{"doi":"10.1101/2025.07.16.665074","title":"Donor-Targeted Anti-HLA-A2 Antibody Shows Nanogram-Level Efficacy in a Novel GVHD Mouse Model","abstract":"Acute graft-versus-host disease (GVHD) remains a life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), with limited treatment options for steroid-refractory cases. Current therapies broadly suppress immune responses, increasing infection risk and impairing graft function. We hypothesized that selective depletion of donor immune cells through HLA allele-specific targeting could offer a safer and more precise alternative. To test this, we developed a monoclonal antibody (AN7) against HLA-A2 by immunizing HLA-A24 transgenic mice with recombinant HLA-A2 tetramers, followed by hybridoma screening. AN7 specifically recognized HLA-A2 and HLA-A68, and was reformatted into murine IgG2a and human chimeric IgG1 recombinant antibodies. These retained binding specificity and mediated robust complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) against HLA-A2+ target cells. To evaluate therapeutic potential, we established a fully MHC-mismatched allo-HSCT model using HLA-A2 transgenic donor bone marrow in lethally irradiated BALB/c recipients. A single ultra-low dose of AN7 (1-100 ng) administered post-transplant significantly improved survival and reduced GVHD while preserving donor hematopoiesis. These findings highlight the potential of allele-specific antibody-mediated clearance as a mechanistically distinct approach to donor immune modulation in GVHD.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":570523,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9555,"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":1471910,"name":"Alyssa H. Chang","orcid":null,"position":1,"is_corresponding":false},{"id":1475753,"name":"J. Kim","orcid":"0000-0002-6456-5057","position":2,"is_corresponding":false},{"id":1314853,"name":"Stéphan Busque","orcid":"0000-0003-1048-1621","position":3,"is_corresponding":false},{"id":492814,"name":"Ravindra Majeti","orcid":"0000-0002-5814-0984","position":4,"is_corresponding":false},{"id":189721,"name":"Hiromitsu Nakauchi","orcid":"0000-0002-9841-6973","position":5,"is_corresponding":false},{"id":492812,"name":"Yusuke Nakauchi","orcid":"0000-0002-6943-3811","position":6,"is_corresponding":false},{"id":1043960,"name":"Kouta Niizuma","orcid":"0000-0003-1183-1873","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":null,"created_at":"2026-07-19T02:57:07.857542Z","pmid":"40791534","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":[]}