH)-scFv, half-DVD-Ig, Dual Variable Domain-immunoglobulin (DVD-Ig), or CrossMab-Fab.

[0223] Depending on the case, modified Fc-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 TriFab.

[0224] Depending on the case, the accompanying IgG-HC fusion antibody may include IgG-HC-scFv, IgG-dAb, IgG-taFv, IgG-CrossFab, IgG-(CαCβ)Fab, scFv-HC-IgG, tandem Fab-IgG, Fab-IgG(CαCβFab), Fab-IgG(CR3), or Fab-Hinge-IgG(CR3).

[0225] Depending on the case, the accompanying IgG-LC fusion antibody may include IgG-scFv(LC), scFv(LC)-IgG, or dAb-IgG.

[0226] Depending on the case, the accompanying IgG-HC&LC fusion antibody may include DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, or Zybody.

[0227] In some examples, Fc fusion antibodies include Di-diabody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-Ig, or scFv2-Fcab.

[0228] In some cases, CH3 fusion antibodies include Di-diabody or scDb-CH3.

[0229] In some cases, IgE / IgM CH2 fusion antibodies include scFv-EHD2-scFv or scFv-MHD2-scFv.

[0230] In some cases, the F(ab')2 fusion antibody contains F(ab')2-scFv2.

[0231] In some examples, the CH1 / CL fusion protein contains scFv2-CH1-hinge / CL.

[0232] In some cases, modified IgG is called DAF (two-in-one-IgG), DutaMab, or mAb. 2 Includes.

[0233] In some cases, the non-immunoglobulin fusion antibody includes DNL-Fab4-IgG.

[0234] In some cases, the anti-ICAM1 antibody includes a bispecific antibody or its conjugated fragment, as illustrated in Figure 1A or Figure 1B.

[0235] In some embodiments, the anti-ICAM1 antibodies described herein include an IgG framework, an IgA framework, an IgE framework, or an IgM framework. In some examples, the anti-CD38 antibody includes an IgG framework (e.g., IgG1, IgG2, IgG3, or IgG4). In such cases, the anti-CD38 antibody includes a framework of IgG1, IgG2, IgG3, or IgG4.

[0236] In some cases, anti-ICAM1 antibodies further contain one or more mutations in the framework region, e.g., the CH1 domain, CH2 domain, CH3 domain, hinge region, or combination thereof. In some cases, the one or more mutations stabilize the antibody and / or extend its half-life. In some cases, the one or more mutations modulate Fc receptor interactions and increase ADCC or CDC. In other cases, the one or more mutations reduce or eliminate Fc effector function such as FcγR, ADCC, or CDC. In additional cases, the one or more mutations modulate glycosylation.

[0237] In some cases, the anti-ICAM1 antibody includes an IgG1 framework. In some embodiments, the constant region of the anti-ICAM1 antibody is modified at one or more amino acid positions to modify the Fc receptor interaction. Typical residues that modulate or modify the 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 1991 Sequences of Proteins of Immunological Interest). In some examples, the mutations include G236A, S239D, T250Q, M252Y, S254T, T256E, K326W, A330L, I332E, E333A, E333S, M428L, H433K, or N434F.

[0238] In some embodiments, modifications at one or more amino acid positions in the constant region of IgG1 aimed at modifying Fc receptor interactions extend the half-life. In some examples, modifications at one or more amino acid positions include T250, M252, S254, T256, M428, H433, N434, or combinations thereof, such as T250Q / M428L or M252Y / S254T / T256E and H433K / N434F.

[0239] In some embodiments, modifications at one or more amino acid positions in the IgG1 constant region aimed at modifying Fc receptor interactions increase ADCC and / or CDC. In some examples, modifications at one or more amino acid positions include S239, K326, A330, I332, E333, or combinations thereof. In some examples, modifications at one or more amino acid positions aimed at increasing ADCC and / or CDC include, for example, E333A, S239D / A330L / I332E, or K326W / E333S. In some cases, modifications at one or more amino acid positions aimed at increasing ADCC include S239D / A330L / I332E. In some cases, modifications at one or more amino acid positions aimed at increasing CDC include K326W / E333S.

[0240] In some embodiments, modifications at one or more amino acid positions in the constant region of IgG1 aimed at modifying Fc receptor interactions increase macrophage phagocytosis. In some examples, 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 aimed at increasing macrophage phagocytosis include the combination of S239D / I332I / G236A.

[0241] In some embodiments, the IgG1 constant region is modified with amino acid N297 (Kabat numbered), in which residue N297 is afucosylated, and the oligosaccharide does not contain a fucose sugar unit.

[0242] In some embodiments, the anti-ICAM1 antibody includes an IgG2 framework. In some examples, one or more amino acid positions in the IgG2 framework are modified to alter Fc receptor interactions, e.g., to increase ADCC and / or CDC. In some cases, one or more amino acid positions in the IgG2 framework are modified to stabilize the antibody and / or extend its half-life. In some examples, one or more amino acid positions in the IgG2 framework are modified to regulate glycosylation. In some cases, the constant region of IgG2 is afucosylated at residue N297.

[0243] In some embodiments, the anti-ICAM1 antibody comprises an IgG3 framework. In some examples, one or more amino acid positions in the IgG3 framework are modified to alter Fc receptor interactions, e.g., to increase ADCC and / or CDC. In some cases, one or more amino acid positions in the IgG3 framework are modified to stabilize the antibody and / or extend its half-life. In some examples, 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 with amino acid R435, e.g., R435H (Kabat numbered), to extend its half-life. In some examples, the constant region is afucosylated at residue N297.

[0244] In some embodiments, the anti-ICAM1 antibody comprises an IgG4 framework. In some examples, one or more amino acid positions in the IgG4 framework are modified to alter Fc receptor interactions, e.g., to increase ADCC and / or CDC. In some cases, one or more amino acid positions in the IgG4 framework are modified to stabilize the antibody and / or extend its half-life. In some examples, 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 examples, the amino acid to be modified is S228 (e.g., S228P).

[0245] In some embodiments, the human IgG constant region is modified to modify ADCC and / or CDC, for example, "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 The amino acid modifications described in "Immunol, 148:3461-3468" and "Reviewed in Kaneko and Niwa, 2011 Biodrugs, 25(1):1-11" are used.

[0246] In some embodiments, the constant region of human IgG is modified to induce heterodimerization. For example, if there is an amino acid modification within the CH3 domain at Thr366, which is substituted with a bulkier amino acid, e.g., Trp(T366W), it can preferentially pair with a second CH3 domain having amino acid modifications to less bulky amino acids at the positions of Thr366, Leu368, and Tyr407, e.g., Ser, Ala, and Val, respectively. In some cases, heterodimerization via CH3 modification is further stabilized by the introduction of disulfide bonds, e.g., by changes from Ser354 to Cys(S354C) and Y349 to Cys(Y349C) in the opposite CH3 domain (Reviewed in Carter, 2001 Journal of Immunological Methods, 248:7-15).

[0247] In some cases, the anti-ICAM1 antibodies described herein have reduced or absent glycosylation but are not modified with amino acid Asn297 (Kabat numbering). In these cases, glycosylation is eliminated, for example, by antibody production in host cells lacking posttranslational glycosylation ability, such as bacterial or yeast-derived systems, or in modified mammalian cell expression systems. In some embodiments, such systems are cell-free expression systems.

