Antibody-drug conjugates targeting TROP-2 and incorporating SN-38: A case study of anti-TROP-2 sacituzumab govitecan

MAbs. 2019 Aug/Sep;11(6):987-995. doi: 10.1080/19420862.2019.1632115. Epub 2019 Jul 18.

Abstract

Antibody-drug conjugates (ADCs) that exploit the active metabolite SN-38, which is derived from the popular anticancer drug, irinotecan (a camptothecin that inhibits the nuclear topoisomerase I enzyme, inducing double-stranded DNA breaks during the mitotic S-phase of affected cells), represent a substantial advance in the ADC field. SN-38 has been conjugated to a humanized antibody against trophoblast cell surface antigen 2 (TROP-2), which is involved in cancer signaling pathways and has increased expression by many cancer cell types, yielding the ADC sacituzumab govitecan. By conjugating a higher number of SN-38 molecules to the immunoglobulin (drug-to-antibody ratio = 7-8:1), and giving higher (10 mg/kg) and repeated therapy cycles (Days 1 and 8 of 21-day cycles), enhanced drug uptake by the targeted cancer cells is achieved. Based on a unique conjugation method, the lactone ring of the SN-38 molecule is stabilized and the molecule is protected from glucuronidation, a process that contributes to the untoward late diarrhea experienced with irinotecan. Finally, while the ADC is internalized, the use of a moderately stable linker permits release of SN-38 in an acidic environment of the tumor cell and its microenvironment, contributing to a bystander effect on neighboring cancer cells. Here, we discuss the development of sacituzumab govitecan and clinical results obtained using it for the management of patients with advanced, refractive breast, lung, and urinary bladder cancers. Sacituzumab govitecan, which is undergoing accelerated approval review by the US Food and Drug Administration while also being studied in Phase 3 clinical studies, was granted Breakthrough Therapy status from the FDA for advanced, refractory, metastatic triple-negative breast cancer patients.

Keywords: Antibody-drug conjugate; IMMU-132; SN-38; TROP-2; sacituzumab govitecan.

Publication types

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

MeSH terms

  • Antibodies, Monoclonal, Humanized* / chemistry
  • Antibodies, Monoclonal, Humanized* / therapeutic use
  • Antigens, Neoplasm
  • Camptothecin / analogs & derivatives*
  • Camptothecin / chemistry
  • Camptothecin / therapeutic use
  • Cell Adhesion Molecules / antagonists & inhibitors*
  • Clinical Trials, Phase III as Topic
  • Drug Delivery Systems*
  • Female
  • Humans
  • Immunoconjugates* / chemistry
  • Immunoconjugates* / therapeutic use
  • Irinotecan* / chemistry
  • Irinotecan* / therapeutic use
  • Male
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Tumor Microenvironment / drug effects*

Substances

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

Grant support

This work was supported by the National Cancer Institute [CA39841].