B7-h3 antibody-drug conjugates

Abstract

The present disclosure is directed to a B7-H3-ADC that comprises the human B7-H3 binding domain of a humanized anti-human B7-H3 antibody conjugated to at least one camptothecin drug moiety. The disclosure is also directed to pharmaceutical compositions that contain such B7-H3-ADCs, and to methods involving the use of any of such B7-H3-ADCs in the treatment of cancer and other diseases and conditions.

Description

B7-H3 Antibody-Drug ConjugatesFIELD

[0001] The present disclosure is directed to a B7-H3 antibody drug conjugate (“B7-H3- ADC”) that comprises the human B7-H3 binding domain of a humanized anti-human B7-H3 antibody conjugated to at least one drug moiety. The disclosure is also directed to pharmaceutical compositions that contain such B7-H3-ADCs, and to methods involving the use of any of such B7-H3-ADCS in the treatment of cancer and other diseases and conditions associated with or characterized by the expression of B7-H3.BACKGROUNDI. B7 Superfamily and B7-H3

[0002] B7-H3 is a member of the B7-CD28 Superfamily and is expressed on antigen- presenting cells. B7-H3 is unique in that the major human form contains two extracellular tandem IgV-IgC domains (z.e., IgV-IgC-IgV-IgC) (Collins, M. et al. (2005) "The B7 Family Of Immune-Regulatory Ligands ," Genome Biol. 6:223.1-223.7). Although initially thought to comprise only 2 Ig domains (IgV-IgC, see, e.g., NCBI Sequence NP_079516) a four immunoglobulin extracellular domain variant ("4Ig-B7-H3") has been identified and found to be the more common human form of the protein (Sharpe, A.H. et al. (2002) "The B7-CD28 Superfamily " Nature Rev. Immunol. 2: 116-126; also see, e.g., NCBI Sequence NP_001019907). B7-H3 mRNA expression has been found in heart, kidney, testes, lung, liver, pancreas, prostate, colon, and osteoblast cells (Collins, M. et al. (2005) "The B7 Family Of Immune-Regulatory Ligands " Genome Biol. 6:223.1-223.7). At the protein level, B7-H3 is found in human liver, lung, bladder, testis, prostate, breast, placenta, and lymphoid organs (Hofmeyer, K. et al. (2008) "The Contrasting Role OfB7-H3," Proc. Natl. Acad. Sci. (U.S.A.) 105(30): 10277-10278).

[0003] Although B7-H3 is not expressed on resting B or T cells, monocytes, or dendritic cells, it is induced on dendritic cells by IFN-y and on monocytes by GM-CSF (Sharpe, A.H. et al. (2002) "The B7-CD28 Superfamily," Nature Rev. Immunol. 2: 116-126). The mode of actionof B7-H3 is complex, and the protein is reported to mediate both T Cell co-stimulation and coinhibition (Hofmeyer, K. etal. (2008) "The Contrasting Role OfB7-H3," Proc. Natl. Acad. Sci. (U.S.A.) 105(30): 10277-10278; Martin-Orozco, N. etal. (2007) "Inhibitory Costimulation And Anti-Tumor Immunity " Semin. Cancer Biol. 17(4):288-298. B7-H3 binds to an unidentified receptor(s) to mediate co-inhibition of T cells. In addition, B7-H3, through interactions with unknown receptor(s) is an inhibitor for NK-cells and osteoblastic cells (Hofmeyer, K. el al. (2008) "The Contrasting Role Of B7-H3," Proc. Natl. Acad. Sci. (U.S.A.) 105(30): 10277- 10278).IL B7-H3 Expressing Tumors

[0004] B7-H3 is expressed on a variety of cancer cells (e.g., neuroblastoma, gastric, ovarian, non-small cell lung cancers, etc., see, e.g., Modak, S., et al. (2001) "Monoclonal antibody 8H9 targets a novel cell surface antigen expressed by a wide spectrum of human solid tumors," Cancer Res 61:4048-54) and cultured cancer stem-like cells. Several independent studies have shown that human malignant tumor cells exhibit a marked increase in expression of B7-H3 protein and that this increased expression was associated with increased disease severity (Tekle, C., etal. (2012) "B7-H3 Contributes To The Metastatic Capacity Of Melanoma Cells By Modulation Of Known Metastasis-Associated Genes," Int. J. Cancer 130:2282-90; Wang, L., et al. (2013) "B7-H 3 Mediated Tumor Immunology: Friend Or Foe?," Int. J. Cancer 134(12):2764-2771), suggesting that B7-H3 is exploited by tumors as an immune evasion pathway (Hofmeyer, K. et al. (2008) "The Contrasting Role OfB7-H3," Proc. Natl. Acad. Sci. (U.S.A.) 105(30):10277-10278).

[0005] The role of B7-H3 in inhibiting the immune system and the increased expression of B7-H3 on human tumors has suggested that this molecule might serve as a therapeutic target for the treatment of cancer. The use of anti-B7-H3 antibodies and other molecules that modulate B7-H3 expression to treat tumors and / or up-modulate an immune response has been proposed (see, Loo, D. etal. (2012) "Development of an Fc-Enhanced Anti B7-H3 Monoclonal Antibody with Potent Antitumor Activity," Clin Cancer Res; 18: 3834-3845; Ahmed, M. et al. (2015) "Humanized Affinity-Matured Monoclonal Antibody 8H9 Has Potent Anti -Tumor Activity and Binds to FG Loop ofB7-H3," J. Biol. Chem. 290: 30018-30029; Nagase-Zembutsu, A. et al. (2016) "Development of DS-5573a: A novel afucosylated monoclonal antibody directed at B7-H 3 with potent antitumor activity ," Cancer Sci. 2016, doi: 10.111 l / cas.12915;; see also, United States Patents No. 7,279,567, 7,527,969,7,718,774, 8,779,098, 8,802,091, US Patent Publication Nos. 2002 / 0168762; 2008 / 0081346, 2008 / 0116219, 2013 / 0078234, 2015 / 0274838, PCT Publications Nos. WO 2009 / 073533; WO 2008 / 066691; WO 2006 / 016276; WO 2008 / 116219; WO 2001 / 094413, WO 2002 / 32375, WO 2004 / 093894, WO 2006 / 016276, WO 2008 / 116219, and WO 2011 / 109400.SUMMARY

[0006] The present disclosure is directed to a B7-H3 antibody drug conjugate (“B7-H3- ADC”) that comprises the human B7-H3 binding domain of a humanized anti-human B7-H3 antibody conjugated to at least one drug moiety. The disclosure is directed to pharmaceutical compositions that contain such B7-H3-ADCs, and to methods involving the use of any of such B7-H3-ADCS in the treatment of cancer and other diseases and conditions.

[0007] In aspects, the disclosure provides an anti-B7-H3 antibody drug conjugate (B7- H3-ADC) that comprises the formula:Ab-(LM)m-(D)n, wherein:Ab is a humanized B7-H3 antibody or B7-H3 binding fragment thereof that binds to B7-H3 and comprises:(i) the CDRLI sequence RASESIYSYLA (SEQ ID NO: 16), the CDRL2 sequence NTKTLPE (SEQ ID NO: 17) and the CDRL3 sequence QHHYGTPPWT (SEQ ID NO: 18) in its Variable Light Chain (VL) domain, and(ii) the CDRHI sequence SYGMS (SEQ ID NO: 19), the CDRH2 sequence TINSGGSNTYY PDSLKG (SEQ ID NO:20) and the CDRH3 sequence HDGGAMDY (SEQ ID NO:21) or HEGGAMDY (SEQ ID NO:26) in its Variable Heavy Chain (VH) domain;D is a cytotoxic drug moiety;LM is a Linker Molecule that covalently links Ab and D; m is an integer between 1 and n and denotes the number of Linker Molecules of the B7-H3-ADC; andn is an integer between 1 and 10 and denotes the number of cytotoxic camptothecin moi eties covalently linked to the B7-H3-ADC molecule.

[0008] In aspects, the disclosure provides an anti-B7-H3 antibody drug conjugate (B7- H3-ADC) that comprises the formula:Ab-(LM)m-(D)n, wherein:Ab is a humanized B7-H3 antibody or B7-H3 binding fragment thereof that binds to B7-H3 and comprises:(iii) the CDRL1 sequence RASESIYSYLA (SEQ ID NO: 16), the CDRL2 sequence NTKTLPE (SEQ ID NO: 17) and the CDRL3 sequence QHHYGTPPWT (SEQ ID NO: 18) in its Variable Light Chain (VL) domain, and(iv) the CDRul sequence SYGMS (SEQ ID NO: 19), the CDRH2 sequence TINSGGSNTYY PDSLKG (SEQ ID NQ:20) and the CDRH3 sequence HDGGAMDY (SEQ ID NO:21) or HEGGAMDY (SEQ ID NO:26) in its Variable Heavy Chain (VH) domain;D is a camptothecin moiety;LM is a Linker Molecule that covalently links Ab and D; m is an integer between 1 and n and denotes the number of Linker Molecules of the B7-H3-ADC; and n is an integer between 1 and 10 and denotes the number of cytotoxic camptothecin moi eties covalently linked to the B7-H3-ADC molecule.

[0009] In aspects, the disclosure further provides such B7-H3-ADC, wherein the Ab comprises: a) a humanized VL Domain comprising the amino acid sequence of SEQ ID NO: 12, and b) a humanized VH Domain comprising the amino acid sequence of SEQID NO: 14 or SEQ ID NO:22

[0010] In aspects, the disclosure further provides such B7-H3-ADC, wherein the Ab is an antibody. In aspects, the disclosure further provides such B7-H3-ADC, wherein the Ab is an antigen binding fragment of an antibody.

[0011] In aspects, the disclosure further provides such B7-H3-ADC, wherein the Ab comprises an Fc Domain of a human IgG. In aspects, the disclosure further provides such B7- H3-ADC, wherein the human IgG is a human IgGl, IgG2, IgG3, or IgG4.

[0012] In aspects, the disclosure further provides such B7-H3-ADC, wherein the Fc Domain is a variant Fc Domain that comprises:(a) one or more amino acid modifications that reduce the affinity of the variant Fc Domain for an FcyR; and / or(b) one or more amino acid modifications that enhance the serum half-life of the variant Fc Domain.

[0013] In aspects, the disclosure further provides such B7-H3-ADC, wherein the modifications that reduce the affinity of the variant Fc Domain for an FcyR comprise the substitution of L234A; L235A; or L234A and L235A, wherein the numbering is that of the EU index as in Kabat. In aspects, the disclosure further provides such B7-H3-ADC, wherein the modifications that that enhance the serum half-life of the variant Fc Domain comprise the substitution of M252Y; M252Y and S254T; M252Y and T256E; M252Y, S254T and T256E; or K288D and H435K, wherein the numbering is that of the EU index as in Kabat.

[0014] In aspects, the disclosure further provides such B7-H3-ADC, wherein the LM comprises a peptidic linker. In aspects, the disclosure further provides such B7-H3-ADC, wherein the LM comprises a cleavable linker.

[0015] In aspects, the disclosure further provides such B7-H3-ADC, wherein the LM comprises the formula (4a) or (4b), or a salt thereof:wherein: a is independently 0 or 1; b is independently 0 or 1; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is an integer in the range of 1 to 150; g is 0 or 1; i is 0 or 1;D is a cytotoxic drug moiety;Q1is an alkenyl group, (hetero)cycloalkenyl group, bicyclo triazole group or cycloalkenyl group; wherein Q1is attached to a functional group of the antibody; wherein Sp1, Sp2, Sp3and Sp4are independently selected from the group consisting of linear or branched C1-C200 alkylene groups, C2-C200 alkenylene groups, C2-C200 alkynylene groups, C3-C200 cycloalkylene groups, C5-C200 cycloalkenylene groups, C8-C200 cycloalkynylene groups, C7-C200 alkylarylene groups, C7-C200 arylalkylene groups, C8-C200 arylalkenylene groups and C9-C200 aryl alkynylene groups, the alkylene groups, alkenylene groups, alkynylene groups, cycloalkylene groups, cycloalkenylene groups, cycloalkynylene groups,alkylarylene groups, arylalkylene groups, arylalkenylene groups and aryl alky nylene groups being optionally substituted and optionally interrupted by one or more heteroatoms selected from the group of O, S and NR3, wherein R3is independently selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C2 - C24 alkenyl groups, C2 - C24 alkynyl groups and C3 - C24 cycloalkyl groups, the alkyl groups, alkenyl groups, alkynyl groups and cycloalkyl groups being optionally substituted;Z1is a connecting group that connects Q1or Sp3to Sp2, O or C(O) or N(R');Z2is a connecting group that connects D or Sp4to Sp1, N(R3), O or C(O); wherein Z1and Z2are independently selected from the group consisting of -O-, -S-, -NR2-, -N=N-, -C(O)-, -C(O)NR2-, -O-C(O)- , -O-C(O)-O-, -O-C(O)-NR2, -NR2-C(O)-, -NR2-C(O)-O-, -NR2-C(O)-NR2-, -S-C(O)-, -S-C(O)-O-, -S-C(O)- NR2-, -S(O)-, -S(O)2-, -O-S(O)2-, -O-S(O)2-O-, -O-S(O)2-NR2-, -O-S(O)-, -O- S(O)-O-, -O-S(O)-NR2-, -O-NR2-C(O)-, -O-NR2-C(O)-O-, -O-NR2-C(O)-NR2- , -NR2-O-C(O)-, -NR2-O-C(O)-O-, -NR2-O-C(O)-NR2-, -O-NR2-C(S)-, -O- NR2-C(S)-O-, -O-NR2-C(S)-NR2-, -NR2-O-C(S)-, -NR2-O-C(S)-O-, -NR2-O- C(S)-NR2-, -O-C(S)-, -O-C(S)-O-, -O-C(S)-NR2-, -NR2-C(S)-, -NR2-C(S)-O-, - NR2-C(S)-NR2-, -S-S(O)2-, -S-S(O)2-O-, -S-S(O)2-NR2-, -NR2-O-S(O)-, -NR2- O-S(O)-O-, -NR2-O-S(O)-NR2-, -NR2-O-S(O)2-, -NR2-O-S(O)2-O-, -NR2-O- S(O)2-NR2-, -O-NR2-S(O)-, -O-NR2-S(O)-O-, -O-NR2-S(O)-NR2-, -O-NR2- S(O)2-O-, -O-NR2-S(O)2-NR2-, -O-NR2-S(O)2-, -O-P(O)(R2)2-, -S-P(O)(R2)2-, - NR2-P(O)(R2)2- and combinations of two or more thereof, wherein R2is independently selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C2- C24 alkenyl groups, C2- C24 alkynyl groups and C3 - C24 cycloalkyl groups, the alkyl groups, alkenyl groups, alkynyl groups and cycloalkyl groups being optionally substituted; andR1is selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C3 - C24 cycloalkyl groups, C2- C24 (hetero)aryl groups, C3 - C24 alkyl(hetero)aryl groups and C3 - C24 (hetero)arylalkyl groups, the Ci - C24 alkyl groups, C3 - C24 cycloalkyl groups, C2- C24 (hetero)aryl groups, C3 - C24 alkyl(hetero)aryl groups and C3 - C24 (hetero)arylalkyl groups optionally substituted and optionallyinterrupted by one or more heteroatoms selected from O, S and NR.3wherein R3is independently selected from the group consisting of hydrogen and Ci - C4 alkyl groups; orR1is D, -[(Sp1)b(Z2)e-(Sp4)i-D] or -[(Sp2)c-(Z1)d-(Sp3)g-Q1], wherein Sp1, Sp2, Sp3, Sp4, Z1, Z2, D, Q1, b, c, d, e, g and i are as defined above.

[0016] In aspects, the disclosure further provides such B7-H3-ADC, wherein the LM comprises the formula (4a) or (4b), or a salt thereofwherein: a is independently 0 or 1; b is independently 0 or 1; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is an integer in the range of 1 to 150; g is 0 or 1; i is 0 or 1;D is a cytotoxic camptothecin moiety;Q1is an alkenyl group, (hetero)cycloalkenyl group, bi cyclo tri azole group or cycloalkenyl group; wherein Q1is attached to a functional group of the antibody; wherein Sp1, Sp2, Sp3and Sp4are independently selected from the group consisting of linear or branched C1-C200 alkylene groups, C2-C200 alkenylene groups, C2-C200 alkynylene groups, C3-C200 cycloalkylene groups, C5-C200 cycloalkenylene groups, C8-C200 cycloalkynylene groups, C7-C200 alkylarylene groups, C7-C200 arylalkylene groups, C8-C200 arylalkenylene groups and C9-C200 aryl alkynylene groups, the alkylene groups, alkenylene groups, alkynylene groups, cycloalkylene groups, cycloalkenylene groups, cycloalkynylene groups, alkylarylene groups, arylalkylene groups, arylalkenylene groups and aryl alkynylene groups being optionally substituted and optionally interrupted by one or more heteroatoms selected from the group of O, S and NR3, wherein R3is independently selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C2 - C24 alkenyl groups, C2 - C24alkynyl groups and C3 - C24 cycloalkyl groups, the alkyl groups, alkenyl groups, alkynyl groups and cycloalkyl groups being optionally substituted;Z1is a connecting group that connects Q1or Sp3to Sp2, O or C(O) or N(RX);Z2is a connecting group that connects D or Sp4to Sp1, N(RX), O or C(O); wherein Z1and Z2are independently selected from the group consisting of -O-, -S-, -NR2-, -N=N-, -C(O)-, -C(O)NR2-, -O-C(O)- , -O-C(O)-O-, -O-C(O)-NR2, -NR2-C(O)-, -NR2-C(O)-O-, -NR2-C(O)-NR2-, -S-C(O)-, -S-C(O)-O-, -S-C(O)- NR2-, -S(O)-, -S(O)2-, -O-S(O)2-, -O-S(O)2-O-, -O-S(O)2-NR2-, -O-S(O)-, -O- S(O)-O-, -O-S(O)-NR2-, -O-NR2-C(O)-, -O-NR2-C(O)-O-, -O-NR2-C(O)-NR2- , -NR2-O-C(O)-, -NR2-O-C(O)-O-, -NR2-O-C(O)-NR2-, -O-NR2-C(S)-, -O- NR2-C(S)-O-, -O-NR2-C(S)-NR2-, -NR2-O-C(S)-, -NR2-O-C(S)-O-, -NR2-O- C(S)-NR2-, -O-C(S)-, -O-C(S)-O-, -O-C(S)-NR2-, -NR2-C(S)-, -NR2-C(S)-O-, - NR2-C(S)-NR2-, -S-S(O)2-, -S-S(O)2-O-, -S-S(O)2-NR2-, -NR2-O-S(O)-, -NR2- O-S(O)-O-, -NR2-O-S(O)-NR2-, -NR2-O-S(O)2-, -NR2-O-S(O)2-O-, -NR2-O- S(O)2-NR2-, -O-NR2-S(O)-, -O-NR2-S(O)-O-, -O-NR2-S(O)-NR2-, -O-NR2- S(O)2-O-, -O-NR2-S(O)2-NR2-, -O-NR2-S(O)2-, -O-P(O)(R2)2-, -S-P(O)(R2)2-, -NR2-P(O)(R2)2- and combinations of two or more thereof, wherein R2is independently selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C2 - C24 alkenyl groups, C2 - C24 alkynyl groups and C3 - C24 cycloalkyl groups, the alkyl groups, alkenyl groups, alkynyl groups and cycloalkyl groups being optionally substituted; andR1is selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C3 - C24 cycloalkyl groups, C2 - C24 (hetero)aryl groups, C3 - C24 alkyl(hetero)aryl groups and C3 - C24 (hetero)arylalkyl groups, the Ci - C24 alkyl groups, C3 - C24 cycloalkyl groups, C2 - C24 (hetero)aryl groups, C3 - C24 alkyl(hetero)aryl groups and C3 - C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR3wherein R3is independently selected from the group consisting of hydrogen and Ci - C4 alkyl groups; orR1is D, -[(Sp^Z CSp D] or -[(Sp ^ Sp Q1], wherein Sp1, Sp2, Sp3, Sp4, Z1, Z2, D, Q1, b, c, d, e, g and i are as defined above.

[0017] In aspects, the disclosure further provides such B7-H3-ADC, wherein Sp1, Sp2, Sp3and Sp4, if present, are independently selected from the group consisting of linear or branched C1-C20 alkylene groups, the alkylene groups being optionally substituted and optionally interrupted by one or more heteroatoms selected from the group consisting of O, S and NR3, wherein R3is independently selected from the group consisting of hydrogen and Ci - C4 alkyl groups

[0018] In aspects, the disclosure further provides such B7-H3-ADC, where the LM comprises a Valine-Alanine (Val-Ala) amino acid linker. In aspects, the disclosure further provides such B7-H3-ADC, wherein the Val-Ala linker is a Val-Ala-PABC linker.

[0019] In aspects, the disclosure further provides such B7-H3-ADC, wherein the camptothecin moiety is selected from the group consisting of SN-38 (5-10- hydroxycamptothecin), topotecan (HYCAMPTIN; (S)-9-N,N-dimethylaminoethyl-10- hydroxycamptothecin), 9-aminocamptothecin (9-amino-20(S)-camptothecin), 9-nitrocamptothecin (also called rubitecan), lurtotecan (7-(4-methylpiperazinomethylene)-10,l 1 - ethylenedioxy-20(S)-camptothecin), exatecan, karenitecin, and a homocamptothecin.

[0020] In aspects, the disclosure further provides such B7-H3-ADC, wherein the camptothecin moiety is exatecan.

[0021] In aspects, the disclosure further provides such B7-H3-ADC, wherein LM and D together comprise:

[0022] In aspects, the disclosure further provides an anti-B7-H3 antibody drug conjugate (B7-H3-ADC) that comprises the formula:Ab-(LM)m-(D)n wherein:Ab is a humanized B7-H3 antibody or B7-H3 binding fragment thereof that binds to B7-H3 and comprises:(i) the CDRLI sequence RASESIYSYLA (SEQ ID NO:16), the CDRL2 sequence NTKTLPE (SEQ ID NO: 17) and the CDRL3 sequence QHHYGTPPWT (SEQ ID NO: 18) in its Variable Light Chain (VL) domain, and(ii) the CDRnl sequence SYGMS (SEQ ID NO: 19), the CDRn2 sequence TINSGGSNTYY PDSLKG (SEQ ID NO:20) and the CDRH3 sequence HDGGAMDY (SEQ ID NO:21) or HEGGAMDY (SEQ ID NO:26) in its Variable Heavy Chain (VH) domain;D and LM together comprise:m is an integer between 0 and n and denotes the number of Linker Molecules of the B7-H3-ADC;and n is an integer between 1 and 10 and denotes the number of cytotoxic camptothecin moieties covalently linked to the B7-H3-ADC molecule.

[0023] In aspects, the disclosure further provides such B7-H3-ADC molecule, wherein the Ab comprises a humanized VL Domain comprising the amino acid sequence of SEQ ID NO: 12, and a humanized VH Domain comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO:22.

[0024] In aspects, the disclosure further provides a pharmaceutical composition that comprises an effective amount of the B7-H3-ADC and a pharmaceutically acceptable carrier, excipient or diluent.

