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%与癌症相关的死亡的原因。目前的治疗方法不能有效地阻断转移，我们发明的新型肌动蛋白靶向ADC将解决这一未得到满足的需求。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是必不可少的。瞄准这种“肌动蛋白成瘾”是这个项目的目标，该项目建立在我们对肌动蛋白天然有效抑制物的详细了解的基础上。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，这些类似物在体外可以阻断转移癌细胞的生长、运动和侵袭。目前，我们正在将这些与肿瘤学中使用的抗体联系起来，并将在与每个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。这些研究将衡量我们的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 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.