Semaphorin perhe, SEMA4D

A different approach to inhibit tumor angiogenesis with anti-Sema4D antibodies was presented by Maurice Zauderer (Vaccinex). Sema4D is a member of the semaphorin family of proteins first identified as mediators in axon guidance. Sema4D is involved in the regulation of several different physiological processes, one of which is endothelial and epithelial cell migration. It also enhances CD40-induced immune and inflammatory cell activation, inhibits neurite extension and axon regeneration, and promotes survival and differentiation of oligodendrocyte precursor cells. As a multifunctional target, Sema4D may be of therapeutic relevance in numerous indications, e.g., cancers, rheumatoid arthritis, multiple sclerosis. Results from mouse models suggest that Sema4D antibodies could indeed have wide applicability. For example, a mouse Sema4D-specific antibody, MAb67, was as efficient as the clinically validated anti-TNF therapy etanercept (Enbrel^®) in haltling disease progression in an established collagen-induced arthritis model. Besides reducing the inflammatory response, the anti-Sema4D antibody also inhibited bone erosion. This may be explained with recent findings that Sema4D mediates osteoclast-osteoblast communication. In addition, Sema4D inhibition was also effective in an EAE model, where the clinical score was reduced by 50% by anti-Sema4D antibody treatment initiated during the onset of the disease.
Due to the abundant Sema4D expression on T cells and to a lesser extent on B cells, monocytes and dendritic cells, Vaccinex chose an IgG4 isotype for their humanized anti-Sema4D antibody VX15/2503 to avoid immune cell depletion. VX15/2503 inhibits membrane-bound human Sema4D, as well as a soluble Sema4D that is generated from the membrane-bound form by ectodomain shedding. VS15/2503 was shown to block Sema4D-induced collapse of the actin cytoskeleton and apoptosis in oligodendrocyte precursor cells in vitro. It also neutralized Sema4D mediated inhibition of oligodendrocyte precursor cell maturation into myelin basic protein-producing cells and reverted the inhibition of remyelation following lysophosphatidyl choline induced injury in postnatal brain slice cultures in vitro, thus indicating possible applications in multiple sclerosis patients.