Semaphorin 4D (SEMA4D; CD100) has been implicated in several key mechanisms of tumor progression, including neovascularization, tumor invasion, and metastasis. SEMA4D binding to its receptor plexin-B1 (PLXNB1) on endothelial cells transactivates 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 recruited inflammatory cells present in the tumor microenvironment. Several recent papers have shown that in an environment lacking SEMA4D, the ability of mouse cancer cells to originate tumor masses and metastases is severely impaired. Furthermore, SEMA4D produced by tumor-associated macrophages has been shown to support tumor angiogenesis and growth.

In addition to its effects on endothelial cells, SEMA4D has a direct effect on tumor invasive growth and migration. A recent clinical study in soft tissue sarcomas correlates strong SEMA4D expression in tumors with a higher mitotic count and poor prognosis. 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 inflammatory cells, functions as a crucial factor in tumor neovascularization, and that expression of the SEMA4D and/ or its high affinity receptor in tumors may further induce tumor growth rate and metastatic potential.

Antibody neutralization of SEMA4D thus may represent a new therapeutic strategy for cancer treatment. We selected a humanized IgG4 antibody that binds with high affinity to rat, mouse, primate, and human SEMA4D, and utilized several in vitro functional assays to demonstrate that this antibody blocks SEMA4D – PLXNB1 interactions. Using syngeneic, xenograft and orthotopic tumor models we demonstrated that antibody mediated neutralization of SEMA4D in vivo inhibits tumor growth and tumor angiogenesis. This humanized antibody has successfully completed IND-enabling toxicology testing and we anticipate the initiation of human clinical trials in early 2011.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3667. doi:10.1158/1538-7445.AM2011-3667