Semaphorin 4D (SEMA4D) plays a role in multiple cellular processes that contribute to pathophysiology of neuroinflammatory/neurodegenerative diseases, such as Huntington’s disease and multiple sclerosis. SEMA4D is, therefore, a unique target for therapeutic development. VX15/2503 is a novel monoclonal antibody that blocks the activity of SEMA4D. Preclinical testing has demonstrated beneficial effects of anti-SEMA4D treatment in a variety of neurodegenerative disease models. Vaccinex is committed to the development of this potentially important antibody that has the potential to help people with different neurodegenerative disorders that share common mechanisms of pathology.
Vaccinex has successfully completed a Phase I, multi-center, randomized, double-blind, placebo-controlled, single-ascending dose clinical trial of VX15/2503 anti-SEMA4D antibody in 50 adult patients with multiple sclerosis. In total, 40 doses of VX15/2503 were administered to patients, ranging in concentration from 1.0 to 20 mg/kg. VX15/2503 was well tolerated and no Maximum Tolerated Dose (MTD) was reached.
The mechanism of action of VX15/2503 in preclinical models has been shown to involve several different cell types. These include oligodendrocyte precursor cells that have the potential to remyelinate damaged nerves and microglia and astrocytes, the main innate inflammatory cells of the brain whose chronic activation is believed to contribute to neurodegenerative processes.
Anti-SEMA4D was tested in several pre-clinical rodent models of experimental autoimmune encephalomyelitis (EAE). As shown in Figure 1, anti-SEMA4D had a statistically significant effect in ameliorating disease induced by active immunization with a myelin-derived peptide (PLP), as well as by adoptive transfer of myelin-specific T-cells into mice. In this latter model, the benefit of treatment with anti-SEMA4D antibody was comparable to IFN-β, an FDA approved drug for relapsing-remitting multiple sclerosis. Importantly, anti-SEMA4D antibody was also shown to ameliorate disease in a transgenic mouse model of Huntington’s disease. In this case, treatment with anti-SEMA4D antibody provided significant protection against the characteristic loss of brain volume in this disease model (Figure 2) as well as preventing loss of spatial memory and suppressing anxiety like behaviors.
In June 2015 we received clearance from the FDA to proceed with a Phase 2 clinical trial in Huntington’s disease. Please see the Clinical Programs overview page for a link to the clinicaltrials.gov page with details about the study.
Vaccinex publications describing preclinical studies of anti-SEMA4D in neurology
Smith et al. Neurobiology of Disease Volume 73, January 2015, Pages 254–268
Southwell et al. Neurobiology of Disease Volume 76, April 2015, Pages 46-56
Click to enlarge:
Anti-SEMA4D antibody treatment significantly improves clinical scores in two different rodent models of experimental autoimmune encephalomyelitis (EAE) an animal modle of MS. Data published in Smith et al, 2014, Neurobiology of Disease (73); 254-268.
VX15 treatment significantly inhibits cortical and corpus callosum degeneration in brains of 12 month-old YAC128 mice, a transgenic model of Huntington’s Disease. The open bars show volume measurements in normal control mice while filled bars represent the transgenic HD animals. Bars in the blue shaded boxes represent the animals that received preventive therapy with anti-SEMA4D antibody.