Multi-parameter optimization of a novel anti-TROP2 MMAE antibody-drug-conjugate for solid tumor therapy

@article{fayadatdilman2026multiparameter,
  title = {{Multi-parameter optimization of a novel anti-TROP2 MMAE antibody-drug-conjugate for solid tumor therapy}},
  author = {Laurence Fayadat-Dilman and Andrew B. Waight and Lauren Adams and Peyman Akbari and Minilik Angagaw and Jeanne Baker and Michelle Castor and Andy Chen and Daoyang Chen and Ming-Tang Chen and Ellen Chien and Jill E. Chrencik and Darcey Clark and James Dutko and Mehabaw Derebe and Alan Goggins and Thomas Griffiths and Mee Ra Heon and Marlene C. Hinton and SuChun Hsieh and Amy Hsu and Zhong L. Hua and Mark Ibrahim and Mengxuan Jia and Rebecca E. Johnson and Simon B. Lang and Su-Yang Liu and Daniel Malashock and Aleksandra Olow and Michael Oropallo and Andrea T. Partridge and Vin Penaflor and Elnaz Rasti Boroujeni and Zhao Ren and Karthik Sathiyamoorthy and Makiko Uchida and Derek Wiswell and Jane Xia and Peng Yang and Jennifer Yearley and Sultan Yilmaz and Yao Yu and John A. Flygare and Bernhard H. Geierstanger and Jianzhong Wen and W. Michael Seganish and Edward P. Bowman},
  journal = {Frontiers in oncology},
  year = {2026},
  month = sep,
  doi = {10.3389/fonc.2026.1915652},
  url = {https://europepmc.org/article/PMC/PMC13662851},
  note = {CC BY},
}

TY  - JOUR
TI  - Multi-parameter optimization of a novel anti-TROP2 MMAE antibody-drug-conjugate for solid tumor therapy
AU  - Laurence Fayadat-Dilman
AU  - Andrew B. Waight
AU  - Lauren Adams
AU  - Peyman Akbari
AU  - Minilik Angagaw
AU  - Jeanne Baker
AU  - Michelle Castor
AU  - Andy Chen
AU  - Daoyang Chen
AU  - Ming-Tang Chen
AU  - Ellen Chien
AU  - Jill E. Chrencik
AU  - Darcey Clark
AU  - James Dutko
AU  - Mehabaw Derebe
AU  - Alan Goggins
AU  - Thomas Griffiths
AU  - Mee Ra Heon
AU  - Marlene C. Hinton
AU  - SuChun Hsieh
AU  - Amy Hsu
AU  - Zhong L. Hua
AU  - Mark Ibrahim
AU  - Mengxuan Jia
AU  - Rebecca E. Johnson
AU  - Simon B. Lang
AU  - Su-Yang Liu
AU  - Daniel Malashock
AU  - Aleksandra Olow
AU  - Michael Oropallo
AU  - Andrea T. Partridge
AU  - Vin Penaflor
AU  - Elnaz Rasti Boroujeni
AU  - Zhao Ren
AU  - Karthik Sathiyamoorthy
AU  - Makiko Uchida
AU  - Derek Wiswell
AU  - Jane Xia
AU  - Peng Yang
AU  - Jennifer Yearley
AU  - Sultan Yilmaz
AU  - Yao Yu
AU  - John A. Flygare
AU  - Bernhard H. Geierstanger
AU  - Jianzhong Wen
AU  - W. Michael Seganish
AU  - Edward P. Bowman
PY  - 2026
DA  - 2026/09/30
JO  - Frontiers in oncology
DO  - 10.3389/fonc.2026.1915652
UR  - https://europepmc.org/article/PMC/PMC13662851
AB  - 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.
SN  - 2234-943X
ER  -