WO2020102777A1 - Cd38 and icam1 antibodies and uses thereof - Google Patents

Cd38 and icam1 antibodies and uses thereof Download PDF

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Publication number
WO2020102777A1
WO2020102777A1 PCT/US2019/061884 US2019061884W WO2020102777A1 WO 2020102777 A1 WO2020102777 A1 WO 2020102777A1 US 2019061884 W US2019061884 W US 2019061884W WO 2020102777 A1 WO2020102777 A1 WO 2020102777A1
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WIPO (PCT)
Prior art keywords
seq
cdr3
cdr2
cdr1
present
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PCT/US2019/061884
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English (en)
French (fr)
Inventor
Bin Liu
Xiaocheng Chen
Scott Bidlingmaier
Leonard Post
Yang Su
Namkyung LEE
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University of California Berkeley
University of California San Diego UCSD
Virtuoso Binco Inc
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University of California Berkeley
University of California San Diego UCSD
Virtuoso Binco Inc
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Priority to EP19885142.0A priority Critical patent/EP3883967A4/en
Priority to CN202510567553.3A priority patent/CN120399084A/zh
Priority to CN201980089423.6A priority patent/CN113302207B/zh
Priority to US17/293,258 priority patent/US12583932B2/en
Priority to JP2021526459A priority patent/JP7785284B2/ja
Publication of WO2020102777A1 publication Critical patent/WO2020102777A1/en
Anticipated expiration legal-status Critical
Priority to JP2025203085A priority patent/JP2026053336A/ja
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2821—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against ICAM molecules, e.g. CD50, CD54, CD102
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/734—Complement-dependent cytotoxicity [CDC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • Antibodies that bind to CD38 are useful for the treatment of cancers that express CD38.
  • 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 is approved for the treatment of adults with multiple myeloma.
  • Reduced CD38 expression can limit the efficacy of anti-CD38 antibodies.
  • Proposals to overcome this limitation include treatment with an antibody having higher affinity for CD38, treatment with an antibody that binds to a different epitope on CD38, treatment with an antibody that more effectively inhibits CD38 enzymatic activity, treatment with a tetravalent anti-CD38 antibody, and concurrent treatment with all-trans retinoic acid to increase CD38 expression.
  • the antibody or an antigen binding fragment thereof that specifically binds to ICAM1 comprises a variable domain of an IgG heavy chain and a variable domain of an IgG light chain.
  • the multispecific protein further comprises an Fc region.
  • the Fc region comprises a heterodimeric Fc region.
  • the Fc region comprises one or more mutations that increases the half-life of the multispecific protein.
  • the Fc region comprises one or more stabilizing mutations.
  • the Fc region comprises one or more mutations that modulate its interaction with an Fc receptor.
  • the Fc region comprises one or more mutations that decrease glycosylation of the Fc region.
  • the one or more mutations that decrease glycosylation of the Fc region comprises a mutation at a position corresponding to position N297 of human IgGl, wherein the numbering is according to the EU index of Kabat et al.
  • the Fc region is afiicosylated.
  • the Fc region comprises one or more mutations that increases ADCC or CDC activity.
  • the knob chain comprises the mutation T366W and the hole chain comprises the mutations T366S, L368A, and Y407V, wherein amino acid position numbering is according to the EU index of Kabat et al.
  • the antibody or antigen binding fragment thereof that specifically binds to CD38 comprises an anti-CD38 IgG
  • the antibody or an antigen binding fragment thereof that specifically binds to ICAM1 comprises an anti-ICAMl single chain variable fragment (anti-ICAMl scFv).
  • the anti-CD38 IgG comprises two light chains and each light chain is fused to a single anti-ICAMl scFv.
  • the multispecific protein further comprises the Fc region.
  • the Fc region is the heterodimeric Fc region comprising a KIH structure, and wherein the multispecific protein is of the common light chain bispecific format.
  • the first component that specifically binds to CD38 comprises a heavy chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein the CDR1, the CDR2, and the CDR3 of the heavy chain comprise a set of sequences selected from the group consisting of 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. 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. 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. 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);
  • the CDR1, the CDR2, and the 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.
  • the first component that specifically binds to CD38 comprises a light chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein the CDR1, the CDR2, and the CDR3 of the light chain comprise sequences selected from the group consisting of 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. 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. 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);
  • CDR1 CDR2: CDR3 (SEQ ID No. 102: SEQ ID No. 84: SEQ ID No. 103).
  • CDR1 CDR2: CDR3
  • CDRECDR2 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
  • CDRECDR2 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
  • CDRECDR2 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
  • SEQ ID No. 50 SEQ ID No: 51 : SEQ ID No. 52
  • SEQ ID No. 98 SEQ ID No: 99: SEQ ID No. 100
  • the second component that specifically binds to ICAM1 comprises a heavy chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein the CDR1, the CDR2, and the CDR3 of the heavy chain comprise sequences selected from the group consisting of 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. 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. 208: SEQ ID No. 234: SEQ ID No. 210);
  • 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);
  • CDR1 CDR2: CDR3 (SEQ ID No. 404: SEQ ID No. 405: SEQ ID No. 406).
  • the CDR1, the CDR2, and the CDR3 of the heavy chain of the second component comprises the following sequence: (CDR1: CDR2: CDR3 (SEQ ID No. 228: SEQ ID No. 229: SEQ ID No. 230).
  • the CDR1, the CDR2, and the 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).
  • the CDR1, the CDR2, and the CDR3 of the heavy chain of the second component comprise the following set of sequences: CDR1: CDR2: CDR3 (SEQ ID No.
  • the CDR1, the CDR2, and the 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).
  • the second component that specifically binds to ICAM1 comprises a light chain comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein the CDR1, the CDR2, and the CDR3 of the light chain comprise a set of sequences selected from the group consisting of 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. 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. 62: SEQ ID No. 63: SEQ ID No. 64);
  • CDR1 CDR2: CDR3 (SEQ ID No. 407: SEQ ID No. 408: SEQ ID No. 409).
  • the CDR1, the CDR2, and the 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).
  • the CDR1, the CDR2, and the 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).
  • the CDR1, the CDR2, and the 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).
  • the CDR1, the CDR2, and the 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).
  • the second component comprises six CDRs comprising a set of sequences selected from the group consisting of the following sets of sequences:
  • HC CDR1: CDR2: CDR3) - LC (CDRECDR2: 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);
  • the second component comprises six CDRs comprising the following sequences: HC (CDR1: CDR2: CDR3)-LC (CDRECDR2: 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).
  • the second component comprises six CDRs comprising the following sequences: HC (CDR1: CDR2: CDR3) - LC (CDRECDR2: CDR3) (SEQ ID No. 222: SEQ ID No: 223: SEQ ID No. 224) - (SEQ ID No.
  • the second component comprises six CDRs comprising the following sequences: HC (CDR1: CDR2: CDR3) - LC (CDRECDR2: 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).
  • the second component comprises six CDRs comprising the following set of sequences: HC (CDR1: CDR2: CDR3) - LC (CDRECDR2: CDR3) (SEQ ID No. 404: SEQ ID No. 405: SEQ ID No.
  • the first component comprises a variable heavy domain and wherein the variable heavy 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.
  • the first component comprises the variable light domain and wherein the variable light 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.
  • the second component comprises a variable heavy domain and wherein the variable heavy 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.
  • the second component comprises a variable light domain wherein the variable light 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.
  • 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.
  • the light chain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID Nos. 182-207.
  • the second component that specifically binds to ICAM1 comprises a full-length antibody comprising a light chain and a heavy chain, wherein the heavy chain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID Nos. 328-349.
  • the light chain comprises a sequence that is at least about 90% identical to a sequence selected from the group consisting of SEQ ID Nos. 183 and 350-366.
  • One embodiment provides a multispecific protein comprising a heavy chain polypeptide (HC) comprising the VH and a light chain polypeptide (LC) comprising the VL, wherein the heavy chain polypeptide and the light chain polypeptide comprise sequences that are at least about 90% identical to sequences 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. 386: SEQ ID No. 394).
  • 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, the LC, and the HC2 comprise sequences that are at least about 90% identical to sequences selected from the group consisting of the following set of sequences:
  • HCELC HC2 (SEQ ID No. 391: SEQ ID No. 186: SEQ ID No. 383);
  • 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 heavy chain polypeptide (LC2), and wherein the HC1, LC1, HC2 and the LC2 comprise sequences that are at least about 90% identical to sequences selected from the group consisting of the following set of sequences:
  • HCELCl HC2:HC3 (SEQ ID No. 390: SEQ I No. 189: SEQ ID No. 348: SEQ ID No. 189);
  • HCELCl HC2:HC3 (SEQ ID No. 391: SEQ ID No. 186: SEQ ID No. 348: SEQ ID No. 186);
  • HCELCl HC2:HC3 (SEQ ID No. 391: SEQ ID No. 186: SEQ ID No. 349: SEQ ID No. 186).
  • 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 as set forth in SEQ ID No. 411.
  • the heavy chain comprises CDR1, CDR2, and CDR3, wherein CDR1 has a sequence of SEQ ID No. 412 (GFSLSZ1Z2AMG), CDR2 has a sequence of SEQ ID No. 413
  • Zi 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; Z h is phenylalanine or tyrosine; Z 7 is aspartic acid or glycine; Zs is aspartic acid or alanine; Z 9 is glycine or alanine; Z 10 is glutamine or glutamic acid; Zn is serine or asparagine; Z 12 is serine or arginine; Z 13 is cysteine or leucine; Z 14 is serine of leucine; Z 15 is valine or leucine; Z 1 ⁇ 2 is serine or glycine; Zn is serine or asparagine; Zi 3 ⁇ 4 is valine or isoleucine; and Z 19 is valine or alanine.
  • the multispecific protein induces an enhanced antigen-dependent cellular cytotoxicity (ADCC) effect on a target cell, compared to an ADCC effect induced on the target cell by a an otherwise identical multispecific protein that does not comprise an Fc region that is afiicosylated.
  • ADCC antigen-dependent cellular cytotoxicity
  • the multispecific protein induces an enhanced ADCC effect on a target cell, compared to an ADCC effect induced on the target cell by an otherwise identical multispecific protein that does not comprises an Fc region comprising the mutations at positions corresponding to positions 239, 332, and 330 of human IgGl, wherein the mutations are S239D, I332E, and A330L, and wherein the amino acid numbering is according to the EU index in Rabat et al.
  • an amount of the multispecific protein that binds to a cell expressing CD38 and ICAM1 is higher than an amount that binds to the cell of a monospecific protein comprising the first component that binds to CD38, wherein binding to the cell is measured by flow cytometry.
  • the multispecific protein induces an enhanced ADCC effect on a target cell compared to an ADCC effect induced on the target cell by a monospecific protein that comprises the first component that specifically binds to CD38 or the second component that specifically binds to ICAM1.
  • the multispecific protein induces an enhanced CDC effect on a target cell, compared to a CDC effect induced on the target cell by a monospecific protein that comprises the first component that specifically binds to CD38 or the second component that specifically binds to ICAM1.
  • the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of a Raji cell.
  • the multispecific protein induces an enhanced ADCC effect on a target cell that expresses ICAM1 to CD38 compared to an ADCC effect induced on the target cell by a monospecific protein that comprises the first component that specifically binds to CD38 or the second component that specifically binds to ICAM1.
  • the cell expresses at least 5000, 10000, 150000, 20000, 30000, 50000, 100000, 150000, 200000, 250000, 300000, 400000, or 500000 ICAM1 proteins on its surface. In some embodiments, the cell expresses at least 50,000 ICAM1 proteins on its surface. In some embodiments, the cell expresses at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on its surface. In some embodiments, the cell expresses at least 300 CD38 proteins on its surface.
  • the cell expresses less than about 350000, 300000, 250000, 200000, 150000, 100000, 50000, 30000, 20000, 15000, 10000, or 5000 CD38 proteins on its surface. In some embodiments, the cell expresses less than about 350,000 CD38 proteins on its surface. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 10.
  • the cell expresses at least as much ICAM1 on its surface as an NCI-H2291 cell. In some embodiments, the cell expresses at least as much CD38 on its surface as an NCI-H2342 cell. In some embodiments, the cell expresses less CD38 on its surface than a Daudi cell. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is greater than or equal to the ratio of ICAM1 to CD38 on the surface of a Raji cell.
  • the multispecific protein has a reduced ability to kill NK (natural killer) cells in a population of fresh peripheral blood mononuclear cells compared to a monospecific protein that comprises the first component that specifically binds to CD38 or the second component that specifically binds to ICAM1.
  • the first component binds to human CD38 with a K D of from 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 K D of from about 0.42 nM to about 13.14 nM, as determined by surface plasmon resonance.
  • the first component binds to human CD38 with a K D of from about 0.15 nM to about 0.45 nM, as determined by surface plasmon resonance.
  • the second component binds to human ICAM1 with a K D of from about 0.2 nM to about 24.4 nM, as determined by surface plasmon resonance.
  • the second component binds to human ICAM1 with a K D of from about 0.2 nM to about 0.6 nM, as determined by surface plasmon resonance.
  • composition comprising the multispecific protein of this disclosure.
  • pharmaceutical composition further comprises a
  • One embodiment provides a method of killing a cell in a subject comprising administering to the subject the multispecific protein of this disclosure or the pharmaceutical composition of this disclosure, wherein the cell expresses CD38 and ICAMl.
  • the cell is lysed.
  • the cell is a tumor cell.
  • One embodiment provides a method of treating a cancer in a subject comprising administering to the subject the multispecific protein of this disclosure or the pharmaceutical composition of this disclosure, wherein the cancer comprises a cell that expresses CD38 and ICAMl.
  • the cancer comprises a solid tumor or a hematological malignancy.
  • the cancer comprises the hematological malignancy.
  • the cancer comprises the hematological malignancy.
  • the hematological malignancy is a multiple myeloma, a leukemia, a non-Hodgkin lymphoma, or a Hodgkin lymphoma.
  • the cancer is a lung cancer or a prostate cancer.
  • the cell expresses at least as much ICAMl on its surface as an NCI-H2291 cell.
  • the cell expresses at least as much CD38 on its surface as an NCI-H2342 cell.
  • the cell expresses less CD38 on its surface than a Daudi cell.
  • the amount of CD38 on the surface of the cell is less than or equal to the amount of CD38 on the surface of a Raji cell.
  • the ratio of ICAMl to CD38 on the surface of the cell is greater than the ratio of ICAMl to CD38 on the surface of a Daudi cell.
  • the cell expresses at least 300 CD38 proteins on its surface. In some embodiments, the cell expresses less than about 350000, 300000, 250000, 200000, 150000, 100000, 50000, 30000, 20000, 15000, 10000, or 5000 CD38 proteins on its surface. In some embodiments, the cell expresses less than about 350,000 CD38 proteins on its surface. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200. In some embodiments, the ratio of ICAM1 to CD38 on the surface of the cell is at least about 1.
  • the ratio of ICAM1 to CD38 on the surface of the cell is at least about 10.
  • the method further comprises administering an additional therapeutic agent.
  • the additional therapeutic agent comprises a chemotherapeutic agent, an immunotherapeutic agent, a targeted therapeutic agent, a hormone -based therapeutic agent, a stem-cell based therapeutic agent, or radiation.
  • the additional therapeutic agent comprises at least one of lenalidomide, dexamethasone, bortezomib, or any combinations thereof.
  • 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.
  • the subject has received a prior therapy.
  • the prior therapy comprises a proteasome inhibitor (PI) therapy and an immunomodulatory agent.
  • the subject is double refractory to a therapy comprising a proteasome inhibitor (PI) therapy and an immunomodulatory agent.
  • the subject is a human.
  • a kit comprising a multispecific protein according to this disclosure or a pharmaceutical composition comprising the same.
  • anti-CD38 antibodies In certain embodiments, are anti-CD38 antibodies, anti-ICAMl antibodies, pharmaceutical compositions comprising anti-CD38 antibodies and/or anti-ICAMl antibodies, and methods of use for treatment of a proliferative disease.
  • multi- specific antibodies e.g., bispecific antibodies
  • a first targeting moiety that specifically binds to CD38
  • a second targeting moiety that specifically binds to ICAM1
  • pharmaceutical compositions comprising the multi -specific antibodies, and methods of use for treatment of a proliferative disease.
  • a bispecific antibody comprising a first targeting moiety that specifically binds to CD38 or ICAM1 and comprising an enhanced complement dependent cytotoxicity (CDC) effect compared to a CDC effect by reference antibody daratumumab.
  • CDC complement dependent cytotoxicity
  • a bispecific antibody 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 an ADCC effect by reference antibody daratumumab.
  • ADCC antibody-dependent cell-mediated cytotoxicity
  • a bispecific antibody comprising a first targeting moiety that specifically binds to CD38 or ICAM1 and comprising a reduced immune cell kill effect compared to an immune cell kill effect of reference antibody daratumumab.
  • the bispecific antibody further comprises a second targeting moiety that specifically binds to CD38 or ICAMl.
  • the enhanced CDC is at least 2-fold, 3 -fold, 4-fold, or higher than the CDC effect of reference antibody daratumumab.
  • the enhanced CDC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher than the CDC effect of reference antibody daratumumab.
  • the enhanced ADCC is at least 2- fold, 3 -fold, 4-fold, 5 -fold, or higher than the ADCC effect of reference antibody daratumumab. In some embodiments, the enhanced ADCC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher than the ADCC effect of reference antibody daratumumab.
  • the immune cell is a Natural Killer cell. In some embodiments, the immune cell viability is improved by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher compared to the immune cell viability in the presence of reference antibody daratumumab.
  • the bispecific antibody is a bivalent antibody or binding fragments thereof.
  • the bivalent antibody or binding fragments thereof comprises an IgG- scFv(LC) C-terminal fusion format, an IgG-HC-scFv C-terminal fusion format, a scFv-HC-IgG N-terminal fusion format, or a DVD-Ig format.
  • the bispecific antibody is a monovalent antibody or binding fragments thereof.
  • the monovalent antibody or binding fragments thereof comprises a Fab-scFv-Fc(KIH) format or a Biclonics common LC format.
  • the scFv portion of the bispecific antibody specifically binds to ICAMl .
  • the first targeting moiety specifically binds to CD38 and the second targeting moiety specifically binds to ICAMl .
  • the first targeting moiety comprises a K D of from about InM to about 100 nM.
  • the first targeting moiety comprises a K D of at least InM, 2nM, 3nM, 3.15nM, 3.2nM, 3.39nM, 3.5nM, 4nM, 4.5nM, 5nM, 5.32nM, 5.5nM, 6nM, 6.5nM, 7nM, 7.5nM, 8nM, 8.5nM, 9nM, 9.5nM, lOnM, 15nM, 18nM, 20nM, 25nM, 30nM, 35nM, 40nM, 45nM, 50nM, 60nM, 70nM, 80nM, 90nM, or lOOnM.
  • the second targeting moiety comprises a K D of from about 0.1 to about 20
  • the bispecific antibody induces an apoptosis that is similar to an apoptosis induced by reference antibody daratumumab.
  • the first targeting moiety comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises: CDR1 sequence X1GX2X3X4X5X6X7X8X9X10X11X12; wherein Xi is present or absent, 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; Xe is selected from V, A, T, R, S, I, or N;
  • X7 is selected from Y, I, N, R, A, G, or D
  • Xg is selected from A, Y, D, G, W, C, or T
  • X9 is selected from M, V, I, W, D, or Y
  • X10 is selected from S, T, M, C, I, Y, A, or G
  • Xu is present or absent, if present, is selected from C or M
  • X12 is present or absent, if present, is C;
  • X13 is selected from A, G, or S :
  • Xi4 is selected from I, F, Y, V, S, or C;
  • X15 is selected from S, I, L, T, or M;
  • Xi 6 is selected from G, Y, S, T, L, or V;
  • Xi7 is selected from S, I, K, Y, T, G, or A;
  • Xis is selected from G, S, T, P, V, or Y;
  • X19 is selected from G, A, D, S, or T;
  • X20 is selected from S, T, I, N, or G;
  • X21 is selected from T, I, D, N, S, or A;
  • X22 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
  • X32 is selected from A, G, or V;
  • X 33 is selected from K, A, R, T, G, or S;
  • X 34 is selected from R, A, V, T, P, I, E, D, or S;
  • X 35 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,
  • X 40 is selected from S, Y, G, R, W, N, L, D, or F;
  • X 41 is present or absent, if present, is selected from F, Y, V, D, A, N, G, E, or L;
  • X 42 is present or absent, if present, is selected from P, L, Y, F, G, or T;
  • X 43 is present or absent, if present, is selected from T, P, F, V, N, Y, or S;
  • X 44 is present or absent, if present, is selected from G, L, S, T, or F;
  • X 45 is present or absent, if present, is selected from F, L, E, N, or S;
  • X 46 is present or absent, if present, is selected from D, S, L, or R;
  • X 47 is present or absent, if present, is selected from Y or L;
  • X 48 is present or absent, if present, is D; and
  • X 49
  • the VH region comprises CDR2 sequence AISGSGGSTX 22 YADSVKG, wherein X 22 is selected from F or Y. In some embodiments, the VH region comprises CDR2 sequence
  • X 13 is selected from A, G, or S .
  • Xi 4 is selected from I, F, Y, V, S, or C;
  • X 15 is selected from I, L, M, or T;
  • Xi 6 is selected from G, Y, S, T, L, or V;
  • Xi 7 is selected from S, I, K, Y, T, G, or A;
  • Xis 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;
  • the VH region comprises CDR2 sequence X 3 X 14 IX k,C I ?
  • X 13 is selected from A or G
  • Xi 4 is selected from I, F, Y, V, S, or C
  • X 1 ⁇ 2 is selected from G, Y, S, T, or L
  • X 17 is selected from S, I, K, Y, T, or G
  • Xis 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 l3 CX l5 X l6 X l7 X l8 X l9 X2oX2 l X22X23YX25X26X27X28X29X3oX31 ⁇
  • X l3 IS S elected frOUl A, or S
  • X l5 is selected from I, L, or T
  • X 1 ⁇ 2 is selected from Y or V
  • Xn is selected from S, T, or A
  • Xis is selected from G, P, or V
  • Xi 9 is selected from D, S, or T
  • X 20 is selected from S, T, or G
  • X 21 is selected from D, N, S, or A
  • X 22 is selected from T, I, or S
  • X 23 is selected from Y, K, or I
  • X 25 is selected from A or Y
  • X 26 is selected from S, T, A, or N
  • X 27 is selected from W, N, or S
  • the VH region comprises CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY, wherein X 38 is selected from A or G; and X 41 is selected from F or Y.
  • the VH region comprises CDR3 sequence X32X33X34X35X36X37X3 8 X3 9 X40X41X42X43X44X45X46 X47X48X49; wherein X32 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,
  • the VH region comprises CDR3 sequence X3 2 X33X3 4 X35X36X37X3 8 X3 9 X 40 X 41 X 42 X 43 X 44 X 45 ; wherein X3 2 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,
  • 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, if present, is selected from P, F, V, or N;
  • X 44 is present or absent, if present, is selected from L, S, or T; and
  • X 45 is present or absent, if present, is selected from L or F.
  • the VH region comprises CDR3 sequence AX33X3 4 X35X36X37X3 8 X3 9 X 40 X 41 X 42 X 43 X 44 X 45 X 46 ; wherein X33 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, if present, is selected from V, Y, or E; X 42 is present or absent, if present, is G; X 43 is present or absent, if present, is Y; X 44 is present or absent, if present, is F; X 45 is present or absent, if present, is selected
  • the VH region comprises CDR1 sequence GFPFX ⁇ X ( ,YAMS. CDR2 sequence AISGSGGSTX 22 YADSVKG, and CDR3 sequence AKRGTYX 38 Y SX 41 PTGFDY ; wherein X 5 is selected from D or G; Xe is selected from V, A, or T; X 22 is selected from F or Y; X 38 is selected from A or G; and X 41 is selected from F or Y.
  • the VH region comprises CDR1 sequence GFSLXsXeXvXsXsXioXii, CDR2 sequence X1 3 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 X3 2 X33X3 4 X3 5 X36X3 7 X3 8 X3 9 X 40 X 41 X 42 X 43 X 44 X 45 ; wherein X5 is selected from S or N; X ( , is selected from R, S, or N; X 7 is selected from Y, I, or N; Xs is selected from Y, D, G, or A; X 9 is selected from V, M, or I; X 10 is selected from T, S, or M; Xu is present or absent, if present, is C; X 13 is selected from A or G; Cm
  • the VH region comprises CDR1 sequence GFSX 4 X5X6X 7 X8X9X 10 X 11 X 12 , CDR2 sequence X 13 CX 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 YX 25 X 26 X 27 X 28 X 29 X 30 X 31 , and CDR3 sequence
  • the VH region comprises 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; 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 CDR3 sequence X32X33X34X35X36X37X38X39X40X41X42X43X44X45X46X47X48X49; wherein X32 is selected from A, G, or V; X33 is selected from K, A, R, T, G, or S; X34 is selected from R, A, V, T, P, I, E, D, or S; X35 is selected from G, W, D, L, K, P, S, A, T, or R; X36 is selected from T, P, A, Y, D, G, S, R, V, or E; X37 is
  • the VH region comprises 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; 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 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.
