A new paradigm for antibody-directed conjugates

描述(申请人提供)：非小细胞肺癌(NSCLC)是最常见和最致命的癌症之一，目前对晚期NSCLC的护理标准仅在总体生存或生活质量方面提供了适度的改善。因此，存在着对治疗非小细胞肺癌的新的有效疗法的重大未满足的需求。在此，我们描述了一种针对非小细胞肺癌的新型抗体药物结合物(ADC)。建议的ADC的核心创新来自于在药物载体(一种新的类固醇糖苷)和抗癌靶向单抗(抗FXYD5)之间使用稳定的共价连接物，这两种单抗都作用于癌细胞的胞外表面。这种非常简单的设计消除了ADC内部化或工程药物货物释放(现有ADC的两个主要缺陷)的需要，从而实现了ADC技术的范式转变。虽然这里描述的I期研究集中在非小细胞肺癌作为模型，但预计这里描述的新型ADC将同样有效地治疗其他难治性癌症。此外，由于还有许多其他合适的细胞外抗原/药物靶点可以应用这一概念，这里描述的概念验证研究的成功可能会为一系列新的有希望的ADC打开大门。 公共卫生相关性：我们建议开发第一个癌症靶向抗体-药物结合物(ADC)，它既不需要内化，也不需要工程药物释放。这种ADC代表了ADC技术的范式转变，因此有望改变未来治疗癌症的靶向疗法的发展。

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is among the most common and lethal cancers yet, the current standard of care for advanced stage NSCLC provides only modest improvements in overall survival or quality of life. Thus, there exists a significant unmet need for new effective therapies to treat NSCLC. Herein we describe an innovative new type of antibody drug conjugate (ADC) to target NSCLC. The core innovation of the proposed ADC derives from the use of a stable covalent linker between the drug cargo (a novel steroidal glycoside) and the cancer-targeting mAb (anti-FXYD5), both of which act upon the extracellular face of the cancer cell. This elegantly simple design eliminates the need for ADC internalization or engineered drug cargo release (the two major liabilities of existing ADCs) and thereby offers a paradigm shift in ADC technology. While the phase I studies described herein are focused upon NSCLC as the model, it is anticipated the novel ADC described herein will be equally effective for the treatment of other difficult cancers. Furthermore, since there exist many other suitable extracellular antigen/drug targets toward which this concept could be applied, success of the proof of concept studies described herein could open the door to an array of new promising ADCs. PUBLIC HEALTH RELEVANCE: We propose to develop the first cancer-targeted antibody-drug conjugate (ADC) that does not require either internalization or engineered drug release. This ADC presents a paradigm shift in ADC technology and is thereby anticipated to transform the future development of targeted therapies to treat cancer.