[0025] In aspects, the disclosure further provides a use of the B7-H3-ADC or the pharmaceutical composition in the treatment of a disease or condition associated with or characterized by the expression of B7-H3.

[0026] In aspects, the disclosure further provides a method of treating a disease or condition associated with or characterized by the expression of B7-H3 comprising administering the B7-H3-ADC or the pharmaceutical composition to a subject.

[0027] In aspects, the disclosure further provides such use or method, wherein the disease or condition associated with or characterized by the expression of B7-H3 is cancer.

[0028] In aspects, the disclosure further provides such use or method, wherein the cancer is selected from the group consisting of: an adrenal gland tumor, an AIDS-associated cancer, an alveolar soft part sarcoma, an astrocytic tumor, an adrenal cancer, a bladder cancer, a bone cancer, a brain and spinal cord cancer, a metastatic brain tumor, a B-cell cancer, a breast cancer, a carotid body tumors, a cervical cancer, a chondrosarcoma, a chordoma, a chromophobe renal cell carcinoma, a clear cell carcinoma, a colon cancer, a colorectal cancer, a cutaneous benign fibrous histiocytoma, a desmoplastic small round cell tumor, an ependymoma, a Ewing's tumor, an extraskeletal myxoid chondrosarcoma, a fibrogenesis imperfecta ossium, a fibrous dysplasia of the bone, a gallbladder or bile duct cancer, a gastric cancer, a gestational trophoblastic disease, a germ cell tumor, a head and neck cancer, a glioblastoma, a hematological malignancy,a hepatocellular carcinoma, an islet cell tumor, a Kaposi's Sarcoma, a kidney cancer, a leukemia (e.g., an acute myeloid leukemia), a liposarcoma / malignant lipomatous tumor, a liver cancer, a lymphoma, a lung cancer (e.g., a non-small-cell lung cancer (NSCLC) or a small cell lung cancer (SCLC)), a medulloblastoma, a melanoma, a meningioma, a mesothelioma pharyngeal cancer, a multiple endocrine neoplasia, a multiple myeloma, a myelodysplastic syndrome, a neuroblastoma, a neuroendocrine tumors, an ovarian cancer, a pancreatic cancer, a papillary thyroid carcinoma, a parathyroid tumor, a pediatric cancer, a peripheral nerve sheath tumor, a phaeochromocytoma, a pituitary tumor, a prostate cancer, a posterious uveal melanoma, a renal metastatic cancer, a rhabdoid tumor, a rhabdomysarcoma, a sarcoma, a skin cancer, a small round blue cell tumor of childhood (including neuroblastoma and rhabdomyosarcoma), a soft- tissue sarcoma, a squamous cell cancer (e.g., a squamous cell cancer of the head and neck (SCCHN), a stomach cancer, a synovial sarcoma, a testicular cancer, a thymic carcinoma, a thymoma, a thyroid cancer (e.g., a thyroid metastatic cancer), and a uterine cancer.

[0029] In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is selected from the group consisting of: adrenal cancer, bladder cancer, breast cancer, colorectal cancer, gastric cancer, glioblastoma, kidney cancer, non-smallcell lung cancer (NSCLC), acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, Burkett's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, mesothelioma pharyngeal cancer, non-Hodgkin's lymphoma, small lymphocytic lymphoma, multiple myeloma, melanoma, ovarian cancer, platinum-resistant ovarian cancer (PROC), pancreatic cancer, prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), skin cancer, renal cell carcinoma, small cell lung cancer (SCLC), extensive-stage small cell lung cancer (ES-SCLC), small round blue cell tumors of childhood (including neuroblastoma and rhabdomyosarcoma), squamous cell cancer (e.g., squamous cell cancer of the head and neck (SCCHN), testicular cancer, thyroid cancer (e.g., thyroid metastatic cancer), and uterine cancer.

[0030] In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is melanoma. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is lung cancer. In aspects, the disclosurefurther provides such use or method for treatment of a cancer, wherein the cancer is squamous cell cancer of the head and neck. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is pancreatic cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is prostate cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is small cell lung cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is small cell ovarian cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is small cell colorectal cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is esophageal squamous cell carcinoma. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is non-small cell lung cancer (NSCLC). In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is bladder cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is sarcoma. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is endometrial cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is metastatic castration-resistant prostate cancer (mCRPC). In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is breast cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is ovarian cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is cervical cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is colorectal cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is gastric or gastricesophageal junction cancer. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is clear cell renal cell carcinoma. In aspects, the disclosure further provides such use or method for treatment of a cancer, wherein the cancer is hepatocellular carcinoma.BRIEF DESCRIPTION OF THE DRAWINGS

[0031] FIG. 1 is a plot of percent cell viability vs. ADC concentration in an in vitro cytotoxicity study toward B7-H3-expressing A375.S2 human melanoma cells as described in Example 1.

[0032] FIGs. 2A-2E show plots of percent cytoxicity vs. monoclonal antibody concentration in ADCC assays of unconjugated MGA017, conjugated MGC018, and conjugated MGC026 in LnCAP cells (2A), Hs700T cells (2B), JIMT1 cells (2C), Calu-6 cells (2D), and A498 cells (2E) as described in Example 2.FIGs. 3 A-3B show plots of resonance units (RU) over time in surface plasmon resonance (SPR) assays of MGC026 and MGA017 with Histagged human or cynomolgus monkey B7H3(4Ig) extracellular domain proteins (3 A) and His-tagged human CD16A extracellular domain proteins (3B) as described in Example 3. FIGs. 3C-3D show plots of resonance units (RU) over time in surface plasmon resonance (SPR) assays of MGA017 (3C) and MGA017 (D96E) (3D) with recombinant B7-H3 as described in Example 3.

[0033] FIG. 4 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 and MGC018 against Calu-6 lung adenocarcinoma tumor cells as described in Example 4.

[0034] FIG. 5 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 and MGC018 against Calu-6 lung adenocarcinoma tumor cells at the minimum efficacious dose as described in Example 4.

[0035] FIG. 6 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 and MGC018 against A375.S2 melanoma tumor cells as described in Example 4.

[0036] FIGs. 7A-7C show plots of mean tumor volume over time showing the antitumor activity of MGC026 and MGC018 against A375.S2 melanoma tumor cells at 3 mg / kg dose (7 A), 1 mg / kg dose (7B), and 0.3 mg / kg dose (7C) as described in Example 4.

[0037] FTG. 8 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 against FaDu pharynx, head and neck squamous cell carcinoma (“HNSCC”) tumor cells as described in Example 4.

[0038] FIG. 9 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 against Hs700T pancreatic adenocarcinoma tumor cells as described in Example 4.

[0039] FIG. 10 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 against 22Rvl prostate carcinoma cell carcinoma tumor cells as described in Example 4.

[0040] FIGs. 11A-11C show plots of mean tumor volume over time showing the antitumor activity of MGC026 and DS-mAb-Dxd (anADC with a M30-H1-L4 antibody, that binds B7-H3, conjugated to deruxtecan (Dxd)) against Calu-6 tumor cells at 3 mg / kg dose (HA), 1 mg / kg dose (1 IB), and 0.3 mg / kg dose (11C) as described in Example 5.

[0041] FIGs. 12A-12C show plots of mean tumor volume over time showing the antitumor activity of MGC026 and DS-mAb-Dxd against A375.S2 melanoma tumor cells at 3 mg / kg dose (12A), 1 mg / kg dose (12B), and 0.3 mg / kg dose (12C) as described in Example 5.

[0042] FIG. 13 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 against small cell lung cancer (SCLC) patient-derived tumor fragments from model 1 as described in Example 9.

[0043] FIG. 14 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 against small cell lung cancer (SCLC) patient-derived tumor fragments from model 2 as described in Example 9.

[0044] FIG. 15 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 against small cell lung cancer (SCLC) patient-derived tumor fragments from model 3 as described in Example 9.10045] FIG. 16 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 against ovarian cancer patient-derived tumor fragments as described in Example 9.

[0046] FIG. 17 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 against melanoma patient-derived tumor fragments as described in Example 9.

[0047] FIG. 18 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 against colorectal cancer patient-derived tumor fragments as described in Example 9.

[0048] FIG. 19 shows a plot of mean tumor volume over time showing the antitumor activity of MGC026 against squamous cell carcinoma of head and neck (SCCHN) patient- derived tumor fragments as described in Example 9.DETAILED DESCRIPTION

[0049] The present disclosure is directed to a B7-H3-ADC that comprises the human B7- H3 binding domain of a humanized anti-human B7-H3 antibody conjugated to at least one drug moiety. The disclosure is also directed to pharmaceutical compositions that contain such B7- H3-ADCS, and to methods involving the use of any of such B7-H3-ADCS in the treatment of cancer and other diseases and conditions. Certain B7-H3-ADCs and their uses in the treatment of cancer are described, for example, in PCT Publication No. WO 2017 / 180813, which is hereby expressly incorporated by reference herein.I. Antibodies and Their Binding Domains

[0050] The antibodies of the present disclosure are immunoglobulin molecules capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the Variable Domain of the immunoglobulin molecule. A B7-H3-ADC of the present disclosure thus comprises an antibody that binds to B7-H3. As used herein, the terms "antibody" and "antibodies" refer to monoclonal antibodies, multispecific antibodies, human antibodies, humanized antibodies, synthetic antibodies, chimeric antibodies, polyclonal antibodies, camelized antibodies, single-chain Fvs (scFv), single-chain antibodies, Fab fragments, F(ab') fragments, disulfide-linked bispecific Fvs (sdFv), intrabodies, and epitope-binding fragments of any of the above. In particular, the term "antibody" includes immunoglobulin molecules and immunologically active fragments of immunoglobulin molecules, i.e., molecules that contain an epitope-binding site. Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGi, IgG2, IgGa, IgG4, IgAi and IgA2) or subclass. Antibodies are capable of "immunospecifically binding" to a polypeptide or protein or a non-protein molecule (or of binding to such molecule in an "immunospecific manner") due to the presence on such molecule of a particular domain or moiety or conformation (an "epitope"). An epitope-containing molecule may have immunogenic activity, such that it elicits an antibody production response in an animal; such molecules are termed "antigens".

[0051] As used herein, an antibody, diabody or other epitope-binding molecule is said to "immunospecifically" bind a region of another molecule i.e., an epitope) if it reacts or associates more frequently, more rapidly, with greater duration and / or with greater affinity with that epitope relative to alternative epitopes. For example, an antibody that immunospecifically binds to a viral epitope is an antibody that binds this viral epitope with greater affinity, avidity, more readily, and / or with greater duration than it immunospecifically binds to other viral epitopes or non-viral epitopes. It is also understood by reading this definition that, for example, an antibody (or moiety or epitope) that immunospecifically binds to a first target may or may not specifically or preferentially bind to a second target. As such, "immunospecific binding" does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means "immunospecific" binding. Two molecules are said to be capable of binding to one another in a "physiospecific" manner, if such binding exhibits the specificity with which receptors bind to their respective ligands.

[0052] The term "monoclonal antibody" refers to a homogeneous antibody population wherein the monoclonal antibody is comprised of amino acids (naturally occurring or non- naturally occurring) that are involved in the selective binding of an antigen. Monoclonal antibodies are highly specific, being directed against a single epitope (or antigenic site). The term "monoclonal antibody" encompasses not only intact monoclonal antibodies and full-length monoclonal antibodies, but also fragments thereof (such as Fab, Fab', F(ab')2, Fv, etc.), single-chain (scFv) binding molecules, mutants thereof, fusion proteins comprising an antibody portion, humanized monoclonal antibodies, chimeric monoclonal antibodies, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site of the required specificity and the ability to bind to an antigen. It is not intended to be limited as regards to the source of the antibody or the manner in which it is made (e.g., by hybridoma, phage selection, recombinant expression, transgenic animals, etc.). The term includes whole immunoglobulins as well as the fragments etc. described above under the definition of "antibody." Methods of making monoclonal antibodies are known in the art. One method which may be employed is the method of Kohler, G. etal. (1975) "Continuous Cultures Of Fused Cells Secreting Antibody Of Predefined Specificity," Nature 256:495-497 or a modification thereof. Typically, monoclonal antibodies are developed in mice, rats or rabbits. The antibodies are produced by immunizing an animal with an immunogenic amount of cells, cell extracts, or protein preparations that contain the desired epitope. The immunogen can be, but is not limited to, primary cells, cultured cell lines, cancerous cells, proteins, peptides, nucleic acids, or tissue. Alternatively, existing monoclonal antibodies and any other equivalent antibodies that are immunospecific for a desired pathogenic epitope can be sequenced and produced recombinantly by any means known in the art. In one aspect, such an antibody is sequenced and the polynucleotide sequence is then cloned into a vector for expression or propagation. The sequence encoding the antibody of interest may be maintained in a vector in a host cell and the host cell can then be expanded and frozen for future use. The polynucleotide sequence of such antibodies may be used for genetic manipulation to generate the monospecific or multispecific (e.g., bispecific, trispecific and tetraspecific) molecules as well as an affinity optimized, a chimeric antibody, a humanized antibody, and / or a caninized antibody, to improve the affinity, or other characteristics of the antibody. The general principle in humanizing an antibody involves retaining the basic sequence of the antigen-binding portion of the antibody, while swapping the non-human remainder of the antibody with human antibody sequences.

[0053] Natural antibodies (such as IgG antibodies) are composed of two "Light Chains" complexed with two "Heavy Chains." Each Light Chain contains a Variable Domain ("VL") and a Constant Domain ("CL"). Each Heavy Chain contains a Variable Domain ("VH"), three Constant Domains ("CHI," "CH2" and "CH3"), and a "Hinge" Region ("H") located between the CHI and CH2 Domains. The basic structural unit of naturally occurring immunoglobulins(e.g., IgG) is thus a tetramer having two light chains and two heavy chains, usually expressed as a glycoprotein of about 150,000 Da. The amino-terminal ("N-terminal") portion of each chain includes a Variable Domain of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal ("C-terminal") portion of each chain defines a constant region, with light chains having a single Constant Domain and heavy chains usually having three Constant Domains and a Hinge Domain. Thus, the structure of the light chains of an IgG molecule is n-VL-CL-c and the structure of the IgG heavy chains is n-VH-CHl-H-CH2- CH3-c (where n and c represent, respectively, the N-terminus and the C-terminus of the polypeptide).A. Characteristics of Antibody Variable Domains

[0054] The Variable Domains of an IgG molecule consist of the complementarity determining regions ("CDR"), which contain the residues in contact with epitope, and non-CDR segments, referred to as framework segments ("FR"), which in general maintain the structure and determine the positioning of the CDR loops so as to permit such contacting (although certain framework residues may also contact antigen). Thus, the VL and VH Domains have the structure n-FRl-CDRl-FR2-CDR2-FR3-CDR3-FR4-c. The amino acid sequences of the CDRs determine whether an antibody will be able to bind to a particular epitope. Interaction of an antibody light chain with an antibody heavy chain and, in particular, interaction of their VL and VH Domains, forms an epitope-binding site of the antibody.

[0055] Amino acids from the Variable Domains of the mature heavy and light chains of immunoglobulins are designated by the position of an amino acid in the chain. Kabat (SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, 5th Ed. Public Health Service, NH1, MD (1991)) described numerous amino acid sequences for antibodies, identified an amino acid consensus sequence for each subgroup, and assigned a residue number to each amino acid, and the CDRs and FRs are identified as defined by Kabat (it will be understood that CDRul as defined by Chothia, C. & Lesk, A. M. ((1987) "Canonical structures for the hypervariable regions of immunoglobulins ," J. Mol. Biol. 196:901-917) begins five residues earlier). Kabat's numbering scheme is extendible to antibodies not included in his compendium by aligning the antibody in question with one of the consensus sequences in Kabat by reference to conserved amino acids. This method for assigning residue numbers has become standard in the field andreadily identifies amino acids at equivalent positions in different antibodies, including chimeric or humanized variants. For example, an amino acid at position 50 of a human antibody light chain occupies the equivalent position to an amino acid at position 50 of a mouse antibody light chain. The positions within the VL and VH Domains at which the CDRs commence and end are thus well defined and can be ascertained by inspection of the sequences of the VL and VH Domains (see, e.g., Martin, C.R. (2010) "Protein Sequence and Structure Analysis of Antibody Variable Domains," In: ANTIBODY ENGINEERING VOL. 2 (Kontermann, R. and Diibel, S. (eds.), Springer-Verlag Berlin Heidelberg, Chapter 3 (pages 33-51)).

[0056] Polypeptides that are (or may serve as) the first, second and third CDR of the LightChain of an antibody are herein respectively designated as: CDRLI Domain, CDRL2 Domain, and CDRL3 Domain. Similarly, polypeptides that are (or may serve as) the first, second and third CDR of the Heavy Chain of an antibody are herein respectively designated as: CDRHI Domain, CDRH2 Domain, and CDRH3 Domain. Thus, the terms CDRLI Domain, CDRL2 Domain, CDRL3 Domain, CDRHI Domain, CDRH2 Domain, and CDRH3 Domain are directed to polypeptides that when incorporated into a protein cause that protein to be able to bind to a specific epitope regardless of whether such protein is an antibody having light and heavy chains or is a diabody or a single-chain binding molecule (e.g., an scFv, a BiTe, etc.), or is another type of protein. Accordingly, as used herein, the term "epitope-binding fragment" denotes a fragment of a molecule capable of immunospecifically binding to an epitope. An epitopebinding fragment may contain any 1, 2, 3, 4, or 5 the CDR Domains of an antibody, or may contain all 6 of the CDR Domains of an antibody and, although capable of immunospecifically binding to such epitope, may exhibit an immunospecificity, affinity or selectivity toward such epitope that differs from that of such antibody. Preferably, however, an epitope-binding fragment will contain all 6 of the CDR Domains of such antibody. An epitope-binding fragment of an antibody may be a single polypeptide chain (e.g., an scFv), or may comprise two or more polypeptide chains, each having an amino terminus and a carboxy terminus (e.g., a diabody, a Fab fragment, an Fab2 fragment, etc.)' . Unless specifically noted, the order of domains of the protein molecules described herein is in the "N-terminal to C-Terminal" direction.

[0057] The disclosure particularly encompasses single-chain Variable Domain fragments ("scFv") comprising a humanized anti-B7-H3-VL and / or VH Domain. Single-chain VariableDomain fragments comprise VL and VH Domains that are linked together using a short "Linker" peptide. Such Linkers can be modified to provide additional functions, such as to permit the attachment of a drug or to permit attachment to a solid support. The single-chain variants can be produced either recombinantly or synthetically. For synthetic production of scFv, an automated synthesizer can be used. For recombinant production of scFv, a suitable plasmid containing polynucleotide that encodes the scFv can be introduced into a suitable host cell, either eukaryotic, such as yeast, plant, insect or mammalian cells, or prokaryotic, such as E. coli. Polynucleotides encoding the scFv of interest can be made by routine manipulations such as ligation of polynucleotides. The resultant scFv can be isolated using standard protein purification techniques known in the art.

[0058] The disclosure particularly encompasses binding molecules (including antibodies and diabodies) that comprise a VL and / or VH Domain of a humanized antibody. The term "humanized" antibody refers to a chimeric molecule, generally prepared using recombinant techniques, having an epitope-binding site of an immunoglobulin from a non-human species and a remaining immunoglobulin structure of the molecule that is based upon the structure and / or sequence of a human immunoglobulin. The polynucleotide sequence of the variable domains of such antibodies may be used for genetic manipulation to generate such derivatives and to improve the affinity, or other characteristics of such antibodies. It is known that the variable domains of both heavy and light chains contain three complementarity determining regions (CDRs) which vary in response to the antigens in question and determine binding capability, flanked by four framework regions (FRs) which are relatively conserved in a given species and which putatively provide a scaffolding for the CDRs. When non-human antibodies are prepared with respect to a particular antigen, the variable domains can be "reshaped" or "humanized." The general principle in humanizing an antibody involves retaining the basic sequence of the epitope-binding portion of the antibody, while swapping the non-human remainder of the antibody with human antibody sequences. There are four general steps to humanize a monoclonal antibody. These are: (1) determining the nucleotide and predicted amino acid sequence of the starting antibody light and heavy variable domains (2) designing the humanized antibody or caninized antibody, i.e., deciding which antibody framework region to use during the humanizing or canonizing process (3) the actual humanizing or caninizingmethodologies / techniques and (4) the transfection and expression of the humanized antibody.See, for example, U.S. Patents Nos. 4,816,567; 5,807,715; 5,866,692; and 6,331,415.

[0059] A number of humanized antibody molecules comprising an epitope-binding site derived from a non-human immunoglobulin have been described, including chimeric antibodies having rodent or modified rodent Variable Domain and their associated complementarity determining regions (CDRs) fused to human constant domains (see, for example, Lobuglio et al. (1989) "Mouse, Human Chimeric Monoclonal Antibody In Man: Kinetics And Immune Response," Proc. Natl. Acad. Sci. (U.S.A.) 86:4220-4224 (1989)). Other references describe rodent CDRs grafted into a human supporting framework region (FR) prior to fusion with an appropriate human antibody Constant Domain (see, for example, Riechmann, L. et al. (1988) "Reshaping Human Antibodies for Therapy," Nature 332:323-327; and Jones et al. (1986) "Replacing The Complementarity-Determining Regions In A Human Antibody With Those From A Mouse," Nature 321:522-525). Another reference describes rodent CDRs supported by recombinantly veneered rodent framework regions. See, for example, European Patent Publication No. 519,596. These "humanized" molecules are designed to minimize unwanted immunological response towards rodent anti-human antibody molecules, which limits the duration and effectiveness of therapeutic applications of those moieties in human recipients. Other methods of humanizing antibodies that may also be utilized are disclosed by Daugherty et al. (1991) "Polymerase Chain Reaction Facilitates The Cloning, CDR-Grafting, And Rapid Expression Of A Murine Monoclonal Antibody Directed Against The CD18 Component Of Leukocyte Integrins," Nucl. Acids Res. 19:2471-2476 and in U.S. Patents Nos. 6,180,377; 6,054,297; 5,997,867; and 5,866,692. In aspects, humanized antibodies preserve all CDR sequences (for example, a humanized mouse antibody which contains all six CDRs from the mouse antibodies). In other aspects, humanized antibodies have one or more CDRs (one, two, three, four, five, or six) which differ in sequence relative to the original antibody.B. Characteristics of Antibody Constant Domains1. Constant Domains of the Light Chain

[0060] As indicated above, each Light Chain of an antibody contains a Variable Domain ("VL") and a Constant Domain ("CL").

[0061] A representative CL Domain is a human IgG CL Kappa Domain. The amino acid sequence of a human CL Kappa Domain is (SEQ ID NO:1):RTVAAPSVFI FPPSDEQLKS GTASWCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

[0062] Another representative CL Domain is a human IgG CL Lambda Domain. The amino acid sequence of a human CL Lambda Domain is (SEQ ID NO:2):QPKAAPSVTL FPPSSEELQA NKATLVCLIS DFYPGAVTVA WKADSSPVKA GVETTPSKQS NNKYAASSYL SLTPEQWKSH RSYSCQVTHE GSTVEKTVAP TECS2. Constant Domains of the Heavy Chain

[0063] As indicated above, the heavy chains of an antibody may comprise CHI, Hinge Domain, CH2 and CH3 constant domains. The CHI Domains of the two heavy chains of an antibody complex with the antibody's Light Chain's CL constant region and are attached to the heavy chains CH2 Domains via an intervening Hinge Domain.

