CD38 and ICAM1 Antibodies and Their Uses

Abstract

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

Description

[Technical Field]

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

[0002] Sequence Listing This application contains a Sequence Listing, which has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The 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 CD38-expressing cancers. Anti-CD38 antibodies are thought to kill cancer cells by various mechanisms, including antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. One such antibody, daratumumab, has been approved for the treatment of adults with multiple myeloma. Decreased CD38 expression can limit the effectiveness of anti-CD38 antibodies. Suggestions to overcome this limitation include treatment with antibodies with higher affinity for CD38, treatment with antibodies that bind to different epitopes on CD38, treatment with antibodies that more effectively inhibit CD38 enzymatic activity, treatment with tetravalent anti-CD38 antibodies, and simultaneous treatment with all-trans retinoic acid to increase CD38 expression.

[0004] Incorporation by Reference All publications, patents, and patent applications herein are incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event of a conflict between the terms of this specification and the terms of the cited documents, the terms of this specification shall control. Summary of the Invention

[0005] One embodiment provides a multispecific protein comprising a first component that specifically binds to CD38 and a second component that specifically binds to ICAM1. In some embodiments, the multispecific protein is bivalent, trivalent, or tetravalent. In some embodiments, the first component comprises an antibody or antigen-binding fragment thereof that specifically binds to CD38. In some embodiments, the second component comprises an antibody or antigen-binding fragment thereof that specifically binds to ICAM1. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to CD38 comprises an IgG heavy chain variable domain and an IgG light chain variable domain. In some embodiments, the antibody or antigen-binding fragment thereof that specifically binds to ICAM1 comprises an IgG heavy chain variable domain and an IgG light chain variable domain. In some embodiments, the multispecific protein further comprises an Fc region. In some embodiments, the Fc region comprises a heterodimeric Fc region. In some embodiments, the Fc region comprises one or more mutations that increase the half-life of the multispecific protein. In some embodiments, the Fc region comprises one or more stabilizing mutations. In some embodiments, the Fc region comprises one or more mutations that modulate interaction with an Fc receptor.

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

[0007] In some embodiments, the first component comprises an anti-CD38 IgG, and the second component comprises two anti-ICAM1 variable heavy domains and two anti-ICAM-1 variable light domains, and each of the variable heavy domains of the anti-CD38 IgG is fused to one of the anti-ICAM1 variable heavy domains, and each of the variable light domains of the anti-CD38 IgG is fused to one of the anti-ICAM1 variable light 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 an anti-CD38 Fab. In some embodiments, the monovalent anti-ICAM1 antibody or antigen-binding fragment comprises an anti-ICAM1 scFv. In some embodiments, the multispecific protein comprises an anti-CD38 Fab, an anti-ICAM1 scFv, and an Fc region. In some embodiments, the Fc region is a heterodimeric Fc region comprising a KIH structure. In some embodiments, the monovalent anti-CD38 antibody or antigen-binding fragment thereof comprises one variable heavy domain (VH) and one variable light domain (VL), and the monovalent anti-ICAM1 antibody or antigen-binding fragment thereof comprises one variable heavy domain (VH).

[0008] In some embodiments, the multispecific protein further comprises an Fc region. In some embodiments, the Fc region is a heterodimeric Fc region comprising a KIH structure, and the multispecific protein is in the general light chain bispecific format. In some embodiments, the first component that specifically binds to CD38 comprises a heavy chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein CDR1, CDR2, and CDR3 of the heavy chain are selected from 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:SEQ ID NO:15:SEQ ID NO:16); CDR1:CDR2:CDR3 (SEQ ID NO:17:SEQ ID NO:18:SEQ ID NO:19); CDR1:CDR2:CDR3 (SEQ ID NO:20:SEQ ID NO:21:SEQ ID NO:22); CDR1:CDR2:CDR3 (SEQ ID NO:23:SEQ ID NO:24:SEQ ID NO:25); CDR1:CDR2:CDR3 (SEQ ID NO:26:SEQ ID NO:27:SEQ ID NO:28); CDR1:CDR2:CDR3 (SEQ ID NO:29:SEQ ID NO:30:SEQ ID NO:31); CDR1:CDR2:CDR3 (SEQ ID NO:32:SEQ ID NO:33:SEQ ID NO:34); CDR1:CDR2:CDR3 (SEQ ID NO:35:SEQ ID NO:36:SEQ ID NO:37); CDR1:CDR2:CDR3 (SEQ ID NO:38:SEQ ID NO:39:SEQ ID NO:40); CDR1:CDR2:CDR3 (SEQ ID NO:41:SEQ ID NO:42:SEQ ID NO:43); CDR1:CDR2:CDR3 (SEQ ID NO:44:SEQ ID NO:45:SEQ ID NO:46); CDR1:CDR2:CDR3 (SEQ ID NO:47:SEQ ID NO:48:SEQ ID NO:49); CDR1:CDR2:CDR3 (SEQ ID NO:50:SEQ ID NO:51:SEQ ID NO:52); CDR1:CDR2:CDR3 (SEQ ID NO:53:SEQ ID NO:54:SEQ ID NO:55); CDR1:CDR2:CDR3 (SEQ ID NO:56:SEQ ID NO:57:SEQ ID NO:58); and It comprises a set of sequences selected from the group consisting of CDR1:CDR2:CDR3 (SEQ ID NO:59:SEQ ID NO:60:SEQ ID NO:61).

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

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

[0011] In some embodiments, the first component comprises 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 It contains six CDRs comprising the sequence described in any one of HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID NO:56:SEQ ID NO:57:SEQ ID NO:58)-(SEQ ID NO:102:SEQ ID NO:84:SEQ ID NO:103).

[0012] In some embodiments, the first component comprises six CDRs comprising the following set of sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID NO:14: SEQ ID NO:15: SEQ ID NO:16)-(SEQ ID NO:68: SEQ ID NO:69: SEQ ID NO:70). In some embodiments, the first component comprises six CDRs comprising the following set of sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID NO:17: SEQ ID NO:18: SEQ ID NO:19)-(SEQ ID NO:71: SEQ ID NO:72: SEQ ID NO:73). In some embodiments, the first component comprises six CDRs comprising one of the following sets of sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID NO:1: SEQ ID NO:2: SEQ ID NO:7)-(SEQ ID NO:62: SEQ ID NO:63: SEQ ID NO:64).

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

[0014] In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the second component comprise the following sequences: CDR1:CDR2:CDR3 (SEQ ID NO:228: SEQ ID NO:229: SEQ ID NO:230). In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the second component comprise the following sequences: CDR1:CDR2:CDR3 (SEQ ID NO:222: SEQ ID NO:223: SEQ ID NO:224). In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the second component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID NO:232: SEQ ID NO:229: SEQ ID NO:233). In some embodiments, the CDR1, CDR2, and CDR3 of the heavy chain of the second component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID NO:404: SEQ ID NO:405: SEQ ID NO:406).

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

[0016] In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the second component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID NO:270:SEQ ID NO:260:SEQ ID NO:271). In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the second component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID NO:267:SEQ ID NO:263:SEQ ID NO:264). In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the second component comprise the following set of sequences: CDR1:CDR2:CDR3 (SEQ ID NO:259:SEQ ID NO:273:SEQ ID NO:266). In some embodiments, the CDR1, CDR2, and CDR3 of the light chain of the second component comprise the following set of sequences: (I) CDR1:CDR2:CDR3 (SEQ ID NO:407:SEQ ID NO:408:SEQ ID NO:409). In some embodiments, the second component comprises 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)(SEQ ID NO:211:SEQ ID NO:212:SEQ ID NO:213)-(SEQ ID NO:256:SEQ ID NO:257:SEQ ID NO:258); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NO:214:SEQ ID NO:215: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)(SEQ ID NO:222:SEQ ID NO:223:SEQ ID NO:226)-(SEQ ID NO:268:SEQ ID NO:263:SEQ ID NO:264); HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3)(SEQ ID NO:222:SEQ ID NO:227: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 It contains six CDRs comprising 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).

[0017] In some embodiments, the second component comprises six CDRs comprising the following sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID NO:228: SEQ ID NO:229: SEQ ID NO:230)-(SEQ ID NO:270: SEQ ID NO:260: SEQ ID NO:271). In some embodiments, the second component comprises six CDRs comprising the following sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID NO:222: SEQ ID NO:223: SEQ ID NO:224)-(SEQ ID NO:267: SEQ ID NO:263: SEQ ID NO:264). In some embodiments, the second component comprises six CDRs comprising the following sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3) (SEQ ID NO:232: SEQ ID NO:229: SEQ ID NO:233)-(SEQ ID NO:259: SEQ ID NO:273: SEQ ID NO:266). In some embodiments, the second component comprises six CDRs comprising the following set of sequences: HC(CDR1:CDR2:CDR3)-LC(CDR1:CDR2:CDR3 (SEQ ID NO:404: SEQ ID NO:405: SEQ ID NO:406)-(SEQ ID NO:407: SEQ ID NO:408: SEQ ID NO:409). In some embodiments, the first component comprises a variable heavy chain domain, and 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the first component that specifically binds to CD38 comprises a full-length antibody comprising a light chain and a heavy chain, wherein the heavy chain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 156-181.In some embodiments, the light chain comprises a sequence at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 182-207. In some embodiments, the second component that specifically binds to ICAM1 comprises a full-length antibody comprising a light chain and a heavy chain, wherein the heavy chain comprises a sequence at least about 90% identical to a sequence selected from the group consisting of SEQ ID NOs: 328-349. In some embodiments, the light chain comprises a sequence 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 multispecific protein comprising a heavy chain polypeptide (HC) comprising a VH and a light chain polypeptide (LC) comprising a VL, wherein the heavy and light chain polypeptides are selected from the following set of sequences: HC:LC (SEQ ID NO:160:SEQ ID NO:397); HC:LC (SEQ ID NO:389:SEQ ID NO:186); HC:LC (SEQ ID NO:163:SEQ ID NO:395); HC:LC (SEQ ID NO:387:SEQ ID NO:189); HC:LC (SEQ ID NO:164:SEQ ID NO:396); HC:LC (SEQ ID NO:388:SEQ ID NO:190); HC:LC (SEQ ID NO:156:SEQ ID NO:393); HC:LC (SEQ ID NO:384:SEQ ID NO:182); HC:LC (SEQ ID NO:385:SEQ ID NO:182); and HC:LC (SEQ ID NO:386:SEQ ID NO:394).

[0019] One embodiment provides a multispecific protein comprising a first heavy chain polypeptide (HC1), a light chain polypeptide (LC), and a second heavy chain polypeptide (HC2), wherein the HC1, LC, and HC2 have 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 present invention includes a sequence that is at least about 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).

[0020] One embodiment provides a multispecific protein comprising a first heavy chain polypeptide (HC1), a first light chain polypeptide (LC1), a second heavy chain polypeptide (HC2), and a second light chain polypeptide (LC2), and wherein the HC1, LC1, HC2, and LC2 are selected from 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 present invention includes a sequence that is at least about 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).

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

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

[0024] In some embodiments, the multispecific protein elicits an enhanced ADCC effect on target cells compared to the ADCC elicited on target cells by the same multispecific protein that does not include an Fc region comprising mutations at positions corresponding to positions 239, 332, and 330 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.

[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 that binds to the cells, wherein the binding to the cells is measured by flow cytometry. In some embodiments, the multispecific protein induces an enhanced ADCC effect on the target cells compared to the ADCC effect on the target cells caused by a monospecific protein that comprises 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 the target cells compared to the CDC effect on the target cells caused by a monospecific protein that comprises 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 that comprises a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is equal to or greater than the ratio of ICAM1 to CD38 on the surface of a Raji cell. In some embodiments, the multispecific protein elicits an enhanced ADCC effect on target cells expressing ICAM1 relative to CD38, compared to the ADCC effect elicited on the target cells by a monospecific protein comprising a first component that specifically binds CD38 or a second component that specifically binds ICAM1. In some embodiments, 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 proteins on their surface, hi some embodiments, the cells express at least 50,000 ICAM1 proteins on their surface.In some embodiments, the cells express at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on their surface. In some embodiments, the cells express at least 300 CD38 proteins on their surface. In some embodiments, the cells express less than about 350,000, less than about 300,000, less than about 250,000, less than about 200,000, less than about 150,000, less than about 100,000, less than about 50,000, less than about 30,000, less than about 20,000, less than about 15,000, less than about 10,000, or less than about 5,000 CD38 proteins on their surface. In some embodiments, the cells express less than about 350,000 CD38 proteins on their surface. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1. The ratio of ICAM1 to CD38 on the surface of the cell is at least about 10. In some embodiments, the cell expresses at least as much ICAM1 on its surface as NCI-H2291 cells. In some embodiments, the cell expresses at least as much CD38 on its surface as NCI-H2342 cells. In some embodiments, the cell expresses less CD38 on its surface than Daudi cells. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is equal to or greater than the ratio of ICAM1 to CD38 on the surface of Raji cells. In some embodiments, the multispecific protein elicits an enhanced complement-dependent cytotoxicity (CDC) effect on target cells expressing CD38 and ICAM 1, compared to the CDC effect elicited on the target cells by a monospecific protein comprising a first component that specifically binds CD38 or a second component that specifically binds ICAM 1. In some embodiments, the ratio of ICAM 1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200.In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is equal to or greater than the ratio of ICAM1 to CD38 on the surface of Raji cells. In some embodiments, the multispecific protein induces an enhanced apoptotic effect on target cells expressing CD38 and ICAM1 compared to the apoptotic effect on target cells by a monospecific protein comprising a first component that specifically binds CD38 or a second component that specifically binds ICAM1. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is equal to or greater than the ratio of ICAM1 to CD38 on the surface of Raji cells. In some embodiments, the multispecific protein exhibits a reduced ability to kill NK (natural killer) cells in a population of fresh peripheral blood mononuclear cells compared to a monospecific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1, relative to the apoptotic effect caused on target cells compared to a monospecific protein comprising a first component that specifically binds to CD38 or a second component that specifically binds to ICAM1. In some embodiments, the first component binds to human CD38 with a KD of about 0.15 nM to about 64 nM, as determined by surface plasmon resonance. In some embodiments, the first component binds to human CD38 with a KD of about 0.42 nM to about 13.14 nM, as determined by surface plasmon resonance. In some embodiments, the first component binds to human CD38 with a KD of about 0.15 nM to about 0.45 nM, as determined by surface plasmon resonance. In some embodiments, the second component binds to human ICAM1 with a KD of about 0.2 nM to about 24.4 nM, as determined by surface plasmon resonance. In some embodiments, the second component binds to human ICAM1 with 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 a multispecific protein of the present disclosure. In some embodiments, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, or any combination thereof.

[0027] One embodiment provides a method of killing cells in a subject, comprising administering a multispecific protein of this disclosure or a pharmaceutical composition of this disclosure to the subject, 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 of treating cancer in a subject, comprising administering a multispecific protein of this disclosure or a pharmaceutical composition of this disclosure to the subject, wherein the cancer comprises cells that express CD38 and ICAM1. In some embodiments, the cancer comprises a solid tumor or a hematological malignancy. In some embodiments, the cancer comprises a hematological malignancy. In some embodiments, the hematological malignancy is multiple myeloma, leukemia, non-Hodgkin's lymphoma, or Hodgkin's lymphoma. In some embodiments, the cancer is lung cancer or prostate cancer. In some embodiments, the cells express at least as much ICAM1 on their surface as NCI-H2291 cells. In some embodiments, the cells express at least as much CD38 on their surface as NCI-H2342 cells. In some embodiments, the cells express less CD38 on their surface than Daudi cells. In some embodiments, the amount of CD38 on the surface of the cells is equal to or less than 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 equal to or greater than the ratio of ICAM1 to CD38 on the surface of Daudi cells.

[0028] In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is equal to or greater than the ratio of ICAM1 to CD38 on the surface of Raji cells. In some embodiments, 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 proteins on its surface. In some embodiments, the cell expresses at least 50,000 ICAM1 proteins on its surface. In some embodiments, the cell expresses at least 100, 200, 300, 400, 500, 1,000, 2,000, 3,000, 4,000, or 5,000 CD38 proteins on its surface. In some embodiments, the cells express at least 300 CD38 proteins on their surface. In some embodiments, the cells express less than about 350,000, less than about 300,000, less than about 250,000, less than about 200,000, less than about 150,000, less than about 100,000, less than about 50,000, less than about 30,000, less than about 20,000, less than about 15,000, less than about 10,000, or less than about 5,000 CD38 proteins on their surface. In some embodiments, the cells express less than about 350,000 CD38 proteins on their surface. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cells is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1. The ratio of ICAM1 to CD38 on the surface of the cell is at least about 10. In some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapy, a hormone-based therapy, a stem cell-based therapy, or radiation. In some embodiments, the additional therapeutic agent comprises at least one of lenalidomide, dexamethasone, bortezomib, or any combination thereof. In some embodiments, the additional therapeutic agent and the multispecific protein are administered simultaneously.In some embodiments, the additional therapeutic agent and the multispecific protein are administered sequentially. In some embodiments, the subject has received a prior treatment. In some embodiments, the prior treatment comprises a proteasome inhibitor (PI) treatment and an immunomodulatory agent. In some embodiments, the subject is double refractory to treatment comprising a proteasome inhibitor (PI) treatment and an immunomodulatory agent. In some embodiments, the subject is human. One embodiment provides a kit comprising a multispecific protein according to the present disclosure or a pharmaceutical composition comprising the multispecific protein.

[0029] In certain embodiments, disclosed herein are anti-CD38 antibodies, anti-ICAM1 antibodies, pharmaceutical compositions comprising anti-CD38 antibodies and / or anti-ICAM1 antibodies, and methods of use for the treatment of proliferative diseases. In certain embodiments, also disclosed herein are multispecific antibodies (e.g., bispecific antibodies) comprising a first targeting moiety that specifically binds CD38 and a second targeting moiety that specifically binds ICAM1, pharmaceutical compositions comprising the multispecific antibodies, and methods of use for the treatment of proliferative diseases.

