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

Qutaina, S.; Zhao, H.; Wang, Z.; Sullivan, A.; Geddie, M.; Kaur, R.; Tian, H.; Yue, H.; Wang, X.; Guo, S.; Bruni, M.; Christen, E.; Campagne, F.; Arthur, H. M.; Andre, P.; Marambaud, P.

doi:10.1101/2025.08.13.670104

bioRxiv · 10.1101/2025.08.13.670104

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

Qutaina, S.·Zhao, H.·Wang, Z.·Sullivan, A.·Geddie, M.·Kaur, R.·Tian, H.·Yue, H.·Wang, X.·Guo, S.·Bruni, M.·Christen, E.·Campagne, F.·Arthur, H. M.·Andre, P.·Marambaud, P.

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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.

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Qutaina, S., Zhao, H., Wang, Z., Sullivan, A., Geddie, M., Kaur, R., Tian, H., Yue, H., Wang, X., Guo, S., Bruni, M., Christen, E., Campagne, F., Arthur, H. M., Andre, P., Marambaud, P.. 2025-08-14. ALK1-BMPRII agonism by clustering bispecific antibodies treats hereditary hemorrhagic telangiectasia. https://doi.org/10.1101/2025.08.13.670104

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