{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T13:01:29Z","timestamp":1790773289518,"version":"4.1.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    TROP2 is expressed in many epithelial tumors including breast and lung cancers. It is a clinically validated ADC target based on approvals of sacituzumab govitecan for triple-negative breast cancer and datopotamab deruxtecan for HR-positive, HER2-negative breast cancer. An alternative cytotoxic approach was previously tested with PF-06664178\/RN927C, an anti-TROP2 ADC with an auristatin payload, which entered clinical studies but could not be dosed efficaciously due to dose-limiting toxicities including skin rash, mucosal inflammation, and neutropenia. TroptimAb-SL-MMAE was engineered using an optimized anti-TROP2 sacituzumab antibody sequence (TroptimAb) to address issues related to hydrophobicity, non-specific uptake, and ADC developability. Sacituzumab was re\n                    <jats:sub>-<\/jats:sub>\n                    humanized and modified to enhance FcRn-mediated salvage which extended systemic half-life and potentially improving tumor distribution. Its affinity was avidity-tuned to preferentially bind cells with higher TROP2 expression to reduce on-target\/off-tumor toxicity. An engineered cysteine in the Fc domain enabled generation of a homogeneous DAR2 ADC and shielded the linker-payload to reduce hydrophobicity and improve biophysical properties. Linker conjugation chemistry was also optimized to improve stability versus earlier cysteine-conjugated ADCs. We describe the preclinical profile of TroptimAb-SL-MMAE including its design, mechanism of action, anti-tumor activity, and pharmacokinetics.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1915652","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T12:46:04Z","timestamp":1790772364000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Multi-parameter optimization of a novel anti-TROP2 MMAE antibody-drug-conjugate for solid tumor therapy"],"prefix":"10.3389","volume":"16","author":[{"given":"Laurence","family":"Fayadat-Dilman","sequence":"first","affiliation":[{"name":"Discovery Biologics, Merck & Co., Inc.","place":["South San Francisco, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew B.","family":"Waight","sequence":"additional","affiliation":[{"name":"Discovery Biologics, Merck & Co., Inc.","place":["South San Francisco, CA, 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