[0030] In certain embodiments, disclosed herein are bispecific antibodies comprising a first targeting moiety that specifically binds to CD38 or ICAM1 and comprising an enhanced complement-dependent cytotoxicity (CDC) effect compared to the CDC effect of the reference antibody daratumumab. Also as described herein, in certain embodiments, disclosed herein are bispecific antibodies comprising a first targeting moiety that specifically binds to CD38 or ICAM1 and comprising an enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) effect compared to the ADCC effect of the reference antibody daratumumab. Also as described herein, in certain embodiments, disclosed herein are bispecific antibodies comprising a first targeting moiety that specifically binds to CD38 or ICAM1 and comprising a reduced immune cell killing effect compared to the immune cell killing effect of the reference antibody daratumumab. In some embodiments, the bispecific antibody further comprises a second cell-targeting moiety that specifically binds to CD38 or ICAM1. In some embodiments, the enhanced CDC is at least 2-fold, 3-fold, 4-fold, or 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-fold, 3-fold, 4-fold, 5-fold, 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 about 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 binding fragment thereof.In some embodiments, the bivalent antibody or binding fragment thereof comprises 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 binding fragment thereof. In some embodiments, the monovalent antibody or binding fragment thereof comprises a Fab-scFv-Fc (KIH) format or Biclonics' common LC format. In some embodiments, the scFv portion of the bispecific antibody specifically binds to ICAM1. In some embodiments, the first targeting moiety specifically binds to CD38 and the second targeting moiety specifically binds to ICAM1. In some embodiments, the first targeting moiety comprises a KD of about 1 nM to about 100 nM. In some embodiments, the first targeting moiety comprises a KD of at least 1 nM, 2 nM, 3 nM, 3.15 nM, 3.2 nM, 3.39 nM, 3.5 nM, 4 nM, 4.5 nM, 5 nM, 5.32 nM, 5.5 nM, 6 nM, 6.5 nM, 7 nM, 7.5 nM, 8 nM, 8.5 nM, 9 nM, 9.5 nM, 10 nM, 15 nM, 18 nM, 20 nM, 25 nM, 30 nM, 35 nM, 40 nM, 45 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, or 100 nM. In some embodiments, the second targeting moiety comprises a KD of from about 0.1 to about 20 nM. In some embodiments, the second targeting moiety comprises about 0.15 nM, 0.2 nM, 0.24 nM, 0.25 nM, 0.29 nM, 0.3 nM, 0.4 nM, 0.5 nM, 0.6 nM, 0.7 nM, 0.8 nM, 0.9 nM, 1 nM, 1.5 nM, 1.72 nM, 2 nM, 2.28 nM, 2.5 nM, 3 nM, 3.5 nM, 4 nM, 4.5 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, or 20 nM. In some embodiments, the bispecific antibody causes apoptosis similar to that caused by the reference antibody daratumumab.In some embodiments, the first targeting moiety comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region has the CDR1 sequence X1GX2X3X4X5X6X7X8X9X. 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from P, S, or D; X4 is selected from F, L, or A; X5 is selected from D, G, S, N, or T; X6 is selected from V, A, T, R, S, I, or N; X7 is selected from Y, I, N, R, A, G, or D; X8 is selected from A, Y, D, G, W, C, or T; X9 is selected from M, V, I, W, D, or Y; 10 is selected from S, T, M, C, I, Y, A, or G; X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C, and said VH region comprises the CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 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 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 present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G, and said VH region comprises the CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 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 present or absent, if present, selected from F, Y, V, D, A, N, G, E, or L; X 42 is present or absent, and if present is selected from P, L, Y, F, G, or T; X 43 is present or absent, and if present is selected from T, P, F, V, N, Y, or S; X 44 is present or absent, and if present is selected from G, L, S, T, or F; X 45 is present or absent, and if present is selected from F, L, E, N, or S; X 46 is present or absent, and if present is selected from D, S, L, or R; X 47 is present or absent, and if present is selected from Y or L, and X 48 is either present or absent, and if present is D; and X 49 is present or absent, and if present is L. In some embodiments, the VH region comprises the CDR1 sequence GFPFX5X6YAMS, where X5 is selected from D or G; and X6 is selected from V, A, or T. In some embodiments, the VH region comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent, and if present is S; X2 is selected from F or I; X3 is selected from S or D; X4 is selected from L, F, or A; X5 is selected from S, N, or T; X6 is selected from R, S, N, I, or T; X7 is selected from Y, I, N, R, A, D, or G; X8 is selected from Y, D, G, A, W, T, or C; X9 is selected from V, M, I, W, Y, or D; 10 is selected from T, S, M, C, I, Y, A, or G; X 11 is present or absent, and if present is selected from C or M, and X 12is present or absent, and if present is C. In some embodiments, the VH region has the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 wherein X5 is selected from S or N; X6 is selected from R, S, or N; X7 is selected from Y, I, or N; X8 is selected from Y, D, G, or A; X9 is selected from V, M, or I; 10 is selected from T, S, or M; and X 11 is present or absent, and if present is C. In some embodiments, the VH region has the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 wherein X4 is selected from F or A; X5 is selected from S, T, or N; X6 is selected from S, T, or N; and X7 is selected from Y, R, A, or G. X8 is selected from W, Y, or C; X9 is selected from I, W, Y, or D; X 10 is selected from C, I, Y, or M; X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C. In some embodiments, the VH region has the CDR2 sequence AISGSGGSTX 22 YADSVKG, where X 22 is selected from F or Y. In some embodiments, the VH region comprises the CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 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 is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G. In some embodiments, the VH region comprises the CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 where X 13 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 is present or absent, and if present is G. In some embodiments, the VH region comprises the CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 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 is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G. In some embodiments, the VH region has the CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY, where X 38 is selected from A or G; and X 41 is selected from F or Y. In some embodiments, the VH region comprises 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 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 is present or absent and, if present, is selected from V, D, Y, A, N, G, L, or E; X 42 is present or absent, and if present is selected from L, Y, F, T, or G; X 43 is present or absent, and if present, is selected from P, F, V, N, S, or Y; X 44 is present or absent, and if present is selected from L, S, T, G, or F; X 45 is present or absent, and if present is selected from L, F, E, S, or N; X 46 is present or absent, and if present, is selected from S, L, or R; X 47 is either present or absent, and if present, is L, and X 48 is either present or absent, and if present is D; and X 49 is present or absent, and if present is L. In some embodiments, the VH region comprises the CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 where X 32 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 is present or absent, and if present is selected from P, F, V, or N; X 44 is present or absent, and if present is selected from L, S, or T; X 45 is present or absent and, if present, is selected from L or F. In some embodiments, the VH region comprises the CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 where X 33 is selected from R or G; X 34 is selected from E, D, or S; X 35 is selected from G, L, P, S, or A; X 36 is selected from D, S, or R; X 37 is selected from Y, T, N, or G; X 38 is selected from G, S, F, or L; X 39 is selected from A, G, S, or I; X 40 is selected from Y, N, or L; X 41 is present or absent, and if present is selected from V, Y, or E; X 42 is either present or absent, and if present, is G; X 43 is either present or absent, and if present, then Y; X 44 is either present or absent, and if present, it is F; X 45 is present or absent, and if present is selected from E or N; and X 46is present or absent, and if present, is selected from S or L. In some embodiments, the VH region has the CDR1 sequence GFPFX5X6YAMS and the CDR2 sequence AISGSGGSTX 22 YADSVKG, and CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY; wherein X5 is selected from D or G; X6 is selected from V, A, or T; 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 has 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 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; and X9 is V, M, or I. Selected from X 10 is selected from T, S, or M; X 11 is either present or absent, and if present, 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 is either present or absent, and if present, 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 is present or absent, and if present is selected from P, F, V, or N; X 44 is present or absent, and if present is selected from L, S, or T; X 45is present or absent and, if present, is selected from L or F. In some embodiments, the VH region has 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 the CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 wherein X4 is selected from F or A; X5 is selected from S, T, or N; X6 is selected from S, T, or N; X7 is selected from Y, R, A, or G; X8 is selected from W, Y, or C; X9 is selected from I, W, Y, or D; 10 is selected from C, I, Y, or M; X 11 is present or absent, and if present is selected from C or M, and X 12 is either present or absent, and if present, is C; X 13 is selected from A or S; X 15 is selected from I, L, or T; X 16 is selected from Y or V; X 17 is selected from S, T, or A; X 18 is selected from G, P, or V; X 19 is selected from D, S, or T; X 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 is present or absent, and if present is selected from G or K, and X 31 is either present or absent, and if present, 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 is present or absent, and if present is selected from V, Y, or E; X 42 is either present or absent, and if present, is G; X 43 is either present or absent, and if present, then Y; X 44 is either present or absent, and if present, it is F; X 45 is present or absent, and if present is selected from E or N; and X 46is present or absent, and if present, is selected from S or L. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from SEQ ID NOs: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 where X 32 is selected from A, G, or V; X 33 is selected from K, A, R, T, G, or S; X 34 is selected from R, A, V, T, P, I, E, D, or S; X 35 is selected from G, W, D, L, K, P, S, A, T, or R; X 36 is selected from T, P, A, Y, D, G, S, R, V, or E; X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I; X 38 is selected from G, A, S, D, K, F, L, or Y; X 39 is selected from Y, T, A, G, S, or I; X 40 is selected from S, Y, G, R, W, N, L, D, or F; X 41 is present or absent, if present, selected from F, Y, V, D, A, N, G, E, or L; X 42 is present or absent, and if present is selected from P, L, Y, F, G, or T; X 43is present or absent, and if present is selected from T, P, F, V, N, Y, or S; X 44 is present or absent, and if present is selected from G, L, S, T, or F; X 45 is present or absent, and if present is selected from F, L, E, N, or S; X 46 is present or absent, and if present is selected from D, S, L, or R; X 47 is present or absent, and if present is selected from Y or L, and X 48 is either present or absent, and if present is D; and X 49is present or absent, and, if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from SEQ ID NOs: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from SEQ ID NOs: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58.In some embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID 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 embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, 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. In some embodiments, the first targeting moiety comprises 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 second targeting moiety comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region has the CDR1 sequence X1X2X3X4X5X6X7X8X9X. 10 X 11 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; 10 is selected from S, G, N, M, or I; and X 11 is present or absent, and if present is C; said VH region comprises 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 where X 12 is selected from G, T, A, I, or Y; X 13 is selected from W, I, Y, or C; X 14 is selected from I, S, or Y; X 15 is selected from S, G, T, D, or P; X 16 is selected from F, S, D, T, or A; X 17 is selected from S, R, G, or D; X 18 is selected from G, D, or S; X 19 is selected from S, R, T, N, Y, A, D, or P; X 20 is selected from T, A, G, or Y; X 21 is selected from Y, H, A, S, or T; X 22 is selected from Y or N; X 23 is selected from A, P, Y, or S; X 24 is selected from S, T, N, D, Y, A, or P; X 25 is selected from W, S, A, or D; X 26 is selected from A, V, T, W, F, or S; X 27 is selected from K, W, A, Q, or V; X 28 is selected from G, A, or K; X 29 is present or absent and, if present, is selected from K or G; and X 30 is present or absent, and if present is G; and said VH region has a 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 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 is present or absent and, if present, is selected from Y, A, G, I, or D; X 42 is present or absent, and if present, is selected from I, Y, R, P, V, or G; X 43 is present or absent and, if present, is selected from L, R, Y, G, or A; X 44 is present or absent, and if present, is selected from N, L, S, Y, or W; X 45 is present or absent and, if present, is selected from L, Y, F, or C; X 46 is present or absent, and if present, is selected from D, A, or F; X 47 is present or absent, and if present, is selected from M, P, Y, or N; X 48 is present or absent, and if present is selected from D or L, and X 49is present or absent, and if present is L. In some embodiments, the VH region has the CDR1 sequence GFSLX5X6X7X8MX 10 wherein 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 is selected from S, G, or N. In some embodiments, the VH region has the CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG, where X 13 is selected from W, I, or Y; X 15 is selected from S or G; X 16 is selected from F, S, D, or T; X 17 is selected from S or R; X 18 is selected from G or D; X 19 is selected from S, R, T, or N; X 20 is selected from T or A; and X 24 is selected from S, T, or N. In some embodiments, the VH region comprises the CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 where X 31 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 is present or absent, and if present, is selected from L, Y, or F; X 46 is either present or absent, and if present, it is D; X 47 is present or absent, and if present is selected from M or P; X 48 is either present or absent, and if present is D; and X 49is present or absent, and, if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from 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. In some embodiments, 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 a CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 241, 247, and 250; a CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252. In some embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283; and a CDR3 sequence selected from SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284. In some embodiments, the second targeting moiety comprises a VH sequence selected from SEQ ID NOs: 289-309 and a VL sequence selected from SEQ ID NOs: 311-326 and 155.In some embodiments, the bispecific antibody comprises a humanized antibody or binding fragment thereof, or a chimeric antibody or binding fragment thereof. In some embodiments, the bispecific antibody comprises an IgG-scFv, a nanobody, a BiTE, a diabody, a DART, a TandAb, a scDiabody, a scDiabody-CH3, a triplebody, a miniantibody, a minibody, a TriBiminibody, a scFv-CH3 KIH, a Fab-scFv-Fc KIH, a Fab-scFv, a scFv-CH-CL-scFv, a F(ab')2, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a diabody-Fc, a tandem scFv-Fc, or an intrabody. In some embodiments, the bispecific antibody comprises an IgG1 framework sequence. In some embodiments, the bispecific antibody comprises an IgG2 framework sequence. In some embodiments, the bispecific antibody comprises an IgG4 framework sequence. In some embodiments, the bispecific antibody further comprises a payload. In some embodiments, the payload comprises a small molecule, peptide, or protein.

[0031] In certain embodiments, disclosed herein are anti-CD38 antibodies comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from P, S, or D; X4 is selected from F, L, or A; X5 is selected from D, G, S, N, or T; X6 is selected from V, A, T, R, S, I, or N; X7 is selected from Y, I, N, R, A, G, or D; X8 is selected from A, Y, D, G, W, C, or T; X9 is selected from M, V, I, W, D, or Y; 10 is selected from S, T, M, C, I, Y, A, or G; X 11 is present or absent, and if present is selected from C or M, and X 12is present or absent, and if present is C, and said VH region comprises the CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 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 S, I, L, T, or M; X 16 is selected from G, Y, S, T, L, or V; X 17 is selected from S, I, K, Y, T, G, or A; X 18 is selected from G, S, T, P, V, or Y; X 19 is selected from G, A, D, S, or T; X 20 is selected from S, T, I, N, or G; X 21 is selected from T, I, D, N, S, or A; X 22 is selected from F, Y, N, T, I, or S; X 23 is selected from Y, D, K, or I; X 24 is selected from A or Y; X 25 is selected from D, T, S, N, R, A, or Y; X 26 is selected from S, W, T, A, or N; X 27 is selected from V, A, W, N, or S; X 28 is selected from K, R, Q, A, or W; X 29 is selected from G, K, or A; X 30 is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G, and 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 where X 32 is selected from A, G, or V; X 33 is selected from K, A, R, T, G, or S; X 34 is selected from R, A, V, T, P, I, E, D, or S; X 35 is selected from G, W, D, L, K, P, S, A, T, or R; X 36 is selected from T, P, A, Y, D, G, S, R, V, or E; X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I; X 38 is selected from G, A, S, D, K, F, L, or Y; X 39 is selected from Y, T, A, G, S, or I; X 40 is selected from S, Y, G, R, W, N, L, D, or F; X 41 is present or absent, if present, selected from F, Y, V, D, A, N, G, E, or L; X 42 is present or absent, and if present is selected from P, L, Y, F, G, or T; X 43 is present or absent, and if present is selected from T, P, F, V, N, Y, or S; X 44 is present or absent, and if present is selected from G, L, S, T, or F; X 45 is present or absent, and if present is selected from F, L, E, N, or S; X 46 is present or absent, and if present is selected from D, S, L, or R; X 47 is present or absent, and if present is selected from Y or L, and X48 is either present or absent, and if present is D; and X 49 is present or absent, and if present is L. In some embodiments, the VH region comprises the CDR1 sequence GFPFX5X6YAMS, where X5 is selected from D or G; and X6 is selected from V, A, or T. In some embodiments, the VH region comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent, and if present is S; X2 is selected from F or I; X3 is selected from S or D; X4 is selected from L, F, or A; X5 is selected from S, N, or T; X6 is selected from R, S, N, I, or T; X7 is selected from Y, I, N, R, A, D, or G; X8 is selected from Y, D, G, A, W, T, or C; X9 is selected from V, M, I, W, Y, or D; 10 is selected from T, S, M, C, I, Y, A, or G; X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C. In some embodiments, the VH region has the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 wherein X5 is selected from S or N; X6 is selected from R, S, or N; X7 is selected from Y, I, or N; X8 is selected from Y, D, G, or A; X9 is selected from V, M, or I; 10 is selected from T, S, or M; and X 11 is present or absent, and if present is C. In some embodiments, the VH region has the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12wherein 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; 10 is selected from C, I, Y, or M; X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C. In some embodiments, the VH region has the CDR2 sequence AISGSGGSTX 22 YADSVKG, where X 22 is selected from F or Y. In some embodiments, the VH region comprises the CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 where X 13 is selected from A, G, or S; 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 is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G. In some embodiments, the VH region comprises the CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 where X 13 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 is present or absent, and if present is G. In some embodiments, the VH region comprises the CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 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, and or V; 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 is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G. In some embodiments, the VH region has the CDR3 sequence AKRGTYX 38 YSX 41PTGFDY, where X 38 is selected from A or G; and X 41 is selected from F or Y. In some embodiments, the VH region comprises 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 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 is present or absent and, if present, is selected from V, D, Y, A, N, G, L, or E; X 42 is present or absent, and if present is selected from L, Y, F, T, or G; X 43 is present or absent, and if present, is selected from P, F, V, N, S, or Y; X 44 is present or absent, and if present, is selected from L, S, T, G, F, and X 45 is present or absent, and if present is selected from L, F, E, S, or N; X 46is present or absent, and if present, is selected from S, L, or R; X 47 is either present or absent, and if present, is L, and X 48 is either present or absent, and if present is D; and X 49 is present or absent, and if present is L. In some embodiments, the VH region comprises the CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 where X 32 is selected from A or G; X 33 is selected from A, R, or T; X 34 is selected from A, V, T, P, I, E, or D; X 35 is selected from G, W, D, L, K, or P; X 36 is selected from P, A, Y, D, or G; X 37 is selected from Y, V, T, S, N, A, or G; X 38 is selected from G, S, D, or K; X 39 is selected from T, A, G, S, or I; X 40 is selected from S, Y, G, R, or W; X 41 is selected from V, D, Y, A, N, or G; X 42 is selected from L, Y, or F; X 43 is present or absent, and if present is selected from P, F, V, or N; X 44 is present or absent, and if present is selected from L, S, or T; X 45 is present or absent and, if present, is selected from L or F. In some embodiments, the VH region comprises the CDR3 sequence AX 33 X 34 X 35 X 36 X 37X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 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 is present or absent, and if present is selected from V, Y, or E; X 42 is either present or absent, and if present, is G; X 43 is either present or absent, and if present, then Y; X 44 is either present or absent, and if present, it is F; X 45 is present or absent, and if present is selected from E or N; and X 46 is present or absent, and if present, is selected from S or L. In some embodiments, the VH region has the CDR1 sequence GFPFX5X6YAMS and the CDR2 sequence AISGSGGSTX 22 YADSVKG, and CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY; wherein X5 is selected from D or G; X6 is selected from V, A, or T; 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 has 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 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; 10 is selected from T, S, or M; X 11 is either 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 is either present or absent, and if present, 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 is present or absent, and if present is selected from P, F, V, or N; X 44 is present or absent, and if present is selected from L, S, or T; X 45 is present or absent and, if present, is selected from L or F. In some embodiments, the VH region has 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 the 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 wherein X4 is selected from F or A; X5 is selected from S, T, or N; X6 is selected from S, T, or N; X7 is selected from Y, R, A, or G; X8 is selected from W, Y, or C; X9 is selected from I, W, Y, or D; 10 is selected from C, I, Y, or M; X 11 is present or absent, and if present is selected from C or M, and X 12 is either present or absent, and if present, is C; X 13 is selected from A or S; X 15 is selected from I, L, or T; X 16 is selected from Y or V; X 17 is selected from S, T, or A; X 18 is selected from G, P, or V; X 19 is selected from D, S, or T; X 20 is selected from S, T, or G; X 21 is selected from D, N, S, or A; X 22 is selected from T, I, or S; X 23 is selected from Y, K, or I; X 25 is selected from A or Y; X 26 is selected from S, T, A, or N; X 27 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 is present or absent, and if present is selected from G or K, and X 31 is either present or absent, and if present, 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 is present or absent, and if present is selected from V, Y, or E; X 42 is either present or absent, and if present, is G; X 43 is either present or absent, and if present, then Y; X 44 is either present or absent, and if present, it is F; X 45 is present or absent, and if present is selected from E or N; and X 46 is present or absent, and if present, is selected from S or L. In some embodiments, the VH region comprises a CDR1 sequence selected from 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 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 is present or absent, if present, selected from F, Y, V, D, A, N, G, E, or L; X 42 is present or absent, and if present is selected from P, L, Y, F, G, or T; X 43 is present or absent, and if present is selected from T, P, F, V, N, Y, or S; X 44 is present or absent, and if present is selected from G, L, S, T, or F; X 45 is present or absent, and if present is selected from F, L, E, N, or S; X 46 is present or absent, and if present is selected from D, S, L, or R; X 47 is present or absent, and if present is selected from Y or L, and X 48 is either present or absent, and if present is D; and X 49is present or absent, and, if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from SEQ ID NOs: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from SEQ ID NOs: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58.In some embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID 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 embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, 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. In some embodiments, the anti-CD38 antibody comprises 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 multispecific antibody comprising a second targeting moiety. In some embodiments, the second targeting moiety specifically binds to ICAM 1. In some embodiments, the second targeting moiety comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region has the CDR1 sequence X1X2X3X4X5X6X7X8X9X. 10 X 11 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; 10 is selected from S, G, N, M, or I; and X 11is present or absent, and if present is C; said VH region comprises CDR2 sequence X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 where X 12 is selected from G, T, A, I, or Y; X 13 is selected from W, I, Y, or C; X 14 is selected from I, S, or Y; X 15 is selected from S, G, T, D, or P; X 16 is selected from F, S, D, T, or A; X 17 is selected from S, R, G, or D; X 18 is selected from G, D, or S; X 19 is selected from S, R, T, N, Y, A, D, or P; X 20 is selected from T, A, G, or Y; X 21 is selected from Y, H, A, S, or T; X 22 is selected from Y or N; X 23 is selected from A, P, Y, or S; X 24 is selected from S, T, N, D, Y, A, or P; X 25 is selected from W, S, A, or D; X 26 is selected from A, V, T, W, F, or S; X 27 is selected from K, W, A, Q, or V; X 28 is selected from G, A, or K; X 29 is present or absent and, if present, is selected from K or G; and X 30 is present or absent, and if present is G; and said VH region has a 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 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 is present or absent and, if present, is selected from Y, A, G, I, or D; X 42 is present or absent, and if present, is selected from I, Y, R, P, V, or G; X 43 is present or absent and, if present, is selected from L, R, Y, G, or A; X 44 is present or absent, and if present, is selected from N, L, S, Y, or W; X 45 is present or absent and, if present, is selected from L, Y, F, or C; X 46 is present or absent, and if present, is selected from D, A, or F; X 47 is present or absent, and if present, is selected from M, P, Y, or N; X48 is present or absent, and if present is selected from D or L, and X 49 is present or absent, and if present is L. In some embodiments, the VH region has the CDR1 sequence GFSLX5X6X7X8MX 10 wherein 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 is selected from S, G, or N. In some embodiments, the VH region has the CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG, where X 13 is selected from W, I, or Y; X 15 is selected from S or G; X 16 is selected from F, S, D, or T; X 17 is selected from S or R; X 18 is selected from G or D; X 19 is selected from S, R, T, or N; X 20 is selected from T or A; and X 24 is selected from S, T, or N. In some embodiments, the VH region comprises the CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 where X 31 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 is present or absent, and if present, is selected from L, Y, or F; X 46 is either present or absent, and if present, it is D; X 47 is present or absent, and if present is selected from M or P; X 48 is either present or absent, and if present is D; and X 49is present or absent, and, if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from 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. In some embodiments, 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 a CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 241, 247, and 250; a CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252. In some embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283; and a CDR3 sequence selected from SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284. In some embodiments, the second targeting moiety comprises a VH sequence selected from SEQ ID NOs: 289-309 and a VL sequence selected from SEQ ID NOs: 311-326 and 155.In some embodiments, the anti-CD38 antibody comprises a humanized antibody or binding fragment thereof, or a chimeric antibody or binding fragment thereof. In some embodiments, the anti-CD38 antibody comprises a bispecific antibody or binding fragment thereof. In some embodiments, the bispecific antibody or binding fragment thereof comprises an IgG-scFv, a nanobody, a BiTE, a diabody, a DART, a TandAb, a scDiabody, a scDiabody-CH3, a triplebody, a miniantibody, a minibody, a TriBiminibody, a scFv-CH3 KIH, a Fab-scFv-Fc KIH, a Fab-scFv, a scFv-CH-CL-scFv, a F(ab')2, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a diabody-Fc, a tandem scFv-Fc, or an intrabody. In some embodiments, the anti-CD38 antibody comprises an IgG1 framework sequence. In some embodiments, the anti-CD38 antibody comprises an IgG2 framework sequence. In some embodiments, the anti-CD38 antibody comprises an IgG4 framework sequence. In some embodiments, the anti-CD38 antibody comprises an HC sequence selected from SEQ ID NOs: 157-181 and an LC sequence selected from SEQ ID NOs: 183-207. In some embodiments, the anti-CD38 antibody further comprises a payload. In some embodiments, the payload comprises a small molecule, peptide, or protein.

