The Tetrazine Ligation for Efficient 18F Labeling and Pretargeted Imaging/Radiotherapy of Cancer

用于高效 18F 标记和癌症预靶向成像/放射治疗的四嗪连接

基本信息

批准号：
8900694
负责人：
Peter Stephen Conti
金额：
$ 34.66万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-23 至 2017-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Proposed is the development of a simple, fast and universal strategy for incorporating radionuclides into biomolecules for applications for cancer imaging and pretargeted immunotherapy. The strategy is based on a bioconjugation reaction developed in the Fox laboratories: the reaction between tetrazines and trans-cyclooctenes (TCO). The fast kinetics of the 'tetrazine-TCO ligation' (k2 e 250,000 L*mol/s-1) enable fast reactivity at low micromolar concentrations within minutes and without an excess of either reactant. This fast reactivity provides unprecedented opportunities for protein and antibody modification and for performing reactions in vivo. This proposal involves collaborative effort from the Molecular Imaging Center (MIC) at University of Southern California (USC) and the Fox group (UD). An objective of this application is to use the tetrazine ligation to develop efficient methods for the construction of 18F labeled proteins with high specific activity for cancer imaging. Moreover, we will also develop a novel pretargeted imaging and radioimmunotherapy method that will allow for universal and straightforward tagging of monoclonal antibodies (mAbs) with an imaging/therapeutic isotope without severe radiation exposure towards normal organs. To achieve these objectives, we will first develop bioconjugation reactions with fast kinetics and robust in vivo stability based on the tetrazine-TCO ligation. As the fast kinetics of tetrazine-TCO ligation enable fast reactivity at low micromolar concentrations within minutes and without an excess of either reactant, we will transform this reaction into efficient methods that could be used for the construction of 18F labeled proteins with high specific activity. At last, we will als establish a chemical pretargeting approach that for pretargeted imaging/radioimmunotherapy of cancer based on the tetrazine-TCO ligation and anti-EphB4 antibody. In summary, in this application, we are developing efficient methods for proteins labeling with 18F, and a chemical pretargeting approach that could be used for pretargeted imaging and radioimmunotherapy of breast cancer. The feasibility of these approaches will be tested with EphB4 antibody, F(ab')2, and Fab. The success of these novel imaging and therapy approached could enable breast cancer diagnosis, make possible direct monitoring of responses to therapeutic interventions, and may significantly improve breast cancer treatment efficacy. Moreover, these newly developed approaches could have important applications in many other cancer types, and thus have a significant clinical impact on a very large number of cancer patients

描述（由申请人提供）：提出的是一种简单，快速和普遍的策略，该策略将放射性核素纳入生物分子中，以进行癌症成像和预先实现的免疫疗法。该策略基于Fox实验室中发展的生物缀合反应：四嗪和反式环弦烯之间的反应（TCO）。 “四嗪-TCO连接”（K2 E 250,000 L*mol/s-1）的快速动力学能够在几分钟内低微摩尔浓度的快速反应性，而没有任何反应物。这种快速反应性为蛋白质和抗体修饰和体内反应提供了前所未有的机会。该建议涉及来自南加州大学（USC）和FOX集团（UD）的分子成像中心（MIC）。该应用的一个目的是利用四嗪连接来开发有效的方法，用于构建具有高特异性活性以进行癌症成像的18F标记的蛋白质。此外，我们还将开发一种有预先的成像和放射免疫疗法方法，该方法将允许对单克隆抗体（MAB）的通用和直接标记，并具有成像/治疗同位素，而无需严重的辐射辐射。为了实现这些目标，我们将首先基于四嗪-TCO连接，以快速动力学和稳健的体内稳定性发展生物缀合反应。作为Tetrazine-TCO的快速动力学连接能够在几分钟内低微摩尔浓度下的快速反应性，而没有任何反应物，我们将把这种反应转化为有效的方法，可用于构建具有高特异性活性的18F标记的蛋白质。最后，我们将建立一种化学预先定位的方法，该方法用于基于四嗪-TCO连接和抗EPHB4抗体的癌症成像/放射免疫疗法。总而言之，在此应用中，我们正在开发具有18F蛋白质标记的有效方法，以及一种可用于预先构型成像和乳腺癌的放射免疫疗法的化学预定方法。这些方法的可行性将使用EPHB4抗体F（AB'）2和Fab进行测试。这些新型成像和治疗方法的成功可以实现乳腺癌的诊断，可以直接监测对治疗干预措施的反应，并可能显着提高乳腺癌治疗效果。此外，这些新开发的方法可能在许多其他癌症类型中具有重要的应用，因此对大量癌症患者产生重大临床影响