Anti-obinutuzumab antibodies in primary membranous nephropathy

BACKGROUND: Rituximab (RTX) is effective first-line therapy for primary membranous nephropathy (PMN), but some patients respond poorly or develop anti-rituximab antibodies (ARA), leading to treatment failure. Obinutuzumab (OBZ), a humanized anti-CD20 monoclonal antibody, shows therapeutic potential in these patients. However, the emergence and clinical relevance of anti-obinutuzumab antibodies (AOA) remain unclear. We aimed to evaluate the role of AOA in PMN patients. METHOD: We retrospectively analyzed 23 PMN patients treated with OBZ, including 7 AOA-positive cases. Baseline characteristics, immunological and clinical remission outcomes were compared between AOA-positive and AOA-negative groups. Associations between AOA status, titer, cumulative exposure, and time to remission were assessed. RESULTS: AOA developed in 7 patients (30.4%), exclusively after ≥ 3 months of therapy (median seroconversion: 12.4 months [8.7-13.6]). AOA-positive patients were more frequently male (100% vs. 56.3%, P = 0.036), had higher baseline serum albumin (30.4 ± 6.2 vs. 24.4 ± 6.0 g/L, P = 0.04), and were more likely ARA-positive (85.7% vs. 18.8%, P = 0.005). No differences were observed in eGFR, UPCR, anti-PLA2R titers, or CD19⁺ B-cell counts at baseline. Immunological remission rates were comparable (100% vs. 92.3%, P = 0.452); clinical remission was achieved in 85.7% vs. 60.0% (P = 0.228). Kaplan-Meier analysis showed no significant difference in time to clinical (P = 0.48) or immunological remission (P = 0.21). Among AOA-positive patients, higher baseline AOA titer (Spearman r = 0.829, P = 0.042) and greater cumulative AOA exposure (AUC; r = 0.943, P = 0.017) strongly correlated with delayed clinical remission. CONCLUSION: 30.4% of PMN patients with OBZ therapy were tested positive for AOA. Although no statistically significant association was observed between AOA status and treatment outcomes, higher AOA titers and greater cumulative exposure were associated with slower clinical remission, suggesting a modulatory effect on OBZ efficacy in our PMN cohort.