[0064] A representative CHI Domain is a human IgGl CHI Domain. The amino acid sequence of a human IgGl CHI Domain is (SEQ ID NO:3):ASTKGPSVFP LAPSSKSTSG GTAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTQT YICNVNHKPS NTKVDKRV

[0065] Another representative CHI Domain is a human IgG4 CHI Domain. The amino acid sequence of a human IgG4 CHI Domain is (SEQ ID NO:4):ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSWT VPSSSLGTKT YTCNVDHKPS NTKVDKRV

[0066] A representative Hinge Domain is a human IgGl Hinge Domain. The amino acid sequence of a human IgGl Hinge Domain is (SEQ ID NO:5): EPKSCDKTHTCPPCP.

[0067] Another representative Hinge Domain is a human IgG4 Hinge Domain. The amino acid sequence of a human IgG4 Hinge Domain is (SEQ ID NO:6): ESKYGPPCPSCP. An IgG4 Hinge Domain may comprise a stabilizing mutation such as the S228P substitution. The amino acid sequence of a S228P-stabilized human IgG4 Hinge Domain is (SEQ ID NO:7):ESKYGPPCPPCP.

[0068] The CH2 and CH3 Domains of the two heavy chains of an antibody interact to form an "Fc Domain," which is a domain that is recognized by cellular Fc Receptors, including but not limited to Fc gamma Receptors (FcyRs). As used herein, the term "Fc Domain" is used to define a C-terminal region of an IgG heavy chain. An Fc Domain is said to be of a particular IgG isotype, class or subclass if its amino acid sequence is most homologous to that isotype relative to other IgG isotypes. In addition to their known uses in diagnostics, antibodies have been shown to be useful as therapeutic agents.

[0069] The amino acid sequence of the CH2-CH3 Domain of a representative human IgGl is (SEQ ID NO:8)231 240 250 260 270 280APELLGGPSV FLFPPKPKDT LMISRTPEVT CWVDVSHED PEVKFNWYVD290 300 310 320 330GVEVHNAKTK PREEQYNSTY RWSVLTVLH QDWLNGKEYK CKVSNKALPA340 350 360 370 380PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE390 400 410 420 430WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE440 447ALHNHYTQKS LSLSPGX as numbered by the EU index as set forth in Kabat, wherein X is a lysine (K) or is absent.

[0070] The amino acid sequence of the CH2-CH3 Domain of a representative human IgG4 is (SEQ ID NO:9)231 240 250 260 270 280APEFLGGPSV FLFPPKPKDT LMISRTPEVT CVWDVSQED PEVQFNWYVD290 300 310 320 330GVEVHNAKTK PREEQFNSTY RWSVLTVLH QDWLNGKEYK CKVSNKGLPS340 350 360 370 380S IEKTISKAK GQPREPQVYT LPPSQEEMTK NQVSLTCLVK GFYPSDIAVE390 400 410 420 430WESNGQPENN YKTTPPVLDS DGSFFLYSRL TVDKSRWQEG NVFSCSVMHE440 447ALHNHYTQKS LSLSLGX as numbered by the EU index as set forth in Kabat, wherein X is a lysine (K) or is absent.

[0071] Throughout the present specification, the numbering of the residues in the constant region of an IgG heavy chain is that of the EU index as in Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, 5thEd. Public Health Service, NH1, MD (1991), expressly incorporated herein by reference. The term "EU index as in Kabat" refers to the numbering of the constant domains of human IgGl EU antibody.

[0072] Polymorphisms have been observed at a number of different positions within antibody constant regions (e.g., Fc positions, including but not limited to positions 270, 272, 312, 315, 356, and 358 as numbered by the EU index as set forth in Kabat), and thus slight differences between the presented sequence and sequences in the prior art can exist. Polymorphic forms of human immunoglobulins have been well-characterized. At present, 18 Gm allotypes are known: Glm (1, 2, 3, 17) or Glm (a, x, f, z), G2m (23) or G2m (n), G3m (5, 6, 10, 11, 13, 14, 15, 16, 21, 24, 26, 27, 28) or G3m (bl, c3, b3, bO, b3, b4, s, t, gl, c5, u, v, g5) (Lefranc, el al. , " The Human IgG Subclasses: Molecular Analysis Of Structure, Function And Regulation." Pergamon, Oxford, pp. 43-78 (1990); Lefranc, G. et al., 1979, Hum. Genet.: 50, 199-211). It is specifically contemplated that the antibodies of the present disclosure may incorporate any allotype, isoallotype, or haplotype of any immunoglobulin gene, and are not limited to the allotype, isoallotype or haplotype of the sequences provided herein. Furthermore, in some expression systems the C-terminal amino acid residue (bolded above) of the CH3 Domain may be post-translationally removed. Accordingly, the C-terminal residue of the CH3 Domain is an optional amino acid residue. Specifically encompassed by the instant disclosure is a B7-H3-ADC lacking the C-terminal residue of the CH3 Domain. Also specifically encompassed by the instant disclosure are such constructs comprising the C-terminal lysine residue of the CH3 Domain.

[0073] The present disclosure particularly encompasses B7-H3-ADCs comprising anti- B7-H3 Variable Domains (i.e., VL and / or VH Domains) that immunospecifically bind to anepitope of a human B7-H3 polypeptide. Such B7-H3-ADCs are capable of immunospecifically binding to human B7-H3. As used herein such B7-H3 Variable Domains are referred to as "anti- B7-H3-VL" and "anti-B7-H3-VH," respectively.IL Anti-B7-H3 Antibody mAb-A

[0074] A representative anti-B7-H3 antibody, designated "mAb-A," was isolated from hybridoma cells that had been produced through immunization with cells expressing human B7-H3, with a B7-H3 polypeptide or a peptide epitope thereof. Antibody mAb-A was humanized.

[0075] Antibody mAb-A was found to be cross-reactive with B7-H3 of cynomolgus monkeys. The amino acid sequences of the VL and VH Domains of mAb-A are provided below. The B7-H3-ADC possesses all 3 of the CDRHS of the VH Domain, all 3 of the CDRLS of the VL Domain, and optionally the entire VH and VL Domains of humanized monoclonal antibody mAb-A ("hmAb-A").A. Murine Anti-B7-H3 Antibody mAb-A

[0076] The amino acid sequence of the VL Domain of the murine anti-B7-H3 antibody mAb-A (SEQ ID NO: 10) is shown below (CDRL residues are shown underlined): DIQMTQSPAS LSVSVGETVT ITCRASESIY SYLAWYQQKQ GKSPQLLVYN TKTLPEGVPS RFSGSGSGTQ FSLKINSLQP EDFGRYYCQH HYGTPPWTFG GGTNLEIK

[0077] The amino acid sequence of the VH Domain of anti-B7-H3 mAb-A (SEQ ID NO:11) is shown below (CDRH residues are shown underlined):EVQQVESGGD LVKPGGSLKL SCAASGFTFS SYGMSWVRQT PDKRLEWVAT INSGGSNTYY PDSLKGRFTI SRDNAKNTLY LQMRSLKSED TAMYYCARHD GGAMDYWGQG TSVTVSSB. Humanized Anti-B7-H3 Antibody hmAb-A

[0078] The Variable Domains of the anti-B7-H3 antibody mAb-A were humanized to generate a humanized mAb-A ("hmAb-A"). In some instances, alternative humanized Variable Domains were generated to optimize binding activity and / or to remove antigenic epitopes and / or to remove potentially labile amino acid residues.

[0079] The amino acid sequence of the VL Domain of hmAb-A (SEQ ID NO:12) is shown below (CDRL residues are shown underlined):DIQMTQSPSS LSASVGDRVT I TCRASESIY SYLAWYQQKP GKAPKLLVYN TKTLPEGVPS RFSGSGSGTD FTLTI SSLQP EDFATYYCQH HYGTPPWTFG QGTRLE IK

[0080] The amino acid sequence of a Light Chain of hmAb-A comprising the VL Domain of hmAb-A and a CL Kappa Domain (SEQ ID NO: 13) is shown below:DIQMTQSPSS LSASVGDRVT I TCRASES IY SYLAWYQQKP GKAPKLLVYNTKTLPEGVPS RFSGSGSGTD FTLTI SSLQP EDFATYYCQH HYGTPPWTFGQGTRLE IKRT VAAPSVFI FP PSDEQLKSGT ASWCLLNNF YPREAKVQWKVDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQGLSSPVTKS F NRGEC

[0081] In SEQ ID NO: 13, amino acid residues 1-108 correspond to the VL Domain of hmAb-A (SEQ ID NO:12), and amino acid residues 109-215 correspond to the Light Chain kappa constant region (SEQ ID NO:1).

[0082] The amino acid sequence of the VH Domain of hmAb-A (SEQ ID NO:14) is shown below (CDRH residues are shown underlined).EVQLVESGGG LVKPGGSLRL SCAASGFTFS SYGMSWVRQA PGKGLEWVAT INSGGSNTYY PDSLKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARHD GGAMDYWGQG T TVTVS S

[0083] The amino acid sequence of a Heavy Chain comprising the VH Domain of hmAb-A and IgGl CH1-H-CH2-CH3 Domains (SEQ ID NO: 15) is shown below:EVQLVESGGG LVKPGGSLRL SCAASGFTFS SYGMSWVRQA PGKGLEWVAT INSGGSNTYY PDSLKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARHD GGAMDYWGQG T TVTVS SAS T KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSWTVPS SSLGTQTYIC NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVWDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RWSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKT I SKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGX wherein, X is a lysine (

[0084] In SEQ ID NO: 15, amino acids 1-117 correspond to the VH Domain of hmAb-A (SEQ ID NO: 14), amino acid residues 118-215 correspond to the IgGl CHI Domain (SEQ ID NO:3), amino acid residues 216-230 correspond to the IgGl Hinge Domain (SEQ ID NO:5), and amino acid residues 231-447 correspond to the IgGl CH2-CH3 Domain (SEQ ID NO:8). An N-linked glycosylation site is present at Kabat position 296 (shown underlined). The C- terminal residue "X" is a lysine (K) or is absent.

[0085] The amino acid sequence of the CDRLI Domain is (SEQ ID NO: 16): RASES IYSYLA.

[0086] The amino acid sequence ofthe CDRul Domain is (SEQ ID NO: 17): NTKTLPE .

[0087] The amino acid sequence of the CDRL3 Domain is (SEQ ID NO: 18): QHHYGTPPWT .

[0088] The amino acid sequence of the CDRHI Domain is (SEQ ID NO:19): SYGMS .

[0089] The amino acid sequence of the CDRH2 Domain is (SEQ ID NO:20): TINSGGSNTYYPDSLKG .

[0090] The amino acid sequence of the CDRH3 Domain is (SEQ ID NO:21): HDGGAMDY .C. Alternative Humanized Anti-B7-H3 Antibody hmAb-A

[0091] Alternative humanized Variable Domains were generated to optimize binding activity and / or to remove antigenic epitopes and / or to remove potentially labile amino acid residues. The amino acid sequence of the VL Domain of hmAb-A (SEQ ID NO: 12) and the amino acid sequence of a Light Chain of hmAb-A comprising the VL Domain of hmAb-A and a CL Kappa Domain (SEQ ID NO: 13) are shown above.

[0092] The amino acid sequence of the alternative VH Domain of hmAb-A (SEQ ID NO:22) is shown below (CDRH residues are shown underlined).EVQLVESGGG LVKPGGSLRL SCAASGFTFS SYGMSWVRQA PGKGLEWVAT INSGGSNTYY PDSLKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARHXGGAMDYWGQG T TVTVS S

[0093] In aspects, the amino acid sequence of the alternative CDRH3 Domain is (SEQ ID NO:23): HXGGAMDY. In aspects, alternative CDRH3 Domain residue "X" is any amino acid. In asepcts, the alternative CDRH3 Domain residue "X" is an aspartate (D), a glutamate (E), an asparagine (N), or a glutamine (Q).For example, the amino acid sequence of an exemplary alternative VH Domain of hmAb-A (SEQ ID NO:24) is shown below (CDRH residues are shown underlined) wherein the residue “X” is a glutamate (E).EVQLVESGGG LVKPGGSLRL SCAASGFTFS SYGMSWVRQA PGKGLEWVAT INSGGSNTYY PDSLKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARHE GGAMDYWGQG T TVTVS S

[0094] The amino acid sequence of an exemplary alternative Heavy Chain comprising theVH Domain of hmAb-A and IgGl CH1-H-CH2-CH3 Domains (SEQ ID NO:25) is shown below:EVQLVESGGG LVKPGGSLRL SCAASGFTFS SYGMSWVRQA PGKGLEWVAT INSGGSNTYY PDSLKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCARHE GGAMDYWGQG TTVTVSSAST KGPSVFPLAP SSKSTSGGTA ALGCLVKDYF PEPVTVSWNS GALTSGVHTF PAVLQSSGLY SLSSWTVPS SSLGTQTYIC NVNHKPSNTK VDKRVEPKSC DKTHTCPPCP APELLGGPSV FLFPPKPKDT LMISRTPEVT CVWDVSHED PEVKFNWYVD GVEVHNAKTK PREEQYNSTY RWSVLTVLH QDWLNGKEYK CKVSNKALPA PIEKTISKAK GQPREPQVYT LPPSREEMTK NQVSLTCLVK GFYPSDIAVE WESNGQPENN YKTTPPVLDS DGSFFLYSKL TVDKSRWQQG NVFSCSVMHE ALHNHYTQKS LSLSPGX wherein, X is a lysine (K) or is absent.

[0095] In SEQ ID NO:25, amino acids 1-117 correspond to the VH Domain of hmAb-A (SEQ ID NO:24), amino acid residues 118-215 correspond to the IgGl CHI Domain (SEQ ID NO:3), amino acid residues 216-230 correspond to the IgGl Hinge Domain (SEQ ID NO:5), and amino acid residues 231-447 correspond to the IgGl CH2-CH3 Domain (SEQ ID NO:8). An N-linked glycosylation site is present at Kabat position 296 (shown underlined). The C- terminal residue "X" is a lysine (K) or is absent.

[0096] The amino acid sequence of an exemplary alternative CDRH3 Domain is (SEQID NO:26): HEGGAMDY .III. Modification of the Fc Domain

[0097] The Fc Domain of the Fc Domain-containing molecules (e.g., antibodies and diabodies) may be either a complete Fc Domain (e.g., a complete IgG Fc Domain) or only a fragment of an Fc Domain. Optionally, the Fc Domain of the Fc Domain-containing molecules lacks the C-terminal lysine amino acid residue.

[0098] In traditional immune function, the interaction of antibody-antigen complexes with cells of the immune system results in a wide array of responses, ranging from effector functions such as antibody dependent cytotoxicity, mast cell degranulation, and phagocytosis to immunomodulatory signals such as regulating lymphocyte proliferation and antibody secretion. All of these interactions are initiated through the binding of the Fc Domain of antibodies or immune complexes to specialized cell surface receptors (singularly referred to as an "Fc gamma receptor," "FcyR," and collectively as "FcyRs") found on the surfaces of multiple types of immune system cells (e.g., B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils and mast cells). The diversity of cellular responses triggered by antibodies and immune complexes results from the structural heterogeneity of the three Fc receptors: FcyRI (CD64), FcyRII (CD32), and FcyRIII (CD 16). FcyRI (CD64), FcyRIIA (CD32A) and FcyRIII (CD16) are activating (i.e., immune system enhancing) receptors; FcyRIIB (CD32B) is an inhibiting i.e., immune system dampening) receptor. In addition, interaction with the neonatal Fc Receptor (FcRn) mediates the recycling of IgG molecules from the endosome to the cell surface and release into the blood. The amino acid sequence of a represenative wild-type IgGl (SEQ ID NO:8) and a representative wildtype IgG4 (SEQ ID NO:9) are presented above.

[0099] Modification of the Fc Domain may lead to an altered phenotype, for example altered serum half-life, altered stability, altered susceptibility to cellular enzymes or altered effector function. Accordingly, in certain aspects, the Fc Domain of the Fc Domain-containing molecules may be an engineered variant Fc Domain. Although the Fc Domain of the Fc Domain-containing molecules may possess the ability to bind to one or more Fc receptors (e.g., FcyR(s)), in particular such variant Fc Domain will have altered binding to FcyRIA (CD64), FcyRII A (CD32A), FcyRIIB (CD32B), FcyRIIIA (CD 16a), or FcyRIIIB (CD 16b) (relative to the binding exhibited by a wild-type Fc Domain), e.g., will have enhanced binding to anactivating receptor and / or will have substantially reduced or no ability to bind to inhibitory receptor(s). Thus, the Fc Domain of the Fc Domain-containing molecules may include some or all of the CH2 Domain and / or some or all of the CH3 Domain of a complete Fc Domain, or may comprise a variant CH2 and / or a variant CH3 sequence (that may include, for example, one or more insertions and / or one or more deletions with respect to the CH2 or CH3 domains of a complete Fc Domain). Such Fc Domains may comprise non-Fc polypeptide portions, or may comprise portions of non-naturally complete Fc Domains, or may comprise non-naturally occurring orientations of CH2 and / or CH3 Domains (such as, for example, two CH2 domains or two CH3 domains, or in the N-terminal to C-terminal direction, a CH3 Domain linked to a CH2 Domain, etc. .

[0100] In certain aspects, the Fc Domains of the binding molecules exhibit decreased (or substantially no) binding to FcyRIA (CD64), FcyRIIA (CD32A), FcyRIIB (CD32B), FcyRIIIA (CD 16a) or FcyRIIIB (CD 16b) (relative to the binding exhibited by the wild-type IgGl Fc Domain (SEQ ID NO:8). In certain aspects, the binding molecules comprise an IgGFc Domain that exhibits reduced ADCC effector function. In a such aspects, the CH2-CH3 Domains of binding molecules include any 1, 2, 3, or 4 of the substitutions: L234A, L235A, D265A, N297Q, and N297G. In another aspect, the CH2-CH3 Domains contain an N297Q substitution, an N297G substitution, L234A and L235A substitutions or a D265A substitution, as these mutations abolish FcR binding. Alternatively, a CH2-CH3 Domain of a naturally occurring Fc Domain that inherently exhibits decreased (or substantially no) binding to FcyRIIIA (CD16a) and / or reduced effector function (relative to the binding and effector function exhibited by the wild-type IgGl Fc Domain (SEQ ID NO:8)) is utilized. In a specific aspect, the binding molecules comprise an IgG4 Fc Domain (SEQ ID:NO:9). When an IgG4 Fc Domain is utilized, the instant disclosure also encompasses the introduction of a stabilizing mutation, such as the Hinge Domain S228P substitution described herein (see, e.g., SEQ ID NO:7).

[0101] The serum half-life of proteins comprising Fc Domains may be increased by increasing the binding affinity of the Fc Domain for FcRn. The term "half-life" as used herein means a pharmacokinetic property of a molecule that is a measure of the mean survival time of the molecules following their administration. Half-life can be expressed as the time required to eliminate fifty percent (50%) of a known quantity of the molecule from a subject's body (e.g.,a human patient or other mammal) or a specific compartment thereof, for example, as measured in serum, i.e., circulating half-life, or in other tissues. In general, an increase in half-life results in an increase in mean residence time (MRT) in circulation for the molecule administered. Modifications capable of increasing the half-life of an Fc Domain-containing molecule are known in the art and include, for example M252Y, S254T, T256E, and combinations thereof. For example, see the modifications described in U.S. Patent Nos. 6,277,375; 7,083,784; 7,217,797; and 8,088,376; U.S. Publication Nos. 2002 / 0147311; 2007 / 0148164; and 2011 / 0081347.IV. B7-H3-ADC

[0102] The present disclosure relates to the above-described anti-B7-H3 antibody hmAb- A conjugated to a cytotoxic drug, a "B7-H3-ADC". Such B7-H3-ADC enhances the cytotoxicity of anti-B7-H3 therapy, particularly in the treatment of cancer. As indicated above, a B7-H3-ADC is represented by the formula:Ab-(LM)m-(D)n, wherein:Ab is an antibody that binds to B7-H3 that comprises a humanized Variable Heavy Chain (VH) Domain and a humanized Variable Light Chain (VL) Domain, or is a B7-H3-binding fragment thereof, and;D is a cytotoxic drug moiety;LM is a a Linker Molecule that covalently links Ab and D; m is an integer between 1 and n and denotes the number of bonds or Linker Molecules of the B7-H3-ADC; and n is an integer between 1 and 10 and denotes the number of cytotoxic camptothecin moi eties covalently linked to the B7-H3-ADC.

[0103] In certain aspects, a B7-H3-ADC comprises a naturally occurring Fc Domain of the IgGl isotype. Such Fc Domain lacks the C-terminal lysine residue of a CH3 Domain. In specific aspects, a B7-H3-ADC will bind to a tumor cell expressing B7-H3 and will then be internalized into such cell through receptor-mediated endocytosis. Once inside a lysosome, aB7-H3-ADC may be be degraded so as to thereby cause the release of the cytotoxic camptothecin moiety inside the cell, resulting in cell death. As will be appreciated, the mechanism of action of cell death can vary based on the class of cytotoxic drug used. Neighboring cancer cells may also be killed when free drug is released into the tumor environment by the dying cell in a process known as the bystander effect (Panowski, S. et al. (2014) "Site-Specific Antibody Drug Conjugates For Cancer Therapy," mAbs 6(l):34-45; Kovtun, Y.V. et al. (2006) "Antibody-Drug Conjugates Designed To Eradicate Tumors With Homogeneous And Heterogeneous Expression Of The Target Antigen," Cancer Res. 66:3214- 3221).[001041 In aspects, the Ab of the B7-H3-ADC is a B7-H3 antibody as described above.

[0105] In aspects, Ab is a humanized B7-H3 antibody or B7-H3 binding fragment thereof that binds to B7-H3 and comprises: (i) the CDRL1 sequence RASESIYSYLA (SEQ ID NO: 16), the CDRL2 sequence NTKTLPE (SEQ ID NO: 17) and the CDRL3 sequence QHHYGTPPWT (SEQ ID NO: 18) in its Variable Light Chain (VL) domain, and (ii) the CDRH1 sequence SYGMS (SEQ ID NO: 19), the CDRH2 sequence TINSGGSNTYY PDSLKG (SEQ ID NO:20) and the CDRH3 sequence HDGGAMDY (SEQ ID NO:21) or HEGGAMDY (SEQ ID NO:26) in its Variable Heavy Chain (VH) domain.

