**5. Conclusions**

IgAN is an autoimmune disease with a disease burden that greatly disrupts patients' lives and increases their risk for chronic kidney disease and, ultimately, ESKD. Safe and

effective disease-modifying agents that target the source of the disease are greatly needed for this patient population. As the scientific community has learned more about the immunopathology of this disease, new approaches are being investigated that may slow or stop disease progression by targeting the underlying disease triggers.

Preliminary data evaluating complement inhibitors in IgAN, which act downstream of plasma cells and immune complex formation, indicate their potential to improve kidney function by reducing levels of chronic inflammation that contribute to disease progression. This approach, however, is aimed at preventing or ameliorating damage but cannot suppress the ongoing production of pathogenic autoantibodies.

Targeting B cell and plasma cell activators BAFF and APRIL have emerged as a promising approach for reducing Gd-IgA1 antibody and autoantibody production. Early clinical studies evaluating both BION-1301, atacicept, and telitacicept have shown that targeting APRIL and BAFF may reduce antibody levels and proteinuria.

An alternative approach is to target the tissues and cell types most associated with production of disease-causing antibodies (Gd-IgA1). This approach was recently validated through approval of targeted release budesonide (Tarpeyo). The clinical data on Tarpeyo showed substantial benefit for patients with IgAN over current standard of care, indicating the potential of a therapy that can interrupt immunopathogenesis by reducing mucosal production of Gd-IgA1. Tarpeyo is designed to act locally on immune cells in the small intestine, potentially missing other sources of Gd-IgA1-producing cells throughout the body, including NALT and tonsils. As plasma cells are found in mucosa throughout the body, specifically targeting all plasma cells may provide even more robust reduction in circulating pathogenic antibodies and immune complexes by removing the main source of autoantigen and/or autoantibody production in all lymphoid tissues [36–39]. Furthermore, targeting CD38 selectively targets plasma cells and allows for continued immune protection by CD38 negative B cells. The anti-CD38 antibody therapy, felzartamab, has shown successful depletion of plasma cells in the autoimmune-driven nephropathy MN and hematologic cancers, such as MM. An anti-CD38 approach may also have grea<sup>t</sup> potential for treatment of patients with IgAN.

Altogether, these data support development of strategies that deplete plasma cells, which aim to stop generation of Gd-IgA1 and anti-Gd-IgA1 antibodies and potentially reduce immune complex deposition, inflammation, and tissue damage, thereby preserving kidney function in patients with IgAN. However, modulating the immune system comes with an increased risk of infection and more clinical data is needed to understand the long-term effects of treatment with these novel immunotherapies.

**Author Contributions:** Conceptualization, D.M., D.E.M., D.V.R., H.Z. and V.T.; resources, D.M., D.V.R., H.Z. and V.T.; writing—original draft preparation, D.E.M.; writing—review and editing, D.M., D.V.R., H.Z. and V.T.; visualization, D.M., D.E.M. and V.T.; supervision, D.M. and V.T.; funding acquisition, D.E.M. All authors have read and agreed to the published version of the manuscript.

**Funding:** Dita Maixnerova and Vladimir Tesar are supported by: Cooperatio 207034 Internal disciplines, MH CZ-DRO-VFN64165, General University Hospital in Prague, Czech Republic. The APC was funded by MorphoSys AG.

**Conflicts of Interest:** D.M. has served as principal investigator for MorphoSys AG clinical trials. D.E.M. is a full-time employee of MorphoSys AG. D.V.R. reports research funding from Reata Pharmaceuticals, Travere Therapeutics (Retrophin), Achillion Pharmaceuticals, Pfizer, Calliditas Therapeutics (Pharmalinks), Otsuka Pharmaceuticals (Visterra); has served as a consultant for Novartis, George Clinical, Otsuka Pharmaceuticals (Visterra), Calliditas Therapeutics (Pharmalinks), Angion Biomedica, Catalyst Biosciences; and has ownership in Reliant Glycosciences LLC. H.Z. has served as a consultant for Janssen, Novartis, Omeros, Calliditas Therapeutics, and Chinook Therapeutics. V.T. has served as a consultant for Calliditas, Novartis, Omeros, Otsuka, Pfizer and Travere and as principal investigator for MorphoSys AG clinical trials. The APC funders had a role in in the writing of the manuscript and in the decision to publish the review.
