Anti-PSCA allosteric CLAMPs

描述(由申请人提供)： 我们建议开发一种新的癌症治疗方法，使用变构试剂将前药浓缩到靶细胞周围。我们以适配子为基础的设计，称为钳夹(用于医疗或微量分析程序的顺式连接适配子)，是一种具有两种功能的核酸，人们可以用它来发展变构。当变构钳结合两个靶点中的一个时，它被激活以结合第二个靶点。然后，激活的适体可以与显像剂或治疗剂结合。变构的性质确保了治疗剂只集中在第一夹持靶蛋白高表达的位置。这最大限度地减少了非特异性相互作用的影响，如果治疗剂直接与钳子相连，就会导致全身毒性。因此，变构钳有望对靶细胞具有高度的选择性。 变构钳将被开发成针对转移性前列腺癌细胞，并将被设计为需要这些细胞的两个特征。这些特征是高表达前列腺干细胞抗原(PSCA)和高表达前列腺特异性抗原(PSA)蛋白酶。变构钳将被设计为仅当菊粉与PSCA结合时才结合菊粉。菊粉可以用一种被设计为PSA的特定底物的多肽前药进行衍生化，PSA将其裂解，释放出一种有毒的试剂，如阿霉素或thapsigargin。PSCA和PSA联合存在的要求应该提供高选择性的治疗。 由于变构钳将癌细胞表面连接到菊粉，通过用Tc99m等造影剂标记菊粉，钳介导的治疗可以与成像技术无缝对接。作为一种小核酸，该夹子将比目前用于选择性细胞靶向的单抗更容易穿透固体组织。因此，我们预计这项技术将比目前的治疗方法提供更高的选择性和更高的杀灭前列腺癌细胞的效率。

DESCRIPTION (provided by applicant): We propose to develop a novel cancer therapy using allosteric reagents for concentrating a prodrug around a target cancer cell. Our aptamer-based design, called a CLAMP (cis-linked aptamers for medical or microanalytical procedures), is a nucleic acid with two functionalities with which one can develop allostery. When an allosteric CLAMP binds one of its two targets, it is activated to bind its second target. The activated aptamer can then bind an imaging agent or a therapeutic agent. The property of allostery ensures that the therapeutic agent is only concentrated in locations of high expression of the first CLAMP target. This minimizes the effect of nonspecific interactions that would cause systemic toxicity if the therapeutic agents were directly linked to the CLAMP. Thus, the allosteric CLAMP is expected to be highly selective for the target cells. The allosteric CLAMP will be developed to target metastatic prostate cancer cells and will be designed to require two characteristics of these cells. These characteristics are high expression of prostate stem cell antigen (PSCA) and high expression of the prostate specific antigen (PSA) protease. The allosteric CLAMP will be designed to bind inulin only when it is bound to PSCA. The inulin can be derivatized with a peptido prodrug that is designed as a specific substrate of PSA, which cleaves it to release a toxic agent such as doxorubicin or thapsigargin. The requirement for a combined presence of PSCA and PSA should provide the therapy with high selectivity. Because the allosteric CLAMP will link the cancer cell surface to inulin, the CLAMP-mediated therapy can be seamlessly interfaced with imaging technology by labeling the inulin with a contrast agent such as Tc99m. Being a small nucleic acid, the CLAMP will more readily penetrate solid tissues than will monoclonal antibodies, which are the currently used technologies for selective cell targeting. Thus, we anticipate this technology will provide higher selectivity and higher efficiency of killing prostate cancer cells than current therapies.