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10. In some embodiments, the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11,
  • CDR2 sequence selected from SEQ ID Nos:
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52.
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58.
  • the VL region comprises CDR1 sequence selected from SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; CDR2 sequence selected from SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and 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.
  • the VL region comprises CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; CDR2 sequence selected from SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.
  • the second targeting moiety comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises: CDR1 sequence X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 ;
  • 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,
  • 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, if present, is selected from K or G; and
  • X 30 is present or absent, if present, is G; and CDR3 sequence
  • 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, if present, is selected from
  • the VH region comprises CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 , wherein X 5 is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y or H; X 8 is selected from G, A, or Y; and X 10 is selected from S, G, or N.
  • the VH region comprises CDR2 sequence
  • VH region comprises CDR3 sequence
  • X 31 is selected from A or V;
  • X 33 is selected from G or D;
  • X 34 is selected from G, P, W, or D;
  • X 35 is selected from D, Y, S, or L;
  • X 36 is selected from Y, D, V, or L;
  • X 37 is selected from G, S, or D;
  • X 38 is selected from G, Y, F, or S;
  • X 39 is selected from S, D, G, or T;
  • X 40 is selected from T, A, D, S, or Y;
  • X 41 is selected from Y, A, G, or I;
  • X 42 is selected from I, Y, or R;
  • X 43 is selected from L, R, Y, or G;
  • X 44 is selected from N, L, Y, or S;
  • X 45 is present or
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 241, 247 and 250; CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251; and CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252.
  • the VL region comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262,
  • 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.
  • the bispecific antibody comprises a humanized antibody or binding fragment thereof or a chimeric antibody or binding fragment thereof.
  • the bispecific antibody comprises an IgGl framework sequence. In some embodiments, the bispecific antibody comprises an IgG2 framework sequence. In some embodiments, the bispecific antibody comprises an IgG4 framework sequence. In some embodiments, the bispecific antibody further comprises a payload. In some embodiments, the payload comprises a small molecule, a peptide, or a protein.
  • Xi is present or absent, if present, is S;
  • X 2 is selected from F or I;
  • X 3 is selected from P, S, or D;
  • X 4 is selected from F, L, or A;
  • X 5 is selected from D, G, S, N, or T;
  • Xe is selected from V, A, T, R, S, I, or N;
  • X 7 is selected from Y, I, N, R, A, G, or D;
  • Xs is selected from A, Y, D, G, W, C, or T;
  • X 9 is selected from M, V, I, W, D, or Y;
  • X 10 is selected from S, T, M, C, I, Y, A, or G;
  • X 11 is present or absent, if present, is selected from C or M;
  • X 12 is present or absent, if present, is C;
  • X32 is selected from A, G, or V;
  • X33 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,
  • the VH region comprises CDR1 sequence GFSX 4 X5X6X7X8X9X 10 X 11 X 12 ; wherein X 4 is selected from F or A; X 5 is selected from S, T, or N; Xe is selected from S, T, or N; X 7 is selected from 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, if present, is selected from G or K; and
  • X 31 is present or absent, if present, is G.
  • the VH region comprises CDR2 sequence X 3X 14 IX k,C X igX 19X20X2 C 22 C 2 C 24 C 2' C 2 ⁇ C 2 C 2c C 29 C 4 ⁇
  • X 13 is selected from A or G
  • Xi 4 is selected from I, F, Y, V, S, or C
  • X 1 ⁇ 2 is selected from G, Y, S, T, or L
  • X 17 is selected from S, I, K, Y, T, or G
  • Xis is selected from G, S, or T
  • X 19 is selected from G, A, D, or S
  • X 20 is selected from T, I, N, or G
  • X21 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
  • the VH region comprises CDR3 sequence X3 2 X33X3 4 X35X36X37X3 8 X3 9 X 40 X 41 X 42 X 43 X 44 X 45 ; wherein X3 2 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,
  • 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, if present, is selected from P, F, V, or N;
  • X 44 is present or absent, if present, is selected from L, S, or T; and
  • X 45 is present or absent, if present, is selected from L or F.
  • the VH region comprises CDR3 sequence AX33X3 4 X35X36X37X3 8 X3 9 X 40 X 41 X 42 X 43 X 44 X 45 X 46 ; wherein X33 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, if present, is selected from V, Y, or E; X 42 is present or absent, if present, is G; X 43 is present or absent, if present, is Y; X 44 is present or absent, if present, is F; X 45 is present or absent, if present, is selected
  • the VH region comprises CDR1 sequence GFPFX ⁇ X ( ,YAMS. CDR2 sequence AISGSGGSTX 22 YADSVKG, and CDR3 sequence AKRGTYX 38 Y SX 41 PTGFDY ; wherein X 5 is selected from D or G; Xe is selected from V, A, or T; X 22 is selected from F or Y; X 38 is selected from A or G; and X 41 is selected from F or Y.
  • the VH region comprises CDR1 sequence GFSFXsXeXvXsXsXioXii, CDR2 sequence X1 3 X14IX16X17X1 8 X19X20X21X22X2 3 X24X25X26X27X2 8 X29X 30 , and CDR3 sequence X3 2 X33X3 4 X35X36X37X3 8 X3 9 X 40 X 41 X 42 X 43 X 44 X 45 ; wherein X5 is selected from S or N; X ( , is selected from R, S, or N; X 7 is selected from Y, I, or N; Xs is selected from Y, D, G, or A; X 9 is selected from V, M, or I; X 10 is selected from T, S, or M; Xu is present or absent, if present, is C; X 13 is selected from A or G; Cm is selected from I, F, Y, V,
  • the VH region comprises CDR1 sequence GFSX 4 X5X6X7X8X9X 10 X 11 X 12 , CDR2 sequence X1 3 CX15X1 6 X17X1 8 X1 9 X20X21X22X2 3 YX25X2 6 X27X2 8 X2 9 X 30 X 31 , and CDR3 sequence
  • X 4 is selected from F or A;
  • X5 is selected from S, T, or N;
  • Xe is selected from S, T, or N;
  • X 7 is selected from Y, R, A, or G;
  • Xs is selected from W, Y, or C;
  • X 9 is selected from I, W, Y, or D;
  • X 10 is selected from C, I, Y, or M;
  • Xu is present or absent, if present, is selected from C or M;
  • X 12 is present or absent, if present, is C;
  • X 13 is selected from A, or S;
  • X 15 is selected from I, F, or T;
  • X 1 ⁇ 2 is selected from Y or V;
  • X 17 is selected from S, T, or A;
  • Xis is selected from G, P, or V;
  • Xi 9 is selected from D, S, or T;
  • the VH region comprises 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; 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 CDR3 sequence X3 2 X33X3 4 X35X36X3 7 X38X39X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 ; wherein X3 2 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,
  • the VH region comprises 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; 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 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.
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10. In some embodiments, the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11,
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52.
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58.
  • the VL region comprises CDR1 sequence selected from SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; CDR2 sequence selected from SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and 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.
  • the VL region comprises CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; CDR2 sequence selected from SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.
  • the VL region comprises CDR1 sequence selected from SEQ ID NOs: 71, 77, 83, 94, and 102; CDR2 sequence selected from SEQ ID NOs: 72, 78, and 84; and CDR3 sequence selected from SEQ ID NOs: 73, 79, 85, 95, and 103.
  • 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.
  • the anti-CD38 antibody is a multi -specific antibody comprising a second targeting moiety.
  • 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, if present, is selected from Y, A, G, I, or D;
  • X 42 is present or absent, if present, is selected from I, Y, R, P, V, or G;
  • X 43 is present or absent, if present, is selected from L, R, Y, G, or A;
  • X 44 is present or absent, if present, is selected from N, L, Y, S, or W;
  • X 45 is present or absent, if present, is selected from L, Y, F, or C;
  • X 46 is present or absent, if present, is selected from D, A, or F;
  • X 47 is present or absent, if present, is selected from M, P
  • the VH region comprises CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 , wherein X 5 is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y or H; X 8 is selected from G, A, or Y; and X 10 is selected from S, G, or N.
  • the VH region comprises CDR2 sequence
  • VH region comprises CDR3 sequence
  • X 31 is selected from A or V;
  • X 33 is selected from G or D;
  • X 34 is selected from G, P, W, or D;
  • X 35 is selected from D, Y, S, or L;
  • X 36 is selected from Y, D, V, or L;
  • X 37 is selected from G, S, or D;
  • X 38 is selected from G, Y, F, or S;
  • X 39 is selected from S, D, G, or T;
  • X 40 is selected from T, A, D, S, or Y;
  • X 41 is selected from Y, A, G, or I;
  • X 42 is selected from I, Y, or R;
  • X 43 is selected from L, R, Y, or G;
  • X 44 is selected from N, L, Y, or S;
  • X 45 is present or
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and 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 VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218,
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 241, 247 and 250; CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251; and CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252.
  • the VL region comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262,
  • 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.
  • 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.
  • the bispecific antibody or binding fragment thereof comprises a IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triple body, mini-antibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv-CH-CL-scFv, F(ab’)2, F(ab’)2-scFv2.
  • an anti-ICAMl antibody comprising a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises: CDR1 sequence X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 ; wherein X 1 is selected from G or E; X 2 is selected from F or Y; X 3 is selected from S or T; X 4 is selected from L, F, or S; X 5 is selected from S or N; X 6 is selected from S, N,
  • X 7 is selected from Y, H, or G;
  • X 8 is selected from G, A, Y, W, or F;
  • X 9 is selected from M, W, Y, or I;
  • X 10 is selected from S, G, N, M, or I; and
  • X 11 is present or absent, if present, is C;
  • 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 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, if present, is selected from K or G; and
  • X 30 is present or absent, if present, is G; and CDR3 sequence
  • 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, if present, is selected from
  • VH region comprises CDR3 sequence
  • X 31 is selected from A or V;
  • X 33 is selected from G or D;
  • X 34 is selected from G, P, W, or D;
  • X 35 is selected from D, Y, S, or L;
  • X 36 is selected from Y, D, V, or L;
  • X 37 is selected from G, S, or D;
  • X 38 is selected from G, Y, F, or S;
  • X 39 is selected from S, D, G, or T;
  • X 40 is selected from T, A, D, S, or Y;
  • X 41 is selected from Y, A, G, or I;
  • X 42 is selected from I, Y, or R;
  • X 43 is selected from L, R, Y, or G;
  • X 44 is selected from N, L, Y, or S;
  • X 45 is present or
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 21 1, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251 ; and CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , wherein X 31 is selected from A or V; X 32 is selected from R or I; X 33 is selected from G, D, P, A, or V; X 34 is selected from G, P, W, D, N, or R; X 35 is selected from D, Y, S, L, G, F, or W; X 36
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227,
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240.
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 241, 247 and 250; CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251; and CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252.
  • the anti-ICAMl antibody is a multi-specific antibody comprising an additional targeting moiety.
  • the additional targeting moiety specifically binds to CD38.
  • the additional targeting moiety comprises a variable heavy chain (VH) region and a variable light chain (VL) region, wherein the VH region comprises: CDR1 sequence X1GX2X3X4X5X6X7X8X9X10X11X12; wherein Xi is present or absent, if present, is S; X2 is selected from F or I; X3 is selected from P, S, or D; XQs selected from F, L, or A; X5 is selected from D, G, S, N, or T; Xe is selected from V, A, T, R, S, I, or N; X7 is selected from Y, I, N, R, A, G, or D; Xs is selected from A, Y, D, G, W, C, or T; X9
  • X13 is selected from A, G, or S;
  • Xi4 is selected from I, F, Y, V, S, or C;
  • X15 is selected from S, I, L, T, or M;
  • X 1 ⁇ 2 is selected from G, Y, S, T, L, or V;
  • Xi7 is selected from S, I, K, Y, T, G, or A;
  • Xis is selected from G, S, T, P, V, or Y;
  • X19 is selected from G, A, D, S, or T;
  • X20 is selected from S, T, I, N, or G;
  • X21 is selected from T, I, D, N, S, or A;
  • X22 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
  • X32 is selected from A, G, or V;
  • X 33 is selected from K, A, R, T, G, or S;
  • X 34 is selected from R, A, V, T, P, I, E, D, or S;
  • X 35 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,
  • the VH region comprises CDR1 sequence G FPFX ⁇ X ( ,Y A MS. wherein X 5 is selected from D or G; and Xe is selected from V, A, or T.
  • the VH region comprises CDR1 sequence X 1 GX 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 ; wherein Xi is present or absent, if present, is S; X 2 is selected from F or I; X 3 is selected from S or D; X 4 is selected from L, F, or A; X 5 is selected from S, N, or T; Xe is selected from R, S, N, I, or T; X 7 is selected from Y, I, N, R, A, D, or G; Xs is selected from Y, D, G, A, W, T, or C; X 9 is selected from V, M, I, W, Y, or D; X 10 is
  • the VH region comprises CDR1 sequence GFSLX 5 X 6 X 7 X 8 X 9 X 10 X 11 ; wherein X 5 is selected from S or N; Xe is selected from R, S, or N; X 7 is selected from Y, I, or N; Xg is selected from Y, D, G, or A; X 9 is selected from V, M, or I; X 10 is selected from T, S, or M; and Xu is present or absent, if present, is C.
  • the VH region comprises CDR1 sequence GFSX 4 X5X6X7X8X9X 10 X 11 X 12 ; wherein X 4 is selected from F or A; X 5 is selected from S, T, or N; Xe is selected from S, T, or N; X 7 is selected from Y,
  • the VH region comprises CDR2 sequence AISGSGGSTX 22 YADSVKG, wherein X 22 is selected from F or Y. In some embodiments, the VH region comprises CDR2 sequence
  • X 13 is selected from A, G, or S .
  • Xi 4 is selected from I, F, Y, V, S, or C;
  • X 15 is selected from I, L, M, or T;
  • Xi 6 is selected from G, Y, S, T, L, or V;
  • Xi 7 is selected from S, I, K, Y, T, G, or A;
  • Xis 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;
  • the VH region comprises CDR2 sequence X 13 X 14 IX k,C I ?
  • X l3 CX l5 X l6 X l7 X l8 X l9 X2oX2 l X22X23YX25X26X27X28X29X3oX31 ⁇
  • X l3 IS S elected frOUl A, or S
  • X l5 is selected from I, L, or T
  • X 1 ⁇ 2 is selected from Y or V
  • Xn is selected from S, T, or A
  • Xis is selected from G, P, or V
  • Xi 9 is selected from D, S, or T
  • X 20 is selected from S, T, or G
  • X 21 is selected from D, N, S, or A
  • X 22 is selected from T, I, or S
  • X 23 is selected from Y, K, or I
  • X 25 is selected from A or Y
  • X 26 is selected from S, T, A, or N
  • X 27 is selected from W, N, or S
  • the VH region comprises CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY, wherein X 38 is selected from A or G; and X 41 is selected from F or Y.
  • the VH region comprises CDR3 sequence X 3 2 X33X3 4 X33 X30X 3 7 X3 8 X39X 40 X 41 X42X43X44X4iX4r > X47X48X49i wherein X3 2 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,
  • the VH region comprises CDR3 sequence X3 2 X33X3 4 X35X36X37X3 8 X3 9 X 40 X 41 X 42 X 43 X 44 X 45 ; wherein X3 2 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,
  • the VH region comprises CDR1 sequence GFPFX ⁇ X ( ,YAMS. CDR2 sequence AISGSGGSTX 22 YADSVKG, and CDR3 sequence AKRGTYX 38 Y SX 41 PTGFDY ; wherein X 5 is selected from D or G; Xe is selected from V, A, or T; X 22 is selected from F or Y; X 38 is selected from A or G; and X 41 is selected from F or Y.
  • the VH region comprises CDR1 sequence GFSLXsXeXvXsXsXioXii, CDR2 sequence X1 3 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 X3 2 X33X3 4 X3 5 X36X3 7 X3 8 X3 9 X 40 X 41 X 42 X 43 X 44 X 45 ; wherein X5 is selected from S or N; X ( , is selected from R, S, or N; X 7 is selected from Y, I, or N; Xs is selected from Y, D, G, or A; X 9 is selected from V, M, or I; X 10 is selected from T, S, or M; Xu is present or absent, if present, is C; X 13 is selected from A or G; Cm
  • the VH region comprises 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; 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 CDR3 sequence X32X33X34X35X36X37X38X39X40X41X42X43X44X45X46X47X48X49; wherein X32 is selected from A, G, or V; X33 is selected from K, A, R, T, G, or S; X34 is selected from R, A, V, T, P, I, E, D, or S; X35 is selected from G, W, D, L, K, P, S, A, T, or R; X36 is selected from T, P, A, Y, D, G, S, R, V, or E; X37 is
  • the VH region comprises 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; 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 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.
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10. In some embodiments, the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11,
  • CDR2 sequence selected from SEQ ID Nos:
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58.
  • the VL region comprises CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; CDR2 sequence selected from SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.
  • the VL region comprises CDR1 sequence selected from SEQ ID NOs: 71, 77, 83, 94, and 102; CDR2 sequence selected from SEQ ID NOs: 72, 78, and 84; and CDR3 sequence selected from SEQ ID NOs: 73, 79, 85, 95, and 103.
  • 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.
  • the anti-ICAMl antibody comprises a humanized antibody or binding fragment thereof or a chimeric antibody or binding fragment thereof.
  • the anti-ICAMl antibody comprises a bispecific antibody or binding fragment thereof.
  • the bispecific antibody or binding fragment thereof comprises a IgG-scFv, nanobody, BiTE, diabody, DART, TandAb, scDiabody, scDiabody-CH3, triple body, mini-antibody, minibody, TriBi minibody, scFv-CH3 KIH, Fab-scFv-Fc KIH, Fab-scFv, scFv- CH-CF-scFv, F(ab’)2, F(ab’)2-scFv2.
  • the anti-ICAMl antibody comprises an IgGl framework sequence. In some embodiments, the anti-ICAMl antibody comprises an IgG2 framework sequence. In some embodiments, the anti-ICAMl antibody comprises an IgG4 framework sequence. In some embodiments, the anti-ICAMl antibody comprises a HC sequence selected from SEQ ID NOs: 329- 349 and a EC sequence selected from SEQ ID NOs: 351-366 and 182. In some embodiments, the anti- ICAMl antibody further comprises a payload. In some embodiments, the payload comprises a small molecule, a peptide, or a protein.
  • a vector comprising a nucleic acid polymer which encodes a bispecific antibody described herein, an anti-CD38 antibody described herein, or an anti-ICAMl antibody described herein.
  • the subject has a solid tumor.
  • the solid tumor is bladder cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, eye cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer.
  • the cancer is a hematologic malignancy.
  • the hematologic malignancy is a B cell lymphoma or T cell lymphoma.
  • the hematologic malignancy is a
  • the hematologic malignancy is chronic lymphocytic leukemia (CEE), 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 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
  • CEE chronic lymphocytic leukemia
  • SLL small lymphocytic lymphoma
  • FL
  • the method further comprises administering an additional therapeutic agent.
  • the additional therapeutic agent comprises chemotherapeutic agent, immunotherapeutic agent, targeted therapeutic agent, hormone-based therapeutic agent, stem-cell based therapeutic agent, or radiation.
  • the additional therapeutic agent comprises a first-line therapeutic agent.
  • the additional therapeutic agent and the antibody are administered simultaneously.
  • the additional therapeutic agent and the antibody are administered sequentially.
  • the additional therapeutic agent is administered prior to the antibody.
  • the additional therapeutic agent is administered after administration of the antibody.
  • the additional therapeutic agent and the antibody are administered as a separate dosage.
  • the subject has undergone surgery.
  • the subject is a human.
  • kits comprising a bispecific antibody described herein, an anti-CD38 antibody described herein, an anti-ICAMl antibody described herein, or a
  • FIG. 1A-FIG. IB illustrate exemplary bispecific antibody formats contemplated herein.
  • FIG. 1A and FIG. IB are adapted from FIG. 2 of Brinkmann and Kontermann,“The making of bispecific antibodies,” MABS 9(2): 182-212 (2017).
  • FIG. 2 illustrates exemplary bispecific formats described herein.
  • FIG. 2A Light chain C-terminal fusion
  • FIG. 2B Heavy chain C-terminal fusion
  • FIG. 2C Heavy chain N-terminal fusion
  • FIG. 2D DVD format
  • FIG. 2E Three chain knobs-into-holes (KIH)
  • FIG. 2F Common light chain bispecific.
  • FIGs. 3A - 3B show levels of CD38 (FIG. 3A) and ICAM1 (FIG. 3B) on the surface of various cell lines as measured by flow cytometry with PE-labeled anti-hCD38 (Biolegend) or AlexaFluor488-labeled anti-hCD54 (Biolegend).
  • FIG. 4A-FIG. 4B show complement-dependent cytotoxicity (CDC) mediated lysis of Daudi cells (FIG. 4A) and Raji cells (FIG. 4B) by selected monoclonal and bispecific antibodies.
  • FIG. 5A-FIG. 5F illustrate antibody-dependent cellular cytotoxicity (ADCC)-mediated lysis of Daudi cells (FIG. 5A), DU145 cells (FIG. 5B), NCI-H2444 cells (FIG. 5C), HCC44 cells (FIG. 5D), NCI- H2291 cells (FIG. 5E) and NCI-H2342 (FIG. 5F) cells using NK92/CD16A as effector cells.
  • ADCC antibody-dependent cellular cytotoxicity
  • FIG. 6A-FIG. 6D show ADCC-mediated lysis of Daudi cells (FIG. 6A), DU145 cells (FIG. 6B), HCC44 cells (FIG. 6C) and NCI-H2444 cells (FIG. 6D) using fresh PBMCs as effector cells.
  • FIG. 7 illustrates induction of cell death and apoptosis in the presence (gray bar) or absence (black bar) of crosslinker by selected monoclonal and bispecific antibodies in Daudi cells.
  • FIG. 8A-FIG. 8B show antibody induced cell death of NK92/CD16a cells (FIG. 8 A) and the NK cells in fresh PBMCs (FIG. 8B).
  • the HC N-fusion and three chain KIH antibodies showed reduced NK killing compared to the anti-CD38 BMK clone (or reference antibody daratumumab).
  • FIG. 9A - FIG. 9B show ELISA binding of exemplary anti-CD38 rabbit human chimeric clones to recombinant human CD38 ECD (FIG. 9A) and cynomolgus CD38 ECD (FIG. 9B).
  • FIG. 10A-FIG. 10B show ELISA binding of exemplary anti -IC AMI rabbit human chimeric clones to the recombinant human ICAM1 ECD (FIG. 10A) and rhesus ICAM1 ECD (FIG. 10B).
  • FIG. 11 shows binding of exemplary anti-CD38 rabbit human chimeric clones to Daudi cells as determined by flow cytometry.
  • FIG. 12 shows binding of anti-ICAMl rabbit human chimeric clones to DU145 cells as determined by flow cytometry.
  • FIG. 13 shows CDC-mediated lysis of Daudi cells by benchmark and exemplary rabbit human chimeric anti-CD38 antibodies.
  • FIG. 14A-FIG. 14B show ADCC-mediated lysis of Daudi cells (FIG. 14A) and HuNSl cells (FIG. 14B) by anti-CD38 antibodies using NK92/CD16A as effector cells.
  • FIG. 15A-FIG. 15B show ADCC-mediated lysis of Daudi cells (FIG. 15A) and HuNSl cells (FIG. 15B) by benchmark and exemplary rabbit human chimeric anti-CD38 antibodies using NK92/CD16A as effector cells.
  • FIG. 16A-FIG. 16C show ADCC-mediated lysis of DU145 (FIG. 16A), Daudi cells (FIG. 16B) and HuNSl cells (FIG. 16C) by the anti-ICAMl clone G12 and exemplary rabbit human chimeric anti-ICAMl antibodies using NK92/CD16A as effector cells.
  • FIG. 17A-FIG. 17C show ADCC-mediated lysis of DU145 cells by exemplary high affinity anti-
  • CD38 4618 _ 1 _ 12 bispecific antibodies (FIG. 17A), exemplary mid affinity anti-CD38 32218 _ 1 bispecific antibodies (FIG. 17B) and exemplary low affinity anti-CD38 33218 2 bispecific antibodies (FIG. 17C) using fresh PBMC as effector cells.
