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

Autor:	Junttila TT; Genentech, Inc., South San Francisco, California. junttila.teemu@gene.com., Li J; Genentech, Inc., South San Francisco, California., Johnston J; Genentech, Inc., South San Francisco, California., Hristopoulos M; Genentech, Inc., South San Francisco, California., Clark R; Genentech, Inc., South San Francisco, California., Ellerman D; Genentech, Inc., South San Francisco, California., Wang BE; Genentech, Inc., South San Francisco, California., Li Y; Genentech, Inc., South San Francisco, California., Mathieu M; Genentech, Inc., South San Francisco, California., Li G; Genentech, Inc., South San Francisco, California., Young J; Genentech, Inc., South San Francisco, California., Luis E; Genentech, Inc., South San Francisco, California., Lewis Phillips G; Genentech, Inc., South San Francisco, California., Stefanich E; Genentech, Inc., South San Francisco, California., Spiess C; Genentech, Inc., South San Francisco, California., Polson A; Genentech, Inc., South San Francisco, California., Irving B; Genentech, Inc., South San Francisco, California., Scheer JM; Genentech, Inc., South San Francisco, California., Junttila MR; Genentech, Inc., South San Francisco, California., Dennis MS; Genentech, Inc., South San Francisco, California., Kelley R; Genentech, Inc., South San Francisco, California., Totpal K; Genentech, Inc., South San Francisco, California., Ebens A; Genentech, Inc., South San Francisco, California.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2014 Oct 01; Vol. 74 (19), pp. 5561-71. Date of Electronic Publication: 2014 Sep 16.
DOI:	10.1158/0008-5472.CAN-13-3622-T
Abstrakt:	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. (©2014 American Association for Cancer Research.)
Databáze:	MEDLINE
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