{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T03:04:06Z","timestamp":1789700646769,"version":"4.0.1"},"reference-count":12,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The standard Douglass ternary binding model (TBM) for three\u2010body equilibria assumes a well\u2010mixed, three\u2010dimensional solution. When applied to bispecific T\u2010cell engagers (BiTEs), however, the productive trimeric complex forms not in bulk solution but within a nanoscale membrane synapse with finite receptor copy numbers. We present a generalization of the TBM to membrane\u2010confined systems that replaces the macroscopic bulk volume with a coarse\u2010grained reactive contact volume defined by synapse geometry and microvillus topology, and extends the deterministic equilibrium to a stochastic description via the chemical master equation. The framework preserves the original algebra while restoring its representational capacity for the regime in which therapeutic activity occurs. A key finding is that conventional bulk mapping places the system in the affinity\u2010limited regime, where antigen density is mathematically inert and the TBM predicts identical dose\u2013response regardless of target expression. Membrane confinement shifts effective antigen concentration by six orders of magnitude\u2014from  nM to  nM\u2014restoring antigen density as a governing variable for trimer formation. Using blinatumomab (anti\u2010CD19 BiTE) as a case study, we introduce the\n                    <jats:italic>absolute formation dose<\/jats:italic>\n                    : the drug concentration required to produce a fixed number of ternary complexes sufficient for T\u2010cell activation. This metric replaces the conventional , which normalizes each cell line to its own maximum, erasing the density dependence that confinement rescues. For NALM\u20106 and HAL\u201001 cell lines (CD19 density ratio ), the framework predicts a corresponding \u2010fold difference in required dose\u2014a prediction structurally invisible to the bulk formulation.\n                  <\/jats:p>","DOI":"10.1002\/psp4.70323","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T15:09:53Z","timestamp":1787929793000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Generalization of the Ternary Binding Model to Membrane\u2010Confined Systems With Finite Copy Number"],"prefix":"10.1002","volume":"15","author":[{"given":"Hamid","family":"Bellout","sequence":"first","affiliation":[{"name":"Bellout. Llc  DeKalb Illinois USA"},{"name":"Takeda Development Center Americas, Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Li","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5641-4056","authenticated-orcid":false,"given":"Dean","family":"Bottino","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9337-6329","authenticated-orcid":false,"given":"Konstantin","family":"Piatkov","sequence":"additional","affiliation":[{"name":"Takeda Development Center Americas, Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"e_1_2_14_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja311795d"},{"key":"e_1_2_14_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature12951"},{"key":"e_1_2_14_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature11220"},{"key":"e_1_2_14_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03127-w"},{"key":"e_1_2_14_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2011.05.013"},{"key":"e_1_2_14_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.aal3118"},{"issue":"40","key":"e_1_2_14_8_1","first-page":"E5916","article-title":"Three\u2010Dimensional Localization of T\u2010Cell Receptors in Relation to Microvilli Using a Combination of Superresolution Microscopies","volume":"113","author":"Jung Y.","year":"2016","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"},{"key":"e_1_2_14_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.347575"},{"key":"e_1_2_14_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(98)74074-3"},{"key":"e_1_2_14_11_1","unstructured":"U.S. Food and Drug Administration \u201cPharmacology Review(s): BLA 125557 BLINCYTO (Blinatumomab) \u201d(2014) https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2014\/125557Orig1s000PharmR.pdf."},{"key":"e_1_2_14_12_1","unstructured":"Pharmaceuticals and Medical Devices Agency \u201cReview Report: Blinatumomab \u201d(2018) https:\/\/www.pmda.go.jp\/drugs\/2018\/P20181015001\/112292000_23000AMX00811_H100_1.pdf."},{"key":"e_1_2_14_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2026.1739493"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70323","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/psp4.70323","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.70323","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T02:35:54Z","timestamp":1789698954000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.70323"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":12,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/psp4.70323"],"URL":"https:\/\/doi.org\/10.1002\/psp4.70323","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]},"assertion":[{"value":"2026-04-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70323"}}