[0106] In aspects, Ab is a humanized B7-H3 antibody or B7-H3 binding fragment thereof that binds to B7-H3 and comprises: (i) the CDRL1 sequence RASESIYSYLA (SEQ ID NO: 16), the CDRL2 sequence NTKTLPE (SEQ ID NO: 17) and the CDRL3 sequence QHHYGTPPWT (SEQ ID NO: 18) in its Variable Light Chain (VL) domain, and (ii) the CDRH1 sequence SYGMS (SEQ ID NO: 19), the CDRH2 sequence TINSGGSNTYY PDSLKG (SEQ ID NO:20) and the CDRH3 sequence HDGGAMDY (SEQ ID NO:21) in its Variable Heavy Chain (VH) domain.

[0107] In aspects, Ab is a humanized B7-H3 antibody or B7-H3 binding fragment thereof that binds to B7-H3 and comprises: (i) the CDRL1 sequence RASESIYSYLA (SEQ ID NO: 16), the CDRL2 sequence NTKTLPE (SEQ ID NO: 17) and the CDRL3 sequence QHHYGTPPWT (SEQ ID NO: 18) in its Variable Light Chain (VL) domain, and (ii) the CDRH1 sequence SYGMS (SEQ ID NO: 19), the CDRH2 sequence TINSGGSNTYYPDSLKG (SEQ ID NQ:20) and the CDRH3 sequence HEGGAMDY (SEQ ID NO:26) in its Variable Heavy Chain (VH) domain.

[0108] In aspects, Ab comprises: (i) a humanized VL Domain comprising the amino acid sequence of SEQ ID NO: 12, and (ii) a humanized VH Domain comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO:24.

[0109] In aspects, Ab comprises: (i) a humanized VL Domain comprising the amino acid sequence of SEQ ID NO: 12, and (ii) a humanized VH Domain comprising the amino acid sequence of SEQ ID NO: 14.

[0110] In aspects, Ab comprises: (i) a humanized VL Domain comprising the amino acid sequence of SEQ ID NO: 12, and (ii) a humanized VH Domain comprising the amino acid sequence of SEQ ID NO:24.

[0111] In aspects, present disclosure provides an antibody Ab that has undergone glycan remodeling. Examples of glycan remodeling are described further below. In aspects, the Ab has undergone glycan remodeling and comprises an azidosugar. In aspects, the azidosugar is GalNAz (N-Azidoacetylgalactosamine), 6-azido-Gal or 6-azido-GalNAc.A. Linker Molecules

[0112] The disclosure particularly contemplates B7-H3-ADCs that possess one or more Linker Molecule LM (z.c., m is an integer from 2 through n, wherein n is an integer from 2 through 10), each of which Linker Molecule LM covalently links a camptothecin moiety D to the Ab of such B7-H3-ADCs.

[0113] The disclosure further provides B7-H3-ADCs whose Ab are linked to more than one Linker Molecule LM, wherein all such Linker Molecules are identical. The camptothecin moi eties D that are covalently linked to the Ab of such B7-H3-ADCS may all be identical or may include 2, 3, 4, or more independently different camptothecin moieties D.

[0114] The disclosure further provides such B7-H3-ADCs whose Ab are linked to more than one Linker Molecule LM, wherein all such Linker Molecules are not identical and may independently differ. The camptothecin moieties D that are linked to the Ab of such B7-H3-ADCs may all be identical or may include 2, 3, 4, or more independently different campothecin moieties D.

[0115] Humanized VH and VL Domains of antibodies that bind to human B7-H3, and human antibody Constant Domains that may be included in a B7-H3-ADC are provided above. As stated above, a B7-H3-ADC additionally comprises at least one cytotoxic drug moiety, which is covalently linked to through an amino acid residue of such VH Domain or VL Domain and / or Constant Domain via a Linker Molecule attached to the side chain and the drug moiety. The Linker Molecule may be a non-peptide molecule, or a molecule that comprises a nonpeptide portion and a peptide portion, or it may be a molecule that is composed solely of amino acid residues. The amino acid residues of any such Linker Molecules may contain naturally occurring or non-naturally occurring amino acid residues, including D-versions of naturally occurring amino acid residues, / ?-acetylphenylalanine, selenocysteine, etc. Optionally, or additionally, particular residues having a desired side chain (e.g., a -CH2-SH side chain, a-CH - OH side chain, a -CH(CH2)-SH side chain, a -CH2-CH2-S-CH3 side chain; a -CH2-C(O)-NH2 side chain, a -CH2-CH2-C(O)-NH2 side chain, a -CH2-C(O)OH- side chain, a CH2-CH2- C(O)OH- side chain, a -CH2-CH2-CH2-CH2-NH2 side chain, a -CH2-CH2-CH2-NH-C(NH2)2 side chain, an imidazole side chain, a benzyl side chain, a phenol side chain, an indole side chain, etc.) may be engineered into a B7-H3-ADC.

[0116] In aspects, cytotoxic drug moi eties may be conjugated to the Ab of the B7-H3- ADC of the disclosure by means known in the art (see, e.g., W02016053107; Yao, H. et al. (2016) "Methods to Design and Synthesize Antibody-Drug Conjugates (ADC)," Inti. J. Molec. Sci. 17(194): 1-16); Behrens, C. R. et al. (2014) "Methods For Site-Specific Drug Conjugation To Antibodies," mAbs 6(l):46-53; Bouchard, H. et al. (2014) "Antibody-Drug Conjugates - A New Wave Of Cancer Drugs," Bioorganic & Medicinal Chem. Lett 24:5357-5363). The thiol group of a cysteine, the amino side group of lysine, glutamine or arginine, or the carboxyl group of glutamate or aspartate can be employed to conjugate the Linker Molecule-cytotoxic drug moiety (LM-D) to the Ab of the B7-H3-ADC of the disclosure. Native antibodies contain numerous lysine conjugation sites, and thus are capable of linking multiple conjugated molecules per antibody. Indeed, peptide mapping has determined that conjugation occurs on both the heavy and light chain at approximately 20 different lysine residues (40 lysines permAb). Therefore, greater than one million different ADC species can be generated. Cysteine conjugation occurs after reduction of one to four inter-chain disulfide bonds, and the conjugation is thus limited in native VL and VH Domains to the eight exposed sulfhydryl groups. However, if desired, additional reactive (e.g., lysine, cysteine, selenocysteine, etc.) residues may be engineered into an antibody (e.g., within a VL Domain and / or a VH Domain and / or a Constant Domain). For example, one or more native amino acid residues may be substituted with a cysteine residue. An unnatural amino acid (e.g. / ?-acetylphenylalanine) may be genetically incorporated into an antibody using an amber stop codon suppressor tRNA / aaRS pair. (See, e.g., Behrens CR, and Liu B. (2014) "Methods For Site-Specific Drug Conjugation To Antibodies," mAbs 6(l):46-53. doi: 10.4161 / mabs.26632; Panowksi, S., et al. (2014) "Site- Specific Antibody Drug Conjugates For Cancer Therapy," mAbs, 6(1), 34-45, doi: 10.4161 / mabs.27022; and WO 2008 / 070593). Alternatively, or additionally, enzymes (e.g., a glycotransferase) may be used to conjugate the Linker Molecule-cytotoxic drug moiety (LM- D) to the Ab of the B7-H3-ADC of the disclosure. The glycotransferase platform attaches a sugar moiety to a glycosylation site on an antibody (for example, position N297 of the Fc Domain of a human IgG antibody), which can then serve as the Linker Molecule (LM) of the present disclosure and conjugate the cytotoxic drug moiety (D) to the Ab of the B7-H3-ADC of the disclosure. Alternatively, a transglutaminase may be used to catalyze the formation of a covalent bond between a free amine group and a glutamine side chain.

[0117] In aspects, the Linker Molecule LM is attached to a glycan moiety attached to a side chain of the Ab. In aspects, the glycan moiety on the side chain is a naturally occurring glycan moiety. In aspects, the glycan moiety has undergone glycan remodeling prior to attachment to the Linker Molecule.

[0118] In aspects, glycan remodeling is performed by contacting the glycan moiety with an endoglycosidase and a glycosyl transferase. In aspects, the glycan remodeling adds an azidosugar to the end of the glycan moiety. In aspects, the azidosugar is GalNAz (N- Azidoacetylgalactosamine), 6-azido-Gal or 6-azido-GalNAc. In aspects, the Linker Molecule LM is attached to the azidosugar on the glycan moiety. In aspects, the Linker Molecule LM is attached to the azidosugar on the glycan moiety by reacting the azido group on the azidosugar to a reactive group on the LM.

[0119] In aspects, glycan remodeling is performed by contacting the glycan moiety with an endoglycosidase and anN-Acetylgalactosamine (GalNAc) transferase. In aspects, the glycan remodeling adds a N-Acetylgalactosamine (GalNAc) sugar to the end of the glycan moiety. In aspects, the GalNAc sugar comprises an azido group. In aspects, the Linker Molecule LM is attached to the GalNAc sugar on the glycan moiety. In aspects, the Linker Molecule LM is attached to the GalNAc sugar on the glycan moiety by reacting the azido group on the GalNAc to a reactive group on the LM.

[0120] In aspects, the glycan remodeling performed is the GlycoConnect™ process (Synaffix). In aspects, glycan remodeling is performed as described in US Patent Nos. US9,504,758, US10,745,488, US9,988,661, US10,858,641, US9,222,940, US10,239,807, and US11,358,921, each of which is hereby incorporated by reference herein.

[0121] In aspects, the Linker Molecule LM may be non-cleavable under physiologic conditions, for example composed of a hydrolytically stable moiety, for example, a thioether linker or a hindered disulfide linker. Hydrolytically stable linkers are substantially stable in water and do not react with water at useful pH values, including but not limited to, under physiological conditions for an extended period of time. In contrast, hydrolytically unstable or degradable linkers are degradable in water or in aqueous solutions, including for example, blood.

[0122] In alternative aspects, the Linker Molecule LM may be cleavable, or may contain a cleavable portion. Examples of such a cleavable portion includes an acid labile linker (e.g., a 4-(4'-acetylpheonxy) butanoic acid linker which forms a hydrazine bond), a cleavable disulfide linker (that is cleaved in the reducing intracellular environment), and a protease cleavable linker. Acid-labile linkers are designed to be stable at pH levels encountered in the blood, but become unstable and degrade when the low pH environment in lysosomes is encountered. Protease-cleavable linkers are also designed to be stable in blood / plasma, but rapidly release free drug inside lysosomes in cancer cells upon cleavage by lysosomal enzymes (Panowski, S. et al. (2014) "Site-Specific Antibody Drug Conjugates For Cancer Therapy," mAbs 6( 1):34- 45). Alternatively, the Linker Molecule LM may be an enzyme-cleavable-substrate or contain an enzyme-cleavable-substrate, such as a cleavable peptide, (e.g., a cleavable dipeptide such asa valine-alanine dipeptide para-aminobenzylalcohol linker (cAClO-mc-va-PABA), a valinealanine dipeptide para-aminocarbamate (Val-Ala-PABC or VA-PABC) a valine-citrulline dipeptide para-aminobenzylalcohol linker (cAClO-mc-vc-PABA) or a valine-citrulline dipeptide para-aminocarbamate (Val-Cit-PABC or VC-PABC), which are selectively cleaved by lysosomal enzymes). Suitable cleavable linkers are known in the art, see, e.g., de Groot, Franciscus M.H., et al. (2002) "Design, Synthesis, and Biological Evaluation of a Dual Tumor- Specific Motive Containing Integrin-Targeted Plasmin-Cleavable Doxorubicin Prodrug ," Molecular Cancer Therapeutics, 1: 901-911; Dubowchik et al., (2002) "Doxorubicin Immunoconjugates Containing Bivalent, Lysosomally-Cleavable Dipeptide Linkages." Bioorganic & Medicinal Chemistry Letters 12: 1529-1532; US Patent Nos. 5,547,667; 6,214,345; 7,585,491; 7,754,681; 8,080,250; 8,461,117; and WO 02 / 083180.

[0123] In aspects, enzymatically unstable or degradable linkers can be employed. Such linkers are degraded by one or more enzymes. By way of example only, PEG and related polymers can include a degradable Linker Molecule(s) in the polymer backbone or in the linker group between the polymer backbone and one or more of the terminal functional groups of the polymer molecule. Such degradable Linker Molecule(s) include, but are not limited to, ester linkages formed by the reaction of PEG carboxylic acids or activated PEG carboxylic acids with alcohol groups on a biologically active agent, wherein such ester groups generally hydrolyze under physiological conditions to release the biologically active agent. Other hydrolytically degradable Linker Molecules include but are not limited to carbonate linkages; imine linkages resulting from reaction of an amine and an aldehyde; phosphate ester linkages formed by reacting an alcohol with a phosphate group; hydrazone linkages that are a reaction product of a hydrazide and an aldehyde; acetal linkages that are the reaction product of an aldehyde and an alcohol; orthoester linkages that are the reaction product of a formate and an alcohol; peptide linkages formed by an amine group, including but not limited to, at an end of a polymer such as PEG, and a carboxyl group of a peptide; and oligonucleotide linkages formed by a phosphoramidite group, including but not limited to, at the end of a polymer, and a 5' hydroxyl group of an oligonucleotide.

[0124] In aspects, the Linker Molecule LM comprises a peptidic linker. In aspects, the peptidic linker is a Valine-Alanine dipeptide linker. In aspects, the Linker Molecule comprisesa cleavable linker. In aspects, the Linker Molecule comprises a Valine-Alanine (Val-Ala) amino acid linker. In aspects, the Vai-Ala linker is a Val-Ala-PABC linker.

[0125] In aspects, the peptidic linker is a Valine-Citrulline dipeptide linker. In aspects, the Linker Molecule comprises a cleavable linker. In aspects, the Linker Molecule comprises a Valine-Citruline (Val-Cit) amino acid linker. In aspects, the Val-Cit linker is a Val-Cit-PABC linker.

[0126] In one aspect, the Linker Molecule LM can be, or can comprise, a cleavable Linker Molecule comprising formula (4a) or (4b), or a salt thereof:wherein: a is independently 0 or 1; b is independently 0 or 1 ; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is an integer in the range of 1 to 150; g is 0 or 1; i is 0 or 1;D is a cytotoxic drug moiety;Q1is an alkenyl group, (hetero)cycloalkenyl group, bi cyclo tri azole group or cycloalkenyl group; wherein Q1is attached to a functional group of the antibody; wherein Sp1, Sp2, Sp3and Sp4are independently selected from the group consisting of linear or branched C1-C200 alkylene groups, C2-C200 alkenylene groups, C2-C200 alkynylene groups, C3-C200 cycloalkylene groups, C5-C200 cycloalkenylene groups, C8-C200 cycloalkynylene groups, C7-C200 alkylarylene groups, C7-C200 arylalkylene groups, C8-C200 arylalkenylene groups and C9-C200 aryl alkynylene groups, the alkylene groups, alkenylene groups, alkynylene groups, cycloalkylene groups, cycloalkenylene groups, cycloalkynylene groups, alkylarylene groups, arylalkylene groups, arylalkenylene groups and aryl alkynylene groups being optionally substituted and optionally interrupted by one or more heteroatoms selected from the group of O, S and NR3, wherein R3is independently selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C2 - C24 alkenyl groups, C2 - C24alkynyl groups and C3 - C24 cycloalkyl groups, the alkyl groups, alkenyl groups, alkynyl groups and cycloalkyl groups being optionally substituted;Z1is a connecting group that connects Q1or Sp3to Sp2, O or C(O) or N(RX);Z2is a connecting group that connects D or Sp4to Sp1, N(RX), O or C(O); wherein Z1and Z2are independently selected from the group consisting of -O-, -S-, -NR2-, -N=N-, -C(O)-, -C(O)NR2-, -O-C(O)- , -O-C(O)-O-, -O-C(O)-NR2, -NR2-C(O)-, -NR2-C(O)-O-, -NR2-C(O)-NR2-, -S-C(O)-, -S-C(O)-O-, -S-C(O)- NR2-, -S(O)-, -S(O)2-, -O-S(O)2-, -O-S(O)2-O-, -O-S(O)2-NR2-, -O-S(O)-, -O- S(O)-O-, -O-S(O)-NR2-, -O-NR2-C(O)-, -O-NR2-C(O)-O-, -O-NR2-C(O)-NR2- , -NR2-O-C(O)-, -NR2-O-C(O)-O-, -NR2-O-C(O)-NR2-, -O-NR2-C(S)-, -O- NR2-C(S)-O-, -O-NR2-C(S)-NR2-, -NR2-O-C(S)-, -NR2-O-C(S)-O-, -NR2-O- C(S)-NR2-, -O-C(S)-, -O-C(S)-O-, -O-C(S)-NR2-, -NR2-C(S)-, -NR2-C(S)-O-, - NR2-C(S)-NR2-, -S-S(O)2-, -S-S(O)2-O-, -S-S(O)2-NR2-, -NR2-O-S(O)-, -NR2- O-S(O)-O-, -NR2-O-S(O)-NR2-, -NR2-O-S(O)2-, -NR2-O-S(O)2-O-, -NR2-O- S(O)2-NR2-, -O-NR2-S(O)-, -O-NR2-S(O)-O-, -O-NR2-S(O)-NR2-, -O-NR2- S(O)2-O-, -O-NR2-S(O)2-NR2-, -O-NR2-S(O)2-, -O-P(O)(R2)2-, -S-P(O)(R2)2-, -NR2-P(O)(R2)2- and combinations of two or more thereof, wherein R2is independently selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C2 - C24 alkenyl groups, C2 - C24 alkynyl groups and C3 - C24 cycloalkyl groups, the alkyl groups, alkenyl groups, alkynyl groups and cycloalkyl groups being optionally substituted; andR1is selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C3 - C24 cycloalkyl groups, C2 - C24 (hetero)aryl groups, C3 - C24 alkyl(hetero)aryl groups and C3 - C24 (hetero)arylalkyl groups, the Ci - C24 alkyl groups, C3 - C24 cycloalkyl groups, C2 - C24 (hetero)aryl groups, C3 - C24 alkyl(hetero)aryl groups and C3 - C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR3wherein R3is independently selected from the group consisting of hydrogen and Ci - C4 alkyl groups; orR1is D, -[(Sp’MZ CSpVD] or -[(Sp2)c-(Z1)d-(Sp3)g-Q1], wherein Sp1, Sp2, Sp3, Sp4, Z1, Z2, D, Q1, b, c, d, e, g and i are as defined above.[00127J In some aspects QI is a triazole derivative of cyclooctyne.

[0128] In some aspects, the Linker Molecule LM further comprises Sp1, Sp2, Sp3and Sp4, if present, which are independently selected from the group consisting of linear or branched Ci- C20 alkylene groups, the alkylene groups being optionally substituted and optionally interrupted by one or more heteroatoms selected from the group consisting of O, S and NR3, wherein R3is independently selected from the group consisting of hydrogen and Ci - C4 alkyl groups

[0129] In aspects, the cleavable linker is a linker as disclosed in US Patent No. US9,636,421, the disclosure of which is hereby incorporated by reference herein.

[0130] In aspects, the Linker Molecule LM comprises one or more polar spacers. In aspects, the polar spacer is a carbamoyl sulfamide. Examples of spacers that can be used are found in US Patent Nos. US9,636,421 and US10,792,369, which are hereby incorporated by reference herein.

[0131] In aspects, the B7-H3-ADC comprises two, three, four, five, six, seven, eight, nine or ten cytotoxic drug moieties, which may be the same, or may independently be the same or different from another cytotoxic drug moiety of the B7-H3-ADC. In one aspect, each such cytotoxic drug moiety is conjugated to the Ab of the B7-H3-ADC via a separate Linker Molecule. Alternatively, more than one cytotoxic drug moiety may be attached to the Ab of the B7-H3-ADC via the same Linker Molecule.

[0132] In aspects, the disclosure contemplates B7-H3-ADCs that comprise one or moreLinker Molecule LM camptothecin moiety D, where the LM and D together comprise:B. Exemplary Cytotoxic Drug Moieties

[0133] In aspects, the cytotoxic drug moiety of the B7-H3-ADC comprises a cytotoxin, a radioisotope, an immunomodulator, a cytokine, a lymphokine, a chemokine, a growth factor,a tumor necrosis factor, a hormone, a hormone antagonist, an enzyme, an oligonucleotide, a DNA molecule, an RNA molecule, an siRNA molecule, an RNAi molecule, a microRNA molecule, a photoactive therapeutic agent, an anti-angiogenic agent, a pro-apoptotic agent, a peptide, a lipid, a carbohydrate, a chelating agent, or a combination thereof.1. Topoisomerase Inhibitors

[0134] In aspects, the B7-H3-ADC can comprise a topoisomerase inhibitor cytotoxic drug moiety. As used herein the term “topoisomerase inhibitor” or “DNA topoisomerase inhibitor” is a compound that interferes with the activity of a topoisomerase.

[0135] Topoisomerase enzymes play a vital role in cellular proliferation and replication, altering the supercoiling of double-stranded DNA by catalyzing the breaking and rejoining of the phosphodiester backbone of DNA strands during the normal cell cycle. DNA strand separation is obligatory to transcribe and replicate genomes by copying each base by RNA and DNA polymerases. (Pommier et al., DNA topoisomerases and their poisoning by anticancer and antibacterial drugs, Chem. & Biol. Review 17 (2010) 421-433). Because of DNA's doublehelical structure, replication generates catenated progenies that have to be unlinked by topoisomerases prior to cytokinesis. Two enzymes that play a role in this uncoiling and recoiling process are topoisomerase I and topoisomerase II. They also play a significant role in fixing DNA damage that occurs as a result of exposure to DNA damaging agents, for example, radiation exposure or chemotherapeutics.

[0136] Topoisomerases are classified as type I and type II. Type I enzymes cleave one DNA strand at a time and type II both strands to perform their catalytic functions. All topoisomerases cleave the DNA phosphodiester backbone by nucleophilic attack from a catalytic tyrosine residue which becomes linked to the phosphate end (P-Y) of the DNA break. Those reactions are highly reversible and leave the DNA sequence unchanged following topoisomerization (Pommier et al., DNA topoisomerases and their poisoning by anti cancer and antibacterial drugs, Chem. & Biol. Review 17 (2010) 421-433).

[0137] A number of topoisomerase type I (Topo 1) inhibitors have been evaluated as anticancer therapeutics. Camptothecin was first identified from the Chinese tree Camptotheca acuminate (Wall et al., “The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminate,” J. Am. Chem. Soc. (1966) 88: 3888-3890.) A number of camptothecin derivatives, including for example topotecan, irinotecan, belotecan, gimatecan, lurtotecan, diflomotecan, S39625, and exatecan, have been further investigated as anticancer agents (Pommier et al., DNA topoisomerases and their poisoning by anticancer and antibacterial drugs, Chem. & Biol. Review 17 (2010) 421-433).

[0138] In addition to the camptothecin derivatives, several non-camptothecin topoisomerase inhibitors have also been investigated as anticancer agents, including the indolocarb azole edotecarin, indenoisoquinolines NSC 706744 (MJ-III-65), NSC 725776 (LMP-776), and NSC 724998 (LMP-400), dibenzonaphthyridiones such as topovale (ARC- 111), and the aromathecin rosettacin (Pommier et al., DNA topoisomerases and their poisoning by anticancer and antibacterial drugs, Chem. & Biol. Review 17 (2010) 421-433).

