Abstract 2531: Reduction of In Vivo Tumor Growth and Angiogenesis by a Humanized IgG4 Monoclonal Antibody to SEMA4D

Abstract

Abstract Semaphorin 4D (SEMA4D; CD100) has been implicated in several key mechanisms of tumor progression, including metastasis, tumor invasion, and neovascularization. SEMA4D binding to its receptor plexin-B1 (PLXNB1) on endothelial cells activates RhoA and AKT signaling pathways, which promotes formation of new blood vessels and tumor growth in vivo. SEMA4D is over-expressed in a wide array of tumor types, and is also produced by inflammatory cells recruited to the tumor microenvironment, such as tumor-associated macrophages. In addition to its effects on endothelial cells, the interaction of PLXNB1 with MET and ERBB2 can lead to SEMA4D-mediated transactivation of these membrane receptor kinases with a direct effect on tumor cell migration and invasive growth. Collectively, these results suggest that expression of SEMA4D, either by tumor cells or by tumor associated inflammatory cells, functions as a crucial factor in tumor metastatic potential, and that expression of SEMA4D and/ or its high affinity receptor in tumors induces neovascularization and increases overall tumor aggressiveness. Antibody neutralization of SEMA4D represents a new therapeutic strategy for cancer treatment. We selected a humanized IgG4 antibody, VX15/2503, that binds with roughly 3 nM affinity to rat, mouse, primate, and human SEMA4D. We utilized cellular collapse, flow cytometric and other in vitro functional assays to demonstrate that this antibody blocks SEMA4D interaction with PLXNB1. Using both this antibody and its mouse IgG1 equivalent, MAb 67-2, we have demonstrated that antibody-mediated SEMA4D neutralization blocks tumor growth in CT26 tumor grafts with a tumor growth delay (TGD) of 42% and BCA34 (TGD 18%) tumor grafts, as well as RIP-Tag2, with a tumor growth inhibition (TGI) of 56%, and Tyr:NRAS (TGD 52%) spontaneous tumor models. In summary, we demonstrate that antibody mediated neutralization of SEMA4D in vivo inhibits tumor growth and tumor angiogenesis in a variety of tumor models. The humanized antibody, VX15/2503, has successfully completed IND-enabling toxicology testing and a Phase I trial is currently being conducted in adult patients with advanced solid tumors. 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 2531. doi:1538-7445.AM2012-2531