Pretargeted Radioimmunotherapy Based on Bioorthogonal Click Chemistry

描述（由申请人提供）：本提案描述了一个培训计划，以促进我在癌症靶向放射治疗策略开发方面的学术生涯。这个奖项的目的是鼓励我的独立研究计划，这段时间将用于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。刘易斯博士是国际公认的放射化学家和无机化学家，在癌症成像和治疗用放射性药物的合成、开发和临床转化方面拥有丰富的经验。Scheinberg博士是纪念斯隆-凯特琳癌症中心分子药理学和化学项目的主席，是靶向放射免疫治疗药物开发和翻译方面的专家。刘易斯和Scheinberg博士都指导过许多科学家和临床研究员，其中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，以及一个开放的科学环境，以促进我实现目标所需的互动。这项研究计划的总体目标是让我学习靶向放射免疫治疗的基本理论和实验室实践，为大肠癌的预靶向放射免疫治疗开发一种新的策略。该建议直接从我以前的研究经验，因为我花了我的博士后奖学金的一个重要部分，调查应用反电子需求狄尔斯-阿尔德“点击”化学既合成放射性药物的正电子发射断层扫描（PET）和创建抗体为基础的，pretargeted PET成像策略。这项研究已经确定，狄尔斯-阿尔德点击化学是一种非常有效的工具，用于快速，简便和模块化的放射性药物的建设;此外，这项工作表明，这种生物正交点击化学可以作为一个高度有效的预靶向PET成像策略的基础。在为期2年的K99奖励期内，该提案的具体目标是预靶向放射免疫治疗系统分子组分的合成、化学表征和体外生物学表征，特别是亲二烯体修饰的结肠直肠癌靶向huA 33抗体和带有四嗪的90 Y和177 Lu标记放射性配体（具体目标1）。3年R 00奖励期的具体目标是从这一目标延伸，研究预靶向系统及其单个分子组分的体内药代动力学和生物分布（具体目标2），并确定这种预靶向放射免疫治疗策略在结直肠癌临床前模型中的体内疗效（具体目标3）。

DESCRIPTION (provided by applicant): 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).