Single-cell transcriptomic analysis of the terminal ileum identifies BCMA as a therapeutic target in IgA nephropathy.

Aberrant mucosal immune responses drive IgA nephropathy (IgAN), yet the cellular drivers of pathogenic IgA production remain undefined. We performed single-cell RNA sequencing (scRNA-seq) and bioinformatic profiling of paired terminal ileal biopsies and blood samples from IgAN patients and healthy controls (HCs) (n = 5 each). Key features identified by scRNA-seq were validated using flow cytometry with circulating samples from an independent group (IgAN = 30, HCs = 30, disease controls [DCs] = 10). Transcriptomic comparison between IgA+ and IgG+ plasma cells identified key regulatory genes further validated in another group (IgAN = 23, HCs = 14, DCs = 24). Finally, we evaluated the therapeutic potency of the CD3 × B-cell maturation antigen (BCMA) T-cell engager cizutamig (EMB-06) in cynomolgus monkeys (0, 1.5, 5, or 15 mg/kg, n = 10 per group) by quantifying B cells and serum immunoglobulins (IgA, IgG, and IgM). We found that intestinal IgA+ plasma cells exhibited a marked expansion in IgAN patients, unlike IgG+ plasma cells, preferentially expressing the receptor BCMA. We validated the high BCMA expression on IgA+ plasmablasts in IgAN patients, which positively correlated with 24 h proteinuria and mesangial hypercellularity degree, while negatively correlating with the estimated glomerular filtration rate. In cynomolgus monkeys, targeting BCMA+ plasmablasts with cizutamig selectively reduced serum immunoglobulins, with a disproportionately greater reduction in IgA than in IgG and IgM. Together, these data identify BCMA as a promising therapeutic target in IgAN and support further clinical evaluation of BCMA-directed therapies.