The brain is a very energy intensive organ that consumes more than 20% of all the energy utilized by the body. Glucose is the main source of energy in the brain and during underlying progression of Alzheimer’s disease (AD) there is a reduction in glucose uptake and energy-dependent brain metabolic activity.  These changes are readily detected by PET imaging following administration of an isotope labeled glucose analog, 18F-fluorodeoxyglucose (FDG-PET). In the present study, Vaccinex plans to test an antibody they have developed, pepinemab (VX15), in patients with MCI or early AD. Pepinemab blocks the activity of a novel biological effector, semaphorin 4D (SEMA4D) that regulates the ability of a cell to extend its actin cytoskeleton so as to form processes that enable the cell to physically interact with other cells and to migrate in the direction in which such processes extend. SEMA4D has been found to regulate activity of astrocytes and microglia, the innate inflammatory cells of the brain; of glial progenitor cells that can repair or replenish damaged glial cells; as well as the ability of brain endothelial cells to form the tight junctions required for integrity of the blood-brain barrier. Although the activity of SEMA4D can be helpful in the context of acute injury, it can aggravate damage in the context of chronic inflammation that is characteristic of many neurodegenerative diseases including AD.

Importantly, it has been previously shown that treatment with pipinemab can restore brain metabolic activity in patients with Huntington’s disease (HD), another slowly progressive neurodegenerative disease, and that restoration of metabolic activity in HD appeared to correlate with reduced brain atrophy and to be associated with clinical benefit. The scientific rationale for activity of anti-SEMA4D blocking antibody and its demonstrated effects in Huntington’s disease make this drug an attractive potential therapeutic in Alzheimer’s disease.