Development of antibody-drug conjugates that use actin-targeting warheads

开发使用肌动蛋白靶向弹头的抗体药物偶联物

• 批准号: 508358-2017
• 负责人: Allingham, John
• 金额: $ 4.98万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Collaborative Health Research Projects
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=621892
• 关键词: Development; antibody; drug; conjugates; use

Cancer metastasis involves the spread of cancer cells from one organ to another and is thecause of 90% of cancer-related deaths. Current therapies fail to block metastasis effectively,and our invention of novel actin-targeted ADCs will address this unmet need. Dynamicmodifications of the actin cytoskeleton are essential for cancer cells to breakthrough tissueand blood vessel barriers during metastasis. Targeting this "actin addiction" is the goal of thisproject, which is built on our detailed knowledge of potent natural inhibitors of actin. Ourmultidisciplinary team has designed, synthesized and tested novel actin toxin analogs thatblock growth, motility and invasion of metastatic cancer cells in vitro. Currently, we are linkingthese to antibodies used in oncology, and will test these novel ADCs in preclinical mousemodels of metastatic cancers relevant to each clinically used antibody. These studies willmeasure effects of our ADCs on tumour progression and metastasis.

癌症转移是指癌细胞从一个器官转移到另一个器官，90%的癌症相关死亡是由癌症转移引起的。目前的治疗方法不能有效地阻止转移，而我们发明的新型肌动蛋白靶向adc将解决这一未满足的需求。肌动蛋白细胞骨架的动态修饰是癌细胞在转移过程中突破组织和血管屏障所必需的。针对这种“肌动蛋白成瘾”是这个项目的目标，这是建立在我们对肌动蛋白强效天然抑制剂的详细了解。我们的多学科团队设计、合成和测试了新的肌动蛋白毒素类似物，可以在体外阻断转移性癌细胞的生长、运动和侵袭。目前，我们正在将这些抗体与肿瘤学中使用的抗体联系起来，并将在与每种临床使用的抗体相关的转移性癌症的临床前小鼠模型中测试这些新型adc。这些研究将测量adc对肿瘤进展和转移的影响。