  • FIG. 18A - FIG. 18C show ADCC-mediated lysis of Raji (FIG. 18A), DU145 (FIG. 18B), and HCC44 (FIG. 18C) using exemplary monovalent anti-CD38 (medium affinity, 32218 1), monovalent anti- ICAMl, and anti-CD38/ICAMl bispecific antibodies
  • FIG. 19A - FIG. 19B show increased ADCC-mediated lysis of Raji (FIG. 19A) and KMS26 (FIG. 19B) cells with a CD38/ICAM1 KIH bispecific antibody having an Fc mutation (ADCC-high) that.
  • FIG. 20A - FIG. 20B show increased ADCC-mediated lysis of Raji (FIG. 20A) and KMS26 (FIG. 20B) cells with an afucosylated CD38/ICAM1 KIH bispecific antibody.
  • FIG. 21 shows the mean volume of Raji cell-derived xenograft tumors treated with monospecific CD38 or ICAM1 antibodies or a three chain KIH CD38/ICAM1 bispecific antibody.
  • FIG. 22 shows the mean volume of Raji cell-derived xenograft tumors treated with a monospecific CD38 antibody, a three chain KIH CD38/ICAM1 bispecific antibody with the anti-CD38-binding domain from anti-CD38 BMK, or a three chain KIH CD38/ICAM1 bispecific antibody with the CD38 -binding domain from 32218 1 (Three chain KIH (Med)).
  • FIG. 23 shows the mean volume of HuNSl cell-derived xenograft tumors treated with monospecific CD38 or ICAM1 antibodies or a three chain KIH CD38/ICAM1 bispecific antibody.
  • low receptor copy numbers on a target cell, or low affinity toward an antigen has hindered the therapeutic effect of an antibody-based therapy.
  • non-specificity of an antibody toward a target antigen, or the presence of a target in both cancer and non-cancer cells have further limited the use of an antibody-based therapy.
  • CD38 also known as cyclic ADP ribose hydrolase, is a type II transmembrane glycoprotein with a long C-terminal extracellular domain and a short N-terminal cytoplasmic domain. CD38 mediates cytokine secretion and activation and proliferation of lymphocytes (Funaro et al, J Immunology 145:2390-6, 1990; Guse et al, Nature 398:70-3, 1999), and via its NAD glycohydrolase activity regulates extracellular NAD+ levels which have been implicated in modulating the regulatory T-cell compartment (Adriouch et al., 14: 1284-92, 2012; Chiarugi et al., Nature Reviews 12:741-52, 2012). In some instances, CD38 is upregulated in different types of cancer, in particular, in hematologic malignancies such as multiple myeloma.
  • anti-CD38 antibodies anti-ICAMl antibodies, and multi-specific antibodies which comprise a targeting moiety to CD38, a targeting moiety to ICAM1, or a combination thereof.
  • bispecific antibodies which comprise a first targeting moiety to CD38 and a second targeting moiety to ICAM1.
  • methods of treating a cancer with use of an anti-CD38 antibody, an anti-ICAMl antibody, or a multi-specific antibody e.g., a bispecific CD38/ICAM1 antibody).
  • multispecific proteins comprising a first component that binds CD38 and a second component that binds ICAMl.
  • 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 an ICAMl binding protein, such as an anti-ICAMl antibody or an anti-ICAMl antibody mimetic. See, e.g., Yu el a/.. Annu Rev Anal Chem (Palo Alto Calif). 2017 June 12; 10(1): 293- 320.
  • the multispecific protein is bispecific, tri-specific, or tetra-specific. In some instances, the multispecific protein is bivalent, trivalent, tetravalent or more than tetravalent. In some instances, the multispecific protein has more than one binding site that binds to CD38. In some instances, the multispecific protein has more than one binding site that binds to ICAMl. In some instances, the multispecific protein has more than one binding sites for each of 1, 2, 3, or 4 different target proteins. In some instances, the multispecific protein binds to more than one epitope on CD38 and/or ICAMl. In some instances, the multispecific protein is bivalent for CD38 and monovalent for ICAMl. In some instances, the multispecific protein is bivalent for ICAMl and monovalent for CD38.
  • the first component comprises an antibody mimetic comprising a binding site specific for CD38 and is an affibody, an adnectin (also referred to as a monobody), an affimer, an affitin (also referred to as a nanofitin), an anticalin, an atrimer, an avimer, a fyonmer, an antibody mimetic comprising armadillo repeat domains, a kuntiz domain, a knottin, a DARpin, or any combinations thereof.
  • an antibody mimetic comprising a binding site specific for CD38 and is an affibody, an adnectin (also referred to as a monobody), an affimer, an affitin (also referred to as a nanofitin), an anticalin, an atrimer, an avimer, a fyonmer, an antibody mimetic comprising armadillo repeat domains, a kuntiz domain, a knottin,
  • the second component comprises an antibody mimetic comprising a binding site specific for ICAMl and is an affibody, an adnectin (also referred to as a monobody), an affimer, an affitin (also referred to as a nanofitin), an anticalin, an atrimer, an avimer, a fyonmer, an antibody mimetic comprising armadillo repeat domains, a kuntiz domain, a knottin, a DARpin, or any combinations thereof.
  • an antibody mimetic comprising armadillo repeat domains, a kuntiz domain, a knottin, a DARpin, or any combinations thereof.
  • the first component comprises an anti-CD38 antibody or an antigen binding fragment thereof.
  • the anti-CD38 antibody includes: an anti-CD38 IgG antibody comprising two polypeptides, each comprising a heavy chain (HC) and a light chain (LC), single domain antibody (sdAb), a VHH domain (or a camelized) antibody, ), a variable heavy domain (VH), a variable light domain (VL), an Fab, an F(ab’)2, a single chain variable fragment (scFv), an scFv comprising an Fc region (scFv Fc), a monovalent IgG, a V-NAR, an IgGNAR, a camelid heavy chain IgG (hcIgG), an scFv fused to a CH3 domain (scFv-CH3).
  • the second component comprises an anti-ICAMl antibody or an antigen binding fragment thereof.
  • the anti-ICAMl antibody includes: an anti-ICAMl IgG antibody comprising two polypeptides, each comprising a heavy chain (HC) and a light chain (LC), single domain antibody (sdAb), a VHH domain (or a camelized) antibody, ), a variable heavy domain (VH), a variable light domain (VL), an Fab, an F(ab’)2, a single chain variable fragment (scFv), an scFv comprising an Fc region (scFv Fc), a monovalent IgG, a V-NAR, an IgGNAR, a camelid heavy chain IgG (hcIgG), an scFv fused to a CH3 domain (scFv-CH3).
  • the multispecific protein comprising a CD38 -binding first component and an ICAM1 -binding second component have different affinities (K D ) for their respective target antigens as measured by surface plasmon resonance.
  • the first component binds to human CD38 with a K D of from about 0.1 nM to about 100 nM, from about 0.15 nM to about 95 nM, from about 0.2 nM to about 90 nM, from 0.25 nM to about 85 nM, from about 0.3 nM to about 80 nM, from about 0.35 nM to about 75 nM, from about 0.4 nM to about 70 nM, from about 0.5 nM to about 70 nM, from about 0.6 nM to about 60 nM, from about 0.7 nM to about 50 nM, from about 0.8 nM to about 40 nM, from about 0.9 nM to about 30 nM, from about 1 nM
  • the second component binds to human ICAM1 with a K D of about 0.1 nM to about 100 nM, from about 0.15 nM to about 95 nM, from about 0.2 nM to about 90 nM, from 0.25 nM to about 85 nM, from about 0.3 nM to about 80 nM, from about 0.35 nM to about 75 nM, from about 0.4 nM to about 70 nM, from about 0.5 nM to about 70 nM, from about 0.6 nM to about 60 nM, from about 0.7 nM to about 50 nM, from about 0.8 nM to about 40 nM, from about 0.9 nM to about 30 nM, from about 1 nM to about 20 nM, from about 1.5 nM to about 10 nM, from about 0.15 nM to about 30 nM, from about 0.16 nM to about 25 nM, from about 0.17 nM to about 20
  • a multispecific protein provided herein binds to a target cell that expresses a higher level of ICAM1 than CD38, on its surface.
  • the ratio of ICAM1 to CD38 protein expression on the target cell surface is from about 1, 1.5, 2.0, 2.5, 5, 10, 15, 20, 50, 100, or 200 as measured by flow cytometry.
  • the ratio of ICAM1 to CD38 protein expression on the target cell surface is from about 1.1 to 700, such as about 2.5, 14.2, 29.1, 64.5, 34.0, 50.3, 357.1, 666.7, based on quantification of surface expression of the proteins.
  • the target cell expresses at least 500, 1000, 2000, 3000, 5000, 10000, 150000, 20000, 30000, 50000, 100000, 150000, 200000, 250000, 300000, 400000, or 500000 ICAM1 proteins on its surface as measured by flow cytometry.
  • the target cell expresses at least 100, 200, 300, 400, 500, 1000, 2000, 3000, 4000, or 5000 CD38 proteins on its surface as measured by flow cytometry. In some instances, the target cell expresses less than 350,000, 300,000, 250,000, 200,000, 150,000, 100,000, 50,000, 25,000 CD38 proteins on its surface as measured by flow cytometry.
  • the number of CD38 proteins on the surface of a target cell is 100 to 350,000, 100 to 300,000, 100 to 250,000, 100 to 200,000, 100 to 150,000, 100 to 100,000, 100 to 80,000, 100 to 60,000, 100 to 50,000, 100 to 40,000, 100 to 30,000, 100 to 20,000, 100 to 10,000, 300 to 350,000, 300 to 300,000, 300 to 250,000, 300 to 200,000, 300 to 150,000, 300 to 100,000,
  • the target cell has fewer CD38 proteins on its surface than a Daudi cell, a Raji cell, a KMS-26 cell, a HuNSl cell, a HCC44 cell, an NCI-H2444 cell, or a DU145 cell. In some instances, the target cell has at least 200 CD38 proteins on its surface but fewer CD38 proteins on its surface than a Daudi cell, a Raji cell, a KMS-26 cell, a HuNSl cell, a HCC44 cell, an NCI-H2444 cell, or a DU145 cell.
  • the target cell is a transformed cell, wherein the ratio of ICAM1 to CD38 proteins is at least 1, 2, 5, 10, 15, 20, 35, 40, 50, or 200.
  • the transformed cell expresses at least 100, 200, 300, 400, 500, 750, 1000, 1250, 1500, 2000, 3000 CD38 cells on its surface.
  • the target cell is a myeloma cell, a lymphoma cell, a pancreatic cancer cell, a lung adenocarcinoma cell, or a prostate carcinoma cell wherein, the ratio of ICAM1 to CD38 protein is at least 0.15, 0.20, 0.3, 0.4, 0.5, 1.0, 2.5, or 5.0.
  • the target cell is derived from a lung adenocarcinoma, wherein the ratio of ICAM1 to CD38 proteins is at least 1, 2, 5, 10, 15, 20, 35, 40, 50, or 200.
  • the myeloma cell, a lymphoma cell, a pancreatic cancer cell, a lung adenocarcinoma cell, or a prostate carcinoma cell expresses at least 100, 200, 300, 400, 500, 750, 1000, 1250, 1500, 2000, 3000 CD38 cells on its surface.
  • a multispecific protein with a CD38 -binding domain and an ICAM1 -binding domain has enhanced affinity for a cell that expresses CD38 and ICAM1 compared to a monospecific protein with a CD38-binding domain and/or a monospecific protein with an ICAM1 -binding domain.
  • the multispecific protein has 1.5, 2, 3, 4, 5, or 10-fold higher affinity for the CD38- expressing cell than a monospecific protein that binds to CD38 or a monospecific protein that binds to ICAM1.
  • a multispecific protein with a CD38 -binding domain and an ICAM1 -binding domain has enhanced affinity for a cell that expresses higher levels of CD38 than ICAM1 compared to a monospecific protein with a CD38-binding domain.
  • the multispecific protein has 1.5, 2,
  • larger amounts of a multispecific protein with a CD38 -binding domain and an ICAM1 -binding domain bind to the surface of cell that expresses CD38 and ICAM compared to a monospecific protein with a CD38-binding domain and/or a monospecific protein with an ICAM1 -binding domain.
  • 1.5, 2, 3, 4, 5, or 10 -fold more of the multispecific protein binds to the CD38- expressing cell than a monospecific protein that binds to CD38 or a monospecific protein that binds to ICAMl.
  • a multispecific protein with a CD38-binding domain and an ICAMl-binding domain has a higher immunologic activity against a CD38 -expressing cell compared to a monospecific protein with a CD38-binding domain and/or a monospecific protein with an ICAMl-binding domain.
  • the multispecific protein has a 1.5, 2, 3, 4, 5, or 10-fold higher immunological activity than a monospecific protein with a CD38-binding domain and/or a monospecific protein with an ICAMl-binding domain.
  • Various immunological activities of a multispecific protein can be measured in in vitro assays such as an ADCC assay and a CDC assay.
  • the multispecific protein has a 1.5, 2, 3, 4, 5, or 10- fold higher ADCC activity than a monospecific protein with a CD38-binding domain and/or a monospecific protein with an ICAMl-binding domain. In some instances, the multispecific protein has a 1.5, 2, 3, 4, 5, or 10-fold higher CDC activity than a monospecific protein with a CD38-binding domain and/or a
  • Immunological activity can also be measured in a cell-line derived xenograft assay, wherein transformed cells are injected into mice and form a tumor.
  • a multispecific protein with a CD38 -binding domain and an ICAMl-binding domain inhibits the growth of a tumor comprising CD38- expressing cells to a greater extent than a monospecific protein with a CD38-binding domain and/or a monospecific protein with an ICAMl-binding domain.
  • the multispecific protein exhibits 1.5, 2, 3, 4, 5, or 10-fold higher inhibition of xenograft tumor growth compared to a monospecific protein with a CD38-binding domain and/or a monospecific protein with an ICAMl-binding domain.
  • “Antibody-dependent cell -mediated cytotoxicity” and“ADCC” refer to a cell- mediated reaction in which non-specific cytotoxic cells (e.g., Natural Killer (NK) cells, neutrophils, and macrophages) recognize bound antibody on a target cell and subsequently cause lysis of the target cell.
  • the target cell is a human cell, such as a tumor cell (e.g., a myeloma cell). While not wishing to be bound by any particular mechanism of action, the cytotoxic cells that mediate ADCC generally express Fc receptors (FcRs).
  • NK cells express FcyRIII
  • monocytes express FcyRI, FcyRII, FcyRIII and/or FcyRIV.
  • FcR expression on hematopoietic cells is summarized in Ravetch and Kinet, Annu. Rev. Immunol., 9:457-92 (1991).
  • an in vitro ADCC assay such as a cytotoxic assay using a cancer cell lines, is carried out, in some embodiments.
  • useful effector cells for such assays include, but are not limited to, peripheral blood mononuclear cells (PBMC) and Natural Killer (NK) cells.
  • PBMC peripheral blood mononuclear cells
  • NK Natural Killer
  • ADCC activity of the multispecific proteins of interest is assessed, in some embodiments, in vivo, e.g.. in an animal.
  • “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 (Clq) to a molecule (e.g., an antibody) complexed with a cognate antigen.
  • a CDC assay e.g., as described in Gazzano-Santaro et al., J. Immunol. Methods, 202: 163 (1996), is performed, in some embodiments.
  • a multispecific protein as described herein, that binds CD38 and ICAM1 mediates complement dependent lysis of at least 50% of the cells in an exponentially growing population of Raji cells, at a concentration of about 2 nM.
  • a multispecific protein as described herein that binds CD38 and ICAM1 mediates ADCC by PBMC cells of 40% of the cells in an exponentially growing population of NCI-H2444 cells, at a concentration of about 1 nM.
  • a multispecific (such as a bispecific), multivalent (such as bivalent, trivalent, tetravalent) protein as described herein, that binds CD38 and ICAM1 does not induce apoptosis without crosslinking.
  • X32 is selected from A, G, or V;
  • X33 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;
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence
  • GFPFXsXeYAMS (SEQ ID No. 423), in which X 5 is selected from D or G; and Xe is selected from V, A, or T.
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence
  • GFSFX5X6X7X8X9X10X11 (SEQ ID No. 426); in which X5 is selected from S or N; Xe is selected from R, S, or N; X 7 is selected from Y, I, or N; Xs is selected from Y, D, G, or A; X 9 is selected from V, M, or I; X 10 is selected from T, S, or M; and Xu is present or absent, if present, is C.
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence
  • GFSX 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 (SEQ ID No. 419); in which X 4 is selected from F or A; X 5 is selected from S, T, or N; Xe is selected from S, T, or N; X 7 is selected from Y, R, A, or G; Xs is selected from W, Y, or C; X 9 is selected from I, W, Y, or D; X 10 is selected from C, I, Y, or M; Xu is present or absent, if present, is selected from C or M; and X 12 is present or absent, if present, is C.
  • the VH region of the anti-CD38 antibody comprises CDR2 sequence
  • AISGSGGSTX22YADSVKG (SEQ ID No. 418), in which X 22 is selected from F or Y.
  • the VH region of the anti-CD38 antibody comprises CDR2 sequence
  • the VH region of the anti-CD38 antibody comprises CDR2 sequence
  • the VH region of the anti-CD38 antibody comprises CDR2 sequence
  • the VH region of the anti-CD38 antibody comprises CDR3 sequence
  • 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, if present, is selected from V, D, Y, A,
  • X 42 is present or absent, if present, is selected from L, Y, F, T, or G
  • X 43 is present or absent, if present, is selected from P, F, V, N, S, or Y
  • X 44 is present or absent, if present, is selected from L, S, T, G,
  • the VH region of the anti-CD38 antibody comprises CDR3 sequence
  • X3 2 is selected from A or G;
  • X33 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, if present, is selected from P, F, V,
  • X33 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, if present, is selected from V, Y, or E;
  • X 42 is present or absent, if present, is G;
  • X 43 is present or absent, if present, is Y;
  • X 44 is present or absent, if present, is F;
  • X 45 is present or absent, if present, is selected from E or N; and
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence
  • GFPFXsXeYAMS SEQ ID NO: 423
  • CDR2 sequence AISGSGGSTX 22 YADSVKG SEQ ID NO: 418
  • CDR3 sequence AKRGTYX 38 YSX 41 PTGFDY SEQ ID NO: 421
  • X 5 is selected from D or G
  • Xe is selected from V, A, or T
  • X 22 is selected from F or Y
  • X 38 is selected from A or G
  • X 41 is selected from F or Y.
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence
  • X 5 is selected from S, T, or N; Xe is selected from S, T, or N; X 7 is selected from Y, R, A, or G; Xs is selected from W, Y, or C; X 9 is selected from I, W, Y, or D; X 10 is selected from C, I, Y, or M; Xu is present or absent, if present, is selected from C or M; X 12 is present or absent, if present, is C; X 13 is selected from A, or S; X 15 is selected from I, F, or T; X 1 ⁇ 2 is selected from Y or V; Xn is selected from S, T, or A; Xis 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;
  • the VH region of the anti-CD38 antibody comprises CDR1, CDR2, and CDR3 sequences selected from Table 1.
  • the VH region of the anti-CD38 antibody comprises 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; 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 CDR3 sequence X32X33X34X35X36X37X38X39X40X41X42X43X44X45X46X47X48X49; wherein X32 is selected from A, G, or V; X33 is selected from K, A, R, T, G, or S; X34 is selected from R, A, V, T, P, I, E, D, or S;
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence AKRGTYX38YSX41PTGFDY (SEQ ID NO: 421), in which X38 is selected from A or G and X41 is selected from F or Y.
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; 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 CDR3 sequence X32X33X34X35X36X37X38X39X40X41X42X43X44X45X46 X47X48X49, in which X32 is selected from A, G, or V; X33 is selected from A, R, T, S, or G; X34 is selected from A, V, T, P, I, E, D, or S; X35 is selected from G, W, D, F, K, P, S, R, or A; X36 is selected from P, A, Y, D, G, S, R, V, E, or T; X37 is selected
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequence X32X33X34X35X36X37X38X39X40X41X42X43X44X45, in which X32 is selected from A or G; X33 is selected from A, R, or T; X34 is selected from A, V, T, P, I, E, or D; X35 is selected from G, W, D, L, K, or P; X36 is selected from P, A, Y, D, or G; X37 is selected from Y, V, T, S, N, A, or G; X38 is selected from G, S, D, or K; X39 is selected from T, A, G, S, or I; X40 is selected from S, Y
  • X41 is selected from V, D, Y, A, N, or G
  • X42 is selected from L, Y, or F
  • X43 is present or absent, if present, is selected from P, F, V, or N
  • X44 is present or absent, if present, is selected from L, S, or T
  • X45 is present or absent, if present, is selected from L or F.
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence AX33X34X35X36X37X38X39X40X41X42X43X44X45X46 (SEQ ID NO: 422), in which X33 is selected from R or G; X34 is selected from E, D, or S; X35 is selected from G, L, P, S, or A; X36 is selected from D, S, or R; X37 is selected from Y, T, N, or G; X38 is selected from G, S, F, or L; X39 is selected from A, G, S, or I; X40 is selected from Y, N, or L; X41 is present or absent, if present, is selected from V, Y, or E; X42 is present or absent, if present,
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence X1GX2X3X4X5X6X7X8X9X10X11X12, wherein Xi is present or absent, if present, is S; X2 is selected from F or I; X3 is selected from P, S, or D; X IS selected from F, L, or A; X5 is selected from D, G, S, N, or T; Xe is selected from V, A, T, R, S, I, or N; X7 is selected from Y, I, N, R, A, G, or D; X is selected from A, Y, D, G, W, C, or T; X9 is selected from M, V, I, W, D, or Y; X10 is selected from S, T, M, C, I, Y, A, or G; Xu is present or absent, if present, is selected from C or M; and X12 is present or
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence GFPFXsXeYAMS (SEQ ID NO: 423), in which X is selected from D or G and Xe is selected from V, A, or T; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10.
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence
  • X1GX2X3X4X5X6X7X8X9X10X11X12 wherein Xi is present or absent, 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; Xe is selected from R, S, N, I, or T; X7 is selected from Y, I, N, R, A, D, or G; Xs is selected from Y, D, G, A, W, T, or C; X9 is selected from V, M, I, W, Y, or D; X10 is selected from T, S, M, C, I, Y, A, or G; Xu is present or absent, if present, is selected from C or M; and X 12 is present or absent, if present, is C; CDR2 sequence selected from SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39,
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence GFSLX5X6X7X8X9X10X11 (SEQ ID No. 426), wherein X5 is selected from S or N; Xe is selected from R, S, or N; X7 is selected from Y, I, or N; Xs is selected from Y, D, G, or A; X9 is selected from V, M, or I; X10 is selected from T, S, or M; and Xu is present or absent, if present, is C; CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52.
  • SEQ ID No. 426 CDR1 sequence GFSLX5X6X7X8X9X10X11
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence GFSX4X5X6X7X8X9X10X11X12 (SEQ ID No. 419), wherein X4 is selected from F or A; X5 is selected from S, T, or N; Xe is selected from S, T, or N; X7 is selected from Y, R, A, or G; Xs is selected from W, Y, or C; X9 is selected from I, W, Y, or D; X10 is selected from C, I, Y, or M; Xu is present or absent, if present, is selected from C or M; and X12 is present or absent, if present, is C; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58.
  • X4 is selected from F or A
  • X5 is selected from S, T, or N
  • Xe is
  • the VH region of the anti-CD38 antibody comprises 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; CDR2 sequence X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28X29X30X31, wherein X13 is selected from A, G, or S; X14 is selected from I, F, Y, V, S, or C; X15 is selected from S, I, L, T, or M; Xi 6 is selected from G, Y, S, T, L, or V; Xn is selected from S, I, K, Y, T, G, or A; Xis is selected from G, S, T, P, V, or Y; X19 is selected from G, A, D, S, or T; X20 is selected from S, T, I,
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence AISGSGGSTX22YADSVKG (SEQ ID No. 418) in which X22 is selected from F or Y; and CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10.