[0248] In some embodiments, the anti-ICAM1 antibody described herein is a full-length antibody comprising a heavy chain (HC) and a light chain (LC). Optionally, the heavy chain (HC) comprises a sequence selected from Table 11. Optionally, the light chain (LC) comprises a sequence selected from Table 12.

[0249] [Table 11-1]

[0250] [Table 11-2]

[0251] [Table 11-3]

[0252] [Table 11-4]

[0253] [Table 12-1]

[0254] [Table 12-2]

[0255] In some embodiments, the anti-ICAM1 antibodies described herein are used to determine ADCC activity using cancer cells, such as human prostate cancer cells, in in vitro cytotoxicity assays at concentrations of approximately 0.001 nM to approximately 2.5 nM, for example, approximately 0.02 nM, 0.03 nM, approximately 0.04 nM, approximately 0.05 nM, approximately 0.06 nM, approximately 0.09 nM, approximately 0.1 nM, approximately 1.2 nM, approximately 1.7 nM, approximately 2.0 nM, and approximately 2.5 nM of EC2. 50 It has.

[0256] Depending on the circumstances, the serum half-life of the anti-ICAM1 antibody described herein may be 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. Depending on the circumstances, the serum half-life of the anti-ICAM1 antibody described herein may be approximately 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.

[0257] Multispecific anti-CD38 antibody and anti-ICAM1 antibody In some embodiments, a multispecific anti-CD38 antibody or a multispecific anti-ICAM1 antibody is described herein. In some examples, the multispecific anti-CD38 antibody or the multispecific anti-ICAM1 antibody includes a target-binding moiety that recognizes two or more antigens. In some cases, the multispecific anti-CD38 antibody includes a target-binding moiety that specifically binds to two or more antigens, for example, three or more, four or more, or five or more antigens. In some cases, the multispecific anti-ICAM1 antibody includes a target-binding moiety that specifically binds to two or more antigens, for example, three or more, four or more, or five or more antigens.

[0258] In some embodiments, bispecific anti-CD38 antibodies are disclosed herein. In some examples, 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. Optionally, the second target may be ICAM1, ephrin type A receptor 2 (EphA2), ephrin type A receptor 3 (EphA3), ephrin type A receptor 4 (EphA4), activated leukocyte adhesion molecule (ALCAM), BCMA (B cell maturation antigen or TNFRSF17), PDL1, CD30, CD33, PSMA, mesothelin, CD44, CD73, cell surface-associated mucin 1 (MUC1), oligomeric mucin 2 (Mucin 2 oligomeric mucus). Examples of metabolites that may be present include, but are not limited to, gel-forming mucin (MUC2), cell surface-associated mucin 16 (MUC16), carcinoembryonic antigen (CEA), cathepsin G, melanoma preferentially expressed antigen (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-dependent chloride channel 2 (CaCC), gplOO, synovial sarcoma X breakpoint 2 (SSX-2), or SAP-1.

[0259] In some embodiments, bispecific anti-ICAM1 antibodies are disclosed herein. In some examples, 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. The non-ICAM1 target may include, but is not limited to, CD38, CD47, receptor tyrosine kinase-like orphan receptor 1 (ROR1), receptor tyrosine kinase-like orphan receptor 2 (ROR2), Erb3, IGFRIR, EGFR, PDL1, PDL2, PD1, CTLA4, or Tim3.

[0260] In some embodiments, the Specified Description describes a bispecific antibody comprising a first targeting moiety that specifically binds to CD38 or ICAM1.

[0261] In some embodiments, the bispecific antibodies of the present disclosure comprise a first component that binds to CD38 and a second component that binds to ICAM1, and bind to cells expressing the bispecific protein on a surface target antigen. The affinity (e.g., preferential binding) is at least 2 to 50 times, 10 to 100 times, 2 times, 5 times, 10 times, 25 times, 50 times, or 100 times, or 20 to 50%, 50 to 100%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% higher than the binding affinity of an antibody that is monospecific to only one of CD38 or ICAM1 that binds to the cells.

[0262] In some cases, the bispecific antibody further enhances the complement-dependent cytotoxicity (CDC) effect compared to the reference antibody, daratumumab. In some cases, the bispecific antibody further enhances the ADCC effect compared to the ADCC effect of the reference antibody, daratumumab. In some cases, the bispecific antibody further reduces the immune cell death effect compared to the immune cell death effect of the reference antibody, daratumumab. In some cases, the enhancement of CDC is at least 2, 3, 4, or more times higher than the CDC effect of the reference antibody, daratumumab. In some cases, the enhancement of CDC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more times higher than the CDC effect of the reference antibody, daratumumab. In some cases, the enhancement of ADCC is at least 2, 3, 4, 5, or more times higher than the ADCC effect of the reference antibody, daratumumab. In some cases, the enhancement of ADCC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more higher than the ADCC effect of the reference antibody, daratumumab. In some cases, the immune cells are natural killer cells. In some embodiments, the survival rate of the immune cells is improved by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to the survival rate of immune cells in the presence of the reference antibody, daratumumab.

[0263] In some embodiments, this specification describes a bispecific antibody comprising a first targeting moiety that specifically binds to CD38 and a second targeting moiety that specifically binds to ICAM1. In some examples, the bispecific antibody further enhances the CDC effect compared to the CDC effect of a reference antibody, daratumumab. In some examples, the bispecific antibody further enhances the ADCC effect compared to the ADCC effect of a reference antibody, daratumumab. In some cases, the CDC enhancement is at least 2, 3, 4, or more times higher than the CDC effect of the reference antibody, daratumumab. In some cases, the CDC enhancement is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more times higher than the CDC effect of the reference antibody, daratumumab. In some cases, the ADCC enhancement is at least 2, 3, 4, 5, or more times higher than the ADCC effect of the reference antibody, daratumumab. In some cases, the enhancement of ADCC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more higher than the ADCC effect of the reference antibody, daratumumab.

[0264] In some embodiments, this specification describes a bispecific antibody comprising a first component that specifically binds to CD38 and a second component that specifically binds to ICAM1, wherein the bispecific antibody mediates ADCC more efficiently than a monospecific antibody containing only either the first or second component, and the activity of the ADCC is determined by an in vitro cytotoxicity assay. In some embodiments, the bispecific antibody mediates maximal cytotoxicity at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 75%, and at least about 100% higher in an in vitro ADCC assay than a monospecific antibody containing only either the first or second component. In some embodiments, the bispecific antibody mediates maximal cytotoxicity at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 10-fold higher in an in vitro ADCC assay than a monospecific antibody containing only either the first or second component.

[0265] In some embodiments, this specification describes a bispecific antibody comprising a first component that specifically binds to CD38 and a second component that specifically binds to ICAM1, wherein the bispecific antibody mediates complement-dependent cytotoxicity (CDC) more efficiently than a monospecific antibody comprising only either the first or second component, and the ADCC activity is determined by an in vitro cytotoxicity assay, and the CDC activity is determined by an in vitro cytotoxicity assay. In some embodiments, the bispecific antibody mediates maximum cytotoxicity at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 75%, and at least about 100% higher in an in vitro CDC assay than a monospecific antibody comprising only either the first or second component.

