• David M Goldenberg and Robert M Sharkey.
• Center for Molecular Medicine and Immunology , Mendham, New Jersey, USA.
• Expert Opin Biol Ther. 2020 Aug 1; 20 (8): 871-885.

IntroductionWe describe a new, third-generation of antibody-drug conjugates (ADCs) having a high drug payload against topoisomerase I, important for DNA function, and targeting selective tumor antigens, predominantly TROP-2.Areas CoveredThe historical development of ADCs is reviewed before presenting the current line of improved, third-generation ADCs targeting topoisomerase I, thus affecting DNA and causing double-stranded DNA breaks. Emphasis is given to explaining why sacituzumab govitecan represents a paradigm change in ADCs by achieving a high therapeutic index due to its novel target, TROP-2, an internalizing antigen/antibody, proprietary linker chemistry, and high drug payload, resulting in a high tumor concentration of the drug given in repeated doses with acceptable tolerability, particularly evidencing a lower percentage of 'late' diarrhea than its prodrug, irinotecan. PubMed was used for the primary search conducted.Expert OpinionThe properties and clinical results of third-generation ADCs, based on sacituzumab govitecan, are discussed, including prospects for future applications, particularly combination therapies with PARP inhibitors and immune checkpoint inhibitors. Since one topoisomerase I ADC has just received regulatory approval for HER2+ breast cancer, and sacituzumab govitecan is under FDA review for accelerated approval in the therapy of triple-negative breast cancer, the prospects for these novel ADCs are discussed.

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