A new paradigm for antibody-directed conjugates

抗体导向缀合物的新范例

基本信息

批准号：
8124678
负责人：
James R. Prudent
金额：
$ 19.91万
依托单位：
CENTROSE, LLC
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-09 至 2012-03-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8124678
关键词：
A549 ATPase inhibitory protein Alkylation Animals Antibodies Antigens Applications Grants Binding Cancer Model Cancer cell line Cells Characteristics Chronic Clinical Complex Data Development Dose Drug Delivery Systems Engineering Evaluation Event Face Funding Future Glycosides Human In Vitro Lead Length MCF7 cell Malignant Neoplasms Modeling Monoclonal Antibodies Mus Na(+)-K(+)-Exchanging ATPase Non-Small-Cell Lung Carcinoma Outcome Pharmaceutical Preparations Phase Process Proteins Quality of life Rattus Reaction Rivers Schedule Signal Transduction Specificity Staging Staining method Stains Structural Models Surface Technology Testing Toxic effect Ursidae Family Xenograft procedure antibody conjugate anticancer activity base cancer cell cross reactivity cytotoxicity design effective therapy extracellular genotoxicity human tissue immunogenicity in vitro testing in vivo innovation nonhuman primate novel phase 1 study phase 2 study scale up standard of care stoichiometry success tris(2-carboxyethyl)phosphine

项目摘要

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.

描述（由申请人提供）：非小细胞肺癌（NSCLC）是最常见和致命的癌症之一，当前的晚期NSCLC护理标准仅提供了整体生存或生活质量的适度改善。因此，对新的有效疗法的治疗NSCLC存在很大的未满足。本文中，我们描述了一种创新的新型抗体药物结合物（ADC），以靶向NSCLC。所提出的ADC的核心创新源于吸毒货物（一种新型的类固醇糖苷）和靶向癌症的MAB（抗FXYD5）之间的稳定共价接头，这两种MAB（抗FXYD5）作用于癌细胞外的细胞外面上。这种优雅的简单设计消除了对ADC内部化或工程毒品释放的需求（现有ADC的两个主要负债），从而提供了ADC技术的范式转变。虽然本文所述的I期研究集中在NSCLC作为模型上，但预计本文所述的新型ADC对于治疗其他困难癌症的治疗也同样有效。此外，由于还有许多其他合适的细胞外抗原/药物靶标可以应用此概念，因此此处描述的概念证明的成功可以为一系列新的有希望的ADC打开大门。公共卫生相关性：我们建议开发不需要内在化或工程药物释放的第一个以癌症为目标的抗体 - 药物结合物（ADC）。该ADC提出了ADC技术的范式转变，因此预计将改变有针对性疗法的癌症的未来发展。