[0266] In some cases, the bispecific antibody exhibits a reduced immune cell killing effect compared to that of the reference antibody, daratumumab. In some embodiments, the survival rate of the immune cells is improved by approximately 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more compared to the survival rate of the immune cells in the presence of the reference antibody, daratumumab. In some cases, the immune cells are natural killer cells.

[0267] In some examples, bispecific antibodies containing both CD38-targeting and ICAM1-targeting moieties are bispecific antibody conjugates, hybrid bispecific IgG, bispecific antibodies with only variable domains, CH1 / CL fusion proteins, Fab fusion proteins, non-immunoglobulin fusion proteins, Fc-modified IgG, associated & Fc-modified IgG, modified Fc and CH3 fusion proteins, associated IgG-HC fusion, Fc fusion, CH3 fusion, IgE / IgM CH2 fusion, or F(ab')2 fusion.

[0268] In some embodiments, bispecific antibodies comprising a CD38-targeting moiety and an ICAM1-targeting moiety are known as Knobs-into-Holes (KIH), Asymmetric Re-engineering Technology-immunoglobulin (ART-Ig), Triomab quadroma, bispecific monoclonal antibodies (BiMAb, BsmAb, BsAb, bsMab, BS-Mab, or Bi-MAb), FcΔAdp, XmAb, Azymetric, bispecific involvement of antibodies based on T cell receptors (BEAT), Bispecific T-cell Engager (BiTE), Biclonics, Fab-scFv-Fc, Two-in-one / Dual Action Fab (DAF), FinomAb, scFv-Fc-(Fab)-lysate, Dock-aNd-Lock (DNL), Adaptir (formerly SCORPION), Tandem Includes diAbody (TandAb), Dual-affinity-ReTargeting (DART), or nanobody.

[0269] In some embodiments, bispecific antibodies containing only the variable domain include tandem scFv(taFv), triple-body, diabody(Db), dsDb, Db(KIH), scDb, dsFv-dsFv', tandAbs, triple-head, tandem dAb / VHH, triple dAb / VHH, or tetravalent dAb / VHH.

[0270] In some embodiments, the CH1 / CL fusion protein includes scFv2-CH1 / CL or VHH2-CH1 / CL.

[0271] In some examples, Fab fusion proteins include Fab-scFv (vibody), Fab-scFv2 (tribody), Fab-Fv, Fab-dsFv, Fab-VHH, or orthogonal Fab-Fab.

[0272] In some examples, non-immunoglobulin fusion proteins include scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, mini-antibodies, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, or ImmTAC(TCR-scFv).

[0273] In some examples, Fc-modified IgG is called 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 * Includes.

[0274] In some examples, associated &Fc modified IgG includes IgG(KIH)-Fv, IgG(HA-TF-FV), IgG(KIH)-scFab, scFab-Fc(KIH)-scFv2, scFab-Fc(KIH)-scFv, half-DVD-Ig, Dual Variable Domain-immunoglobulin (DVD-Ig), or CrossMab-Fab.

[0275] Depending on the case, modified Fc-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 TriFab.

[0276] Depending on the case, the accompanying IgG-HC fusion antibody may include IgG-HC-scFv, IgG-dAb, IgG-taFv, IgG-CrossFab, IgG-(CαCβ)Fab, scFv-HC-IgG, tandem Fab-IgG, Fab-IgG(CαCβFab), Fab-IgG(CR3), or Fab-Hinge-IgG(CR3).

[0277] Depending on the case, the accompanying IgG-LC fusion antibody may include IgG-scFv(LC), scFv(LC)-IgG, or dAb-IgG.

[0278] Depending on the case, the accompanying IgG-HC&LC fusion antibody may include DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, or Zybody.

[0279] In some examples, Fc fusion antibodies include Di-diabody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-Ig, or scFv2-Fcab.

[0280] In some cases, CH3 fusion antibodies include Di-diabody or scDb-CH3.

[0281] In some cases, IgE / IgM CH2 fusion antibodies include scFv-EHD2-scFv or scFv-MHD2-scFv.

[0282] In some cases, the F(ab')2 fusion antibody contains F(ab')2-scFv2.

[0283] In some examples, the CH1 / CL fusion protein contains scFv2-CH1-hinge / CL.

[0284] In some cases, modified IgG is called DAF (two-in-one-IgG), DutaMab, or mAb. 2 Includes.

[0285] In some cases, the non-immunoglobulin fusion antibody includes DNL-Fab4-IgG.

[0286] In some examples, bispecific antibodies containing both CD38-targeting and ICAM1-targeting moieties include antibody formats such as those illustrated in Figure 1A or Figure 1B.

[0287] In some examples, a bispecific antibody containing a CD38-targeting moiety and an ICAM1-targeting moiety is a bivalent antibody or its binding fragment. In some examples, the bivalent antibody or its binding fragment includes an IgG-scFv(LC) C-terminal fusion format (Figure 2A), an IgG-HC-scFv C-terminal format (Figure 2B), an scFv-HC-IgG N-terminal fusion format (Figure 2C), or a DVD-Ig format (Figure 2D).

[0288] In some cases, a bispecific antibody containing a CD38-targeting moiety and an ICAM1-targeting moiety is a monovalent antibody or its conjugated fragment. In some cases, the monovalent antibody or its conjugated fragment includes a Fab-scFv-Fc (KIH) format (also referred herein as a three-chain knob-into-holes) (Figure 2E) or a Biclonics common LC format (also referred herein as a common light-chain bispecificity) (Figure 2F).

[0289] In some embodiments, a bispecific antibody comprising a CD38-targeting moiety and an ICAM1-targeting moiety contains a KD of approximately 1 nM to approximately 100 nM for CD38. In some examples, the KD is 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.

[0290] In some embodiments, a bispecific antibody comprising a CD38-targeting moiety and an ICAM1-targeting moiety contains a KD of approximately 0.1 nM to approximately 20 nM for ICAM1. In some examples, the KD is approximately 0.15nM, 0.2nM, 0.24nM, 0.25nM, 0.29nM, 0.3nM, 0.4nM, 0.5nM, 0.6nM, 0.7nM, 0.8nM, 0.9nM, 1nM, 1.5nM, 1.72nM, 2nM, 2.28nM, 2.5nM, 3nM, 3.5nM, 4nM, 4.5nM, 5nM, 6nM, 7nM, 8nM, 9nM, 10nM, 11nM, 12nM, 13nM, 14nM, 15nM, 16nM, 17nM, 18nM, 19nM, or 20nM.

