Immunotherapy of membranous nephropathy: strategic evolution from CD20 monoclonal antibodies to future vaccines

Membranous nephropathy (MN) arises from autoantibody-mediated attack on podocyte antigens, with immune deposits forming subepithelially at the glomerular basement membrane to trigger complement activation and subsequent podocyte damage, eventually manifesting as proteinuria. Traditional therapy hinges on nonspecific immunosuppression, which is characterized by modest effectiveness and a substantial side-effect profile. In recent years, CD20-targeting monoclonal antibodies, most notably rituximab (RTX), have curtailed autoantibody production through peripheral B-cell depletion and consequently emerged as a first-line treatment option for patients at intermediate-to-high risk. However, a considerable proportion of patients still show no initial response or later relapse. Resistance mechanisms are heterogeneous, encompassing Fc receptor polymorphisms, plasma cell longevity, and anti-RTX antibody formation. To address these hurdles, novel biologics that target the BAFF/APRIL signaling axis, CD38-positive plasma cells, and the complement cascade have entered the clinical arena, further broadening the immunotherapeutic landscape for MN. In parallel, as our understanding of immune memory and autoantibody-generating cells continues to expand, a so-called "immune reset" approach is gaining traction, with its core rationale being the restoration of a robust yet self-tolerant immune system. This review charts the progression of MN therapies, from CD20 monoclonal antibodies and their optimized use, through novel biologics, to vaccine-based strategies that target autoantibody-specific B or T cells (including CAAR-T, Treg therapies, B-cell epitope vaccines, and T-cell vaccines). We further consider their theoretical promise for inducing antigen-specific immune tolerance and the barriers to clinical implementation.