Antitumor efficacy of a bispecific antibody that targets HER2 and activates T cells

Teemu T. Junttila, Ji Li, Jennifer A. Johnston, Maria L. Hristopoulos, Robyn A. Clark, Diego A. Ellerman, Bu Er Wang, Yijin Li, Mary A. Mathieu, Guangmin Li, Judy C. Young, Elizabeth A. Luis, Gail D. Lewis Phillips, Eric G. Stefanich, Christoph Spiess, Andrew G. Polson, Bryan A. Irving, Justin M. Scheer, Melissa R. Junttila, Mark S. DennisRobert F. Kelley, Klára Tótpál, Allen J. Ebens

Research output: Contribution to journalArticlepeer-review

82 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)5561-5571
Number of pages11
JournalCancer Research
Volume74
Issue number19
DOIs
Publication statusPublished - Oct 2014
Externally publishedYes

Keywords

  • Antitumor efficacy
  • bisphecific antibody
  • HER2
  • T cell activation
  • immunotherapies

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