[0291] In some embodiments, a first targeting region that specifically binds to CD38 includes a VH region and a VL region, the VH region comprising 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 This includes, 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 The letter is selected from G, W, D, L, K, P, S, A, T, or R, and 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 It may or may not exist, and if it exists, it is selected from F, Y, V, D, A, N, G, E, or L, and X 42 It may or may not exist, and if it exists, it is selected from P, L, Y, F, G, or T, X 43It may or may not exist, and if it exists, it is selected from T, P, F, V, N, Y, or S, X 44 It may or may not exist, and if it exists, it is selected from G, L, S, T, or F, X 45 It may or may not exist, and if it exists, it is selected from F, L, E, N, or S, X 46 It may or may not exist, and if it exists, it is selected from D, S, L, or R, and X 47 It may or may not exist, and if it exists, it is selected from Y or L, X 48 It either exists or does not exist, and if it exists, it is D, and X 49 The VL region may or may not exist, and if it exists, it is L, and the VL region includes a CDR1 sequence selected from sequence numbers 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102, a CDR2 sequence selected from sequence numbers 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from sequence numbers 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0292] In some embodiments, a first targeting region that specifically binds to CD38 includes a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9, a CDR2 sequence selected from SEQ ID NOs: 2 and 5, and a CDR3 sequence AKRGTYX 38 YSX 41 Includes PTGFDY (sequence number 421), where X 38 is selected from A or G, X 41 The VL region is selected from F or Y, and the VL region includes a CDR1 sequence consisting of sequence number 62, a CDR2 sequence consisting of sequence number 63, and a CDR3 sequence consisting of sequence number 64.

[0293] In some embodiments, the VH region includes a first targeting region that specifically binds to CD38, the VH region comprising 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 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 This includes, where 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 The letter is selected from G, W, D, L, K, P, S, R, or A, and 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 It may or may not exist, and if it exists, it is selected from V, D, A, N, G, L, or E, X 42 It may or may not exist, and if it exists, it is selected from L, Y, F, T, or G, and X 43 It may or may not exist, and if it exists, it is selected from P, F, V, N, S, or Y, X 44It may or may not exist, and if it exists, it is selected from L, S, T, G, or F, and X 45 It may or may not exist, and if it exists, it is selected from L, F, E, S, or N, and X 46 It may or may not exist, and if it exists, it is selected from S, L, or R, and X 47 It either exists or does not exist, and if it exists, it is L, and X 48 It either exists or does not exist, and if it exists, it is D, and X 49 The VL region may or may not exist, and if it exists, it is L, and the VL region includes a CDR1 sequence selected from sequence numbers 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102, a CDR2 sequence selected from sequence numbers 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from sequence numbers 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0294] In some embodiments, a first targeting region that specifically binds to CD38 includes a VH region and a VL region, the VH region comprising 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 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 This includes, where 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 The letter is selected from G, W, D, L, K, or P, and X 36is 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 The value is selected from S, Y, G, R, or W, and X 41 is selected from V, D, Y, A, N, or G, X 42 is selected from L, Y, or F, X 43 It may or may not exist, and if it exists, it is selected from P, F, V, or N, X 44 It may or may not exist, and if it exists, it is selected from L, S, or T, and X 45 The VL region may or may not exist, and if present, it is selected from L or F, and the VL region includes a CDR1 sequence selected from sequence numbers 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from sequence numbers 66, 69, 78, 81, 90, and 99, and a CDR3 sequence selected from sequence numbers 67, 70, 82, 87, 88, 91, 93, and 100.

[0295] In some embodiments, the first targeting region that specifically binds to CD38 includes a VH region and a VL region, the VH region comprising a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56, a CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57, and a CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 (Sequence ID 422) is included, where X 33 is selected from R or G, X 34 is selected from E, D, or S, X 35 The first letter is selected from G, L, P, S, or A, and X36 is selected from D, S, or R, X 37 is selected from Y, T, N, or G, X 38 It is selected from G, S, F, or L, X 39 is selected from A, G, S, or I, X 40 The value is selected from Y, N, or L, and X 41 It may or may not exist, and if it exists, it is selected from V, Y, or E, and X 42 It either exists or does not exist, and if it exists, it is G, and X 43 It either exists or does not exist, and if it exists, it is Y, and X 44 It either exists or does not exist, and if it exists, it is F, and X 45 It may or may not exist, and if it exists, it is selected from E or N, and X 46 The VL region may or may not exist, and if present, it is selected from S or L, and the VL region includes a CDR1 sequence selected from sequence numbers 71, 77, 83, 94, and 102, a CDR2 sequence selected from sequence numbers 72, 78, and 84, and a CDR3 sequence selected from sequence numbers 73, 79, 85, 95, and 103.

[0296] In some embodiments, a first targeting region that specifically binds to CD38 includes a VH region and a VL region, wherein the VH region is the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 This includes, where X1 is either present or absent, and if present it 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 It may or may not exist, and if it exists, it is selected from C or M, and X12 is present or absent, and if present, is C, and the VH region further includes a CDR2 sequence selected from sequence numbers 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 sequence numbers 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58, and the VL region is It includes a CDR1 sequence selected from sequence numbers 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from sequence numbers 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from sequence numbers 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0297] In some embodiments, a first targeting region that specifically binds to CD38 comprises a VH region and a VL region, the VH region comprising a CDR1 sequence GFPFX5X6YAMS (sequence number 423), where X5 is selected from D or G, and X6 is selected from V, A, or T, the VH region further comprising a CDR2 sequence selected from sequence numbers 2 and 5, and a CDR3 sequence selected from sequence numbers 3, 7, and 10, the VL region comprising a CDR1 sequence consisting of sequence number 62, a CDR2 sequence consisting of sequence number 63, and a CDR3 sequence consisting of sequence number 64.

[0298] In some embodiments, a first targeting region that specifically binds to CD38 includes a VH region and a VL region, wherein the VH region is the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12This includes, where X1 is either present or absent, 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 is selected from T, S, M, C, I, Y, A, or G, X 11 It may or may not exist, and if it exists, it is selected from C or M, and X 12 It may or may not exist, and if it exists, it is C, and the VH region further includes a CDR2 sequence selected from sequence numbers 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57, and a CDR3 sequence selected from sequence numbers 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58, and the VL region is It includes a CDR1 sequence selected from sequence numbers 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from sequence numbers 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from sequence numbers 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0299] In some embodiments, a first targeting region that specifically binds to CD38 includes a VH region and a VL region, wherein the VH region is the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (Sequence ID 426) includes, where 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 11The function may or may not exist, and if present, it is C, and the VH region further inc...

Claims

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

2. The polyspecific protein according to claim 1, wherein the polyspecific protein is divalent, trivalent, or tetravalent.

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

4. The second component is a polyspecific protein according to any one of claims 1 to 3, comprising an antibody or antigen-binding fragment thereof that specifically binds to ICAM1.

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

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

7. A polyspecific protein according to any one of claims 1 to 6, further comprising an Fc region.

8. The polyspecific protein according to claim 7, wherein the Fc region includes 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 polyspecific protein according to any one of claims 7-9, wherein the Fc region contains one or more stabilizing mutations.

11. The polyspecific protein according to any one of claims 7-10, wherein the Fc region comprises one or more mutations that modulate interaction with the Fc receptor.

12. The polyspecific protein according to claim 11, wherein the Fc region comprises one or more mutations that increase the binding of the Fc region to the Fc receptor.

13. The polyspecific protein according to any one of claims 7-12, wherein the Fc region comprises one or more mutations that reduce glycosylation of the Fc region.

14. The polyspecific protein according to claim 13, wherein one or more mutations that reduce glycosylation of the Fc region include a mutation at a position corresponding to the N297 position of human IgG1, where the numbering is according to the EU index by Kabat et al.

