{"doi":"10.1182/blood.2020008940","title":"Structure of blood coagulation factor VIII in complex with an anti–C1 domain pathogenic antibody inhibitor","abstract":"Antibody inhibitor development in hemophilia A represents the most significant complication resulting from factor VIII (fVIII) replacement therapy. Recent studies have demonstrated that epitopes present in the C1 domain contribute to a pathogenic inhibitor response. In this study, we report the structure of a group A anti-C1 domain inhibitor, termed 2A9, in complex with a B domain-deleted, bioengineered fVIII construct (ET3i). The 2A9 epitope forms direct contacts to the C1 domain at 3 different surface loops consisting of Lys2065-Trp2070, Arg2150-Tyr2156, and Lys2110-Trp2112. Additional contacts are observed between 2A9 and the A3 domain, including the Phe1743-Tyr1748 loop and the N-linked glycosylation at Asn1810. Most of the C1 domain loops in the 2A9 epitope also represent a putative interface between fVIII and von Willebrand factor. Lastly, the C2 domain in the ET3i:2A9 complex adopts a large, novel conformational change, translocating outward from the structure of fVIII by 20 Å. This study reports the first structure of an anti-C1 domain antibody inhibitor and the first fVIII:inhibitor complex with a therapeutically active fVIII construct. Further structural understanding of fVIII immunogenicity may result in the development of more effective and safe fVIII replacement therapies.","journal":"Blood","year":2021,"id":175117,"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":22,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9585,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":716188,"name":"Lexi Jarvis","orcid":null,"position":1,"is_corresponding":false},{"id":715473,"name":"Kenneth Childers","orcid":"0000-0003-0472-7859","position":2,"is_corresponding":false},{"id":715474,"name":"Shaun C. Peters","orcid":"0000-0002-5997-9685","position":3,"is_corresponding":false},{"id":716189,"name":"Connor S Garrels","orcid":null,"position":4,"is_corresponding":false},{"id":715475,"name":"Ian W. M. Smith","orcid":"0000-0002-1424-6832","position":5,"is_corresponding":false},{"id":380171,"name":"H. Trent Spencer","orcid":"0000-0001-8062-2202","position":6,"is_corresponding":false},{"id":380170,"name":"Christopher B. Doering","orcid":"0000-0002-5662-0060","position":7,"is_corresponding":false},{"id":409323,"name":"Pete Lollar","orcid":"0000-0002-1206-8104","position":8,"is_corresponding":false},{"id":715476,"name":"Paul Spiegel","orcid":"0000-0001-7982-5424","position":9,"is_corresponding":false},{"id":716187,"name":"Joseph S. Gish","orcid":null,"position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":null,"created_at":"2026-07-18T23:47:11.249697Z","pmid":"33529335","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":[]}