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Update on the Application of Monoclonal Antibody Therapy in Primary Membranous Nephropathy

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Abstract

When first introduced, rituximab (RTX), a chimeric anti-CD20 monoclonal antibody, brought about an alternative therapeutic paradigm for primary membranous nephropathy (PMN). Rituximab was shown to be effective and safe in PMN patients with kidney dysfunction, with. patients receiving second-line rituximab therapy achieving remission as effectively as those patients who had not previously received immunotherapy. No safety issues were reported. The B cell-driven protocol seems to be as efficient as the 375 mg/m2 × 4 regimen or 1 g × 2 regimen in achieving B cell depletion and remission, but patients with high M-type phospholipase A2 receptor (PLA2R) antibody levels may benefit from a higher dose of rituximab. While rituximab added another therapeutic option to the treatment regimen, it does have limitations as 20 to 40% of patients do not respond. Not all patients respond to RTX therapy for lymphoproliferative disorders either, therefore further novel anti-CD20 monoclonal antibodies have been developed and these may provide alternative therapeutic options for PMN. Ofatumumab, a fully human monoclonal antibody, specifically recognizes an epitope encompassing both the small and large extracellular loops of the CD20 molecule, resulting in increased complement-dependent cytotoxic activity. Ocrelizumab binds an alternative but overlapping epitope region to rituximab and displays enhanced antibody-dependent cellular cytotoxic (ADCC) activities. Obinutuzumab is designed to have a modified elbow-hinge amino acid sequence, leading to increased direct cell death induction and ADCC activities. In PMN clinical studies, ocrelizumab and obinutuzumab showed promising results, while ofatumumab displayed mixed results. However, there is a lack of randomized controlled trials with large samples, especially direct head-to-head comparisons. Alternative molecular mechanisms have been suggested in this context to explore novel therapeutic strategies. B cell activator-targeted, plasma cell-targeted and complement-directed treatments may lead to novel therapy paradigms for PMN. Exploratory strategies for the use of drugs with different mechanisms, such as a combination of rituximab and cyclophosphamide and a steroid, a combination of rituximab and a calcineurin inhibitor, may provide more rapid and efficient remission, but the combination of standard immunosuppression with rituximab could increase infection risk.

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  1. Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, 330006, Jiangxi, China

    Le Deng & Gaosi Xu

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Correspondence to Gaosi Xu.

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LD and GX conceived and designed the study, authored or reviewed drafts of the paper, and approved the final draft.

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 81970583 and 82060138), the Nature Science Foundation of Jiangxi Province (No. 2020BABL206025), and the Key Project of Natural Science Foundation of Jiangxi Province (No. 20224ACB206008), and the Renal Disease Engineering Technology Research Center of Jiangxi Province (No. 20164BCD40095).

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“Le Deng and Gaosi Xu declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.”

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Deng, L., Xu, G. Update on the Application of Monoclonal Antibody Therapy in Primary Membranous Nephropathy. Drugs 83, 507–530 (2023). https://doi.org/10.1007/s40265-023-01855-y

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