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; CDR2 sequence X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28X29X30X31, wherein X13 is selected from A, G, or S; Xi 4 is selected from I, F, Y, V, S, or C; X 15 is selected from I, L, M, or T; X 1 ⁇ 2 is selected from G, Y, S, T, L, or V; Xi 7 is selected from S, I, K, Y, T, G, or A; Xis is selected from G, S, T, P, or V; X19 is selected from G, A, D, S, or T; X 20 is selected from S, T, I, N, or G; X 21 is selected
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID Nos: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence
  • X13 is selected from A or G;
  • X14 is selected from I, F, Y, V, S, or C;
  • X 1 ⁇ 2 is selected from G, Y, S, T, or L;
  • Xn is selected from S, I, K, Y, T, or G;
  • Xis is selected from G, S, or T;
  • X19 is selected from G, A, D, or S;
  • X20 is selected from T, I, N, or G;
  • X21 is selected from T, I, or D;
  • X22 is selected from Y, N, or T;
  • X23 is selected from Y or D;
  • X24 is selected from A or Y;
  • X25 is selected from T, S, N, R, or A;
  • X26 is selected from W or T;
  • X27 is selected from A or W;
  • X28 is selected from K, R, Q, or A;
  • X13 is selected from A or G;
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID Nos: 17, 23, 29, 44, and 56; CDR2 sequence
  • the VH region of the anti-CD38 antibody comprises 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; 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 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.
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10.
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; 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 CDR3 sequence selected from SEQ ID NOs: 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, and 58.
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52.
  • the VH region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58.
  • the VL region of the anti-CD38 antibody comprises CDR1, CDR2, and CDR3 sequences selected from Table 2.
  • 4618_1 shares the same VL CDR1, CDR2, and CDR3 sequence with 4618_5, 4618 _ 12, 4618 _ 1 _ 12,
  • the VL region of the anti-CD38 antibody comprises CDR1 sequence selected from SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; CDR2 sequence selected from SEQ ID NOs: 63, 66, 69, 72, 75, 78, 81, 84, 90, and 99; and 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.
  • the VL region comprises CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; CDR2 sequence selected from SEQ ID NOs: 66, 69, 81, 78, 90, and 99; and CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.
  • the VL region comprises CDR1 sequence selected from SEQ ID NOs: 71, 77, 83, 94, and 102; CDR2 sequence selected from SEQ ID NOs: 72, 78, and 84; and CDR3 sequence selected from SEQ ID NOs: 73, 79, 85, 95, and 103.
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29,
  • 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 CDR3 sequence
  • X32 is selected from A, G, or V;
  • X33 is selected from K, A, R, T, G, or S;
  • X34 is selected from R, A, V, T, P, I, E, D, or S;
  • X35 is selected from G, W, D, L, K, P, S, A, T, or R;
  • X36 is selected from T, P, A, Y, D, G, S, R, V, or E;
  • X37 is selected from Y, V, T, S, N, A, G, Q, F, or I;
  • X38 is selected from G, A, S, D, K, F, L, or Y;
  • X39 is selected from Y, T, A, G, S, or I;
  • X40 is selected from S, Y, G, R, W, N, L, D, or F;
  • X41 is present
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence AKRGTYX38Y SX41PTGFDY (SEQ ID No. 421), in which X38 is selected from A or G and X41 is selected from F or Y; and wherein the VL region comprises CDR1 sequence consisting of SEQ ID NO: 62, CDR2 sequence consisting of SEQ ID NO: 63, and CDR3 sequence consisting of SEQ ID NO: 64.
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence AKRGTYX38Y SX41PTGFDY (SEQ ID No. 421), in which X38 is selected from A or G and X41 is selected from F or
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; CDR2 sequence selected from SEQ ID NOs: 12, 15, 18, 21, 24, 27, 30, 33, 36, 39,
  • X47X48X49 in which X32 is selected from A, G, or V; X33 is selected from A, R, T, S, or G; X34 is selected from A, V, T, P, I, E, D, or S; X35 is selected from G, W, D, L, K, P, S, R, or A; X36 is selected from P, A, Y, D, G, S, R, V, E, or T; X37 is selected from Y, V, T, S, N, A, G, Q, F, or I; X38 is selected from G, S, D, K, F, L, or Y; X39 is selected from T, A, G, S, I, or Y; X40 is selected from S, Y, G, R, W, N, L, D, or F; X41 is present or absent, if present, is selected from V, D, Y, A, N, G, F, or E; X42 is present or absent, if
  • the anti-CD38 antibody comprises a VH region and a VF region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequence
  • X3 2 is selected from A or G;
  • X33 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, F, 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 F, Y, or F;
  • X 43 is present or absent, if present, is selected from P,
  • the anti-CD38 antibody comprises a VH region and a VF region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence
  • AX33X34X35X36X37X38X39X40X41X42X43X44X45X46 (SEQ ID No. 422), in which X33 is selected from R or G; X34 is selected from E, D, or S; X35 is selected from G, F, P, S, or A; X36 is selected from D, S, or R; X37 is selected from Y, T, N, or G; X38 is selected from G, S, F, or F; X39 is selected from A, G, S, or I; X40 is selected from Y, N, or F; X41 is present or absent, if present, is selected from V, Y, or E; X42 is present or absent, if present, is G; X43 is present or absent, if present, is Y; X44 is present or absent, if present, is F; X45 is present or absent, if present, is selected from E or N; and X 46 is present or absent, if present,
  • the anti-CD38 antibody comprises a VH region and a VF region, wherein the VH region comprises CDR1 sequence X1GX2X3X4X5X6X7X8X9X10X11X12, wherein Xi is present or absent, if present, is S; X2 is selected from F or I; X3 is selected from P, S, or D; X 4 IS selected from F, F, or A; X5 is selected from D, G, S, N, or T; Xe is selected from V, A, T, R, S, I, or N; X7 is selected from Y, I, N, R, A, G, or D; Xs is selected from A, Y, D, G, W, C, or T; Xg is selected from M, V, I, W, D, or Y; Xio is selected from S, T, M, C, I, Y, A, or G; Xu is present or absent,
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence X1GX2X3X4X5X6X7X8X9X10X11X12, wherein Xi is present or absent, 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; Xe is selected from R, S, N, I, or T; X7 is selected from Y, I, N, R, A, D, or G; Xs is selected from Y, D, G, A, W, T, or C; X9 is selected from V, M, I, W, Y, or D; Xio is selected from T, S, M, C, I, Y, A, or G; Xu is present or absent, if present, is selected from C or M; and
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence GFSLX 5 X 6 X 7 X 8 X 9 X 10 X 11 (SEQ ID NO: 426), wherein X 5 is selected from S or N; Xe is selected from R, S, or N; X 7 is selected from Y, I, or N; Xs is selected from Y, D, G, or A; X 9 is selected from V, M, or I; Xio is selected from T, S, or M; and Xu is present or absent, if present, is C; CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89,
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence GFSX 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 (SEQ ID NO: 419), wherein X 4 is selected from F or A; X 5 is selected from S, T, or N; Xe is selected from S, T, or N; X 7 is selected from Y, R, A, or G; Xs is selected from W, Y, or C; X9 is selected from I, W, Y, or D; X10 is selected from C, I, Y, or M; Xu is present or absent, if present, is selected from C or M; and X12 is present or absent, if present, is C; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58; and
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, 9, 11, 14, 17, 20, 23, 26, 29,
  • X13 is selected from A, G, or S;
  • Xi4 is selected from I, F, Y, V, S, or C;
  • X15 is selected from S, I, L, T, or M;
  • Xi 6 is selected from G, Y, S, T, L, or V;
  • Xi7 is selected from S, I, K, Y, T, G, or A;
  • Xis is selected from G, S, T, P, V, or Y;
  • X19 is selected from G, A, D, S, or T;
  • X20 is selected from S, T, I, N, or G;
  • X21 is selected from T, I, D, N, S, or A;
  • X22 is selected from F, Y, N, T, I, or S;
  • X23 is selected from Y, D, K, or I;
  • X24 is selected from A or
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; CDR2 sequence X13X14X15X16X17X18X19X20X21X22X23X24X25X26X27X28X29X30X31, wherein X13 is selected from A, G, or S; Cm is selected from I, F, Y, V, S, or C; X15 is selected from I, L, M, or T; Xi 6 is selected from G, Y, S, T, L, or V; X17 is selected from S, I, K, Y, T, G, or A; Xis is selected from G, S, T, P, or V; X19 is selected from G, A, D, S, or T; X20 is selected from S, T, I,
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; 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 X30, wherein X 13 is selected from A or G; Xi 4 is selected from I, F, Y, V, S, or C; X 1 ⁇ 2 is selected from G, Y, S, T, or L; X 17 is selected from S, I, K, Y, T, or G; Xis 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,
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; 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 X30X3 1 , wherein X 13 is selected from A, or S; X 15 is selected from I, L, or T; Xi 6 is selected from Y or V; X 17 is selected from S, T, or A; Xis is selected from G, P, or V; Xi 9 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
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10; and wherein the VL region comprises CDR1 sequence consisting of SEQ ID NO: 62, CDR2 sequence consisting of SEQ ID NO: 63, and CDR3 sequence consisting of SEQ ID NO: 64.
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; CDR2 sequence selected from SEQ ID NOs: 66, 69, 78, 81, 90, and 99; and CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence selected from SEQ ID NOs
  • the anti-CD38 antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58; and wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 71, 77,
  • CDR2 sequence selected from SEQ ID NOs: 72, 78, and 84; and CDR3 sequence selected from 73, 79, 85, 95, and 103.
  • the anti-CD38 antibody comprises a VH region and a VL region in which 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.
  • the VH region comprises a sequence selected from Table 3 and the VL region comprises a sequence selected from Table 4.
  • an anti-CD38 antibody described supra is a full-length antibody.
  • the anti-CD38 antibody is a binding fragment.
  • 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.
  • the anti-CD38 antibody comprises a monovalent Fab, a divalent 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.
  • the anti-CD38 antibody comprises a bispecific antibody or binding fragment thereof.
  • the bispecific antibody or binding fragment thereof is a bispecific antibody conjugate, a hybrid bispecific IgG, a variable domain only bispecific antibody, a CHI/CL fusion protein, a Fab fusion protein, a non-immunoglobulin fusion protein, a Fc-modified IgG, an appended & Fc-modified IgG, a modified Fc and CH3 fusion protein, an appended IgG-HC fusion, a Fc fusion, a CH3 fusion, an IgE/IgM CH2 fusion, or a F(ab’)2 fusion.
  • a bispecific antibody or binding fragment includes a 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), Fc ⁇ Adp.
  • KH Knobs-into-Holes
  • ART-Ig Asymmetric Re-engineering Technology-immunoglobulin
  • Triomab quadroma bispecific monoclonal antibody
  • BiMAb bispecific monoclonal antibody
  • Fc ⁇ Adp Fc ⁇ Adp.
  • XmAb Azymetric, Bispecific Engagement by Antibodies based on the T-cell receptor (BEAT), Bispecific T-cell Engager (BiTE), Biclonics, Fab-scFv-Fc, Two-in-one/Dual Action Fab (DAF), FinomAb, scFv-Fc-(Fab)-fusion, Dock-aNd-Lock (DNL), Adaptir (previously SCORPION), Tandem diAbody (TandAb), Dual-affmity- ReTargeting (DART), or nanobody.
  • BEAT T-cell receptor
  • BiTE Bispecific T-cell Engager
  • Biclonics Fab-scFv-Fc
  • DAF Two-in-one/Dual Action Fab
  • DNF Two-in-one/Dual Action Fab
  • FinomAb FinomAb
  • scFv-Fc-(Fab)-fusion Dock-aNd-Lock (DNL)
  • DNL Dock-aNd-
  • a variable domain only bispecific antibody comprises a tandem scFv (taFv), triplebody, diabody (Db), dsDb, Db(KIH), scDb, dsFv-dsFv’, tandAbs, triple heads, tandem dAb/VHH, triple dAb/VHH, or tetravalent dAb VHH.
  • a CHI/CL fusion protein comprises a scFv2-CHl/CL or VHH2-CH1/CL.
  • Fab fusion protein comprises a Fab-scFv (bibody), Fab-scFv2 (tribody), Fab-Fv, Fab-dsFv, Fab-VHH, or orthogonal Fab-Fab.
  • a non-immunoglobulin fusion protein comprises a scFv2 -albumin, scDb-albumin, taFv-albumin, taFv-toxin, miniantibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, or ImmTAC (TCR-scFv).
  • a Fc-modified IgG comprises a 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 + CHI/CL charge pair, hinge/CH3 charge pair, DuoBody, four-in- one-CrossMab (KIH), LUZ-Y common LC, LUZ-Y scFab-IgG, or FcFc.
  • an appended & Fc-modified IgG comprises an 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.
  • a modified Fc and CH3 fusion protein comprises a 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, F ab -F c(KIH) -scFv, Fab-scFv-Fc(KIH), Fab -scFv-Fc(BEAT) , DART-Fc, scFv-CH3(KIH), or TriFabs.
  • an appended IgG-HC fusion antibody comprises IgG-HC-scFv, IgG-dAb, IgG-taFv, IgG-CrossFab, IgG-orthogonal Fab, IgG-(CaC ) Fab, scFv-HC-IgG, tandem Fab-IgG, Fab-IgG(CaC Fab), Fab-IgG(CR3), or Fab-hinge-IgG(CR3).
  • an appended IgG-LC fusion antibody comprises IgG-scFv(LC), scFv(LC)-IgG, or dAb-IgG.
  • an appended IgG-HC & LC fusion antibody comprises DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, or Zybody.
  • a Fc fusion antibody comprises Di-diabody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-Ig, or scFv2-Fcab.
  • a CH3 fusion antibody comprises Di-diabody or scDb-CH3.
  • an IgE/IgM CH2 fusion antibody comprises scFv-EHD2-scFv or scFv-MHD2- scFv.
  • F(ab’)2 fusion antibody comprises F(ab’)2-scFv2.
  • a CHI/CL fusion protein comprises scFv2-CHl-hinge/CL.
  • a modified IgG comprises DAF (two-in-one-IgG), DutaMab, or mAb 2 .
  • a non-immunoglobulin fusion antibody comprises DNL-Fab4-IgG.
  • the anti-CD38 antibody comprises a bispecific antibody or binding fragment thereof as illustrated in Fig. 1A or Fig. IB.
  • an anti-CD38 antibody described herein comprises an IgG framework, an IgA framework, an IgE framework, or an IgM framework.
  • the anti-CD38 antibody comprises an IgG framework (e.g., IgGl, IgG2, IgG3, or IgG4).
  • the anti-CD38 antibody comprises an IgGl, IgG2, IgG3, or an IgG4 framework.
  • the anti-CD38 antibody further comprises one or more mutations in a framework region, e.g., in the CHI domain, CH2 domain, CH3 domain, hinge region, or a combination thereof.
  • the one or more mutations are to stabilize the antibody and/or to increase half-life.
  • the one or more mutations are to modulate Fc receptor interactions, to increase ADCC or complement-dependent cytotoxicity (CDC).
  • the one or more mutations are to reduce or eliminate Fc effector functions such as FcyR-binding. ADCC or CDC.
  • the one or more mutations are to modulate glycosylation.
  • the anti-CD38 antibody comprises an IgGl framework.
  • the constant region of the anti-CD38 antibody is modified at one or more amino acid positions to alter Fc receptor interaction.
  • Exemplary residues that modulate or alter Fc receptor interaction include, but are not limited to, G236, S239, T250, M252, S254, T256, K326, A330, 1332, E333A, M428, H433, or N434 (Rabat numbering; EU index of Rabat et al 1991 Sequences of Proteins of Immunological Interest).
  • the mutation comprises G236A, S239D, T250Q, M252Y, S254T, T256E, R326W, A330L, I332E, E333A, E333S, M428L, H433R, or N434F.
  • the modification at one or more amino acid positions in the IgGl constant region to alter Fc receptor interaction leads to increased half-life.
  • the modification at one or more amino acid positions comprise T250, M252, S254, T256, M428, H433, N434, or a combination thereof; e.g., comprising T250Q/M428L or M252Y/S254T/T256E and H433K/N434F.
  • the modification at one or more amino acid positions in the IgGl constant region to alter Fc receptor interaction leads to increased ADCC and/or CDC.
  • the modification at one or more amino acid positions comprises S239, K326, A330, 1332, E333, or a combination thereof.
  • the modification at one or more amino acid positions for increased ADCC and/or CDC comprises, e.g., E333A, S239D/A330L/I332E, or K326W/E333S.
  • the modification at one or more amino acid positions for increased ADCC comprises S239D/A330L/I332E.
  • the modification at one or more amino acid positions for increased CDC comprises
  • the modification at one or more amino acid positions in the IgGl constant region to alter Fc receptor interaction leads to increased macrophage phagocytosis.
  • the modification at one or more amino acid positions comprises G236, S239, 1332, or a combination thereof.
  • the modification at one or more amino acid positions for increased macrophage phagocytosis comprises the combination S239D/I332EG236A.
  • the IgGl constant region is modified at amino acid N297 (Kabat numbering), for example to N297C.
  • the anti-CD38 antibody comprises an IgG2 framework.
  • one or more amino acid positions in the IgG2 framework are modified to alter Fc receptor interaction, e.g., to increase ADCC and/or CDC.
  • one or more amino acid positions in the IgG2 framework are modified to stabilize the antibody and/or to increase half-life.
  • one or more amino acid positions in the IgG2 framework are modified to modulate glycosylation.
  • the IgG2 constant region is afiicosylated.
  • the anti-CD38 antibody comprises an IgG3 framework.
  • one or more amino acid positions in the IgG3 framework are modified to alter Fc receptor interaction, e.g., to increase ADCC and/or CDC.
  • one or more amino acid positions in the IgG3 framework are modified to stabilize the antibody and/or to increase half-life.
  • one or more amino acid positions in the IgG3 framework are modified to modulate glycosylation.
  • the constant region of the antibody is modified at amino acid R435 to extend the half-life, e.g., R435H (Kabat numbering). In some instances, the constant region is afucosylated.
  • the anti-CD38 antibody comprises an IgG4 framework.
  • one or more amino acid positions in the IgG4 framework are modified to alter Fc receptor interaction, e.g., to increase ADCC and/or CDC.
  • mutations to increase ADCC comprises, in some embodiments, S239D, I332E, and A330L (amino acid numbering is according to the EU index in Kabat et al), such as described in U.S. Patent No. 8,093,359.
  • one or more amino acid positions in the IgG4 framework are modified to stabilize the antibody and/or to increase half-life.
  • one or more amino acid positions in the IgG4 framework are modified to modulate glycosylation.
  • the constant region is modified at a hinge region to prevent or reduce strand exchange.
  • the amino acid that is modified is S228 (e.g., S228P).
  • the human IgG constant region is modified to ADCC and/or CDC, e.g., with an amino acid modification described in Natsume et al., 2008 Cancer Res, 68(10): 3863-72; Idusogie el al., 2001 J Immunol, 166(4): 2571-5; Moore et al., 2010 mAbs, 2(2): 181- 189; Lazar et al., 2006 PNAS,
  • the human IgG constant region is modified to induce heterodimerization.
  • heterodimerization via CH3 modifications is further stabilized by the introduction of a disulfide bond, for example by changing Ser354 to Cys (S354C) and Y349 to Cys (Y349C) on opposite CH3 domains (Reviewed in Carter, 2001 Journal of Immunological Methods, 248: 7-15).
  • an anti-CD38 antibody described herein has reduced or lacks glycosylation but is not modified at amino acid Asn297 (Rabat numbering).
  • the glycosylation is, for example, eliminated by production of the antibody in a host cell that lacks a post-translational glycosylation capacity, for example a bacterial or yeast derived system or a modified mammalian cell expression system.
  • a host cell that lacks a post-translational glycosylation capacity, for example a bacterial or yeast derived system or a modified mammalian cell expression system.
  • such a system is a cell-free expression system.
  • an anti-CD38 antibody described herein is a full-length antibody, comprising a heavy chain (HC) and a light chain (LC).
  • the heavy chain (HC) comprises a sequence selected from Table 5.
  • the light chain (LC) comprises a sequence selected from Table 6.
  • an anti-CD38 antibody described herein has an enhanced ADCC and/or CDC compared to daratumumab as a reference antibody.
  • the enhanced ADCC and/or CDC is an increase of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, or more compared to daratumumab.
  • the enhanced ADCC and/or CDC is an increase of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, or more compared to daratumumab.
  • the enhanced ADCC and/or CDC is an increase of at least 1-fold, 2-fold, 3-fold, 4- fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or more compared to reference antibody daratumumab. In some cases, the enhanced ADCC and/or CDC is an increase of about 1 -fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or more compared to reference antibody daratumumab.
  • an anti-CD38 antibody described herein has an EC50 of from about 1 x 10 6 nM to about 2 nM, such as about 4 x 10 6 nM, about 0.000014 nM, 0.00007 nM, 0.00006 nM, about 0.00010 nM, about 0.0002 nM, about 0.0003 nM, 0.1 nM, about 0.2 nM, about 0.3 nM, about 0.4 nM, about 0.5 nM, about 0.6 nM, about 0.7 nM, about 0.8 nM, about 0.9 nM, about 1.0 nM, or from about 0.00001 to about 0.00003 nM in an in vitro cytotoxicity assay to determine ADCC activity, for instance, using PBMC effector cells and targeting cancer cells such as B-lymphoblast cells from a lymphoma, for example, Daudi cells.
  • an anti-CD38 antibody described herein has an improved cell kill effect compared to reference antibody daratumumab.
  • the improved cell kill effect is an increase of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, or more compared to reference antibody daratumumab.
  • the improved cell kill effect is an increase of about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, or more compared to reference antibody daratumumab.
  • the improved cell kill effect is an increase of at least 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or more compared to reference antibody daratumumab. In some cases, the improved cell kill effect is an increase of about 1- fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 15-fold, 20-fold, 30-fold, 40-fold, 50-fold, or more compared to reference antibody daratumumab.
  • an anti-CD38 antibody described herein has an improved serum half-life compared to reference antibody daratumumab.
  • the improved serum half-life is at least 30 minutes, 1 hour, 1.5 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or longer than reference antibody daratumumab.
  • the serum half-life of an anti-CD38 antibody described herein is at least 30 minutes
  • the anti- ICAM1 antibody comprises a variable heavy chain (VH) region and a variable light chain (VL) region, in which the VH region comprises CDR1 sequence X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 ; wherein X 1 is selected from G or E; X 2 is selected from F or Y; X 3 is selected from S or T; X 4 is selected from L, F, or S; X 5 is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y, H, or G; X 8 is selected from G, A, Y, W, or F; X 9 is selected from M, W, Y, or I; X 10 is selected from S, G, N, M, or I; and X 11 is present or absent, if present, is C; CDR
  • GFSFX 5 X 6 X 7 X 8 MX 10 (SEQ ID NO: 425), wherein X 5 is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y or H; X 8 is selected from G, A, or Y; and X 10 is selected from S, G, or N.
  • 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.
  • the VH region of the anti-ICAMl antibody comprises CDR3 sequence
  • 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 F;
  • X 36 is selected from Y, D, V, or F;
  • 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
  • the VH region of the anti-ICAMl antibody comprises CDR1 sequence
  • GFSLX 5 X 6 X 7 X 8 MX 10 (SEQ ID NO: 425), CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG (SEQ ID NO: 420), and CDR3 sequence X 31 RX 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 (SEQ ID NO: 424), wherein X 5 is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y or H; X 8 is selected from G, A, or Y; X 10 is selected from S, G, or N; X 13 is selected from W, I, or Y; X 15 is selected from S or G; X 16 is selected from F, S, D, or T; X 17 is selected from S or R; X 18 is selected
  • 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,
  • 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, if present, is selected from L, Y, or F; X 46 is present or absent, if present, is D; X 47 is present or absent, if present, is selected from M or P; X 48 is present or absent, if present, is D; and X 49 is present or absent, if present, is L.
  • the VH region of the anti-ICAMl antibody comprises CDR1, CDR2, and CDR3 sequences selected from Table 7.
  • the VH region of the anti-ICAMl antibody comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , wherein X 31 is selected from A or V; X 32 is selected from R or I; X 33 is selected from G, D, P, A, or V; X 34 is selected from G, P, W, D, N, or R; X 35 is selected from D, Y, S,
  • X 40 is selected from T, A, D, S, Y, L, or F;
  • X 41 is present or absent, if present, is selected from Y, A, G, I, or D;
  • X 42 is present or absent, if present, is selected from I, Y, R, P, V, or G;
  • X 43 is present or absent, if present, is selected from L, R, Y, G, or A;
  • X 44 is present or absent, if present, is selected from N, L, Y, S, or W;
  • X 45 is present or absent, if present, is selected from L, Y, F, or C;
  • X 46 is present or absent, if present, is selected from D, A, or F;
  • X 47 is present or absent, if present, is selected from M, P, Y, or N;
  • X 48 is present or absent, if present, is selected from D or F; and
  • X 49 is present or absent, if present,
  • the VH region of the anti-ICAMl antibody comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and CDR3 sequence
  • 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 F;
  • X 36 is selected from Y, D, V, or F;
  • 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
  • the VH region of the anti-ICAMl antibody comprises CDR1 sequence X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 , wherein X 1 is selected from G or E; X 2 is selected from F or Y; X 3 is selected from S or T; X 4 is selected from L, F, or S; X s is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y, H, or G; X 8 is selected from G, A, Y, W, or F; X 9 is selected from M, W, Y, or I; X 10 is selected from S, G, N, M, or I; and X 11 is present or absent, if present, is C; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 24
  • the VH region of the anti-ICAMl antibody comprises CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 (SEQ ID NO: 425), wherein X 5 is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y or H; X 8 is selected from G, A, or Y; and X 10 is selected from S, G, or N; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240.
