A new paradigm for antibody-directed conjugates

抗体导向缀合物的新范例

• 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
• 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

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) 是迄今为止最常见和致命的癌症之一，目前晚期 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，对治疗 NSCLC 的新有效疗法存在显着未满足的需求。在此，我们描述了一种针对 NSCLC 的创新型新型抗体药物偶联物 (ADC)。所提出的 ADC 的核心创新源于在药物货物（一种新型甾体糖苷）和癌症靶向单克隆抗体（抗 FXYD5）之间使用稳定的共价连接体，两者均作用于癌细胞的细胞外表面。这种优雅简单的设计消除了 ADC 内化或工程药物释放的需要（现有 ADC 的两个主要缺点），从而实现了 ADC 技术的范式转变。虽然本文描述的I期研究集中于NSCLC作为模型，但预计本文描述的新型ADC对于治疗其他疑难癌症同样有效。此外，由于存在许多其他合适的细胞外抗原/药物靶标可以应用该概念，因此本文描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。 公共健康相关性：我们建议开发第一个针对癌症的抗体药物偶联物（ADC），不需要内化或工程药物释放。该 ADC 代表了 ADC 技术的范式转变，因此有望改变癌症靶向疗法的未来发展。