[0032] In certain embodiments, disclosed herein are anti-ICAM1 antibodies comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region has the CDR1 sequence: X1X2X3X4X5X6X7X8X9X 10 X 11 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; 10is selected from S, G, N, M, or I; and X 11 is present or absent, and if present is C; said VH region comprises CDR2 sequence X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 where X 12 is selected from G, T, A, I, or Y; X 13 is selected from W, I, Y, or C; X 14 is selected from I, S, or Y; X 15 is selected from S, G, T, D, or P; X 16 is selected from F, S, D, T, or A; X 17 is selected from S, R, G, or D; X 18 is selected from G, D, or S; X 19 is selected from S, R, T, N, Y, A, D, or P; X 20 is selected from T, A, G, or Y; X 21 is selected from Y, H, A, S, or T; X 22 is selected from Y or N; X 23 is selected from A, P, Y, or S; X 24 is selected from S, T, N, D, Y, A, or P; X 25 is selected from W, S, A, or D; X 26 is selected from A, V, T, W, F, or S; X 27 is selected from K, W, A, Q, or V; X 28 is selected from G, A, or K; X 29 is present or absent and, if present, is selected from K or G; and X 30is present or absent, and if present is G; and said VH region has a CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 where X 31 is selected from A or V; X 32 is selected from R or I; X 33 is selected from G, D, P, A, or V; X 34 is selected from G, P, W, D, N, or R; X 35 is selected from D, Y, S, L, G, F, or W; X 36 is selected from Y, D, V, L, S, G, or P; X 37 is selected from G, S, D, V, or E; X 38 is selected from G, Y, F, S, or D; X 39 is selected from S, D, G, T, N, A, or V; X 40 is selected from T, A, D, S, Y, L, or F; X 41 is present or absent and, if present, is selected from Y, A, G, I, or D; X 42 is present or absent, and if present, is selected from I, Y, R, P, V, or G; X 43 is present or absent and, if present, is selected from L, R, Y, G, or A; X 44 is present or absent, and if present, is selected from N, L, S, Y, or W; X 45 is present or absent and, if present, is selected from L, Y, F, or C; X 46 is present or absent, and if present, is selected from D, A, or F; X 47is present or absent, and if present, is selected from M, P, Y, or N; X 48 is present or absent, and if present is selected from D or L, and X 49 is present or absent, and if present is L. In some embodiments, the VH region has the CDR1 sequence GFSLX5X6X7X8MX 10 wherein 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 is selected from S, G, or N. In some embodiments, the VH region has the CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG, where X 13 is selected from W, I, or Y; X 15 is selected from S or G; X 16 is selected from F, S, D, or T; X 17 is selected from S or R; X 18 is selected from G or D; X 19 is selected from S, R, T, or N; X 20 is selected from T or A; and X 24 is selected from S, T, or N. In some embodiments, the VH region comprises the CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 where X 31 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 is present or absent, and if present, is selected from L, Y, or F; X 46 is either present or absent, and if present, it is D; X 47 is present or absent, and if present is selected from M or P; X 48 is either present or absent, and if present is D; and X 49 is present or absent, and if present is L. In some embodiments, the VH region comprises 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 said VH region comprises 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 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 is present or absent and, if present, is selected from Y, A, G, I, or D; X 42 is present or absent, and if present, is selected from I, Y, R, P, V, or G; X 43 is present or absent and, if present, is selected from L, R, Y, G, or A; X 44 is present or absent, and if present, is selected from N, L, S, Y, or W; X 45 is present or absent and, if present, is selected from L, Y, F, or C; X 46 is present or absent, and if present, is selected from D, A, or F; X 47 is present or absent, and if present, is selected from M, P, Y, or N; X 48 is present or absent, and if present is selected from D or L, and X 49is present or absent, and, if present, is L. In some embodiments, the VH region 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 selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, 243, 245, 249, and 252. In some embodiments, the VH region comprises a CDR1 sequence selected from 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 selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 241, 247, and 250; a CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251; and a CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252. In some embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283; In some embodiments, the second targeting moiety comprises a CDR3 sequence selected from SEQ ID NOs: 258, 261, 264, 266, 271, 276, 278, 281, and 284. In some embodiments, the second targeting moiety comprises a VH sequence selected from SEQ ID 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 multispecific antibody comprising an additional targeting moiety. In some embodiments, the additional targeting moiety specifically binds to CD38. In some embodiments, the additional targeting moiety comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from P, S, or D; X4 is selected from F, L, or A; X5 is selected from D, G, S, N, or T; X6 is selected from V, A, T, R, S, I, or N; X7 is selected from Y, I, N, R, A, G, or D; X8 is selected from A, Y, D, G, W, C, or T; X9 is selected from M, V, I, W, D, or Y; 10 is selected from S, T, M, C, I, Y, A, or G; X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C, and said VH region comprises the CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 where X 13 is selected from A, G, or S; X14 is selected from I, F, Y, V, S, or C; X 15 is selected from S, I, L, T, or M; X 16 is selected from G, Y, S, T, L, or V; X 17 is selected from S, I, K, Y, T, G, or A; X 18 is selected from G, S, T, P, V, or Y; X 19 is selected from G, A, D, S, or T; X 20 is selected from S, T, I, N, or G; X 21 is selected from T, I, D, N, S, or A; X 22 is selected from F, Y, N, T, I, or S; X 23 is selected from Y, D, K, or I; X 24 is selected from A or Y; X 25 is selected from D, T, S, N, R, A, or Y; X 26 is selected from S, W, T, A, or N; X 27 is selected from V, A, W, N, or S; X 28 is selected from K, R, Q, A, or W; X 29 is selected from G, K, or A; X 30 is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G, and the CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 where X 32 is selected from A, G, or V; X 33 is selected from K, A, R, T, G, or S; X 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 is present or absent, if present, selected from F, Y, V, D, A, N, G, E, or L; X 42 is present or absent, and if present is selected from P, L, Y, F, G, or T; X 43 is present or absent, and if present is selected from T, P, F, V, N, Y, or S; X 44 is present or absent, and if present is selected from G, L, S, T, or F; X 45 is present or absent, and if present is selected from F, L, E, N, or S; X 46 is present or absent, and if present is selected from D, S, L, or R; X 47 is present or absent, and if present is selected from Y or L, and X 48 is either present or absent, and if present is D; and X 49 is present or absent, and if present is L. In some embodiments, the VH region comprises the 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 12wherein 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; 10 is selected from T, S, M, C, I, Y, A, or G; X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C. In some embodiments, the VH region has the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 wherein X5 is selected from S or N; X6 is selected from R, S, or N; X7 is selected from Y, I, or N; X8 is selected from Y, D, G, or A; X9 is selected from V, M, or I; 10 is selected from T, S, or M; and X 11 is present or absent, and if present is C. In some embodiments, the VH region has the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 wherein X4 is selected from F or A; X5 is selected from S, T, or N; X6 is selected from S, T, or N; X7 is selected from Y, R, A, or G; X8 is selected from W, Y, or C; X9 is selected from I, W, Y, or D; 10 is selected from C, I, Y, or M; X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C. In some embodiments, the VH region has the CDR2 sequence AISGSGGSTX 22 YADSVKG, where X 22 is selected from F or Y. In some embodiments, the VH region comprises the CDR2 sequence 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 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 is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G. In some embodiments, the VH region comprises the CDR2 sequence X 13 X 14 IX 16 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 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 is present or absent, and if present is G. In some embodiments, the VH region comprises the CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X31 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 is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G. In some embodiments, the VH region has the CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY, where X 38 is selected from A or G; and X 41 is selected from F or Y. In some embodiments, the VH region comprises 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 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 is present or absent and, if present, is selected from V, D, Y, A, N, G, L, or E; X 42 is present or absent, and if present is selected from L, Y, F, T, or G; X 43 is present or absent, and if present, is selected from P, F, V, N, S, or Y; X 44 is present or absent, and if present is selected from L, S, T, G, or F; X 45 is present or absent, and if present is selected from L, F, E, S, or N; X 46 is present or absent, and if present, is selected from S, L, or R; X 47 is either present or absent, and if present, is L, and X 48 is either present or absent, and if present is D; and X 49 is present or absent, and if present is L. In some embodiments, the VH region comprises the CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45where X 32 is selected from A or G; X 33 is selected from A, R, or T; X 34 is selected from A, V, T, P, I, E, or D; X 35 is selected from G, W, D, L, K, or P; X 36 is selected from P, A, Y, D, or G; X 37 is selected from Y, V, T, S, N, A, or G; X 38 is selected from G, S, D, or K; X 39 is selected from T, A, G, S, or I; X 40 is selected from S, Y, G, R, or W; X 41 is selected from V, D, Y, A, N, or G; X 42 is selected from L, Y, or F; X 43 is present or absent, and if present is selected from P, F, V, or N; X 44 is present or absent, and if present is selected from L, S, or T; X 45 is present or absent and, if present, is selected from L or F. In some embodiments, the VH region comprises the CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 where X 33 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 is present or absent, and if present is selected from V, Y, or E; X 42 is either present or absent, and if present, is G; X 43 is either present or absent, and if present, then Y; X 44 is either present or absent, and if present, it is F; X 45 is present or absent, and if present is selected from E or N; and X 46 is present or absent, and if present, is selected from S or L. In some embodiments, the VH region has the CDR1 sequence GFPFX5X6YAMS and the CDR2 sequence AISGSGGSTX 22 YADSVKG, and CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY; wherein X5 is selected from D or G; X6 is selected from V, A, or T; 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 has 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 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; 10 is selected from T, S, or M; X 11 is either 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 27 is selected from A or W; X 28 is selected from K, R, Q, or A; X 29 is selected from G or K; X 30 is either present or absent, and if present, 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 is present or absent, and if present is selected from P, F, V, or N; X 44 is present or absent, and if present is selected from L, S, or T; X 45 is present or absent and, if present, is selected from L or F. In some embodiments, the VH region has 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 the CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 wherein X4 is selected from F or A; X5 is selected from S, T, or N; X6 is selected from S, T, or N; X7 is selected from Y, R, A, or G; X8 is selected from W, Y, or C; X9 is selected from I, W, Y, or D; 10 is selected from C, I, Y, or M; X 11 is present or absent, and if present is selected from C or M, and X12 is either present or absent, and if present, is C; X 13 is selected from A or S; X 15 is selected from I, L, or T; X 16 is selected from Y or V; X 17 is selected from S, T, or A; X 18 is 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 is present or absent, and if present is selected from G or K, and X 31 is either present or absent, and if present, 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 is present or absent, and if present is selected from V, Y, or E; X 42 is either present or absent, and if present, is G; X 43 is either present or absent, and if present, then Y; X 44 is either present or absent, and if present, it is F; X45 is present or absent, and if present is selected from E or N; and X 46 is present or absent, and if present, is selected from S or L. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from SEQ ID NOs: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 where X 32 is selected from A, G, or V; X 33 is selected from K, A, R, T, G, or S; X 34 is selected from R, A, V, T, P, I, E, D, or S; X 35 is selected from G, W, D, L, K, P, S, A, T, or R; X 36 is selected from T, P, A, Y, D, G, S, R, V, or E; X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I; X 38 is selected from G, A, S, D, K, F, L, or Y; X 39 is selected from Y, T, A, G, S, or I; X 40 is selected from S, Y, G, R, W, N, L, D, or F; X 41 is present or absent, if present, selected from F, Y, V, D, A, N, G, E, or L; X 42is present or absent, and if present is selected from P, L, Y, F, G, or T; X 43 is present or absent, and if present is selected from T, P, F, V, N, Y, or S; X 44 is present or absent, and if present is selected from G, L, S, T, or F; X 45 is present or absent, and if present is selected from F, L, E, N, or S; X 46 is present or absent, and if present is selected from D, S, L, or R; X 47 is present or absent, and if present is selected from Y or L, and X 48 is either present or absent, and if present is D; and X 49is present or absent, and, if present, is L. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from SEQ ID NOs: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from SEQ ID NOs: 3, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; a CDR2 sequence selected from SEQ ID NOs: 2 and 5; and a CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence selected from SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; a CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and a CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52. In some embodiments, the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; a CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and a CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58.In some embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID 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 embodiments, the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; a CDR2 sequence selected from SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100. In some embodiments, 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. In some embodiments, the anti-CD38 antibody comprises 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 binding fragment thereof, or a chimeric antibody or binding fragment thereof. In some embodiments, the anti-ICAM1 antibody comprises a bispecific antibody or binding fragment thereof. In some embodiments, the bispecific antibody or binding fragment thereof comprises an IgG-scFv, a nanobody, a BiTE, a diabody, a DART, a TandAb, a scDiabody, a scDiabody-CH3, a triplebody, a miniantibody, a minibody, a TriBiminibody, a scFv-CH3 KIH, a Fab-scFv-Fc KIH, a Fab-scFv, a scFv-CH-CL-scFv, a F(ab')2, a F(ab')2-scFv2, a scFv-KIH, a Fab-scFv-Fc, a tetravalent HCAb, a scDiabody-Fc, a diabody-Fc, a tandem scFv-Fc, or an intrabody.In some embodiments, the anti-ICAM1 antibody comprises an IgG1 framework sequence. In some embodiments, the anti-ICAM1 antibody comprises an IgG2 framework sequence. In some embodiments, the anti-ICAM1 antibody comprises an IgG4 framework sequence. In some embodiments, the anti-ICAM1 antibody comprises an HC sequence selected from SEQ ID NOs: 157-181 and an LC sequence selected from SEQ ID NOs: 183-207. In some embodiments, the anti-ICAM1 antibody further comprises a payload. In some embodiments, the payload comprises a small molecule, peptide, or protein.

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

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

[0035] In certain embodiments, disclosed herein are 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. 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, disclosed herein are methods of treating cancer in a subject, the methods comprising administering to the subject a bispecific antibody described herein, an anti-CD38 antibody described herein, an anti-ICAM1 antibody described herein, or a pharmaceutical composition described herein, thereby treating the cancer in the subject. In some embodiments, the subject has a solid tumor. In some embodiments, the solid tumor is bladder cancer, bone cancer, brain cancer, breast cancer, colon 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 Hodgkin's lymphoma or non-Hodgkin's lymphoma. In some embodiments, the hematological malignancy is selected from the group consisting of chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, Burkitt's lymphoma, non-Burkitt's lymphoma, and leukemia. The cancer is selected from the group consisting of lymphoid high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, and lymphomatoid granulomatosis. In some embodiments, the cancer is metastatic cancer. In some embodiments, the cancer is relapsed or refractory cancer. In some embodiments, the method further comprises administering an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapy, a hormone-based therapy, a stem cell-based therapy, or radiation. In some embodiments, the additional therapeutic agent is a primary therapeutic agent. In some embodiments, the additional therapeutic agent and the antibody are administered simultaneously. In some embodiments, the additional therapeutic agent and the antibody are administered sequentially.In some embodiments, the additional therapeutic agent is administered before the antibody. In some embodiments, the additional therapeutic agent is administered after administration of the antibody. In some embodiments, the additional therapeutic agent and the antibody are administered as separate doses. In some embodiments, the subject has undergone surgery. In some embodiments, the subject is human.

[0037] In certain embodiments, disclosed herein are 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. [Brief explanation of the drawings]

