Abstract 2723: Sarilumab (REGN88), a fully-human anti-IL6R antibody, inhibits tumor growth in preclinical models, as a single agent and in combination with the VEGF blocker aflibercept

Abstract

Abstract IL6 is a pro-inflammatory cytokine that is expressed in multiple cancer types. Clinical studies have shown that increased serum IL6 levels are associated with worse patient outcomes. Elevated expression of IL6 can result from the activation of oncogenic signaling pathways and/or as a consequence of chronic inflammation, which has long been associated with the development of cancer. IL6 signals through its heterodimeric receptor IL6R/gp130 to activate the JAK/STAT and Ras signaling pathways. In particular, IL6 strongly activates STAT3, which has been shown to promote tumor cell proliferation, invasion and survival. Inhibition of IL6 signaling with monoclonal antibodies directed against IL6 or IL6R has been shown to inhibit tumor growth in preclinical models of prostate carcinoma, squamous cell carcinoma and myeloma, suggesting that the IL6 pathway is an attractive therapeutic target for cancer. Sarilumab (REGN88) is a monoclonal antibody that binds human IL6R and prevents binding of IL6, thereby inhibiting activation of downstream signaling pathways. Positive results from a Phase 2 trial of sarilumab in rheumatoid arthritis have recently been reported. Given the proposed role of IL6 in cancer, we tested the effects of sarilumab in human tumor xenograft models. Sarilumab provided partial growth inhibition of a subset of the tumor cell lines tested, e.g., DU145 (prostate), Calu3 (lung) and A549 (lung). An inhibitory effect of sarilumab on tumor growth was observed only in cell lines that exhibit autocrine IL6/STAT3 signaling in vitro, i.e., basal STAT3 phosphorylation that can be blocked by sarilumab. Histological analysis of sarilumab-treated tumors revealed an increase in tumor cell apoptosis, suggesting that IL6 provides a survival signal to tumor cells. Since REGN88 does not block IL6R on mouse stromal cells, these findings indicate that IL6 can promote tumor growth via direct actions on human tumor cells. Combination treatment with sarilumab plus the potent VEGF blocker aflibercept provided better inhibition of tumor growth than either single agent in several tumor models, including an aflibercept-resistant variant of A431 epidermoid carcinoma that expresses higher levels of IL6 (∼6-fold) than the parental A431 cells. Interestingly, sarilumab monotherapy did not inhibit the growth of the A431 variant tumor line at all, yet sarilumab potentiated the effect of aflibercept, suggesting that IL6 signaling may be particularly important under conditions where tumor cells are stressed. In summary, sarilumab inhibits the growth of tumors with active IL6/STAT3 signaling, both as a single agent and in combination with aflibercept, suggesting that it is a potential candidate for the treatment of multiple types of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2723. doi:1538-7445.AM2012-2723