Small pretargeting constructs with infinite affinity for radiochelates

描述（由申请人提供）：预靶向是放射成像和放射治疗的显着进步。它允许肿瘤抗体和其他靶向分子，具有良好的特异性和亲和力，但药物动力学特性差，与小放射性效应器（例如，放射性螯合物），具有优越的药代动力学行为联合使用。关键是一种双功能的预靶向探针，其中靶向模块（例如，肿瘤抗体）与另一个模块连接，该模块专门捕获放射性效应物。然后，预先定位方案分两个阶段进行。在第一种方法中，双功能探针通过其靶向模块被施用并允许在体内返回到肿瘤或其他靶细胞或组织。虽然由于非靶向探针的药代动力学较差，它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，也没有短寿命同位素的损失。一旦探测器被清除，第二阶段就开始了：放射性效应物的管理。它从体内迅速清除，但在其短暂停留期间，一些被目标结合的双功能探针分子通过其效应捕获模块捕获。因此，可以将有效的放射成像或放射治疗载荷传递到目标，同时对受试者施加非常低的本底或非偶共价体内治疗辐射负担。迄今为止，效应捕获模块都是大分子的。我们希望证明小的靶向肽也能起到同样的作用。利用新型噬菌体展示模块肽共价技术，我们将选择快速偶联的肽，选择性地捕获效应，并与具有模块优异药代动力学特性的小放射性螯合效应物共价。与大分子效应捕获模块相比，这种多肽重靶向具有重要的优势：(1)它们很容易在基因上融合或化学上偶联（如果合适的话，在多个拷贝中）到任何靶向模块；单一的通用放射性螯合物可以与无限的稳定，非放射性双功能探针一起使用。(2)它们可以化学合成，使完全合成的预靶向探针成为可能；镜像肽将捕获相反的放射螯合异构体，并抵抗蛋白水解降解。(3)它们不具有免疫原性，因此可以在同一受试者中多次使用。

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.