New Treatment Strategies for IgA Nephropathy: Targeting Plasma Cells as the Main Source of Pathogenic Antibodies

Abstract

Immunoglobulin A nephropathy (IgAN) is a rare autoimmune disorder and the leading cause of biopsy-reported glomerulonephritis (GN) worldwide. Disease progression is driven by the formation and deposition of immune complexes composed of galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1 autoantibodies (anti-Gd-IgA1 antibodies) in the glomeruli, where they trigger complement-mediated inflammation that can result in loss of kidney function and end-stage kidney disease (ESKD). With the risk of progression and limited treatment options, there is an unmet need for therapies that address the formation of pathogenic Gd-IgA1 antibody and anti-Gd-IgA1 antibody-containing immune complexes. New therapeutic approaches target immunological aspects of IgAN, including complement-mediated inflammation and pathogenic antibody production by inhibiting activation or promoting depletion of B cells and CD38-positive plasma cells. This article will review therapies, both approved and in development, that support the depletion of Gd-IgA1-producing cells in IgAN and have the potential to modify the course of this disease. Ultimately, we propose here a novel therapeutic approach by depleting CD38-positive plasma cells, as the source of the autoimmunity, to treat patients with IgAN.

Keywords: CD38; IgA nephropathy; galactose-deficient IgA1; plasma cells; renal pathology.

Figure 1

Immunopathogenesis of IgAN and potential therapeutic targets. Early CD20⁺ B cells produce small amounts of antibodies (Gd-IgA1), whereas CD38⁺ plasma cells can produce both these antibodies and high quantities of autoantibodies (anti-Gd-IgA1). The antibodies and autoantibodies form Gd-IgA1 and anti-Gd-IgA1 antibody immune complexes that can deposit and accumulate in mesangial cells. The deposition of immune complexes activates the alternative and lectin pathways of the complement system leading to chronic inflammation, which contributes to podocyte damage and, ultimately, loss of renal function that manifests in patients as hypertension, hematuria, proteinuria and reduction in glomerular filtration rate. The targets of novel therapies aim to inhibit pathogenesis by affecting the immune system at various stages of pathogenesis. Atacicept and telitacicept are recombinant fusion proteins able to bind cytokines BAFF and APRIL and interfere with B cell and plasma cell survival. BION-1301 and sibeprenlimab are monoclonal antibodies targeting the cytokine APRIL, which may reduce levels of Gd-IgA1 and IgG autoantibodies. Velcade^® is a proteasome inhibitor that targets and depletes plasma cells. Felzartamab, an anti-CD38 antibody, is designed to target the highly expressed CD38 cell surface antigen on plasma cells. Tarpeyo™, a targeted-release glucocorticoid that aims at the highest concentration of Peyer’s patches in the distal ileum to reduce production of Gd-IgA1. Iptacopan, a small molecule factor B inhibitor of the alternative complement pathway, acts to reduce damage caused by accumulation of immune complexes in the mesangial cells. Narsoplimab, a MASP-2 monoclonal antibody, acts as an inhibitor of the lectin complement pathway. Abs, antibodies; APRIL, a proliferation inducing ligand; BAFF, B cell activating factor; CD, cluster of differentiation; GD-IgA1, galactose-deficient immunoglobulin A1; GFR, glomerular filtration rate; MASP, mannan-binding lectin serine protease.

Figure 2

Proposed mechanism of action of felzartamab (MOR202/TJ202) for depleting antibody and auto-antibody-producing CD38⁺ plasma cells. ADCC, antibody-dependent cell-mediated cytotoxicity; ADCP, antibody-dependent cell mediated phagocytosis; CD, cluster of differentiation; FcγR, Fc-gamma receptor; NK, natural killer.