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Small pretargeting constructs with infinite affinity for radiochelates

对放射性螯合物具有无限亲和力的小型预靶向构建体

基本信息

批准号：
7647975
负责人：
GEORGE PEARSON SMITH
金额：
$ 16.66万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7647975
关键词：
Abbreviations Adverse effects Affinity Amides Antibodies Bacteriophages Behavior Binding Blood Blood Circulation Cells Chelating Agents Complex Coupled Couples Cysteine Data Diagnosis Diagnostic Imaging Disease Drug Kinetics Escherichia coli Future Generic Drugs Home environment Image In Vitro Isomerism Isotopes Kinetics Libraries Life Link Malignant Neoplasms Metals Mus Mutagenesis Normal tissue morphology Operative Surgical Procedures Optics Output Patients Peptides Performance Phage Display Play Population Positioning Attribute Preparation Procedures Property Radiation Radiation therapy Radioactive Radioisotopes Random Peptide Libraries Research Residual state Resistance Side Specificity Staging Streptavidin Sulfhydryl Compounds Technology Testing Therapeutic Tissues Treatment Protocols Variant Virion base cancer cell cancer imaging experience follow-up immunogenic improved in vivo mutant novel pharmacokinetic characteristic public health relevance purge residence streptavidin-binding peptide success tumor

项目摘要

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.

描述（由申请人提供）：预靶向是放射成像和放射治疗的显著进步。它允许具有优异的特异性和亲和力但药物动力学性质差的亲肿瘤抗体和其他靶向分子与小的放射性效应物（例如，放射性螯合物），具有上级药代动力学行为。关键是双功能预靶向探针，其中靶向模块（例如，肿瘤亲合抗体）与另一个特异性捕获放射性效应物的模块连接。预靶向疗法分两个阶段进行。在第一种方法中，施用双功能探针并允许其凭借其靶向模块在体内归巢至肿瘤或其他靶细胞或组织。尽管由于其不良的药代动力学，非靶向探针可能需要一天或更长时间才能清除身体，但它不是放射性的，因此受试者不会经历辐射负担，并且不会损失短寿命同位素。一旦探针被清除，第二阶段就开始了：放射性效应物的施用。它从体内迅速清除，但在其短暂停留期间，其中一些被靶结合的双功能探针分子通过其效应器捕获模块捕获。因此，可以将有效的放射成像或放射治疗有效载荷递送到目标，同时对受试者施加非常低的背景或非共价偶联体内治疗辐射负荷。迄今为止，效应子捕获模块是大分子。我们希望证明小的靶向肽也可以发挥同样的作用。使用新的噬菌体展示模块肽共价技术，我们将选择快速耦合的肽，选择性地捕获效应子，并共价连接到具有模块优良药代动力学特性的小放射性螯合效应子。这样的肽重靶向将具有优于大分子效应子捕获模块的重要优点：（1）它们易于遗传融合或化学偶联（如果合适的话，以多个拷贝）至任何靶向模块;单个通用放射性螯合物可以与稳定的非放射性双功能探针的无限库一起使用。(2)它们可以化学合成，使完全合成的预靶向探针成为可能;镜像肽将捕获相反的放射性螯合物异构体，并对蛋白水解降解具有抗性。(3)它们不会具有免疫原性，因此可以在同一受试者中使用一次以上。癌症医生越来越依赖于放射性探针，专门针对病人的癌细胞。放射性探针既可用于对癌症进行成像以进行有效诊断，也可用于向细胞特异性提供致命辐射以帮助治愈疾病，而无需进行侵入性手术。这项研究的目的是改进和简化“预瞄准”，这是一种使用探头的新程序，可以显着锐化诊断图像并减少患者遭受的有害辐射副作用。