15. The multispecific protein according to any one of claims 7-14, wherein the Fc region is afucosylated.

16. The polyspecific protein according to any one of claims 7-15, wherein the Fc region comprises one or more mutations that increase the activity of ADCC or CDC.

17. The multispecific protein according to claim 16, wherein the Fc region comprises one or more mutations that increase ADCC, where the mutations that increase ADCC are located at positions corresponding to positions 239, 332, and 330 of human IgG1, and the mutations are S239D, I332E, and A330L, and the amino acid numbering is according to the EU index by Kabat et al.

18. A polyspecific protein according to any one of claims 8-17, comprising a heterodimer Fc region, wherein the heterodimer Fc region comprises a knob chain and a hole chain, forming a knob-in-hole (KIH) structure.

19. The multispecific protein according to claim 18, wherein the knob chain contains mutant T366W, and the whole chain contains mutants T366S, L368A, and Y407V, where the amino acid position numbering is according to the EU index by Kabat et al.

20. The polyspecific protein according to any one of claims 4-19, wherein the antibody or antigen-binding fragment that specifically binds to CD38 comprises anti-CD38 IgG, and the antibody or antigen-binding fragment that specifically binds to ICAM1 comprises anti-ICAM1 single-chain variable fragment (anti-ICAM1 scFv).

21. The polyspecific protein according to claim 20, wherein anti-CD38 IgG comprises two light chains, each light chain being fused to a single anti-ICAM1 scFv.

22. The polyspecific protein according to claim 21, wherein the C-terminus of each light chain of anti-CD38 IgG is fused to a single anti-ICAM1 scFv.

23. The multispecific protein according to claim 21, wherein the N-terminus of each heavy chain of anti-CD38 IgG is fused to a single anti-ICAM1 scFv.

24. The polyspecific protein according to claim 21, wherein 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 polyspecific protein according to any one of claims 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-ICAM-1 variable light chain domains, and each variable heavy chain domain of anti-CD38 IgG is fused to one of the anti-ICAM1 variable heavy chain domains, and each variable light chain domain of anti-CD38 IgG is fused to one of the anti-ICAM1 variable light chain domains.

26. The polyspecific protein according to any one of claims 3-20, wherein the antibody or antigen-binding fragment that specifically binds to CD38 is a monovalent anti-CD38 antibody or its antigen-binding fragment.

27. The polyspecific protein according to any one of claims 4-20 and 26, wherein the antibody or antigen-binding fragment that specifically binds to ICAM1 is a monovalent anti-ICAM1 antibody or its antigen-binding fragment.

28. The monovalent anti-CD38 antibody or its antigen-binding fragment comprises an anti-CD38 Fab, as described in claim 26 or 27, for a polyspecific protein.

29. The monovalent anti-ICAM1 antibody or its antigen-binding fragment comprises an anti-ICAM1 scFv, the polyspecific protein according to any one of claims 26-28.

30. The multispecific protein according to claim 29, wherein the multispecific protein comprises an anti-CD38 Fab, an anti-ICAM1 scFv, and an Fc region.

31. The polyspecific protein according to claim 30, wherein the Fc region is a heterodimer Fc region containing a KIH structure.

32. The monovalent anti-CD38 antibody or its antigen-binding fragment comprises one variable heavy chain domain (VH) and a variable light chain domain (VL), and the monovalent anti-ICAM1 antibody or its antigen-binding fragment comprises one variable heavy chain domain (VH), wherein the multispecific protein is as described in claim 27.

33. The multispecific protein according to claim 32, further comprising an Fc region.

34. The polyspecific protein according to claim 33, wherein the Fc region is a heterodimeric Fc region containing a KIH structure, and the polyspecific protein is in a general light chain bispecificity format.

35. The first component that specifically binds to CD38 includes a heavy chain containing complementarity-determining regions CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 of the heavy chain are the following set of sequences: 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: 15: 16); CDR1: CDR2: CDR3 (SEQ ID NO: 17: 18: 19); CDR1: CDR2: CDR3 (SEQ ID NO: 20: 21: 22); CDR1: CDR2: CDR3 (SEQ ID NO: 23: 24: 25); CDR1: CDR2: CDR3 (SEQ ID NO: 26; SEQ ID NO: 27; SEQ ID NO: 28); CDR1: CDR2: CDR3 (SEQ ID NO: 29:30:31); CDR1: CDR2: CDR3 (SEQ ID NO: 32: 33: 34); CDR1: CDR2: CDR3 (SEQ ID NO: 35; SEQ ID NO: 36; SEQ ID NO: 37); CDR1: CDR2: CDR3 (SEQ ID NO: 38: 39: 40); CDR1: CDR2: CDR3 (SEQ ID NO: 41: SEQ ID NO: 42: SEQ ID NO: 43); CDR1: CDR2: CDR3 (SEQ ID NO: 44, 45, 46); CDR1: CDR2: CDR3 (SEQ ID NO: 47: 48: 49); CDR1: CDR2: CDR3 (SEQ ID NO: 50: 51: 52); CDR1: CDR2: CDR3 (SEQ ID NO: 53: SEQ ID NO: 54: SEQ ID NO: 55); CDR1: CDR2: CDR3 (SEQ ID NO: 56: 57: 58); and, CDR1: CDR2: A polyspecific protein according to any one of claims 1 to 34, comprising a set of sequences selected from the group consisting of CDR3 (SEQ ID NO: 59: SEQ ID NO: 60: SEQ ID NO: 61).

36. The polyspecific protein according to claim 35, wherein the heavy chain CDR1, CDR2, and CDR3 comprises the following sequence set: CDR1:CDR2:CDR3 (SEQ ID NO: 14:SEQ ID NO: 15:SEQ ID NO: 16).

37. The polyspecific protein according to claim 35, wherein the heavy chain CDR1, CDR2, and CDR3 comprises the following sequence set: CDR1:CDR2:CDR3 (SEQ ID NO: 17:SEQ ID NO: 18:SEQ ID NO: 19).

38. The polyspecific protein according to claim 35, wherein the heavy chains CDR1, CDR2, and CDR3 comprise the following sequence: CDR1:CDR2:CDR3 (SEQ ID NO: 1:SEQ ID NO: 2:SEQ ID NO: 7).

39. The first component that specifically binds to CD38 includes a light chain containing complementarity-determining regions CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 of the light chain are the following set of sequences: CDR1: CDR2: CDR3 (SEQ ID NO: 62: 63: 64); CDR1: CDR2: CDR3 (SEQ ID NO: 65: 66: 67); CDR1: CDR2: CDR3 (SEQ ID NO: 68; SEQ ID NO: 69; SEQ ID NO: 70); CDR1: CDR2: CDR3 (SEQ ID NO: 71: 72: 73); CDR1: CDR2: CDR3 (SEQ ID NO: 74: 75: 76); CDR1: CDR2: CDR3 (SEQ ID NO: 77; SEQ ID NO: 78; SEQ ID NO: 79); CDR1: CDR2: CDR3 (SEQ ID NO: 80: 81: 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: 90: 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: 99: 100); CDR1: CDR2: CDR3 (SEQ ID NO: 77; SEQ ID NO: 72; SEQ ID NO: 101); and, CDR1: CDR2: A polyspecific protein according to any one of claims 1 to 38, comprising a sequence selected from the group consisting of CDR3 (SEQ ID NO: 102: SEQ ID NO: 84: SEQ ID NO: 103).

