A new paradigm for antibody-directed conjugates

描述（由申请人提供）：非小细胞肺癌（NSCLC）是最常见和最致命的癌症之一，然而，目前晚期NSCLC的护理标准仅能适度改善总生存期或生活质量。因此，对于治疗NSCLC的新的有效疗法存在显著未满足的需求。在此，我们描述了一种创新的新型抗体药物偶联物（ADC）靶向NSCLC。所提出的ADC的核心创新来自于在药物货物（一种新型甾体糖苷）和癌症靶向mAb（抗FXYD5）之间使用稳定的共价接头，两者都作用于癌细胞的细胞外表面。这种优雅简单的设计消除了对ADC内化或工程药物货物释放（现有ADC的两个主要缺点）的需要，从而提供了ADC技术的范式转变。虽然本文所述的I期研究集中于NSCLC作为模型，但预期本文所述的新型ADC对于治疗其他困难的癌症将同样有效。此外，由于存在许多其他合适的细胞外抗原/药物靶标，可以对其应用该概念，因此本文所述的概念验证研究的成功可以为一系列新的有前途的ADC打开大门。 公共卫生相关性：我们建议开发第一种不需要内化或工程药物释放的癌症靶向抗体-药物偶联物（ADC）。这种ADC代表了ADC技术的范式转变，因此预计将改变靶向治疗癌症的未来发展。

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.