{"doi":"10.1126/scitranslmed.abm5663","title":"Soluble CTLA-4 mutants ameliorate immune-related adverse events but preserve efficacy of CTLA-4– and PD-1–targeted immunotherapy","abstract":"Immune checkpoint inhibitors (ICIs), such as nivolumab and ipilimumab, not only elicit antitumor responses in a wide range of human cancers but also cause severe immune-related adverse events (irAEs), including death. A largely unmet medical need is to treat irAEs without abrogating the immunotherapeutic effect of ICIs. Although abatacept has been used to treat irAEs, it risks neutralizing the anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) monoclonal antibodies administered for cancer therapy, thereby reducing the efficacy of anti-CTLA-4 immunotherapy. To avoid this caveat, we compared wild-type abatacept and mutants of CTLA-4-Ig for their binding to clinically approved anti-CTLA-4 antibodies and for their effect on both irAEs and immunotherapy conferred by anti-CTLA-4 and anti-PD-1 antibodies. Here, we report that whereas abatacept neutralized the therapeutic effect of anti-CTLA-4 antibodies, the mutants that bound to B7-1 and B7-2, but not to clinical anti-CTLA-4 antibodies, including clinically used belatacept, abrogated irAEs without affecting cancer immunotherapy. Our data demonstrate that anti-CTLA-4-induced irAEs can be corrected by provision of soluble CTLA-4 variants and that the clinically available belatacept may emerge as a broadly applicable drug to abrogate irAEs while preserving the therapeutic efficacy of CTLA-4-targeting ICIs.","journal":"Science Translational Medicine","year":2023,"id":336980,"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":18,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.94,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1067920,"name":"Xu Wang","orcid":"0000-0002-2724-5388","position":1,"is_corresponding":false},{"id":418656,"name":"Xuexiang Du","orcid":"0000-0002-7424-7343","position":2,"is_corresponding":false},{"id":498892,"name":"Wei Wu","orcid":"0000-0002-4894-7178","position":3,"is_corresponding":false},{"id":418657,"name":"Yan Zhang","orcid":"0000-0002-6962-8782","position":4,"is_corresponding":false},{"id":280723,"name":"Peng Zhang","orcid":"0000-0002-6218-1885","position":5,"is_corresponding":false},{"id":934540,"name":"Chunxia Ai","orcid":null,"position":6,"is_corresponding":false},{"id":419377,"name":"Martin Devenport","orcid":null,"position":7,"is_corresponding":false},{"id":1067921,"name":"Juanjuan Su","orcid":"0000-0001-8142-5518","position":8,"is_corresponding":false},{"id":742471,"name":"Musleh M. Muthana","orcid":"0000-0003-1242-5631","position":9,"is_corresponding":false},{"id":255662,"name":"Lishan Su","orcid":"0000-0002-0350-5560","position":10,"is_corresponding":false},{"id":285172,"name":"Yang Liu","orcid":"0000-0002-9442-700X","position":11,"is_corresponding":false},{"id":418660,"name":"Pan Zheng","orcid":"0000-0003-2598-3544","position":12,"is_corresponding":false},{"id":1067919,"name":"Mingyue Liu","orcid":"0000-0001-9822-0682","position":0,"is_corresponding":true}],"reference_count":46,"raw_metadata":null,"created_at":"2026-07-19T01:10:21.947540Z","pmid":"36857433","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":[]}