First-in-Class Antigen-Specific Extracellular Protein Degrader, BHV-1400 for IgA Nephropathy, Selectively Targets Galactose-Deficient IgA for Rapid and Efficient Endolysosomal Degradation in the Liver

Background: IgA nephropathy (IgAN) is the most prevalent form of glomerulonephritis, affecting 2.5 of 100,000 people worldwide. The production of galactose-deficient IgA1 (Gd-IgA1), and the subsequent formation and deposition of Gd-IgA1-IgG immune complexes in the kidney mesangium drive the onset and progression of IgAN. Targeting pathogenic Gd-IgA1 in IgAN patients offers a promising strategy to decrease immune complex formation, potentially leading to a reduction in kidney inflammation and pathology. Methods: Biohaven engineered a novel, bifunctional antibody-based, protein degrader, BHV-1400, that specifically targets extracellular Gd-IgA1 for degradation via the ASGPR-mediated endolysosomal pathway in the liver. Here, we present data illustrating the reactivity of BHV-1400 with IgAN patient samples. Results: In in vitro assays, BHV-1400 mediates efficient specific cellular internalization and degradation of monomeric and multimeric deglycosylated IgA (dg-IgA). Pharmacological data indicates that BHV-1400 facilitates a rapid reduction of exogenous dg-IgA both in the bloodstream and tissues, most notably within kidney glomeruli. Conclusion: Thus, Gd-IgA1 degradation with BHV-1400 offers significant promise as a novel and effective precision, disease-modifying approach for treating IgAN. Funding: Commercial Support - Biohaven Pharmaceuticals