{"doi":"10.1101/2023.01.04.522664","title":"Drug-Mediated Control of Receptor Valency Enhances Immune Cell Potency","abstract":"Designer T cells offer a novel paradigm for treating diseases like cancer, yet they are often hindered by target recognition evasion and limited in vivo control. To overcome these challenges, we develop valency-controlled receptors (VCRs), a novel class of synthetic receptors engineered to enable precise modulation of immune cell activity. VCRs use custom-designed valency-control ligands (VCLs) to modulate T cell signaling via spatial molecular clustering. Using multivalent DNA origami as VCL, we first establish that valency is important for tuning the activity of CD3-mediated immune activation. We then generate multivalent formats of clinically relevant drugs as VCL and incorporate VCR into the architecture of chimeric antigen receptors (CARs). Our data demonstrate that VCL-mediated VCRs can significantly amplify CAR activities and improve suboptimal CARs. Finally, through medicinal chemistry, we synthesize programmable, bioavailable VCL drugs that potentiate targeted immune response against low-antigen tumors both in vitro and in vivo. Our findings establish receptor valency as a core mechanism for enhancing CAR functionality and offer a synthetic chemical biology platform for strengthening customizable, potent, and safer cell therapies.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":395608,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"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":287432,"name":"Michael Chavez","orcid":null,"position":1,"is_corresponding":false},{"id":843791,"name":"Xinyi Chen","orcid":"0000-0002-3365-4284","position":2,"is_corresponding":false},{"id":605585,"name":"Haifeng Wang","orcid":"0000-0003-4792-2005","position":3,"is_corresponding":false},{"id":863126,"name":"Draven A. Rane","orcid":"0000-0001-9445-7260","position":4,"is_corresponding":false},{"id":1170886,"name":"Jitendra Gurjar","orcid":"0000-0002-9104-2809","position":5,"is_corresponding":false},{"id":233741,"name":"Lei S. Qi","orcid":"0000-0002-3965-3223","position":6,"is_corresponding":false},{"id":434430,"name":"Paul B. Finn","orcid":"0000-0002-1253-1314","position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-19T01:19:22.857556Z","pmid":"36712002","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":[]}