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.
Autoimmune diseases as a group impose a major health burden. While most autoimmune diseases are individually rare, in the aggregate they affect 5-8% of Americans and can be life-threatening. Current treatments are moderately effective, yet carry a heavy risk of adverse effects. We have identified a monoclonal antibody specific to B cells which shows efficacy in animal models of rheumatoid arthritis and systemic lupus erythematosus. This antibody therapy is safer than competing approaches, because its effects are transient and can be quickly reversed, if necessary. With further development, this antibody will greatly improve the therapeutic options for autoimmune diseases.
