Discovery of Novel <i>N</i> -Linked Camptothecin Linker-Payloads to Access Antibody–Drug Conjugates with High Target-Mediated In Vivo Efficacy
-aminobenzyl carbamate (PABC) linkers with a focus on stability and polarity leads to the discovery of promising α-amino-isobutyramido-exatecan constructs. The corresponding high-DAR ADCs showed low aggregation, good in vitro potency, and robust target-mediated efficacy in vivo across two antibody-antigen pairs. These results demonstrate the potential of these linker-payloads and the broad applicability of this design strategy.
Authors
- Vlad Bacauanu (ORCID: https://orcid.org/0000-0003-3089-0692)
- Esther Kofman
- Ryan V. Quiroz (ORCID: https://orcid.org/0000-0001-6840-9636)
- Laurence Fayadat‐Dilman (ORCID: https://orcid.org/0000-0001-6285-8924)
- Simon B. Lang (ORCID: https://orcid.org/0000-0001-5380-2996)
- Bernhard H. Geierstanger
- Zhong L. Hua
- Michael Judo
- Alan B. Northrup
- Ian Knemeyer (ORCID: https://orcid.org/0000-0001-6254-882X)
- Christian L. Morales
- Daniela M. Tomazela
- Manoj B. Charati (ORCID: https://orcid.org/0009-0000-0680-8236)
- Nancy Zepeda
- John A. Flygare
- Mengxuan Jia (ORCID: https://orcid.org/0000-0001-9173-1084)
- Si-Jie Chen (ORCID: https://orcid.org/0000-0001-9836-6892)
- Rebecca Johnson (ORCID: https://orcid.org/0000-0001-6315-278X)
- Evan R. Barry (ORCID: https://orcid.org/0009-0001-7720-1893)
- Song Yang (ORCID: https://orcid.org/0000-0003-1301-3030)
- Qingyun Yan (ORCID: https://orcid.org/0009-0001-2633-8654)
- Peyman Akbari
- Edward P. Bowman
- Olivia R Chastain
- W Michael Seganish
- Alycia K Uyeoka
- Fan Zhang
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-04-30
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c03693
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00