[0038] The novel features of the invention are set forth with particularity in the appended claims. For a better understanding of the features and advantages of the present invention, reference should be made to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings. [Figure 1A] 1A and 1B illustrate exemplary bispecific antibody formats contemplated herein. Figures 1A and 1B are adapted from Figure 2 of Brinkmann and Kontermann, "The making of bispecific antibodies," MABS 9(2):182-212 (2017). [Figure 1B] 1A and 1B illustrate exemplary bispecific antibody formats contemplated herein. Figures 1A and 1B are adapted from Figure 2 of Brinkmann and Kontermann, "The making of bispecific antibodies," MABS 9(2):182-212 (2017). [Figure 2] 2 illustrates exemplary bispecific formats described herein: A: light chain C-terminal fusion; B: heavy chain C-terminal fusion; C: heavy chain N-terminal fusion; D: DVD format; E: three-chain knob-into-hole (KIH); and F: generic light chain bispecific in FIG. 2. [Figure 3]A-B show 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 and bispecific antibodies. [Figure 5A] Figure 5 illustrates antibody-dependent cell-mediated cytotoxicity-mediated lysis of Daudi (Figure 5A), DU145 (Figure 5B), NCI-H2444 (Figure 5C), HCC44 (Figure 5D), NCI-H2291 (Figure 5E), and NCI-H2342 (Figure 5F) cells using NK92 / CD16A as effector cells. [Figure 5B] Figure 5 illustrates antibody-dependent cell-mediated cytotoxicity-mediated lysis of Daudi (Figure 5A), DU145 (Figure 5B), NCI-H2444 (Figure 5C), HCC44 (Figure 5D), NCI-H2291 (Figure 5E), and NCI-H2342 (Figure 5F) cells using NK92 / CD16A as effector cells. [Figure 5C] Figure 5 illustrates antibody-dependent cell-mediated cytotoxicity-mediated lysis of Daudi (Figure 5A), DU145 (Figure 5B), NCI-H2444 (Figure 5C), HCC44 (Figure 5D), NCI-H2291 (Figure 5E), and NCI-H2342 (Figure 5F) cells using NK92 / CD16A as effector cells. [Figure 5D] Figure 5 illustrates antibody-dependent cell-mediated cytotoxicity-mediated lysis of Daudi (Figure 5A), DU145 (Figure 5B), NCI-H2444 (Figure 5C), HCC44 (Figure 5D), NCI-H2291 (Figure 5E), and NCI-H2342 (Figure 5F) cells using NK92 / CD16A as effector cells. [Figure 5E]Figure 5 illustrates antibody-dependent cell-mediated cytotoxicity-mediated lysis of Daudi (Figure 5A), DU145 (Figure 5B), NCI-H2444 (Figure 5C), HCC44 (Figure 5D), NCI-H2291 (Figure 5E), and NCI-H2342 (Figure 5F) cells using NK92 / CD16A as effector cells. [Figure 5F] Figure 5 illustrates antibody-dependent cell-mediated cytotoxicity-mediated lysis of Daudi (Figure 5A), DU145 (Figure 5B), NCI-H2444 (Figure 5C), HCC44 (Figure 5D), NCI-H2291 (Figure 5E), and NCI-H2342 (Figure 5F) cells using NK92 / CD16A as effector cells. [Figure 6A] ADCC-mediated lysis of Daudi (Figure 6A), DU145 (Figure 6B), HCC44 (Figure 6C), and NCI-H2444 (Figure 6D) cells is shown using fresh PBMCs as effector cells. [Figure 6B] ADCC-mediated lysis of Daudi (Figure 6A), DU145 (Figure 6B), HCC44 (Figure 6C), and NCI-H2444 (Figure 6D) cells is shown using fresh PBMCs as effector cells. [Figure 6C] ADCC-mediated lysis of Daudi (Figure 6A), DU145 (Figure 6B), HCC44 (Figure 6C), and NCI-H2444 (Figure 6D) cells is shown using fresh PBMCs as effector cells. [Figure 6D] ADCC-mediated lysis of Daudi (Figure 6A), DU145 (Figure 6B), HCC44 (Figure 6C), and NCI-H2444 (Figure 6D) cells is shown using fresh PBMCs as effector cells. [Figure 7] Illustrates induction of cell death and apoptosis in the presence (gray bars) and absence (black bars) of cross-linking of Daudi cells with selected monoclonal and bispecific antibodies. [Figure 8A]Figure 8A shows antibody-induced cell death of NK cells from NK92 / CD16a cells (Figure 8A) and fresh PBMCs (Figure 8B). HC N-fusion and three-chain KIH antibodies showed reduced NK killing compared to the anti-CD38 BMK clone (or the reference antibody daratumumab). [Figure 8B] Figure 8A shows antibody-induced cell death of NK cells from NK92 / CD16a cells (Figure 8A) and fresh PBMCs (Figure 8B). HC N-fusion and three-chain KIH antibodies showed reduced NK killing compared to the anti-CD38 BMK clone (or the reference antibody daratumumab). [Figure 9A] ELISA binding of exemplary anti-CD38 rabbit-human chimeric clones to recombinant human CD38 ECD (FIG. 9A) and cynomolgus monkey CD38 ECD (FIG. 9B) is shown. [Figure 9B] ELISA binding of exemplary anti-CD38 rabbit-human chimeric clones to recombinant human CD38 ECD (FIG. 9A) and cynomolgus monkey CD38 ECD (FIG. 9B) is shown. [Figure 10A] ELISA binding of exemplary anti-ICAM1 rabbit-human chimeric clones to recombinant human ICAM1 ECD (FIG. 10A) and rhesus ICAM1 ECD (FIG. 10B) is shown. [Figure 10B] ELISA binding of exemplary anti-ICAM1 rabbit-human chimeric clones to recombinant human ICAM1 ECD (FIG. 10A) and rhesus ICAM1 ECD (FIG. 10B) is shown. [Figure 11] Figure 1 shows the binding of an exemplary anti-CD38 rabbit-human chimeric clone to Daudi cells as determined by flow cytometry. [Figure 12] Figure 1 shows the binding of anti-ICAM1 rabbit-human chimeric clones to DU145 cells as determined by flow cytometry. [Figure 13] CDC-mediated lysis of Daudi cells by a benchmark and exemplary rabbit-human chimeric anti-CD38 antibody is shown. [Figure 14A]14A and 14B show ADCC-mediated lysis of Daudi cells (FIG. 14A) and HuNS1 cells (FIG. 14B) by anti-CD38 antibodies using NK92 / CD16A as effector cells. [Figure 14B] 14A and 14B show ADCC-mediated lysis of Daudi cells (FIG. 14A) and HuNS1 cells (FIG. 14B) by anti-CD38 antibodies using NK92 / CD16A as effector cells. [Figure 15A] Figure 15A shows ADCC-mediated lysis of Daudi cells (Figure 15A) and HuNS1 cells (Figure 15B) by an exemplary rabbit-human chimeric anti-CD38 antibody using NK92 / CD16A as effector cells. [Figure 15B] Figure 15A shows ADCC-mediated lysis of Daudi cells (Figure 15A) and HuNS1 cells (Figure 15B) by an exemplary rabbit-human chimeric anti-CD38 antibody using NK92 / CD16A as effector cells. [Figure 16A] Figure 16A shows ADCC-mediated lysis of DU145 (Figure 16A), Daudi cells (Figure 16B), and HuNS1 cells (Figure 16C) by anti-ICAM1 clone G12 and an exemplary rabbit-human chimeric anti-ICAM1 antibody using NK92 / CD16A as effector cells. [Figure 16B] Figure 16A shows ADCC-mediated lysis of DU145 (Figure 16A), Daudi cells (Figure 16B), and HuNS1 cells (Figure 16C) by anti-ICAM1 clone G12 and an exemplary rabbit-human chimeric anti-ICAM1 antibody using NK92 / CD16A as effector cells. [Figure 16C] Figure 16A shows ADCC-mediated lysis of DU145 (Figure 16A), Daudi cells (Figure 16B), and HuNS1 cells (Figure 16C) by anti-ICAM1 clone G12 and an exemplary rabbit-human chimeric anti-ICAM1 antibody using NK92 / CD16A as effector cells. [Figure 17A]Using fresh PBMCs as effector cells, ADCC-mediated lysis of DU145 cells by an exemplary high affinity anti-CD38 4618_1_12 bispecific antibody (Figure 17A), an exemplary medium affinity anti-CD38 32218_1 bispecific antibody (Figure 17B), and an exemplary low affinity anti-CD38 33218_2 bispecific antibody (Figure 17C) is shown. [Figure 17B] Using fresh PBMCs as effector cells, ADCC-mediated lysis of DU145 cells by an exemplary high affinity anti-CD38 4618_1_12 bispecific antibody (Figure 17A), an exemplary medium affinity anti-CD38 32218_1 bispecific antibody (Figure 17B), and an exemplary low affinity anti-CD38 33218_2 bispecific antibody (Figure 17C) is shown. [Figure 17C] Using fresh PBMCs as effector cells, ADCC-mediated lysis of DU145 cells by an exemplary high affinity anti-CD38 4618_1_12 bispecific antibody (Figure 17A), an exemplary medium affinity anti-CD38 32218_1 bispecific antibody (Figure 17B), and an exemplary low affinity anti-CD38 33218_2 bispecific antibody (Figure 17C) is shown. [Figure 18A] Using exemplary monovalent anti-CD38 (medium affinity, 32218_1), monovalent anti-ICAM1, and anti-CD38 / ICAM1 bispecific antibodies, we demonstrate ADCC-mediated lysis of Raji (Figure 18A), DU145 (Figure 18B), and HCC44 (Figure 18C). [Figure 18B] Using exemplary monovalent anti-CD38 (medium affinity, 32218_1), monovalent anti-ICAM1, and anti-CD38 / ICAM1 bispecific antibodies, we demonstrate ADCC-mediated lysis of Raji (Figure 18A), DU145 (Figure 18B), and HCC44 (Figure 18C). [Figure 18C] Using exemplary monovalent anti-CD38 (medium affinity, 32218_1), monovalent anti-ICAM1, and anti-CD38 / ICAM1 bispecific antibodies, we demonstrate ADCC-mediated lysis of Raji (Figure 18A), DU145 (Figure 18B), and HCC44 (Figure 18C). [Figure 19A]Figure 19 shows increased ADCC-mediated lysis of Raji (Figure 19A) and KMS26 (Figure 19B) cells using CD38 / ICAM1 KIH bispecific antibodies with Fc mutations (high ADCC). [Figure 19B] Figure 19 shows increased ADCC-mediated lysis of Raji (Figure 19A) and KMS26 (Figure 19B) cells using CD38 / ICAM1 KIH bispecific antibodies with Fc mutations (high ADCC). [Figure 20A] Figure 20 shows increased ADCC-mediated lysis of Raji (Figure 20A) and KMS26 (Figure 20B) cells using an afucosylated CD38 / ICAM1 KIH bispecific antibody. [Figure 20B] Figure 20 shows increased ADCC-mediated lysis of Raji (Figure 20A) and KMS26 (Figure 20B) cells using an afucosylated CD38 / ICAM1 KIH bispecific antibody. [Figure 21] The mean volume of xenograft tumors derived from Raji cells treated with monospecific CD38 or ICAM1 antibodies or with the three-chain KIH CD38 / ICAM1 bispecific antibody is shown. [Figure 22] 1 shows the mean volume of xenograft tumors derived from Raji cells treated with a monospecific CD38 antibody, a triple-chain KIH CD38 / ICAM1 bispecific antibody with the anti-CD38 binding domain from anti-CD38 BMK, or a triple-chain KIH CD38 / ICAM1 bispecific antibody with the CD38 binding domain from 32218_1 (triple-chain KIH(Med)). [Figure 23] The mean volume of xenograft tumors derived from HuNS1 cells treated with monospecific CD38 or ICAM1 antibodies or the three-chain KIH CD38 / ICAM1 bispecific antibody is shown. [Figure 24]1 shows the mean volumes 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 domains, and fucosylated and afucosylated forms of a monospecific anti-CD38 reference antibody (anti-CD38 BMK). DETAILED DESCRIPTION OF THE INVENTION

[0039] Antibody-based therapies have emerged as an effective cancer treatment option due to their high specificity and affinity for target binding and the ease of chemical and molecular modification. Approved antibody-based therapies include monoclonal antibodies such as rituximab, tositumomab, and trastuzumab; and bispecific T-cell engagers such as blinatumomab.

[0040] In some cases, the therapeutic efficacy of antibody-based therapies has been hindered by low copy numbers of receptors on target cells or low affinity for the antigen. In other cases, the use of antibody-based therapies has been further limited by the nonspecificity of the antibody for the target antigen or the presence of the target antigen on both cancer and non-cancerous cells.

[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, lymphocyte activation, and proliferation (Funaro et al., J Immunology 145:2390-6, 1990; Guse et al., Nature 398:70-3, 1999), and through its NAD glycohydrolase activity, regulates extracellular NAD levels, which are involved in regulating regulatory T cell compartmentalization (Adriouch et al., J Immunology 14:1284-92, 2012; Chiarugi et al., Nature Reviews 12:741-52, 2012). In some instances, 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. It is a transmembrane protein associated with endothelial cells and leukocytes, and is involved in stabilizing cell-cell interactions and promoting leukocyte migration across the endothelium. ICAM1 is expressed on various cell types, including endothelial cells and leukocytes, and can be expressed and / or overexpressed on various cancer cells, including myeloma, pancreatic cancer, glioma, lung cancer, melanoma, colorectal cancer, and lymphoma.

[0043] Disclosed herein, in some embodiments, are anti-CD38 antibodies, anti-ICAM1 antibodies, and multispecific antibodies that comprise a targeting moiety for CD38, a targeting moiety for ICAM1, or a combination thereof. Also described herein, in some embodiments, are bispecific antibodies that comprise a first targeting moiety for CD38 and a second targeting moiety for ICAM1. Also described herein, in additional embodiments, are methods of treating cancer using anti-CD38 antibodies, anti-ICAM1 antibodies, or multispecific antibodies (e.g., bispecific CD38 / ICAM1 antibodies).

[0044] Multispecific Proteins In certain embodiments, the present disclosure provides multispecific proteins comprising a first component that binds to CD38 and a second component that binds to ICAM1. The first component, in some instances, is a CD38-binding protein, such as an anti-CD38 antibody or an anti-CD38 antibody mimetic. The second component, in some instances, is a CD38-binding protein, such as an anti-ICAM1 antibody or an anti-ICAM1 antibody mimetic. See, e.g., Yu et al., Annu Rev Anal Chem (Palo Alto Calif). 2017 June 12; 10(1):293-320.

[0045] In some examples, the multispecific protein is bispecific, trispecific, or tetraspecific. In some examples, the multispecific protein is bivalent, trivalent, tetravalent, or greater than tetravalent. In some examples, the multispecific protein has more than one binding site that binds to CD38. In some examples, the multispecific protein has more than one binding site that binds to ICAM1. In some examples, the multispecific protein has more than one binding site for each of one, two, three, or four different target proteins. In some examples, the multispecific protein binds to more than one epitope on CD38 and / or ICAM1. In some examples, the multispecific protein is bivalent for CD38 and monovalent for ICAM1. In some examples, the multispecific protein is bivalent for ICAM1 and monovalent for CD38.

[0046] In some embodiments, the first component comprises an antibody mimic comprising a binding site specific for CD38, and is an affibody, adnectin (also called monobody), affimer, affitin (also called nanophytin), an anticalin, attrimer, avimer, fyonmer, an antibody mimic comprising an armadillo repeat domain, a Kunitz domain, a knottin, a DARpin, or any combination thereof. In some embodiments, the second component comprises an antibody mimic comprising a binding site specific for ICAM1, and is an affibody, adnectin (also called monobody), affimer, affitin (also called nanophytin), an anticalin, attrimer, avimer, fyonmer, an armadillo repeat domain, a Kunitz domain, a knottin, a DARpin, or any combination thereof.

[0047] In some embodiments, the first component comprises an anti-CD38 antibody or antigen-binding fragment thereof. Non-limiting examples of anti-CD38 antibodies include anti-CD38 IgG antibodies comprising two polypeptides, each comprising a heavy chain (HC) and a light chain (LC), single domain antibodies (sdAbs), VHH domains (or camelized antibodies), variable heavy domains (VH), variable light domains (VL), Fab, F(ab')2, single-chain variable fragments (scFv), scFvs comprising an Fc region (scFv Fc), monovalent IgG, V-NAR, IgGNAR, camel heavy chain IgG (hcIgG), and scFvs fused to a CH3 domain (scFv-CH3).

[0048] In some embodiments, the second component comprises an anti-ICAM1 antibody or antigen-binding fragment thereof. Non-limiting examples of anti-ICAM1 antibodies include anti-ICAM1 IgG antibodies comprising two polypeptides, each comprising a heavy chain (HC) and a light chain (LC), single domain antibodies (sdAbs), VHH domains (or camelized antibodies), variable heavy domains (VH), variable light domains (VL), Fab, F(ab')2, single-chain variable fragments (scFv), scFvs comprising an Fc region (scFv Fc), monovalent IgG, V-NAR, IgGNAR, camel heavy chain IgG (hcIgG), and scFvs fused to a CH3 domain (scFv-CH3).

[0049] In some embodiments, multispecific proteins comprising a first component that binds to CD38 and a second component that binds to ICAM1 have varying affinities (KD) for their respective target antigens as measured by surface plasmon resonance. In some embodiments, the first component has a KD of about 0.1 nM to about 100 nM, about 0.15 nM to about 95 nM, about 0.2 nM to about 90 nM, 0.25 nM to about 85 nM, about 0.3 nM to about 80 nM, about 0.35 nM to about 75 nM, about 0.4 nM to about 70 nM, about 0.5 nM to about 70 nM, about 0.6 nM to about 60 nM, about 0.7 nM to about 50 nM, about 0.8 nM to about 40 nM, or about 0.9 nM to about 30 nM. It binds to human CD38 with a KD of 0 nM, about 1 nM to about 20 nM, about 1.5 nM to about 10 nM, about 0.01 nM to about 25 nM, about 0.01 nM to about 20 nM, about 0.01 nM to about 10 nM, about 0.01 nM to about 5 nM, about 0.02 nM to about 20 nM, about 0.04 nM to about 20 nM, about 0.06 nM to about 20 nM, about 0.08 nM to about 20 nM, or about 0.1 nM to about 20 nM.

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

[0051] In some embodiments, the multispecific proteins provided herein bind to target cells expressing higher levels of ICAM1 than CD38 on their surface. For example, the ratio of ICAM1 to CD38 protein expression 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 to CD38 protein expression on the target cell surface is about 1.1 to 700, e.g., about 2.5, 14.2, 29.1, 64.5, 34.0, 50.3, 357.1, or 666.7, based on quantification of protein surface expression.

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

[0053] In some embodiments, the target cells express at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on their surface as measured by flow cytometry. In some examples, the target cells express less 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 between 100 and 350,000, 100 and 300,000, 100 and 250,000, 100 and 200,000, 100 and 150,000, 100 and 100,000, 100 and 80,000, 100 and 60,000, 100 and 50,000, 100 and 40,000, 100 and 30,000, 100 and 20,000. In some examples, the target cells have less CD38 protein on their surface than Daudi cells, Raji cells, KMS-26 cells, HuNS1 cells, HCC44 cells, NCI-H2444 cells, or DU145 cells. In some examples, the target cells have at least 200 CD38 proteins on their surface, but have fewer CD38 proteins on their surface than Daudi cells, Raji cells, KMS-26 cells, HuNS1 cells, HCC44 cells, NCI-H2444 cells, or DU145 cells.

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

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

[0056] In some embodiments, a larger amount of a multispecific protein having a CD38-binding domain and an ICAM1-binding domain binds to the surface of cells expressing CD38 and ICAM1 compared to a monospecific protein having a CD38-binding domain and / or a monospecific protein having an ICAM1-binding domain. In some examples, 1.5, 2, 3, 4, 5, or 10-fold more of the multispecific protein binds to cells expressing CD38 than a monospecific protein that binds CD38 or a monospecific protein that binds ICAM1. In some embodiments, a larger amount of a multispecific protein having a CD38-binding domain and an ICAM1-binding domain binds to the surface of cells that express ICAM1 more than CD38 compared to a monospecific protein having a CD38-binding domain. In some examples, 1.5, 2, 3, 4, 5, or 10-fold more of the multispecific protein binds to cells that express ICAM1 more than CD38 compared to a monospecific protein that binds CD38.

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

[0058] Immune activity can be measured in cell line-derived xenograft assays, in which the transformed cells are injected into mice to form tumors. In some examples, multispecific proteins having a CD38-binding domain and an ICAM1-binding domain inhibit the growth of tumors containing cells expressing CD38 to a greater extent than monospecific proteins having a CD38-binding domain and / or monospecific proteins having an ICAM1-binding domain. In some examples, the multispecific proteins exhibit 1.5-, 2-, 3-, 4-, 5-, or 10-fold greater inhibition of xenograft growth compared to monospecific proteins having a CD38-binding domain and / or monospecific proteins having an ICAM1-binding domain.

[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 antibody on a target cell and subsequently cause lysis of the target cell. In one embodiment, the target cell is a human cell, such as a tumor cell (e.g., a myeloma cell). Without wishing to be bound by any particular mechanism of action, cytotoxic cells that mediate ADCC generally express Fc receptors (FcR). NK cells, which are cells that mediate ADCC, express FcγRIII, whereas 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] To assess the ADCC activity of a multispecific protein as described herein, in some embodiments, an in vitro ADCC assay, such as a cytotoxicity assay using a cancer cell line, is performed. 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 a subject multispecific protein is assessed in vivo, e.g., in an animal subject, in some embodiments.

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

[0062] In some embodiments, a multispecific protein as described herein that binds CD38 and ICAM1 mediates complement-dependent lysis of at least 50% of cells in an exponentially growing Raji cell population at a concentration of about 2 nM. In some embodiments, a multispecific protein as described herein that binds CD38 and ICAM1 mediates ADCC by PBMCs against 40% of cells in an exponentially growing NCI-H2444 cell population at a concentration of about 1 nM. In certain embodiments, a multispecific (e.g., bispecific), multivalent (e.g., bivalent, trivalent, tetravalent) protein as described herein that binds CD38 and ICAM1 does not induce apoptosis without cross-linking.

[0063] Anti-CD38 antibody In some embodiments, disclosed herein are anti-CD38 antibodies. In some examples, the anti-CD38 antibodies comprise a variable heavy (VH) region and a variable light (VL) region, wherein the VH region has the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from P, S, or D; X4 is selected from F, L, or A; X5 is selected from D, G, S, N, or T; X6 is selected from V, A, T, R, S, I, or N; X7 is selected from Y, I, N, R, A, G, or D; X8 is selected from A, Y, D, G, W, C, or T; X9 is selected from M, V, I, W, D, or Y; 10 is selected from S, T, M, C, I, Y, A, or G, and X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C, and said VH region comprises the 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 where X 13 is selected from A, G, or S, and X 14 is selected from I, F, Y, V, S, or C, and X 15 is selected from S, I, L, T, or M, and X 16 is selected from G, Y, S, T, L, or V, and X 17 is selected from S, I, K, Y, T, G, or A, and X 18 is selected from G, S, T, P, V, or Y, and X 19 is selected from G, A, D, S, or T, and X 20 is selected from S, T, I, N, or G, and X 21 is selected from T, I, D, N, S, or A, and X 22 is selected from F, Y, N, T, I, or S, and X 23 is selected from Y, D, K, or I, and X 24 is selected from A or Y, and X 25 is selected from D, T, S, N, R, A, or Y, and X 26 is selected from S, W, T, A, or N, and X 27 is selected from V, A, W, N, or S, and X 28 is selected from K, R, Q, A, or W, and X 29 is selected from G, K, or A, and X 30 is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G, and said VH region comprises the CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X44 X 45 X 46 X 47 X 48 X 49 where X 32 is selected from A, G, or V, and X 33 is selected from K, A, R, T, G, or S, and X 34 is selected from R, A, V, T, P, I, E, D, or S, and X 35 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, and X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I, and X 38 is selected from G, A, S, D, K, F, L, or Y, and X 39 is selected from Y, T, A, G, S, or I, and X 40 is selected from S, Y, G, R, W, N, L, D, or F, and X 41 is present or absent, and if present is selected from F, Y, V, D, A, N, G, E, or L; X 42 is present or absent, and if present is selected from P, L, Y, F, G, or T; X 43 is present or absent, and if present is selected from T, P, F, V, N, Y, or S; X 44 is present or absent, and if present is selected from G, L, S, T, or F; X 45 is present or absent, and if present is selected from F, L, E, N, or S; X 46 is present or absent, and if present is selected from D, S, L, or R; X 47 is present or absent, and if present is selected from Y or L, and X 48 is present or absent, and if present, is D, and X 49 is either present or absent and, if present, is L.

[0064] In some examples, 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.

[0065] In some instances, the VH region of an anti-CD38 antibody has the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent, and if present is S, X2 is selected from F or I, X3 is selected from S or D, X4 is selected from L, F, or A, X5 is selected from S, N, or T, X6 is selected from R, S, N, I, or T, X7 is selected from Y, I, N, R, A, D, or G, X8 is selected from Y, D, G, A, W, T, or C, X9 is selected from V, M, I, W, Y, or D, and X 10 is selected from T, S, M, C, I, Y, A, or G, and X 11 is present or absent, and if present is selected from C or M, and X 12 is either present or absent, and if present, is C.

[0066] In some instances, the VH region of an anti-CD38 antibody has the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (SEQ ID NO: 426), wherein X5 is selected from S or N, X6 is selected from R, S, or N, X7 is selected from Y, I, or N, X8 is selected from Y, D, G, or A, X9 is selected from V, M, or I, and X 10 is selected from T, S, or M, and X 11 is either present or absent, and if present, is C.

[0067] In some instances, the VH region of an anti-CD38 antibody has the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12(SEQ ID NO: 419), wherein X4 is selected from F or A, X5 is selected from S, T, or N, X6 is selected from S, T, or N, X7 is selected from Y, R, A, or G, X8 is selected from W, Y, or C, X9 is selected from I, W, Y, or D, and X 10 is selected from C, I, Y, or M, and X 11 is present or absent, and if present is selected from C or M, and X 12 is either present or absent, and if present, is C.

[0068] Optionally, the VH region of the anti-CD38 antibody has the CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID NO: 418), wherein X 22 is selected from F or Y.

