{"doi":"10.1136/jitc-2024-009013","title":"Developing a membrane-proximal CD33-targeting CAR T cell","abstract":"BACKGROUND: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking. METHODS: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice. RESULTS: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both low antigen density and clinically relevant patient-derived xenograft models. Increased activation and enhanced polyfunctionality led to enhanced efficacy. CONCLUSIONS: Showing for the first time that a membrane-proximal CAR is superior to a membrane-distal one in the setting of CD33 targeting, our results demonstrate the rationale for targeting membrane-proximal epitopes with high-affinity binders. We also demonstrate the importance of optimizing CAR T cells for functionality in settings of both low antigen density and clinically relevant patient-derived models.","journal":"Journal for ImmunoTherapy of Cancer","year":2024,"id":425065,"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":20,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9613,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1222645,"name":"Sanam Shahid","orcid":"0000-0003-4281-4910","position":1,"is_corresponding":false},{"id":697278,"name":"Abdul G. Khan","orcid":null,"position":2,"is_corresponding":false},{"id":1223205,"name":"Serena C Mathew","orcid":null,"position":3,"is_corresponding":false},{"id":1222646,"name":"Sydney Souness","orcid":"0009-0002-4738-3910","position":4,"is_corresponding":false},{"id":1223206,"name":"Erin R. Burns","orcid":null,"position":5,"is_corresponding":false},{"id":1222647,"name":"Jasmine S. Um","orcid":"0009-0004-5907-6453","position":6,"is_corresponding":false},{"id":1222648,"name":"Kento Tanaka","orcid":"0000-0002-8513-7748","position":7,"is_corresponding":false},{"id":332081,"name":"Winson Cai","orcid":"0000-0001-7121-0986","position":8,"is_corresponding":false},{"id":604714,"name":"Sarah Yoo","orcid":"0009-0000-8418-0843","position":9,"is_corresponding":false},{"id":259769,"name":"Andrew Dunbar","orcid":"0000-0003-0339-4220","position":10,"is_corresponding":false},{"id":283150,"name":"Young Joo Park","orcid":"0000-0002-3671-6364","position":11,"is_corresponding":false},{"id":1030851,"name":"Devin McAvoy","orcid":"0000-0001-7807-6775","position":12,"is_corresponding":false},{"id":388092,"name":"Kinga Hosszu","orcid":"0000-0002-1190-1491","position":13,"is_corresponding":false},{"id":35287,"name":"Ross L. Levine","orcid":"0000-0002-7884-1905","position":14,"is_corresponding":false},{"id":297903,"name":"Jaap Jan Boelens","orcid":"0000-0003-2232-6952","position":15,"is_corresponding":false},{"id":477729,"name":"Ivo C. Lorenz","orcid":"0000-0002-7373-1176","position":16,"is_corresponding":false},{"id":243186,"name":"Renier J. Brentjens","orcid":"0000-0002-3364-5388","position":17,"is_corresponding":false},{"id":268587,"name":"Anthony F. Daniyan","orcid":"0009-0002-2742-2281","position":18,"is_corresponding":false},{"id":1223204,"name":"Ruby Freeman","orcid":null,"position":0,"is_corresponding":true}],"reference_count":35,"raw_metadata":null,"created_at":"2026-07-19T01:58:26.927596Z","pmid":"38772686","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":[]}