[0139] In one embodiment, the topoisomerase inhibitor is selected from a topoisomerase I inhibitor. Known topoisomerase I inhibitors useful in the present invention include, but are not limited to, (S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-lH- pyrano[3',4':6,7]indolizino[l,2-b]quinoline-3,14(4H, 12H)-dione monohydrochloride (topotecan), (S)-4-ethyl-4-hydroxy-lH-pyrano[3',4':6,7]indolizino[l,2-b]quinoline-3,14-(4H, 12H)-dione (camptothecin), (lS,9S)-l-Amino-9-ethyl-5-fluoro-l,2,3,9,12,15-hexahydro-9- hydroxy-4-methyl-l OH, 13H-benzo(de)pyrano(3',4':6,7)indolizino(l,2-b)quinoline-l 0,13- dione (exatecan), (7-(4-methylpiperazinomethylene)-10,l 1 -ethylenedi oxy-20(S)-camptothecin (lurtotecan), or (S)-4, l l-diethyl-3,4,12,14-tetrahydro-4-hydroxy-3, 14-dioxolH- pyrano[3',4':6,7]-indolizino[l,2-b]quinolin-9-yl-[l,4'bipiperidine]-l'-carboxylate (irinotecan), (R)-5-ethyl-9,10-difluoro-5-hydroxy-4,5-dihydrooxepino[3',4':6,7]indolizino[l,2-b]quinoline- 3,15(1H, 13H)-dione (diflomotecan), (4S)-l l-((E)-((l,l-Dimethylethoxy)imino)methyl)-4- ethyl-4-hydroxy-l,12-dihydro-14H-pyrano(3',4':6,7)indolizino(l,2-b)quinoline-3,14(4H)- dione (gimatecan), (S)-8-ethyl-8-hydroxy-15-((4-methylpiperazin-l-yl)methyl)-l l,14- dihydro-2H-[l,4]dioxino[2,3-g]pyrano[3',4':6,7]indolizino[l,2-b]quinoline-9,12(3H,8H)- dione (lurtotecan), (4S)-4-Ethyl-4-hydroxy-l l-[2-[(l-methylethyl)amino]ethyl]-lH-pyrano[3?,4?:6,7]indolizino[l ,2-b]quinoline-3,14(4H, 12H)-dione (belotecan), 6-((l,3- dihydroxypropan-2-yl)amino)-2,10-dihydroxy-12-((2R,3R,4S,5S,6R)-3,4,5-trihydroxy-6- (hydroxymethyl)tetrahydro-2H-pyran-2-yl)-12,13-dihydro-5H-indolo[2,3-a]pyrrolo[3,4- c]carbazole-5,7(6H)-dione (edotecarin), 8,9-dimethoxy-5-(2-N,N-dimethylaminoethyl)-2,3- methylenedioxy-5H-dibenzo(c,h)(l,6)naphthyridin-6-one (topovale), benzo[6,7]indolizino[l,2-b]quinolin-l l(13H)-one (rosettacin), (S)-4-ethyl-4-hydroxy-l l-(2- (trimethylsilyl)ethyl)-lH-pyrano[3',4':6,7]indolizino[l,2-b]quinoline-3,14(4H, 12H)-dione (cositecan), tetrakis{(4S)-9-[([l,4'-bipiperidinyl]-l'-carbonyl)oxy]-4,l l-diethyl-3,14-dioxo- 3,4,12,14-tetrahydro-lH-pyrano[3',4':6,7]indolizino[l,2-b]quinolin-4-yl} N,N',N",N"'-{methanetetrayltetrakis[methylenepoly(oxyethylene)oxy(l -oxoethylene)] } tetraglycinate tetrahydrochloride (etirinotecan pegol), 10-hydroxy -camptothecin (HOCPT), 9- nitrocamptothecin (rubitecan), SN38 (7-ethyl-10-hydroxycamptothecin), and 10-hydroxy-9- nitrocamptothecin (CPT109), (R)-9-chloro-5-ethyl-5-hydroxy-10-methyl-12-((4- methylpiperidin-l-yl)methyl)-4,5-dihydrooxepino[3',4':6,7]indolizino[l,2-b]quinoline- 3,15(lH,13H)-dione (elmotecan).

[0140] In addition to the Topo 1 inhibitors, a number of anti-cancer agents have been investigated that target topoisomerase type II (Topo 2) enzymes, including etoposide, teniposide, and the DNA intercalators doxorubicin, daunorubicin, aclarubicin, amsacrine, dexrazoxane, TAS-103, the quinolone CP-115,963, the ellipticines including ellipticinium, azatoxins, genistein, VP- 16, VM-26, mitoxantrone, amonafidem, and saintopin.

[0141] In one embodiment, the topoisomerase inhibitor is selected from a topoisomerase II inhibitor. Known topoisomerase II inhibitors useful in the present invention include, but are not limited to, amonafide and derivatives and analogs thereof, etoposide, teniposide, doxorubicin, daunorubicin, aclarubicin, amsacrine, dexrazoxane, TAS-103, the quinolone CP- 115,963, the ellipticines including ellipticinium, azatoxins, genistein, VP-16, VM-26, mitoxantrone, amonafidem, and saintopin.2. Camptothecin Cytotoxic Drug Moieties

[0142] In aspects, the B7-H3-ADC can comprise a camptothecin cytotoxic drug moiety:

[0143] As used herein the term "camptothecin" means that class of compounds considered to be camptothecins, camptothecin analogs, camptothecin derivatives or camptothecin conjugates. These compounds are based on the characteristic five-ring backbone of camptothecin.

[0144] Camptothecin (CPT), a plant alkaloid, was found to have anticancer activity in the late 1950's. Camptothecin, whether substituted or unsubstituted, is believed to intervene in the mechanism of action of the nuclear enzyme topoisomerase I (topo I), arresting cells in the S phase. Without being bound by theory, it is believed that CPT accomplishes this by stabilizing the covalently linked complexes of DNA-topo I (termed cleavable complexes), thus halting the progression of replication forks. This collision of the replication fork with the cleavable complexes is believed to trigger the apoptotic pathway. Z. Darzynkiewicz et al., The Cell Cycle Effects of Camptothecin, 803 Annals of the New York Academy of Sciences 93 (1996). DNA strand breaks are also implicated in the cytotoxic effects of CPT. F. Traganos et al., Induction of Apoptosis by Camptothecin and Topotecan, 803 Annals of the New York Academy of Sciences 101 (1996).

[0145] Examples of camptothecin include SN-38 (5-10-hydroxycamptothecin), irinotecan (CAMPTOSAR; 7-ethyl-10-[4-(l-piperidino)-l-piperidino]- carbonyloxycamptothecin), topotecan (HYCAMPTIN; (S)-9-N,N-dimethylaminoethyl-10- hydroxycamptothecin), 9-aminocamptothecin (9-amino-20(S)-camptothecin), 9- nitrocamptothecin (also called rubitecan), lurtotecan (7-(4-methylpiperazinomethylene)-10,l l- ethylenedioxy-20(S)-camptothecin), exatecan, karenitecin, and a homocamptothecin. The structures and clinical information for some camptothecin compounds can be found in Garcia- Carbonero, et al., Clin. Cancer Res. (March 2002) 8: 641-661. Examples of camptothecincompounds can also be found in U.S. Pat. Nos. 4,604,463, 6,403,569, and 5,004,758, and in WO 2004 / 012661, WO 2003 / 101998, WO 2003 / 101996, WO 2003 / 101406, WO 2003 / 093274, WO 2003 / 086471, WO 01 / 76597, WO 01 / 64194, WO 00 / 70275, WO 00 / 53607, WO 99 / 17805, WO 99 / 17804, WO 99 / 05103, WO 98 / 35969, WO 97 / 28164, WO 97 / 25332, WO 97 / 16454, the contents of all of which are incorporated herein by reference.

[0146] SN-38 (S-10-hydroxycamptothecin), Topotecan, irinotecan, belotecan, and deruxtecan are CPT analogues approved and are used in cancer chemotherapy today:Deruxtecaii

[0147] In aspects, the camptothecin cytotoxic drug moiety is exatecan.3. Pyrrolobenzodiazepine dimers

[0148] In aspects, the B7-H3-ADC can comprise a pyrrolobenzodiazepine (PBD) dimer cytotoxic drug moiety. PBD dimers bind irreversibly to two guanines from opposite DNA strands in the minor groove of DNA without distorting the double helix. As the PBD dimers do not distort the double helix, they are less likely to be removed by DNA repair mechanisms. In aspects the PBD dimer is a dimeric PBD compound as provided in US Patent Nos. 6,562,806 and 11,135,303, each of which is hereby incorporated by reference in its entirety.4. Auristatins

[0149] In aspects, the B7-H3-ADC can comprise an auristatin cytotoxic drug moiety. In aspects, the auristatin is monomethyl auristatin (MMAE). In aspects, the auristatin is monomethyl auristatin F (MMAF). In aspects, the auristatin is auristatin E (AE). In aspects, the auristatin is an auristatin disclosed in United States Patents Nos. 5,208,020; 5,416,064; 6,333,410; 6,340,701; 6,372,738; 6,436,931; 6,441,163; 6,596,757; 7,276,497; 7,585,857; or 7,851,432, each of which is hereby incorporated by reference in its entirety.C. MGC026

[0150] In certain aspects, the B7-H3-ADC is MGC026. MGC026 comprises the Light Chain and Heavy Chain of anti-B7-H3 hmAb-A conjugated to an exatecan payload. The amino acid sequences of the Ab, the cytotoxic exatecan moiety D, and the Linker molecule, LM, in MGC026 are shown below: the Ab comprises:(i) a light chain comprising the amino acid sequence of SEQ ID NO: 13; and(ii) a heavy chain comprising the amino acid sequence of SEQ ID NO: 15; the D comprises exatecan; and the LM comprises a Linker Molecule as described above.

[0151] In aspects, the Linker Molecule and exatecan together as conjugated to the Ab has the structure:V. Methods of Production

[0152] The anti-B7-H3 antibody hmAb-A of the disclosure may be made recombinantly and expressed using any method known in the art for the production of recombinant proteins. For example, nucleic acids encoding the polypeptide chains of such binding molecules can be constructed, introduced into an expression vector, and expressed in suitable host cells. The binding molecules may be recombinantly produced in bacterial cells (e.g., E. coli cells), or eukaryotic cells (e.g., CHO, 293E, COS, NSO cells). In addition, the binding molecules can be expressed in a yeast cell such as Pichia, or Saccharomyces.

[0153] To produce the anti-B7-H3 antibody hmAb-A, one or more polynucleotides encoding the molecule may be constructed, introduced into an expression vector, and then expressed in suitable host cells. Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the hostcells and recover the molecules (See, for example, the techniques described in Green, M R. et al., (2012), MOLECULAR CLONING, A LABORATORY MANUAL, 4th Ed., Cold Spring Harbor Laboratory, Cold Spring Harbor, NY and Ausubel et al. eds., 1998, CURRENT P OTOCOLS IN MOLECULAR BIOLOGY, John Wiley & Sons, NY). The expression vector(s) should have characteristics that permit replication of the vector in the host cell. The vector should also have promoter and signal sequences necessary for expression in the host cells. Such sequences are well known in the art. In addition to the nucleic acid sequence(s) encoding such binding molecules, the recombinant expression vectors may carry additional sequences, such as sequences that regulate replication of the vector in host cells (e.g., origins of replication) and selectable marker genes. Another method that may be employed is to express the gene sequence in plants (e.g., tobacco) or a transgenic animal. Suitable methods useful for expressing such binding molecules recombinantly in plants or milk have been disclosed (see, for example, Peeters et al. (2001) "Production Of Antibodies And Antibody Fragments In Plants," Vaccine 19:2756; U.S. Patent No. 5,849,992; and Pollock et al. (1999) " Transgenic Milk As A Method For The Production Of Recombinant Antibodies," J. Immunol Methods 231 :147-157).[00154J Once an anti-B7-H3 antibody hmAb-A has been recombinantly expressed, it may be purified from inside or outside (such as from culture media) of the host cell by any method known in the art for purification of polypeptides or polyproteins. Methods for isolation and purification commonly used for antibody purification (e.g., antibody purification schemes based on antigen selectivity) may be used for the isolation and purification of such molecules and are not limited to any particular method. For example, by for example, column chromatography, filtration, ultrafiltration, salting out, solvent precipitation, solvent extraction, distillation, immunoprecipitation, SDS-polyacrylamide gel electrophoresis, isoelectric focusing, dialysis, and recrystallization. Chromatography includes, e.g., ion exchange, affinity, particularly by affinity for the specific antigen, sizing column chromatography, hydrophobic, gel filtration, reverse-phase, and adsorption (Marshak et al. (1996) STRATEGIES FOR PROTEIN PURIFICATION AND CHARACTERIZATION: A Laboratory Course Manual. (Eds.), Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY).VT. Pharmaceutical Compositions

[0155] Pharmaceutical compositions for formulating B7-H3 ADCs as described herein include bulk drug compositions useful in the manufacture of pharmaceutical compositions (e.g., impure or non-sterile compositions) and pharmaceutical compositions (i.e., compositions that are suitable for administration to a subject or patient) that can be used in the preparation of unit dosage forms. Such compositions comprise a prophylactically or therapeutically effective amount of the B7-H3-ADC described herein, or a combination of such agents and a pharmaceutically acceptable carrier. Preferably, the pharmaceutical compositions comprise a prophylactically or therapeutically effective amount of the B7-H3-ADC and a pharmaceutically acceptable carrier. Also contemplated are such pharmaceutical compositions that additionally include a second therapeutic antibody (e.g., tumor-specific monoclonal antibody) that is specific for a particular cancer antigen, and a pharmaceutically acceptable carri er.

[0156] As used herein, the term "pharmaceutically acceptable carrier" means a diluent, solvent, dispersion media, antibacterial and antifungal agents, excipient, or vehicle approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia as being suitable for administration to animals, and more particularly to humans. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. These compositions can take the form of solutions, suspensions, emulsion, tablets, pills, capsules, powders, sustained-release formulations and the like.

[0157] Generally, the ingredients of compositions are supplied either separately or mixed together in a dose form, for example, as a dry lyophilized powder or water-free concentrate, or as an aqueous solution in a hermetically sealed container such as a vial, ampoule or sachet indicating the quantity of active agent. Where the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the composition is administered by injection, an ampoule of sterile water forinjection, saline or other diluent can be provided so that the ingredients may be mixed prior to administration.VII. Pharmaceutical Kits

[0158] The disclosure also provides a pharmaceutical pack or kit comprising one or more containers containing a pharmaceutical composition or pharmaceutical compositions and instructional material (e. ., a notice, package insert, instruction, etc.). Additionally, one or more other prophylactic or therapeutic agents useful for the treatment of a disease can also be included in the pharmaceutical kit. The containers of such pharmaceutical kits may, for example, comprise one or more hermetically sealed vials, ampoules, sachets, etc., indicating the quantity of active agent contained therein. Where the composition is to be administered by infusion, the container may be an infusion bottle, bag, etc. containing a sterile pharmaceuticalgrade solution (e.g. , water, saline, a buffer, etc.). Where the compositions are to be administered by injection, the pharmaceutical kit may contain an ampoule of sterile water, saline or other diluent for injection, so as to facilitate the mixing of the components of the pharmaceutical kit for administration to a subject (e.g., a human patient or other mammal). In aspects, a pharmaceutical pack or kit comprises a B7-H3-ADC pharmaceutical composition and instructional material.

[0159] In one aspect, a B7-H3-ADC of such kit is supplied as a dry sterilized lyophilized powder or water-free concentrate in a hermetically sealed container and can be reconstituted, e.g., with water, saline, or other diluent to the appropriate concentration for administration to a subject. In another aspect, a B7-H3-ADC of such kit is supplied as an aqueous solution in a hermetically sealed container and can be diluted, e.g., with water, saline, or other diluent, to the appropriate concentration for administration to a subject. The kit can further comprise one or more other prophylactic and / or therapeutic agents useful for the treatment of cancer, in one or more containers; and / or the kit can further comprise one or more cytotoxic antibodies that bind one or more cancer antigens associated with cancer. In certain aspects, the other prophylactic or therapeutic agent is a chemotherapeutic agent. In other aspects, the prophylactic or therapeutic agent is a biological agent or hormonal therapeutic agent.

[0160] The included instructional material of the pharmaceutical kits may, for example, be of a content and format prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, and may indicate approval by the agency of the manufacture, sale or use of the pharmaceutical composition for human administration and / or for human therapy. The instructional material may, for example provide information relating to the contained dose of the pharmaceutical composition, modes of how it may be prepared (e.g, reconstituted), and how it may be administered, etc. Such instructions may further provide information relating to the dose and administration of one or more pharmaceutical composition that are not provided in the kit.VIII. Uses of B7-H3-ADCs

[0161] A B7-H3-ADC as described herein may be used to treat or prevent a variety of disorders, including cancer, including for example a cancer in which B7-H3 is expressed. Accordingly, the disclosure provides methods of treating cancer, such methods comprising administering a B7-H3-ADC to a subject in need thereof. In certain aspects, the disclosure provides methods of treating cancer, such methods comprising administering MGC026 to a subject in need thereof. As used herein, the term "subject" refers to a human (i.e., a human patient) or other mammal. Non-limiting dosing regimens for administering such therapy to a subject in need thereof are provided herein.

[0162] In aspects, the cancers that may be treated by the B7-H3-ADCS described herein include cancers selected from the group consisting of: an adrenal gland tumor, an AIDS- associated cancer, an alveolar soft part sarcoma, an astrocytic tumor, an adrenal cancer, a bladder cancer, a bone cancer, a brain and spinal cord cancer, a metastatic brain tumor, a B-cell cancer, a breast cancer, a carotid body tumors, a cervical cancer, a chondrosarcoma, a chordoma, a chromophobe renal cell carcinoma, a clear cell carcinoma, a colon cancer, a colorectal cancer, a cutaneous benign fibrous histiocytoma, a desmoplastic small round cell tumor, an ependymoma, a Ewing's tumor, an extraskeletal myxoid chondrosarcoma, a fibrogenesis imperfecta ossium, a fibrous dysplasia of the bone, a gallbladder or bile duct cancer, a gastric cancer, a gestational trophoblastic disease, a germ cell tumor, a head and neck cancer, a glioblastoma, a hematological malignancy, a hepatocellular carcinoma, an islet cell tumor, a Kaposi's Sarcoma, a kidney cancer, a leukemia (e.g., an acute myeloid leukemia), aliposarcoma / malignant lipomatous tumor, a liver cancer, a lymphoma, a lung cancer (e.g, a non-small-cell lung cancer (NSCLC or a small cell lung cancer (SCLC))), a medulloblastoma, a melanoma, a meningioma, a mesothelioma pharyngeal cancer, a multiple endocrine neoplasia, a multiple myeloma, a myelodysplastic syndrome, a neuroblastoma, a neuroendocrine tumors, an ovarian cancer, a pancreatic cancer, a papillary thyroid carcinoma, a parathyroid tumor, a pediatric cancer, a peripheral nerve sheath tumor, a phaeochromocytoma, a pituitary tumor, a prostate cancer, a posterious uveal melanoma, a renal metastatic cancer, a rhabdoid tumor, a rhabdomysarcoma, a sarcoma, a skin cancer, a small round blue cell tumor of childhood (including neuroblastoma and rhabdomyosarcoma), a soft-tissue sarcoma, a squamous cell cancer (e.g., a squamous cell cancer of the head and neck (SCCHN), a stomach cancer, a synovial sarcoma, a testicular cancer, a thymic carcinoma, a thymoma, a thyroid cancer (e.g., a thyroid metastatic cancer), and a uterine cancer.

[0163] In aspects, a B7-H3-ADC may be used in the treatment of adrenal cancer, bladder cancer, breast cancer, colorectal cancer, gastric cancer, gastricesophageal junction cancer, glioblastoma, kidney cancer, lung cancer, non-small-cell lung cancer (NSCLC), acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, Burkett's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, mesothelioma pharyngeal cancer, non-Hodgkin's lymphoma, small lymphocytic lymphoma, multiple myeloma, melanoma, ovarian cancer, platinum-resistant ovarian cancer (PROC), pancreatic cancer, prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), sarcoma, skin cancer, renal cell carcinoma, a small cell lung cancer (SCLC), extensive-stage small cell lung cancer (ES-SCLC), small round blue cell tumors of childhood (including neuroblastoma and rhabdomyosarcoma), squamous cell cancer (e.g, squamous cell cancer of the head and neck (SCCHN), esophageal squamous cell carcinoma), testicular cancer, thyroid cancer (e. ., thyroid metastatic cancer), endometrial cancer, cervical cancer, clear cell renal cell carcinoma, hepatocellular carcinoma, small cell ovarian cancer, small cell colorectal cancer, and uterine cancer.

[0164] In apsects, a B7-H3-ADC may be used in the treatment of colorectal cancer, nonsmall-cell lung cancer (NSCLC), small cell lung cancer (SCLC), melanoma, ovarian cancer,pancreatic cancer, prostate cancer, and squamous cell cancer (e.g., squamous cell cancer of the head and neck (SCCHN).

[0165] In aspects, a B7-H3-ADC may be used in the treatment of melanoma.

[0166] In aspects, a B7-H3-ADC may be used in the treatment of ovarian cancer.

[0167] In aspects, a B7-H3-ADC may be used in the treatment of platinum-resistant ovarian cancer (PROC).

[0168] In aspects, a B7-H3-ADC may be used in the treatment of pancreatic cancer.

[0169] In aspects, a B7-H3-ADC may be used in the treatment of prostate cancer.

[0170] In aspects, a B7-H3-ADC may be used in the treatment of metastatic castrationresistant prostate cancer (mCRPC)

[0171] In aspects, a B7-H3-ADC may be used in the treatment of squamous cell cancer (c. ., squamous cell cancer of the head and neck (SCCHN).

[0172] In aspects, a B7-H3-ADC may be used in the treatment of non-small-cell lung cancer (NSCLC).

[0173] In aspects, a B7-H3-ADC may be used in the treatment of small cell lung cancer (SCLC).

[0174] In aspects, a B7-H3-ADC may be used in the treatment of extensive stage-small- cell lung cancer (ES-SCLC).IX. Methods of Administration

[0175] A B7-H3-ADC of the disclosure can be administered by a variety of methods to a subject, e.g., a subject in need thereof, for example a human patient. For many applications, the route of administration is one of: intravenous injection or infusion (IV), subcutaneous injection (SC), intraperitoneally (IP), or intramuscular injection. It is also possible to use intraarticular delivery. Other modes of parenteral administration can also be used. Examples of suchmodes include: intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, transtracheal, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, and epidural and intrastemal injection.

[0176] A B7-H3-ADC of the disclosure can be administered as a weight-based dose or as a flat dose. The dose can also be selected to reduce or avoid production of antibodies against the administered molecules. Dosage regimens are adjusted to provide the desired response, e.g., a therapeutic response or a combinatorial therapeutic effect. Generally, doses of a B7-H3-ADC (and optionally a further agent) can be used in order to provide a subject with the agent in bioavailable quantities. As used herein, the term "dose" refers to a specified amount of medication taken at one time. The term "dosage" refers to the administering of a specific amount, number, and frequency of doses over a specified period of time; the term dosage thus includes chronological features, such as duration and periodicity.

