Department of Nephrology, The Second Affiliated Hospital of Nanchang University, No. 1, Minde Road, Donghu District, Nanchang, 330006, Jiangxi, China.
Drugs. 2023 Apr;83(6):507-530. doi: 10.1007/s40265-023-01855-y. Epub 2023 Apr 5.
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/m × 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.
当利妥昔单抗（RTX），一种嵌合抗 CD20 单克隆抗体首次被引入时，它为原发性膜性肾病（PMN）带来了一种替代的治疗模式。在肾功能障碍的 PMN 患者中，利妥昔单抗显示出有效且安全，接受二线利妥昔单抗治疗的患者与未接受过免疫治疗的患者一样有效地达到缓解。没有报告安全问题。B 细胞驱动方案在实现 B 细胞耗竭和缓解方面似乎与 375mg/m2×4 方案或 1g×2 方案一样有效，但 M 型磷脂酶 A2 受体（PLA2R）抗体水平较高的患者可能受益于更高剂量的利妥昔单抗。虽然利妥昔单抗为治疗方案增加了另一种治疗选择，但它确实存在局限性，因为 20%至 40%的患者没有反应。并非所有患有淋巴增生性疾病的患者对 RTX 治疗都有反应，因此进一步开发了新型抗 CD20 单克隆抗体，这些抗体可能为 PMN 提供替代的治疗选择。奥瑞珠单抗，一种完全人源化的单克隆抗体，特异性识别 CD20 分子的小和大细胞外环所包含的表位，从而导致补体依赖性细胞毒性增加。奥克珠单抗与利妥昔单抗结合一个替代但重叠的表位区域，并显示增强的抗体依赖性细胞毒性（ADCC）活性。奥滨尤妥珠单抗设计为具有修饰的铰链氨基酸序列，导致增加的直接细胞死亡诱导和 ADCC 活性。在 PMN 的临床研究中，奥克珠单抗和奥滨尤妥珠单抗显示出有希望的结果，而奥瑞珠单抗显示出混合结果。然而，缺乏大样本的随机对照试验，特别是直接的头对头比较。在这种情况下，已经提出了替代的分子机制来探索新的治疗策略。B 细胞激活剂靶向、浆细胞靶向和补体靶向治疗可能为 PMN 带来新的治疗模式。探索使用具有不同机制的药物的策略，例如利妥昔单抗和环磷酰胺和类固醇的组合、利妥昔单抗和钙调神经磷酸酶抑制剂的组合，可能提供更快和更有效的缓解，但标准免疫抑制与利妥昔单抗的联合可能会增加感染风险。
