Chemically Programmed Bispecific Antibodies in Diabody Format

J Biol Chem. 2016 Sep 9;291(37):19661-73. doi: 10.1074/jbc.M116.745588. Epub 2016 Jul 21.

Abstract

Chemically programmed bispecific antibodies (biAbs) endow target cell-binding small molecules with the ability to recruit and activate effector cells of the immune system. Here we report a platform of chemically programmed biAbs aimed at redirecting cytotoxic T cells to eliminate cancer cells. Two different antibody technologies were merged together to make a novel chemically programmed biAb. This was achieved by combining the humanized anti-hapten monoclonal antibody (mAb) h38C2 with the humanized anti-human CD3 mAb v9 in a clinically investigated diabody format known as Dual-Affinity Re-Targeting (DART). We show that h38C2 × v9 DARTs can readily be equipped with tumor-targeting hapten-derivatized small molecules without causing a systemic response harming healthy tissues. As a proof of concept, we chemically programmed h38C2 × v9 with hapten-folate and demonstrated its selectivity and potency against folate receptor 1 (FOLR1)-expressing ovarian cancer cells in vitro and in vivo Unlike conventional biAbs, chemically programmed biAbs in DART format are highly modular with broad utility in terms of both target and effector cell engagement. Most importantly, they provide tumor-targeting compounds access to the power of cancer immunotherapy.

Keywords: T-cell; antibody engineering; cancer therapy; chemical modification; folate; immunotherapy; ovarian cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Antibodies, Bispecific / chemistry*
  • Antibodies, Bispecific / immunology
  • Antibodies, Monoclonal, Humanized / chemistry*
  • Antibodies, Monoclonal, Humanized / immunology
  • Antibodies, Neoplasm / chemistry*
  • Antibodies, Neoplasm / immunology
  • Cell Line, Tumor
  • Female
  • Folate Receptor 1 / antagonists & inhibitors
  • Folate Receptor 1 / chemistry
  • Folate Receptor 1 / immunology
  • HEK293 Cells
  • Humans
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / chemistry
  • Neoplasm Proteins / immunology
  • Ovarian Neoplasms / chemistry
  • Ovarian Neoplasms / immunology

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neoplasm
  • FOLR1 protein, human
  • Folate Receptor 1
  • Neoplasm Proteins