Targeting Neuroinflammation with Nasal Administration of Anti-CD3 Monoclonal Antibody to Treat Alzheimer’s Disease

Nasally administered anti-CD3 monoclonal antibody induces an anti-inflammatory immune response that attenuates neuroinflammation in the brain resident microglia and astrocytes. The mechanism of action of nasal anti-CD3 is associated with the induction of regulatory T cells (Tregs) in the cervical lymph node and the subsequent migration of these Tregs to the brain to modulate glial cells. Microglia and astrocytes have been shown to acquire an activated/inflammatory phenotype in Alzheimer’s disease (AD) due to danger signals, including dead neurons. In our studies of animal models of AD, nasal anti-CD3 inhibited microglia inflammatory gene signature, which was associated with improved cognition. In this proposal, we will investigate the mechanisms by which nasal anti-CD3 regulates microglia and astrocyte activation; the crosstalk between nasal anti-CD3-induced Tregs and microglia/astrocytes; and whether nasal anti-CD3 potentiates anti- amyloid therapies in ameliorating disease progression in a mouse model of AD. In our preclinical and human studies performed to date of nasal administration of anti-CD3 (Foralumab), no side effects were observed. Moreover, the treatment is given by a nasal spray, which makes it easy to administer and applicable to all disease stages. Furthermore, we have initiated the treatment of secondary progressive multiple sclerosis patients under the FDA expanded access program and found positive results, including decrease of microglia activation as measured by PET scan. Together, we will provide the basis for treating AD and related dementia patients following the studies being performed in this proposal.