Neonatal Fc receptor in human immunity: Function and role in therapeutic intervention

Abstract

The humoral immune response provides specific, long-lived protection against invading pathogens, via immunoglobulin production and other memory functions. IgG, the most abundant immunoglobulin isotype, has the longest half-life and protects against bacterial and viral infections. The neonatal Fc receptor (FcRn) transports IgG across barriers, for example, the placenta, enhancing fetal humoral immunity to levels similar to their mothers'. Importantly, FcRn, by protecting IgG from intracellular degradation, results in an approximately 21-day circulating IgG half-life and high plasma levels; similarly, FcRn recycles albumin and is the portal of entry for enteric cytopathic human orphan (echo) virus infection. Dysregulated immune responses may lead to antibodies against self-antigens (autoantibodies), resulting in organ-specific or systemic autoimmune diseases. Autoantibody-mediated diseases have been treated by nonspecific immunoglobulin-lowering/ modulating therapies, including immunoadsorption, plasma exchange, and high-dose intravenous immunoglobulin. However, targeting FcRn with specific inhibitors results in reduction in only IgG levels. The effectiveness of FcRn inhibitors in autoimmune diseases, including myasthenia gravis and immune thrombocytopenia, provides further evidence that IgG is a primary driver in these autoantibody-mediated diseases. We describe the role of FcRn in human biology, including insights that clinical testing of FcRn inhibitors have provided into FcRn biology and autoimmune disease mechanisms, allowing fact-based speculation on their therapeutic potential.

Fc-Receptor Targeted Therapies for the Treatment of Myasthenia gravis

“…Exposure to a neutral pH of 7.4 facilitates release of IgG from the receptor. This FcRn-mediated recycling mechanism, ultimately leads to the half-life extension of all IgG subclasses [102] (Figure 4). FcRn does not interact with IgG at a neutral pH of 7.4.…”

Dissecting the mechanism of action of intravenous immunoglobulin in human autoimmune disease: Lessons from therapeutic modalities targeting Fcγ receptors

“…The other important approach is to target FcRn to directly remove pathogenic autoantibodies; although specific aspects will be summarized here, the reader is directed to another review in this issue that is focused on this therapeutic approach. 25 The major features of the therapeutic approaches targeting the FcgRs discussed below are summarized in Fig 2, and also in Fig 3, which takes ITP as a prototypic autoimmune disorder.…”

“…Much attention in relation to potential therapeutic options for targeting FcgRs in autoimmune disease has been given to directly targeting FcRn, the natural recycling receptor that is responsible for the long half-life of IgG (and of IgG autoantibodies), discussed in another article in this issue. 25 It is plausible that multivalent Fc of various types could also mimic the actions of IVIg by blocking the activity of FcRn. This, however, seems not to be the case for hexameric IgG 1 at least: Fc hexamers that contained mutations that were shown to improve the affinity for (and ability to block function of) FcRn in vitro relative to wild-type did not influence the pharmacokinetics of such molecules in mice or increase the clearance of human IgG dosed to mice transgenic for human FcRn.…”

Inhibition of Maternal-to-Fetal Transfer of IgG Antibodies by FcRn Blockade in a Mouse Model of Arthrogryposis Multiplex Congenita

“…11 Monoclonal antibodies that inhibit FcRn, such as rozanolixizumab, have been developed to treat IgG autoantibodymediated diseases. 12,13 However, there are no in vivo studies describing the use of these FcRn-inhibiting antibodies to prevent maternal-to-fetal transfer of pathogenic antibodies. Rozanolixizumab does not bind to rodent FcRn, but a surrogate monoclonal antibody (mAb), called 4470, has been produced and previously shown efficacy in mouse models of autoimmune disease.…”