肿瘤特异性释药的偶氮还原酶裂解型抗体偶联药物研究

Currently, the treatment of solid tumors is still limited. Chemotherapy drugs usually cause toxic and side effects because of poor targeting, and monoclonal antibodies generally have weak deficiencies and drug resistance. Antibody-drug conjugate (ADC) combines the advantages of the both, which uses antibody to target cytotoxin to tumors to achieve “enhanced efficacy and reduced toxicity”, and has become an important research direction. However, the designs of current ADC still have core defects: the drug release mechanism lacks tumor specificity, and it is designed by using non-tumor characteristics (lysosomal enzyme, etc.), which is difficult to effectively avoid ADC off-target toxicity. This application is the first to propose a novel concept for the development of ADC that using solid tumor-specific azoreductase, which may controls cytotoxin only released in tumors to reduce the risk of ADC off-target. The enzyme is overexpressed in solid tumor, and can selectively catalyzing the formation of an amino group by an azo group under anoxic conditions; although it has been fully validated in the field of probes, the toxicity caused by insufficient targeting of small molecules has prevented its use in drug development. The present application is based on the scientific understanding of the release mechanism of ADC electron transfer driving, then the targeting of antibodies and the tumor-specific drug-releasing process driven by azoreductase were organically incorporated into the target ADC. On the basis of previous research, by optimizing the design of the ADC, systematic comparison studies such as release mechanism, efficacy, and safety evaluation at the molecular, cellular, and animal levels are used to fully verify the feasibility of the strategy and clarify its advantages. The development of this application is expected to open up a new direction for ADC research.

目前实体瘤的治疗手段依然有限，化疗药易导致毒副作用，单抗存在活性偏弱和耐药等不足。抗体偶联药物（ADC）技术联合两者优势，利用抗体将细胞毒素靶向肿瘤实现“增效减毒”，已成为重要研究方向。但当前ADC设计仍存在核心缺陷：释药机制多利用非肿瘤特征（溶酶体酶等）进行设计，难以有效规避脱靶ADC的系统毒性。本申请创新提出利用实体瘤特异表达的偶氮还原酶发展ADC，以期使毒素仅在肿瘤靶向释放。该酶过表达于实体瘤、并在缺氧环境可选择性催化偶氮形成氨基，其已在探针领域广泛应用、但尚未用于药物开发。本申请旨在基于对ADC电子转移驱动的释药机制的科学理解，首次将抗体的靶向性和偶氮还原酶的肿瘤释药特异性有机地融入ADC。在前期已有的研究基础上优化ADC的设计，通过分子、细胞、动物等层面的释药机制、药效、安全性评价等系统性对比研究，充分验证该策略的可行性并阐明其优势。本申请的开展，有望为ADC研究开拓全新的方向。

目前实体瘤的治疗手段依然有限，化疗药易导致毒副作用，单抗存在活性偏弱和耐药等不足。抗体偶联药物（ADC）技术联合两者优势，利用抗体将细胞毒素靶向肿瘤实现“增效减毒”，已成为重要研究方向。但当前ADC设计仍存在核心缺陷：释药机制多利用非肿瘤特征（溶酶体酶等）进行设计，难以有效规避脱靶ADC的系统毒性。本申请创新提出利用实体瘤特异表达的偶氮还原酶发展ADC，以期使毒素仅在肿瘤靶向释放。该酶过表达于实体瘤、并在缺氧环境可选择性催化偶氮形成氨基，其已在探针领域广泛应用、但尚未用于药物开发。本申请旨在基于对ADC电子转移驱动的释药机制的科学理解，首次将抗体的靶向性和偶氮还原酶的肿瘤释药特异性有机地融入ADC。在前期已有的研究基础上优化ADC的设计，通过分子、细胞、动物等层面的释药机制、药效、安全性评价等系统性对比研究，充分验证该策略的可行性并阐明其优势。本申请的开展，有望为ADC研究开拓全新的方向。