{"doi":"10.1101/2025.08.13.670104","title":"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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558812,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9619,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1165208,"name":"Haitian Zhao","orcid":"0000-0003-3438-1991","position":1,"is_corresponding":false},{"id":1459612,"name":"Zhiming Wang","orcid":"0000-0003-0594-3684","position":2,"is_corresponding":false},{"id":1460044,"name":"Andy Sullivan","orcid":null,"position":3,"is_corresponding":false},{"id":1460045,"name":"Melissa L. Geddie","orcid":null,"position":4,"is_corresponding":false},{"id":1460046,"name":"Raminderjeet Kaur","orcid":null,"position":5,"is_corresponding":false},{"id":1459613,"name":"Hong Tian","orcid":"0000-0002-1764-4916","position":6,"is_corresponding":false},{"id":1459614,"name":"Huan Yue","orcid":"0000-0002-0482-511X","position":7,"is_corresponding":false},{"id":1459615,"name":"Xin Wang","orcid":"0000-0002-5132-4465","position":8,"is_corresponding":false},{"id":1459616,"name":"Siyang Guo","orcid":"0000-0003-2352-829X","position":9,"is_corresponding":false},{"id":1459617,"name":"Margherita Bruni","orcid":"0000-0003-4113-813X","position":10,"is_corresponding":false},{"id":1460047,"name":"Erica Christen","orcid":null,"position":11,"is_corresponding":false},{"id":627962,"name":"Fabien Campagne","orcid":"0000-0001-6237-3564","position":12,"is_corresponding":false},{"id":323270,"name":"Helen M. Arthur","orcid":"0000-0001-6522-1363","position":13,"is_corresponding":false},{"id":1460048,"name":"Patrick André","orcid":null,"position":14,"is_corresponding":false},{"id":451439,"name":"Philippe Marambaud","orcid":"0000-0002-8983-1497","position":15,"is_corresponding":false},{"id":1243988,"name":"Sima Qutaina","orcid":null,"position":0,"is_corresponding":true}],"reference_count":43,"raw_metadata":null,"created_at":"2026-07-19T02:55:30.312295Z","pmid":"40832159","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}