Pretargeted Radioimmunotherapy Based on Bioorthogonal Click Chemistry

项目总结/摘要 这份建议书描述了一个培训计划，以促进我的学术生涯的发展， 癌症的靶向放射治疗策略。这个奖项的目的是鼓励我的独立 研究计划，这段时间将用来扩大我的科学知识和指导技能。 在K99奖期间，我将由杰森刘易斯博士指导，并由大卫Scheinberg博士共同指导。 博士刘易斯是一个国际公认的放射化学家和无机化学家与丰富的经验， 用于成像和治疗的放射性药物的合成、开发和临床转化 癌症。Scheinberg博士是纪念医院分子药理学和化学项目的主席 Sloan-Kettering癌症中心是开发和翻译靶向 放射免疫治疗刘易斯博士和Scheinberg博士都指导过许多科学家和临床研究员， 他们中的一些人已经过渡到成功的学术生涯。纪念斯隆-凯特琳癌症中心 （MSKCC）将提供机构支持，包括进行实验室研究的资源， 促进职业发展和继续教育的机会，以及开放的科学环境， 促进我实现目标所需的互动。 这个研究计划的总体目标是让我学习基础理论和实验室实践 靶向放射免疫治疗的背景下，开发一种新的战略， 放射免疫治疗结直肠癌这个建议直接从我以前的研究延伸而来 经验，因为我花了我的博士后奖学金的一个重要部分调查的应用程序， 逆电子需求狄尔斯-阿尔德“点击”化学既用于合成放射性药物的正电子 发射断层扫描（PET）和创建基于抗体的，预先靶向的PET成像策略。这 研究已经确定，Diels-Alder点击化学是用于快速、容易和有效地制备药物的极其有效的工具。 放射性药物的模块化结构;此外，这项工作表明，这种生物正交点击 化学可以用作高效预靶向PET成像策略的基础。 在为期2年的K99奖期间，该提案的具体目标是合成，化学 预靶向药物的分子组分的体外生物学表征 放射免疫治疗系统，特别是亲二烯体修饰的结肠直肠癌靶向huA 33抗体 以及带有四嗪的90 Y和177 Lu标记的放射性配体（特异性目标1）。具体目标为3- R 00年奖励期从该目标延伸，并研究体内药代动力学， 预靶向系统及其单个分子组分的生物分布（特定目标2），以及 确定这种预靶向放射免疫治疗策略在临床前模型中的体内功效， 结直肠癌（具体目标3）。

Project Summary/Abstract This proposal describes a training program to advance my academic career in the development of strategies for the targeted radiotherapy of cancer. The purpose of this award is to encourage my independent research program, and this period will be used to expand both my scientific knowledge and mentoring skills. During the K99 award period, I will be mentored by Dr. Jason Lewis and co-mentored by Dr. David Scheinberg. Dr. Lewis is an internationally recognized radiochemist and inorganic chemist with tremendous experience in the synthesis, development, and clinical translation of radiopharmaceuticals for both the imaging and therapy of cancer. Dr. Scheinberg, the chair of the Program in Molecular Pharmacology and Chemistry at Memorial Sloan-Kettering Cancer Center, is an expert in the development and translation of targeted radioimmunotherapeutics. Both Drs. Lewis and Scheinberg have mentored many scientists and clinical fellows, several of whom have transitioned to successful academic careers. Memorial Sloan-Kettering Cancer Center (MSKCC) will provide institutional support, including the resources to conduct laboratory research, opportunities to foster career development and continuing education, and an open scientific environment to foster the interaction required for me to achieve my goals. The overall goal of this research proposal is for me to learn the fundamental theory and laboratory practice of targeted radioimmunotherapy in the context of developing a novel strategy for the pretargeted radioimmunotherapy of colorectal cancer. The proposal extends directly from my previous research experience, as I have spent a significant portion of my postdoctoral fellowship investigating the application of inverse electron-demand Diels-Alder `click' chemistry both to the synthesis of radiopharmaceuticals for positron emission tomography (PET) and to the creation of antibody-based, pretargeted PET imaging strategies. This research has established that Diels-Alder click chemistry is an extremely effective tool for the rapid, facile, and modular construction of radiopharmaceuticals; further, this work has shown that this bioorthogonal click chemistry can be employed as the foundation of a highly effective pretargeted PET imaging strategy. The specific aim of this proposal during the 2-year K99 award period is the synthesis, chemical characterization, and in vitro biological characterization of the molecular components of the pretargeted radioimmunotherapy system, specifically the dienophile-modified, colorectal-cancer targeting huA33 antibody and the tetrazine-bearing, 90Y- and 177Lu-labeled radioligands (Specific Aim 1). The specific aims for the 3- year R00 award period extend from this aim and are to investigate the in vivo pharmacokinetics and biodistribution of the pretargeted system and its individual molecular components (Specific Aim 2) and to determine the in vivo efficacy of this pretargeted radioimmunotherapy strategy in preclinical models of colorectal cancer (Specific Aim 3).