Antitumor Efficacy of a Bispecific Antibody That Targets HER2 and Activates T Cells

Cancer Res. 2014 Oct 1;74(19):5561-71. doi: 10.1158/0008-5472.CAN-13-3622-T. Epub 2014 Sep 16.

Abstract

Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti-PD-L1 treatment. Thus, combining HER2-TDB with anti-PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response.

MeSH terms

  • Animals
  • Antibodies, Bispecific / immunology*
  • Antibodies, Bispecific / pharmacology
  • Antibodies, Monoclonal, Humanized / pharmacology
  • Breast Neoplasms / immunology
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Female
  • Humans
  • Lymphocyte Activation*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, ErbB-2 / immunology*
  • T-Lymphocytes / immunology*
  • Trastuzumab

Substances

  • Antibodies, Bispecific
  • Antibodies, Monoclonal, Humanized
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • Trastuzumab