Monoclonal antibody for autoimmune disease

Monoclonal antibody for autoimmune disease AbstractB cells play a major role in the pathogenesis of many autoimmune disordersincluding rheumatoid arthritisRAsystemic lupus erythematosusSLEmultiple sclerosisand type I diabetes mellitusT Das indicated by the efficacy of B cell targeted therapiese grituximabin these diseasesUnfortunatelycurrent therapies are predicated on B cell depletionwhich is problematic from a safety standpointDue to consequent immunosuppressionexisting standard of care therapies generate adverse effectsnotably opportunistic infections and activation of viruses from latencydue to long termsevere B cell depletionRecentlyan alternative approach involving the targeting of CDthe transducer subunit of the B cell receptorBCRhas been suggested by our groupUnlike anti CDmAbsthe protective effects of CDtargeted mAbs do not require cell depletionratherthey act by inducing a reversible unresponsive or anergic stateand thus do not participate in immune response generationIn the murine MRL lpr model of SLEanti CDantibodies were potently immunosuppressive and effective at decreasing inflammation and improving survivalLiIn a collagen induced arthritis model of rheumatoid arthritisanti CDantibodies delayed the onset of arthritis and decreased arthritis scores by inducing anergy with transientreversible B cell redistributionHardyBased on these studiesPhasework identified and characterized a potent humanized monoclonal antihuman CDantibodyThe activity of the antibody does not require ADCCcomplement fixationbut rather acts by induction of a transient and reversible state of polyclonal B cell anergyDuring this Phase II projectwe will expand preclinical studies in a transgenic mouse model expressing huCDand in a NOD mouse model of T DIn additionwe will explore the molecular basis of unresponsiveness and analyze toxicityand pharmacokineticsas well as activity in non human primatesWe expect this second generation immunosuppressive therapeutic to be significantly safer than existing B cell targeted antibodies for T D and potentially other autoimmune diseases NarrativeAutoimmune diseases as a group impose a major health burdenWhile specific autoimmune diseases are infrequent in the populationin the aggregate they affectof Americans and can be life threateningCurrent treatments are moderately effectiveyet carry a heavy risk of adverse effectsWe have identified a monoclonal antibody specific to B cells which shows efficacy in animal models of rheumatoid arthritissystemic lupus erythematosusand typediabetesThis antibody therapy is safer than competing approachesbecause its effects are transient andif necessarycan be quickly reversedWith further developmentthis antibody will greatly improve the therapeutic options for autoimmune diseases