[0069] Optionally, the VH region of the anti-CD38 antibody comprises the CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 where X 13 is selected from A, G, or S, and X 14 is selected from I, F, Y, V, S, or C, and X 15 is selected from I, L, M, or T, and X 16 is selected from G, Y, S, T, L, or V, and X 17 is selected from S, I, K, Y, T, G, or A, and X 18 is selected from G, S, T, P, or V, and X 19 is selected from G, A, D, S, or T, and X 20 is selected from S, T, I, N, or G, and X21 is selected from T, I, D, N, S, or A, and X 22 is selected from Y, N, T, I, or S, and X 23 is selected from Y, D, K, or I, and X 24 is selected from A or Y, and X 25 is selected from T, S, N, R, A, or Y, and X 26 is selected from S, W, T, A, or N, and X 27 is selected from A, W, N, or S, and X 28 is selected from K, R, Q, A, or W, and X 29 is selected from G, K, or A, and X 30 is present or absent, and if present is selected from G or K, and X 31 is either present or absent, and if present, is G.

[0070] Optionally, the VH region of the anti-CD38 antibody comprises 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 where X 13 is selected from A or G, and X 14 is selected from I, F, Y, V, S, or C, and X 16 is selected from G, Y, S, T, or L, and X 17 is selected from S, I, K, Y, T, or G, and X 18 is selected from G, S, or T, and X 19 is selected from G, A, D, or S, and X 20 is selected from T, I, N, or G, and X 21 is selected from T, I, or D, and X 22 is selected from Y, N, or T, and X 23is selected from Y or D, and X 24 is selected from A or Y, and X 25 is selected from T, S, N, R, or A, and X 26 is selected from W or T, and X 27 is selected from A or W, and X 28 is selected from K, R, Q, or A, and X 29 is selected from G or K, and X 30 is either present or absent, and if present, is G.

[0071] Optionally, the VH region of the anti-CD38 antibody comprises the CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 where X 13 is selected from A or S, and X 15 is selected from I, L, or T, and X 16 is selected from Y or V, and X 17 is selected from S, T, or A, and X 18 is selected from G, P, or V, and X 19 is selected from D, S, or T, and X 20 is selected from S, T, or G, and X 21 is selected from D, N, S, or A, and X 22 is selected from T, I, or S, and X 23 is selected from Y, K, or I, and X 25 is selected from A or Y, and X 26 is selected from S, T, A, or N, and X 27 is selected from W, N, or S, and X 28 is selected from A or W, and X 29 is selected from K or A, and X 30is present or absent, and if present is selected from G or K, and X 31 is either present or absent, and if present, is G.

[0072] Optionally, the VH region of the anti-CD38 antibody has the CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY (SEQ ID NO: 421), wherein X 38 is selected from A or G, and X 41 is selected from F or Y.

[0073] Optionally, the VH region of the anti-CD38 antibody comprises the CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 where X 32 is selected from A, G, or V, and X 33 is selected from A, R, T, S, or G, and X 34 is selected from A, V, T, P, I, E, D, or S, and X 35 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, and X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I, and X 38 is selected from G, S, D, K, F, L, or Y, and X 39 is selected from T, A, G, S, I, or Y, and X 40 is selected from S, Y, G, R, W, N, L, D, or F, and X 41 is present or absent, and if present is selected from V, D, A, N, G, L, or E; X 42is present or absent, and if present is selected from L, Y, F, T, or G; X 43 is present or absent, and if present is selected from P, F, V, N, S, or Y; X 44 is present or absent, and if present is selected from L, S, T, G, F, and X 45 is present or absent, and if present is selected from L, F, E, S, or N; X 46 is present or absent, and if present is selected from S, L, or R; X 47 is either present or absent, and if present, is L, and X 48 is present or absent, and if present, is D, and X 49 is either present or absent and, if present, is L.

[0074] Optionally, the VH region of the anti-CD38 antibody comprises the CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 where X 32 is selected from A or G, and X 33 is selected from A, R, or T, and X 34 is selected from A, V, T, P, I, E, or D, and X 35 is selected from G, W, D, L, K, or P, and X 36 is selected from P, A, Y, D, or G, and X 37 is selected from Y, V, T, S, N, A, or G, and X 38 is selected from G, S, D, or K, and X 39 is selected from T, A, G, S, or I, and X 40 is selected from S, Y, G, R, or W, and X 41 is selected from V, D, Y, A, N, or G, and X 42is selected from L, Y, or F, and X 43 is present or absent, and if present is selected from P, F, V, or N; X 44 is present or absent, and if present is selected from L, S, or T, and X 45 is present or absent and, if present, is selected from L or F.

[0075] Optionally, the VH region of the anti-CD38 antibody comprises the CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 422), wherein X 33 is selected from R or G, and X 34 is selected from E, D, or S, and X 35 is selected from G, L, P, S, or A, and X 36 is selected from D, S, or R, and X 37 is selected from Y, T, N, or G, and X 38 is selected from G, S, F, or L, and X 39 is selected from A, G, S, or I, and X 40 is selected from Y, N, or L, and X 41 is present or absent, and if present is selected from V, Y, or E; X 42 is either present or absent, and if present, it is G, and X 43 is either present or absent, and if present, it is Y and X 44 is either present or absent, and if present, it is F, and X 45 is present or absent, and if present is selected from E or N, and X 46 is present or absent and, if present, is selected from S or L.

[0076] In some examples, the VH region of the anti-CD38 antibody has 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 PTGFDY (SEQ ID NO: 421), wherein X5 is selected from D or G; X6 is selected from V, A, or T; 22 is selected from F or Y, and X 38 is selected from A or G, and X 41 is selected from F or Y.

[0077] In some examples, the VH region of the anti-CD38 antibody has the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (SEQ ID NO: 426), CDR2 sequence X 13 X 14 IX 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 , and CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 wherein X5 is selected from S or N, X6 is selected from R, S, or N, X7 is selected from Y, I, or N, X8 is selected from Y, D, G, or A, X9 is selected from V, M, or I, and X 10 is selected from T, S, or M, and X 11is either present or absent, and if present, it is C, and X 13 is selected from A or G, and X 14 is selected from I, F, Y, V, S, or C, and X 16 is selected from G, Y, S, T, or L, and X 17 is selected from S, I, K, Y, T, or G, and X 18 is selected from G, S, or T, and X 19 is selected from G, A, D, or S, and X 20 is selected from T, I, N, or G, and X 21 is selected from T, I, or D, and X 22 is selected from Y, N, or T, and X 23 is selected from Y or D, and X 24 is selected from A or Y, and X 25 is selected from T, S, N, R, or A, and X 26 is selected from W or T, and X 27 is selected from A or W, and X 28 is selected from K, R, Q, or A, and X 29 is selected from G or K, and X 30 is either present or absent, and if present, it is G, and X 32 is selected from A or G, and X 33 is selected from A, R, or T, and X 34 is selected from A, V, T, P, I, E, or D, and X 35 is selected from G, W, D, L, K, or P, and X 36 is selected from P, A, Y, D, or G, and X 37 is selected from Y, V, T, S, N, A, or G, and X 38 is selected from G, S, D, or K, and X 39 is selected from T, A, G, S, or I, and X 40 is selected from S, Y, G, R, or W, and X 41 is selected from V, D, Y, A, N, or G, and X 42 is selected from L, Y, or F, and X 43 is present or absent, and if present is selected from P, F, V, or N; X 44is present or absent, and if present is selected from L, S, or T, and X 45 is present or absent and, if present, is selected from L or F.

[0078] In some examples, the VH region of the anti-CD38 antibody has the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (SEQ ID NO: 419), CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 , and 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 (SEQ ID NO: 422), wherein X4 is selected from F or A, X5 is selected from S, T, or N, X6 is selected from S, T, or N, X7 is selected from Y, R, A, or G, X8 is selected from W, Y, or C, and X9 is selected from I, W, Y, or D; 10 is selected from C, I, Y, or M, and X 11 is present or absent, and if present is selected from C or M, and X 12 is either present or absent, and if present, it is C, and X 13 is selected from A or S, and X 15 is selected from I, L, or T, and X 16is selected from Y or V, and X 17 is selected from S, T, or A, and X 18 is selected from G, P, or V, and X 19 is selected from D, S, or T, and X 20 is selected from S, T, or G, and X 21 is selected from D, N, S, or A, and X 22 is selected from T, I, or S, and X 23 is selected from Y, K, or I, and X 25 is selected from A or Y, and X 26 is selected from S, T, A, or N, and X 27 is selected from W, N, or S, and X 28 is selected from A or W, and X 29 is selected from K or A, and X 30 is present or absent, and if present is selected from G or K, and X 31 is either present or absent, and if present, it is G, and X 33 is selected from R or G, and X 34 is selected from E, D, or S, and X 35 is selected from G, L, P, S, or A, and X 36 is selected from D, S, or R, and X 37 is selected from Y, T, N, or G, and X 38 is selected from G, S, F, or L, and X 39 is selected from A, G, S, or I, and X 40 is selected from Y, N, or L, and X 41 is present or absent, and if present is selected from V, Y, or E; X 42 is either present or absent, and if present, it is G, and X 43 is either present or absent, and if present, it is Y and X 44 is either present or absent, and if present, it is F, and X 45 is present or absent, and if present is selected from E or N, and X 46 is present or absent and, if present, is selected from S or L.

[0079] In some embodiments, the VH region of the anti-CD38 antibody comprises a CDR1, CDR2, and CDR3 sequence 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 and where X 32 is selected from A, G, or V, and X 33 is selected from K, A, R, T, G, or S, and X 34 is selected from R, A, V, T, P, I, E, D, or S, and X 35 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, and X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I, and X 38 is selected from G, A, S, D, K, F, L, or Y, and X 39 is selected from Y, T, A, G, S, or I, and X 40is selected from S, Y, G, R, W, N, L, D, or F, and X 41 is present or absent, and if present is selected from F, Y, V, D, A, N, G, E, or L; X 42 is present or absent, and if present is selected from P, L, Y, F, G, or T; X 43 is present or absent, and if present is selected from T, P, F, V, N, Y, or S; X 44 is present or absent, and if present is selected from G, L, S, T, or F; X 45 is present or absent, and if present is selected from F, L, E, N, or S; X 46 is present or absent, and if present is selected from D, S, L, or R; X 47 is present or absent, and if present is selected from Y or L, and X 48 is present or absent, and if present, is D, and X 49 is either present or absent and, if present, 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 PTGFDY (SEQ ID NO: 421), wherein X 38 is selected from A or G, and X 41 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 and where X 32 is selected from A, G, or V, and X 33 is selected from A, R, T, S, or G, and X 34 is selected from A, V, T, P, I, E, D, or S, and X 35 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, and X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I, and X 38 is selected from G, S, D, K, F, L, or Y, and X 39 is selected from T, A, G, S, I, or Y, and X 40 is selected from S, Y, G, R, W, N, L, D, or F, and X 41 is present or absent, and if present is selected from V, D, A, N, G, L, or E; X 42 is present or absent, and if present is selected from L, Y, F, T, or G; X 43 is present or absent, and if present is selected from P, F, V, N, S, or Y; X 44 is present or absent, and if present is selected from L, S, T, G, or F; X 45 is present or absent, and if present is selected from L, F, E, S, or N; X 46 is present or absent, and if present is selected from S, L, or R; X 47 is either present or absent, and if present, is L, and X 48 is present or absent, and if present, is D, and X 49 is either present or absent and, if present, 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 and where X 32 is selected from A or G, and X 33 is selected from A, R, or T, and X 34 is selected from A, V, T, P, I, E, or D, and X 35 is selected from G, W, D, L, K, or P, and X 36 is selected from P, A, Y, D, or G, and X 37 is selected from Y, V, T, S, N, A, or G, and X 38 is selected from G, S, D, or K, and X 39 is selected from T, A, G, S, or I, and X 40 is selected from S, Y, G, R, or W, and X 41 is selected from V, D, Y, A, N, or G, and X 42 is selected from L, Y, or F, and X 43 is present or absent, and if present is selected from P, F, V, or N; X 44 is present or absent, and if present is selected from L, S, or T, and X 45 is present or absent and, if present, 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 (SEQ ID NO: 422), wherein X 33 is selected from R or G, and X 34 is selected from E, D, or S, and X 35 is selected from G, L, P, S, or A, and X 36 is selected from D, S, or R, and X 37 is selected from Y, T, N, or G, and X 38 is selected from G, S, F, or L, and X 39 is selected from A, G, S, or I, and X 40 is selected from Y, N, or L, and X 41 is present or absent, and if present is selected from V, Y, or E; X 42 is either present or absent, and if present, it is G, and X 43 is either present or absent, and if present, it is Y and X 44 is either present or absent, and if present, it is F, and X 45 is present or absent, and if present is selected from E or N, and X 46 is present or absent and, if present, is selected from S or L.

[0086] In some embodiments, the VH region of the anti-CD38 antibody has the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from P, S, or D; X4 is selected from F, L, or A; X5 is selected from D, G, S, N, or T; X6 is selected from V, A, T, R, S, I, or N; X7 is selected from Y, I, N, R, A, G, or D; X8 is selected from A, Y, D, G, W, C, or T; X9 is selected from M, V, I, W, D, or Y; 10 is selected from S, T, M, C, I, Y, A, or G, and X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C, and said VH region further comprises 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.

[0087] In some embodiments, the VH region of an 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 a CDR2 sequence selected from SEQ ID NOs: 2 and 5, and a CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10. In some embodiments, the VH region of an anti-CD38 antibody comprises the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent, and if present is S, X2 is selected from F or I, X3 is selected from S or D, X4 is selected from L, F, or A, X5 is selected from S, N, or T, X6 is selected from R, S, N, I, or T, X7 is selected from Y, I, N, R, A, D, or G, X8 is selected from Y, D, G, A, W, T, or C, X9 is selected from V, M, I, W, Y, or D, and X10 is selected from T, S, M, C, I, Y, A, or G, and X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C, and said VH region further comprises 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.

[0088] In some embodiments, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (SEQ ID NO: 426), wherein X5 is selected from S or N, X6 is selected from R, S, or N, X7 is selected from Y, I, or N, X8 is selected from Y, D, G, or A, X9 is selected from V, M, or I, and X 10 is selected from T, S, or M, and X 11 is present or absent, and if present is C, and said VH region further comprises 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.

[0089] In some embodiments, the VH region of the anti-CD38 antibody comprises the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (SEQ ID NO: 419), wherein X4 is selected from F or A, X5 is selected from S, T, or N, X6 is selected from S, T, or N, X7 is selected from Y, R, A, or G, X8 is selected from W, Y, or C, X9 is selected from I, W, Y, or D, and X 10 is selected from C, I, Y, or M, and X 11is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C, and said VH region further comprises 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.

[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 and where X 13 is selected from A, G, or S, and X 14 is selected from I, F, Y, V, S, or C, and X 15 is selected from S, I, L, T, or M, and X 16 is selected from G, Y, S, T, L, or V, and X 17 is selected from S, I, K, Y, T, G, or A, and X 18 is selected from G, S, T, P, V, or Y, and X 19 is selected from G, A, D, S, or T, and X 20 is selected from S, T, I, N, or G, and X 21 is selected from T, I, D, N, S, or A, and X 22 is selected from F, Y, N, T, I, or S, and X 23 is selected from Y, D, K, or I, and X 24 is selected from A or Y, and X25 is selected from D, T, S, N, R, A, or Y, and X 26 is selected from S, W, T, A, or N, and X 27 is selected from V, A, W, N, or S, and X 28 is selected from K, R, Q, A, or W, and X 29 is selected from G, K, or A, and X 30 is present or absent, and if present is selected from G or K, and X 31 is present or absent and, if present, is G, and said VH region further comprises 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.

[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), wherein X 22 is selected from F or Y, and said VH region further comprises a CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10.

[0092] 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 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 and where X 13is selected from A, G, or S, and X 14 is selected from I, F, Y, V, S, or C, and X 15 is selected from I, L, M, or T, and X 16 is selected from G, Y, S, T, L, or V, and X 17 is selected from S, I, K, Y, T, G, or A, and X 18 is selected from G, S, T, P, or V, and X 19 is selected from G, A, D, S, or T, and X 20 is selected from S, T, I, N, or G, and X 21 is selected from T, I, D, N, S, or A, and X 22 is selected from Y, N, T, I, or S, and X 23 is selected from Y, D, K, or I, and X 24 is selected from A or Y, and X 25 is selected from T, S, N, R, A, or Y, and X 26 is selected from S, W, T, A, or N, and X 27 is selected from A, W, N, or S, and X 28 is selected from K, R, Q, A, or W, and X 29 is selected from G, K, or A, and X 30 is present or absent, and if present is selected from G or K, and X 31 is present or absent and, if present, is G, and said VH region further comprises 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.

[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 and where X 13 is selected from A or G, and X 14 is selected from I, F, Y, V, S, or C, and X 16 is selected from G, Y, S, T, or L, and X 17 is selected from S, I, K, Y, T, or G, and X 18 is selected from G, S, or T, and X 19 is selected from G, A, D, or S, and X 20 is selected from T, I, N, or G, and X 21 is selected from T, I, or D, and X 22 is selected from Y, N, or T, and X 23 is selected from Y or D, and X 24 is selected from A or Y, and X 25 is selected from T, S, N, R, or A, and X 26 is selected from W or T, and X 27 is selected from A or W, and X 28 is selected from K, R, Q, or A, and X 29 is selected from G or K, and X 30 is present or absent and, if present, is G, and said VH region further comprises a CDR3 sequence selected from SEQ ID NOs: 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 and where X 13 is selected from A or S, and X 15 is selected from I, L, or T, and X 16 is selected from Y or V, and X 17 is selected from S, T, or A, and X 18 is selected from G, P, or V, and X 19 is selected from D, S, or T, and X 20 is selected from S, T, or G, and X 21 is selected from D, N, S, or A, and X 22 is selected from T, I, or S, and X 23 is selected from Y, K, or I, and X 25 is selected from A or Y, and X 26 is selected from S, T, A, or N, and X 27 is selected from W, N, or S, and X 28 is selected from A or W, and X 29 is selected from K or A, and X 30 is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G, and the VH region further comprises a CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58.

[0095] In some examples, 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 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 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 selected from SEQ ID NOs: 3, 7, and 10.

[0097] In some examples, 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 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 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 selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52.

[0099] In some examples, 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 selected from SEQ ID NOs: 19, 25, 31, 46, and 58.

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

[0101] [Table 2]

[0102] In some embodiments, the VL region of the anti-CD38 antibody comprises a CDR1 sequence selected from SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from SEQ ID NOs: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103. In some examples, the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from SEQ ID NOs: 66, 69, 81, 78, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100. In some examples, 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.

[0103] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from SEQ ID NOs: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR3 sequence X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 and where X32 is selected from A, G, or V, and X 33 is selected from K, A, R, T, G, or S, and X 34 is selected from R, A, V, T, P, I, E, D, or S, and X 35 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, and X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I, and X 38 is selected from G, A, S, D, K, F, L, or Y, and X 39 is selected from Y, T, A, G, S, or I, and X 40 is selected from S, Y, G, R, W, N, L, D, or F, and X 41 is present or absent, and if present is selected from F, Y, V, D, A, N, G, E, or L; X 42 is present or absent, and if present is selected from P, L, Y, F, G, or T; X 43 is present or absent, and if present is selected from T, P, F, V, N, Y, or S; X 44 is present or absent, and if present is selected from G, L, S, T, or F; X 45 is present or absent, and if present is selected from F, L, E, N, or S; X 46 is present or absent, and if present is selected from D, S, L, or R; X 47 is present or absent, and if present is selected from Y or L, and X 48 is present or absent, and if present, is D, and X 49is present or absent and, if present, is L, and said VL region comprises a CDR1 sequence selected from SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from SEQ ID NOs: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0104] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9, a CDR2 sequence selected from SEQ ID NOs: 2 and 5, and a CDR3 sequence selected from AKRGTYX 38 YSX 41 PTGFDY (SEQ ID NO: 421), wherein X 38 is selected from A or G, and X 41 is selected from F or Y, and said 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.

[0105] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 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 and where X 32 is selected from A, G, or V, and X 33 is selected from A, R, T, S, or G, and X 34 is selected from A, V, T, P, I, E, D, or S, and X 35 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, and X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I, and X 38 is selected from G, S, D, K, F, L, or Y, and X 39 is selected from T, A, G, S, I, or Y, and X 40 is selected from S, Y, G, R, W, N, L, D, or F, and X 41 is present or absent, and if present is selected from V, D, A, N, G, L, or E; X 42 is present or absent, and if present is selected from L, Y, F, T, or G; X 43 is present or absent, and if present is selected from P, F, V, N, S, or Y; X 44 is present or absent, and if present is selected from L, S, T, G, or F; X 45 is present or absent, and if present is selected from L, F, E, S, or N; X 46 is present or absent, and if present is selected from S, L, or R; X 47 is either present or absent, and if present, is L, and X 48 is present or absent, and if present, is D, and X 49is present or absent and, if present, is L, and said VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from SEQ ID NOs: 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from SEQ ID NOs: 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, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50, a CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51, and a CDR3 sequence 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 and where X 32 is selected from A or G, and X 33 is selected from A, R, or T, and X 34 is selected from A, V, T, P, I, E, or D, and X 35 is selected from G, W, D, L, K, or P, and X 36 is selected from P, A, Y, D, or G, and X 37 is selected from Y, V, T, S, N, A, or G, and X 38 is selected from G, S, D, or K, and X 39 is selected from T, A, G, S, or I, and X 40 is selected from S, Y, G, R, or W, and X 41 is selected from V, D, Y, A, N, or G, and X 42 is selected from L, Y, or F, and X 43is present or absent, and if present is selected from P, F, V, or N; X 44 is present or absent, and if present is selected from L, S, or T, and X 45 is present or absent, and if present is selected from L or F, and said VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from SEQ ID NOs: 66, 69, 78, 81, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 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, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56, a CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57, and a CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 422), wherein X 33 is selected from R or G, and X 34 is selected from E, D, or S, and X 35 is selected from G, L, P, S, or A, and X 36 is selected from D, S, or R, and X 37 is selected from Y, T, N, or G, and X 38 is selected from G, S, F, or L, and X 39 is selected from A, G, S, or I, and X 40 is selected from Y, N, or L, and X 41 is present or absent, and if present is selected from V, Y, or E; X 42 is either present or absent, and if present, it is G, and X 43is either present or absent, and if present, it is Y and X 44 is either present or absent, and if present, it is F, and X 45 is present or absent, and if present is selected from E or N, and X 46 is present or absent, and if present is selected from S or L, and said 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.

