Development of Optimized Exatecan-Based Immunoconjugates with Potent Antitumor Efficacy in HER2-Positive Breast Cancer

  • J Med Chem. 2025 Sep 25;68(18):19122-19142. doi: 10.1021/acs.jmedchem.5c01184.
Etienne Auvert  1 ,  Emmanuel Douez  2  3 ,  Louis Jolivet  4 ,  Tiffany Witkowski  5 ,  Anne-Catherine Jallas  6 ,  Fanny Boursin  4 ,  Ioana Molnar  5 ,  Cyril Colas  7 ,  Sandrine Valsesia Wittmann  6 ,  Manon Auriol  5 ,  Jean-Michel Chezal  5 ,  Nicolas Aubrey  4 ,  Emilie Allard-Vannier  2 ,  Aurélie Maisonial-Besset  5 ,  Nicolas Joubert  1 ,  Caroline Denevault-Sabourin  1
Affiliations
  • 1. UMR 1100, Research Center for Respiratory Diseases (CEPR), Team Proteolytic enzymes and their pharmacological targeting in lung diseases, University of Tours, Inserm, F-37032 Tours, France.
  • 2. UPR 4301, Center of molecular Biophysics (CBM), CNRS, NMNS department, University of Tours, F-37200 Tours, France.
  • 3. Pharmacy Department, Tours University Hospital, F-37200 Tours, France.
  • 4. UMR 1282 ISP, Team BioMAP, University of Tours-INRAE, F-37200 Tours, France.
  • 5. UMR 1240, Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Université Clermont Auvergne, Inserm, F-63000 Clermont-Ferrand, France.
  • 6. Inserm U1296 Radiations: Défense, Santé, Environnement, Centre Léon Bérard, F-69008 Lyon, France.
  • 7. Institute of Organic and Analytical Chemistry, ICOA UMR 7311 CNRS, University of Orléans, F-45100 Orléans, France.
PMID: 40912684 DOI: 10.1021/acs.jmedchem.5c01184
Abstract

The prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast Cancer has significantly improved with the advent of anti-HER2 therapies, especially antibody-drug conjugates (ADCs). In this field, ADCs, like trastuzumab deruxtecan (T-DXd), using camptothecin analogs, represent a promising strategy. However, T-DXd can induce resistance and serious adverse effects, potentially driven by a non-specific Fcγ receptor-mediated endocytosis. Here, we report the development of novel HER2-targeting conjugates, using the camptothecin derivative exatecan and a linker optimized to control hydrophobicity. Three formats were evaluated: a high drug-to-antibody ratio (DAR) 8 IgG-based ADC (IgG(8)-EXA), and two DAR 4 Fc-free constructs (Mb(4)-EXA and Db(4)-EXA). Thus, IgG(8)-EXA and Mb(4)-EXA displayed potent, specific cytotoxicity against HER2-positive breast Cancer cells and strong antitumor activity in vivo. Notably, IgG(8)-EXA exhibited a favorable pharmacokinetic profile, despite its high DAR, supporting the potential of this drug-linker design. These two conjugates represent promising candidates for further preclinical development.

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