{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:16:41Z","timestamp":1790713001320,"version":"4.1.0"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"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":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:p>ISB 2001 is a trispecific antibody that binds to two tumor\u2010associated antigens (TAA), CD38 and BCMA, and crosslinks to CD3 on T cells resulting in T cell\u2010mediated cytotoxicity of tumor cells expressing these TAAs. ISB 2001 is currently being tested in relapsed and\/or refractory multiple myeloma (RRMM) patients in the first\u2010in\u2010human (FIH) TRIgnite\u20101 study (NCT05862012). The CD3\u03b5\u2010binding domain of ISB 2001 does not cross\u2010react with CD3 in cynomolgus monkeys. Therefore, no pharmacokinetic, efficacy, or toxicology data could be generated in a fully cross\u2010reactive preclinical species to facilitate prediction of optimal FIH dose or the clinical efficacy dose range. For T\u00a0cell engagers (TCEs), the minimum anticipated biological effect level (MABEL) approach is widely used to derive FIH doses. While this method is considered safe, this standard approach may result in starting doses that are sometimes too low to elicit meaningful clinical activity, potentially leading to several dose escalation cohorts at subtherapeutic levels in seriously ill patients. We used a novel quantitative systems pharmacology (QSP) model to inform FIH dose selection and predict the clinical efficacy dose range for ISB 2001. This modeling strategy enabled an efficient dose escalation design for the TRIgnite\u20101. This approach is consistent with the emerging FDA roadmap to reduce animal testing by utilizing computational modeling methodologies for FIH dose selection. Finally, we demonstrate the validation of the QSP model and approach by comparing its predictions with evolving preliminary safety, PK, and antimyeloma activity data from the ongoing TRIgnite\u20101 clinical trial.<\/jats:p>","DOI":"10.1002\/cpt.70319","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T11:34:46Z","timestamp":1779968086000},"page":"452-464","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Clinical Validation of a\n                    <scp>QSP<\/scp>\n                    Model for\n                    <scp>ISB<\/scp>\n                    2001, a Trispecific T Cell Engager to Support Optimal\n                    <scp>FIH<\/scp>\n                    Study Design in\n                    <scp>RRMM<\/scp>\n                    Patients"],"prefix":"10.1002","volume":"120","author":[{"given":"Vinu","family":"Chandralayam Ayyappa Menon","sequence":"first","affiliation":[{"name":"IGI Inc. 1 World Trade Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomi","family":"Matsuura","sequence":"additional","affiliation":[{"name":"Certara UK Limited Canterbury Innovation Centre  Canterbury UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beata","family":"Holkova","sequence":"additional","affiliation":[{"name":"IGI Inc. 1 World Trade Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Girish S.","family":"Gudi","sequence":"additional","affiliation":[{"name":"IGI Inc. 1 World Trade Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Drake","sequence":"additional","affiliation":[{"name":"IGI Inc. 1 World Trade Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Pihlgren","sequence":"additional","affiliation":[{"name":"IGI Inc. 1 World Trade Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Piet H.","family":"van der Graaf","sequence":"additional","affiliation":[{"name":"Certara UK Limited Canterbury Innovation Centre  Canterbury UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunitha","family":"GN","sequence":"additional","affiliation":[{"name":"Glenmark Pharmaceuticals Ltd Mahape  Navi Mumbai Maharashtra India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Garton","sequence":"additional","affiliation":[{"name":"IGI Inc. 1 World Trade Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Perro","sequence":"additional","affiliation":[{"name":"IGI Inc. 1 World Trade Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Konto","sequence":"additional","affiliation":[{"name":"IGI Inc. 1 World Trade Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lida","family":"Pacaud","sequence":"additional","affiliation":[{"name":"IGI Inc. 1 World Trade Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmmed.2023.1140977"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2024.07.002"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-024-00821-1"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2017.09.001"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3316"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.3487"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.393"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-019-0332-z"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-14726-5"},{"key":"e_1_2_10_11_1","first-page":"1184","article-title":"1062\u2009mechanistic QSP modeling and translational strategy for determining an FIH dose for ZW171, a bispecific 2+1 T\u2010cell engager molecule targeting mesothelin and CD3","volume":"12","author":"Afacan N.","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"e_1_2_10_12_1","first-page":"1479","article-title":"A quantitative systems pharmacology model for first\u2010in\u2010human dosing of MDX2001, a multispecific antibody for the treatment of advanced solid tumors","volume":"12","author":"Presler M.","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"e_1_2_10_13_1","first-page":"2249","article-title":"Endocytosis and degradation of murine anti\u2010human CD3 monoclonal antibodies by normal and malignant T\u2010lymphocytes","volume":"48","author":"Press O.W.","year":"1988","journal-title":"Cancer Res."},{"key":"e_1_2_10_14_1","article-title":"Daratumumab induces CD38 internalization and impairs myeloma cell adhesion","volume":"7","author":"Ghose J.","year":"2018","journal-title":"Onco. Targets Ther."},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1111\/bjh.14145"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-017-0183-4"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-015-1703-5"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-014-9372-2"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-013-9332-2"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1177\/0141076809701003"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-022-00893-y"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01771"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-2752"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2020002393"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.0902-4441.2003.00199.x"},{"key":"e_1_2_10_26_1","unstructured":"Monocytes: Function Range & Related Conditions<https:\/\/my.clevelandclinic.org\/health\/body\/22110\u2010monocytes>. Accessed September 14 2022."},{"key":"e_1_2_10_27_1","unstructured":"Frequencies of Cell Types in Human Peripheral Blood<https:\/\/www.stemcell.com\/media\/files\/wallchart\/WA10006\u2010Frequencies_Cell_Types_Human_Peripheral_Blood.pdf>. Accessed September 14 2022."},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2016.158303"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2019.01.034"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2016.00051"},{"key":"e_1_2_10_31_1","unstructured":"Diagnostic Testing for Multiple Myeloma<https:\/\/themmrf.org\/multiple\u2010myeloma\/diagnosis\/>. Accessed September 14 2022."},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-18-1597"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.02.002"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-319-16104-4_15"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-09-0195"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1177\/1534735419847285"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.109.164129"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(21)01338-6"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-187106"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2024-208189"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2025.43.16_suppl.7514"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1158\/1538-7445.AM2025-3694"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2018.12.758"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(16)30206-6"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1592\/phco.26.6.813"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41540-020-00145-7"},{"key":"e_1_2_10_47_1","unstructured":"*Center for Drug Evaluation and Research (CDER).Multidisciplinary review: Elrexfio (elranatamab\u2010bcmm). Application Number: 761345Orig1s000 US Food and Drug Administration <https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2024\/761344Orig1s000MultidisciplineR.pdf> (2023). Accessed August 17 2025."},{"key":"e_1_2_10_48_1","unstructured":"*Center for Drug Evaluation and Research (CDER).Multidisciplinary review: Talvey (talquetamab\u2010tgvs). Application Number: 761342Orig1s000 US Food and Drug Administration <https:\/\/www.accessdata.fda.gov\/drugsatfda_docs\/nda\/2023\/761342Orig1s000MultidisciplineR.pdf> (2023). Accessed September 17 2025."},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-48479-8"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2021-147983"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-182388"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70319","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70319","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70319","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,13]],"date-time":"2026-07-13T03:17:24Z","timestamp":1783912644000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70319"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":50,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,8]]}},"alternative-id":["10.1002\/cpt.70319"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70319","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]},"assertion":[{"value":"2025-10-07","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}