Thursday, November 21, 2024
11/21/2024
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 (T1D), as indicated by the efficacy of B cell–targeted therapies, e.g. rituximab, in these diseases. Unfortunately, current therapies are predicated on B-cell depletion, which is problematic from a safety standpoint. Due to consequent immunosuppression, existing standard-of-care therapies generate adverse effects, notably opportunistic infections and activation of viruses from latency, due to 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 suggested by our group. Unlike anti-CD20 mAbs, the protective effects of CD79-targeted mAbs do not require cell depletion; rather, they act by inducing a reversible unresponsive or anergic state, and thus do not 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 identified and characterized a potent humanized monoclonal anti- human CD79 antibody. The activity of the antibody does not require ADCC, complement fixation, but rather acts by induction of a transient and reversible state of polyclonal B cell anergy. During this Phase II project, we will expand preclinical studies in a transgenic mouse model expressing huCD79 and in a NOD mouse model of T1D. In addition, we will explore the molecular basis of unresponsiveness and analyze toxicity, and pharmacokinetics, as well as activity in non-human primates. We expect this second generation immunosuppressive therapeutic to be significantly safer than existing B cell-targeted antibodies for T1D and potentially other autoimmune diseases.
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