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

癌症转移涉及癌细胞从一个器官扩散到另一个器官，是90%癌症相关死亡的原因。目前的疗法不能有效地阻断转移，** 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对于癌细胞在转移过程中突破组织和血管屏障至关重要。针对这种“肌动蛋白成瘾”是这个 ** 项目的目标，它建立在我们对肌动蛋白有效天然抑制剂的详细了解之上。我们的多学科团队设计、合成并测试了新型肌动蛋白毒素类似物，这些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 ** 这些与肿瘤学中使用的抗体连接起来，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 ** 测量我们的ADC对肿瘤进展和转移的影响。

Cancer metastasis involves the spread of cancer cells from one organ to another and is the**cause 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. Dynamic**modifications of the actin cytoskeleton are essential for cancer cells to breakthrough tissue**and blood vessel barriers during metastasis. Targeting this "actin addiction" is the goal of this**project, which is built on our detailed knowledge of potent natural inhibitors of actin. Our**multidisciplinary team has designed, synthesized and tested novel actin toxin analogs that**block growth, motility and invasion of metastatic cancer cells in vitro. Currently, we are linking**these to antibodies used in oncology, and will test these novel ADCs in preclinical mouse**models of metastatic cancers relevant to each clinically used antibody. These studies will**measure effects of our ADCs on tumour progression and metastasis.