Pretargeted Radioimmunotherapy Based on Bioorthogonal Click Chemistry

描述（由申请人提供）：此提案描述了一个培训计划，以促进我在癌症靶向放疗策略发展方面的学术生涯。这个奖项的目的是鼓励我的独立研究计划，这段时间将用于扩展我的科学知识和指导技能。在K99奖励期间，我将由Jason Lewis博士指导，David Scheinberg博士共同指导。Lewis博士是国际公认的放射化学家和无机化学家，在癌症成像和治疗的放射性药物的合成、开发和临床转化方面拥有丰富的经验。谢恩伯格博士是纪念斯隆-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开发和转化方面的专家。Drs。刘易斯和谢恩伯格指导了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。本次研究计划的总体目标是在开发结直肠癌预靶向放射免疫治疗新策略的背景下，学习靶向放射免疫治疗的基础理论和实验室实践。这个提议直接延伸了我以前的研究经验，因为我花了我的博士后研究的很大一部分逆电按需Diels-Alder“点击”化学的应用，既用于正电子发射断层扫描（PET）的放射性药物的合成，也用于基于抗体的，预靶向PET成像策略的创建。本研究表明，Diels-Alder点击化学是一种非常有效的工具，可以快速、简便、模块化地构建放射性药物；此外，这项工作表明，这种生物正交点击化学可以作为高效的预靶向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先靶向放射免疫治疗系统的分子组分的合成、化学表征和体外生物学表征，特别是二烯亲和修饰的结直肠癌靶向huA33抗体和含四氮、90Y和177lu标记的放射配体（specific aim 1）。为期3年的R00奖励期的具体目标是从这一目标延伸而来的，即研究预先靶向系统及其单个分子成分的体内药代动力学和生物分布（特异性目标2），并确定这种预先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（特异性目标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).