40. The polyspecific protein according to claim 39, wherein the light chain CDR1, CDR2, and CDR3 comprise the following sequence set: CDR1:CDR2:CDR3 (SEQ ID NO: 68:SEQ ID NO: 69:SEQ ID NO: 70).

41. The polyspecific protein according to claim 39, wherein the light chain CDR1, CDR2, and CDR3 comprise the following sequence set: CDR1:CDR2:CDR3 (SEQ ID NO: 71:SEQ ID NO: 72:SEQ ID NO: 73).

42. The polyspecific protein according to claim 39, wherein the light chain CDR1, CDR2, and CDR3 comprise the following sequence set: CDR1:CDR2:CDR3 (SEQ ID NO: 62:SEQ ID NO: 63:SEQ ID NO: 64).

43. The first component is the following set of sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NO: 1:SEQ ID NO: 2:SEQ ID NO: 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 ID NO: 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 ID NO: 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 ID NO: 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 ID NO: 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 ID NO: 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 ID NO: 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 ID NO: 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 ID NO: 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: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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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, The polyspecific protein according to claim 39, comprising six CDRs, each containing a sequence described by any one of the following: 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 polyspecific protein according to claim 43, wherein the first component comprises six CDRs including the following sequence set: 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 first component comprises six CDRs including the following sequence set: 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), the polyspecific protein according to any one of claims 39-44.

46. The polyspecific protein according to claim 43, wherein the first component comprises six CDRs, including one of the following sequence sets: 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 second component that specifically binds to ICAM1 includes a heavy chain containing complementarity-determining regions CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 of the heavy chain are the following set of sequences: CDR1: CDR2: CDR3 (SEQ ID NO: 208: 209: 210); CDR1: CDR2: CDR3 (SEQ ID NO: 211:212:213); CDR1: CDR2: CDR3 (SEQ ID NO: 214: 215: 216); CDR1: CDR2: CDR3 (SEQ ID NO: 217: 218: 219); CDR1: CDR2: CDR3 (SEQ ID NO: 214: 220: 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: 229: 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: 242: 243); CDR1: CDR2: CDR3 (SEQ ID NO: 241: 244: 245); CDR1: CDR2: CDR3 (SEQ ID NO: 241: 246: 245); CDR1: CDR2: CDR3 (SEQ ID NO: 247; SEQ ID NO: 248; SEQ ID NO: 249); CDR1: CDR2: CDR3 (SEQ ID NO: 250: 251: 252); and, CDR1: CDR2: A polyspecific protein according to any one of claims 1 to 46, comprising a sequence selected from the group consisting of CDR3 (SEQ ID NO: 404: SEQ ID NO: 405: SEQ ID NO: 406).

48. The polyspecific protein according to claim 47, wherein the heavy chains CDR1, CDR2, and CDR3 comprise the following sequences: CDR1: CDR2: CDR3 (SEQ ID NO: 228: SEQ ID NO: 220: SEQ ID NO: 231).

49. The polyspecific protein according to claim 47, wherein the heavy chains CDR1, CDR2, and CDR3 comprise the following sequence: CDR1:CDR2:CDR3 (SEQ ID NO: 222:SEQ ID NO: 223:SEQ ID NO: 224).

50. The polyspecific protein according to claim 47, wherein the heavy chain CDR1, CDR2, and CDR3 comprises the following sequence set: CDR1:CDR2:CDR3 (SEQ ID NO: 232:SEQ ID NO: 229:SEQ ID NO: 233).

51. The polyspecific protein according to claim 45, wherein the heavy chain CDR1, CDR2, and CDR3 comprises the following sequence set: CDR1:CDR2:CDR3 (SEQ ID NO: 404:SEQ ID NO: 405:SEQ ID NO: 406).

52. The second component that specifically binds to ICAM1 includes a light chain containing complementarity-determining regions CDR1, CDR2, and CDR3, where CDR1, CDR2, and CDR3 of the light chain are the following set of sequences: CDR1: CDR2: CDR3 (SEQ ID NO: 253: 254: 255); CDR1: CDR2: CDR3 (SEQ ID NO: 256; SEQ ID NO: 257; SEQ ID NO: 258); CDR1: CDR2: CDR3 (SEQ ID NO: 259: 260: 261); CDR1: CDR2: CDR3 (SEQ ID NO: 262: 263: 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: 275: 276); CDR1: CDR2: CDR3 (SEQ ID NO: 277; SEQ ID NO: 275; SEQ ID NO: 278); CDR1: CDR2: CDR3 (SEQ ID NO: 279: 280: 281); CDR1: CDR2: CDR3 (SEQ ID NO: 282; SEQ ID NO: 283; SEQ ID NO: 284); CDR1: CDR2: CDR3 (SEQ ID NO: 62: 63: 64); and, CDR1: CDR2: A polyspecific protein according to any one of claims 1 to 51, comprising a set of sequences selected from the group consisting of CDR3 (SEQ ID NO: 407: SEQ ID NO: 408: SEQ ID NO: 409).

53. The polyspecific protein according to claim 51, wherein the light chain CDR1, CDR2, and CDR3 comprise the following sequence set: CDR1:CDR2:CDR3 (SEQ ID NO: 270:SEQ ID NO: 260:SEQ ID NO: 271).

54. The polyspecific protein according to claim 51, wherein the light chain CDR1, CDR2, and CDR3 comprise the following sequence set: CDR1:CDR2:CDR3 (SEQ ID NO: 267:SEQ ID NO: 263:SEQ ID NO: 264).

55. The polyspecific protein according to claim 51, wherein the light chain CDR1, CDR2, and CDR3 comprise the following sequence set: CDR1:CDR2:CDR3 (SEQ ID NO: 259:SEQ ID NO: 273:SEQ ID NO: 266).

56. The polyspecific protein according to claim 51, wherein the light chain CDR1, CDR2, and CDR3 comprises the following sequence set: (i) CDR1:CDR2:CDR3 (SEQ ID NO: 407:SEQ ID NO: 408:SEQ ID NO: 409).

57. The second component is the following set of sequences: 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)(Sequence ID 211:Sequence ID 212:Sequence ID 213)-(Sequence ID 256:Sequence ID 257:Sequence ID 258); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NO: 214:SEQ ID NO: 215:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID NO: 224)-(SEQ ID NO: 268:SEQ ID NO: 263:SEQ ID NO: 264); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(Sequence ID 222:Sequence ID 223:Sequence ID 226)-(Sequence ID 268:Sequence ID 263:Sequence ID 264); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NO: 222:SEQ ID NO: 227:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID 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:SEQ ID NO: 252)-(SEQ ID NO: 62:SEQ ID NO: 63:SEQ ID NO: 64); and, A polyspecific protein according to claim 47-56, comprising six CDRs, each containing a set of sequences selected from the group consisting of 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).

58. The polyspecific protein according to claim 57, wherein the second component comprises six CDRs including the following sequence: 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).

59. The polyspecific protein according to claim 57, wherein the second component comprises six CDRs including the following sequence: 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).

