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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.<\/jats:p>","DOI":"10.1101\/2025.08.13.670104","type":"posted-content","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T19:50:15Z","timestamp":1755201015000},"source":"Crossref","is-referenced-by-count":1,"title":["ALK1-BMPRII agonism by clustering bispecific antibodies treats hereditary hemorrhagic telangiectasia"],"prefix":"10.64898","author":[{"given":"Sima","family":"Qutaina","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haitian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Sullivan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Geddie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raminderjeet","family":"Kaur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Yue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margherita","family":"Bruni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Christen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabien","family":"Campagne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen M.","family":"Arthur","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Andr\u00e9","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8983-1497","authenticated-orcid":false,"given":"Philippe","family":"Marambaud","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025081805300448000_2025.08.13.670104v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.07.036"},{"key":"2025081805300448000_2025.08.13.670104v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.blre.2010.07.001"},{"key":"2025081805300448000_2025.08.13.670104v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/path.4844"},{"key":"2025081805300448000_2025.08.13.670104v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2015.8"},{"key":"2025081805300448000_2025.08.13.670104v1.5","doi-asserted-by":"publisher","DOI":"10.7326\/M20-1443"},{"key":"2025081805300448000_2025.08.13.670104v1.6","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.27756"},{"key":"2025081805300448000_2025.08.13.670104v1.7","doi-asserted-by":"crossref","unstructured":"M.-J. 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