A new study on the development of therapeutic monoclonal antibodies to treat neuroinflammatory and demyelinating disease entitled “SEMA4D compromises blood–brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease” was published in the journal Neurobiology of Disease by Ernest S. Smith part of Maurice Zauderer’s group from Vaccinex, Inc.
Vaccinex, Inc. is a private clinical-stage biotechnology company located in Rochester, New York, focused on the discovery and development of human therapeutic monoclonal antibodies as therapy against cancer and neurodegenerative diseases, such as multiple sclerosis and Huntington’s disease. The company uses their ActivMAb® Antibody Discovery Technology for quick, mammalian cell-based antibody selection using the rapid and sensitive virus panning selection and cell sorting to form its antibody collection.
Multiple sclerosis (MS) is defined by an immune-mediated demyelinating process, where damage of the protective covering (myelin sheath) of nerve fibers in the brain and spinal cord occurs, and is a neurodegenerative disease of the human central nervous system (CNS). Although MS pathogenesis is not clear, it seems that cerebral endothelial cells, which constitute the barrier that separates and protects the CNS from the peripheral circulation, play a crucial role in this process. Also, cerebral endothelial permeability, i.e. the flow of small molecules or immune cells in and out of the vessel into the CNS is altered in different clinical forms of MS. There is an urgent need to find new therapeutic targets and approaches to inhibit the development of MS. Semaphorin 4D (SEMA4D) triggers signaling cascades that induce glial activation, failure of the neuronal process, inhibition of the migration and differentiation of oligodendrocyte precursor cells (OPCs), and disruption of endothelial tight junctions that constitute the blood-brain barrier (BBB).
In this study, the research team generated a monoclonal antibody that binds SEMA4D from mouse, rat, monkey and human with high affinity and inhibits the binding between SEMA4D and its receptors. The anti-SEMA4D binds in vitro to the recombinant SEMA4D, not allowing the inhibition of oligodendrocyte precursor cells survival and differentiation. Using experimental autoimmune encephalomyelitis in multiple rodent models, the anti-SEMA4D inhibits significantly the development of the disease by maintaining the BBB integrity and axonal myelination. Moreover, anti-SEMA4D favored migration of OPC to the site of lesions and improved myelin status after inducing demyelination chemically.
In conclusion, this study suggests SEMA4D as a crucial player in the pathogenesis of CNS and highlights the need for additional development of against SEMA4D as a promising therapeutic strategy for MS and other neurologic diseases by targeting the demyelination and/or the neurovascular processes.
Presently, Vaccinex is performing a phase 1 clinical trial to assess the safety and tolerability of VX15/2503, an antibody that blocks human SEMA4D, in patients with multiple sclerosis. The results from this clinical study are expected to be released in early 2015.