Research Project
8981498
? DESCRIPTION (provided by applicant): Monoclonal antibody for autoimmune disease Abstract B cells play a major role in the pathogenesis of many autoimmune disorders, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis, and type I diabetes mellitus, as indicated by the efficacy of B cell-targeted therapies like rituximab in thes diseases. Unfortunately, current therapies are predicated on B-cell depletion, which is problematic from a safety standpoint. Due to immunosuppression, existing standard-of-care therapies generate adverse effects, notably opportunistic infections resulting from long-term, severe B cell depletion. Recently, an alternative approach involving the targeting of CD79, the transducer subunit of the B cell receptor (BCR) has been described. Unlike anti-CD20 mAbs, the protective effects of CD79-targeted mAbs do not require cell depletion; rather, they act by inducing an unresponsive or anergic state in which B cells physically relocate and are unavailable to participate in immune response generation. In the murine MRL/lpr model of SLE, anti-CD79 antibodies were potently immunosuppressive and effective at decreasing inflammation and improving survival (Li, 2008). In a collagen-induced arthritis model of rheumatoid arthritis, anti-CD79 antibodies delayed the onset of arthritis and decreased arthritis scores, by inducing anergy with transient, reversible B cell redistribution (Hardy, 2014). Based on these studies, Phase 1 work will identify and characterize a potent anti-CD79 human monoclonal antibody. Unlike other B cell targeted biologics that induce B cell death by ADCC, complement fixation or survival factor starvation-mediated cell death, this approach will induce a transient state of polyclonal B cell anergy. We expect this second generation immunosuppressive therapeutic to be significantly safer than existing B cell targeted antibodies.