60. The polyspecific protein according to claim 57, wherein the second component comprises six CDRs including the following sequence: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NO: 232:SEQ ID NO: 229:SEQ ID NO: 233)-(SEQ ID NO: 259:SEQ ID NO: 273:SEQ ID NO: 266).

61. The polyspecific protein according to claim 57, wherein the second component comprises six CDRs including the following sequence set: 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).

62. The polyspecific protein according to any one of claims 35-61, wherein the first component comprises a variable heavy chain domain, and the variable heavy chain domain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 104-129.

63. The polyspecific protein according to any one of claims 35-62, wherein the first component comprises a variable light chain domain, and the variable light chain domain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 130-155.

64. The polyspecific protein according to any one of claims 47-63, wherein the second component comprises a variable heavy chain domain, and the variable heavy chain domain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 288-309.

65. The polyspecific protein according to any one of claims 47-64, wherein the second component comprises a variable light chain domain, and the variable light chain domain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 310-326.

66. The polyspecific protein according to any one of claims 1 to 65, wherein the first component that specifically binds to CD38 comprises a full-length antibody including a light chain and a heavy chain, wherein the heavy chain includes a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 156-181.

67. The polyspecific protein according to claim 66, wherein the light chain contains a sequence that is at least about 90% identical to a sequence selected from the group consisting of sequence numbers 182-207.

68. The polyspecific protein according to any one of claims 1 to 67, wherein the second component that specifically binds to ICAM1 comprises a full-length antibody including a light chain and a heavy chain, wherein the heavy chain includes a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 328-349.

69. The polyspecific protein according to claim 68, wherein the light chain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of sequence numbers 183 and 350-366.

70. A polyspecific protein comprising a heavy chain polypeptide (HC) containing VH and a light chain polypeptide (LC) containing VL, wherein the heavy chain polypeptide and the light chain polypeptide are the following sequence sets: 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: A polyspecific protein containing sequences that are at least approximately 90% identical to sequences selected from LC (Sequence ID 386:Sequence ID 394).

71. A polyspecific protein comprising a first heavy chain polypeptide (HC1), a light chain polypeptide (LC), and a second heavy chain polypeptide (HC2), where HC1, LC, and HC2 are the following sequence sets: 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, A polyspecific protein containing a sequence that is at least approximately 90% identical to a sequence selected from the group consisting of HC1:LC:HC2 (SEQ ID NO: 156:SEQ ID NO: 182:SEQ ID NO: 383).

72. A polyspecific 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), wherein HC1, LC1, HC2, and LC2 are the following sequence set: HC1:LC1:HC2:HC3 (SEQ ID NO: 390:SEQ ID NO: 189:SEQ ID NO: 348:SEQ ID NO: 189); HC1:LC1:HC2:HC3 (SEQ ID NO: 390:SEQ ID NO: 189:SEQ ID NO: 349:SEQ ID NO: 189); HC1:LC1:HC2:HC3 (SEQ ID NO: 391:SEQ ID NO: 186:SEQ ID NO: 348:SEQ ID NO: 186); and, A polyspecific protein containing a sequence that is at least approximately 90% identical to a sequence selected from the group consisting of HC1:LC1:HC2:HC3 (SEQ ID NO: 391:SEQ ID NO: 186:SEQ ID NO: 349:SEQ ID NO: 186).

73. A polyspecific protein comprising a heavy chain sequence that is at least approximately 95% identical to the sequence described in SEQ ID NO: 410, and a light chain sequence that is at least approximately 95% identical to the sequence described in SEQ ID NO:

411.

74. The heavy chain comprises CDR1, CDR2, and CDR3, where CDR1 has the sequence of SEQ ID NO: 412 (GFSLSZ １ Z ２ AMG), CDR2 has the sequence of SEQ ID NO: 413 (GIIGSSZ ３ Z ４ TYYAZ ５ WAKG), and CDR3 has the sequence of SEQ ID NO: 414 (VRDPYDSZ ６ Z ７ Z ８ Z ９ YRL), the multispecific protein according to claim 73.

75. The light chain comprises CDR1, CDR2, and CDR3, where CDR1 is sequence number 415 (QASZ １０ Z １１ IYZ １２ YZ １３ Z １４ ) has the sequence, and CDR2 is sequence number 416 (DASKZ １５ The sequence AS is present, and CDR3 is sequence number 417 (QQAYSSZ １６ Z １７ Z １８ DNZ １９ The polyspecific protein according to claim 73 or 74, having the sequence of ).

76. Z １ It is serine or threonine; Z ２ is histidine or tyrosine; Z ３ It is aspartic acid or glycine; Z ４ It is arginine or serine; Z ５ It is serine or threonine; Z ６ It is phenylalanine or tyrosine; Z ７ It is aspartic acid or glycine; Z ８ It is aspartic acid or alanine; Z ９ It is glycine or alanine; Z １０ It is glutamine or glutamic acid; Z １１ It is serine or asparagine; Z １２ It is serine or arginine; Z １３ It is cysteine ​​or leucine; Z １４ It is serine or leucine; Z １５ It is valine or leucine; Z １６ It is serine or glycine; Z １７ It is serine or asparagine; Z １８ is valine or isoleucine; and, Z １９ The polyspecific protein according to claim 74 or 75, wherein is valine or alanine.

77. The multispecific protein according to any one of claims 15-76, wherein the multispecific protein induces an enhanced ADCC effect on target cells compared to antigen-dependent cell cytotoxicity (ADCC) induced on target cells by the same multispecific protein that does not contain an afucosylated Fc region.

78. The multispecific protein induces an enhanced ADCC effect on target cells compared to the ADCC effect induced on target cells by the same multispecific protein that does not contain an Fc region with mutations at positions corresponding to human IgG1 positions 239, 332, and 330, wherein the mutations are S239D, I332E, and A330L, and the amino acid numbering is according to the EU index of Kabat et al., according to any one of claims 17-77.

79. The amount of the multispecific protein that binds to cells expressing CD38 and ICAM1 is higher than the amount of the monospecific protein containing a first component that binds to CD38 that binds to cells, wherein the binding to cells is measured by flow cytometry, according to any one of claims 1 to 78.

80. The multispecific protein according to any one of claims 1 to 79, wherein the multispecific protein induces an enhanced ADCC effect on target cells compared to an ADCC effect induced on target cells by a single-specific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1.

81. The multispecific protein according to any one of claims 1 to 80, wherein the multispecific protein induces an enhanced CDC effect on target cells compared to a CDC effect induced on target cells by a single-specific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1.

82. The multispecific protein according to any one of claims 1 to 81, wherein the multispecific protein binds to target cells expressing CD38 and ICAM1 with enhanced affinity compared to a single-specific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1.

83. The polyspecific protein according to claim 82, wherein 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.

84. The polyspecific protein according to claim 82, wherein the ratio of ICAM1 to CD38 on the surface of cells is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raj cells.

85. The multispecific protein according to any one of claims 1 to 84, which induces an enhanced ADCC effect on target cells expressing ICAM1 in relation to CD38, compared to an ADCC effect induced on target cells by a single-specific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1.

86. The multispecific protein according to claim 85, wherein the cell expresses at least 5,000, 10,000, 150,000, 20,000, 30,000, 50,000, 100,000, 150,000, 200,000, 250,000, 300,000, 400,000, or 500,000 ICAM1 protein on its surface.

