Multiple autoimmune diseases are characterized by the involvement of autoreactive antibodies in pathogenesis. Problems associated with existing therapeutics such as the delivery of intravenous immunoglobulin (IVIG) have led to interest in developing alternative approaches using recombinant or synthetic methods. Towards this aim, in the current study we demonstrate that the use of Fc-engineered antibodies (Abdegs, for antibodies that enhance IgG degradation) to block FcRn through high affinity, Fc region binding is an effective strategy for the treatment of antibody-mediated disease. Specifically, Abdegs can be used at low, single doses to treat disease in the K/BxN serum-transfer model of arthritis using BALB/c mice as recipients. 25–50 fold higher doses of IVIG are required to induce similar therapeutic effects. Importantly, we show that FcRn blockade is a primary contributing factor towards the observed reduction in disease severity. The levels of albumin, which is also recycled by FcRn, are not affected by Abdeg delivery. Consequently, Abdegs do not alter FcRn expression levels or subcellular trafficking behavior. The engineering of antibody constant regions to generate potent FcRn blockers therefore holds promise for the therapy of antibody-mediated autoimmunity.

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