Corvaglia Valentina, Ait Mohamed Amar Imène, Garambois Véronique, Letast Stéphanie, Garcin Aurélie, Gongora Céline, Del Rio Maguy, Denevault-Sabourin Caroline, Joubert Nicolas, Huc Ivan, Pourquier Philippe
Center for Integrated Protein Science, Department of Pharmacy, Ludwig-Maximilians-Universität, 81377 Munich, Germany.
GICC EA7501, Equipe IMT, Université de Tours, 10 Boulevard Tonnellé, F-37032 Tours, France.
Pharmaceuticals (Basel). 2021 Jun 28;14(7):624. doi: 10.3390/ph14070624.
Inhibition of protein-DNA interactions represents an attractive strategy to modulate essential cellular functions. We reported the synthesis of unique oligoamide-based foldamers that adopt single helical conformations and mimic the negatively charged phosphate moieties of B-DNA. These mimics alter the activity of DNA interacting enzymes used as targets for cancer treatment, such as DNA topoisomerase I, and they are cytotoxic only in the presence of a transfection agent. The aim of our study was to improve internalization and selective delivery of these highly charged molecules to cancer cells. For this purpose, we synthesized an antibody-drug conjugate (ADC) using a DNA mimic as a payload to specifically target cancer cells overexpressing HER2. We report the bioconjugation of a 16-mer DNA mimic with trastuzumab and its functional validation in breast and ovarian cancer cells expressing various levels of HER2. Binding of the ADC to HER2 increased with the expression of the receptor. The ADC was internalized into cells and was more efficient than trastuzumab at inhibiting their growth in vitro. These results provide proof of concept that it is possible to site-specifically graft high molecular weight payloads such as DNA mimics onto monoclonal antibodies to improve their selective internalization and delivery in cancer cells.
抑制蛋白质与DNA的相互作用是调节细胞基本功能的一种有吸引力的策略。我们报道了基于独特寡酰胺的折叠体的合成，这些折叠体采用单螺旋构象并模拟B-DNA带负电荷的磷酸基团。这些模拟物改变了用作癌症治疗靶点的DNA相互作用酶的活性，如DNA拓扑异构酶I，并且它们仅在转染剂存在的情况下具有细胞毒性。我们研究的目的是改善这些高电荷分子向癌细胞的内化和选择性递送。为此，我们使用DNA模拟物作为有效载荷合成了一种抗体-药物偶联物（ADC），以特异性靶向过表达HER2的癌细胞。我们报道了一种16聚体DNA模拟物与曲妥珠单抗的生物偶联及其在表达不同水平HER2的乳腺癌和卵巢癌细胞中的功能验证。ADC与HER2的结合随着受体的表达而增加。ADC被内化到细胞中，并且在体外抑制细胞生长方面比曲妥珠单抗更有效。这些结果提供了概念证明，即有可能将高分子量有效载荷（如DNA模拟物）位点特异性地连接到单克隆抗体上，以改善它们在癌细胞中的选择性内化和递送。
