Small pretargeting constructs with infinite affinity for radiochelates

描述(申请人提供)：定位是放射成像和放射治疗领域的一项显著进步。它允许肿瘤亲和性抗体和其他靶向分子具有良好的特异性和亲和力，但药代动力学性质较差，可与具有优越药代动力学行为的小放射性效应物(例如，放射性螯合物)结合使用。关键是一种双功能预靶向探针，其中靶向模块(例如，肿瘤亲和抗体)连接到另一个专门捕获放射性效应器的模块。然后，预靶向疗法分两个阶段进行。在第一种方法中，通过其靶向模块，双功能探针被给予并允许在体内定位于肿瘤或其他靶细胞或组织。尽管由于药代动力学较差，非靶向探针可能需要一天或更长时间才能清除体内，但它没有放射性，因此受试者没有辐射负担，也不会损失短暂的同位素。一旦探测器通过，第二阶段就实施了：放射性效应器的管理。它从体内迅速清除，但在其短暂的停留期间，其中一些通过其效应器捕获模块被靶向结合的双功能探针分子捕获。因此，可以将有效的放射成像或放射治疗有效载荷递送到靶区，同时对受试者施加非常低的本底或非配对共价体内治疗性放射负荷。迄今为止，效应器捕获模块一直是大分子的。我们希望证明小的靶向多肽也能起到同样的作用。利用新型噬菌体展示模组多肽共价技术，我们将筛选出快速偶联、选择性捕获效应、共价结合到具有良好药代动力学特性的小分子放射螯合效应物的多肽。与大分子效应器捕获模块相比，L重定目标多肽具有重要的优势：(1)它们易于通过基因融合或化学偶联(如果合适，可以有多个副本)与任何靶向模块；单一的通用放射螯合物可以与无限的稳定、非放射性双功能探针库一起使用。(2)它们可以化学合成，使完全合成的预靶向探针成为可能；镜像多肽将捕获相反的放射性螯合异构体，并抵抗蛋白质降解。(3)它们不具有免疫原性，因此可以在同一对象中多次使用。 与公共健康相关癌症医生越来越依赖于专门检测患者癌细胞的放射性探测器。放射性探针既可以用于对癌症进行有效诊断，也可以专门向细胞传递致命辐射，以帮助治愈疾病，这两种方法都不需要侵入性手术。这项研究的目的是改进和简化“预靶向”，这是一种使用探针的新程序，可以显著提高诊断图像的清晰度，减少患者遭受的有害辐射副作用。

DESCRIPTION (provided by applicant): Pretargeting is a notable advance in radioimaging and radiotherapy. It allows tumor-avid antibodies and other targeting molecules that have excellent specificity and affinity but poor pharmacokinetic properties to be used in conjunction with small radioactive effectors (e.g., radiochelates) that have superior pharmacokinetic behavior. The key is a bifunctional pretargeting probe, in which the targeting module (e.g., tumor-avid antibody) is linked to another module that specifically captures the radioactive effector. A pretargeting regimen then plays out in two stages. In the first, the bifunctional probe is administered and allowed to home in vivo to the tumor or other target cells or tissue by virtue of its targeting module. Although it may take a day or more for non-targeted probe to clear the body because of its poor pharmacokinetics, it is not radioactive, so the subject experiences no radiation burden and there is no loss of short-lived isotope. Once the probe has cleared, the second stage is implemented: administration of the radioactive effector. It clears from the body rapidly, but during its brief residence some of it is captured by target-bound bifunctional probe molecules via their effector-capture modules. Thus can an effective radioimaging or radiotherapy payload be delivered to the target while imposing a very low background or non- Couples covalently in vivo therapeutic radiation burden on the subject. hel To date, effector-capture modules have been macromolecular. We hope to demonstrate that small Targeting peptides can serve just as well. Using novel phage display module Peptide covalent technology, we will select peptides that couple rapidly, effector-capture selectively, and covalently to small radiochelate effectors with module excellent pharmacokinetic characteristics. Such peptides l retargeti would have important advantages over macromolecular effector-capture modules: (1) They are easy to fuse genetically or couple chemically (in multiple copies if appropriate) to any targeting module; a single generic radiochelate could be used with an unlimited repertoire of stable, non-radioactive bifunctional probes. (2) They can be synthesized chemically, making fully synthetic pretargeting probes possible; mirror-image peptides would capture the opposite radiochelate isomer and be resistant to proteolytic degradation. (3) They will not be immunogenic, and therefore can be used more than once in the same subject. PUBLIC HEALTH RELEVANCE Cancer doctors increasingly rely on radioactive probes that home specifically to a patient's cancer cells. The radioactive probes can be used both to image the cancers for effective diagnosis and to deliver lethal radiation specifically to the cells to help cure the disease, both without invasive surgery. The purpose of this research is to improve and simplify "pretargeting," a new procedure for using probes that can dramatically sharpen diagnostic images and reduce the harmful radiation side-effects patients suffer.