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

Gururaj Shivange, Karol Urbanek, Piotr Przanowski, Justin S.A. Perry, James Jones, Robert Haggart, Christina Kostka, Tejal Patki, Edward Stelow, Yuliya Petrova, Danielle Llaneza, Marty Mayo, Kodi S. Ravichandran, Charles N. Landen, Sanchita Bhatnagar, Jogender Tushir-Singh

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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. Shivange et al. design antibodies combining specificities against FOLR1 and DR5 that restrict DR5-mediated apoptotic activation toward FOLR1-expressing ovarian cancer cells while eliminating ADCC dependency to induce cell death. These antibodies outperformed reported clinically tested DR5 agonist antibodies.

Original languageEnglish
Pages (from-to)331-345.e11
JournalCancer Cell
Volume34
Issue number2
DOIs
StatePublished - Aug 13 2018

Keywords

  • TRAIL-R2
  • antibody therapy
  • cancer
  • cancer signaling
  • caspases
  • cell signaling
  • dual-specificity targeting
  • folate receptor alpha-1
  • ovarian cancer
  • targeted therapies

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