  • the VH region of the anti-ICAMl antibody comprises CDR1 sequence selected from SEQ ID NOs: 208, 21 1, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; CDR2 sequence X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 , X 12 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,
  • 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, if present, is selected from K or G; and
  • X 30 is present or absent, if present, is G; and
  • the VH region of the anti-ICAMl antibody comprises CDR1 sequence selected from SEQ ID NOs: 208, 21 1, 214, 217, 222, 225, 228, 232, 235, and 238; CDR2 sequence
  • X 13 is selected from W, I, or Y;
  • X 15 is selected from S or G;
  • X 16 is selected from F, S, D, or T;
  • X 17 is selected from S or R;
  • X 18 is selected from G or D;
  • X 19 is selected from S, R, T, or N;
  • X 20 is selected from T or A; and
  • X 24 is selected from S, T, or N; and CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240.
  • the VH region of the anti-ICAMl antibody comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, and 412; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, and 413; and CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, 240, and 414.
  • the VH region of the anti-ICAMl antibody comprises CDR1 sequence selected from SEQ ID NOs: 241, 247, and 250; CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251; and CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252.
  • the VL region of the anti-ICAMl antibody comprises CDR1, CDR2, and CDR3 sequences selected from Table 8.
  • the VL region of the anti-ICAMl antibody comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 415; CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, 283, and 416; and CDR3 sequence selected from SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 417.
  • the VL region of the anti-ICAMl antibody comprises CDR1, CDR2, and CDR3 sequences SEQ ID NOs: 62-64, respectively.
  • the anti-ICAMl antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and CDR3 sequence
  • 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, if present, is selected from
  • the anti-ICAMl antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 21 1, 214, 217, 222, 225, 228, 232, 235, and 238; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234,
  • X 31 is selected from A or V; X 33 is selected from G or D; X 34 is selected from G, P, W, or D; X 35 is selected from D, Y, S, or L; X 36 is selected from Y, D, V, or L; X 37 is selected from G, S, or D; X 38 is selected from G, Y, F, or S; X 39 is selected from S, D, G, or T; X 40 is selected from T, A, D, S, or Y; X 41 is selected from Y, A, G, or I; X 42 is selected from I, Y, or R; X 43 is selected from L, R, Y, or G; X 44 is
  • CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283; and CDR3 sequence selected from SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284.
  • the anti-ICAMl antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 , wherein X 1 is selected from G or E; X 2 is selected from F or Y; X 3 is selected from S or T; X 4 is selected from L, F, or S; X 5 is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y, H, or G; X 8 is selected from G, A, Y, W, or F; X 9 is selected from M, W, Y, or I; X 10 is selected from S, G, N, M, or I; and X 11 is present or absent, if present, is C; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227,
  • the anti-ICAMl antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 (SEQ ID NO: 425), wherein X 5 is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y or H; X 8 is selected from G, A, or Y; and X 10 is selected from S, G, or N; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240; and wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 2
  • the anti-ICAMl antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; CDR2 sequence
  • 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,
  • 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, if present, is selected from K or G; and
  • X 30 is present or absent, if present, is G; and
  • VL region comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277,
  • CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, 283, and 63; and CDR3 sequence selected from SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 64.
  • the anti-ICAMl antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; CDR2 sequence GX 13 IX 15 X 16 X 17 X 18 X 19 X 20 YYAX 24 WAKG (SEQ ID No.
  • X 13 is selected from W, I, or Y;
  • X 15 is selected from S or G;
  • X 16 is selected from F, S, D, or T;
  • X 17 is selected from S or R;
  • X 18 is selected from G or D;
  • X 19 is selected from S, R, T, or N;
  • X 20 is selected from T or A; and
  • X 24 is selected from S, T, or N; and CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240; and wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282;
  • the anti-ICAMl antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and 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 wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, 282, and 62; CDR2 sequence selected from SEQ ID NOs: 25
  • the anti-ICAMl antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228,
  • CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231,
  • VL region comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282; CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283; and CDR3 sequence selected from SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284.
  • the anti-ICAMl antibody comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 241, 247, and 250; CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251; and CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252; and wherein the VL region comprises CDR1, CDR2, and CDR3 sequences SEQ ID NOs: 62-64, respectively.
  • the anti-ICAMl antibody comprises a VH region and a VL region in which the sequence of the VH region comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 289-309 and the sequence of the VL region comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to SEQ ID NOs: 311-326 and 155.
  • the VH region comprises a sequence selected from Table 9 and the VL region comprises a sequence selected from Table 10.
  • an anti-ICAMl antibody described supra is a full-length antibody.
  • the anti-ICAMl antibody is a binding fragment.
  • the anti-ICAMl 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.
  • the anti-CD38 antibody comprises a monovalent Fab, a divalent 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.
  • the anti-ICAMl antibody comprises a bispecific antibody or binding fragment thereof.
  • the bispecific antibody or binding fragment thereof is a bispecific antibody conjugate, a hybrid bispecific IgG, a variable domain only bispecific antibody, a CHI/CL fusion protein, a Fab fusion protein, a non-immunoglobulin fusion protein, a Fc-modified IgG, an appended & Fc- modified IgG, a modified Fc and CH3 fusion protein, an appended IgG-HC fusion, a Fc fusion, a CH3 fusion, an IgE/IgM CH2 fusion, or a F(ab’)2 fusion.
  • a bispecific antibody or binding fragment includes a 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), Fc ⁇ Adp.
  • KH Knobs-into-Holes
  • ART-Ig Asymmetric Re-engineering Technology-immunoglobulin
  • Triomab quadroma bispecific monoclonal antibody
  • BiMAb bispecific monoclonal antibody
  • Fc ⁇ Adp Fc ⁇ Adp.
  • XmAb Azymetric, Bispecific Engagement by Antibodies based on the T-cell receptor (BEAT), Bispecific T-cell Engager (BiTE), Biclonics, Fab-scFv-Fc, Two-in-one/Dual Action Fab (DAF), FinomAb, scFv-Fc-(Fab)-fusion, Dock-aNd-Lock (DNL), Adaptir (previously SCORPION), Tandem diAbody (TandAb), Dual-affmity- ReTargeting (DART), or nanobody.
  • BEAT T-cell receptor
  • BiTE Bispecific T-cell Engager
  • Biclonics Fab-scFv-Fc
  • DAF Two-in-one/Dual Action Fab
  • DNF Two-in-one/Dual Action Fab
  • FinomAb FinomAb
  • scFv-Fc-(Fab)-fusion Dock-aNd-Lock (DNL)
  • DNL Dock-aNd-
  • a variable domain only bispecific antibody comprises a tandem scFv (taFv), triplebody, diabody (Db), dsDb, Db(KIH), scDb, dsFv-dsFv’, tandAbs, triple heads, tandem dAb/VHH, triple dAb/VHH, or tetravalent dAb VHH.
  • a CHI/CL fusion protein comprises a scFv2-CHl/CL or VHH2-CH1/CL.
  • Fab fusion protein comprises a Fab-scFv (bibody), Fab-scFv2 (tribody), Fab-Fv, Fab-dsFv, Fab-VHH, or orthogonal Fab-Fab.
  • a non-immunoglobulin fusion protein comprises a scFv2 -albumin, scDb-albumin, taFv-albumin, taFv-toxin, miniantibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, or ImmTAC (TCR-scFv).
  • an appended & Fc-modified IgG comprises an 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.
  • a modified Fc and CH3 fusion protein comprises a 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, F ab -F c(KIH) -scFv, Fab-scFv-Fc(KIH), Fab -scFv-Fc(BEAT) , DART-Fc, scFv-CH3(KIH), or TriFabs.
  • an appended IgG-HC fusion antibody comprises IgG-HC-scFv, IgG-dAb, IgG-taFv, IgG-CrossFab, IgG-orthogonal Fab, IgG-(CaC ) Fab, scFv-HC-IgG, tandem Fab-IgG, Fab-IgG(CaC Fab), Fab-IgG(CR3), or Fab-hinge-IgG(CR3).
  • an appended IgG-LC fusion antibody comprises IgG-scFv(LC), scFv(LC)-IgG, or dAb-IgG.
  • an appended IgG-HC & LC fusion antibody comprises DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, or Zybody.
  • a Fc fusion antibody comprises Di-diabody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-Ig, or scFv2-Fcab.
  • a CH3 fusion antibody comprises Di-diabody or scDb-CH3.
  • an IgE/IgM CH2 fusion antibody comprises scFv-EHD2-scFv or scFv-MHD2- scFv.
  • F(ab’)2 fusion antibody comprises F(ab’)2-scFv2.
  • a CHI/CL fusion protein comprises scFv2-CHl-hinge/CL.
  • a modified IgG comprises DAF (two-in-one-IgG), DutaMab, or mAb 2 .
  • a non-immunoglobulin fusion antibody comprises DNL-Fab4-IgG.
  • the anti-ICAMl antibody comprises a bispecific antibody or binding fragment thereof as illustrated in Fig. 1A or Fig. IB.
  • an anti-ICAMl antibody described herein comprises an IgG framework, an IgA framework, an IgE framework, or an IgM framework.
  • the anti-CD38 antibody comprises an IgG framework (e.g., IgGl, IgG2, IgG3, or IgG4).
  • the anti-CD38 antibody comprises an IgGl, IgG2, IgG3, or an IgG4 framework.
  • the anti-ICAMl antibody further comprises one or more mutations in a framework region, e.g., in the CHI domain, CH2 domain, CH3 domain, hinge region, or a combination thereof.
  • the one or more mutations are to stabilize the antibody and/or to increase half-life.
  • the one or more mutations are to modulate Fc receptor interactions, to increase ADCC or CDC.
  • the one or more mutations are to reduce or eliminate Fc effector functions such as FcyR, ADCC or CDC.
  • the one or more mutations are to modulate glycosylation.
  • the anti-ICAMl antibody comprises an IgGl framework.
  • the constant region of the anti-ICAMl antibody is modified at one or more amino acid positions to alter Fc receptor interaction.
  • Exemplary residues that modulate or alter Fc receptor interaction include, but are not limited to, G236, S239, T250, M252, S254, T256, K326, A330, 1332, E333A, M428, H433, or N434 (Rabat numbering; EU index of Rabat et al 1991 Sequences of Proteins of Immunological Interest).
  • the mutation comprises G236A, S239D, T250Q, M252Y, S254T, T256E, R326W, A330L, I332E, E333A, E333S, M428L, H433R, or N434F.
  • the modification at one or more amino acid positions in the IgGl constant region to alter Fc receptor interaction leads to increased half-life.
  • the modification at one or more amino acid positions comprise T250, M252, S254, T256, M428, H433, N434, or a combination thereof; e.g., comprising T250Q/M428L or M252Y/S254T/T256E and H433R/N434F.
  • the modification at one or more amino acid positions in the IgGl constant region to alter Fc receptor interaction leads to increased ADCC and/or CDC.
  • the modification at one or more amino acid positions comprises S239, R326, A330, 1332, E333, or a combination thereof.
  • the modification at one or more amino acid positions for increased ADCC and/or CDC comprises, e.g., E333A, S239D/A330L/I332E, or R326W/E333S.
  • the modification at one or more amino acid positions for increased ADCC comprises S239D/A330L/I332E.
  • the modification at one or more amino acid positions for increased CDC comprises
  • the modification at one or more amino acid positions in the IgGl constant region to alter Fc receptor interaction leads to increased macrophage phagocytosis.
  • the modification at one or more amino acid positions comprises G236, S239, 1332, or a combination thereof.
  • the modification at one or more amino acid positions for increased macrophage phagocytosis comprises the combination S239D/I332EG236A.
  • the IgGl constant region is modified at amino acid N297 (Rabat numbering) in which residue N297 is afucosylated, wherein the oligosaccharides do not contain fucose sugar units.
  • the anti-ICAMl antibody comprises an IgG2 framework.
  • one or more amino acid positions in the IgG2 framework are modified to alter Fc receptor interaction, e.g., to increase ADCC and/or CDC.
  • one or more amino acid positions in the IgG2 framework are modified to stabilize the antibody and/or to increase half-life.
  • one or more amino acid positions in the IgG2 framework are modified to modulate glycosylation.
  • the IgG2 constant region is afucosylated at residue N297.
  • the anti-ICAMl antibody comprises an IgG3 framework.
  • one or more amino acid positions in the IgG3 framework are modified to alter Fc receptor interaction, e.g., to increase ADCC and/or CDC. In some cases, one or more amino acid positions in the IgG3 framework are modified to stabilize the antibody and/or to increase half-life. In some instances, one or more amino acid positions in the IgG3 framework are modified to modulate glycosylation. In some cases, the constant region of the antibody is modified at amino acid R435 to extend the half-life, e.g., R435H (Rabat numbering). In some instances, the constant region is afucosylated at residue N297.
  • the anti-ICAMl antibody comprises an IgG4 framework.
  • one or more amino acid positions in the IgG4 framework are modified to alter Fc receptor interaction, e.g., to increase ADCC and/or CDC.
  • one or more amino acid positions in the IgG4 framework are modified to stabilize the antibody and/or to increase half-life.
  • one or more amino acid positions in the IgG4 framework are modified to modulate glycosylation.
  • the constant region is modified at a hinge region to prevent or reduce strand exchange.
  • the amino acid that is modified is S228 (e.g., S228P).
  • the human IgG constant region is modified to alter ADCC and/or CDC, e.g., with an amino acid modification described in Natsume et al, 2008 Cancer Res, 68(10): 3863-72; Idusogie el al., 2001 JImmunol, 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.
  • the human IgG constant region is modified to induce heterodimerization.
  • heterodimerization via CH3 modifications is further stabilized by the introduction of a disulfide bond, for example by changing Ser354 to Cys (S354C) and Y349 to Cys (Y349C) on opposite CH3 domains (Reviewed in Carter, 2001 Journal of Immunological Methods, 248: 7-15).
  • such a system is a cell-free expression system.
  • an anti-ICAMl antibody described herein is a full-length antibody, comprising a heavy chain (HC) and a light chain (LC).
  • the heavy chain (HC) comprises a sequence selected from Table 11.
  • the light chain (LC) comprises a sequence selected from Table 12. Table 11.
  • an anti-ICAMl antibody described herein has an EC50 of from about 0.001 nM to about 2.5 nM, such as about 0.02 nM, 0.03 nM, about 0.04 nM, about 0.05 nM, about 0.06 nM, about 0.09 nM, about 0.1 nM, about 1.2 nM, about 1.7 nM, about 2.0 nM, about 2.5 nM, in an in vitro cytotoxicity assay to determine ADCC activity, for instance, using cancer cells such as human prostate cancer cells.
  • the serum half-life of an anti-ICAMl antibody described herein is at least 30 minutes, 1 hour, 1.5 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or longer.
  • the serum half-life of an anti-ICAMl antibody described herein is about 30 minutes, 1 hour, 1.5 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 18 hours, 24 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 14 days, 30 days, or longer.
  • the multi-specific anti-CD38 antibody or multi-specific anti-ICAMl antibody comprises target binding moieties that recognize two or more antigens.
  • the multi-specific anti-CD38 antibody comprises target binding moieties that specifically binds to two or more antigens, e.g., three or more, four or more, or five or more antigens.
  • the multi -specific anti- ICAMl antibody comprises target binding moieties that specifically binds to two or more antigens, e.g., three or more, four or more, or five or more antigens.
  • the bispecific anti-CD38 antibody comprises a first targeting moiety that specifically binds to CD38 and a second targeting moiety that specifically binds to a non-CD38 target.
  • the bispecific anti-ICAMl antibody comprises a targeting moiety that specifically binds to ICAM1 and a targeting moiety that specifically binds to a non-ICAMl target.
  • the non-ICAMl 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.
  • bispecific antibody which comprises a first targeting moiety that specifically binds to CD38 or ICAMl.
  • a bispecific antibody of the present disclosure that comprises a first component that binds CD38 and a second component that binds ICAMl, binds to a cell that expresses on its surface target antigens of the bispecific protein, with at least 2-50 fold, 10-100 fold, 2-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold, or 20-50%, 50-100%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% or more higher affinity (e.g., preferentially binds) compared to the binding affinity of an antibody that is monospecific to only one of CD38 or ICAMl, to the cell.
  • affinity e.g., preferentially binds
  • the bispecific antibody further comprises an enhanced complement dependent cytotoxicity (CDC) effect compared to a CDC effect by reference antibody daratumumab.
  • the bispecific antibody further comprises an enhanced ADCC effect compared to an ADCC effect by reference antibody daratumumab.
  • the bispecific antibody further comprises a reduced immune cell kill effect compared to an immune cell kill effect of reference antibody daratumumab.
  • the enhanced CDC is at least 2-fold, 3 -fold, 4-fold, or higher than the CDC effect of reference antibody daratumumab.
  • the enhanced CDC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher than the CDC effect of reference antibody daratumumab.
  • the enhanced ADCC is at least 2-fold, 3-fold, 4-fold, 5-fold, or higher than the ADCC effect of reference antibody daratumumab. In some cases, the enhanced ADCC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher than the ADCC effect of reference antibody daratumumab.
  • the immune cell is a Natural Killer cell. In some cases, the immune cell viability is improved by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher compared to the immune cell viability in the presence of reference antibody daratumumab.
  • a bispecific antibody which comprises a first targeting moiety that specifically binds to CD38 and a second targeting moiety that specifically binds to ICAMl.
  • the bispecific antibody further comprises an enhanced CDC effect compared to a CDC effect by reference antibody daratumumab.
  • the bispecific antibody further comprises an enhanced ADCC effect compared to an ADCC effect by reference antibody daratumumab.
  • the enhanced CDC is at least 2-fold, 3 -fold, 4-fold, or higher than the CDC effect of reference antibody daratumumab.
  • the enhanced CDC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher than the CDC effect of reference antibody daratumumab. In some cases, the enhanced ADCC is at least 2-fold, 3-fold, 4-fold, 5-fold, or higher than the ADCC effect of reference antibody daratumumab. In some cases, the enhanced ADCC is at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher than the ADCC effect of reference antibody daratumumab.
  • the bispecific antibody mediates at least 2 fold, at least 3 fold, at least 4 fold, at least 5 fold or at least 10 fold higher maximum cytotoxicity in an in vitro ADCC assay than the monospecific antibody that comprises either the first component or the second component.
  • bispecific antibody comprising a first component that binds specifically to CD38 and a second component that binds specifically to ICAMl, wherein the bispecific antibody mediates complement-dependent cytotoxicity (CDC) more efficiently than a monospecific antibody that comprises either the first component or the second component, wherein the ADCC activity is determined using an in vitro cytotoxicity assay, wherein the CDC activity is determined using an in vitro cytotoxicity assay.
  • CDC complement-dependent cytotoxicity
  • the bispecific antibody mediates at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 75%, at least about 100% higher maximum cytotoxicity in an in vitro CDC assay than the monospecific antibody that comprises either the first component or the second component.
  • the bispecific antibody further comprises a reduced immune cell kill effect compared to an immune cell kill effect of reference antibody daratumumab.
  • the immune cell viability is improved by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or higher compared to the immune cell viability in the presence of reference antibody daratumumab.
  • the immune cell is a Natural Killer cell.
  • the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety comprises a bispecific antibody conjugate, a hybrid bispecific IgG, a variable domain only bispecific antibody, a CHI/CL fusion protein, a Fab fusion protein, a non-immunoglobulin fusion protein, a Fc-modified IgG, an appended & Fc-modified IgG, a modified Fc and CH3 fusion protein, an appended IgG-HC fusion, a Fc fusion, a CH3 fusion, an IgE/IgM CH2 fusion, or a F(ab’)2 fusion.
  • the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety comprises a 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), Fc ⁇ Adp.
  • KH Knobs-into-Holes
  • ART-Ig Asymmetric Re-engineering Technology- immunoglobulin
  • Triomab quadroma Triomab quadroma
  • bispecific monoclonal antibody BiMAb, BsmAb, BsAb, bsMab, BS-Mab, or Bi-MAb
  • XmAb Azymetric, Bispecific Engagement by Antibodies based on the T-cell receptor (BEAT), Bispecific T-cell Engager (BiTE), Biclonics, Fab-scFv-Fc, Two-in-one/Dual Action Fab (DAF), FinomAb, scFv-Fc-(Fab)-fusion, Dock-aNd-Lock (DNL), Adaptir (previously
  • SCORPION Tandem diAbody
  • DART Dual-affinity-ReTargeting
  • a variable domain only bispecific antibody comprises a tandem scFv (taFv), triplebody, diabody (Db), dsDb, Db(KIH), scDb, dsFv-dsFv’, tandAbs, triple heads, tandem dAb/VHH, triple dAb/VHH, or tetravalent dAb/VHH.
  • a CHI/CL fusion protein comprises a scFv2-CHl/CL or VHH2-CH1/CL.
  • Fab fusion protein comprises a Fab-scFv (bibody), Fab-scFv2 (tribody), Fab-Fv, Fab-dsFv, Fab-VHH, or orthogonal Fab-Fab.
  • a non-immunoglobulin fusion protein comprises a scFv2 -albumin, scDb-albumin, taFv-albumin, taFv-toxin, miniantibody, DNL-Fab2, DNL-Fab2-scFv, DNL-Fab2-IgG-cytokine2, or ImmTAC (TCR-scFv).
  • a Fc-modified IgG comprises a 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 + CHI/CL charge pair, hinge/CH3 charge pair, DuoBody, four-in- one-CrossMab (KIH), LUZ-Y common LC, LUZ-Y scFab-IgG, or FcFc*.
  • an appended & Fc-modified IgG comprises an 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.
  • a modified Fc and CH3 fusion protein comprises a 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, F ab -F c(KIH) -scFv, Fab-scFv-Fc(KIH), Fab -scFv-Fc(BEAT) , DART-Fc, scFv-CH3(KIH), or TriFabs.
  • an appended IgG-HC fusion antibody comprises IgG-HC-scFv, IgG-dAb, IgG-taFv, IgG-CrossFab, IgG-orthogonal Fab, IgG-(CaC ) Fab, scFv-HC-IgG, tandem Fab-IgG, Fab-IgG(CaC Fab), Fab-IgG(CR3), or Fab-hinge-IgG(CR3).
  • an appended IgG-LC fusion antibody comprises IgG-scFv(LC), scFv(LC)-IgG, or dAb-IgG.
  • an appended IgG-HC & LC fusion antibody comprises DVD-Ig, TVD-Ig, CODV-Ig, scFv4-IgG, or Zybody.
  • a Fc fusion antibody comprises Di-diabody, scDb-Fc, taFv-Fc, scFv-Fc-scFv, HCAb-VHH, Fab-scFv-Fc, scFv4-Ig, or scFv2-Fcab.
  • a CH3 fusion antibody comprises Di-diabody or scDb-CH3.
  • an IgE/IgM CH2 fusion antibody comprises scFv-EHD2-scFv or scFv-MHD2- scFv.
  • F(ab’)2 fusion antibody comprises F(ab’)2-scFv2.
  • a CHI/CL fusion protein comprises scFv2-CHl-hinge/CL.
  • a modified IgG comprises DAF (two-in-one-IgG), DutaMab, or mAb 2 .
  • a non-immunoglobulin fusion antibody comprises DNL-Fab4-IgG.
  • the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety comprises an antibody format as illustrated in Fig. 1A or Fig. IB.
  • the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety is a bivalent antibody or binding fragments thereof.
  • the bivalent antibody or binding fragments thereof comprises an IgG-scFv(LC) C-terminal fusion format (Fig. 2A), an IgG-HC-scFv C-terminal fusion format (Fig. 2B), a scFv-HC-IgG N-terminal fusion format (Fig. 2C), or a DVD-Ig format (Fig. 2D).
  • the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety is a monovalent antibody or binding fragments thereof.
  • the monovalent antibody or binding fragments 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 a common light chain bispecific) (Fig 2F).
  • the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety comprises a K D to CD38 from about InM to about 100 nM.
  • the K D is at least InM, 2nM, 3nM, 3.15nM, 3.2nM, 3.39nM, 3.5nM, 4nM, 4.5nM, 5nM, 5.32nM, 5.5nM, 6nM, 6.5nM, 7nM, 7.5nM, 8nM, 8.5nM, 9nM, 9.5nM, lOnM, 15nM, 18nM, 20nM, 25nM, 30nM, 35nM, 40nM, 45nM, 50nM, 60nM, 70nM, 80nM, 90nM, or lOOnM.
