Novel approaches to primary membranous nephropathy: Beyond the KDIGO guidelines.

Primary membranous nephropathy (PMN) is an immune-mediated glomerular disease. Rituximab (RTX) is recommended as a first-line immunosuppressive therapy and shows high clinical efficacy, but the optimal doses remain controversial. Approximately 20%-40% of PMN patients experience RTX resistance and failure. Reduced bioavailability, RTX internalization and attack, anti-RTX antibody production, autoreactive B-cell reservoirs and chronic and irreversible renal damage may contribute to this problem. Therefore, new treatment modalities are needed to compensate for this deficit. New interventions and new dose combinations are being proposed. Multiple drug combination therapies show comparable clinical efficacy to conventional treatments by blocking the production of disease-causing antibodies in multiple directions, and can reduce single-agent doses without increasing adverse effects. New therapies that directly target B cells, plasma cells, and antibody production have shown encouraging results. In addition, new techniques for sweeping antibodies and chimeric antigen receptor T-cell therapy also may be promising strategies for PMN. Immunoadsorption could be used as an auxiliary choice for severe cases. This article explores new treatments for PMN and highlights possible mechanisms for potential new technologies that offer new ideas for treatment.

Elimination of plasma soluble antigen in cynomolgus monkeys by combining pH-dependent antigen binding and novel Fc engineering.

A conventional antibody targeting a soluble antigen in circulation typically requires a huge dosage and frequent intravenous administration to neutralize the antigen. This is because antigen degradation is reduced by the formation of antigen-antibody immune complexes, which escape from lysosomal degradation using neonatal Fc receptor (FcRn)-mediated recycling. To address this, we developed an antigen-sweeping antibody that combines pH-dependent antigen binding and Fc engineering to enhance Fc receptor binding. The sweeping antibody actively eliminates the plasma antigens by increasing the cellular uptake of the immune complex and dissociating the antigens in the acidic endosome for degradation. Strong antigen sweeping can reduce the dosage, potentially achieve higher efficacy, and expand the scope of antigen space available for targeting by antibodies. In this study, to further improve the sweeping efficacy, we developed a novel antibody Fc variant by enhancing Fcγ receptor IIb (FcγRIIb) binding and modulating charge characteristics for increased cellular uptake of the immune complex, together with enhancing FcRn binding for efficient salvage of the antigen-free antibodies. Our Fc variant achieved strong antigen sweeping in cynomolgus monkeys with antibody pharmacokinetics comparable to a wild-type human IgG1 antibody. The positive-charge substitutions enhanced uptake of the immune complex by FcγRIIb-expressing cells in vitro, which was completely inhibited by an anti-FcγRIIb antibody. This suggests that the strong in vivo sweeping efficacy improved by the charge engineering is more likely achieved by FcγRIIb-dependent uptake of the immune complex rather than nonspecific uptake. We expect this novel Fc engineering can maximize the antigen sweeping efficacy even in humans and create novel therapeutic antibodies that meet unmet medical needs for patients.

Strategies Towards Antigen-Specific Treatments for Membranous Nephropathy.

Membranous nephropathy (MN) is a rare but potentially severe autoimmune disease and a major cause of nephrotic syndrome in adults. Traditional treatments for patients with MN include steroids with alkylating agents such as cyclophosphamide or calcineurin inhibitors such as cyclosporine, which have an undesirable side effect profile. Newer therapies like rituximab, although superior to cyclosporine in maintaining disease remission, do not only affect pathogenic B or plasma cells, but also inhibit the production of protective antibodies and therefore the ability to fend off foreign organisms and to respond to vaccination. These are undesired effects of general B or plasma cell-targeted treatments. The discovery of several autoantigens in patients with MN offers the great opportunity for more specific treatment approaches. Indeed, such treatments were recently developed for other autoimmune diseases and tested in different preclinical models, and some are about to jump to clinical practice. As such treatments have enormous potential to enhance specificity, efficacy and compatibility also for MN, we will discuss two promising strategies in this perspective: The elimination of pathogenic antibodies through endogenous degradation systems and the depletion of pathogenic B cells through chimeric autoantibody receptor T cells.

Identification of human IgG1 variant with enhanced FcRn binding and without increased binding to rheumatoid factor autoantibody.

Various studies have demonstrated that Fc engineering to enhance neonatal Fc receptor (FcRn) binding is effective for elongating half-life or increasing cellular uptake of IgG. A previous study has shown that a N434H mutation to enhance FcRn binding resulted in increased binding to rheumatoid factor (RF) autoantibody, which is not desirable for therapeutic use in autoimmune disease. In this study, we first showed that all the existing Fc variants with enhanced FcRn binding also show increased RF binding, and then identified specific mutations that could be introduced to those Fc variants to reduce the RF binding. Furthermore, we generated novel Fc variants that do not increase RF binding and show half-lives of 45 d in cynomolgus monkey, which is longer than those of previously reported Fc variants. In addition, we generated novel Fc variants with antigen sweeping activity that do not increase RF binding. We expect that these novel Fc variants will be useful as antibody therapeutics against autoimmune diseases.

Sweeping antibody as a novel therapeutic antibody modality capable of eliminating soluble antigens from circulation.

Monoclonal antibodies have become a general modality in therapeutic development, and a variety of monoclonal antibodies targeting soluble antigens have been developed. However, even with infinite binding affinity to an antigen, a conventional antibody can bind to the antigen only once and results in an increase in total plasma antigen concentration in vivo. This antibody-mediated antigen accumulation generally occurs because the clearance from circulation of an antibody-antigen complex is much slower than that of a free antigen. This limitation has recently been overcome by sweeping antibodies, which are capable of actively eliminating soluble antigens from circulation. A sweeping antibody incorporates two antibody engineering technologies: one is variable region engineering to enable the antibody to bind to an antigen in plasma and dissociate from the antigen in endosome (after which the antigen undergoes lysosomal degradation), and the other is constant region engineering to increase the cellular uptake of the antibody-antigen complex into endosome. By enhancing the elimination of soluble antigens from circulation, sweeping antibodies can therapeutically target soluble antigens that conventional antibodies cannot. This review discusses the features, engineering technologies, advantages, and applications of sweeping antibodies that target soluble antigens.