Complementation Dependent Enzyme Prodrug Therapy Enables Targeted Activation of Prodrug on HER2-Positive Cancer Cells.
Complementation Dependent Enzyme Prodrug Therapy Enables Targeted Activation of Prodrug on HER2-Positive Cancer Cells.
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DOI：
10.1021/acsmedchemlett.2c00394
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发表时间：
2022-10
影响因子：
4.2
通讯作者：
Christine S. Nervig;Samuel T Hatch;S. Owen
中科院分区：
文献类型：
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作者：
Christine S. Nervig;Samuel T Hatch;S. Owen
几十年来，人们一直在探索将小分子细胞毒素直接输送到患病细胞的抗体。在抗体导向的酶前药疗法(ADEPT)中，抗体携带激活肿瘤部位的无毒前药的酶。然而，这一策略在临床上失败了，原因是与酶系统激活前药相关的靶外毒性。我们在这里描述了一种抗体-片段裂解酶平台的设计，该平台在与HER2结合后恢复活性，允许小分子前体药物的位点特异性激活。我们评估了有效靶向和互补的融合构建体库，以确定最有希望的分裂酶对。在显色底物、荧光底物和前药底物中筛选出最优的底物专一性。该系统对HER2阳性细胞的评估显示，激活的前药的毒性是单独前药治疗的7倍。针对已知的临床靶点展示这一策略的潜力，为肿瘤学中独特的治疗平台提供基础。
Antibodies have been explored for decades for the delivery of small molecule cytotoxins directly to diseased cells. In antibody-directed enzyme prodrug therapy (ADEPT), antibodies are armed with enzymes that activate nontoxic prodrugs at tumor sites. However, this strategy failed clinically due to off-target toxicity associated with the enzyme prematurely activating prodrug systemically. We describe here the design of an antibody-fragment split enzyme platform that regains activity after binding to HER2, allowing for site-specific activation of a small molecule prodrug. We evaluated a library of fusion constructs for efficient targeting and complementation to identify the most promising split enzyme pair. The optimal pair was screened for substrate specificity among chromogenic, fluorogenic, and prodrug substrates. Evaluation of this system on HER2-positive cells revealed 7-fold higher toxicity of the activated prodrug over prodrug treatment alone. Demonstrating the potential of this strategy against a known clinical target provides the basis for a unique therapeutic platform in oncology.