Antibody – VX15 Multiple Sclerosis SEMA4D is an important mediator of immune activation. Sema4D, through its immune associated receptor, CD72, activates B cells and dendritic cells to promote B cell survival, T cell activation, and to enhance CD40-induced proliferation and antibody production (REF 1-3). In addition, through a second broadly expressed high affinity receptor, Plexin-B1, Sema4D activates microglial cells that contribute to neuroinflammation. We and others (REF 4) have shown that antibody neutralization of Sema4D inhibits experimental autoimmune encephalomyelitis. In addition, several studies demonstrate that Sema4D signaling through Plexin-B1 can inhibit oligodendrocyte differentiation and remyelination in vitro and in vivo (REF 5-9).
Taken together, these observations suggest that antibody neutralization of SEMA4D may, through inhibition of immune and inflammatory mechanisms as well as its neuroprotective activity, be a novel and uniquely promising therapeutic for multiple sclerosis and other neuroinflammatory diseases. We have selected a high affinity human IgG4 antibody that is specific for both mouse and human SEMA4D, and demonstrated in vitro that this antibody blocks the interaction of SEMA4D with its high affinity receptor, PLXNB1. Using mouse models of EAE, we demonstrate that a mouse monoclonal (67-2), anti-SEMA4D antibody that binds to the same epitope as our human lead is capable of reducing disease severity by as much as 50%. A Phase I clinical trial of VX15/Anti-SEMA4D antibody for multiple sclerosis is planned in 2012. 
Figure 1. The anti-SEMA4D antibody 67-2 is able to reduce disease severity in a peptide-based mouse model of multiple sclerosis.
6 to 8 week old SJL mice were administered a combination of PLP peptide 139-151 in CFA to induce disease. Mice were given 600ugs of a negative control mouse IgG antibody or of antibody 67-2 intraperitoneally starting at day 7. Dosing continued 1X per week for a total of 6 doses. Comparing with the IgG control, 67-2 treatment reduces group mean score by 53%. Experiment has been repeated four times with similar results. 
Figure 2. The anti-SEMA4D antibody 67-2 is able to reduce disease severity in a T cell adoptive transfer-based mouse model of multiple sclerosis.
CD4+ T cells were isolated from mice immunized with myelin-derived peptide and restimulated in vitro for 10 days. Two million T cells were transferred into each naïve recipient mouse to induce disease. Animals were treated once per week with 600 ug antibody.
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