Targeting breast cancer via site-specific antibody-drug conjugates based on biosynthetically modified enediyne natural products

通过基于生物合成修饰的烯二炔天然产物的位点特异性抗体药物缀合物靶向乳腺癌

• 批准号: 514898299
• 负责人: Dr. Alexander Kiefer
• 金额: --
• 依托单位: Department of Chemistry
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2022
• 资助国家: 德国
• 起止时间: 2021-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/514898299?language=en
• 关键词: Targeting; breast; cancer; via; site

The number of patients diagnosed with breast cancer in 2020 was nearly 2.3 million, of which one third of the cases resulted in death. Despite tremendous progress in the field of cancer chemotherapy, small molecule anticancer drugs still face the major problem of nonspecific toxicity, by targeting all rapidly dividing cells. Antibody-drug conjugates (ADCs) represent an innovative approach that combines the high specificity of monoclonal antibodies with the potency of small molecule agents that are too cytotoxic to be administered systemically. Novel enediyne natural products, such as the tiancimycins (TNMs), are excellent payload candidates due to their superb potency, validated DNA-damaging mode of action, with yet limited use due to their effects on healthy cells. This project therefore aims to develop novel, TNM-based, site-specific antibody-drug conjugates, that target breast cancer cells expressing HER2 and ROR1 receptors. Fermentation of actinobacteria and subsequent natural product isolation, will provide an excellent starting point to produce TNM derivatives with unique functional groups. Further biocatalytic transformations of the analogs, as well as co-developed linker chemistry, will enable site-specific conjugation to dual variable domain (DVD) antibodies, which utilized either a catalytic lysine or engineering arginine residue, to generate homogeneous ADCs with defined drug antibody ratios and advantageous biochemical and pharmacological properties. Ultimately, complementary targeting of HER2 and ROR1 will help to evaluate the potency and selectivity of the novel enediyne-based ADCs towards breast cancer cells.

2020年确诊乳腺癌患者近230万人，其中三分之一的病例导致死亡。尽管在癌症化疗领域取得了巨大进展，但小分子抗癌药物仍然面临着靶向所有快速分裂细胞的非特异性毒性的主要问题。抗体-药物缀合物（ADC）代表了一种创新方法，其将单克隆抗体的高特异性与小分子药剂的效力相结合，所述小分子药剂具有太大的细胞毒性而不能全身施用。新的烯二炔天然产物，如天降霉素（TNM），由于其极好的效力、经验证的DNA损伤作用模式而成为优异的有效载荷候选物，但由于其对健康细胞的作用而使用有限。因此，该项目旨在开发新型的、基于TNM的、位点特异性抗体-药物缀合物，其靶向表达HER 2和ROR 1受体的乳腺癌细胞。放线菌的发酵和随后的天然产物分离，将提供一个很好的起点，生产具有独特功能基团的TNM衍生物。类似物的进一步生物催化转化以及共同开发的接头化学将使得能够位点特异性缀合至双可变结构域（DVD）抗体，其利用催化赖氨酸或工程改造精氨酸残基，以产生具有限定的药物抗体比率和有利的生物化学和药理学性质的均质ADC。最终，HER 2和ROR 1的互补靶向将有助于评估新型烯二炔类ADC对乳腺癌细胞的效力和选择性。