  • the bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety comprises a K D to ICAM1 from about O. lnM to about 20nM.
  • the K D is about 0.15nM, 0.2nM, 0.24nM, 0.25nM, 0.29nM, 0.3nM, 0.4nM, 0.5nM, 0.6nM, 0.7nM, 0.8nM, 0.9nM, InM, 1.5nM, 1.72nM, 2nM, 2.28nM, 2.5nM, 3nM, 3.5nM, 4nM, 4.5nM, 5nM, 6nM, 7nM, 8nM, 9nM, lOnM, 1 InM, 12nM, 13nM, 14nM, 15nM, 16nM, 17nM, 18nM, 19nM, or 20nM.
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises 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; 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 CDR3 sequence
  • X32 is selected from A, G, or V;
  • X33 is selected from K, A, R, T, G, or S;
  • X34 is selected from R, A, V, T, P, I, E, D, or S;
  • X35 is selected from G, W, D, L, K, P, S, A, T, or R;
  • X36 is selected from T, P, A, Y, D, G, S, R, V, or E;
  • X37 is selected from Y, V, T, S, N, A, G, Q, F, or I;
  • X38 is selected from G, A, S, D, K, F, L, or Y;
  • X39 is selected from Y, T, A, G, S, or I;
  • X40 is selected from S, Y, G, R, W, N, L, D, or F;
  • X41 is present
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VF region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence
  • AKRGTYX38YSX41PTGFDY (SEQ ID No. 421), in which X38 is selected from A or G and X41 is selected from F or Y; and wherein the VF region comprises CDR1 sequence consisting of SEQ ID NO: 62, CDR2 sequence consisting of SEQ ID NO: 63, and CDR3 sequence consisting of SEQ ID NO: 64.
  • X32 is selected from A, G, or V
  • X33 is selected from A, R, T, S, or G
  • X34 is selected from A, V, T, P, I, E, D, or S
  • X35 is selected from G, W, D, F, K, P, S, R, or A
  • X36 is selected from P, A, Y, D, G, S, R, V, E, or T
  • X37 is selected from Y, V, T, S, N,
  • X38 is selected from G, S, D, K, F, F, or Y;
  • X39 is selected from T, A, G, S, I, or Y;
  • X40 is selected from S, Y, G, R, W, N, F, D, or F;
  • X41 is present or absent, if present, is selected from V, D, Y, A,
  • X42 is present or absent, if present, is selected from F, Y, F, T, or G; X43 is present or absent, if present, is selected from P, F, V, N, S, or Y; X44 is present or absent, if present, is selected from F, S, T, G, or F; X45 is present or absent, if present, is selected from F, F, E, S, or N; X46 is present or absent, if present, is selected from S, F, or R; X47 is present or absent, if present, is F; X48 is present or absent, if present, is D; and X49 is present or absent, if present, is F; and wherein the VF region comprises CDR1 sequence selected from SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; CDR2 sequence selected from SEQ ID NOs: 65, 68,
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VF region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequence X32X33X34X35X36X37X38X39X40X41X42X43X44X45, in which X32 is selected from A or
  • X33 is selected from A, R, or T;
  • X34 is selected from A, V, T, P, I, E, or D;
  • X35 is selected from G, W, D, L, K, or P;
  • X36 is selected from P, A, Y, D, or G;
  • X37 is selected from Y, V, T, S, N, A, or G;
  • X38 is selected from G, S, D, or K;
  • X39 is selected from T, A, G, S, or I;
  • X40 is selected from S, Y, G, R, or W;
  • X41 is selected from V, D, Y, A, N, or G;
  • X42 is selected from L, Y, or F;
  • X43 is present or absent, if present, is selected from P, F, V, or N;
  • X44 is present or absent, if present, is selected from F, S, or T;
  • X45 is present or absent
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VF region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence
  • AX33X34X35X36X37X38X39X40X41X42X43X44X45X46 (SEQ ID No. 422), in which X33 is selected from R or G;
  • X34 is selected from E, D, or S; X35 is selected from G, F, P, S, or A; X36 is selected from D, S, or R; X37 is selected from Y, T, N, or G; X38 is selected from G, S, F, or F; X39 is selected from A, G, S, or I; X40 is selected from Y, N, or F; X41 is present or absent, if present, is selected from V, Y, or E; X42 is present or absent, if present, is G; X43 is present or absent, if present, is Y; X44 is present or absent, if present, is F; X45 is present or absent, if present, is selected from E or N; and X46 is present or absent, if present, is selected from S or F, and wherein the VF region comprises CDR1 sequence selected from SEQ ID NOs: 71, 77, 83, 94, and 102; CDR2 sequence selected from S
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VF region, wherein the VH region comprises CDR1 sequence X1GX2X3X4X5X6X7X8X9X10X11X12, wherein Xi is present or absent, if present, is S; X2 is selected from F or I; X3 is selected from P, S, or D; XQs selected from F, L, or A; X5 is selected from D, G, S, N, or T; Xe is selected from V, A, T, R, S, I, or N; X7 is selected from Y, I, N, R, A, G, or D; Xs is selected from A, Y, D, G, W, C, or T; X9 is selected from M, V, I, W, D, or Y; X10 is selected from S, T, M, C, I, Y, A, or G; Xu
  • CDR2 sequence selected from SEQ ID NOs: 63, 66,
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence GFPFX ⁇ X ( ,YAMS (SEQ ID NO: 423), in which X5 is selected from D or G and Xe is selected from V, A, or T; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10; and wherein the VL region comprises CDR1 sequence consisting of SEQ ID NO: 62, CDR2 sequence consisting of SEQ ID NO: 63, and CDR3 sequence consisting of SEQ ID NO: 64.
  • the VH region comprises CDR1 sequence GFPFX ⁇ X ( ,YAMS (SEQ ID NO: 423), in which X5 is selected from D or G and Xe is selected from V, A, or T; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence selected from SEQ
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence
  • Xi is present or absent, if present, is S;
  • X 2 is selected from F or I;
  • X 3 is selected from S or D;
  • X 4 is selected from L, F, or A;
  • X 5 is selected from S, N, or T;
  • Xe is selected from R, S, N, I, or T;
  • X 7 is selected from Y, I, N, R, A, D, or G;
  • Xs is selected from Y, D, G, A, W, T, or C;
  • X 9 is selected from V, M, I, W, Y, or D;
  • X 10 is selected from T, S, M, C, I, Y, A, or G;
  • Xu is present or absent, if present, is selected from C or M;
  • X 12 is present or absent, if present, is C;
  • CDR2 sequence selected from SEQ ID NOs: 12, 15,
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence GFSLX5X6X7X8X9X10X11 (SEQ ID NO: 426), wherein X 5 is selected from S or N; Xe is selected from R, S, or N; X 7 is selected from Y, I, or N; Xs is selected from Y, D, G, or A; X 9 is selected from V, M, or I; X 10 is selected from T, S, or M; and Xu is present or absent, if present, is C; CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89,
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence GFSX4X5X6X7X8X9X10X11X12 (SEQ ID NO: 419), wherein X4 is selected from F or A; X5 is selected from S, T, or N; Xe is selected from S, T, or N; X 7 is selected from Y, R, A, or G; Xs is selected from W, Y, or C; X 9 is selected from I, W, Y, or D; X 10 is selected from C, I, Y, or M; Xu is present or absent, if present, is selected from C or M; and X 12 is present or absent, if present, is C; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58; and wherein X4 is selected from F
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises 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; CDR2 sequence
  • X13 is selected from A, G, or S;
  • Xi4 is selected from I, F, Y, V, S, or C;
  • X15 is selected from S, I, L, T, or M;
  • Xi 6 is selected from G, Y, S, T, L, or V;
  • Xi7 is selected from S, I, K, Y, T, G, or A;
  • Xis is selected from G, S, T, P, V, or Y;
  • X19 is selected from G, A, D, S, or T;
  • X20 is selected from S, T, I, N, or G;
  • X21 is selected from T, I, D, N, S, or A;
  • X22 is selected from F, Y, N, T, I, or S;
  • X23 is selected from Y, D, K, or I;
  • X24 is selected from A or
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence AISGSGGSTX22YADSVKG (SEQ ID NO: 418) in which X22 is selected from F or Y; and CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10; and wherein the VL region comprises CDR1 sequence consisting of SEQ ID NO: 62, CDR2 sequence consisting of SEQ ID NO: 63, and CDR3 sequence consisting of SEQ ID NO: 64.
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; CDR2 sequence
  • X13 is selected from A, G, or S;
  • Xi 4 is selected from I, F, Y, V, S, or C;
  • X 15 is selected from I, L, M, or T;
  • X 1 ⁇ 2 is selected from G, Y, S, T, L, or V;
  • Xi 7 is selected from S, I, K, Y, T, G, or A;
  • Xis is selected from G, S, T, P, or V;
  • X19 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
  • VL region comprises CDR1 sequence selected from SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; CDR2 sequence selected from SEQ ID NOs: 66, 69, 72, 75, 78, 81, 84, 90, and 99; and CDR3 sequence selected from SEQ ID NOs: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence X13X14IX16X17X18X19X20X21X22X23X24X25X26X27X28X29X30, wherein X13 is selected from A or G; Cm is selected from I, F, Y, V, S, or C; Xie is selected from G, Y, S, T, or L; Xi7 is selected from S, I, K, Y, T, or G; Xis is selected from G, S, or T; X19 is selected from G, A, D, or S; X20 is selected from T, I, N, or G; X21 is selected from T, I, or D; X22 is selected from Y, N, or T; X23 is selected
  • CDR2 sequence selected from SEQ ID NOs: 66, 69, 78, 81, 90, and 99
  • CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; 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 X30X3 1 , wherein Xi 3 is selected from A, or S; X 15 is selected from I, L, or T; Xi 6 is selected from Y or V; X 17 is selected from S, T, or A; Xis 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
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises 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; 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 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 wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 62, 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; CDR2 sequence selected from SEQ ID NOs: 63, 66, 69, 72,
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 1, 4, 6, 8, and 9; CDR2 sequence selected from SEQ ID NOs: 2 and 5; and CDR3 sequence selected from SEQ ID NOs: 3, 7, and 10; and wherein the VL region comprises CDR1 sequence consisting of SEQ ID NO: 62, CDR2 sequence consisting of SEQ ID NO: 63, and CDR3 sequence consisting of SEQ ID NO: 64.
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 17, 20, 23, 26, 29, 32, 35, 38, 41, 44, 47, 50, 53, and 56; CDR2 sequence selected from SEQ ID NOs: 12, 15,
  • VL region comprises CDR1 sequence selected from SEQ ID NOs: 65, 68, 71, 74, 77, 80, 83, 86, 89, 92, 94, 96, 98, and 102; CDR2 sequence selected from SEQ ID NOs: 66, 69, 72, 75, 78, 81, 84, 90, and 99; and CDR3 sequence selected from SEQ ID NOs: 67, 70, 73, 76, 79, 82, 85, 87, 88, 91, 93, 95, 97, 100, 101, and 103.
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence selected from SEQ ID NOs: 12, 15, 27, 33, 36, 39, 42, and 51; and CDR3 sequence selected from SEQ ID NOs: 13, 16, 28, 34, 37, 40, 43, and 52; and wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 65, 68, 80, 86, 89, 92, and 98; CDR2 sequence selected from SEQ ID NOs: 66, 69, 78, 81, 90, and 99; and CDR3 sequence selected from SEQ ID NOs: 67, 70, 82, 87, 88, 91, 93, and 100.
  • the VH region comprises CDR1 sequence selected from SEQ ID NOs: 11, 14, 26, 32, 35, 38, 41, and 50; CDR2 sequence
  • the first targeting moiety that specifically binds to CD38 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 17, 23, 29, 44, and 56; CDR2 sequence selected from SEQ ID NOs: 18, 24, 30, 45, and 57; and CDR3 sequence selected from SEQ ID NOs: 19, 25, 31, 46, and 58; and wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 71, 77, 83, 94, and 102; CDR2 sequence selected from SEQ ID NOs: 72, 78, and 84; and CDR3 sequence selected from 73, 79, 85, 95, and 103.
  • the second targeting moiety that specifically binds to ICAM1 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, 238, 241, 247, and 250; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, 239, 242, 244, 246, 248, and 251; and CDR3 sequence X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 X 46 X 47 X 48 X 49 , wherein X 31 is selected from A or V; X 32 is selected from R or I; X 33 is selected from G, D, P, A, or V; X 34 is selected from G, P, W
  • the second targeting moiety that specifically binds to ICAM1 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 21 1, 214, 217, 222, 225, 228, 232, 235, and 238; CDR2 sequence selected from SEQ ID NOs: 209,
  • X 31 is selected from A or V;
  • X 33 is selected from G or D;
  • X 34 is selected from G, P, W, or D;
  • X 35 is selected from D, Y, S, or L;
  • X 36 is selected from Y, D, V, or L;
  • X 37 is selected from G, S, or D;
  • X 38 is selected from G, Y, F, or S;
  • X 39 is selected from S, D, G, or T;
  • X 40 is selected from T, A, D, S, or Y;
  • X 41 is selected from Y, A, G, or I;
  • X 42 is selected from I, Y, or R;
  • X 43 is selected from L, R, Y, or G;
  • X 44 is selected from N, L, Y, or S
  • the second targeting moiety that specifically binds to ICAM1 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence
  • the second targeting moiety that specifically binds to ICAM1 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence GFSLX 5 X 6 X 7 X 8 MX 10 (SEQ ID NO: 425), wherein X 5 is selected from S or N; X 6 is selected from S, N, T, or D; X 7 is selected from Y or H; X 8 is selected from G, A, or Y; and X 10 is selected from S, G, or N; CDR2 sequence selected from SEQ ID NOs: 209, 212, 218, 220, 223, 227, 229, 234, 236, and 239; and CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240; and wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 26
  • CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, and 283; and CDR3 sequence selected from SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, and 284.
  • 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,
  • 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, if present, is selected from K or G; and
  • X 30 is present or absent, if present, is G; and
  • VL region comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277,
  • CDR2 sequence selected from SEQ ID NOs: 254, 257, 260, 263, 273, 275, 280, 283, and 63; and CDR3 sequence selected from SEQ ID NOs: 255, 258, 261, 264, 266, 271, 276, 278, 281, 284, and 64.
  • X 13 is selected from W, I, or Y;
  • X 15 is selected from S or G;
  • X 16 is selected from F, S, D, or T;
  • X 17 is selected from S or R;
  • X 18 is selected from G or D;
  • X 19 is selected from S, R, T, or N;
  • X 20 is selected from T or A; and
  • X 24 is selected from S, T, or N; and CDR3 sequence selected from SEQ ID NOs: 210, 213, 216, 219, 221, 224, 226, 230, 231, 233, 237, and 240; and wherein the VL region comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282;
  • the second targeting moiety that specifically binds to ICAM1 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 208, 211, 214, 217, 222, 225, 228, 232, 235, and 238; CDR2 sequence selected from SEQ ID NOs: 209,
  • VL region comprises CDR1 sequence selected from SEQ ID NOs: 253, 256, 259, 262, 265, 267, 268, 269, 270, 272, 274, 277, 279, and 282;
  • the second targeting moiety that specifically binds to ICAM1 comprises a VH region and a VL region, wherein the VH region comprises CDR1 sequence selected from SEQ ID NOs: 241, 247, and 250; CDR2 sequence selected from SEQ ID NOs: 242, 244, 246, 248, and 251; and CDR3 sequence selected from SEQ ID NOs: 243, 245, 249, and 252; and wherein the VL region comprises CDR1, CDR2, and CDR3 sequences SEQ ID NOs: 62-64, respectively.
  • the constant region of a bispecific antibody comprising a CD38 targeting moiety and an ICAM1 targeting moiety is from IgG (e.g., IgGl, IgG2, IgG3, or IgG4), IgA, IgE, or IgM.
  • the constant region further comprises one or more mutations in, e.g., the CHI domain, CH2, domain, CH3 domain, hinge region, or a combination thereof. In some cases, the one or more mutations enhance stability, increase half-life, decrease
  • Exemplary mutations that modulate Fc receptor interaction include, but are not limited to, E333A, S239D/A330L/I332E, K326W/E333S, or S239D/I332I/G236A, the residue numbering are in Rabat numbering in reference to IgGl.
  • Exemplary mutations that increases half-life include, but are not limited to, T250Q/M428L or M252Y/S254T/T256E and H433K/N434F (Rabat numbering) in reference to IgGl; and R435H (Rabat numbering) in reference to IgG3.
  • Exemplary mutations that prevent or reduce strand exchange comprise S228P (Kabat numbering) in reference to IgG4.
  • Exemplary mutation that modulate glycosylation include N297 (Kabat numbering) in reference to IgGl, in which the residue is afucosylated to increase ADCC.
  • a bispecific antibody described above comprises a knobs-into-holes (KIH) format.
  • the KIH is located in the Fc region, in which the residues within the CH3 domain are optionally modified based on the disclosure of W096/027011; Ridgway, et. al., Protein Eng. 9 (1996) 617- 621; or Merchant, et. al., Nat. Biotechnol. 16 (1998) 677-681.
  • one of the CH3 domain pair is the“knob” chain while the other is the“hole” chain and additional disulfide bridges are optionally introduced to further stabilize the antibody and/or to increase yield.
  • the CH3 domain of the“knob” chain comprises a T366W mutation and the CH3 domain of the“hole” chain comprises mutations T366S, L368A, and Y407V.
  • the CH3 domain of the“knob” chain further comprises a Y349C mutation which forms an interchain disulfide bridge with either E356C or S354C in the CH3 domain of the“hole” chain.
  • the CH3 domain of the“knob” chain comprises R409D and K370E mutations and the CH3 domain of the“hole” chain comprises D399K and E357K.
  • the CH3 domain of the“knob” chain further comprises a T366W mutation and the CH3 domain of the“hole” chain further comprises mutations T366S, L368A, and Y407V.
  • polypeptides described herein are produced using any method known in the art to be useful for the synthesis of polypeptides (e.g., antibodies), in particular, by chemical synthesis or by recombinant expression, and are preferably produced by recombinant expression techniques.
  • an antibody or its binding fragment thereof is expressed recombinantly, and the nucleic acid encoding the antibody or its binding fragment is assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier et al., 1994, BioTechniques 17:242), which involves the synthesis of overlapping oligonucleotides containing portions of the sequence encoding the antibody, annealing and ligation of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR.
  • chemically synthesized oligonucleotides e.g., as described in Kutmeier et al., 1994, BioTechniques 17:242
  • a nucleic acid molecule encoding an antibody is optionally generated from a suitable source (e.g., an antibody cDNA library, or cDNA library generated from any tissue or cells expressing the immunoglobulin) by PCR amplification using synthetic primers hybridizable to the 3' and 5' ends of the sequence or by cloning using an oligonucleotide probe specific for the particular gene sequence.
  • a suitable source e.g., an antibody cDNA library, or cDNA library generated from any tissue or cells expressing the immunoglobulin
  • an antibody or its binding is optionally generated by immunizing an animal, such as a rabbit, to generate polyclonal antibodies or, more preferably, by generating monoclonal antibodies, e.g., as described by Kohler and Milstein (1975, Nature 256:495-497) or, as described by Kozbor et al. (1983, Immunology Today 4:72) or Cole et al. (1985 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96).
  • a clone encoding at least the Fab portion of the antibody is optionally obtained by screening Fab expression libraries (e.g., as described in Huse et al., 1989, Science 246: 1275- 1281) for clones of Fab fragments that bind the specific antigen or by screening antibody libraries (See, e.g., Clackson et al., 1991, Nature 352:624; Hane et al., 1997 Proc. Natl. Acad. Sci. USA 94:4937).
  • chimeric antibodies techniques developed for the production of“chimeric antibodies” (Morrison et al., 1984, Proc. Natl. Acad. Sci. 81:851-855; Neuberger et al., 1984, Nature 312:604-608; Takeda et al., 1985, Nature 314:452-454) by splicing genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity are used.
  • a chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine monoclonal antibody and a human
  • single chain antibodies are adapted to produce single chain antibodies.
  • Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide.
  • Techniques for the assembly of functional Fv fragments in E. coli are also optionally used (Skerra et al., 1988, Science 242: 1038-1041).
  • an expression vector comprising the nucleotide sequence of an antibody or the nucleotide sequence of an antibody is transferred to a host cell by conventional techniques (e.g., electroporation, liposomal transfection, and calcium phosphate precipitation), and the transfected cells are then cultured by conventional techniques to produce the antibody.
  • the expression of the antibody is regulated by a constitutive, an inducible or a tissue, specific promoter.
  • host-expression vector systems is utilized to express an antibody, or its binding fragment described herein.
  • host-expression systems represent vehicles by which the coding sequences of the antibody is produced and subsequently purified, but also represent cells that are, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody or its binding fragment in situ.
  • host-expression systems represent vehicles by which the coding sequences of the antibody is produced and subsequently purified, but also represent cells that are, when transformed or transfected with the appropriate nucleotide coding sequences, express an antibody or its binding fragment in situ.
  • microorganisms such as bacteria (e.g., E. coli and B. suhtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing an antibody or its binding fragment coding sequences; yeast (e.g., E. coli and B. suhtilis) transformed with recombinant bacteriophage DNA, plasmid DNA or co
  • Saccharomyces Pichia transformed with recombinant yeast expression vectors containing an antibody or its binding fragment coding sequences; insect cell systems infected with recombinant virus expression vectors (e.g., baculovirus) containing an antibody or its binding fragment coding sequences; plant cell systems infected with recombinant virus expression vectors (e.g., cauliflower mosaic virus (CaMV) and tobacco mosaic virus (TMV)) or transformed with recombinant plasmid expression vectors (e.g., Ti plasmid) containing an antibody or its binding fragment coding sequences; or mammalian cell systems (e.g., COS, CHO, BH, 293, 293T, 3T3 cells) harboring recombinant expression constructs containing promoters derived from the genome of mammalian cells (e.g., metallothionein promoter) or from mammalian viruses (e.g. the adenovirus late promoter; the vaccinia virus
  • the selectable marker in the recombinant plasmid confers resistance to the selection and allows cells to stably integrate the plasmid into their chromosomes and grow to form foci that in turn are cloned and expanded into cell lines.
  • This method can advantageously be used to engineer cell lines which express the antibody or its binding fragments.
  • a number of selection systems are used, including but not limited to the herpes simplex virus thymidine kinase (Wigler et ah, 1977, Cell 11:223), hypoxanthine -guanine
  • phosphoribosyltransferase (Szybalska & Szybalski, 192, Proc. Natl. Acad. Sci. USA 48:202), and adenine phosphoribosyltransferase (Lowy et ah, 1980, Cell 22:817) genes are employed in tk-, hgprt- or aprt- cells, respectively. Also, antimetabolite resistance are used as the basis of selection for the following genes: dhfir, which confers resistance to methotrexate (Wigler et ah, 1980, Proc. Natl. Acad. Sci. USA 77:357; O'Hare et ah, 1981, Proc. Natl. Acad. Sci. USA 78: 1527); gpt, which confers resistance to mycophenolic acid
  • the expression levels of an antibody are increased by vector amplification (for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol. 3. (Academic Press, New York, 1987)).
  • vector amplification for a review, see Bebbington and Hentschel, The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in DNA cloning, Vol. 3. (Academic Press, New York, 1987)).
  • a marker in the vector system expressing an antibody is amplifiable
  • an increase in the level of inhibitor present in culture of host cell will increase the number of copies of the marker gene. Since the amplified region is associated with the nucleotide sequence of the antibody, production of the antibody will also increase (Crouse et al., 1983, Mol. Cell Biol. 3:257).
  • any method known in the art for purification of an antibody is used, for example, by chromatography (e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins.
  • chromatography e.g., ion exchange, affinity, particularly by affinity for the specific antigen after Protein A, and sizing column chromatography
  • centrifugation e.g., centrifugation, differential solubility, or by any other standard technique for the purification of proteins.
  • vectors include any suitable vectors derived from either a eukaryotic or prokaryotic sources.
  • vectors are obtained from bacteria (e.g. E. coli), insects, yeast (e.g. Pichia pastoris), algae, or mammalian sources.
  • Exemplary bacterial vectors include pACYC177, pASK75, pBAD vector series, pBADM vector series, pET vector series, pETM vector series, pGEX vector series, pHAT, pHAT2, pMal-c2, pMal-p2, pQE vector series, pRSET A, pRSET B, pRSET C, pTrcHis2 series, pZA31 -Luc, pZE21-MCS-l, pFLAG ATS, pFLAG CTS, pFLAG MAC, pFLAG Shift- 12c, pTAC-MAT-1, pFLAG CTC, or pTAC-MAT-2.
