{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:41:57Z","timestamp":1792798917915,"version":"4.5.0"},"reference-count":31,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Science"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Deruxtecan\u2010based antibody\u2010drug conjugates (DXd ADCs) provide substantial clinical benefit across multiple malignancies but are associated with clinically significant interstitial lung disease (ILD), for which the underlying mechanisms remain incompletely understood. To enable mechanistic and translational studies, we established a transgenic rat model expressing human trophoblast cell\u2010surface antigen 2 (hTROP2) under the control of the surfactant protein C promoter, driving selective expression in alveolar type II (AT2) cells. Repeated administration of a TROP2\u2010directed DXd ADC with an average drug\u2010to\u2010antibody ratio of 7.9 (TROP2\u2010DXd) reproducibly induced lung injury characterized by alveolar epithelial damage, inflammatory cell infiltration, and fibroblast\/myofibroblast proliferation. These pathological changes were accompanied by inflammatory and tissue\u2010remodeling transcriptomic responses, including increased expression of fibrosis\u2010associated genes and decreased expression of AT2\u2010associated genes. These molecular alterations showed partial concordance with molecular programs observed in a cynomolgus monkey ILD model. In hTROP2 transgenic rats, prednisolone markedly attenuated TROP2\u2010DXd\u2010related lung injury and inflammatory and tissue\u2010remodeling transcriptomic responses without altering systemic exposure. Although hTROP2 expression is transgene\u2010driven and does not fully recapitulate physiological expression patterns and distribution in normal human lungs, this model provides a controlled experimental system for evaluating epithelial injury\u2010associated mechanisms. Notably, parallel studies in BALB\/c and C57BL\/6 mice showed no pulmonary findings despite prolonged high\u2010exposure dosing, suggesting species\u2010dependent susceptibility. Collectively, this transgenic rat model represents a unique rodent ILD model that recapitulates key pathological and molecular features and provides a scalable, experimentally tractable platform for mechanistic and translational evaluation across DXd ADCs.<\/jats:p>","DOI":"10.1111\/cas.70572","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:34:36Z","timestamp":1792798476000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Transgenic Rat Model of\n                    <scp>DXd ADC<\/scp>\n                    \u2010Related Interstitial Pneumonitis for Mechanistic and Translational Research"],"prefix":"10.1111","author":[{"given":"Kazuyoshi","family":"Kumagai","sequence":"first","affiliation":[{"name":"Medicinal Safety Research Laboratories Daiichi Sankyo Co., Ltd.  Tokyo Japan"},{"name":"Medicinal Safety Daiichi Sankyo Inc.  Basking Ridge USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuma","family":"Nagai","sequence":"additional","affiliation":[{"name":"Medicinal Safety Research Laboratories Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Shirai","sequence":"additional","affiliation":[{"name":"Medicinal Safety Research Laboratories Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunori","family":"Fujimoto","sequence":"additional","affiliation":[{"name":"Medicinal Safety Research Laboratories Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masako","family":"Imaoka","sequence":"additional","affiliation":[{"name":"Medicinal Safety Research Laboratories Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuyoshi","family":"Chiba","sequence":"additional","affiliation":[{"name":"Medicinal Safety Research Laboratories Daiichi Sankyo Co., Ltd.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,23]]},"reference":[{"issue":"3","key":"e_1_2_12_2_1","doi-asserted-by":"crossref","first-page":"430","DOI":"10.1016\/j.annonc.2019.11.019","article-title":"The Art of Innovation: Clinical Development of Trastuzumab Deruxtecan and Redefining How Antibody\u2010Drug Conjugates Target HER2\u2010Positive Cancers","volume":"31","author":"Yver A.","year":"2020","journal-title":"Annals of Oncology"},{"issue":"12","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1056\/NEJMoa2115022","article-title":"Trastuzumab Deruxtecan Versus Trastuzumab Emtansine for Breast Cancer","volume":"386","author":"Cort\u00e9s J.","year":"2022","journal-title":"New