[0177] The term "weight-based dose" as used herein, refers to a discrete amount of a molecule to be administered per a unit of patient weight, for example milligrams of drug per kilograms of a subject's body weight (mg / kg body weight, abbreviated herein as "mg / kg"). The calculated dose will be administered based on the subject's body weight at baseline. The term "flat dose," as used herein, refers to a dose that is independent of the weight of the patient, and includes physically discrete units of a molecule that are suited as a unitary dose for the subjects to be treated; wherein each unit contains a predetermined quantity of a drug. Typically, a significant (> 10%) change in body weight from baseline or established plateau weight will generally prompt recalculation of dose. Single or multiple doses may be given. Compositions comprising a B7-H3-ADC may be administered to a subject in need thereof via infusion.

[0178] The term "fractionated dose" as used herein, refers to two or more separate administrations of a molecule to be administered to achieve a particular desired dose. A fractionated dose provides that the desired dose can be fractionated into two or more separate administrations. The dose may be fractionated equally and / or unequally between such two or more administrations. In certain aspects, the fractionated dose can be two or more separate administrations within a cycle (e.g., a 3-week or 4-week cycle).EXAMPLES

[0179] Having now generally described the above aspects, the same will be more readily understood through reference to the following Examples. The following examples illustrate various methods for compositions in the diagnostic or treatment methods of the disclosure. The examples are intended to illustrate, but in no way limit, the scope of the appended claims.Example 1 In vitro Cytotoxicity of MGC026

[0180] The ability of MGC026 to mediate cytotoxicity toward B7-H3 -expressing A375.S2 human melanoma cells in vitro was investigated. MGC026 as investigated is the same ADC as described above. The negative control ADC (Ctrl-SYNtecan E) is a humanized control ADC that does not bind to either B7-H3 or any other human and murine protein. Human tumor cells were cultured in DMEM / F-12 + 10% FBS. Cells were washed with PBS and lifted using 0.05% trypsin-EDTA. Antibodies and ADCs were diluted in a 9-point dose response curve (plus no antibody control well) with a final top concentration of lOug / ml (67 nM antibody concentration) and diluted 1 :3 or 1 : 10, depending on cell line sensitivity. ADCs were made up at 5X final concentration and 20 ul are added to 96-well tissue culture treated plates. Suspended cells were plated at 5,000 cells / well and added to ADC wells at 80 ul / well (100 ul / well total volume).

[0181] Plates were incubated at 37°C for 7 days. Cell viability was measured using alamarBlue (Trek Diagnostics #00-100; lOul added to each well) and allowed to develop. Plates were read on a Gemini plate reader (Molecular Devices) according to specifications for alamarBlue.

[0182] Data was analyzed using Graph Pad Prism (4-parameter curve fit analysis) to determine IC50 values.

[0183] The cytotoxicity curves from this study are presented in FIG. 1. MGC026 mediated dose-dependent cytotoxicity toward the A375.S2 human melanoma line in vitro, with an IC50 = 31pM. The negative control ADC (Ctrl-SYNtecan E) was approximately 1000-fold less active than MGC026, confirming the specificity of the cytotoxic activity of MGC026.Example 2 ADCC Assay

[0184] The ability of unconjugated MGA017 (unconjugated B7-H3 antibody equivalent to the antibody used in conjugates), conjugated MGC018 (a B7-H3 ADC with the same antibody and duocarmycin cytotoxic drug moiety; see, W02017 / 180813A1) and conjugated MGC026 (as described above) to mediate antibody-dependent cellular cytotoxicity (ADCC) was assessed. The ADCC assay utilizes primary peripheral blood mononuclear cells (PBMCs) as a source of natural killer (NK) cells. The ADCC assay tests the ability of antibodies to bridge an interaction between the antigen-positive target cells and NK effector cells, and subsequent killing of the target cells by NK cells. Adherent target tumor cells grown in F-12 / DMEM containing 10% fetal bovine serum (FBS) were detached with 0.25% Trypsin-EDTA solution and collected by centrifugation at 1000 rpm for 5 min. Collected tumor cells were rinsed once with PBS then re-suspended in assay medium (RPMI without phenol red + 5% FBS) and plated into 96-well U-bottom cell culture treated plate at 20,000 cells / well. Test antibodies were serially diluted and plated onto the cells in triplicate. Then 600,000 fresh PBMCs were added to the wells (30: 1 effector: target ratio; E: T) and plates were incubated at 37° C / 5% CO2 overnight.

[0185] Following incubation, 15 pL of 10X lysis solution (Promega # G182A) were added to the maximum release control wells for 10 minutes to completely lyse the target cells, then the plates were centrifuged at 1200 rpm for 5 minutes. 50 pL of supernatant were transferred from each assay plate well to a clear flat bottom ELISA plate and 50 pL of lactate dehydrogenase (LDH) substrate solution (Promega # G1780) was added to each well. Plates were incubated for 5-10 minutes at room temperature in the dark, then 50 pL of Stop solution was added. The optical density was measured at 490 nm within 1 hour on a Emax plate reader (Molecular Devices). The percent cytotoxicity was calculated as described below and further analyzed using GraphPad Prism5 software.

[0186] Specific cell lysis was calculated from optical density (OD) data using the following formula where maximum release (MR), antibody-indpendent cytotoxicity (AICC), and cell spontaneous release (SR) were incorprated:Cytotoxicity (%) = 100 x (OD of Sample - OD of AICC) / (OD of MR - OD of SR)

[0187] The ADCC assay results are presented in FIGs. 2A-2E. MGA017 and MGC018 mediated ADCC toward the five B7-H3-expressing tumor cell lines tested. MGC026 did not mediate ADCC toward the five tumor cell lines.Example 3 Surface Plasmon Resonance Assay

[0188] Surface Plasmon Resonance (SPR) was used to analyze binding to B7-H3. Anti-penta-His tag mAb was immobilized on the SPR CM5 sensor chip according to the procedure recommended by the manufacturer. Briefly, the carboxyl groups on the sensor chip surface were activated with an injection of a solution containing 0.2 M N-ethyl-N-(3dietylamino-propyl) carbodimide and 0.05-M N-hydroxy-succinimide. The mAb (5 pg / mL) was injected over the activated CM5 surface in 10-mM sodium acetate, pH 5.0, at a flow rate 5 pL / min, followed by 1-M ethanolamine for deactivation of remaining amine-reactive groups.

[0189] The His-tagged human or cynomolgus monkey B7-H3(4Ig) extracellular domain proteins were injected at a flow rate of 20 pL / min for 10 seconds to reach approximately 30 resonance units (RU) of captured ligand suitable for kinetic studies.

[0190] MGC026 or MGA017 (both as described above) was injected for 120 seconds at a flow rate of 30 pL / min (in duplicate) in HBS-EP buffer at concentrations of 0, 12.5, 25, 50, 100, and 200 nM. Regeneration of the immobilized anti -penta His mAb surface was performed by pulse injection of 10 mM glycine, pH 1.5.

[0191] Reference curves were obtained by injection of each dilution of MGC026 or MGA017 over the treated surface with no immobilized protein. Binding curves at zero concentration were subtracted as a blank. The kinetic constants kaand kafor single-arm affinity interactions were estimated by global analysis of the association / dissociation (ka / ka) curves to the bivalent analyte interaction model (BIA evaluation software v4.1). The dissociation equilibrium constant (KD) was calculated as KD = ka / ka.

[0192] The antibodies MGC026 and MGA017 both demonstrated similar single-arm affinity binding to captured human and cynomolgus monkey B7-H3(4Ig) (FIG. 3A). Kinetic constants calculated by the bivalent analyte model for single-arm interaction are shown in Table 1. The KD values determined for interaction with captured human B7-H3(4Ig) were similar for all interactions and varied between 16 and 18 nM or 6 and 8 nM for human or cynomolgus monkey B7-H3(4Ig), respectively. The difference in the magnitude of the overall binding responses may be due to differences in the available binding sites of the two antigens as captured on the sensor chip surface and does not reflect the kinetic parameters.* Average data from two independent experiments (shown in parenthesis)

[0193] The His tagged human CD16A (Fc gamma RIIIA) extracellular domain proteins were injected at a flow rate of 20 pL / min for 10 seconds to reach approximately 120 resonance units (RU) of captured ligand. MGC026 or MGA017 was injected for 120 seconds at a flow rate of 30 pL / min (in duplicate) in HBS EP buffer at concentrations of 0, 62.5, 125, 250, 500, and 1000 nM. Regeneration of the immobilized anti penta His mAb surface was performed by pulse injection of 10 mM glycine, pH 1.5. The plot of equilibrium binding responses of Fc part of antibodies to captured human CD16A alleles versus mAb concentrations was fitted to Steady State affinity model to obtain KD values.

[0194] The unconjugated antibody MGA017 bound to captured human CD16 alleles. MGA017 bound with higher affinity to the higher affinity CD16A 158V allele, compared to the lower affinity CD16A158F allele, as expected. MGC026, the conjugated antibody, did not bind to either CD16A allele (FIG. 3B). Therefore, MGC026 would not be expected to mediate effector function through Fc gamma receptor CD16A, and this is consistent with the inability of MGC026 to mediate ADCC in vitro (see Example 2). The absence of effector function is potentially advantageous for MGC026, as binding of an ADC to effector cells could reduce tumor localization, hinder internalization and lead to off-target toxicities (McDonagh, Mol Cancer Ther 2008; Perez, Drug Discovery Today 2013).

[0195] Surface Plasmon Resonance was also used to analyze binding of recombinant B 7- H3 comprising amino acids L29 to G245 of human B7-H3 fused to HSV and lOxHis tags at the C-terminus to MGA017 and MGA017 (D96E) (MGA017 with D96E mutation in the heavy chain). Binding studies were performed in HBS-EP plus buffer (10 mM HEPES, pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.05% P20 surfactant). MGA017 or MGA017 (D96E) was captured by a polyclonal goat-anti-human Fc antibody immobilized on a CM4 chip. Binding of recombinant B7-H3 protein was analyzed at concentrations of 12.5, 50 and 200 nM. Equilibrium dissociation constant (KD), association rate (ka) and dissociation rate (kd) values were determined by a global fit of binding curves to the Langmuir 1 :1 binding model (BIAevaluation software, Version 4.1) as shown in Table 2. MGA017 (D96E) (FIG. 3D) exhibited similar binding affinity to the recombinant B7-H3 as MGA017 (FIG. 3C).Example 4 MGC026 Exhibits Potent in vivo Activity

[0196] In order to further demonstrate the antitumor activity of MGC026, the abovedescribed MGC026 molecule was evaluated for in vivo toxicity in a CD-I nude mouse modelusing different tumor cell lines. In brief, approximately 5 x 106viable tumor cells suspended in 1: 1 serum-free media and Matrigel Basement Membrane Matrix were subcutaneously inoculated into the flank of the CD-I nude mice (Charles River Laboratories). When tumors had reached a mean volume ranging from approximately 100-140 mm3, the mice were randomized and MGC026 or vehicle control were administered intravenously. Select studies included a nontargeting control ADC or MGC018 (as described above). In these studies, one dose of the MGC026, MGC018, nontargeting control ADC, or vehicle control was administered once weekly (QW). Tumors were measured twice weekly by orthogonal measurements with electronic calipers, with tumor volumes calculated as: (length x width x height) / 2. An animal was considered to have a Partial Regression ("PR") when tumor volume was reduced by 50% or greater when compared to the tumor volume at the day of first dose administration. A finding that the tumor volume of treated animals had decreased to < 5 mm3during the study period was considered to denote a Complete Response ("CR"). The tumor volume (relative to vehicle control) was determined ("T / C"). Antitumor activity was evaluated according to National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.In vivo Activity Against Calu-6 Non-Small Cell Lung Cancer Tumor Cells

[0197] The results of this study with respect to subcutaneously inoculated Calu-6 lung adenocarcinoma tumor cells are presented in Table 3 and in FIG. 4, and show responsiveness against the Calu-6 tumor cells.a % T / C - percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 1147 mm on Day 49. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody; mg: milligram; kg: kilogram; IV: intravenous: PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or when the tumor volume was non-measurable ( 5 mm3) during the course of the study).

[0198] Female CD-I Nude (Homozygous) mice (n = 6 / group) were implanted subcutaneously with Calu-6 (lung adenocarcinoma) tumor cells (5 x 106cells) suspended in serum free culture media / Matrigel (1 : 1) in a volume of 0.1 mL per mouse. When tumors reached approximately 100 mm3(104 ± 25 mm3mean tumor volume ± standard deviation) on Day 22, mice were randomized and treated intravenously with vehicle control (IX PBS) or targeting ADC (MGC026 or MGC018), on Day 22 (arrow) at the dose levels indicated for a total of one dose. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed at all three dose levels following treatment with MGC026 and both dose levels with MGC018.

[0199] MGC026 reduced tumor volumes by 99% on Day 49 for all dose levels tested and was highly active at each dose based on NCI standards (1% T / C). MGC018 was highly active at 10 mg / kg (1% T / C) and active at 3 mg / kg (22% T / C). MGC026 induced partial regressions in 6 / 6 animals at doses of 10 mg / kg, 6 mg / kg, and 3 mg / kg and complete regressions in 5 / 6, 6 / 6, and 4 / 6 animals at doses of 10 mg / kg, 6 mg / kg, and 3 mg / kg, respectively. MGC018 induced partial regressions in 6 / 6 animals at 10 mg / kg and 2 / 6 animals at 3 mg / kg with 4 / 6 complete regressions at a dose of 10 mg / kg. MGC026 antitumor activity and tumor regressions persisted through the end of the study at all dose levels tested whereas MGC018 tumor regressions persisted at the 10 mg / kg dose. The tumor H-score was determined to be 95 by immunohistochemistry (IHC).In vivo Activity at the Minimum Efficacious Dose Against Calu-6 Lung Adenocarcinoma Tumor Cells

[0200] The results of this study with respect to subcutaneously inoculated Calu-6 lung adenocarcinoma tumor cells are presented in Table 4 and in FIG. 5, and show responsiveness against the Calu-6 tumor cells.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 1168 mm3on Day 41. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody; mg: milligram; kg: kilogram; IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0201] Female CD-I Nude (Homozygous) mice (n = 5 / group) were implanted subcutaneously with Calu-6 (lung adenocarcinoma) tumor cells (5 x io6cells) suspended in serum free culture media / Matrigel (1 : 1) in a volume of 0.1 mb per mouse. When tumors reached approximately 100 mm3(100 ± 22 mm3mean tumor volume ± standard deviation) on Day 16, mice were randomized and treated intravenously with vehicle control (IX PBS), or targeting ADCs (MGC026 or MGC018), on Day 16 (arrow) at the dose level indicated for a total of one dose. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed following treatment with MGC026 and MGC018.

[0202] MGC026 reduced tumor volumes by 87% on Day 41 and was active at the dose level tested (3 mg / kg) based on NCI standards (13% T / C). MGC018 was active at 3 mg / kg (34% T / C). MGC026 induced partial regressions in 2 / 5 animals and no complete regressions. At 3 mg / kg, MGC018 did not induce partial or complete regressions (0 / 5 animals). The tumor H-score was determined to be 210 by IHC.In vivo Activity Against A375.S2 Melanoma Tumor Cells

[0203] The results of this study with respect to subcutaneously inoculated A375.S2 melanoma tumor cells are presented in Table 5 and in FIG. 6, and show responsiveness against the A375.S2 tumor cells.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C) Calculated when the vehicle tumor volume reached a mean of 1133 mm3on Day 57. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody: mg: milligram; kg: kilogram: IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or w hen the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0204] Female CD-I Nude (Homozygous) mice (n = 6 / group) were implanted subcutaneously with A375.S2 (melanoma) tumor cells (5 x 106cells) suspended in serum free culture media / Matrigel (1 : 1) in a volume of 0.1 mL per mouse. When tumors reached approximately 100 mm3(102 ± 33 mm3mean tumor volume ± standard deviation) on Day 24, mice were randomized and treated intravenously with vehicle control (IX PBS) or targeting ADC (MGC026 or MGC018), on Day 25 (arrow) at the dose levels indicated for a total of one dose. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed at all three dose levels of MGC026 and both dose levels of MGC018.

[0205] A decrease in tumor volume was observed following treatment with MGC026 at 10 mg / kg with a 99% reduction in tumor volume on Day 57. Treatment with 6 mg / kg and 3 mg / kg MGC026 resulted in a 100% reduction in tumor volume. Based on NCI standards, MGC026 was highly active at 10 mg / kg (1% T / C), 6 mg / kg (0% T / C) and 3 mg / kg (0% T / C). MGC018 was highly active at both 10 mg / kg and 3 mg / kg (0% T / C). MGC026 induced partial regressions and complete regressions in 6 / 6 animals at doses of 10 mg / kg, 6 mg / kg, and 3 mg / kg. MGC018 induced partial regression and complete regressions in 6 / 6 animals at dosesof 10 mg / kg and 3 mg / kg. MGC026 and MGC018 antitumor activity and complete tumor regressions persisted through the end of the study for all dose levels tested. The tumor H-score was determined to be 180 by IHC.In vivo Activity at the Minimum Efficacious Dose Against A375.S2 Melanoma Tumor Cells

[0206] The results of this study with respect to subcutaneously inoculated A375.S2 melanoma tumor cells are presented in Table 6 and in FIGs. 7A-7C, and show responsiveness against the A375.S2 tumor cells.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 1090 mm on Day 80. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards: a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody: mg: milligram; kg: kilogram; IV: intravenous: PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0207] Female CD-I Nude (Homozygous) mice (n = 5 / group) were implanted subcutaneously with A375.S2 (melanoma) tumor cells (5 x 106cells) suspended in serum free culture media / Matrigel (1:1) in a volume of 0.1 mL per mouse. When tumors reached approximately 100 mm3(87 ± 21 mm3mean tumor volume ± standard deviation) on Day 26, mice were randomized and treated intravenously with vehicle control (IX PBS), or targeting ADC (MGC026 or MGC018) on Day 26 (arrow) at the dose levels indicated (A, B, C) for a total of one dose. Tumor volume is shown as group mean ± standard error of the mean (SEM)with the upper SEM bar visible. Antitumor activity was observed following treatment with MGC026 and MGC018 at the 3 doses tested.

[0208] MGC026 reduced tumor volumes by 100% on Day 80 and was highly active at 3 mg / kg (0% T / C) and 1 mg / kg (7% TC) and active at 0.3 mg / kg (16% T / C) based on NCI standards. Treatment with MGC018 was highly active at 3 mg / kg (0% T / C), active at 1 mg / kg (41% T / C) and inactive at 0.3 mg / kg (54% T / C). Although the nontargeting control ADC exhibited antitumor activity at 3 mg / kg and 0.3 mg / kg, the activity was limited and significantly less than that observed with targeted MGC026s and based on NCI standards was considered inactive at 3 mg / kg and 0.3 mg / kg (74%, 50% T / C). MGC026 induced partial regressions in 5 / 5 animals at the 3 mg / kg and 1 mg / kg dose levels and 4 / 5 at the 0.3 mg / kg dose level. Complete regressions were seen with 5 / 5 and 3 / 5 for 3 mg / kg and 1 mg / kg, respectively. MGC018 induced partial regressions in 5 / 5 and 3 / 5 at 3 mg / kg and 1 mg / kg, respectively and complete regressions in 4 / 5 animals at 3 mg / kg. Treatment with MGC026 and MGC018 maintained antitumor control at the 3 mg / kg dose level. The tumor H-score was determined to be 210 by IHC.In vivo Activity Against FaDu Pharynx, Head and Neck Squamous Cell Carcinoma Tumor Cells

[0209] The results of this study with respect to subcutaneously inoculated FaDu pharynx, head and neck squamous cell carcinoma tumor cells are presented in Table 7 and in FIG. 8, and show responsiveness against the FaDu tumor cells.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 1243 mmson Day 35. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody: mg: milligram; kg: kilogram; IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0210] Female CD-I Nude (Homozygous) mice (n = 7 / group) were implanted subcutaneously with FaDu (pharynx, head and neck squamous cell carcinoma) tumor cells (5 x 106cells) suspended in serum free culture media / Matrigel (1 : 1) in a volume of 0.1 mL per mouse. When tumors reached approximately 100 mm3(125 ± 25 mm3mean tumor volume ± standard deviation) on Day 15, mice were randomized and treated intravenously with vehicle control (IX PBS), targeting ADC (MGC026), or nontargeting control ADC on Day 15 (arrow) at the dose levels indicated for a total of one dose. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Dose response antitumor activity was observed at all three dose levels of MGC026.

[0211] A decrease in tumor volume was observed following treatment with MGC026 at 10 mg / kg with an 88% reduction in tumor volume on Day 35 compared to the vehicle control. Treatment at 6 mg / kg and 3 mg / kg with MGC026 resulted in an 93% and 86% reduction in tumor volume, respectively. Based on NCI standards, MGC026 was highly active at 6 mg / kg (7% T / C) and active at 10 mg / kg (12% T / C) and 3 mg / kg (14% T / C). Although the nontargeting control ADC exhibited antitumor activity, the activity was limited, significantly less than that observed with MGC026 and based on NCI standards was considered inactive at 10 mg / kg, 6 mg / kg, and 3 mg / kg (60%, 74%, 87% T / C). MGC026 induced partial regressions in 6 / 7, 4 / 7, and 3 / 7 animals at doses of 10 mg / kg, 6 mg / kg, and 3 mg / kg, respectively, and complete regressions in 1 / 7 animals at all three doses tested. By comparison, the nontargeting control ADC exhibited 1 / 7 partial regressions at doses of 6 mg / kg and 3 mg / kg and 1 / 7 complete regressions when dosed at 6 mg / kg. The tumor H-score was determined to be 200 by IHC.In vivo Activity Against Hs700T Pancreatic Adenocarcinoma Tumor Cells

[0212] The results of this study with respect to subcutaneously inoculated Hs700T pancreatic adenocarcinoma tumor cells are presented in Table 8 and in FIG. 9, and show responsiveness against the Hs700T tumor cells.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 1286 mm3on Day 96. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody: mg: milligram; kg: kilogram; IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm ) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0213] Female CD-I Nude (Homozygous) mice (n = 7 / group) were implanted subcutaneously with Hs700T (pancreatic adenocarcinoma) tumor cells (5 x io6cells) suspended in serum free culture media / Matrigel (1 : 1) in a volume of 0.1 mL per mouse. When tumors reached approximately 100 mm3(114 ± 27 mm3mean tumor volume ± standard deviation) on Day 46, mice were randomized and treated intravenously with vehicle control (IX PBS), targeting ADC (MGC026), or nontargeting control ADC on Day 46 (arrow) at the dose levels indicated for a total of one dose. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. MGC026 dose levels differ from the nontargeting control ADC dose levels as the certificate of testing for MGC026 was corrected after study initiation. Antitumor activity was observed at all three dose levels of MGC026 compared to the vehicle control.

