Abstract A89: Istiratumab (MM-141), a bispecific antibody co-targeting IGF-1R and ErbB3, potentiates the activity of immune checkpoint inhibitors (2015)

Abstract Purpose: Regulatory T cells (Tregs) help maintain immunological tolerance to cancer cells by suppressing T cell effector function. The depletion of Tregs with the CTLA-4 inhibitor antibody ipilimumab has been proven to be a productive therapeutic strategy in melanoma. Additionally, levels of insulin-like growth factor 1 (IGF-1) are often elevated following chemotherapy treatment and have been associated with poor prognosis in multiple malignances. We demonstrate that IGF-1 can stimulate Treg proliferation. Istiratumab, a tetravalent bispecific antibody that targets both the IGF-1 receptor (IGF-1R) and ErbB3, inhibits IGF-1 signaling by blocking ligand binding and inducing rapid receptor internalization. Based on its mechanism of action, we evaluated the activity of istiratumab on Treg proliferation and in combination with immune checkpoint targeting antibodies in murine models of cancer. Experimental Procedures: Mouse-derived splenocytes were harvested to evaluate the effect of IGF-1 and/or istiratumab treatment on Treg expansion and proliferation in vitro. Flow cytometry studies assessed surface receptor expression of T cell populations isolated from murine splenocytes. Efficacy studies using immunocompetent mice bearing syngeneic murine tumors determined the activity of istiratumab and immune checkpoint targeting antibodies, alone and in combination, on tumor growth alongside isotype-matched controls. Mice whose tumors were eradicated by treatment were maintained and subsequently used in tumor re-challenge studies to assess the development of tumor-specific, immunological, long-term memory. In addition, pharmacodynamic studies analyzed the expression of tumor cell signaling pathway markers, effects on relevant T cell sub-populations and effects on post-treatment cytokine profiles. Data Summary: Our in vitro T cell analyses indicated that sub-populations of murine CD4+ CD25+ FoxP3+ Tregs express IGF-1R, and that istiratumab can reverse IGF-1 driven Treg proliferation in vitro. In addition, istiratumab monotherapy treatment had significant anti-tumor activity in vivo in immunogenic, syngeneic murine tumor models. Moreover, istiratumab potentiated the activity of immune checkpoint targeting antibodies in efficacy studies leading to curative outcomes in a subset of treated animals. These animals developed long-term immunological memory directed against the original tumor cell line. A pharmacodynamic analysis of tumor cell signaling- and immunology-related markers demonstrated that istiratumab impacts tumor cell survival signaling and contributes to overall immunological changes that favor breaking immunological tolerance in relevant syngeneic tumor models, thus enabling the development of an effective and durable anti-tumor immune response. Conclusions: Our in vitro and in vivo pre-clinical studies demonstrate that istiratumab (MM-141) inhibits both tumor cell survival and Treg proliferation in host mice, thereby potentiating the anti-tumor activity of clinically-relevant immune checkpoint inhibitor antibodies. Citation Format: Sharlene Adams, Michael D. Curley, Adam J. Camblin, Sergio Iadevaia, Lin Nie, Gege Tan, Chrystal U. Louis, Alexey A. Lugovskoy. Istiratumab (MM-141), a bispecific antibody co-targeting IGF-1R and ErbB3, potentiates the activity of immune checkpoint inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A89.