Semaphorin 4D (SEMA4D/CD100) is expressed on neural and immune cells, and its high affinity receptor, Plexin B1 (PLXNB1), is expressed on neural, endothelial, and dendritic cells. SEMA4D signaling through PLXNB1 has been shown to modulate glial cell activation, inhibit differentiation and migration of oligodendrocyte precursor cells (OPCs), disrupt CNS endothelial tight junctions, and induce neuronal process collapse. Multiple sclerosis (MS) is characterized by CNS immune cell infiltration, blood-brain barrier (BBB) breakdown, myelin destruction, and neuronal degeneration. Antibody neutralization of SEMA4D could, therefore, ameliorate multiple sclerosis through multiple mechanisms. Blocking SEMA4D could promote survival, migration and differentiation of oligodendrocyte precursors and remyelination.
In addition, preventing SEMA4D-mediated breakdown of the blood brain barrier (BBB) may suppress immune cell infiltration into the CNS and reduce inflammation and secondary immune responses to CNS antigens. We generated a monoclonal antibody that binds with high affinity to mouse, rat, monkey, and human SEMA4D and blocks the binding of Sema4D to its cognate receptors. Anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation in vitro, and promotes migration of OPC to the sites of demyelinating lesions in vivo. Anti-SEMA4D significantly attenuates experimental autoimmune encephalomyelitis in multiple rodent models by preserving BBB integrity and axonal myelination. In a transgenic model of Huntington’s disease, anti-SEMAD can be shown to prevent loss of brain volume and to restore behavioral deficits. This model may be better aligned to progressive neurodegenerative disease than is EAE. Collectively, these data suggest that antibody-mediated neutralization of SEMA4D represents a viable therapeutic strategy for multiple sclerosis. To this end, a randomized, placebo-controlled, double blind, single ascending dose Phase 1 study in MS patients using a humanized anti-SEMA4D antibody (VX15/2503 ) was initiated and will soon be completed.
Anti-SEMA4D reduces EAE clinical scores:
Anti-SEMA4D preserves brain volume...
This was a poster presented at this years ECTRIMS (to see the poster follow this link: http://www.vaccinex.com/Collateral/Documents/English-US/ectrims4.pdf). Anti-SEMA4D antibody appears to be both anti-inflammatory (the EAE figure) and neuroprotective (the Huntington's model) - a rare combination. Importantly, SEMA4D is an axon guidance molecule and its primary role is to inhibit axonal growth (similar to LINGO1 - which is currently in clinical trial); it is plausible that the observed improvement in atrophy and cognition/memory is the result of new axonal growth and synapse/neuronal connections. I assume Vaccinex (the company) will be selling the product on to 'Big Pharma' once the Phase I safety study is 'safely' completed (their collaborating partners are Teva, GSK, Biocon and Bayer!).