title: Trop-2 is a novel target for solid cancer therapy with sacituzumab govitecan (IMMU-132), an antibody-drug conjugate (ADC).
abstract: Trop-2 is a novel target for ADC therapy because of its high expression by many solid cancers. The rational development of IMMU-132 represents a paradigm shift as an ADC that binds a well-known moderately-cytotoxic drug, SN-38, to the anti-Trop-2 antibody. In vitro and in vivo studies show enhanced efficacy, while there is a gradual release of SN-38 that contributes to the overall effect. IMMU-132 is most efficacious at a high drug:antibody ratio (DAR) of 7.6:1, which does not affect binding and pharmacokinetics. It targets up to 136-fold more SN-38 to a human cancer xenograft than irinotecan, SN-38's prodrug. IMMU-132 delivers SN-38 in its most active, non-glucuronidated form, which may explain the lower frequency of severe diarrhea than with irinotecan. Thus, this ADC, carrying a moderately-toxic drug targeting Trop-2 represents a novel cancer therapeutic that is showing promising activity in patients with several metastatic cancer types, including triple-negative breast cancer, non-small-cell and small-cell lung cancers.
authors.affiliation: Immunomedics, Inc., Morris Plains, NJ, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Goldenberg
authors.affiliation: Immunomedics, Inc., Morris Plains, NJ, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Cardillo
authors.affiliation: Immunomedics, Inc., Morris Plains, NJ, USA.
authors.forename: Serengulam V
authors.initials: SV
authors.lastname: Govindan
authors.affiliation: Immunomedics, Inc., Morris Plains, NJ, USA.
authors.forename: Edmund A
authors.initials: EA
authors.lastname: Rossi
authors.affiliation: Immunomedics, Inc., Morris Plains, NJ, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sharkey
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000096:biosynthesis / Q000276:immunology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D000077146:Irinotecan; D061986:MCF-7 Cells; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D018796:Immunoconjugates; C499380:TACSTD2 protein, human; D000077146:Irinotecan; C000608132:sacituzumab govitecan; D002166:Camptothecin
keywords: SN-38; Trop-2; antibody-drug conjugate; solid cancers; triple-negative breast cancer