Authors
Laurence Fayadat-Dilman, Andrew B Waight, Lauren Adams, Peyman Akbari, Minilik Angagaw, Jeanne Baker, Michelle Castor, Andy Chen, Daoyang Chen, Ming-Tang Chen, Ellen Chien, Jill E Chrencik, Darcey Clark, James Dutko, Mehabaw Derebe, Alan Goggins, Thomas Griffiths, Mee Ra Heon, Marlene C Hinton, SuChun Hsieh, Amy Hsu, Zhong L Hua, Mark Ibrahim, Mengxuan Jia, Rebecca E Johnson, Simon B Lang, Su-Yang Liu, Daniel Malashock, Aleksandra Olow, Michael Oropallo, Andrea T Partridge, Vin Penaflor, Elnaz Rasti Boroujeni, Zhao Ren, Karthik Sathiyamoorthy, Makiko Uchida, Derek Wiswell, Jane Xia, Peng Yang, Jennifer Yearley, Sultan Yilmaz, Yao Yu, John A Flygare, Bernhard H Geierstanger, Jianzhong Wen, W Michael Seganish, Edward P Bowman
Published in
Frontiers in oncology. Volume 16. Pages 1915652. Epub Sep 30, 2026.
Abstract
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-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.
PMID:
42877637
Bibliographic data and abstract were imported from PubMed on 16 Oct 2026.
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