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

Abzena was acknowledged in a recent ACS publication in the Journal of Medicinal Chemistry for a study that was conducted at the University of Tours, France, on the design, production, and evaluation of several exatecan-based immunoconjugates targeting HER2, and notably a highly loaded ADC produced from trastuzumab.

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)- XA), 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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Abzena acknowledgement: Fabio Rossi, Scientific Lead and the team from the Abzena Cambridge, UK site supported the study with serum stability analysis.

J. Med. Chem. 2025, XXXX, XXX, XXX-XXX