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

Abstract

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.apoptosis ͉ breast cancer ͉ herceptin ͉ immunity H uman epidermal growth factor receptor-2 (ErbB-2/HER2) is overexpressed in 20-30% of patients with breast cancer and is associated with a poor prognosis (1). The use of trastuzumab (Herceptin; Genentech), a mAb that blocks the activity of ErbB-2, in combination with chemotherapy has been associated with an increased median survival in patients with advanced ErbB-2-positive breast cancer (2-4). In addition to its inhibitory effect on ErbB-2 signaling, trastuzumab mediates its therapeutic effect through the recruitment of immune cells such as monocytes and natural killer (NK) cells (1, 5). Accordingly, trastuzumab-like mAb unable to bind Fc receptors has less therapeutic activity (6), and complete or partial remission induced by trastuzumab correlates with higher antibody-dependent cell cytotoxicity (7-9).Although the development of trastuzumab constitute a major advance in the treatment of ErbB-2-overexpressing breast cancer, there remains an unmet medical need for new therapies. Proapoptotic receptor agonists (PARAs), including recombinant Apo2L/ tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and mAbs, have now emerged as promising anticancer agents (10, 11). PARAs exploit the enhanced susceptibility of cancer cells versus nontransformed cells to TRAIL-mediated apoptosis. Activation of TRAIL-R1 (DR4) or TRAIL-R2 (DR5) triggers the formation of a death-inducing signaling complex (DISC) that activates caspase-8. In some cells (type I), the activation of the ensuing caspase cascade is sufficient t...

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