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Despite several marketing approvals, the development of bsTCEs remains challenging, especially at early clinical translational stages. The intricate design of bsTCEs makes their pharmacologic effects and safety profiles highly dependent on patient's immunological and tumor conditions. Such context\u2010dependent pharmacology introduces considerable uncertainty into translational efforts. In this study, we developed a Quantitative Systems Pharmacology (QSP) model, through context unification, that can facilitate the translation of bsTCEs preclinical data into clinical activity. Through characterizing the formation dynamics of immunological synapse (IS) induced by bsTCEs, this model unifies a broad range of contexts related to target affinity, tumor characteristics, and immunological conditions. After rigorous calibration using both experimental and clinical data, the model enables consistent translation of drug potency observed under diverse experimental conditions into predictable exposure\u2013response relationships in patients. Moreover, the model can help identify optimal target\u2010binding affinities and minimum efficacious concentrations across different clinical contexts. This QSP approach holds significant promise for the future development of bsTCEs.<\/jats:p>","DOI":"10.1002\/cpt.3302","type":"journal-article","created":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T04:40:39Z","timestamp":1715834439000},"page":"415-425","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Optimizing Clinical Translation of Bispecific T\u2010cell Engagers through Context Unification with a Quantitative Systems Pharmacology Model"],"prefix":"10.1002","volume":"116","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9925-5892","authenticated-orcid":false,"given":"Xiaozhi","family":"Liao","sequence":"first","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4359-8271","authenticated-orcid":false,"given":"Timothy","family":"Qi","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3317-0311","authenticated-orcid":false,"given":"Jiawei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4947-2677","authenticated-orcid":false,"given":"Can","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3974-9073","authenticated-orcid":false,"given":"Yanguang","family":"Cao","sequence":"additional","affiliation":[{"name":"Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"},{"name":"Lineberger Comprehensive Cancer Center University of North Carolina at Chapel Hill  Chapel Hill North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,15]]},"reference":[{"key":"e_1_2_11_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-01225-5"},{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017-06-741041"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13020287"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-0547"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-019-0332-z"},{"key":"e_1_2_11_6_1","unstructured":"U.S. Food and Drug Administration.Bispecific Antibodies: An Area of Research and Clinical Applications<https:\/\/www.fda.gov\/drugs\/news\u2010events\u2010human\u2010drugs\/bispecific\u2010antibodies\u2010area\u2010research\u2010and\u2010clinical\u2010applications> (2023). 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