Sacituzumab govitecan, a novel, third-generation, antibody-drug conjugate (ADC) for cancer therapy

Expert Opin Biol Ther. 2020 Aug;20(8):871-885. doi: 10.1080/14712598.2020.1757067. Epub 2020 May 12.

Abstract

Introduction: We 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 covered: The 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 opinion: The 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.

Keywords: Antibody-drug conjugate; SN-38; TROP-2; camptothecin; monoclonal antibody; topoisomerase I; triple-negative breast cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Monoclonal, Humanized / metabolism
  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Antigens, Neoplasm / immunology
  • Camptothecin / analogs & derivatives*
  • Camptothecin / immunology
  • Camptothecin / metabolism
  • Camptothecin / therapeutic use
  • Cell Adhesion Molecules / immunology
  • Clinical Trials as Topic
  • Humans
  • Immunoconjugates / immunology
  • Immunoconjugates / metabolism
  • Immunoconjugates / therapeutic use*
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal, Humanized
  • Antigens, Neoplasm
  • Cell Adhesion Molecules
  • Immunoconjugates
  • TACSTD2 protein, human
  • sacituzumab govitecan
  • Camptothecin