A bispecific CD3×CD19 antibody for systemic lupus erythematosus: a phase 1 trial

Le résumé fourni par la source

Early-phase studies of deep B cell depletion with anti-CD19 chimeric antigen receptor (CAR) T have produced prolonged, drug-free remission in refractory autoimmune disease. However, CAR T cell therapy requires lymphodepleting chemotherapy, autologous cell manufacturing and specialized infrastructure, limiting reach to a fraction of patients who might benefit. Bispecific T cell engagers (TCEs) offer a potent, off-the-shelf approach to deep B cell depletion; however, controlled clinical evaluation in rheumatic disease remains limited. Here we report results from the intravenous treatment arm of an ongoing, first-in-disease, phase 1 trial of A-319, a next-generation CD3×CD19 TCE, in 12 patients with active systemic lupus erythematosus (SLE) with 52 weeks of follow-up. Patients received A-319 (0.3−1.2 μg kg−1) three times weekly for 3 weeks after 1 week of priming doses (0.05 μg kg−1). The primary endpoint was safety and tolerability. A-319 demonstrated a favorable safety profile, with no treatment-related serious adverse events, deaths, grade 3 or higher cytokine release syndrome (CRS) or neurotoxicity; CRS was predominantly grade 1 (91.6%, 11/12), and hematologic toxicity was minimal. Secondary endpoints (pharmacokinetics, pharmacodynamics and immunogenicity) demonstrated linear pharmacokinetics and dose-dependent B cell depletion, with complete peripheral depletion in higher-dose cohorts. Among exploratory efficacy endpoints, 80% (8/10) of patients achieved Lupus Low Disease Activity State (LLDAS), and 60% (6/10) achieved Definition of Remission in SLE (DORIS) at 12 months, accompanied by sustained reductions in Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, autoantibody titers and proteinuria. Exploratory serial single-cell RNA sequencing revealed broad immune reprogramming mechanistically similar to that after CD19 CAR T cell therapy in SLE, including multi-lineage suppression of SLE-associated interferon response signatures across B cell, T cell and myeloid compartments and near-complete reconstitution of the B cell repertoire. Together, these findings demonstrate the feasibility, safety and preliminary efficacy of CD3×CD19 T cell engagement in SLE and support further clinical development of TCEs in controlled, pivotal studies. ClinicalTrials.gov identifier: NCT06400537 . In a phase 1 trial evaluating intravenous delivery of a next-generation CD3×CD19 bispecific T cell engager in patients with active systemic lupus erythematosus, treatment was well tolerated, and there were improvements in disease activity scores for most patients.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.