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Objectives The REGENCY trial ( NCT04221477) demonstrated superiority of obinutuzumab (OBI) plus standard therapy (+ST) vs placebo (PBO) +ST in achieving complete renal response (CRR) at Week 76 (W76) in adults with active lupus nephritis (LN). These exploratory analyses aimed to evaluate histological remission and kidney tissue-level B-cell depletion at W76 in patients treated with OBI+ST vs PBO+ST.Methods Paired baseline and W76 kidney biopsies from REGENCY participants with biopsy-proven proliferative LN were analysed. Histological analysis: 64 biopsies (32 OBI+ST, 32 PBO+ST) were evaluated using the 2018 ISN/RPS LN classification, along with the NIH activity (AI) and chronicity indices. The proportion of patients achieving histological or near-histological remission (AI=0 or <=1) was determined. B-cell analysis: 29 participants (14 OBI+ST, 15 PBO+ST) were assessed. CD79a+/CD138– B cells were quantified by immunofluorescence microscopy and digital whole-slide analysis. Changes in B-cell counts at W76 were compared using an ANCOVA model, adjusting for baseline B-cell counts and stratification factors.Results Baseline characteristics were balanced, despite higher tissue B-cell levels in the OBI+ST group. At W76, significantly more patients achieved AI=0 or <=1 with OBI+ST vs PBO+ST ( figure 1). Among patients not achieving CRR, 52.6% (10/19) in the OBI+ST group had an AI=0 at W76, vs 8.3% (2/24) in the PBO+ST group. Most patients in the OBI+ST group had substantial drops in kidney tissue B-cell counts by W76 (figure 2). The adjusted mean change in B-cell counts from baseline to W76 was -28.5 (95% CI, -33.3 to -23.6) for OBI+ST vs -11.9 (95% CI, -16.6 to -7.2) for PBO+ST, a significant difference of -16.6 (95% CI, -23.4 to -9.7; P<0.0001).Abstract PT2:06 Figure 1(A) Proportion of patients achieving AI≤1 and AI=0, (B) change in AI from first to repeat post-W76 biopsy and (C) change in chronicity index from first to repeat post-W76 biopsyAbstract PT2:06 Figure 2Tissue CD79a+/CD138− B cells and plasma cells at baseline and week 76 in the REGENCY longitudinal kidney biopsy B-cell cohortConclusions In the largest longitudinal kidney biopsy cohort ever reported for a registrational LN clinical trial, significantly more patients achieved complete or near-complete histological remission with OBI+ST vs PBO+ST. This is the first demonstration of deep kidney tissue B-cell depletion by any anti-CD20 agent, in any glomerular disease. Obinutuzumab’s potent B-cell clearance from kidney tissue may drive kidney function improvement and LN flare reduction. These findings support assessment of histological outcomes in future LN trials and highlight a potential mechanism for obinutuzumab in preserving long-term kidney health.