Abstract 2510: Increased Fc-FcR interaction of human phosphatidylserine targeting antibody enhances pro-inflammatory and ADCC anti-tumor mechanisms

Anionic phospholipids, principally phosphatidylserine (PS), become exposed on the external surface of vascular endothelial cells in tumors, providing an excellent marker for tumor vascular targeting. Binding of antibodies targeting PS on the tumor endothelial cells and tumors recruits immune cells and engages the immune system to destroy tumor vasculature. The antibodies also enhance anti-tumor immunity by blocking the immunosuppressive action of PS. A chimeric anti-PS antibody, bavituximab, is being used in combination with chemotherapy to treat patients with solid tumors in Phase II trials. We have engineered mutations in the Fc region of fully human PS-targeting antibody PGN635 that enhance the interaction with FcRgammaIIIa and have characterized their ability to exert anti-tumor effects through various mechanisms, including ADCC and cytokine induction. Mutations that enhance Fc-FcR interaction of PS targeting antibodies enhance production of pro-inflammatory chemokines such as MCP-1 (CCL2), MIP-1alpha (CCL3) and MIP-1beta (CCL4). In addition, the same Fc mutations enhance ADCC of PS expressing tumor targets. Our data indicate that improvement of multiple immune effector functions via enhanced interaction of Fc-FcR interaction of PS-targeting antibodies may improve the treatment 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 2510. doi:1538-7445.AM2012-2510