It has been demonstrated that semaphorin 4D (SEMA4D; CD100) is a potent pro-angiogenic molecule. SEMA4D binding to its receptor plexin-B1 (PLXNB1) on endothelial cells transactivates c-MET and 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 present in the tumor microenvironment. It has recently been demonstrated that in an environment lacking SEMA4D, the ability of mouse breast cancer cells to originate tumor masses and metastases is severely impaired, and that SEMA4D produced by tumor associated macrophages is required for tumor angiogenesis and growth.

In addition to its effects on endothelial cells, SEMA4D binding to PLXNB1 on tumor cells results in MET transactivation and migration of tumor cells. It has been further reported that overexpression of PLXNB1 and MET in breast and ovarian cancers is a negative prognostic factor. Tumors co-expressing PLXNB1 and MET were characterized as having a higher grade and an increased frequency of metastases.

Collectively, these results suggest that expression of SEMA4D, either by tumor cells or by tumor associated macrophages, may represent a mechanism of tumor neovascularization, and that expression of the SEMA4D receptor in tumors may further induce tumor invasion, thereby enhancing their growth, survival, and metastatic potential.

Antibody neutralization of SEMA4D thus may represent a new therapeutic strategy for cancer treatment. We selected a high affinity human IgG4 antibody that is specific for both mouse and human SEMA4D, and utilized several in vitro functional assays to demonstrate that this antibody blocks SEMA4D - PLXNB 1 interactions. Using both transplanted and orthotopic tumor models we demonstrated that antibody mediated SEMA4D neutralization in vivo inhibits tumor growth and tumor angiogenesis. This human antibody is currently in IND-enabling toxicology testing and we anticipate the initiation of human clinical trials in 2H 2010.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-36.