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Open Access 01-12-2018 | Research article

Polyfunctional anti-human epidermal growth factor receptor 3 (anti-HER3) antibodies induced by HER3 vaccines have multiple mechanisms of antitumor activity against therapy resistant and triple negative breast cancers

Authors: Takuya Osada, Zachary C. Hartman, Junping Wei, Gangjun Lei, Amy C. Hobeika, William R. Gwin, Marcio A. Diniz, Neil Spector, Timothy M. Clay, Wei Chen, Michael A. Morse, H. Kim Lyerly

Published in: Breast Cancer Research | Issue 1/2018

Abstract

Background

Upregulation of human epidermal growth factor receptor 3 (HER3) is a major mechanism of acquired resistance to therapies targeting its heterodimerization partners epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), but also exposes HER3 as a target for immune attack. We generated an adenovirus encoding full length human HER3 (Ad-HER3) to serve as a cancer vaccine. Previously we reported the anti-tumor efficacy and function of the T cell response to this vaccine. We now provide a detailed assessment of the antitumor efficacy and functional mechanisms of the HER3 vaccine-induced antibodies (HER3-VIAs) in serum from mice immunized with Ad-HER3.

Methods

Serum containing HER3-VIA was tested in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) assays and for its effect on HER3 internalization and degradation, downstream signaling of HER3 heterodimers and growth of metastatic HER2+ (BT474M1), HER2 therapy-resistant (rBT474), and triple negative (MDA-MB-468) breast cancers.

Results

HER3-VIAs mediated CDC and ADCC, HER3 internalization, interruption of HER3 heterodimer-driven tumor signaling pathways, and anti-proliferative effects against HER2+ tumor cells in vitro and significant antitumor effects against metastatic HER2+ BT474M1, treatment refractory HER2+ rBT474 and triple negative MDA-MB-468 in vivo.

Conclusions

In addition to the T cell anti-tumor response induced by Ad-HER3, the HER3-VIAs provide additional functions to eliminate tumors in which HER3 signaling mediates aggressive behavior or acquired resistance to HER2-targeted therapy. These data support clinical studies of vaccination against HER3 prior to or concomitantly with other therapies to prevent outgrowth of therapy-resistant HER2+ and triple negative clones.

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Title: Polyfunctional anti-human epidermal growth factor receptor 3 (anti-HER3) antibodies induced by HER3 vaccines have multiple mechanisms of antitumor activity against therapy resistant and triple negative breast cancers
Authors: Takuya Osada
Zachary C. Hartman
Junping Wei
Gangjun Lei
Amy C. Hobeika
William R. Gwin
Marcio A. Diniz
Neil Spector
Timothy M. Clay
Wei Chen
Michael A. Morse
H. Kim Lyerly
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Breast Cancer Research / Issue 1/2018
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/s13058-018-1023-x

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