[0214] A dose response was seen with the 3 dose levels of MGC026. A decrease in tumor volume was observed following treatment with MGC026 at 7.4 mg / kg with a 96% reduction in tumor volume on Day 96 compared to the vehicle control. Treatment with 4.5 mg / kg and 2.2 mg / kg MGC026 resulted in an 93% and 85% reduction in tumor volume on day 96, respectively. Based on NCI standards, MGC026 was highly active at 7.4 mg / kg (4% T / C) and 4.5 mg / kg (7% T / C) and active at 2.2 mg / kg (15% T / C), whereas the nontargeting control ADC was inactive at 10 mg / kg, 6 mg / kg, and 3 mg / kg (70%, 69%, and 77% T / C). MGC026 inducedpartial regressions in 5 / 7, 4 / 7, and 2 / 7 animals at doses of 7.4 mg / kg, 4.5 mg / kg, and 2.2 mg / kg, respectively, and complete regressions in 1 / 7 and 1 / 7 animals at doses of 7.4 mg / kg and 2.2 mg / kg respectively. By comparison, the nontargeting control ADC group exhibited no partial or complete regressions at any of the 3 dose levels. The tumor H-score was determined to be 295 by IHC.In vivo Activity Against 22Rvl Prostate Carcinoma Tumor Cells

[0215] The results of this study with respect to subcutaneously inoculated 22Rvl prostate carcinoma cell carcinoma tumor cells are presented in Table 9 and in FIG. 10, and show responsiveness against the 22Rvl tumor cells.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 1161 mm3on Day 72. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards: a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody: mg: milligram; kg: kilogram; IV: intravenous: PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0216] Female CD-I Nude (Homozygous) mice (n = 7 / group) were implanted subcutaneously with 22Rvl (prostate carcinoma) tumor cells (5 x 106cells) suspended in serum free culture media / Matrigel (1:1) in a volume of 0.1 mb per mouse. When tumors reached approximately 100 mm3(126 ± 26 mm3mean tumor volume ± standard deviation) on Day 31, mice were randomized and treated intravenously with vehicle control (IX PBS), targeting ADC (MGC026), or nontargeting control ADC on Day 32 (arrow) at the dose levels indicated for a total of one dose. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. MGC026 dose levels differ from the nontargeting control ADCdose levels as the certificate of testing for MGC026 was corrected after study initiation.Antitumor activity was observed at all three dose levels of MGC026.

[0217] A dose response was seen with the 3 dose levels of MGC026. A decrease in tumor volume was observed following treatment with MGC026 at 7.4 mg / kg with a 78% reduction in tumor volume on Day 72 compared to the vehicle control. Treatment with 4.5 mg / kg and 2.2 mg / kg MGC026 resulted in an 77% and 65% reduction in tumor volume, respectively. Based on NCI standards, MGC026 was active at 7.4 mg / kg (22% T / C), 4.4 mg / kg (23% T / C), and 2.2 mg / kg (35% T / C), whereas nontargeting control ADC was inactive at 10 mg / kg, 6 mg / kg, and 3 mg / kg (81%, 72%, 78% T / C). MGC026 induced partial regressions in 5 / 7, 3 / 7, and 2 / 7 animals at doses of 7.4 mg / kg, 4.5 mg / kg, and 2.2 mg / kg, respectively, and no complete regressions. By comparison, the nontargeting control ADC group exhibited no partial or complete regressions at any of the 3 dose levels. The tumor H-score was determined to be 155 by IHC.

[0218] The results of these in vivo studies demonstrate that the MGC026 tested exhibited dose-dependent anti-tumor activity toward B7-H3 -positive tumors in murine xenograft models of lung, head and neck squamous cell carcinoma, pancreatic, prostate, and melanoma.Example 5 MGC026 Exhibits Enhanced Potency in vivo

[0219] In order to further analyze the antitumor activity of MGC026, the antitumor activity of MGC026 or DS-mAb-Dxd (anADC with a M30-H1-L4 antibody, that binds B7-H3, conjugated to deruxtecan (Dxd); see, WO2012147713A1) was assessed using two different tumor cell lines.In vivo Activity Against CaIu-6 Lung Adenocarcinoma Tumor Cells

[0220] The results of this study with respect to subcutaneously inoculated Calu-6 lung adenocarcinoma tumor cells are presented in Table 10 and in FIG. 11A-11C, and show responsiveness against the Calu-6 tumor cells.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 1168 mm3on Day 41. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody: mg: milligram; kg: kilogram; IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm ) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0221] Female CD-I Nude (Homozygous) mice (n = 5 / group) were implanted subcutaneously with Calu-6 (lung adenocarcinoma) tumor cells (5 x io6cells) suspended in serum free culture media / Matrigel (1 : 1) in a volume of 0.1 mL per mouse. When tumors reached approximately 100 mm3(100 ± 22 mm3mean tumor volume ± standard deviation) on Day 16, mice were randomized and treated intravenously with vehicle control (IX PBS) or targeting ADC (MGC026 or DS-mAb-Dxd), on Day 16 (arrow) at the dose levels indicated (A, B, C) for a total of one dose. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed at the 3 mg / kg dose level following treatment with MGC026, whereas no antitumor activity was observed at the 3 mg / kg dose level following treatment with DS-mAb-Dxd.

[0222] MGC026 reduced tumor volumes by 87% on Day 41 at 3 mg / kg and was active at this dose based on NCI standards (13% T / C). DS-mAb-Dxd was inactive at 3 mg / kg. MGC026 induced partial regressions in 2 / 5 animals and no complete regressions at a dose of 3 mg / kg whereas DS-mAb-Dxd had no partial regression or complete regressions at 3 mg / kg. The tumor H-score was determined to be 210 by immunohistochemistry (IHC).In vivo Activity Against A375.S2 Melanoma Tumor Cells

[0223] The antitumor activity of conjugated MGC026 or DS-mAb-Dxd was assessedusing A375.S2 melanoma tumor cells. The results of this study with respect to subcutaneously inoculated A375.S2 melanoma tumor cells are presented in Table 11 and in FIGs. 12A-12C, and show responsiveness against the A375.S2 tumor cells.a. % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 1090 mm3on Day 80. b. Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody; mg: milligram; kg: kilogram; IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0224] Female CD-I Nude (Homozygous) mice (n = 5 / group) were implanted subcutaneously with A375.S2 (melanoma) tumor cells (5 * 106cells) suspended in serum free culture media / Matrigel (1 : 1) in a volume of 0.1 mL per mouse. When tumors reached approximately 100 mm3(87 ± 21 mm3mean tumor volume ± standard deviation) on Day 26, mice were randomized and treated intravenously with vehicle control (IX PBS), or targeting ADC (MGC026 or DS-mAb-Dxd) on Day 26 (arrow) at the dose levels indicated (A, B, C) for a total of one dose. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed following treatment with MGC026 at the 3 doses tested and at 3 mg / kg with DS-mAb-Dxd.

[0225] MGC026 reduced tumor volumes by 100% on Day 80 and was highly active at 3 mg / kg (0% T / C) and 1 mg / kg (7% TC) and active at 0.3 mg / kg (16% T / C) based on NCI standards. Treatment with DS-mAb-Dxd was active at 3 mg / kg (13% T / C) and inactive at 1 mg / kg (84% T / C) and 0.3 mg / kg (100% T / C). MGC026 induced partial regressions in 5 / 5 animals at the 3 mg / kg and 1 mg / kg dose levels and 4 / 5 at the 0.3 mg / kg dose level. Complete regressions were seen with 5 / 5 and 3 / 5 for 3 mg / kg and 1 mg / kg, respectively. D-mAb-Dxdinduced partial regressions in 5 / 5 and complete regressions in 1 / 5 animals at 3 mg / kg. Treatment with MGC026 maintained antitumor control at the 3 mg / kg dose level. The tumor H-score was determined to be 210 by IHC.Example 6 Tolerability Study of MGC026 in Cynomolgus Monkeys

[0226] In order to determine the tolerability of MGC026 (as described above), a preclinical animal study with cynomolgus monkeys was conducted. The study included both a non-GLP and a GLP study.

[0227] In a non-GLP study, doses of 7.4, 22.2, and 44.4 mg / kg of MGC026 were administered by a 4-minute intravenous (IV) infusion to 2 animals each, at once every two weeks (Q2W) dose interval for a total of two doses, to a total of 6 cynomolgus monkeys (Macaca fascicularis) (Table 12).

[0228] MGC026 administration of 7.4, 22.2, or 44.4 mg / kg / dose at Q2W (study days 1 and 15) was well tolerated. Study evaluations included: toxicokinetic evaluation, body weight, food consumption, clinical observations, clinical pathology (hematology, clinical chemistry), and anatomical pathology. Study findings were limited to anatomical pathology and consisted of decreased cellularity observed (lymphocytes) in the thymus in one of two animals administered 7.4 mg / kg (minimal), and both animals administered 44.4 mg / kg (minimal and mild)

[0229] In a GLP study, doses of 10, 30, and 50 mg / kg of MGC026 were administered by a 15-minute intravenous (IV) infusion to 6, 10, and 10 animals, respectively, at once every threeweeks (Q3W) dose interval for a total of three doses, to a total of 26 cynomolgus monkeys(Table 13)

[0230] MGC026 administration of 10, 30, or 50 mg / kg / dose at Q3W (study days 1, 22, and 43) was well tolerated. Study evaluations included: toxicokinetic evaluation, body weight, food consumption, clinical observations, clinical pathology (hematology, clinical chemistry, coagulation, or urinalysis), ECGs, blood pressure, respiratory rate, heart rate, or neurological assessment (reactions to environmental stimuli, body temperature, ocular, motor reflex and proprioceptive functions), and anatomical pathology. Both Cmaxand AUC parameters increased with the increase in MGC026 dose level and were close to dose proportional. Study findings were limited to anatomical pathology. At the terminal necropsy (study day 49), decreased thymus weights correlated to decreased thymus cellularity (lymphocytes) in three of ten animals administered 30 mg / kg (mild to moderate), and six of ten animals administered 50 mg / kg (mild to moderate). This finding was not considered adverse as animals with moderate severity had substantial thymus tissue remaining, evidence of opportunistic infections was lacking, and other components of the immune system (spleen, mesenteric lymph node, mandibular lymph nodes, gut associated immune system) were normal. Recovery necropsy (study day 91) did not have any findings.Example 7 Tolerability Study of MGC018 in Cynomolgus Monkeys

[0231] In order to determine the tolerability of MGC018 (as described above), a preclinical animal study with cynomolgus monkeys was conducted. The study included both a non-GLP and a GLP study.

[0232] The non-GLP studies include a single-dose non-GLP PK study in which 14 animals were dosed with 1, 3, 10, 20, or 27 mg / kg MGC018 and a repeat-dose non-GLP toxicology study in which 6 animals (3 / group) received MGC018 dosed every 2-weeks (Q2W) at 6 or 20 mg / kg (Table 14).

[0233] The data collected from the two non-GLP MGC018 studies indicated that a singledose up to 27 mg / kg was well tolerated based on body weight, food consumption, clinical observations, clinical pathology (hematology, clinical chemistry), and anatomical pathology. However, repeat-dosing at 20 mg / kg Q2W was not tolerated and animals required veterinary treatment for fever (with possible infection), skin changes (including dryness, erythema and / or weeping abrasions / skin erosion) and watery feces. Veterinary treatments did not impact study data or interpretation because treatment effects were well known and / or were of short duration. One animal that received 20 mg / kg / dose on study days 1 and 15 presented with erythema in the left inguinal area that progressed to dry, erythemic skin in both the inguinal and axillary regions and skin erosion in the left inguinal area. The animal had decreased activity, hunched posture and inappetence starting on Day 20. By Day 22, skin lesions were present in both inguinal and axillary regions and on the left hindlimb. Skin lesions were cleaned with topical antiseptic (chlorhexidine) and treated with a topical soothing agent (Douxo) and antibiotic (Neo-predef) from Days 14 to 22 as needed. A nonsteroidal anti-inflammatory drug (Metacam) was administered on Days 21 and 22 for pain and decreased mobility. Cleaning the skin lesions on Day 22 caused the skin to deglove and based on the size of this lesion the animal was euthanized in extremis. The remaining two animals at the 20 mg / kg / dose were also terminated on Day 22 to evaluate the degree of skin erosion, dryness, and hyperpigmentation present.

[0234] Other MGC018-related clinical signs following repeat 6 and 20 mg / kg dose Q2W administration included sporadic watery feces, increased incidence of dry skin (starting on orafter Day 8), and skin discoloration (red, black, and brown). Additional observations at 20 mg / kg / dose of MGC018 included green feces within 3 days of dose administration, decreased activity, inappetence, hunched posture, increased incidence of abrasions (primarily in the inguinal area), and yellow discharge (from abrasions), which were most prominent on or after Day 18.

[0235] Minimal decreases in mean body weight were observed in animals after 2 doses of 20 mg / kg / dose MGC018 (-6.5% between Days -1 and 21) that may have been due to inappetence was observed in all animals at the 20 mg / kg dose level.

[0236] Moderate decreases in red cell mass were more pronounced at 20 mg / kg / dose beginning on Day 15 and associated with decreases in absolute reticulocyte counts. These were MGC018-related and the decreased or suppressed hematopoiesis correlated with decreased hematopoietic cellularity of the sternal bone marrow in 2 of 3 animals at 20 mg / kg / dose. Decreases in lymphocytes (mild), neutrophils (moderate) and platelets (mild) were also observed beginning on Day 15 at 20 mg / kg / dose. Similar levels of decreased lymphocyte and platelet counts occurred at later timepoints at the 6 mg / kg / dose without a decrease in neutrophils. These decreases are MGC018-related and correlated with lymphoid depletion in the thymus in 2 of 3 animals at 20 mg / kg / dose.

[0237] Concurrent increased fibrinogen (moderate), CRP (mild to moderate), globulin (mild), and decreased albumin (mild) concentrations, are indicative of an inflammatory response, and noted in animals after the second dose of 20 mg / kg / dose (Day 22). These were considered MGC018 related and most likely associated with cutaneous lesions on the forelimbs, hindlimbs and ventral abdomen among these animals. Findings in animals that received 6 mg / kg / dose were limited to a mild increase in CRP.

[0238] Animals receiving 6 or 20 mg / kg / dose of MGC018 had a spectrum of related skin findings observed in multiple locations including the face, forelimbs, hindlimbs, and ventral abdomen. The findings ranged in severity across sites within an individual animal and across animals, but the features of the findings were generally similar within a dose group, present in all animals at these doses, and displayed a clear dose response in severity and extent of the findings.

[0239] At the 20 mg / kg / dose, abrasions / scabs were observed on the forelimbs, hindlimbs, and ventral abdomen and correlated microscopically with ulcers. Minimal to mild lymphocytic inflammation was present at the interface between the epidermis and dermis and surrounding superficial dermal blood vessels with edema often present within the superficial dermis in these areas. The overlying epidermis had minimal to mild single cell necrosis, which ranged from vacuolation and degeneration of the basal layer of the epidermis to necrosis of individual epithelial cells. Minimal to mild epidermal hyperplasia with increased keratin was occasionally present. Minimal to moderate epidermal detachment occurred in areas with inflammation and consisted of separation of the epidermis from the underling basement membrane and dermis. The separation occurred below the basal cell layer and formed multiple small to larger coalescing bullae. When the detachment was more extensive, the epidermis was no longer present leaving variably sized, grossly visible ulcers that ranged in severity from minimal to severe and correlated with the abrasions / scabs noted macroscopically. One of three animals had a minimal erosion / ulcer present within the perianal skin and anus.

[0240] At the 6 mg / kg / dose, black discoloration of the skin was observed on the face, forelimbs, hindlimbs, and / or ventral abdomen and correlated microscopically to a minimal increase in pigment present within the epidermis and occasionally extending into the superficial dermis. Minimal to mild lymphocytic inflammation was present at the interface between the epidermis and dermis and surrounding superficial dermal blood vessels with a variable amount of edema present within the superficial dermis in these areas. The overlying epidermis and occasionally hair follicles had minimal single cell necrosis, which ranged from vacuolation and degeneration of the basal layer of the epidermis to necrosis of individual epithelial cells. Minimal epidermal hyperplasia with increased keratin was also occasionally present.

[0241] The GLP study was an 8-week repeat-dose GLP toxicology study in which 40 animals (10 / group) received MGC018 administered every 3 weeks (Q3W, total of 3 doses) at dose levels of 1, 3, 6, or 10 mg / kg (Table 15).

[0242] Evaluations in the MGC018 GLP toxicology study included: toxicokinetic evaluation, body weight, food consumption, clinical observations, clinical pathology (hematology, clinical chemistry, coagulation, or urinalysis), ECGs, blood pressure, respiratory rate, heart rate, or neurological assessment (reactions to environmental stimuli, body temperature, ocular, motor reflex and proprioceptive functions), and anatomical pathology.

[0243] MGC018 PK was linear between 6 and 10 mg / kg / dose in cynomolgus monkeys, but showed nonlinearity at doses < 6 mg / kg likely due to target-dependent clearance at low doses and / or saturation of target specific clearance mechanisms at the higher doses.

[0244] MGC018-related clinical signs were predominantly dose-dependent and included findings in the skin, hyperpigmentation (males at > 1 mg / kg / dose and females at > 3 mg / kg / dose) and dry skin ± erythema at > 3 mg / kg / dose, an increased incidence in soft / watery feces predominantly at 3 and 6 mg / kg / dose, occasional inappetence, soft / watery feces, thin body condition (single females at > 6 mg / kg / dose), and sparse hair noted in a subset of animals particularly at > 6 mg / kg / dose.

[0245] MGC018-related changes in clinical pathology parameters included indicators of an acute inflammatory response (transient increases in CRP and fibrinogen), transient decreases in neutrophils and lymphocytes, diminished or suppressed erythropoiesis (decreases in red cell mass and reticulocyte counts), and transient increases in AST and / or ALT all of which were dose responsive in nature, reversed prior to or during the recovery phase without microscopiccorrelates and were not considered adverse as changes frequently remained in or very close to the historical control range for these parameters in cynomolgus monkeys.

[0246] Microscopically, a spectrum of findings was present in the skin from the routine section of skin (flank), the infusion site, and additional locations including the forelimbs, hindlimbs, and head. The findings ranged in severity and / or presence across sites within an individual animal and across animals, but the features of the findings were generally similar within a dose group and displayed a clear dose response in severity and extent which were generally more prominent at > 6 mg / kg / dose and included increases in pigment, lymphocytic inflammation, epidermal hyperplasia, and single cell necrosis. Inflammation and single cell necrosis were reversed at the end of the recovery phase while pigment changes and hyperplasia showed ongoing resolution at the end of recovery.Example 8Toxicology Study Comparison Between MGC026 and MGC018 in Cynomolgus Monkeys

[0247] Table 16 provides a comparison of the MGC026 and MGC018 toxicology studies conducted in cynomolgus monkeys as described in Examples 6 and 7. The comparison demonstrates a cleaner profile in MGC026 as compared to MGC018 which caused hyperpigmentation in animals as well as lymphocytic inflammation, epidermal hyperplasia, and single cell necrosis in the skin. These findings were more severe when the dose interval was decreased in Q2W and resulted in euthanasia of animals that received 20 mg / kg.Example 9MGC026 Exhibits In Vivo Activity in Patient-Derived Xenografts

[0248] In order to further demonstrate the antitumor activity of MGC026, the abovedescribed MGC026 molecule was evaluated for in vivo toxicity in an Athymic Nude-Foxnlnu(Envigo, Charles River Laboratories) mouse model using different patient-derived tumor fragments. In brief, low passage tumor fragments were implanted into Athymic Nude-Foxnlnustock mice. When sufficient stock mice tumors reached 1000-1500 mm3, tumors were harvested, and tumor fragments were re-implanted unilaterally on the left flank of pre-study mice. When tumors reached 150-300 mm3, pre-study mice were randomized by tumor volume and treated with MGC026 or vehicle control (formulation buffer (FB)). The mice were assigned to each group and dosed intravenously by tail vein injection (approximately 100 pL). In these studies, MGC026 or vehicle control was administered once every two weeks for a total of two doses (Q2W x 2). Tumors were measured twice weekly by orthogonal measurements with electronic calipers, with tumor volumes calculated as: (width x 2) x length x 0.52. An animal was considered to have a Partial Regression ("PR") when tumor volume was reduced by 50% or greater when compared to the tumor volume at the day of first dose administration. A finding that the tumor volume of treated animals had decreased to < 5 mm3during the study period was considered to denote a Complete Response ("CR"). The tumor volume (relative to vehicle control) was determined ("T / C"). Antitumor activity was evaluated according to National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.In vivo Activity Against Small Cell Lung Cancer Patient-Derived Tumors

[0249] The results of this study with respect to subcutaneously inoculated small cell lung cancer patient-derived tumor fragments from model 1 are presented in Table 17 and in FTG. 13, and show responsiveness against the small cell lung cancer patient-derived tumor fragments.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 1776 mm3on Day 10. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody; mg: milligram; kg: kilogram; IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0250] Female Athymic Nude-Foxnlnumice (n = 3 / group) were implanted subcutaneously with small cell lung cancer patient-derived tumor fragments from stock mice. When tumors reached an average of 150-300 mm3(257 ± 46 mm3mean tumor volume ± standard deviation), pre-study mice were randomized by tumor volume and treated with MGC026 or vehicle control (formulation buffer) on days 0 and 14 (arrows) for a total of two doses at the dose level indicated. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed at the dose level tested following treatments with MGC026.

[0251] MGC026 reduced tumor volumes by 78% on Day 10 at the 10 mg / kg Q2W x 2 dose level and was active (22% T / C) based on NCI standards. MGC026 induced 1 / 3 partial regressions and no complete regressions at this dose level.In vivo Activity Against Small Cell Lung Cancer Patient-Derived Tumors

[0252] The results of this study with respect to subcutaneously inoculated small cell lung cancer patient-derived tumor fragments from model 2 are presented in Table 18 and in FIG. 14, and show responsiveness against the small cell lung cancer patient-derived tumor fragments.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 1733 mm3on Day 52. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody; mg: milligram; kg: kilogram; IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm ) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0253] Female Athymic Nude-Foxnlnumice (n = 3 / group) were implanted subcutaneously with small cell lung cancer patient-derived tumor fragments from stock mice. When tumors reached an average of 150-300 mm3(268 ± 10 mm3mean tumor volume ± standard deviation), pre-study mice were randomized by tumor volume and treated with MGC026 or vehicle control (formulation buffer) on days 0 and 14 (arrows) for a total of two doses at the dose level indicated. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed at the dose level tested following treatments with MGC026.

