Therapeutic Efficacy and Antigenicity of a Novel PEGylated IgA Protease in Preclinical Models of IgA Nephropathy.

Abstract

IgA nephropathy is the most common primary glomerulonephritis worldwide, characterized by IgA deposition and a high risk of progression to kidney failure. While emerging therapies target IgA production or downstream inflammation, strategies to directly clear established IgA deposits from the kidney remain underexplored. Here, we evaluate a novel therapeutic IgA protease for its ability to clear glomerular IgA deposits and restore normal histology. The recombinant IgA protease was derived from Thomasclavelia ramosa (strain AK183), a human commensal bacterium presumed to have evolved for mutual tolerance within the microbiome with the host. The enzyme was PEGylated to reduce immunogenicity and prolong its half-life, producing the drug product PEG-AK183. We characterized its ex vivo potency and pharmacokinetic-pharmacodynamic profile in mice, then assessed therapeutic efficacy over eight weeks. In vitro, a single molecule of PEG-AK183 cleaved between 500 and 1000 hIgA1 molecules in 60 minutes, demonstrating high catalytic efficiency. A single injection into human IgA1 (hIgA1) transgenic mice induced complete clearance of serum hIgA1 for up to eight days. Following eight-week weekly treatments, PEG-AK183 reduced circulating IgA and immune complex levels by approximately 80% and completely cleared glomerular IgA and associated complement C3 deposits. This was accompanied by a 45.5% reduction in proteinuria and significant improvements in histopathological indices, including mesangial proliferation and endocapillary hypercellularity. No treatment-related adverse effects were observed, including abnormalities in intestinal plasma B cells, hepatotoxicity, or the anti-drug antibody development, supporting a favorable safety profile for long-term, repeated administration. Our preclinical study demonstrated that the engineered IgA degrader PEGAK183 is a potent, effective, and safe therapeutic in a humanized IgA nephropathy mouse model. By achieving sustained clearance of pathogenic IgA from both circulation and glomerular deposits, this IgA-protease-based therapy represents a promising candidate for the future treatment of IgA nephropathy.