[0108] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region has the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from P, S, or D; X4 is selected from F, L, or A; X5 is selected from D, G, S, N, or T; X6 is selected from V, A, T, R, S, I, or N; X7 is selected from Y, I, N, R, A, G, or D; X8 is selected from A, Y, D, G, W, C, or T; X9 is selected from M, V, I, W, D, or Y; 10 is selected from S, T, M, C, I, Y, A, or G, and X 11 is present or absent, and if present is selected from C or M, and X 12is present or absent, and if present is C, and the VH region further comprises 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, and the VL region is , SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; CDR2 sequences selected from SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and CDR3 sequences selected from SEQ ID NOs: 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, wherein the VH region 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; 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 comprises a VH region and a VL region, wherein the VH region has the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12wherein 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, and X 10 is selected from T, S, M, C, I, Y, A, or G, and X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C, said VH region further comprising 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; and said VL region and a CDR3 sequence selected from SEQ ID NOs: 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 comprises a VH region and a VL region, wherein the VH region has the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (SEQ ID NO: 426), wherein X5 is selected from S or N, X6 is selected from R, S, or N, X7 is selected from Y, I, or N, X8 is selected from Y, D, G, or A, X9 is selected from V, M, or I, and X 10 is selected from T, S, or M, and X 11is present or absent and, if present, is C; the VH region further comprises 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; and the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from SEQ ID NOs: 66, 69, 78, 81, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.

[0112] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region has the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (SEQ ID NO: 419), wherein 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, and X9 is selected from I, W, Y, or D; 10 is selected from C, I, Y, or M, and X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent and, if present, is C; the VH region further comprises 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.

[0113] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, 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 and where X 13 is selected from A, G, or S, and X 14 is selected from I, F, Y, V, S, or C, and X 15 is selected from S, I, L, T, or M, and X 16 is selected from G, Y, S, T, L, or V, and X 17 is selected from S, I, K, Y, T, G, or A, and X 18 is selected from G, S, T, P, V, or Y, and X 19 is selected from G, A, D, S, or T, and X 20 is selected from S, T, I, N, or G, and X 21 is selected from T, I, D, N, S, or A, and X 22 is selected from F, Y, N, T, I, or S, and X 23 is selected from Y, D, K, or I, and X 24 is selected from A or Y, and X 25 is selected from D, T, S, N, R, A, or Y, and X 26 is selected from S, W, T, A, or N, and X 27 is selected from V, A, W, N, or S, and X 28 is selected from K, R, Q, A, or W, and X 29 is selected from G, K, or A, and X 30is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G, said VH region further comprises 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; and said VL region is 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.

[0114] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region has a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9, and a CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID NO: 418), wherein X 22 is selected from F or Y, the VH region further comprises 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.

[0115] In some embodiments, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 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 and where X 13 is selected from A, G, or S, and X 14 is selected from I, F, Y, V, S, or C, and X 15 is selected from I, L, M, or T, and X 16 is selected from G, Y, S, T, L, or V, and X 17 is selected from S, I, K, Y, T, G, or A, and X 18 is selected from G, S, T, P, or V, and X 19 is selected from G, A, D, S, or T, and X 20 is selected from S, T, I, N, or G, and X 21 is selected from T, I, D, N, S, or A, and X 22 is selected from Y, N, T, I, or S, and X 23 is selected from Y, D, K, or I, and X 24 is selected from A or Y, and X 25 is selected from T, S, N, R, A, or Y, and X 26 is selected from S, W, T, A, or N, and X 27 is selected from A, W, N, or S, and X 28 is selected from K, R, Q, A, or W, and X 29 is selected from G, K, or A, and X 30 is present or absent, and if present is selected from G or K, and X 31is present or absent and, if present, is G, and the VH region further comprises 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; and the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102, a CDR2 sequence selected from SEQ ID NOs: 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 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, wherein the VH region 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 X 25 X 26 X 27 X 28 X 29 X 30 and where X 13 is selected from A or G, and X 14 is selected from I, F, Y, V, S, or C, and X 16 is selected from G, Y, S, T, or L, and X 17 is selected from S, I, K, Y, T, or G, and X 18 is selected from G, S, or T, and X 19 is selected from G, A, D, or S, and X 20 is selected from T, I, N, or G, and X 21 is selected from T, I, or D, and X 22 is selected from Y, N, or T, and X 23 is selected from Y or D, and X24 is selected from A or Y, and X 25 is selected from T, S, N, R, or A, and X 26 is selected from W or T, and X 27 is selected from A or W, and X 28 is selected from K, R, Q, or A, and X 29 is selected from G or K, and X 30 is present or absent and, if present, is G, and the VH region further comprises a CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from SEQ ID NOs: 66, 69, 78, 81, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 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, wherein the VH region 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 X 30 X 31 and where X 13 is selected from A or S, and X 15 is selected from I, L, or T, and X 16 is selected from Y or V, and X 17 is selected from S, T, or A, and X 18 is selected from G, P, or V, and X 19 is selected from D, S, or T, and X 20 is selected from S, T, or G, and X 21is selected from D, N, S, or A, and X 22 is selected from T, I, or S, and X 23 is selected from Y, K, or I, and X 25 is selected from A or Y, and X 26 is selected from S, T, A, or N, and X 27 is selected from W, N, or S, and X 28 is selected from A or W, and X 29 is selected from K or A, and X 30 is present or absent, and if present is selected from G or K, and X 31 is present or absent and, if present, is G, and the VH region further comprises 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.

[0118] In some examples, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; a CDR2 sequence selected from SEQ ID NOs: 2, 5, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, and 57; and a CDR2 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, and the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102, a CDR2 sequence selected from SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0119] In some examples, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9, a CDR2 sequence selected from SEQ ID NOs: 2 and 5, and a CDR3 sequence 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 comprises 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 a CDR2 sequence selected from SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117 , 55, and 58, and the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102, a CDR2 sequence selected from SEQ ID NOs: 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0121] In some examples, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 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; and the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from SEQ ID NOs: 66, 69, 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, the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56, a CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57, and a CDR3 sequence 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 comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 104-128, and the sequence of the VL region comprises about 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 130-154.

[0124] In some embodiments, the VH region comprises a sequence selected from Table 3 and the VL region comprises a sequence 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 is a full-length antibody. In other embodiments, the anti-CD38 antibody is a binding fragment. In some examples, the anti-CD38 antibody comprises an antibody or binding fragment thereof, a chimeric antibody or binding fragment thereof, a monoclonal antibody or binding fragment thereof, or a bispecific antibody or binding fragment thereof. Optionally, the anti-CD38 antibody comprises a monovalent Fab, a bivalent Fab'2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody or binding fragment thereof.

[0130] In some embodiments, the anti-CD38 antibody comprises a bispecific antibody or binding fragment thereof. In some examples, the bispecific antibody or binding fragment thereof is a bispecific antibody conjugate, a hybrid bispecific IgG, a variable domain-only bispecific antibody, a CH1 / CL fusion protein, a Fab fusion protein, a non-immunoglobulin fusion protein, an Fc-modified IgG, an 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, the bispecific antibody or binding fragment includes Knobs-into-Hole (KIH), Asymmetric Re-engineering Technology-immunoglobulin (ART-Ig), Triomab quadroma, bispecific monoclonal antibody (BiMAb, BsmAb, BsAb, bsMab, BS-Mab, or Bi-MAb), FcΔAdp, XmAb, Azymetric, Bispecific Engagement by T-cell Receptor-Based Antibodies (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 nanobody.

[0132] In some embodiments, variable domain-only bispecific antibodies comprise tandem scFvs (taFvs), triplebodies, diabodies (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 comprises scFv2-CH1 / CL or VHH2-CH1 / CL.

[0134] In some examples, the Fab fusion protein comprises a Fab-scFv (bibody), a Fab-scFv2 (tribody), a Fab-Fv, a Fab-dsFv, a Fab-VHH, or an orthogonal Fab-Fab.

[0135] In some examples, the non-immunoglobulin fusion protein comprises scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, miniantibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, or ImmTAC(TCR-scFv).

[0136] In some examples, the Fc-modified IgG comprises IgG(KIH), IgG(KIH) common LC, ZW1 IgG commom LC, Biclonics commom 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, the associated & Fc-modified IgG comprises IgG(KIH)-Fv, IgG(HA-TF-FV), IgG(KIH)-scFab, scFab-Fc(KIH)-scFv2, scFab-Fc(KIH)-scFv, half DVD-Ig, Dual Variable Domain-immunoglobulin (DVD-Ig), or CrossMab-Fab.

[0138] Optionally, the modified Fc and CH3 fusion protein comprises scFv-Fc(KIH), scFv-Fc(CH3 charge pair), scFv-FC(EW-RVT), scFv-Fc(HA-TF), scFv-Fc(SEEDbody), taFv-Fc(KIH), scFv-Fc(KIH)-Fv, Fab-Fc(KIH)-scFv, Fab-scFv-Fc(KIH), Fab-scFv-Fc(BEAT), DART-Fc, scFv-CH3(KIH), or TriFab.

[0139] Optionally, the associated IgG-HC fusion antibody comprises an IgG-HC-scFv, an IgG-dAb, an IgG-taFv, an IgG-CrossFab, an IgG-orthogonal Fab, an IgG-(CαCβ)Fab, an scFv-HC-IgG, a tandem Fab-IgG, an Fab-IgG(CαCβFab), an Fab-IgG(CR3), or an Fab-hinge-IgG(CR3).

[0140] Optionally, the accompanying IgG-LC fusion antibody comprises an IgG-scFv(LC), an scFv(LC)-IgG, or a dAb-IgG.

[0141] Optionally, the accompanying IgG-HC&LC fusion antibody comprises a DVD-Ig, a TVD-Ig, a CODV-Ig, an scFv4-IgG, or a Zybody.

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

[0143] In some examples, the CH3 fusion antibody comprises a Di-diabody or scDb-CH3.

[0144] In some examples, the IgE / IgM CH2 fusion antibody comprises scFv-EHD2-scFv or scFv-MHD2-scFv.

[0145] In some examples, the F(ab')2 fusion antibody comprises a F(ab')2-scFv2.

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

[0147] In some examples, the modified IgG is a DAF (two-in-one-IgG), a DutaMab, or a mAb 2 Includes:

[0148] Optionally, the non-immunoglobulin fusion antibody comprises DNL-Fab4-IgG.

[0149] In some examples, the anti-CD38 antibody comprises a bispecific antibody or binding fragment thereof as depicted in FIG. 1A or FIG. 1B.

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

[0151] Optionally, the anti-CD38 antibody further comprises one or more mutations in a framework region, such as the CH1 domain, CH2 domain, CH3 domain, hinge region, or a combination thereof. In some examples, the one or more mutations stabilize the antibody and / or increase half-life. In some examples, the one or more mutations modulate Fc receptor interaction and increase ADCC or complement-dependent cytotoxicity (CDC). In other examples, the one or more mutations reduce or eliminate an Fc effector function, such as FcγR binding, ADCC, or CDC. In additional examples, the one or more mutations modulate glycosylation.

[0152] In some cases, the anti-CD38 antibody comprises an IgG1 framework. In some embodiments, the constant region of the anti-CD38 antibody is modified at one or more amino acid positions to modify Fc-receptor interaction. Exemplary residues that modulate or modify 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 IgG1 constant region aimed at improving Fc receptor interactions increase half-life. In some examples, the 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 improving 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 a combination 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. Optionally, modifications at one or more amino acid positions aimed at increasing ADCC include S239D / A330L / I332E. Optionally, 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 IgG1 constant region to improve Fc receptor interactions increase phagocytosis by macrophages. In some examples, the modifications at one or more amino acid positions include G236, S239, I332, or a combination thereof. In some cases, the modifications at one or more amino acid positions to increase phagocytosis by macrophages include the combination S239D / I332I / G236A.

[0156] In some embodiments, the IgG1 constant region is modified at amino acid N297 (Kabat numbering), eg, N297C.

[0157] In some embodiments, the anti-CD38 antibody comprises an IgG2 framework. In some examples, one or more amino acid positions in the IgG2 framework are modified to improve Fc receptor interaction, for example, to increase ADCC and / or CDC. Optionally, one or more amino acid positions in the IgG2 framework are modified to stabilize the antibody and / or extend half-life. In some examples, one or more amino acid positions in the IgG2 framework are modified to regulate glycosylation. Optionally, the IgG2 constant region 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 improve Fc receptor interaction, for example, to increase ADCC and / or CDC. Optionally, one or more amino acid positions in the IgG3 framework are modified to stabilize the antibody and / or increase half-life. In some examples, one or more amino acid positions in the IgG3 framework are modified to regulate glycosylation. Optionally, the constant region of the antibody is modified at amino acid R435, e.g., R435H (Kabat numbering), to increase 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 improve Fc receptor interaction, for example, to increase ADCC and / or CDC. For example, mutations that increase ADCC in some embodiments include S239D, I332E, and A330L, such as those described in U.S. Pat. No. 8,093,359 (amino acid numbering according to 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 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 modified amino acid is S228 (e.g., S228P).

[0160] In some embodiments, the human IgG constant region is modified for ADCC and / or CDC, e.g., 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 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 human IgG constant region is modified to induce heterodimerization. For example, if there is an amino acid modification in the CH3 domain at Thr366, which is replaced with a bulkier amino acid, such as Trp (T366W), it can preferentially pair with a second CH3 domain that has amino acid modifications to less bulky amino acids at Thr366, Leu368, and Tyr407, such as Ser, Ala, and Val, respectively. In some cases, heterodimerization via CH3 modification can be further stabilized by introducing disulfide bonds, for example, by changing 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 instances, the anti-CD38 antibodies described herein have reduced or absent glycosylation but are not modified at amino acid Asn297 (Kabat numbering). In these instances, glycosylation is eliminated by, for example, producing the antibody in a host cell lacking post-translational glycosylation capabilities, such as a bacterial or yeast-derived system, or a modified mammalian cell expression system. In certain embodiments, such a system is a cell-free expression system.

[0163] In some embodiments, the anti-CD38 antibodies described herein are full-length antibodies and comprise 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 have enhanced ADCC and / or CDC compared to daratumumab as a reference antibody. Optionally, the enhanced ADCC and / or CDC is at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, or more increase compared to daratumumab. Optionally, the enhanced ADCC and / or CDC is about a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, or more increase compared to daratumumab.

[0173] Optionally, the enhanced ADCC and / or CDC is at least a 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 increase compared to the reference antibody, daratumumab. Optionally, the enhanced ADCC and / or CDC is about a 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 increase compared to the reference antibody, daratumumab.

[0174] In some embodiments, the anti-CD38 antibodies described herein are administered in an in vitro cytotoxicity assay to determine ADCC activity, e.g., using PBMC effector cells and target cancer cells, such as B lymphoblast cells from lymphoma, e.g., Daudi cells, at a concentration of about 1x10 -6 nM to about 2 nM, e.g., about 4 x 10 -6nM, about 0.000014 nM, 0.00007 nM, 0.00006 nM, about 0.00010 nM, about 0.0002 nM, about 0.0003 nM, 0.1 nM, about 0.2 nM, about 0.3 nM, about 0.4 nM, about 0.5 nM, about 0.6 nM, about 0.7 nM, about 0.8 nM, about 0.9 nM, about 1.0 nM, or an EC 50 It has the following characteristics.

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

[0176] In some instances, the improved cell killing effect is at least a 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 increase compared to the reference antibody, daratumumab. In some instances, the improved cell killing effect is about a 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 increase compared to the reference antibody, daratumumab.

[0177] In some embodiments, the anti-CD38 antibodies described herein have an improved serum half-life compared to the reference antibody daratumumab. In some examples, the improved serum half-life is at least 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or more, compared to the reference antibody daratumumab.

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

[0179] Anti-ICAM1 antibody In some embodiments, the present disclosure provides anti-ICAM1 antibodies. In some examples, the anti-ICAM1 antibodies include a variable heavy (VH) region and a variable light (VL) region, wherein the VH region has the CDR1 sequence X1X2X3X4X5X6X7X8X9X 10 X 11 wherein 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, and X 10 is selected from S, G, N, M, or I, and X 11 is present or absent, and if present is C, and said VH region comprises the CDR2 sequence X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28X 29 X 30 where X 12 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, and X 15 is selected from S, G, T, D, or P, and X 16 is selected from F, S, D, T, or A, and X 17 is selected from S, R, G, or D, and X 18 is selected from G, D, or S, and X 19 is selected from S, R, T, N, Y, A, D, or P, and X 20 is selected from T, A, G, or Y, and X 21 is selected from Y, H, A, S, or T, and X 22 is selected from Y or N, and X 23 is selected from A, P, Y, or S, and X 24 is selected from S, T, N, D, Y, A, or P, and X 25 is selected from W, S, A, or D, and X 26 is selected from A, V, T, W, F, or S, and X 27 is selected from K, W, A, Q, or V, and X 28 is selected from G, A, or K, and X 29 is present or absent, and if present is selected from K or G, and X 30 is present or absent, and if present is G, and said VH region comprises the CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 where X 31is selected from A or V, and X 32 is selected from R or I, and X 33 is selected from G, D, P, A, or V, and X 34 is selected from G, P, W, D, N, or R, and X 35 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, and X 37 is selected from G, S, D, V, or E, and X 38 is selected from G, Y, F, S, or D, and X 39 is selected from S, D, G, T, N, A, or V, and X 40 is selected from T, A, D, S, Y, L, or F, and X 41 is present or absent, and if present is selected from Y, A, G, I, or D; X 42 is present or absent, and if present is selected from I, Y, R, P, V, or G; X 43 is present or absent, and if present is selected from L, R, Y, G, or A; X 44 is present or absent, and if present is selected from N, L, S, Y, S, or W; X 45 is present or absent, and if present is selected from L, Y, F, or C; X 46 is present or absent, and if present is selected from D, A, or F, and X 47 is present or absent, and if present is selected from M, P, Y, or N; X 48 is present or absent, and if present is selected from D or L, and X 49 is either present or absent and, if present, is L.

[0180] In some instances, the VH region of the anti-ICAM1 antibody has the CDR1 sequence GFSLX5X6X7X8MX 10 (SEQ ID NO: 425), wherein 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 10is selected from S, G, or N.

[0181] In some instances, the VH region of the anti-ICAM1 antibody comprises the CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG (SEQ ID NO: 420), wherein X 13 is selected from W, I, or Y, and X 15 is selected from S or G, and X 16 is selected from F, S, D, or T, and X 17 is selected from S or R, and X 18 is selected from G or D, and X 19 is selected from S, R, T, or N, and X 20 is selected from T or A, and X 24 is selected from S, T, or N.

[0182] In some instances, the VH region of an anti-ICAM1 antibody comprises the CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 (SEQ ID NO: 424), wherein X 31 is selected from A or V, and X 33 is selected from G or D, and X 34 is selected from G, P, W, or D, and X 35 is selected from D, Y, S, or L, and X 36 is selected from Y, D, V, or L, and X 37 is selected from G, S, or D, and X 38is selected from G, Y, F, or S, and X 39 is selected from S, D, G, or T, and X 40 is selected from T, A, D, S, or Y, and X 41 is selected from Y, A, G, or I, and X 42 is selected from I, Y, or R, and X 43 is selected from L, R, Y, or G, and X 44 is selected from N, L, Y, or S, and X 45 is present or absent, and if present is selected from L, Y, or F; X 46 is either present or absent, and if present, it is D, and X 47 is present or absent, and if present is selected from M or P, and X 48 is present or absent, and if present, is D, and X 49 is either present or absent and, if present, is L.

[0183] In some instances, the VH region of the anti-ICAM1 antibody has the CDR1 sequence GFSLX5X6X7X8MX 10 (SEQ ID NO: 425) and CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG (SEQ ID NO: 420) and CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49(SEQ ID NO: 424), wherein 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 is selected from S, G, or N, and X 13 is selected from W, I, or Y, and X 15 is selected from S or G, and X 16 is selected from F, S, D, or T, and X 17 is selected from S or R, and X 18 is selected from G or D, and X 19 is selected from S, R, T, or N, and X 20 is selected from T or A, and X 24 is selected from S, T, or N, and X 31 is selected from A or V, and X 33 is selected from G or D, and X 34 is selected from G, P, W, or D, and X 35 is selected from D, Y, S, or L, and X 36 is selected from Y, D, V, or L, and X 37 is selected from G, S, or D, and X 38 is selected from G, Y, F, or S, and X 39 is selected from S, D, G, or T, and X 40 is selected from T, A, D, S, or Y, and X 41 is selected from Y, A, G, or I, and X 42 is selected from I, Y, or R, and X 43 is selected from L, R, Y, or G, and X 44 is selected from N, L, Y, or S, and X 45 is present or absent, and if present is selected from L, Y, or F; X 46 is either present or absent, and if present, it is D, and X 47 is present or absent, and if present is selected from M or P, and X 48 is present or absent, and if present, is D, and X 49 is either present or absent and, if present, is L.