87. The multispecific protein according to claim 86, wherein the cell expresses at least 50,000 ICAM1 proteins on its surface.

88. The polyspecific protein according to any one of claims 85-87, wherein the cell expresses at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on its surface.

89. The multispecific protein according to claim 88, wherein the cell expresses at least 300 CD38 proteins on its surface.

90. Cells express approximately 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 their surface.

91. The multispecific protein according to claim 90, wherein the cell expresses fewer than approximately 350,000 CD38 proteins on its surface.

92. The polyspecific protein according to any one of claims 85-91, wherein the ratio of ICAM1 to CD38 on the cell surface is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200.

93. The polyspecific protein according to claim 92, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1.

94. The multispecific protein according to claim 92, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least about 10.

95. The multispecific protein according to any one of claims 85-94, wherein the cell expresses at least the same amount of ICAM1 on its surface as NCI-H2291 cells.

96. The polyspecific protein according to any one of claims 85-95, wherein the cell expresses at least the same amount of CD38 on its surface as NCI-H2342 cells.

97. The multispecific protein according to any one of claims 85-96, wherein the cell expresses less CD38 on its surface than Daudi cells.

98. The polyspecific protein according to any one of claims 85 to 97, wherein the ratio of ICAM1 to CD38 on the surface of cells is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raj cells.

99. The multispecific protein according to any one of claims 1 to 98, which induces an enhanced complement-dependent cytotoxicity (CDC) effect on target cells expressing CD38 and ICAM1, compared to a complement-dependent cytotoxicity (CDC) effect induced on target cells by a single-specific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1.

100. The polyspecific protein according to claim 99, wherein 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.

101. The polyspecific protein according to claim 99, wherein the ratio of ICAM1 to CD38 on the surface of cells is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raj cells.

102. The multispecific protein according to any one of claims 1 to 101, which induces an enhanced apoptotic effect on target cells expressing CD38 and ICAM1, compared to an apoptotic effect induced on target cells by a single-specific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1.

103. The polyspecific protein according to claim 102, wherein 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.

104. The polyspecific protein according to claim 102, wherein the ratio of ICAM to CD38 on the surface of cells is greater than or equal to the ratio of ICAM1 to CD38 on the surface of Raj cells.

105. The multispecific protein according to any one of claims 1-104, wherein the multispecific protein has a reduced ability to kill NK (natural killer) cells in a population of fresh peripheral blood mononuclear cells compared to a single-specific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1.

106. The polyspecific protein according to any one of claims 1-105, wherein the first component binds to human CD38 at a KD of about 0.15 nM to about 64 nM, as determined by surface plasmon resonance.

107. The multispecific protein according to claim 106, wherein the first component binds to human CD38 at a KD of about 0.42 nM to about 13.14 nM, as determined by surface plasmon resonance.

108. The multispecific protein according to claim 106, wherein the first component binds to human CD38 at a KD of about 0.15 nM to about 0.45 nM, as determined by surface plasmon resonance.

109. The polyspecific protein according to any one of claims 1-108, wherein the second component binds to human ICAM1 at a KD of about 0.2 nM to about 24.4 nM, as determined by surface plasmon resonance.

110. The polyspecific protein according to claim 109, wherein the second component binds to human ICAM1 at a KD of about 0.2 nM to about 0.6 nM, as determined by surface plasmon resonance.

111. A pharmaceutical composition comprising a multispecific protein according to any one of claims 1 to 110.

112. The pharmaceutical composition according to claim 111, further comprising a pharmaceutically acceptable carrier, excipient, or any combination thereof.

113. A method for killing cells in a subject, comprising the step of administering to a subject any one of the polyspecific proteins of claims 1 to 110 or the pharmaceutical composition of claim 111 or 112, wherein the cells express CD38 and ICAM1.

114. The method according to claim 113, wherein the cells are lysed.

115. The method according to claim 113 or 114, wherein the cells are tumor cells.

116. A method for treating cancer in a subject, comprising the step of administering to a subject any one of the polyspecific proteins of claims 1 to 110 or the pharmaceutical composition of claim 111 or 112, wherein the cancer comprises cells expressing CD38 and ICAM1.

117. The method according to claim 116, wherein the cancer includes solid tumors or hematological malignancies.

118. The method according to claim 117, wherein cancer includes hematological malignancies.

119. The method according to claim 118, wherein the hematological malignancy is multiple myeloma, leukemia, non-Hodgkin lymphoma, or Hodgkin lymphoma.

120. The method according to claim 116, wherein the cancer is lung cancer or prostate cancer.

121. The method according to any one of claims 113-120, wherein the cells express at least the same amount of ICAM1 on their surface as NCI-H2291 cells.

122. The method according to claim 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 claims 113-122, wherein the cells express less CD38 on their surface than Daudi cells.

124. The method according to claim 123, wherein the amount of CD38 on the cell surface is less than or equal to the amount of CD38 on the surface of Raj cells.

125. The method according to any one of claims 113 to 124, 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 Daudi cells.

126. The method according to claim 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 Razi cells.

127. The method according to any one of claims 113-126, wherein the cells express at least 5,000, 10,000, 150,000, 20,000, 30,000, 50,000, 100,000, 150,000, 200,000, 250,000, 300,000, 400,000, or 500,000 ICAM1 protein on their surface.

128. The method according to claim 127, wherein the cells express at least 50,000 ICAM1 proteins on their surface.

129. The method according to any one of claims 113-128, wherein the cells express at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 units of CD38 protein on their surface.

130. The method according to claim 129, wherein the cells express at least 300 CD38 proteins on their surface.

131. The method according to claim 129 or 130, wherein the cells express about 350,000, about 300,000, about 250,000, about 200,000, about 150,000, about 100,000, about 50,000, about 30,000, about 20,000, about 15,000, about 10,000, or about 5,000 CD38 proteins on their surface.

132. The method according to claim 131, wherein the cells express fewer than approximately 350,000 CD38 proteins on their surface.

133. The method according to any one of claims 113-132, wherein 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.

134. The method according to claim 133, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1.

135. The method according to claim 133, wherein the ratio of ICAM1 to CD38 on the surface of the cell is at least about 10.

136. The method according to any one of claims 113-135, further comprising the step of administering an additional therapeutic agent.

137. The method according to claim 136, wherein the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapy agent, a targeted therapy agent, a hormone-based therapy agent, a stem cell-based therapy agent, or radiation.

138. The method according to claim 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 claims 136-138, wherein the additional therapeutic agent and the multispecific protein are administered simultaneously.

140. The method according to any one of claims 136-139, wherein additional therapeutic agents and multispecific proteins are administered sequentially.

141. The method according to any one of claims 136-140, wherein the subject has received prior treatment.

142. The method according to claim 141, wherein the prior treatment comprises proteasome inhibitor (PI) therapy and immunomodulatory agents.

143. The method according to any one of claims 136-142, wherein the subject is dually resistant to proteasome inhibitor (PI) therapy and to therapy comprising an immunomodulator.

144. The method according to any one of claims 136-143, wherein the subject is a human being.

145. A kit comprising any one of the multispecific proteins of claims 1 to 110 or the pharmaceutical composition of claim 111 or 112.

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