No abstract

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.

No abstract

The maintenance of the homeostasis of immunoglobulin G (IgG) represents a fundamental aspect of humoral immunity that has direct relevance to the successful delivery of antibody-based therapeutics. The ubiquitously expressed neonatal Fc receptor (FcRn) salvages IgG from cellular degradation following pinocytic uptake into cells, conferring prolonged in vivo persistence on IgG. However, the cellular sites of FcRn function are poorly defined. Pinocytic uptake is a prerequisite for FcRn-mediated IgG salvage, prompting us to investigate the consequences of IgG uptake and catabolism by macrophages, which represent both abundant and highly pinocytic cells in the body. Site-specific deletion of FcRn to generate mice harboring FcRn-deficient macrophages results in IgG hypercatabolism and ~threefold reductions in serum IgG levels, whereas these effects were not observed in mice that lack functional FcRn in B cells and dendritic cells. Consistent with the degradative activity of FcRn-deficient macrophages, depletion of these cells in FcRn-deficient mice leads to increased persistence and serum levels of IgG. These studies demonstrate a pivotal role for FcRn-mediated salvage in compensating for the high pinocytic and degradative activities of macrophages to maintain IgG homeostasis.