Rovin Brad H, Ronco Pierre M, Wetzels Jack F M, Adler Sharon G, Ayoub Isabelle, Zaoui Philippe, Han Seung Hyeok, Dudani Jaideep S, Gilbert Houston N, Patel Uptal D, Manser Paul T, Jauch-Lembach Julia, Faulhaber Nicola, Boxhammer Rainer, Härtle Stefan, Sprangers Ben
Department of Medicine and Division of Nephrology, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
Sorbonne Université and INSERM UMRS 1155, Paris France.
Kidney Int Rep. 2024 Jun 20;9(9):2635-2647. doi: 10.1016/j.ekir.2024.06.018. eCollection 2024 Sep.
Primary membranous nephropathy (PMN) is most often caused by autoantibodies to phospholipase A2 receptor (PLA2R). M-PLACE (NCT04145440) is an open-label, phase 1b/2a study that assessed the safety and efficacy of the fully human anti-CD38 monoclonal antibody felzartamab in high-risk anti-PLA2R+ PMN.
Patients with newly diagnosed or relapsed PMN (cohort 1 [C1]; = 18) or PMN refractory to immunosuppressive therapy (IST) (cohort 2 [C2]; = 13) received 9 infusions of felzartamab 16 mg/kg in the 24-week treatment period, followed by a 28-week follow-up. The primary end point was the incidence and severity of treatment-emergent adverse events (TEAEs).
A total of 31 patients were enrolled and received felzartamab. Twenty-seven patients (87.1%) had TEAEs, including infusion-related reactions (IRRs) (29.0%), hypogammaglobulinemia (25.8%), peripheral edema (19.4%), and nausea (16.1%). Five patients (16.1%) had serious TEAEs that all resolved. Immunologic response (anti-PLA2R titer reduction ≥50%) was achieved by 20 of 26 efficacy-evaluable patients (76.9%) (C1, 13/15 [86.7%]; C2, 7/11 [63.6%]). Anti-PLA2R titer reductions were rapid (week 1 response, 44.0%; response 7 months after last felzartamab dose [end of study, EOS], 53.8%). Partial proteinuria remission (urine protein-to-creatinine ratio [UPCR] reduction ≥50%, UPCR <3.0 g/g, and stable estimated glomerular filtration rate [eGFR]) was achieved by 9 of 26 patients (34.6%) (C1, 7/15 [46.7%]; C2, 2/11 [18.2%]) before or at EOS (median follow-up, 366 days). Serum albumin increased from baseline to EOS in 20 of 26 patients (76.9%) (C1, 12/15 [80.0%]; C2, 8/11 [72.7%]).
In this population with high-risk anti-PLA2R+ PMN, felzartamab was tolerated and resulted in rapid partial and complete immunologic responses and partial improvements in proteinuria and serum albumin in some patients.
原发性膜性肾病（PMN）最常见的病因是针对磷脂酶A2受体（PLA2R）的自身抗体。M-PLACE（NCT04145440）是一项开放标签的1b/2a期研究，评估了全人源抗CD38单克隆抗体非扎妥单抗在高危抗PLA2R阳性PMN中的安全性和有效性。
新诊断或复发的PMN患者（队列1 [C1]；n = 18）或对免疫抑制治疗（IST）难治的PMN患者（队列2 [C2]；n = 13）在24周的治疗期内接受9次16 mg/kg的非扎妥单抗输注，随后进行28周的随访。主要终点是治疗期间出现的不良事件（TEAE）的发生率和严重程度。
共有31例患者入组并接受了非扎妥单抗治疗。27例患者（87.1%）发生TEAE，包括输液相关反应（IRR）（29.0%）、低丙种球蛋白血症（25.8%）、外周水肿（19.4%）和恶心（16.1%）。5例患者（16.1%）发生严重TEAE，均已缓解。26例可评估疗效的患者中有20例（76.9%）实现了免疫反应（抗PLA2R滴度降低≥50%）（C1组，13/15 [86.7%]；C2组，7/11 [63.6%]）。抗PLA2R滴度降低迅速（第1周时反应率为44.0%；最后一剂非扎妥单抗后7个月[研究结束，EOS]时反应率为53.8%）。26例患者中有9例（34.6%）在EOS之前或之时实现了部分蛋白尿缓解（尿蛋白与肌酐比值[UPCR]降低≥50%，UPCR<3.0 g/g，且估计肾小球滤过率[eGFR]稳定）（C1组，7/15 [46.7%]；C2组，2/11 [18.2%]）（中位随访时间为366天）。26例患者中有20例（76.9%）的血清白蛋白从基线升至EOS（C1组，12/15 [80.0%]；C2组，8/11 [72.7%]）。
在这个高危抗PLA2R阳性PMN人群中，非扎妥单抗耐受性良好，在部分患者中可迅速产生部分和完全免疫反应，并使蛋白尿和血清白蛋白得到部分改善。
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