Pretargeted Radioimmunotherapy Based on Bioorthogonal Click Chemistry

项目摘要/摘要 这项建议描述了一个培训计划，以促进我的学术生涯发展 癌症靶向放射治疗的策略。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颁奖期间，我将由Jason Lewis博士指导，David 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 影像和治疗用放射性药物的合成、开发和临床翻译 癌症的威胁。Scheinberg博士，纪念馆分子药理学和化学项目主席 斯隆-凯特琳癌症中心，是开发和翻译目标词的专家 放射免疫疗法。刘易斯博士和舍恩伯格博士都曾指导过许多科学家和临床研究员， 其中几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，包括开展实验室研究的资源， 促进职业发展和继续教育的机会，以及开放的科学环境 培养我实现目标所需的互动。 本研究方案的总体目标是学习基础理论和实验室实践。 在为预靶向制定新战略的背景下进行靶向放射免疫治疗 结直肠癌的放射免疫治疗。这项建议直接从我以前的研究中延伸出来 经验，因为我花了很大一部分博士后研究应用 反电子需求Diels-Alder化学在正电子放射性药物合成中的应用 发射断层扫描(PET)和创建基于抗体的、预靶向的PET成像策略。这 研究表明，Diels-Alder点击化学是一种非常有效的工具，可以快速、方便和 放射性药物的模块化结构；此外，这项工作已经表明，这种生物正交点击 化学可以作为高效的前靶向PET成像策略的基础。 在两年的K99获奖期内，这项建议的具体目标是合成、化学 预靶向分子组成的表征和体外生物学特性 放射免疫治疗系统，特别是以huA33抗体为靶点的双亲性修饰的结直肠癌 以及含四嗪、90Y和177Lu标记的放射性配体(特定目标1)。三个项目的具体目标是： R00年授权期从这一目标延伸而来，旨在研究阿司匹林的体内药代动力学和 前靶系统及其单个分子成分的生物分布(特定目标2)和 确定这一预靶向放射免疫治疗策略在临床前模型中的体内疗效 结直肠癌(特定目标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).