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

• Applicant: Dr. Alexander Kiefer
• Subject Area: Biological and Biomimetic Chemistry ; Pharmacy
• Term: from 2022 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514898299

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.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Ben Shen, Ph.D.