Semaphorin 4D (SEMA4D; CD100) has been implicated in several key mechanisms of tumor progression, including transactivation of several oncogenes, metastasis, tumor invasion, and neovascularization. Expression of SEMA4D and its receptor plexin-B1 (PLXNB1) correlates with invasive disease in humans. SEMA4D is over-expressed in a wide array of tumor types and is also produced by inflammatory cells recruited to the tumor microenvironment. SEMA4D binding to PLXNB1 on endothelial cells activates RhoA and AKT signaling pathways, which promotes formation of new blood vessels and tumor growth in vivo. 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. It is well known that tumor growth and metastasis involve a complex process of cross talk amongst the tumor cells, stroma and immune infiltrate, as well as the endothelial cells and vasculature. Our understanding of the role of SEMA4D in this process is evolving.
We selected a humanized IgG4 antibody, VX15/2503, that blocks SEMA4D interaction with the high affinity receptor PLXNB1 and a lower affinity receptor, CD72, expressed on immune cells. The antibody binds with between 1-5 nM affinity to rat, mouse, primate, and human recombinant SEMA4D. Affinity to native cell-associated SEMA4D on primary human T cells was, however, determined to be 0.5 nM. We demonstrate that antibody-mediated SEMA4D neutralization delays tumor growth in several primary and metastatic in vivo models. Inhibition of SEMA4D regulates angiogenesis and vascular permeability in these models. Additionally, tumor growth delay results from modulation of the tumor microenvironment, such as infiltrating immune cells. We also demonstrate direct effects of SEMA4D/PLXNB1 interaction acting as a guidance signal for tumors, as previously described for axons, whereby tumor migration is affected ∼80%. Antibody blockade restores these functional activities. Moreover, using a genetic fingerprinting approach, we identified a unique gene signature that is related to changes in PLXNB1 expression and sensitivity to existing targeted therapies. This signature sheds light on combination therapies with anti-SEMA4D antibodies that may produce additive anti-tumor effects. In summary, blockade of SEMA4D reduces tumor growth through effects on tumor microenvironment, angiogenesis and vascular permeability, as well as direct effects on tumor. Therefore, antibody neutralization of SEMA4D represents a new therapeutic strategy for cancer treatment. 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: Elizabeth E. Evans, Alan S. Jonason, Mark Paris, Terrence L. Fisher, Sebold Torno, Holm Bussler, Jessica Decker, Maria Scrivens, He Huang, Laurie A. Winter, Tracy Pandina, Leslie Balch, Michael A. Doherty, Renee Kirk, Alan Howell, Jennifer Seils, Christine Reilly, Maurice Zauderer, John E. Leonard, Ernest S. Smith. Reduction of tumor growth and metastasis by a humanized IgG4 monoclonal antibody to SEMA4D (VX15/2503). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1245. doi:10.1158/1538-7445.AM2013-1245
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.