  • yeast vectors include Gateway ® pDEST TM 14 vector, Gateway ® pDEST TM 15 vector, Gateway ® pDEST TM 17 vector, Gateway ® pDEST TM 24 vector, Gateway ® pYES-DEST52 vector, pBAD- DEST49 Gateway ® destination vector, pA0815 Pichia vector, pFLDl Pichi pastoris vector, pGAPZA,B, & C Pichia pastoris vector, pPIC3.5K Pichia vector, pPIC6 A, B, & C Pichia vector, pPIC9K Pichia vector, pTEFl/Zeo, pYES2 yeast vector, pYES2/CT yeast vector, pYES2/NT A, B, & C yeast vector, or pYES3/CT yeast vector.
  • Exemplary algae vectors include pChlamy-4 vector or MCS vector.
  • mammalian vectors include transient expression vectors or stable expression vectors.
  • Mammalian transient expression vectors may include pRK5, p3xFLAG-CMV 8, pFLAG-Myc-CMV 19, pFLAG-Myc-CMV 23, pFLAG-CMV 2, pFLAG-CMV 6a,b,c, pFLAG-CMV 5.1, pFLAG-CMV 5a,b,c, p3xFLAG-CMV 7.1, pFLAG-CMV 20, p3xFLAG-Myc-CMV 24, pCMV -FLAG-MAT 1 , pCMV-FLAG- MAT2, pBICEP-CMV 3, or pBICEP-CMV 4.
  • Mammalian stable expression vector may include pFLAG- CMV 3, p3xFLAG-CMV 9, p3xFLAG-CMV 13, pFLAG-Myc-CMV 21, p3xFLAG-Myc-CMV 25, pFLAG-CMV 4, p3xFLAG-CMV 10, p3xFLAG-CMV 14, pFLAG-Myc-CMV 22, p3xFLAG-Myc-CMV 26, pBICEP-CMV 1, or pBICEP-CMV 2.
  • a cell-free system is a mixture of cytoplasmic and/or nuclear components from a cell and is used for in vitro nucleic acid synthesis.
  • a cell-free system utilizes either prokaryotic cell components or eukaryotic cell components.
  • a nucleic acid synthesis is obtained in a cell-free system based on for example Drosophila cell, Xenopus egg, or HeLa cells.
  • Exemplary cell-free systems include, but are not limited to, E. coli S30 Extract system, E. coli T7 S30 system, or PURExpress®. Host Cells
  • a host cell includes any suitable cell such as a naturally derived cell or a genetically modified cell.
  • a host cell is a production host cell.
  • a host cell is a eukaryotic cell.
  • a host cell is a prokaryotic cell.
  • a eukaryotic cell includes fungi (e.g., yeast cells), animal cell or plant cell.
  • a prokaryotic cell is a bacterial cell. Examples of bacterial cell include gram -positive bacteria or gram -negative bacteria. Sometimes the gram negative bacteria is anaerobic, rod-shaped, or both.
  • a bacterial cell can be Escherichia coli, Clostridium botulinum, or Coli bacilli.
  • Exemplary prokaryotic host cells include, but are not limited to, BL21, MachlTM, DH10BTM, TOP10, DH5a, DHlOBacTM, OmniMaxTM, MegaXTM, DH12STM, INV110, TOP10F’, INVaF, TOP10/P3, ccdB Survival, PIR1, PIR2, Stbl2TM, Stbl3TM, or Stbl4TM.
  • animal cells include a cell from a vertebrate or from an invertebrate.
  • an animal cell includes a cell from a marine invertebrate, fish, insects, amphibian, reptile, or mammal.
  • a fungus cell includes a yeast cell, such as brewer’s yeast, baker’s yeast, or wine yeast.
  • Fungi include ascomycetes such as yeast, mold, filamentous fungi, basidiomycetes, or zygomycetes.
  • yeast includes Ascomycota or Basidiomycota.
  • Ascomycota includes Saccharomycotina (true yeasts, e.g. Saccharomyces cerevisiae (baker’s yeast)) or Taphrinomycotina (e.g. Schizosaccharomycetes (fission yeasts)).
  • Basidiomycota includes Agaricomycotina (e.g. Tremellomycetes) or Pucciniomycotina (e.g. Microbotryomycetes).
  • Exemplary yeast or filamentous fungi include, for example, the genus: Saccharomyces,
  • yeast or filamentous fungi include, for example, the species: Saccharomyces cerevisiae, Schizosaccharomyces pombe, Candida utilis, Candida boidini, Candida albicans, Candida tropicalis, Candida stellatoidea, Candida glabrata, Candida krusei, Candida parapsilosis, Candida guilliermondii, Candida viswanathii, Candida lusitaniae,
  • Rhodotorula mucilaginosa Pichia metanolica, Pichia angusta, Pichia pastoris, Pichia anomala, Hansenula polymorpha, Kluyveromyces lactis, Zygosaccharomyces rouxii, Yarrowia lipolytica, Trichosporon pullulans, Rhodosporidium toru-Aspergillus niger, Aspergillus nidulans, Aspergillus awamori, Aspergillus oryzae, Trichoderma reesei, Yarrowia lipolytica, Brettanomyces bruxellensis, Candida stellata,
  • yeast host cells include, but are not limited to, Pichia pastoris yeast strains such as GS115, KM71H, SMD1168, SMD1168H, and X-33; and Saccharomyces cerevisiae yeast strain such as INVScl.
  • additional animal cells include cells obtained from a mollusk, arthropod, annelid or sponge.
  • an additional animal cell is a mammalian cell, e.g., from a primate, ape, equine, bovine, porcine, canine, feline or rodent.
  • a rodent includes mouse, rat, hamster, gerbil, hamster, chinchilla, fancy rat, or guinea pig.
  • Exemplary mammalian host cells include, but are not limited to, 293A cell line, 293FT cell line, 293F cells , 293 H cells, CHO DG44 cells, CHO-S cells, CHO-K1 cells, Expi293FTM cells, Flp-InTM T- RExTM 293 cell line, Flp-InTM-293 cell line, Flp-InTM-3T3 cell line, Flp-InTM-BHK cell line, Flp-InTM-CHO cell line, Flp-InTM-CV-l cell line, Flp-InTM-Jurkat cell line, FreeStyleTM 293 -F cells, FreeStyleTM CHO-S cells, GripTiteTM 293 MSR cell line, GS-CHO cell line, HepaRGTM cells, T-RExTM Jurkat cell line, Per.C6 cells, T-RExTM-293 cell line, T-RExTM-CHO cell line, and T-RExTM-HeFa cell line.
  • 293A cell line 293FT
  • a mammalian host cell is a stable cell line, or a cell line that has incorporated a genetic material of interest into its own genome and has the capability to express the product of the genetic material after many generations of cell division.
  • a mammalian host cell is a transient cell line, or a cell line that has not incorporated a genetic material of interest into its own genome and does not have the capability to express the product of the genetic material after many generations of cell division.
  • Exemplary insect host cells include, but are not limited to, Drosophila S2 cells, Sf9 cells, Sf21 cells, High FiveTM cells, and expresSF+® cells.
  • plant cells include a cell from algae.
  • Exemplary insect cell lines include, but are not limited to, strains from Chlamydomonas reinhardtii 137c, or Synechococcus elongatus PPC 7942.
  • an anti-CD38 antibody described herein, an anti-ICAMl antibody described herein, or a multi-specific antibody described herein is further conjugated to one or more payloads.
  • the one or more payloads comprise a small molecule, a protein or peptide, or a nucleic acid polymer.
  • the one or more payloads are conjugated directed to the anti-CD38 antibody, the anti-ICAMl antibody, or the multi -specific antibody.
  • the one or more payloads are conjugated to the anti-CD38 antibody, the anti-ICAMl antibody, or the multi -specific antibody indirectly via a linker.
  • the antibody is an anti-CD38 antibody and the number of payloads conjugated to the antibody (e.g., the drug-to-antibody ratio or DAR) is about 1: 1, one payload to one anti-CD38 antibody.
  • the ratio of the payload to the anti-CD38 antibody is about 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11 : 1, or 12: 1.
  • the ratio of the payload to the anti-CD38 antibody is about 2: 1.
  • the ratio of the payload to the anti-CD38 antibody is about 4: 1.
  • the ratio of the payload to the anti-CD38 antibody is about 8: 1.
  • the ratio of the payload to the anti-CD38 antibody is about 12: 1.
  • the antibody is an anti-ICAMl antibody and the number of payloads conjugated to the antibody (e.g., the drug -to -antibody ratio or DAR) is about 1: 1, one payload to one anti-ICAMl antibody.
  • the ratio of the payload to the anti-ICAMl antibody is about 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, or 12: 1.
  • the ratio of the payload to the anti-ICAMl antibody is about 2: 1.
  • the ratio of the payload to the anti-ICAMl antibody is about 4: 1.
  • the ratio of the payload to the anti-ICAMl antibody is about 8: 1.
  • the ratio of the payload to the anti-ICAMl antibody is about 12: 1.
  • the antibody is a multi -specific antibody comprising a targeting moiety to either CD38 or ICAM1 and the number of payloads conjugated to the multi -specific antibody (e.g., the drug-to- antibody ratio or DAR) is about 1 : 1.
  • the ratio of the payload to the multi -specific antibody is about 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, or 12: 1.
  • the ratio of the payload to the multi -specific antibody is about 2: 1.
  • the ratio of the payload to the multi-specific antibody is about 4: 1.
  • the ratio of the payload to the multi -specific antibody is about 8: 1.
  • the ratio of the payload to the multi -specific antibody is about 12: 1.
  • the antibody is a bispecific antibody comprising a first targeting moiety to CD38 and a second targeting moiety to ICAM1 and the number of payloads conjugated to the bispecific antibody (e.g., the drug-to-antibody ratio or DAR) is about 1 : 1.
  • the ratio of the payload to the bispecific antibody is about 2: 1, 3: 1, 4: 1, 5: 1, 6: 1, 7: 1, 8: 1, 9: 1, 10: 1, 11: 1, or 12: 1.
  • the ratio of the payload to the bispecific antibody is about 2: 1.
  • the ratio of the payload to the bispecific antibody is about 4: 1.
  • the ratio of the payload to the bispecific antibody is about 8: 1.
  • the ratio of the payload to the bispecific antibody is about 12: 1.
  • the payload is a small molecule.
  • the small molecule is a cytotoxic payload.
  • cytotoxic payloads include, but are not limited to, microtubule disrupting agents, DNA modifying agents, or Akt inhibitors.
  • the payload comprises a microtubule disrupting agent.
  • microtubule disrupting agents include, but are not limited to, 2-methoxyestradiol, auristatin, chalcones, colchicine, combretastatin, cryptophycin, dictyostatin, discodermolide, dolastain, eleutherobin, epothilone, halichondrin, laulimalide, maytansine, noscapinoid, pacbtaxel, peloruside, phomopsin, podophyllotoxin, rhizoxin, spongistatin, taxane, tubulysin, vinca alkaloid, vinorelbine, or derivatives or analogs thereof.
  • the tubulysin is a tubulysin analog or derivative such as described in U.S. Patent Nos. 8580820 and 8980833 and in U.S. Publication Nos. 20130217638, 20130224228, and
  • the maytansine is a maytansinoid.
  • the maytansinoid is DM1, DM4, or ansamitocin.
  • the maytansinoid is DM1.
  • the maytansinoid is DM4.
  • the maytansinoid is ansamitocin.
  • the maytansinoid is a maytansionid derivative or analog such as described in U.S. Patent Nos. 5208020, 5416064, 7276497, and 6716821 or U.S. Publication Nos. 2013029900 and US20130323268.
  • the payload is a dolastatin, or a derivative or analog thereof.
  • the dolastatin is dolastatin 10 or dolastatin 15, or derivatives or analogs thereof.
  • the dolastatin 10 analog is auristatin, soblidotin, symplostatin 1, or symplostatin 3.
  • the dolastatin 15 analog is cemadotin ortasidotin.
  • the dolastatin 10 analog is auristatin or an auristatin derivative.
  • the auristatin or auristatin derivative is auristatin E (AE), auristatin F (AF), auristatin E5- benzoylvaleric acid ester (AEVB), monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), or monomethyl auristatin D (MMAD), auristatin PE, or auristatin PYE.
  • the auristatin derivative is monomethyl auristatin E (MMAE).
  • the auristatin derivative is monomethyl auristatin F (MMAF).
  • MMAF monomethyl auristatin F
  • the auristatin is an auristatin derivative or analog such as described in U.S. Patent No. 6884869, 7659241, 7498298, 7964566, 7750116, 8288352, 8703714 and 8871720.
  • the payload comprises a DNA modifying agent.
  • the DNA modifying agent comprises DNA cleavers, DNA intercalators, DNA transcription inhibitors, or DNA cross-linkers.
  • the DNA cleaver comprises bleomycine A2, calicheamicin, or derivatives or analogs thereof.
  • the DNA intercalator comprises doxorubicin, epirubicin, PNU- 159682, duocarmycin, pyrrolobenzodiazepine, oligomycin C, daunorubicin, valrubicin, topotecan, or derivatives or analogs thereof.
  • the DNA transcription inhibitor comprises dactinomycin.
  • the DNA cross-linker comprises mitomycin C.
  • the DNA modifying agent comprises amsacrine, anthracycline,
  • camptothecin camptothecin, doxorubicin, duocarmycin, enediyne, etoposide, indolinobenzodiazepine, netropsin, teniposide, or derivatives or analogs thereof.
  • the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, mithramycin, nemorubicin, pixantrone, sabarubicin, or valrubicin.
  • the analog of camptothecin is topotecan, irinotecan, silatecan, cositecan, exatecan, lurtotecan, gimatecan, belotecan, rubitecan, or SN-38.
  • the duocarmycin is duocarmycin A, duocarmycin Bl, duocarmycin B2, duocarmycin Cl, duocarmycin C2, duocarmycin D, duocarmycin SA, or CC-1065.
  • the enediyne is a calicheamicin, esperamicin, or dynemicin A.
  • the pyrrolobenzodiazepine is anthramycin, abbeymycin, chicamycin, DC-81, mazethramycin, neothramycins A, neothramycin B, porothramycin, prothracarcin, sibanomicin (DC- 102), sibiromycin, or tomaymycin.
  • the pyrrolobenzodiazepine is atomaymycin derivative, such as described in U.S. Patent Nos. 8404678 and 8163736.
  • the pyrrolobenzodiazepine is atomaymycin derivative, such as described in U.S. Patent Nos. 8404678 and 8163736.
  • pyrrolobenzodiazepine is such as described in U.S. Patent Nos. 8426402, 8802667, 8809320, 6562806, 6608192, 7704924, 7067511, US7612062, 7244724, 7528126, 7049311, 8633185, 8501934, and 8697688 and U.S. Publication No. US20140294868.
  • the payload comprises an Akt inhibitor.
  • the Akt inhibitor comprises ipatasertib (GDC-0068) or derivatives thereof.
  • the payload comprises a polymerase inhibitor, including, but not limited to polymerase II inhibitors such as a-amanitin, and poly(ADP-ribose) polymerase (PARP) inhibitors.
  • a polymerase inhibitor including, but not limited to polymerase II inhibitors such as a-amanitin, and poly(ADP-ribose) polymerase (PARP) inhibitors.
  • PARP poly(ADP-ribose) polymerase
  • Exemplary PARP inhibitors include but are not limited to Iniparib (BSI 201), Talazoparib (BMN-673), Olaparib (AZD-2281), Olaparib, Rucaparib (AG014699, PF-01367338), Veliparib (ABT-888), CEP 9722, MK 4827, BGB-290, or 3-aminobenzamide.
  • the payload is an imaging agent.
  • the payload comprises a "radio -opaque" label, e.g. a label visualized using x-rays.
  • Radio-opaque materials are well known to those of skill in the art. Exemplary radio-opaque materials include iodide, bromide or barium salts. Additional radiopaque materials include, but are not limited to, organic bismuth derivatives ⁇ see, e.g., U.S. Patent 5,939,045), radio-opaque polyurethanes (see, e.g., U.S. Patent 5,346,981), organobismuth composites (see, e.g., U.S. Patent 5,256,334), radio-opaque barium polymer complexes (see, e.g., U.S. Patent 4,866, 132), and the like.
  • the payload comprises a detectable label, for example, for use in
  • immunoconjugates include any composition detectable by spectroscopic, photochemical, biochemical, immunochemical, electrical, optical or chemical means.
  • Useful labels in the include magnetic beads (e.g., DYNABEADSTM), fluorescent dyes (e.g. , fluorescein isothiocyanate, texas red, rhodamine, green fluorescent protein, and the like), radiolabels (e.g., 3 H, 125 1, 35 S, 14 C, or 32 P), enzymes (e.g., horse radish peroxidase, alkaline phosphatase and others commonly used in an ELISA), and colorimetric labels such as colloidal gold or colored glass or plastic (e.g. polystyrene, polypropylene, latex, etc.) beads, nanoparticles, quantum dots, and the like.
  • colloidal gold or colored glass or plastic e.g. polystyrene, polypropylene, latex, etc.
  • the payload comprises a radiosensitizer that enhances the cytotoxic effect of ionizing radiation (e.g, such as might be produced by 60 Co or an x-ray source) on a cell.
  • a radiosensitizer that enhances the cytotoxic effect of ionizing radiation (e.g, such as might be produced by 60 Co or an x-ray source) on a cell.
  • radiosensitizing agents include, but are not limited to benzoporphyrin derivative compounds (see, e.g., U.S. Patent 5,945,439), 1,2,4-benzotriazine oxides (see, e.g, U.S. Patent 5,849,738), compounds containing certain diamines (see, e.g., U.S. Patent 5,700,825), BCNT (see, e.g., U.S.
  • Patent 5,872,107 radiosensitizing nitrobenzoic acid amide derivatives (see, e.g., U.S. Patent 4,474,814 ), various heterocyclic derivatives (see, e.g., U.S. Patent 5,064,849), platinum complexes (see, e.g., U.S. Patent 4,921,963), and the like.
  • Suitable alpha emitters include, but are not limited to 2 l 'Bi. 211 At, and the like.
  • the payload comprises an immunomodulatory agent.
  • immunomodulatory agents include anti-hormones that block hormone action on tumors and immunosuppressive agents that suppress cytokine production, down-regulate self-antigen expression, or mask MHC antigens.
  • anti-hormones include anti -estrogens including, for example, tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, UY 117018, onapnstone, and toremifene; and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and anti-adrenal agents.
  • anti -estrogens including, for example, tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, UY 117018, onapnstone, and toremifene
  • anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and go
  • immunosuppressive agents include but are not limited to 2-amino-6-aryl- 5-substituted pyrimidines, azathioprine, cyclophosphamide, bromocryptine, danazol, dapsone,
  • glutaraldehyde anti -idiotypic antibodies for MHC antigens and MHC fragments
  • cyclosporin A steroids such as glucocorticosteroids, streptokinase, or rapamycin.
  • the payload comprises a protein or peptide toxin or fragment thereof.
  • Exemplary enzymatically active toxins and fragments thereof include, but are not limited to, diphtheria toxin A fragment, nonbinding active fragments of diphtheria toxin, exotoxin A (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, a-sacrin, certain A leurites fordii proteins, certain Dianthin proteins, Phytolacca americana proteins (PAP, PAPII and PAP-S), Morodica charantia inhibitor, curcin, crotin, Saponaria officinalis inhibitor, gelonin, mitogillin, restrictocin, phenomycin, enomycin, and tricothecenes.
  • diphtheria toxin A fragment nonbinding active fragments of diphtheria toxin
  • exotoxin A from Pseudomonas aeruginosa
  • ricin A chain abrin A chain,
  • the payload comprises a cytokine.
  • the cytokine comprises IL-2, IL-2, IL-3, IL-6, IL-10, IL-12, IL-18, IL-21, interferon (e.g., IFNa, PTMb), or TNFa.
  • the payload is a nucleic acid polymer.
  • the nucleic acid polymers include those for use in gene therapy, such as in RNA interference (RNAi) or gene silencing (or antisense oligonucleotide) techniques.
  • RNAi RNA interference
  • Exemplary nucleic acid polymers that participate in the RNA interference process include short interfering nucleic acid (siNA), short interfering RNA (siRNA), double- stranded RNA (dsRNA), micro-RNA (miRNA), or short hairpin RNA (shRNA).
  • the nucleic acid polymer is an mRNA.
  • the mRNA encodes a cytotoxic protein or peptide.
  • cytotoxic proteins or peptides include a bacterial cytotoxin such as an alpha-pore forming toxin (e.g., cytolysin A from E. coli), a beta-pore-forming toxin (e.g., a-Hemolysin, PVL— panton Valentine leukocidin, aerolysin, clostridial Epsilon-toxin, Clostridium
  • perfringens enterotoxin binary toxins (anthrax toxin, edema toxin, C. botulinum C2 toxin, C spirofome toxin, C. perfringens iota toxin, C.
  • cyto-lethal toxins A and B
  • prion parasporin, a cholesterol- dependent cytolysins (e.g., pneumolysin), a small pore-forming toxin (e.g., Gramicidin A), a cyanotoxin (e.g., microcystins, nodularins), a hemotoxin, a neurotoxin (e.g., botulinum neurotoxin), a cytotoxin, cholera toxin, diphtheria toxin, Pseudomonas exotoxin A, tetanus toxin, or an immunotoxin (idarubicin, ricin A, CRM9, Pokeweed antiviral protein, DT).
  • a cholesterol-dependent cytolysins e.g., pneumolysin
  • small pore-forming toxin e.g., Gramicidin A
  • cyanotoxin e.
  • the mRNA encodes a cytotoxic peptide or peptide related to the immune system such as a cytotoxic T cell or B cell epitope to stimulate a specific immune response via presentation of such epitope with an MHC I complex, an membrane attack complex protein (MAC) of the complement system, perforin, a granzyme and a granulysin.
  • a cytotoxic peptide or peptide related to the immune system such as a cytotoxic T cell or B cell epitope to stimulate a specific immune response via presentation of such epitope with an MHC I complex, an membrane attack complex protein (MAC) of the complement system, perforin, a granzyme and a granulysin.
  • MAC membrane attack complex protein
  • the mRNA encodes an apoptotic triggering protein or peptide such as an apoptotic protease activating factor-1 (Apaf-1), cytochrome-c, caspase initiator proteins (CASP2, CASP8, CASP9, CASP10), apoptosis inducing factor (AIF), p53, p73, p63, Bcl-2, Bax, granzyme B, poly-ADP ribose polymerase (PARP), and P 21 -activated kinase 2 (PAK2).
  • an apoptotic triggering protein or peptide such as an apoptotic protease activating factor-1 (Apaf-1), cytochrome-c, caspase initiator proteins (CASP2, CASP8, CASP9, CASP10), apoptosis inducing factor (AIF), p53, p73, p63, Bcl-2, Bax, granzyme B, poly-ADP
  • the nucleic acid polymer is a nucleic acid decoy.
  • the nucleic acid decoy is a mimic of protein-binding nucleic acids such as RNA-based protein-binding mimics.
  • Exemplary nucleic acid decoys include transactivating region (TAR) decoy and Rev response element (RRE) decoy.
  • the payload is an aptamer.
  • Aptamers are small oligonucleotide or peptide molecules that bind to specific target molecules.
  • Exemplary nucleic acid aptamers include DNA aptamers, RNA aptamers, or XNA aptamers which are RNA and/or DNA aptamers comprising one or more unnatural nucleotides.
  • Exemplary nucleic acid aptamers include ARC19499 (Archemix Corp.), REG1 (Regado Biosciences), and ARC1905 (Ophthotech).
  • SR N3 ⁇ 4, NHR, NR or CN, wherein R is C -G, alkyl, alkenyl, or alkynyl, and halo is F, Cl, Br, or I.
  • modified linkages include phosphorothioate and 5’-N-phosphoramidite linkages.
  • nucleic acids having a variety of different nucleotide analogs, modified backbones, or non-naturally occurring intemucleoside linkages are utilized in accordance with the embodiments described herein.
  • nucleic acids include natural nucleosides (i.e., adenosine, thymidine, guanosine, cytidine, uridine, deoxyadenosine, deoxythymidine, deoxyguanosine, and deoxycytidine) or modified nucleosides.
