开发在HER2阳性乳腺癌中具有强大抗肿瘤功效的基于依喜替康的优化免疫缀合物。

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

作者信息

Auvert Etienne, Douez Emmanuel, Jolivet Louis, Witkowski Tiffany, Jallas Anne-Catherine, Boursin Fanny, Molnar Ioana, Colas Cyril, Wittmann Sandrine Valsesia, Auriol Manon, Chezal Jean-Michel, Aubrey Nicolas, Allard-Vannier Emilie, Maisonial-Besset Aurélie, Joubert Nicolas, Denevault-Sabourin Caroline

机构信息

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.

UPR 4301, Center of molecular Biophysics (CBM), CNRS, NMNS department, University of Tours, F-37200 Tours, France.

出版信息

J Med Chem. 2025 Sep 5. doi: 10.1021/acs.jmedchem.5c01184.

DOI:10.1021/acs.jmedchem.5c01184

PMID:40912684

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.

摘要

随着抗人表皮生长因子受体2（HER2）疗法的出现，尤其是抗体药物偶联物（ADC）的出现，HER2阳性乳腺癌的预后有了显著改善。在这一领域，使用喜树碱类似物的ADC，如曲妥珠单抗德曲妥珠单抗（T-DXd），是一种很有前景的策略。然而，T-DXd可能会诱导耐药性和严重不良反应，这可能是由非特异性Fcγ受体介导的内吞作用驱动的。在此，我们报告了新型HER2靶向偶联物的研发，该偶联物使用喜树碱衍生物依喜替康和经过优化以控制疏水性的连接子。评估了三种形式：一种高药物与抗体比率（DAR）为8的基于IgG的ADC（IgG(8)-EXA），以及两种DAR为4的无Fc构建体（Mb(4)-EXA和Db(4)-EXA）。因此，IgG(8)-EXA和Mb(4)-EXA对HER2阳性乳腺癌细胞显示出强效、特异性的细胞毒性，并在体内具有强大的抗肿瘤活性。值得注意的是，IgG(8)-EXA尽管DAR较高，但仍表现出良好的药代动力学特征，这支持了这种药物-连接子设计的潜力。这两种偶联物是进一步临床前开发的有希望的候选物。