A Single-Agent Dual-Specificity Targeting of FOLR1 and DR5 as an Effective Strategy for Ovarian Cancer

Cancer Cell. 2018 Aug 13;34(2):331-345.e11. doi: 10.1016/j.ccell.2018.07.005.

Abstract

Therapeutic antibodies targeting ovarian cancer (OvCa)-enriched receptors have largely been disappointing due to limited tumor-specific antibody-dependent cellular cytotoxicity. Here we report a symbiotic approach that is highly selective and superior compared with investigational clinical antibodies. This bispecific-anchored cytotoxicity activator antibody is rationally designed to instigate "cis" and "trans" cytotoxicity by combining specificities against folate receptor alpha-1 (FOLR1) and death receptor 5 (DR5). Whereas the in vivo agonist DR5 signaling requires FcγRIIB interaction, the FOLR1 anchor functions as a primary clustering point to retain and maintain a high level of tumor-specific apoptosis. The presented proof of concept study strategically makes use of a tumor cell-enriched anchor receptor for agonist death receptor targeting to potentially generate a clinically viable strategy for OvCa.

Keywords: TRAIL-R2; antibody therapy; cancer; cancer signaling; caspases; cell signaling; dual-specificity targeting; folate receptor alpha-1; ovarian cancer; targeted therapies.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Bispecific / therapeutic use*
  • Cell Line, Tumor
  • Female
  • Folate Receptor 1 / antagonists & inhibitors*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / pathology
  • Receptors, IgG / physiology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / antagonists & inhibitors*

Substances

  • Antibodies, Bispecific
  • FCGR2B protein, human
  • FOLR1 protein, human
  • Folate Receptor 1
  • Receptors, IgG
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human