[0254] MGC026 reduced tumor volumes by 99% on Day 52 at the 10 mg / kg Q2W x 2 dose level and was highly active (1% T / C) based on NCI standards. MGC026 induced 3 / 3 partial regressions and 1 / 3 complete regressions at this dose level. Treatment with MGC026 maintained antitumor control at the 10 mg / kg Q2W x 2 dose level through the end of the study.In vivo Activity Against Small Cell Lung Cancer Patient-Derived Tumors

[0255] The results of this study with respect to subcutaneously inoculated small cell lung cancer patient-derived tumor fragments from model 3 are presented in Table 19 and in FIG. 15, and show responsiveness against the small cell lung cancer patient-derived tumor fragments.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 2565 mm3on Day 23. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody; mg: milligram; kg: kilogram; IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0256] Female Athymic Nude-Foxnlnumice (n = 3 / group) were implanted subcutaneously with small cell lung cancer patient-derived tumor fragments from stock mice. When tumors reached an average of 150-300 mm3(236 ± 80 mm3mean tumor volume ± standard deviation), pre-study mice were randomized by tumor volume and treated with MGC026 or vehicle control (formulation buffer) on days 0 and 14 (arrows) for a total of two doses at the dose level indicated. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed at the dose level tested following treatments with MGC026.

[0257] MGC026 reduced tumor volumes by 100% on Day 23 at the 10 mg / kg Q2W x 2 dose level and was highly active (0% T / C) based on NCI standards. MGC026 induced 3 / 3 partial regressions and 2 / 3 complete regressions at this dose level. Treatment with MGC026 maintained antitumor control at the 10 mg / kg Q2W x 2 dose level through the end of the study.In vivo Activity Against Ovarian Cancer Patient-Derived Tumors

[0258] The results of this study with respect to subcutaneously inoculated ovarian cancer patient-derived tumor fragments are presented in Table 20 and in FIG. 16, and show responsiveness against the ovarian cancer patient-derived tumor fragments.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 2302 mm3on Day 48. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody; mg: milligram; kg: kilogram; IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0259] Female Athymic Nude-Foxnlnumice (n = 3 / group) were implanted subcutaneously with ovarian cancer patient-derived tumor fragments from stock mice. When tumors reached an average of 150-300 mm3(211 ± 82 mm3mean tumor volume ± standard deviation), pre-study mice were randomized by tumor volume and treated with MGC026 or vehicle control (formulation buffer) on days 0 and 14 (arrows) for a total of two doses at the dose level indicated. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed at the dose level tested following treatments with MGC026.

[0260] MGC026 reduced tumor volumes by 98% on Day 48 at the 10 mg / kg Q2W x 2 dose level and was highly active (2% T / C) based on NCI standards. MGC026 induced 3 / 3 partial regressions and no complete regressions at this dose level. Treatment with MGC026 maintained antitumor control at the 10 mg / kg Q2W x 2 dose level through the end of the study.In vivo Activity Against Melanoma Patient-Derived Tumors

[0261] The results of this study with respect to subcutaneously inoculated melanoma patient-derived tumor fragments are presented in Table 21 and in FIG. 17, and show responsiveness against the melanoma patient-derived tumor fragments.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 3003 mm3on Day 30. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody; mg: milligram; kg: kilogram; IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0262] Female Athymic Nude-Foxnlnumice (n = 3 / group) were implanted subcutaneously with melanoma patient-derived tumor fragments from stock mice. When tumors reached an average of 150-300 mm3(202 ± 78 mm3mean tumor volume ± standard deviation), pre-study mice were randomized by tumor volume and treated with MGC026 or vehicle control (formulation buffer) on days 0 and 14 (arrows) for a total of two doses at the dose level indicated. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed at the dose level tested following treatments with MGC026.

[0263] MGC026 reduced tumor volumes by 97% on Day 30 at the 10 mg / kg Q2W x 2 dose level and was highly active (3% T / C) based on NCI standards. MGC026 induced 2 / 3 partial regressions and 1 / 3 complete regressions at this dose level. Treatment with MGC026 maintained antitumor control at the 10 mg / kg Q2W x 2 dose level through the end of the study.In vivo Activity Against Colorectal Cancer Patient-Derived Tumors

[0264] The results of this study with respect to subcutaneously inoculated colorectal cancer patient-derived tumor fragments are presented in Table 22 and in FIG. 18, and show responsiveness against the colorectal cancer patient-derived tumor fragments.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C). Calculated when the vehicle tumor volume reached a mean of 1102 mm3on Day 29. b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody; mg: milligram; kg: kilogram; IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or when the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0265] Female Athymic Nude-Foxnlnumice (n = 3 / group) were implanted subcutaneously with colorectal cancer patient-derived tumor fragments from stock mice. When tumors reached an average of 150-300 mm3(248 ± 93 mm3mean tumor volume ± standard deviation), pre-study mice were randomized by tumor volume and treated with MGC026 or vehicle control (formulation buffer) on days 0 and 14 (arrows) for a total of two doses at the dose level indicated. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed at the dose level tested following treatments with MGC026.

[0266] MGC026 reduced tumor volumes by 76% on Day 29 at the 10 mg / kg Q2W x 2 dose level and was active (24% T / C) based on NCI standards. MGC026 induced 1 / 3 partial regressions and no complete regressions at this dose level.In vivo Activity Against Squamous Cell Carcinoma of Head and Neck (SCCHN) Patient- Derived Tumors

[0267] The results of this study with respect to subcutaneously inoculated SCCHN patient-derived tumor fragments are presented in Table 23 and in FIG. 19, and show responsiveness against the SCCHN cancer patient-derived tumor fragments.a % T / C = percentage of mean tumor size in treatment group (T) relative to mean tumor size of vehicle control group (C) Calculated when the vehicle tumor volume reached a mean of 1292 mm3on Day 34 b Antitumor Activity: Evaluated based on National Cancer Institute (NCI) standards; a T / C < 42% is the minimum level of antitumor activity, while a T / C value of > 42% is inactive. A T / C < 10% is considered highly active.Abbreviations: Ab: antibody: mg: milligram; kg: kilogram: IV: intravenous; PR: partial regression (tumor volume was reduced by 50% or greater from dosing day during study); CR: complete regression (defined as when no palpable tumor could be detected (0 mm3) or w hen the tumor volume was non-measurable (< 5 mm3) during the course of the study).

[0268] Female Athymic Nude-Foxnlnumice (n = 3 / group) were implanted subcutaneously with SCCHN patient-derived tumor fragments from stock mice. When tumors reached an average of 150-300 mm3(258 ± 50 mm3mean tumor volume ± standard deviation), pre-study mice were randomized by tumor volume and treated with MGC026 or vehicle control (formulation buffer) on days 0 and 14 (arrows) for a total of two doses at the dose level indicated. Tumor volume is shown as group mean ± standard error of the mean (SEM) with the upper SEM bar visible. Antitumor activity was observed at the dose level tested following treatments with MGC026.

[0269] MGC026 reduced tumor volumes by 92% on Day 34 at the 10 mg / kg Q2W x 2 dose level and was highly active (8% T / C) based on NCI standards. MGC026 induced 3 / 3 partial regressions and no complete regressions at this dose level.

[0270] All publications and patents mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety. While specific aspects are described herein, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the aspects.

Claims

WHAT IS CLAIMED IS:Claim 1. An anti-B7-H3 antibody drug conjugate (B7-H3-ADC) that comprises the formula:Ab-(LM)m-(D)n, wherein:Ab is a humanized B7-H3 antibody or B7-H3 binding fragment thereof that binds to B7-H3 and comprises:(i) the CDRLI sequence RASESIYSYLA (SEQ ID NO: 16), the CDRL2 sequence NTKTLPE (SEQ ID NO: 17) and the CDRL3 sequence QHHYGTPPWT (SEQ ID NO: 18) in its Variable Light Chain (VL) domain, and(ii) the CDRHI sequence SYGMS (SEQ ID NO: 19), the CDRH2 sequence TINSGGSNTYY PDSLKG (SEQ ID NO:20) and the CDRH3 sequence HDGGAMDY (SEQ ID NO:21) or HEGGAMDY (SEQ ID NO:26) in its Variable Heavy Chain (VH) domain;D is a campt othecin moiety;LM is a Linker Molecule that covalently links Ab and D; m is an integer between 1 and n and denotes the number of Linker Molecules of the B7-H3-ADC; and n is an integer between 1 and 10 and denotes the number of cytotoxic camptothecin moi eties covalently linked to the B7-H3-ADC molecule.Claim 2. The B7-H3-ADC of claim 1, wherein the Ab comprises:(i) a humanized VL Domain comprising the amino acid sequence of SEQ ID NO: 12, and(ii) a humanized VH Domain comprising the amino acid sequence of SEQ ID NO: 14 or SEQ ID NO:22Claim 3. The B7-H3-ADC of claim 1 or 2, wherein the Ab is an antibody.Claim 4. The B7-H3-ADC of any one of claims 1-3, wherein the Ab is an antigen binding fragment of an antibody.Claim 5. The B7-H3-ADC of any one of claims 1-4, wherein the Ab comprises an Fc Domain of a human IgG.Claim 6. The B7-H3-ADC of claim 5, wherein the human IgG is a human IgGl, IgG2, IgG3, or IgG4.Claim 7. The B7-H3-ADC of claims 5 or 6, wherein the Fc Domain is a variant Fc Domain that comprises:(a) one or more amino acid modifications that reduce the affinity of the variant Fc Domain for an FcyR; and / or(b) one or more amino acid modifications that enhance the serum half-life of the variant Fc Domain.Claim 8. The B7-H3-ADC of claim 7, wherein the modifications that reduce the affinity of the variant Fc Domain for an FcyR comprise the substitution of L234A; L235A; or L234A and L235A, wherein the numbering is that of the EU index as in Kabat.Claim 9. The B7-H3-ADC of claim 7 or 8, wherein the modifications that that enhance the serum half-life of the variant Fc Domain comprise the substitution of M252Y; M252Y and S254T; M252Y and T256E; M252Y, S254T and T256E; or K288D and H435K, wherein the numbering is that of the EU index as in Kabat.Claim 10. The B7-H3-ADC of claim 1, wherein the LM comprises a peptidic linker.Claim 11. The B7-H3-ADC of claim 1, wherein the LM comprises a cleavable linker.Claim 12. The B7-H3-ADC of claim 1, wherein the LM comprises the formula (4a) or(4b), or a salt thereof:wherein: a is independently 0 or 1; b is independently 0 or 1; c is 0 or 1; d is 0 or 1; e is 0 or 1; f is an integer in the range of 1 to 150; g is 0 or 1; i is 0 or 1;D is a cytotoxic camptothecin moiety;Q1is an alkenyl group, (hetero)cycloalkenyl group, bicyclo triazole group or cycloalkenyl group; wherein Q1is attached to a functional group of the antibody; wherein Sp1, Sp2, Sp3and Sp4are independently selected from the group consisting of linear or branched C1-C200 alkylene groups, C2-C200 alkenylene groups, C2-C200 alkynylene groups, C3-C200 cycloalkylene groups, C5-C200 cycloalkenylene groups, C8-C200 cycloalkynylene groups, C7-C200 alkylarylene groups, C7-C200 arylalkylene groups, C8-C200 arylalkenylene groups and C9-C200 aryl alkynylene groups, the alkylene groups, alkenylene groups, alkynylene groups, cycloalkylene groups, cycloalkenylene groups, cycloalkynylene groups,alkylarylene groups, arylalkylene groups, arylalkenylene groups and aryl alky nylene groups being optionally substituted and optionally interrupted by one or more heteroatoms selected from the group of O, S and NR3, wherein R3is independently selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C2 - C24 alkenyl groups, C2 - C24 alkynyl groups and C3 - C24 cycloalkyl groups, the alkyl groups, alkenyl groups, alkynyl groups and cycloalkyl groups being optionally substituted;Z1is a connecting group that connects Q1or Sp3to Sp2, O or C(O) or N(R3);Z2is a connecting group that connects D or Sp4to Sp1, N(R3), O or C(O); wherein Z1and Z2are independently selected from the group consisting of -O-, -S-, -NR2-, -N=N-, -C(O)-, -C(O)NR2-, -O-C(O)- , -O-C(O)-O-, -O-C(O)-NR2, -NR2-C(O)-, -NR2-C(O)-O-, -NR2-C(O)-NR2-, -S-C(O)-, -S-C(O)-O-, -S-C(O)- NR2-, -S(O)-, -S(O)2-, -O-S(O)2-, -O-S(O)2-O-, -O-S(O)2-NR2-, -O-S(O)-, -O- S(O)-O-, -O-S(O)-NR2-, -O-NR2-C(O)-, -O-NR2-C(O)-O-, -O-NR2-C(O)-NR2- , -NR2-O-C(O)-, -NR2-O-C(O)-O-, -NR2-O-C(O)-NR2-, -O-NR2-C(S)-, -O- NR2-C(S)-O-, -O-NR2-C(S)-NR2-, -NR2-O-C(S)-, -NR2-O-C(S)-O-, -NR2-O- C(S)-NR2-, -O-C(S)-, -O-C(S)-O-, -O-C(S)-NR2-, -NR2-C(S)-, -NR2-C(S)-O-, - NR2-C(S)-NR2-, -S-S(O)2-, -S-S(O)2-O-, -S-S(O)2-NR2-, -NR2-O-S(O)-, -NR2- O-S(O)-O-, -NR2-O-S(O)-NR2-, -NR2-O-S(O)2-, -NR2-O-S(O)2-O-, -NR2-O- S(O)2-NR2-, -O-NR2-S(O)-, -O-NR2-S(O)-O-, -O-NR2-S(O)-NR2-, -O-NR2- S(O)2-O-, -O-NR2-S(O)2-NR2-, -O-NR2-S(O)2-, -O-P(O)(R2)2-, -S-P(O)(R2)2-, - NR2-P(O)(R2)2- and combinations of two or more thereof, wherein R2is independently selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C2 - C24 alkenyl groups, C2 - C24 alkynyl groups and C3 - C24 cycloalkyl groups, the alkyl groups, alkenyl groups, alkynyl groups and cycloalkyl groups being optionally substituted; andR1is selected from the group consisting of hydrogen, Ci - C24 alkyl groups, C3 - C24 cycloalkyl groups, C2 - C24 (hetero)aryl groups, C3 - C24 alkyl(hetero)aryl groups and C3 - C24 (hetero)arylalkyl groups, the Ci - C24 alkyl groups, C3 - C24cycloalkyl groups, C2 - C24 (hetero)aryl groups, C3 - C24 alkyl(hetero)aryl groups and C3 - C24 (hetero)arylalkyl groups optionally substituted and optionally interrupted by one or more heteroatoms selected from O, S and NR3wherein R3is independently selected from the group consisting of hydrogen and Ci - C4 alkyl groups; orR1is D, -[(Sp’MZ CSp D] or -[(Sp CZ CSp Q1], wherein Sp1, Sp2, Sp3, Sp4, Z1, Z2, D, Q1, b, c, d, e, g and i are as defined above.Claim 13. The B7-H3-ADC of claim 12, wherein Sp1, Sp2, Sp3and Sp4, if present, are independently selected from the group consisting of linear or branched C1-C20 alkylene groups, the alkylene groups being optionally substituted and optionally interrupted by one or more heteroatoms selected from the group consisting of O, S and NR3, wherein R3is independently selected from the group consisting of hydrogen and Ci - C4 alkyl groups.Claim 14. The B7-H3-ADC of any one of claims 1-13, where the LM comprises a valine-alanine (Val-Ala) amino acid linker.Claim 15. The B7-H3-ADC of claim 14, wherein the Val-Ala linker is a Val-Ala-PABC linker.Claim 16. The B7-H3-ADC of any one of claims 1-15, wherein the camptothecin moiety is selected from the group consisting of SN-38 (5- 10-hydroxy camptothecin), topotecan (HYCAMPTIN; (S)-9-N,N-dimethylaminoethyl-l Cihydroxy camptothecin), 9-aminocamptothecin (9-amino-20(S)-camptothecin), 9-nitrocamptothecin (also called rubitecan), lurtotecan (7-(4- methylpiperazinomethylene)-10,l l-ethylenedioxy-20(S)-camptothecin), exatecan, belotecan, karenitecin, and a homocamptothecin.Claim 17. The B7-H3-ADC of any one of claims 1-16, wherein the camptothecin moiety is exatecan.Claim 18. The B7-H3-ADC of any one of claims 1-17, wherein LM and D togethercomprise:Claim 19. An anti-B7-H3 antibody drug conjugate (B7-H3-ADC) that comprises the formula:Ab-(LM)m-(D)n, wherein:Ab is a humanized B7-H3 antibody or B7-H3 binding fragment thereof that binds to B7-H3 and comprises:(i) the CDRLI sequence RASESIYSYLA (SEQ ID NO: 16), the CDRL2 sequence NTKTLPE (SEQ ID NO: 17) and the CDRL3 sequence QHHYGTPPWT (SEQ ID NO: 18) in its Variable Light Chain (VL) domain, and(ii) the CDRHI sequence SYGMS (SEQ ID NO: 19), the CDRH2sequence TINSGGSNTYY PDSLKG (SEQ ID NO:20) and the CDRH3 sequence HDGGAMDY (SEQ ID NO:21) or HEGGAMDY (SEQ ID NO:26) in its Variable Heavy Chain (VH) domain;m is an integer between 0 and n and denotes the number of Linker Molecules of the B7-H3-ADC; and n is an integer between 1 and 10 and denotes the number of cytotoxic camptothecin moi eties covalently linked to the B7-H3-ADC molecule.Claim 20. The B7-H3-ADC of claim 19, wherein the Ab comprises:(i) a humanized VL Domain comprising the amino acid sequence of SEQID NO: 12, and(ii) a humanized VH Domain comprising the amino acid sequence of SEQID NO: 14 or SEQ ID NO:22.Claim 21. A pharmaceutical composition that comprises an effective amount of the B7- H3-ADC of any of claims 1-20 and a pharmaceutically acceptable carrier, excipient or diluent.Claim 22. Use of the B7-H3-ADC of any one of claims 1-20 or the pharmaceutical composition of claim 21 in the treatment of a disease or condition associated with or characterized by the expression of B7-H3.Claim 23. A method of treating a disease or condition associated with or characterized by the expression of B7-H3 comprising administering the B7-H3-ADC of any one of claims 1-20 or the pharmaceutical composition of claim 21 to a subject.Claim 24. The use of claim 22 or the method of claim 23, wherein the disease or condition associated with or characterized by the expression of B7-H3 is cancer.Claim 25. The use or method of claim 24, wherein the cancer is selected from the group consisting of: an adrenal gland tumor, an AIDS-associated cancer, an alveolar soft part sarcoma, an astrocytic tumor, an adrenal cancer, a bladder cancer, a bone cancer, a brain and spinal cord cancer, a metastatic brain tumor, a B-cell cancer, a breast cancer, a carotid body tumors, a cervical cancer, a chondrosarcoma, a chordoma, a chromophobe renal cell carcinoma, a clear cell carcinoma, a colon cancer, a colorectal cancer, a cutaneous benign fibrous histiocytoma, a desmoplastic small round cell tumor, an ependymoma, a Ewing's tumor, an extraskeletal myxoid chondrosarcoma, a fibrogenesis imperfecta ossium, a fibrous dysplasia of the bone, a gallbladder or bile duct cancer, a gastric cancer, a gestational trophoblastic disease, a germ cell tumor, a head and neck cancer, a glioblastoma, a hematological malignancy, a hepatocellular carcinoma, an islet cell tumor, a Kaposi's Sarcoma, a kidney cancer, a leukemia (e.g, an acute myeloid leukemia), a liposarcoma / malignant lipomatous tumor, aliver cancer, a lymphoma, a lung cancer (e.g, a non-small-cell lung cancer (NSCLC) or a small cell lung cancer (SCLC)), a medulloblastoma, a melanoma, a meningioma, a mesothelioma pharyngeal cancer, a multiple endocrine neoplasia, a multiple myeloma, a myelodysplastic syndrome, a neuroblastoma, a neuroendocrine tumors, an ovarian cancer, a pancreatic cancer, a papillary thyroid carcinoma, a parathyroid tumor, a pediatric cancer, a peripheral nerve sheath tumor, a phaeochromocytoma, a pituitary tumor, a prostate cancer, a posterious uveal melanoma, a renal metastatic cancer, a rhabdoid tumor, a rhabdomysarcoma, a sarcoma, a skin cancer, a small round blue cell tumor of childhood (including neuroblastoma and rhabdomyosarcoma), a soft-tissue sarcoma, a squamous cell cancer e.g., a squamous cell cancer of the head and neck (SCCHN), a stomach cancer, a synovial sarcoma, a testicular cancer, a thymic carcinoma, a thymoma, a thyroid cancer (e.g., a thyroid metastatic cancer), and a uterine cancer.Claim 26. The use or method of claim 25, wherein the cancer is selected from the group consisting of: adrenal cancer, bladder cancer, breast cancer, colorectal cancer, gastric cancer, glioblastoma, kidney cancer, non-small-cell lung cancer (NSCLC), acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cell leukemia, Burkett's lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, marginal zone lymphoma, mesothelioma pharyngeal cancer, nonHodgkin's lymphoma, small lymphocytic lymphoma, multiple myeloma, melanoma, ovarian cancer, platinum-resistant ovarian cancer (PROC), pancreatic cancer, prostate cancer, metastatic castration-resistant prostate cancer (mCRPC), skin cancer, renal cell carcinoma, small cell lung cancer, (SCLC), extensive-stage small cell lung cancer (ES-SCLC), small round blue cell tumors of childhood (including neuroblastoma and rhabdomyosarcoma), squamous cell cancer (e. , squamous cell cancer of the head and neck (SCCHN), testicular cancer, thyroid cancer (e.g., thyroid metastatic cancer), and uterine cancer cell selected from the group consisting of a cell of: an adrenal gland.Claim 27. The use or method of claim 24, wherein the cancer is melanoma.Claim 28. The use or method of claim 24, wherein the cancer is lung cancer.Claim 29. The use or method of claim 24, wherein the cancer is squamous cell cancer of the head and neck (SCCHN).Claim 30. The use or method of claim 24, wherein the cancer is pancreatic cancer.Claim 31. The use or method of claim 24, wherein the cancer is prostate cancer.Claim 32. The use or method of claim 24, wherein the cancer is small cell lung cancer(SCLC).Claim 33. The use or method of claim 24, wherein the cancer is small cell ovarian cancer.Claim 34. The use or method of claim 24, wherein the cancer is small cell colorectal cancer.Claim 35. The use or method of claim 24, wherein the cancer is esophageal squamous cell carcinoma.Claim 36. The use or method of claim 24, wherein the cancer is non-small cell lung cancer (NSCLC).Claim 37. The use or method of claim 24, wherein the cancer is bladder cancer.Claim 38. The use or method of claim 24, wherein the cancer is sarcoma.Claim 39. The use or method of claim 24, wherein the cancer is endometrial cancer.Claim 40. The use or method of claim 24, wherein the cancer is metastatic castrationresistant prostate cancer (mCRPC).Claim 41. The use or method of claim 24, wherein the cancer is breast cancer.Claim 42. The use or method of claim 24, wherein the cancer is ovarian cancer.Claim 43. The use or method of claim 24, wherein the cancer is cervical cancer.Claim 44. The use or method of claim 24, wherein the cancer is colorectal cancer.Claim 45. The use or method of claim 24, wherein the cancer is gastric or gastricesophageal junction cancer.Claim 46. The use or method of claim 24, wherein the cancer is clear cell renal cell carcinoma.Claim 47. The use or method of claim 24, wherein the cancer is hepatocellular carcinoma.

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