  • modified nucleotides include base modified nucleoside (e.g., aracytidine, inosine, isoguanosine, nebularine, pseudouridine, 2,6-diaminopurine, 2-aminopurine, 2-thiothymidine, 3-deaza-5-azacytidine, 2'- deoxyuridine, 3-nitorpyrrole, 4-methylindole, 4-thiouridine, 4-thiothymidine, 2-aminoadenosine, 2- thiothymidine, 2-thiouridine, 5-bromocytidine, 5-iodouridine, inosine, 6-azauridine, 6-chloropurine, 7- deazaadenosine, 7-deazaguanosine, 8-azaadenosine, 8-azidoadenosine, benzimidazole, Ml- methyladenosine, pyrrolo-pyrimidine, 2-amino-6-chloro
  • nucleic acids Natural and modified nucleotide monomers for the chemical synthesis of nucleic acids are readily available.
  • nucleic acids comprising such modifications display improved properties relative to nucleic acids consisting only of naturally occurring nucleotides.
  • nucleic acid modifications described herein are utilized to reduce and/or prevent digestion by nucleases (e.g. exonucleases,
  • nucleic acid may be stabilized by including nucleotide analogs at the 3' end of one or both strands order to reduce digestion.
  • nucleotide modifications and/or backbone structures may exist at various positions in the nucleic acid.
  • modification include morpholinos, peptide nucleic acids (PNAs), methylphosphonate nucleotides, thiolphosphonate nucleotides, 2’-fluoro N3-P5’-phosphoramidites, G, 5’- anhydrohexitol nucleic acids (HNAs), or a combination thereof.
  • PNAs peptide nucleic acids
  • HNAs anhydrohexitol nucleic acids
  • the payload is conjugated to an anti-CD38 antibody, an anti-ICAMl antibody, or a multi-specific antibody (e.g., a bispecific anti-CD38/ICAMl antibody) described herein by a native ligation.
  • the conjugation is as described in: Dawson, et al.“Synthesis of proteins by native chemical ligation,” Science 1994, 266, 776-779; Dawson, et al.“Modulation of Reactivity in Native Chemical Ligation through the Use of Thiol Additives,” J. Am. Chem. Soc. 1997, 119, 4325-4329; hackeng, et al.“Protein synthesis by native chemical ligation: Expanded scope by using straightforward
  • the payload is conjugated to an anti-CD38 antibody, an anti-ICAMl antibody, or a multi-specific antibody (e.g., a bispecific anti-CD38/ICAMl antibody) described herein by a site-directed method utilizing a“traceless” coupling technology (Philochem).
  • the“traceless” coupling technology utilizes an N-terminal 1,2-aminothiol group on the binding moiety which is then conjugate with a polynucleic acid molecule containing an aldehyde group.
  • the payload is conjugated to an anti-CD38 antibody, an anti-ICAMl antibody, or a multi-specific antibody (e.g., a bispecific anti-CD38/ICAMl antibody) described herein by a site-directed method utilizing an unnatural amino acid incorporated into the binding moiety.
  • the unnatural amino acid comprises /i-acctylphcnylalaninc (pAcPhe).
  • the keto group of pAcPhe is selectively coupled to an alkoxy-amine derivatived conjugating moiety to form an oxime bond.
  • the payload is conjugated to an anti-CD38 antibody, an anti-ICAMl antibody, or a multi-specific antibody (e.g., a bispecific anti-CD38/ICAMl antibody) described herein by a site-directed method utilizing an enzyme -catalyzed process.
  • the site-directed method utilizes
  • the SMARTagTM technology comprises generation of a formylglycine (FGly) residue from cysteine by formylglycine-generating enzyme (FGE) through an oxidation process under the presence of an aldehyde tag and the subsequent conjugation of FGly to an alkylhydraine -functionalized polynucleic acid molecule via hydrazino-Pictet-Spengler (HIPS) ligation.
  • FGE formylglycine residue from cysteine by formylglycine-generating enzyme
  • HIPS hydrazino-Pictet-Spengler
  • the enzyme -catalyzed process comprises microbial transglutaminase (mTG).
  • the payload is conjugated to the anti-CD38 antibody, the anti-ICAMl antibody, or the multi- specific antibody (e.g., the bispecific anti-CD38/ICAMl antibody) utilizing a microbial transglutaminze catalyzed process.
  • mTG catalyzes the formation of a covalent bond between the amide side chain of a glutamine within the recognition sequence and a primary amine of a functionalized polynucleic acid molecule.
  • mTG is produced from Streptomyces moharensis . ( see Strop et al,“Location matters: site of conjugation modulates stability and pharmacokinetics of antibody drug conjugates,” Chemistry and Biology 20(2) 161-167 (2013)).
  • the payload is conjugated to an anti-CD38 antibody, an anti-ICAMl antibody, or a multi-specific antibody (e.g., a bispecific anti-CD38/ICAMl antibody) described herein by a method as described in PCT Publication No. W02014/140317, which utilizes a sequence -specific transpeptidase.
  • an anti-CD38 antibody an anti-ICAMl antibody
  • a multi-specific antibody e.g., a bispecific anti-CD38/ICAMl antibody
  • the payload is conjugated to an anti-CD38 antibody, an anti-ICAMl antibody, or a multi-specific antibody (e.g., a bispecific anti-CD38/ICAMl antibody) described herein by a method as described in U.S. Patent Publication Nos. 2015/0105539 and 2015/0105540.
  • the payload is conjugated to an anti-CD38 antibody, an anti-ICAMl antibody, or a multi-specific antibody (e.g., a bispecific anti-CD38/ICAMl antibody) described herein indirectly via a linker.
  • the linker comprises a natural or synthetic polymer, consisting of long chains of branched or unbranched monomers, and/or cross-linked network of monomers in two or three dimensions.
  • the linker includes a polysaccharide, lignin, rubber, or polyalkylene oxide (e.g., polyethylene glycol).
  • the linker includes, but is not limited to, alpha-, omega- dihydroxylpolyethyleneglycol, biodegradable lactone -based polymer, e.g. polyacrylic acid, polylactide acid (PLA), poly(glycolic acid) (PGA), polypropylene, polystyrene, polyolefin, polyamide, polycyanoacrylate, polyimide, polyethylenterephthalate (PET, PETG), polyethylene terephthalate (PETE), polytetramethylene glycol (PTG), or polyurethane as well as mixtures thereof.
  • a mixture refers to the use of different polymers within the same compound as well as in reference to block copolymers.
  • block copolymers are polymers wherein at least one section of a polymer is built up from monomers of another polymer.
  • the linker comprises polyalkylene oxide.
  • the linker comprises PEG.
  • the linker comprises polyethylene imide (PEI) or hydroxy ethyl starch (HES).
  • the polyalkylene oxide (e.g., PEG) is a polydispers or monodispers compound.
  • polydispers material comprises disperse distribution of different molecular weight of the material, characterized by mean weight (weight average) size and dispersity.
  • the monodisperse PEG comprises one size of molecules.
  • the linker is poly- or monodispersed polyalkylene oxide (e.g., PEG) and the indicated molecular weight represents an average of the molecular weight of the polyalkylene oxide, e.g., PEG, molecules.
  • a dPEG comprises about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 35, 40, 42, 48, 50 or more repeating ethylene oxide units. In some instances, a dPEG comprises about 2 or more repeating ethylene oxide units. In some cases, a dPEG is synthesized as a single molecular weight compound from pure (e.g., about 95%, 98%, 99%, or 99.5%) staring material in a step wise fashion. In some cases, a dPEG has a specific molecular weight, rather than an average molecular weight. In some cases, a dPEG described herein is a dPEG from Quanta Biodesign, LMD.
  • the linker is a discrete PEG, optionally comprising from 2 to 60, from 2 to 50, or from 2 to 48 repeating ethylene oxide units.
  • the linker comprises a dPEG comprising about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 24, 26, 28, 30, 35, 40, 42, 48, 50 or more repeating ethylene oxide units.
  • the linker is a dPEG from Quanta Biodesign, LMD.
  • the linker is a polypeptide linker.
  • the polypeptide linker comprises at least 2, 3, 4, 5, 6, 7, 8, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, or more amino acid residues.
  • the polypeptide linker comprises at least 2, 3, 4, 5, 6, 7, 8, or more amino acid residues.
  • the polypeptide linker comprises at most 2, 3, 4, 5, 6, 7, 8, or less amino acid residues.
  • the polypeptide linker is a cleavable polypeptide linker (e.g., either
  • the polypeptide linker is a non-cleavable polypeptide linker.
  • the polypeptide linker comprises Val-Cit (valine-citrulline), Gly-Gly-Phe-Gly (SEQ ID NO: 429), Phe-Lys, Val-Lys, Gly-Phe-Lys, Phe-Phe-Lys, Ala-Lys, Val-Arg, Phe-Cit, Phe-Arg, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Ala, Ala-Leu-Ala-Leu (SEQ ID NO: 428), or Gly-Phe-Leu-Gly (SEQ ID NO: 427).
  • the polypeptide linker comprises a peptide such as: Val-Cit (valine-citrulline), Gly-Gly-Phe-Gly (SEQ ID NO: 429), Phe-Lys, Val-Lys, Gly-Phe-Lys, Phe-Phe-Lys, Ala-Lys, Val-Arg, Phe-Cit, Phe-Arg, Leu-Cit, Ile-Cit, Trp-Cit, Phe-Ala, Ala-Leu-Ala-Leu (SEQ ID NO: 428), or Gly-Phe-Leu-Gly (SEQ ID NO: 427).
  • the polypeptide linker comprises L-amino acids, D-amino acids, or a mixture of both L- and D-amino acids.
  • the linker comprises a homobifuctional linker.
  • exemplary homobifuctional linkers include, but are not limited to, Lomant's reagent dithiobis (succinimidylpropionate) DSP, 3'3'- dithiobis(sulfosuccinimidyl proprionate (DTSSP), disuccinimidyl suberate (DSS),
  • the linker comprises a heterobifunctional linker.
  • heterobifunctional linker include, but are not limited to, amine-reactive and sulfhydryl cross-linkers such as N-succinimidyl 3-(2-pyridyldithio)propionate (sPDP), long-chain N-succinimidyl 3-(2- pyridyldithio)propionate (LC-sPDP), water-soluble-long-chain N-succinimidyl 3-(2-pyridyldithio) propionate (sulfo-LC-sPDP), succinimidyloxycarbonyl-a-methyl-a-(2-pyridyldithio)toluene (sMPT), sulfosuccinimidyl-6-[a-methyl-a-(2-pyridyldithio)toluamido]hexanoate (sulfo-LC-sMPT), succinimidyl-4- (N-maleimidomethyl)
  • sulfosuccinimidyl-2-(p-azidosalicylamido)ethyl- 1 ,3 '-dithiopropionate sAsD
  • N-hydroxysuccinimidyl-4- azidobenzoate HsAB
  • N-hydroxysulfosuccinimidyl-4-azidobenzoate sulfo-HsAB
  • sulfosuccinimidyl-6-(4'-azido-2'- nitrophenylamino)hexanoate sulfo-sANPAH
  • N-5-azido-2-nitrobenzoyloxysuccinimide ANB-NOs
  • the linker comprises one or more of a maleimide group, a peptide moiety, and/or a benzoic acid group, in any combination. In some embodiments, the linker comprises a combination of a maleimide group, a peptide moiety, and/or a benzoic acid group. In some instances, the maleimide group is maleimidocaproyl (me). In some instances, the peptide group is val-cit. In some instances, the benzoic acid group is PABA. In some instances, the linker comprises a me -val-cit group. In some cases, the linker comprises a val-cit-PABA group. In additional cases, the linker comprises a mc-val-cit-PABA group.
  • the linker is a self-immolative linker or a self-elimination linker. In some cases, the linker is a self-immolative linker. In other cases, the linker is a self-elimination linker (e.g., a cyclization self-elimination linker). In some instances, the linker comprises a linker described in U.S. Patent No. 9,089,614 or PCT Publication No. WO2015038426.
  • the linker is a traceless linker or a linker in which after cleavage does not leave behind a linker moiety (e.g., an atom or a linker group) to the antibody or payload.
  • a linker moiety e.g., an atom or a linker group
  • Exemplary traceless linkers include, but are not limited to, germanium linkers, silicium linkers, sulfur linkers, selenium linkers, nitrogen linkers, phosphorus linkers, boron linkers, chromium linkers, or phenylhydrazide linker.
  • the linker is a traceless aryl-triazene linker as described in Hejesen, et al.,“A traceless aryl- triazene linker for DNA-directed chemistry,” Org Biomol Chem 11(15): 2493-2497 (2013).
  • the linker is a traceless linker described in Blaney, et al.,“Traceless solid-phase organic synthesis,” Chem. Rev. 102: 2607-2024 (2002).
  • a linker is a traceless linker as described in U.S. Patent No. 6,821,783.
  • the anti-CD38 antibody, the anti-ICAMl antibody, or the multi -specific antibody (e.g., the bispecific CD38/ICAM1 antibody) described above is used for the treatment of bladder cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, eye cancer, head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, thyroid cancer, or uterine cancer.
  • the solid tumor is a metastatic, relapsed, or refractory solid tumor.
  • an anti-CD38 antibody, an anti-ICAMl antibody, or a multi-specific antibody e.g., a bispecific CD38/ICAM1 antibody
  • a multi-specific antibody e.g., a bispecific CD38/ICAM1 antibody
  • CD38/ICAM1 antibody described above is used for the treatment 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 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, intra
  • the anti-CD38 antibody, the anti-ICAMl antibody, or the multi-specific antibody is further administered with an additional therapeutic agent.
  • the additional therapeutic agent is a chemotherapeutic agent, an anti-CD38 antibody, an anti-ICAMl antibody, or an anti-CD38 antibody, or an anti-CD38 antibody.
  • the additional therapeutic agent is a first -line therapeutic agent.
  • the additional therapeutic agent comprises a chemotherapeutic agent.
  • chemotherapeutic agents include, but are not limited to, alkylating agents such as cyclophosphamide, mechlorethamine, chlorambucil, melphalan, dacarbazine, or nitrosoureas; anthracyclines such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, or valrubicin; cytoskeletal disruptors such as paclitaxel, docetaxel, abraxane, ortaxotere; epothilones; histone deacetylase inhibitors such as vorinostat or romidepsin; topoisomerase I inhibitors such as irinotecan or topotecan; topoisomerase II inhibitors such as etoposide, teniposide, or tafluposide; kinase inhibitors such as bortezomib, erlotinib, gefitin
  • the additional therapeutic agent comprises an immunotherapeutic agent.
  • the immunotherapy is an adoptive cell therapy.
  • Exemplary adoptive cell therapies include AFP TCR, MAGE-A10 TCR, or NY-ESO-TCR from Adaptimmune; ACTR087/rituximab from Unum
  • anti-BCMA CAR-T cell therapy anti-CD19“armored” CAR-T cell therapy
  • JCAR017 from Juno Therapeutics anti-BCMA CAR-T cell therapy, anti-CD19“armored” CAR-T cell therapy, JCAR014, JCAR018, JCAR020, JCAR023, JCAR024, or JTCR016 from Juno Therapeutics; JCAR017 from
  • Celgene/Juno Therapeutics anti-CD 19 CAR-T cell therapy from Intrexon; anti-CD19 CAR-T cell therapy, axicabtagene ciloleucel, KITE-718, KITE-439, or NY-ESO-1 T-cell receptor therapy from Kite Pharma; anti-CEA CAR-T therapy from Sorrento Therapeutics; anti-PSMA CAR-T cell therapy from TNK
  • Therapeutics/Sorrento Therapeutics ATA520 from Atara Biotherapeutics; AU101 and AU105 from Aurora BioPharma; baltaleucel-T (CMD-003) from Cell Medica; bb2121 from bluebird bio; BPX-501, BPX-601, or BPX-701 from Bellicum Pharmaceuticals; BSK01 from Kiromic; IMCgplOO from Immunocore; JTX-2011 from Jounce Therapeutics; LN-144 or LN-145 from Lion Biotechnologies; MB-101 or MB-102 from Mustang Bio; NKR-2 from Celyad; PNK-007 from Celgene; tisagenlecleucel-T from Novartis
  • the immunotherapy is a dendritic cell-based therapy.
  • the immunotherapy comprises a cytokine -based therapy, comprising e.g., an interleukin (IL) such as IL-2, IL-15, or IL-21, interferon (IFN)-a, or granulocyte macrophage colony- stimulating factor (GM-CSF).
  • IL interleukin
  • IFN interferon
  • GM-CSF granulocyte macrophage colony- stimulating factor
  • the immunotherapy comprises an immune checkpoint modulator.
  • immune checkpoint modulators include PD-1 modulators such as nivolumab (Opdivo) from Bristol-Myers Squibb, pembrolizumab (Keytruda) from Merck, AGEN 2034 from Agenus, BGB-A317 from BeiGene, Bl- 754091 from Boehringer-Ingelheim Pharmaceuticals, CBT-501 (genolimzumab) from CBT
  • LAG3 modulators such as BMS-986016 from Bristol-Myers Squibb, IMP701 from Novartis Pharmaceuticals, LAG525 from Novartis Pharmaceuticals, or REGN3767 from Regeneron Pharmaceuticals
  • 0X40 modulators such as BMS-986178 from Bristol-Myers Squibb
  • GSK3174998 from GlaxoSmithKline, INCAGN1949 from Agenus/Incyte, MEDI0562 from Medlmmune, PF-04518600 from Pfizer, or RG7888 from Genentechp; GITR modulators such as GWN323 from Novartis Pharmaceuticals, INCAGN1876 from Agenus/Incyte, MEDI1873 from Medlmmune, MK-4166 from Merck, or TRX518 from Leap Therapeutics; KIR modulators such as lirilumab from Bristol-Myers Squibb; or TIM modulators such as MBG453 from Novartis Pharmaceuticals or TSR-022 from Tesaro.
  • the additional therapeutic agent comprises a hormone-based therapeutic agent.
  • hormone-based therapeutic agents include, but are not limited to, aromatase inhibitors such as letrozole, anastrozole, exemestane, or aminoglutethimide; gonadotropin-releasing hormone (GnRH) analogues such as leuprorelin or goserelin; selective estrogen receptor modulators (SERMs) such as tamoxifen, raloxifene, toremifene, or fulvestrant; antiandrogens such as flutamide or bicalutamide;
  • progestogens such as megestrol acetate or medroxyprogesterone acetate
  • androgens such as
  • estrogens such as estrogen diethylstilbestrol (DES), Estrace, or polyestradiol phosphate
  • somatostatin analogs such as octreotide
  • the additional therapeutic agent and the antibody are administered simultaneously.
  • the antibody e.g., the anti-CD38 antibody, anti-ICAMl antibody, or the multi -specific antibody such as the bispecific CD38/ICAM1 antibody
  • the antibody e.g., the anti-CD38 antibody, anti-ICAMl antibody, or the multi -specific antibody such as the bispecific CD38/ICAM1 antibody
  • the additional therapeutic agent and the antibody are administered sequentially.
  • the additional therapeutic agent is administered to a subject prior to administering the antibody (e.g., the anti-CD38 antibody, anti-ICAMl antibody, or the multi -specific antibody such as the bispecific CD38/ICAM1 antibody).
  • the additional therapeutic agent is administered to a subject after the antibody (e.g., the anti-CD38 antibody, anti-ICAMl antibody, or the multi-specific antibody such as the bispecific CD38/ICAM1 antibody) is administered.
  • the antibody e.g., the anti-CD38 antibody, anti-ICAMl antibody, or the multi -specific antibody such as the bispecific CD38/ICAM1 antibody
  • the antibody is administered after the subject has undergone more than three treatments of a chemotherapeutic agent, a proteasome inhibitor and/or an immunomodulatory agent.
  • the antibody e.g., the anti-CD38 antibody, anti-ICAMl antibody, or the multi -specific antibody such as the bispecific CD38/ICAM1 antibody
  • the subject is double refractory to the proteasome inhibitor and/or immunomodulatory agent.
  • the subject is a human.
  • the pharmaceutical formulations further include pH-adjusting agents or buffering agents which include acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids; bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; and buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids such as acetic, boric, citric, lactic, phosphoric and hydrochloric acids
  • bases such as sodium hydroxide, sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate and tris-hydroxymethylaminomethane
  • buffers such as citrate/dextrose, sodium bicarbonate and ammonium chloride.
  • acids, bases and buffers are included in an amount required to maintain pH of the composition in an acceptable range.
  • the pharmaceutical formulation includes one or more salts in an amount required to bring osmolality of the composition into an acceptable range.
  • salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate.
  • Solubilizers include compounds such as triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium lauryl sulfate, sodium doccusate, vitamin E TPGS, dimethylacetamide, N-methylpyrrolidone, N- hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol, bile salts, polyethylene glycol 200-600, glycofurol, transcutol, propylene glycol, dimethyl isosorbide, and the like.
  • Surfactants include compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ® (BASF), and the like.
  • compounds such as sodium lauryl sulfate, sodium docusate, Tween 60 or 80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl monostearate, copolymers of ethylene oxide and propylene oxide, e.g., Pluronic ® (BASF), and the like.
  • Pluronic ® Pluronic ®
  • Additional surfactants include polyoxyethylene fatty acid glycerides and vegetable oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10, octoxynol 40. Sometimes, surfactants is included to enhance physical stability or for other purposes.
  • one or more pharmaceutical compositions are administered simultaneously, sequentially, or at an interval period of time. In some embodiments, one or more pharmaceutical compositions are administered simultaneously. In some cases, one or more pharmaceutical compositions are administered sequentially. In additional cases, one or more pharmaceutical compositions are administered at an interval period of time (e.g., the first administration of a first pharmaceutical composition is on day one followed by an interval of at least 1, 2, 3, 4, 5, or more days prior to the administration of at least a second pharmaceutical composition).
  • two or more different pharmaceutical compositions are coadministered. In some instances, the two or more different pharmaceutical compositions are coadministered simultaneously. In some cases, the two or more different pharmaceutical compositions are coadministered sequentially without a gap of time between administrations. In other cases, the two or more different pharmaceutical compositions are coadministered sequentially with a gap of about 0.5 hour, 1 hour, 2 hour, 3 hour, 12 hours,
  • the dose reduction during a drug holiday is from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.
  • a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, are optionally reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
  • the amount of a given agent that correspond to such an amount varies depending upon factors such as the particular compound, the severity of the disease, the identity (e.g., weight) of the subject or host in need of treatment, but nevertheless is routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, and the subject or host being treated.
  • the desired dose is conveniently presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.
  • toxicity and therapeutic efficacy of such therapeutic regimens are determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between the toxic and therapeutic effects is the therapeutic index and it is expressed as the ratio between LD50 and ED50.
  • Compounds exhibiting high therapeutic indices are preferred.
  • the data obtained from cell culture assays and animal studies are used in formulating a range of dosage for use in human.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage varies within this range depending upon the dosage form employed and the route of administration utilized. Kits/Articles of Manufacture
  • kits include a carrier, package, or container that is compartmentalized to receive one or more containers such as vials, tubes, and the like, each of the container(s) comprising one of the separate elements to be used in a method described herein.
  • suitable containers include, for example, bottles, vials, syringes, and test tubes hi one embodiment, the containers are formed from a variety of materials such as glass or plastic.
  • pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, bags, containers, bottles, and any packaging material suitable for a selected formulation and intended mode of administration and treatment.
  • the container(s) include anti-CD38 antibodies, anti-ICAMl antibodies, or multi- specific antibodies (e.g., bispecific CD38/ICAM1 antibodies) described herein and reagents for use with the antibodies as disclosed herein.
  • kits optionally include an identifying description or label or instructions relating to its use in the methods described herein.
  • a label is on or associated with the container.
  • a label is on a container when letters, numbers or other characters forming the label are attached, molded or etched into the container itself; a label is associated with a container when it is present within a receptacle or carrier that also holds the container, e.g., as a package insert.
  • a label is used to indicate that the contents are to be used for a specific therapeutic application. The label also indicates directions for use of the contents, such as in the methods described herein.
  • ranges and amounts can be expressed as“about” a particular value or range. About also includes the exact amount. Hence“about 5 pF” means“about 5 pF” and also“5 pF.” Generally, the term“about” includes an amount that would be expected to be within experimental error. [0452]
  • the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

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EP19885142.0A EP3883967A4 (en) 2018-11-16 2019-11-15 CD38 AND ICAM1 ANTIBODIES AND USES THEREOF
CN202510567553.3A CN120399084A (zh) 2018-11-16 2019-11-15 Cd38和icam1抗体及其用途
CN201980089423.6A CN113302207B (zh) 2018-11-16 2019-11-15 Cd38和icam1抗体及其用途
US17/293,258 US12583932B2 (en) 2018-11-16 2019-11-15 CD38 and ICAM1 antibodies and uses thereof
JP2021526459A JP7785284B2 (ja) 2018-11-16 2019-11-15 Ｃｄ３８抗体とｉｃａｍ１抗体およびそれらの使用
JP2025203085A JP2026053336A (ja) 2018-11-16 2025-11-25 Ｃｄ３８抗体とｉｃａｍ１抗体およびそれらの使用

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