[0184] In some embodiments, the VH region of the anti-ICAM1 antibody comprises a CDR1, CDR2, and CDR3 sequence 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 and where X 31 is selected from A or V, and X 32 is selected from R or I, and X 33 is selected from G, D, P, A, or V, and X 34 is selected from G, P, W, D, N, or R, and X 35 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, and X 37 is selected from G, S, D, V, or E, and X 38 is selected from G, Y, F, S, or D, and X 39 is selected from S, D, G, T, N, A, or V, and X 40is selected from T, A, D, S, Y, L, or F, and X 41 is present or absent, and if present is selected from Y, A, G, I, or D; X 42 is present or absent, and if present is selected from I, Y, R, P, V, or G; X 43 is present or absent, and if present is selected from L, R, Y, G, or A; X 44 is present or absent, and if present is selected from N, L, S, Y, S, or W; X 45 is present or absent, and if present is selected from L, Y, F, or C; X 46 is present or absent, and if present is selected from D, A, or F, and X 47 is present or absent, and if present is selected from M, P, Y, or N; X 48 is present or absent, and if present is selected from D or L, and X 49 is either present or absent and, if present, 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 (SEQ ID NO: 424), wherein X 31 is selected from A or V, and X 33is selected from G or D, and X 34 is selected from G, P, W, or D, and X 35 is selected from D, Y, S, or L, and X 36 is selected from Y, D, V, or L, and X 37 is selected from G, S, or D, and X 38 is selected from G, Y, F, or S, and X 39 is selected from S, D, G, or T, and X 40 is selected from T, A, D, S, or Y, and X 41 is selected from Y, A, G, or I, and X 42 is selected from I, Y, or R, and X 43 is selected from L, R, Y, or G, and X 44 is selected from N, L, Y, or S, and X 45 is present or absent, and if present is selected from L, Y, or F; X 46 is either present or absent, and if present, it is D, and X 47 is present or absent, and if present is selected from M or P, and X 48 is present or absent, and if present, is D, and X 49 is either present or absent and, if present, is L.

[0188] In some embodiments, the VH region of the anti-ICAM1 antibody comprises the CDR1 sequence X1X2X3X4X5X6X7X8X9X 10 X 11 wherein 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, and X 10 is selected from S, G, N, M, or I, and X 11is present or absent, and if present is C, and said VH region further comprises 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.

[0189] In some embodiments, the VH region of the anti-ICAM1 antibody comprises the CDR1 sequence GFSLX5X6X7X8MX 10 (SEQ ID NO: 425), wherein 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 is selected from S, G, or N, and said VH region further comprises a CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239, and a CDR3 sequence selected from SEQ ID NOs: 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 comprises 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 and where X 12is 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, and X 15 is selected from S, G, T, D, or P, and X 16 is selected from F, S, D, T, or A, and X 17 is selected from S, R, G, or D, and X 18 is selected from G, D, or S, and X 19 is selected from S, R, T, N, Y, A, D, or P, and X 20 is selected from T, A, G, or Y, and X 21 is selected from Y, H, A, S, or T, and X 22 is selected from Y or N, and X 23 is selected from A, P, Y, or S, and X 24 is selected from S, T, N, D, Y, A, or P, and X 25 is selected from W, S, A, or D, and X 26 is selected from A, V, T, W, F, or S, and X 27 is selected from K, W, A, Q, or V, and X 28 is selected from G, A, or K, and X 29 is present or absent, and if present is selected from K or G, and X 30 is present or absent and, if present, is G, and said VH region further comprises 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.

[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 24WAKG (SEQ ID NO: 420), wherein X 13 is selected from W, I, or Y, and X 15 is selected from S or G, and X 16 is selected from F, S, D, or T, and X 17 is selected from S or R, and X 18 is selected from G or D, and X 19 is selected from S, R, T, or N, and X 20 is selected from T or A, and X 24 is selected from S, T, or N, and said VH region further comprises a CDR3 sequence selected from SEQ ID NOs: 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 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 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 comprises 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 comprises a CDR1 sequence selected from SEQ ID NOs: 241, 247, and 250, a CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251, and a CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252.

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

[0196] [Table 8]

[0197] In some embodiments, the VL region of the anti-ICAM1 antibody comprises 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 comprises a CDR1 sequence, a CDR2 sequence, and a CDR3 sequence selected from SEQ ID NOs: 62-64, respectively.

[0199] 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, 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 and where X 31 is selected from A or V, and X 32 is selected from R or I, and X 33 is selected from G, D, P, A, or V, and X 34 is selected from G, P, W, D, N, or R, and X 35 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, and X 37 is selected from G, S, D, V, or E, and X 38 is selected from G, Y, F, S, or D, and X 39 is selected from S, D, G, T, N, A, or V, and X 40 is selected from T, A, D, S, Y, L, or F, and X 41 is present or absent, and if present is selected from Y, A, G, I, or D; X 42 is present or absent, and if present is selected from I, Y, R, P, V, or G; X 43 is present or absent, and if present is selected from L, R, Y, G, or A; X 44 is present or absent, and if present is selected from N, L, S, Y, S, or W; X 45 is present or absent, and if present is selected from L, Y, F, or C; X 46 is present or absent, and if present is selected from D, A, or F, and X 47 is present or absent, and if present is selected from M, P, Y, or N; X 48is present or absent, and if present is selected from D or L, and X 49 is present or absent and, if present, is L, and said VL region comprises a CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62; a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, 283, and 63; and a CDR3 sequence selected from SEQ ID NOs: 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, 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 a CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 (SEQ ID NO: 424), wherein X 31 is selected from A or V, and X 33 is selected from G or D, and X 34 is selected from G, P, W, or D, and X 35 is selected from D, Y, S, or L, and X 36 is selected from Y, D, V, or L, and X 37 is selected from G, S, or D, and X 38 is selected from G, Y, F, or S, and X 39is selected from S, D, G, or T, and X 40 is selected from T, A, D, S, or Y, and X 41 is selected from Y, A, G, or I, and X 42 is selected from I, Y, or R, and X 43 is selected from L, R, Y, or G, and X 44 is selected from N, L, Y, or S, and X 45 is present or absent, and if present is selected from L, Y, or F; X 46 is either present or absent, and if present, it is D, and X 47 is present or absent, and if present is selected from M or P, and X 48 is present or absent, and if present, is D, and X 49 is present or absent and, if present, is L, and said VL region comprises a CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283; and a CDR3 sequence selected from SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284.

[0201] In some embodiments, the anti-ICAM1 antibody comprises a VH domain and a VL domain, wherein the VH domain has the CDR1 sequence X1X2X3X4X5X6X7X8X9X 10 X 11 wherein 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, and X 10 is selected from S, G, N, M, or I, and X 11is present or absent, and if present is C, said VH region further comprising 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; The VL region comprises a CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62; a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, 283, and 63; and a CDR3 sequence selected from SEQ ID NOs: 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 has the CDR1 sequence GFSLX5X6X7X8MX 10 (SEQ ID NO: 425), wherein 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 is selected from S, G, or N, the VH region further comprises a CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239, and a CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240, and the VL region is selected from SEQ ID NOs: 253, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 300, 301, 302, 303, 304, 305, 306, 307, 308, 309, 310, 311, 312, 313, 314, 315, 316, 317, 318, 319, 320, 321, 322, 323, 324, 325, 326, 327, 330, 331, 332, 333, 334, 3 59, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283; and a CDR3 sequence selected from SEQ ID NOs: 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, wherein the VH region comprises 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 and where X 12 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, and X 15 is selected from S, G, T, D, or P, and X 16 is selected from F, S, D, T, or A, and X 17 is selected from S, R, G, or D, and X 18 is selected from G, D, or S, and X 19 is selected from S, R, T, N, Y, A, D, or P, and X 20 is selected from T, A, G, or Y, and X 21 is selected from Y, H, A, S, or T, and X 22 is selected from Y or N, and X 23 is selected from A, P, Y, or S, and X 24 is selected from S, T, N, D, Y, A, or P, and X 25 is selected from W, S, A, or D, and X 26 is selected from A, V, T, W, F, or S, and X 27 is selected from K, W, A, Q, or V, and X 28 is selected from G, A, or K, and X29 is present or absent, and if present is selected from K or G, and X 30 is present or absent, and if present is G, said VH region further comprising 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; and said VL region is selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269 , 270, 272, 274, 277, 279, 282, and 62; a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, 283, and 63; and a CDR3 sequence selected from SEQ ID NOs: 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, wherein the VH region 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 24 WAKG (SEQ ID NO: 420), wherein X 13 is selected from W, I, or Y, and X 15 is selected from S or G, and X 16 is selected from F, S, D, or T, and X 17 is selected from S or R, and X 18 is selected from G or D, and X 19 is selected from S, R, T, or N, and X 20 is selected from T or A, and X 24is selected from S, T, or N, and the VH region further comprises a CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240; and the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282, a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283, and a CDR3 sequence selected from SEQ ID NOs: 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, wherein the VH region 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 CDR2 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240. , 243, 245, 249, and 252, and the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62, a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, 283, and 63, and a CDR3 sequence selected from SEQ ID NOs: 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 a CDR2 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240. and a CDR3 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282, a CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283, and a CDR3 sequence selected from SEQ ID NOs: 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, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 241, 247, and 250, a CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251, and a CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252, and the VL region comprises 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 comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 289-309, and the sequence of the VL region comprises approximately 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 311-326 and 155.

[0209] In some embodiments, the VH region comprises a sequence selected from Table 9 and the VL region comprises a sequence 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 is a full-length antibody. In other embodiments, the anti-ICAM1 antibody is a binding fragment. In some examples, the anti-ICAM1 antibody comprises an antibody or binding fragment thereof, a chimeric antibody or binding fragment thereof, a monoclonal antibody or binding fragment thereof, or a bispecific antibody or binding fragment thereof. Optionally, the anti-CD38 antibody comprises a monovalent Fab, a bivalent Fab'2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), or a camelid antibody or binding fragment thereof.

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

[0216] In some embodiments, the bispecific antibody or binding fragment includes Knobs-into-Hole (KIH), Asymmetric Re-engineering Technology-immunoglobulin (ART-Ig), Triomab quadroma, bispecific monoclonal antibody (BiMAb, BsmAb, BsAb, bsMab, BS-Mab, or Bi-MAb), FcΔAdp, XmAb, Azymetric, Bispecific Engagement by T-cell Receptor-Based Antibodies (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 nanobody.

[0217] In some embodiments, variable domain-only bispecific antibodies comprise tandem scFvs (taFvs), triple bodies, diabodies (Db), dsDb, Db(KIH), scDb, dsFv-dsFv', tandAbs, triple heads, tandem dAb / VHH, triple dAb / VHH, or tetravalent dAb / VHH.

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

[0219] In some examples, the Fab fusion protein comprises a Fab-scFv (bibody), a Fab-scFv2 (tribody), a Fab-Fv, a Fab-dsFv, a Fab-VHH, or an orthogonal Fab-Fab.

[0220] In some examples, the non-immunoglobulin fusion protein comprises scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, miniantibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, or ImmTAC(TCR-scFv).

[0221] In some examples, the Fc-modified IgG is selected from the group consisting of 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, and FcFc. * Includes:

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

[0223] Optionally, the modified Fc and CH3 fusion protein comprises scFv-Fc(KIH), scFv-Fc(CH3 charge pair), scFv-FC(EW-RVT), scFv-Fc(HA-TF), scFv-Fc(SEEDbody), taFv-Fc(KIH), scFv-Fc(KIH)-Fv, Fab-Fc(KIH)-scFv, Fab-scFv-Fc(KIH), Fab-scFv-Fc(BEAT), DART-Fc, scFv-CH3(KIH), or TriFab.

[0224] Optionally, the associated IgG-HC fusion antibody comprises an IgG-HC-scFv, an IgG-dAb, an IgG-taFv, an IgG-CrossFab, an IgG-orthogonal Fab, an IgG-(CαCβ)Fab, an scFv-HC-IgG, a tandem Fab-IgG, an Fab-IgG(CαCβFab), an Fab-IgG(CR3), or an Fab-hinge-IgG(CR3).

[0225] Optionally, the accompanying IgG-LC fusion antibody comprises an IgG-scFv(LC), an scFv(LC)-IgG, or a dAb-IgG.

[0226] Optionally, the accompanying IgG-HC&LC fusion antibody comprises a DVD-Ig, a TVD-Ig, a CODV-Ig, an scFv4-IgG, or a Zybody.

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

[0228] In some examples, the CH3 fusion antibody comprises a Di-diabody or scDb-CH3.

[0229] In some examples, the IgE / IgM CH2 fusion antibody comprises scFv-EHD2-scFv or scFv-MHD2-scFv.

[0230] In some examples, the F(ab')2 fusion antibody comprises a F(ab')2-scFv2.

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

[0232] In some examples, the modified IgG is a DAF (two-in-one-IgG), a DutaMab, or a mAb 2 Includes:

[0233] Optionally, the non-immunoglobulin fusion antibody comprises DNL-Fab4-IgG.

[0234] In some examples, the anti-ICAM1 antibody comprises a bispecific antibody or binding fragment thereof as depicted in FIG. 1A or FIG. 1B.

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

[0236] Optionally, the anti-ICAM1 antibody further comprises one or more mutations in a framework region, such as the CH1 domain, CH2 domain, CH3 domain, hinge region, or a combination thereof. In some examples, the one or more mutations stabilize the antibody and / or increase half-life. In some examples, the one or more mutations modulate Fc receptor interaction and increase ADCC or CDC. In other examples, the one or more mutations reduce or eliminate an Fc effector function, such as FcγR, ADCC, or CDC. In additional examples, the one or more mutations modulate glycosylation.

[0237] In some embodiments, the anti-ICAM1 antibody comprises an IgG1 framework. In some embodiments, the constant region of the anti-ICAM1 antibody is modified at one or more amino acid positions to modify Fc-receptor interaction. Exemplary residues that modulate or modify 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 IgG1 constant region aimed at improving Fc receptor interactions increase half-life. In some examples, the 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 improving 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 a combination 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. Optionally, modifications at one or more amino acid positions aimed at increasing ADCC include S239D / A330L / I332E. Optionally, 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 IgG1 constant region to improve Fc receptor interactions increase phagocytosis by macrophages. In some examples, the modifications at one or more amino acid positions include G236, S239, I332, or a combination thereof. In some cases, the modifications at one or more amino acid positions to increase phagocytosis by macrophages include the combination S239D / I332I / G236A.

[0241] In some embodiments, the IgG1 constant region is modified at amino acid N297 (Kabat numbering) where residue N297 is afucosylated, and wherein the oligosaccharide does not contain a fucose sugar unit.

[0242] In some embodiments, the anti-ICAM1 antibody comprises an IgG2 framework. In some examples, one or more amino acid positions in the IgG2 framework are modified to improve Fc receptor interaction, e.g., to increase ADCC and / or CDC. Optionally, one or more amino acid positions in the IgG2 framework are modified to stabilize the antibody and / or extend half-life. In some examples, one or more amino acid positions in the IgG2 framework are modified to regulate glycosylation. Optionally, the IgG2 constant region 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 improve Fc receptor interaction, for example, to increase ADCC and / or CDC. Optionally, one or more amino acid positions in the IgG3 framework are modified to stabilize the antibody and / or increase half-life. In some examples, one or more amino acid positions in the IgG3 framework are modified to regulate glycosylation. Optionally, the constant region of the antibody is modified at amino acid R435, e.g., R435H (Kabat numbering), to increase 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 improve Fc receptor interaction, for example, to increase ADCC and / or CDC. Optionally, one or more amino acid positions in the IgG4 framework are modified to stabilize the antibody and / or extend 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 modified amino acid is S228 (e.g., S228P).

[0245] In some embodiments, the human IgG constant region is modified to improve ADCC and / or CDC, e.g., as described in Natsume et al., 2008 Cancer Res, 68(10):3863-72; Idusogie et al., 2001 J Immunol, 166(4):2571-5; Moore et al., 2010 mAbs, 2(2):181-189; Lazar et al., 2006 PNAS, 103(11):4005-4010; Shields et al., 2001 JBC, 276(9):6591-6604; Stavenhagen et al., 2007 Cancer Res, 67(18):8882-8890; Stavenhagen et al., 2008 Advan. Enzyme Regul., 48:152-164; Alegre et al., 1992 J 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 human IgG constant region is modified to induce heterodimerization. For example, if there is an amino acid modification in the CH3 domain at Thr366, which is replaced with a more bulky amino acid, such as Trp (T366W), it can preferentially pair with a second CH3 domain that has amino acid modifications to less bulky amino acids at Thr366, Leu368, and Tyr407, for example, Ser, Ala, and Val, respectively. In some cases, heterodimerization via CH3 modification can be further stabilized by introducing disulfide bonds, for example, by changing 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 instances, the anti-ICAM1 antibodies described herein have reduced or absent glycosylation but are not modified at amino acid Asn297 (Kabat numbering). In these instances, glycosylation is eliminated by, for example, producing the antibody in a host cell lacking post-translational glycosylation capabilities, such as a bacterial or yeast-derived system, or a modified mammalian cell expression system. In some embodiments, such a system is a cell-free expression system.

[0248] In some embodiments, the anti-ICAM1 antibodies described herein are full-length antibodies and comprise 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 have an EC of about 0.001 nM to about 2.5 nM, e.g., about 0.02 nM, 0.03 nM, about 0.04 nM, about 0.05 nM, about 0.06 nM, about 0.09 nM, about 0.1 nM, about 1.2 nM, about 1.7 nM, about 2.0 nM, or about 2.5 nM, in an in vitro cytotoxicity assay to determine ADCC activity using cancer cells, e.g., human prostate cancer cells. 50 It has the following characteristics.

[0256] In some cases, the serum half-life of the anti-ICAM1 antibodies described herein is at least 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or more. In some cases, the serum half-life of the anti-ICAM1 antibodies described herein is about 30 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or more.

[0257] Multispecific anti-CD38 and anti-ICAM1 antibodies In some embodiments, the present specification describes multispecific anti-CD38 antibodies or multispecific anti-ICAM1 antibodies. In some examples, the multispecific anti-CD38 antibodies or multispecific anti-ICAM1 antibodies comprise target-binding moieties that recognize two or more antigens. Optionally, the multispecific anti-CD38 antibodies comprise target-binding moieties that specifically bind to two or more antigens, e.g., three or more, four or more, or five or more antigens. Optionally, the multispecific anti-ICAM1 antibodies comprise target-binding moieties that specifically bind to two or more antigens, e.g., 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 antibodies comprise 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 is selected from ICAM1, ephrin type A receptor 2 (EphA2), ephrin type A receptor 3 (EphA3), ephrin type A receptor 4 (EphA4), activated leukocyte cell adhesion molecule (ALCAM), BCMA (B cell maturation antigen or TNFRSF17), PDL1, CD30, CD33, PSMA, mesothelin, CD44, CD73, mucin 1 cell surface associated (MUC1), oligomeric mucus gel-forming mucin 2 (Mucin 2 oligomeric mucus), and the like. gel-forming (MUC2), cell surface-associated mucin 16 (MUC16), carcinoembryonic antigen (CEA), cathepsin G, preferentially expressed antigen in melanoma (PRAME), CD52, EpCAM, tumor-associated glycoprotein 72 (TAG-72), carbonic anhydrase IX, PSMA, folate-binding protein, ganglioside, Lewis-Y, immature laminin receptor, BING-4, calcium-activated chloride channel 2 (CaCC), 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 antibodies comprise a targeting moiety that specifically binds to ICAM1 and a targeting moiety that specifically binds to a non-ICAM1 target. Optionally, the non-ICAM1 target includes, but is not limited to, CD38, CD47, receptor tyrosine kinase-like orphan receptor 1 (ROR1), receptor tyrosine kinase-like orphan receptor 2 (ROR2), Erb3, IGFRIR, EGFR, PDL1, PDL2, PD1, CTLA4, or Tim3.

[0260] In some embodiments, described herein are bispecific antibodies that include a first targeting moiety that specifically binds to CD38 or ICAM1.

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

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

[0263] In some embodiments, the present 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 exhibits enhanced CDC efficacy compared to the CDC efficacy of a reference antibody, daratumumab. In some examples, the bispecific antibody further exhibits enhanced ADCC efficacy compared to the ADCC efficacy of a reference antibody, daratumumab. Optionally, the enhanced CDC is at least 2-fold, 3-fold, 4-fold, or more than the CDC efficacy of the reference antibody, daratumumab. Optionally, the enhanced CDC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more than the CDC efficacy of the reference antibody, daratumumab. Optionally, the enhanced ADCC is at least 2-fold, 3-fold, 4-fold, 5-fold, or more than the ADCC efficacy of the reference antibody, daratumumab. In some cases, the ADCC enhancement is at least 30%, 40%, 50%, 60%, 70%, 80%, 90% or more greater than the ADCC effect of the reference antibody, daratumumab.

