ALK1-BMPRII agonism by clustering bispecific antibodies treats hereditary hemorrhagic telangiectasia

Abstract Hereditary hemorrhagic telangiectasia (HHT) is characterized by arteriovenous malformations (AVMs) and severe bleeding caused by loss-of-function mutations in the ALK1 receptor pathway. We developed clustering agonist bispecific antibodies (BsAbs) targeting ALK1 and its activating partner, the Ser/Thr receptor kinase BMPRII. These BsAbs induced ALK1-BMPRII proximity association, stimulated the downstream Smad1/5/8 signaling cascade, and treated HHT pathologies in various mouse models. BsAb treatment reduced AVM burden by up to 95% in HHT mice, preventing anemia, cardiomegaly, and premature death. The BsAbs also enhanced Smad1/5/8 signaling in endothelial cells derived from HHT patients with ALK1 mutations and prevented retinal AVMs in a newly developed knock-in mouse carrying an HHT-causing ALK1 mutation. These findings establish ALK1-BMPRII agonism as a promising therapeutic strategy for HHT. Competing Interest Statement P.A., M.G., A.S., H.Y., X.W., and S.G. are employees of Diagonal Therapeutics. P.M. serves as a scientific advisor for Diagonal Therapeutics and received financial compensation from the company. Patent applications owned by Diagonal Therapeutics cover DIAG100 and DIAG723. The other authors declare no competing interests.