Antibodies targeted to TRAIL receptor-2 and ErbB-2 synergize in vivo and induce an antitumor immune response

• DOI: 10.1073/pnas.0806849105
• Publication Date: 2008-10-07T00:54:22Z
• Authors: John Stagg; Janelle Sharkey; Sandra Pommey; Richard Young; Kazuyoshi Takeda; Hideo Yagita; Ricky W. Johnstone; Mark J. Smyth
• Keywords: 0301 basic medicine; Time Factors; Receptor, ErbB-2; Immunity; Antibodies, Monoclonal; Apoptosis; Breast Neoplasms; Drug Synergism; Hypoxia-Inducible Factor 1, alpha Subunit; Cell Line; 3. Good health; Mice; Receptors, TNF-Related Apoptosis-Inducing Ligand; 03 medical and health sciences; Breast cancer; Herceptin; 1000 General; 616; Animals; Immunotherapy

Despite the development of human epidermal growth factor receptor-2 (ErbB-2/HER2)-targeted therapies, there remains an unmet medical need for breast cancer patients with ErbB-2 overexpression. We investigated the therapeutic activity of an agonist mAb to mouse tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 (DR5) against ErbB2-driven breast cancer. Established tumors in BALB/c transgenic mice expressing a constitutively active ErbB-2/neuT were treated with anti-DR5 mAb and/or anti-ErbB-2 mAb and monitored for tumor progression. Treatment with anti-DR5 or anti-ErbB2 mAb as single agents significantly delayed tumor growth, although all tumors eventually progressed. Remarkably, treatment with a combination of anti-DR5 and anti-ErbB-2 mAbs induced complete response in a majority of mice. In vivo blockade of CD11b + cells, but not natural killer cell depletion, significantly abrogated the early antitumor response. Notably, depletion of CD8 + T cells provoked primary and secondary tumor relapse, revealing the induction of antitumor immunity by the combination treatment. Combined therapy with anti-DR5 and anti-ErbB-2 mAbs further significantly suppressed the growth of advanced spontaneous tumors in ErbB-2/neuT transgenic mice, even when treatment was delayed until tumors were palpable. We thus demonstrated that the combination of anti-DR5 and anti-ErbB2 mAbs might be an effective form of treatment for ErbB-2-overexpressing breast cancer.