[0264] In some embodiments, described herein are bispecific antibodies comprising a first component that specifically binds CD38 and a second component that specifically binds ICAM1, wherein the bispecific antibodies mediate ADCC more efficiently than monospecific antibodies comprising only the first component or the second component, where the ADCC activity is determined using an in vitro cytotoxicity assay. In some embodiments, the bispecific antibodies mediate a maximal cytotoxicity in an in vitro ADCC assay that is at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 75%, or at least about 100% greater than a monospecific antibody comprising only the first component or the second component. In some embodiments, the bispecific antibodies mediate a maximal cytotoxicity in an in vitro ADCC assay that is at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, or at least 10-fold greater than a monospecific antibody comprising only the first component or the second component.

[0265] In some embodiments, described herein are bispecific antibodies comprising a first component that specifically binds CD38 and a second component that specifically binds ICAM1, wherein the bispecific antibodies mediate complement-dependent cytotoxicity (CDC) more efficiently than monospecific antibodies comprising only either the first component or the second component, wherein ADCC activity is determined using an in vitro cytotoxicity assay, and the CDC activity is determined using an in vitro cytotoxicity assay. In some embodiments, the bispecific antibodies mediate maximal cytotoxicity in an in vitro CDC assay that is at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 75%, or at least about 100% greater than monospecific antibodies comprising only either the first component or the second component.

[0266] In some examples, the bispecific antibody further has a reduced immune cell killing effect compared to the immune cell killing effect of the reference antibody daratumumab. In some embodiments, the viability of the immune cells is improved by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more compared to immune cell viability in the presence of the reference antibody daratumumab. Optionally, the immune cells are natural killer cells.

[0267] In some examples, the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety is a bispecific antibody conjugate, a hybrid bispecific IgG, a variable domain-only bispecific antibody, a CH1 / CL fusion protein, a Fab fusion protein, a non-immunoglobulin fusion protein, an Fc-modified IgG, a concatenated & Fc-modified IgG, a modified Fc and CH3 fusion protein, a concatenated IgG-HC fusion, an Fc fusion, a CH3 fusion, an IgE / IgM CH2 fusion, or an F(ab')2 fusion.

[0268] In some embodiments, the bispecific antibody comprising a CD38-targeting moiety and an ICAM1-targeting moiety is known as Knobs-into-Holes (KIH), Asymmetric Re-engineering Technology-immunoglobulin (ART-Ig), Triomab quadroma, bispecific monoclonal antibody (BiMAb, BsmAb, BsAb, bsMab, BS-Mab, or Bi-MAb), FcΔAdp, XmAb, Azymetric, Bispecific Engagement by T-cell Receptor-Based Antibodies (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 including diAbodies (TandAbs), Dual-affinity-ReTargeting (DART), or nanobodies.

[0269] In some embodiments, variable domain-only bispecific antibodies comprise tandem scFvs (taFvs), triple bodies, diabodies (Db), dsDb, Db(KIH), scDb, dsFv-dsFv', tandAbs, triple heads, tandem dAb / VHH, triple dAb / VHH, or tetravalent dAb / VHH.

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

[0271] In some examples, the Fab fusion protein comprises a Fab-scFv (bibody), a Fab-scFv2 (tribody), a Fab-Fv, a Fab-dsFv, a Fab-VHH, or an orthogonal Fab-Fab.

[0272] In some examples, the non-immunoglobulin fusion protein comprises scFv2-albumin, scDb-albumin, taFv-albumin, taFv-toxin, miniantibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, or ImmTAC(TCR-scFv).

[0273] In some examples, the Fc-modified IgG is selected from the group consisting of 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, and FcFc. * Includes:

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

[0275] Optionally, the modified Fc and CH3 fusion protein comprises scFv-Fc(KIH), scFv-Fc(CH3 charge pair), scFv-FC(EW-RVT), scFv-Fc(HA-TF), scFv-Fc(SEEDbody), taFv-Fc(KIH), scFv-Fc(KIH)-Fv, Fab-Fc(KIH)-scFv, Fab-scFv-Fc(KIH), Fab-scFv-Fc(BEAT), DART-Fc, scFv-CH3(KIH), or TriFab.

[0276] Optionally, the associated IgG-HC fusion antibody comprises an IgG-HC-scFv, an IgG-dAb, an IgG-taFv, an IgG-CrossFab, an IgG-orthogonal Fab, an IgG-(CαCβ)Fab, an scFv-HC-IgG, a tandem Fab-IgG, an Fab-IgG(CαCβFab), an Fab-IgG(CR3), or an Fab-hinge-IgG(CR3).

[0277] Optionally, the accompanying IgG-LC fusion antibody comprises an IgG-scFv(LC), an scFv(LC)-IgG, or a dAb-IgG.

[0278] Optionally, the accompanying IgG-HC&LC fusion antibody comprises a DVD-Ig, a TVD-Ig, a CODV-Ig, an scFv4-IgG, or a Zybody.

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

[0280] In some examples, the CH3 fusion antibody comprises a Di-diabody or scDb-CH3.

[0281] In some examples, the IgE / IgM CH2 fusion antibody comprises scFv-EHD2-scFv or scFv-MHD2-scFv.

[0282] In some examples, the F(ab')2 fusion antibody comprises a F(ab')2-scFv2.

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

[0284] In some examples, the modified IgG is a DAF (two-in-one-IgG), a DutaMab, or a mAb 2 Includes:

[0285] Optionally, the non-immunoglobulin fusion antibody comprises DNL-Fab4-IgG.

[0286] In some examples, a bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety comprises an antibody format as illustrated in FIG. 1A or FIG. 1B.

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

[0288] In some examples, a bispecific antibody comprising a CD38-targeting moiety and an ICAM1-targeting moiety is a monovalent antibody or binding fragment thereof. Optionally, the monovalent antibody or binding fragment thereof comprises a Fab-scFv-Fc (KIH) format (also referred to herein as three-chain knobs-into-holes) (FIG. 2E), or a Biclonics common LC format (also referred to herein as general light chain bispecific) (FIG. 2F).

[0289] In some embodiments, a bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety comprises a KD for CD38 of about 1 nM to about 100 nM, 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 comprises a KD for ICAM1 of about 0.1 nM to about 20 nM. In some examples, the KD is about 0.15nM, 0.2nM, 0.24nM, 0.25nM, 0.29nM, 0.3nM, 0.4nM, 0.5nM, 0.6nM, 0.7nM, 0.8nM, 0.9nM, 1nM, 1.5nM, 1.72nM, 2nM, 2.28nM, 2.5nM, 3nM, 3.5nM, 4nM, 4.5nM, 5nM, 6nM, 7nM, 8nM, 9nM, 10nM, 11nM, 12nM, 13nM, 14nM, 15nM, 16nM, 17nM, 18nM, 19nM, or 20nM.

[0291] In some embodiments, the first targeting moiety that specifically binds CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 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 and where X 32 is selected from A, G, or V, and X 33 is selected from K, A, R, T, G, or S, and X 34 is selected from R, A, V, T, P, I, E, D, or S, and X 35 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, and X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I, and X 38 is selected from G, A, S, D, K, F, L, or Y, and X 39 is selected from Y, T, A, G, S, or I, and X 40 is selected from S, Y, G, R, W, N, L, D, or F, and X 41 is present or absent, and if present is selected from F, Y, V, D, A, N, G, E, or L; X 42 is present or absent, and if present is selected from P, L, Y, F, G, or T; X 43is present or absent, and if present is selected from T, P, F, V, N, Y, or S; X 44 is present or absent, and if present is selected from G, L, S, T, or F; X 45 is present or absent, and if present is selected from F, L, E, N, or S; X 46 is present or absent, and if present is selected from D, S, L, or R; X 47 is present or absent, and if present is selected from Y or L, and X 48 is present or absent, and if present, is D, and X 49 is present or absent and, if present, is L, and said VL region comprises a CDR1 sequence selected from SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from SEQ ID NOs: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0292] In some embodiments, the first targeting moiety that specifically binds CD38 comprises a VH region and a VL region, wherein the VH region has a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9, a CDR2 sequence selected from SEQ ID NOs: 2 and 5, and a CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY (SEQ ID NO: 421), wherein X 38 is selected from A or G, and X 41 is selected from F or Y, and said 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.

[0293] In some embodiments, a first targeting moiety that specifically binds CD38 comprises 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 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 and where X 32 is selected from A, G, or V, and X 33 is selected from A, R, T, S, or G, and X 34 is selected from A, V, T, P, I, E, D, or S, and X 35 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, and X 37 is selected from Y, V, T, S, N, A, G, Q, F, or I, and X 38 is selected from G, S, D, K, F, L, or Y, and X 39 is selected from T, A, G, S, I, or Y, and X 40 is selected from S, Y, G, R, W, N, L, D, or F, and X 41 is present or absent, and if present is selected from V, D, A, N, G, L, or E; X 42 is present or absent, and if present is selected from L, Y, F, T, or G; X 43 is present or absent, and if present is selected from P, F, V, N, S, or Y; X 44is present or absent, and if present is selected from L, S, T, G, or F; X 45 is present or absent, and if present is selected from L, F, E, S, or N; X 46 is present or absent, and if present is selected from S, L, or R; X 47 is either present or absent, and if present, is L, and X 48 is present or absent, and if present, is D, and X 49 is present or absent and, if present, is L, and said VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; a CDR2 sequence selected from SEQ ID NOs: 66, 69, 72, 75, 78, 81, 84, 90, and 99; and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0294] In some embodiments, the first targeting moiety that specifically binds CD38 comprises a VH region and a VL region, wherein the VH region has 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 and where X 32 is selected from A or G, and X 33 is selected from A, R, or T, and X 34 is selected from A, V, T, P, I, E, or D, and X 35 is selected from G, W, D, L, K, or P, and X 36is selected from P, A, Y, D, or G, and X 37 is selected from Y, V, T, S, N, A, or G, and X 38 is selected from G, S, D, or K, and X 39 is selected from T, A, G, S, or I, and X 40 is selected from S, Y, G, R, or W, and X 41 is selected from V, D, Y, A, N, or G, and X 42 is selected from L, Y, or F, and X 43 is present or absent, and if present is selected from P, F, V, or N; X 44 is present or absent, and if present is selected from L, S, or T, and X 45 is present or absent, and if present is selected from L or F, and said VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from SEQ ID NOs: 66, 69, 78, 81, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.

[0295] In some embodiments, the first targeting moiety that specifically binds CD38 comprises a VH region and a VL region, wherein the VH region has a CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56, a CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57, and a CDR3 sequence AX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 (SEQ ID NO: 422), wherein X 33 is selected from R or G, and X 34 is selected from E, D, or S, and X 35 is selected from G, L, P, S, or A, and X36 is selected from D, S, or R, and X 37 is selected from Y, T, N, or G, and X 38 is selected from G, S, F, or L, and X 39 is selected from A, G, S, or I, and X 40 is selected from Y, N, or L, and X 41 is present or absent, and if present is selected from V, Y, or E; X 42 is either present or absent, and if present, it is G, and X 43 is either present or absent, and if present, it is Y and X 44 is either present or absent, and if present, it is F, and X 45 is present or absent, and if present is selected from E or N, and X 46 is present or absent, and if present is selected from S or L, and said 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.

[0296] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region has the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12 wherein X1 is present or absent and, if present, is S; X2 is selected from F or I; X3 is selected from P, S, or D; X4 is selected from F, L, or A; X5 is selected from D, G, S, N, or T; X6 is selected from V, A, T, R, S, I, or N; X7 is selected from Y, I, N, R, A, G, or D; X8 is selected from A, Y, D, G, W, C, or T; X9 is selected from M, V, I, W, D, or Y; 10 is selected from S, T, M, C, I, Y, A, or G, and X 11 is present or absent, and if present is selected from C or M, and X12 is present or absent, and if present is C, and the VH region further comprises 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, and the VL region is , SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; CDR2 sequences selected from SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and CDR3 sequences selected from SEQ ID NOs: 64, 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0297] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises the CDR1 sequence GFPFX5X6YAMS (SEQ ID NO: 423), 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.

[0298] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region has the CDR1 sequence X1GX2X3X4X5X6X7X8X9X 10 X 11 X 12wherein 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, and X 10 is selected from T, S, M, C, I, Y, A, or G, and X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent, and if present is C, said VH region further comprising 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; and said VL region and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0299] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region has the CDR1 sequence GFSLX5X6X7X8X9X 10 X 11 (SEQ ID NO: 426), wherein X5 is selected from S or N, X6 is selected from R, S, or N, X7 is selected from Y, I, or N, X8 is selected from Y, D, G, or A, X9 is selected from V, M, or I, and X 10 is selected from T, S, or M, and X 11is present or absent and, if present, is C; the VH region further comprises 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; and the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from SEQ ID NOs: 66, 69, 78, 81, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.

[0300] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region has the CDR1 sequence GFSX4X5X6X7X8X9X 10 X 11 X 12 (SEQ ID NO: 419), wherein 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, and X9 is selected from I, W, Y, or D; 10 is selected from C, I, Y, or M, and X 11 is present or absent, and if present is selected from C or M, and X 12 is present or absent and, if present, is C; the VH region further comprises 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.

[0301] In some embodiments, the first targeting moiety that specifically binds CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 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 and where X 13 is selected from A, G, or S, and X 14 is selected from I, F, Y, V, S, or C, and X 15 is selected from S, I, L, T, or M, and X 16 is selected from G, Y, S, T, L, or V, and X 17 is selected from S, I, K, Y, T, G, or A, and X 18 is selected from G, S, T, P, V, or Y, and X 19 is selected from G, A, D, S, or T, and X 20 is selected from S, T, I, N, or G, and X 21 is selected from T, I, D, N, S, or A, and X 22 is selected from F, Y, N, T, I, or S, and X 23 is selected from Y, D, K, or I, and X 24 is selected from A or Y, and X 25 is selected from D, T, S, N, R, A, or Y, and X 26 is selected from S, W, T, A, or N, and X 27 is selected from V, A, W, N, or S, and X 28 is selected from K, R, Q, A, or W, and X 29 is selected from G, K, or A, and X30 is present or absent, and if present is selected from G or K, and X 31 is present or absent, and if present is G, the VH region further comprises 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; and the VL region is 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.

[0302] In some embodiments, the first targeting moiety that specifically binds CD38 comprises a VH region and a VL region, wherein the VH region has a CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9, and a CDR2 sequence AISGSGGSTX 22 YADSVKG (SEQ ID NO: 418), wherein X 22 is selected from F or Y, the VH region further comprises 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.

[0303] In some embodiments, a first targeting moiety that specifically binds CD38 comprises 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, and a CDR2 sequence X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 and where X 13 is selected from A, G, or S, and X 14 is selected from I, F, Y, V, S, or C, and X 15 is selected from I, L, M, or T, and X 16 is selected from G, Y, S, T, L, or V, and X 17 is selected from S, I, K, Y, T, G, or A, and X 18 is selected from G, S, T, P, or V, and X 19 is selected from G, A, D, S, or T, and X 20 is selected from S, T, I, N, or G, and X 21 is selected from T, I, D, N, S, or A, and X 22 is selected from Y, N, T, I, or S, and X 23 is selected from Y, D, K, or I, and X 24 is selected from A or Y, and X 25 is selected from T, S, N, R, A, or Y, and X 26 is selected from S, W, T, A, or N, and X 27 is selected from A, W, N, or S, and X 28 is selected from K, R, Q, A, or W, and X 29 is selected from G, K, or A, and X 30 is present or absent, and if present is selected from G or K, and X 31is present or absent and, if present, is G, and the VH region further comprises 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; and the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102, a CDR2 sequence selected from SEQ ID NOs: 66, 69, 72, 75, 78, 81, 84, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.

[0304] In some embodiments, the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises a CDR1 sequence selected from SEQ ID NOs: 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 and where X 13 is selected from A or G, and X 14 is selected from I, F, Y, V, S, or C, and X 16 is selected from G, Y, S, T, or L, and X 17 is selected from S, I, K, Y, T, or G, and X 18 is selected from G, S, or T, and X 19 is selected from G, A, D, or S, and X 20 is selected from T, I, N, or G, and X 21 is selected from T, I, or D, and X 22 is selected from Y, N, or T, and X 23is selected from Y or D, and X 24 is selected from A or Y, and X 25 is selected from T, S, N, R, or A, and X 26 is selected from W or T, and X 27 is selected from A or W, and X 28 is selected from K, R, Q, or A, and X 29 is selected from G or K, and X 30 is present or absent and, if present, is G, and the VH region further comprises a CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and the VL region comprises a CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98, a CDR2 sequence selected from SEQ ID NOs: 66, 69, 78, 81, 90, and 99, and a CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.

[0305] In some embodiments, the first targeting moiety that specifically...

Claims

1. 1. A bispecific protein comprising a first component comprising an antibody or antigen-binding fragment thereof that specifically binds to CD38 and a second component comprising an antibody or antigen-binding fragment thereof that specifically binds to ICAM1, (i) the first component that specifically binds to CD38 is a) a heavy chain variable domain (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the sequences of SEQ ID NOs: 1, 2, and 7, respectively; and b) a light chain variable domain (VL) comprising complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the sequences of SEQ ID NOs: 62, 63, and 64, respectively; and (ii) the second component that specifically binds to ICAM1 is a) a heavy chain variable domain (VH) comprising complementarity determining regions HCDR1, HCDR2, and HCDR3 comprising the sequences of SEQ ID NOs: 228, 229, and 230, respectively; and b) a light chain variable domain (VL) comprising complementarity determining regions LCDR1, LCDR2, and LCDR3 comprising the sequences of SEQ ID NOs: 270, 260, and 271, respectively; Bispecific proteins.

2. The bispecific protein of claim 1, wherein the bispecific protein comprises an Fc region that is a heterodimeric Fc region.

3. The bispecific protein of claim 1 , wherein the Fc region is afucosylated.

4. 2. The bispecific protein of claim 1 , wherein the Fc region comprises one or more mutations that increase antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC) activity.

5. 5. The bispecific protein of claim 4, wherein the Fc region comprises one or more mutations that increase ADCC, wherein the mutations that increase ADCC are at positions corresponding to positions 239, 332, and 330 of human IgG1, the mutations being S239D, I332E, and A330L, and wherein the amino acid numbering is according to the EU index of the Kabat numbering system as described in U.S. Pat. No. 8,093,359.

6. 3. The bispecific protein of claim 2, comprising a heterodimeric Fc region, wherein the heterodimeric Fc region comprises a knob strand and a hole strand, forming a knob-in-hole (KIH) structure.

7. 2. The bispecific protein of claim 1 , wherein the antibody or antigen-binding fragment thereof that specifically binds to ICAM1 comprises a Fab and the antibody or antigen-binding fragment thereof that specifically binds to CD38 comprises an scFv.

8. 2. The bispecific protein of claim 1 , wherein the first component comprises a heavy chain variable domain (VH) comprising a sequence that is at least 90% identical to SEQ ID NO:

107.

9. 2. The bispecific protein of claim 1 , wherein the first component comprises a light chain variable domain (VL) comprising a sequence that is at least 90% identical to SEQ ID NO:

133.

10. 2. The bispecific protein of claim 1 , wherein the second component comprises a heavy chain variable domain (VH) comprising a sequence that is at least 90% identical to SEQ ID NO:

298.

11. 2. The bispecific protein of claim 1, wherein the second component comprises a light chain variable domain (VL) comprising a sequence at least 90% identical to SEQ ID NO:

320.

12. 2. The bispecific protein of claim 1, wherein the second component that specifically binds to ICAM1 comprises a full-length antibody comprising a light chain (LC) and a heavy chain (HC), wherein the HC comprises a sequence that is at least 90% identical to SEQ ID NO:

338.

13. The bispecific protein of claim 12, wherein the light chain (LC) of the second component comprises a sequence that is at least 90% identical to SEQ ID NO:

360.

14. 2. The bispecific protein of claim 1, wherein the bispecific protein induces an enhanced ADCC effect on the target cells compared to the ADCC effect induced on the target cells by a monospecific protein comprising the antibody or antigen-binding fragment thereof that specifically binds to CD38, or the antibody or antigen-binding fragment thereof that specifically binds to ICAM1.

15. The bispecific protein has the following structure: a) the first component comprises an intact anti-CD38 immunoglobulin (IgG) molecule and the second component comprises an anti-ICAM1 single-chain variable fragment (scFv); b) the first component comprises a Fab fragment of an anti-CD38 IgG and the second component comprises an anti-ICAM1 scFv, or c) the first component comprises a heavy chain variable domain (VH) and a light chain variable domain (VL) of an anti-CD38 IgG, and the second component comprises a heavy chain variable domain (VH) and a light chain variable domain (VL); 10. The bispecific protein of claim 1, wherein the bispecific protein is a general light chain bispecific format.

16. The bispecific protein of claim 15, wherein the complete anti-CD38 IgG comprises two LCs, each LC fused to a single anti-ICAM1 scFv.

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

18. The bispecific protein of claim 16, wherein the N-terminus of each HC of the complete anti-CD38 IgG is fused to a single anti-ICAM1 scFv.

19. The bispecific protein of claim 16, wherein the complete anti-CD38 IgG comprises two HCs, the C-terminus of each HC being conjugated to a single anti-ICAM1 scFv.

20. the first component comprises a complete anti-CD38 IgG comprising two HCs and two LCs; the second component comprises two anti-ICAM-1 heavy chain variable domains and two anti-ICAM-1 light chain variable domains; and wherein the N-terminus of each HC of said complete anti-CD38 IgG is fused to one of the anti-ICAM1 VH domains; and The bispecific protein of claim 1 , wherein the N-terminus of each LC of the complete anti-CD38 IgG is fused to one of the anti-ICAM1 LC domains.

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