England Journal of Medicine"},{"key":"e_1_2_12_4_1","article-title":"Datopotamab Deruxtecan in Patients With Untreated, Advanced Triple\u2010Negative Breast Cancer (TROPION\u2010Breast02): A Randomised, Open\u2010Label, International, Phase III Trial","author":"Dent R.","year":"2026","journal-title":"Annals of Oncology"},{"issue":"4","key":"e_1_2_12_5_1","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1200\/JCO-25-02142","article-title":"Ifinatamab Deruxtecan in Patients With Extensive\u2010Stage Small Cell Lung Cancer: Primary Analysis of the Phase II IDeate\u2010Lung01 Trial","volume":"44","author":"Rudin C. M.","year":"2026","journal-title":"Journal of Clinical Oncology"},{"issue":"12","key":"e_1_2_12_6_1","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1001\/jamaoncol.2021.3595","article-title":"Interstitial Lung Disease Induced by Anti\u2010ERBB2 Antibody\u2010Drug Conjugates: A Review","volume":"7","author":"Tarantino P.","year":"2021","journal-title":"JAMA Oncology"},{"issue":"2","key":"e_1_2_12_7_1","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1158\/1535-7163.MCT-24-0267","article-title":"Potential Mechanisms of Interstitial Lung Disease Induced by Antibody\u2010Drug Conjugates Based on Quantitative Analysis of Drug Distribution","volume":"24","author":"Koganemaru S.","year":"2025","journal-title":"Molecular Cancer Therapeutics"},{"issue":"1","key":"e_1_2_12_8_1","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3390\/jcm10010107","article-title":"Imaging Biomarkers in Animal Models of Drug\u2010Induced Lung Injury: A Systematic Review","volume":"10","author":"Persson I. 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L.","year":"2022","journal-title":"Breast Cancer Research and Treatment"},{"key":"e_1_2_12_28_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.ctrv.2022.102378","article-title":"Multidisciplinary Clinical Guidance on Trastuzumab Deruxtecan (T\u2010DXd)\u2013Related Interstitial Lung Disease\/Pneumonitis\u2014Focus on Proactive Monitoring, Diagnosis, and Management","volume":"106","author":"Swain S. M.","year":"2022","journal-title":"Cancer Treatment Reviews"},{"issue":"6","key":"e_1_2_12_29_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.esmoop.2023.102043","article-title":"Multidisciplinary Clinical Guidelines in Proactive Monitoring, Early Diagnosis, and Effective Management of Trastuzumab Deruxtecan (T\u2010DXd)\u2010Induced Interstitial Lung Disease (ILD) in Breast Cancer Patients","volume":"8","author":"Wekking D.","year":"2023","journal-title":"ESMO Open"},{"key":"e_1_2_12_30_1","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.2147\/DDDT.S508773","article-title":"A Systematic Review of Mechanisms, Incidence, and Management of Trastuzumab Deruxtecan Induced ILD\/Pneumonitis in Solid Tumors","volume":"19","author":"Liao D.","year":"2025","journal-title":"Drug Design, Development and Therapy"},{"issue":"4","key":"e_1_2_12_31_1","doi-asserted-by":"crossref","DOI":"10.1183\/13993003.02776-2021","article-title":"Drug\u2010Induced Interstitial Lung Disease","volume":"60","author":"Spagnolo P.","year":"2022","journal-title":"European Respiratory Journal"},{"issue":"11","key":"e_1_2_12_32_1","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1158\/2159-8290.CD-24-0708","article-title":"The Journey of Antibody\u2010Drug Conjugates: Lessons Learned From 40\u2009Years of Development","volume":"14","author":"Colombo R.","year":"2024","journal-title":"Cancer Discovery"}],"container-title":["Cancer Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70572","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cas.70572","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cas.70572","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T23:34:41Z","timestamp":1792798481000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cas.70572"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,23]]},"references-count":31,"alternative-id":["10.1111\/cas.70572"],"URL":"https:\/\/doi.org\/10.1111\/cas.70572","archive":["Portico"],"relation":{},"ISSN":["1347-9032","1349-7006"],"issn-type":[{"value":"1347-9032","type":"print"},{"value":"1349-7006","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,23]]},"assertion":[{"value":"2026-08-19","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-18","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-10-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"cas.70572"}}