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

2020年，被诊断患有乳腺癌的患者人数接近230万，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的进步，但小分子抗癌药物仍然面临着非特异性毒性的主要问题，因为它针对的是所有快速分裂的细胞。抗体-药物偶联物（adc）代表了一种创新的方法，它结合了单克隆抗体的高特异性和小分子药物的效力，小分子药物的细胞毒性太大，无法全身给药。新型烯二炔天然产物，如天西米霉素（TNMs），由于其极好的效力，有效的dna损伤作用模式，是极好的有效载荷候选者，但由于其对健康细胞的影响，使用有限。因此，该项目旨在开发新的、基于tnm的、位点特异性抗体-药物偶联物，以表达HER2和ROR1受体的乳腺癌细胞为靶点。放线菌的发酵和随后的天然产物分离，将为生产具有独特官能团的TNM衍生物提供一个很好的起点。类似物的进一步生物催化转化，以及共同开发的连接物化学，将使双可变结构域（DVD）抗体的位点特异性偶联成为可能，该抗体利用催化赖氨酸或工程精氨酸残基，生成具有确定的药物抗体比率和有利的生化和药理学特性的均匀adc。最终，HER2和ROR1的互补靶向将有助于评估新型基于烯二炔的adc对乳腺癌细胞的效力和选择性。

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.