Pretargeted Radioimmunotherapy Based on Bioorthogonal Click Chemistry

基于生物正交点击化学的预靶向放射免疫治疗

基本信息

批准号：
8700927
负责人：
Brian Matthew Zeglis
金额：
$ 10.77万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2015-01-27
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8700927
关键词：
90Y Adverse effects Affinity Alder plant Animals Antibodies Antibody Affinity Antibody Specificity Antigens Award Background Radiation Behavior Biodistribution Biological Blood Chemistry Clinical Colorectal Cancer Complement Complication Continuing Education Coupled Data Deposition Development Disease model Dose Drug Kinetics Electrons Environment Equilibrium Exposure to Fellowship Fostering Foundations Future GPA33 gene Glycols Goals Hand Health Image Immunoconjugates In Vitro Individual Injection of therapeutic agent Investigation Isotopes Knowledge Label Laboratories Laboratory Research Lead Learning Length Ligation Link Magnetic Resonance Imaging Malignant Neoplasms Measurement Measures Memorial Sloan-Kettering Cancer Center Mentors Methodology Molecular Monitor Mus Organ Patients Pharmacology Phase Positron Positron-Emission Tomography Pre-Clinical Model Radiation Radiation therapy Radioactivity Radioimmunotherapy Radioisotopes Radiolabeled Radiopharmaceuticals Reaction Research Research Proposals Resources Scientist Series Site Specificity Structure System Targeted Radiotherapy Testing Therapeutic Therapeutic Effect Therapeutic Uses Therapeutic antibodies Tissues Training Training Programs Translations Work Xenograft procedure antibody conjugate base cancer cell cancer imaging cancer therapy career career development chemical synthesis cytotoxic design design and construction experience immunoreactivity improved in vivo insight molecular imaging novel novel strategies programs radiochemical radioligand radiotracer research study scaffold skills small molecule subcutaneous theories tool tumor uptake vector

项目摘要

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).

描述（由申请人提供）：该提案描述了一项培训计划，旨在促进我在制定癌症靶向放射治疗策略方面的学术生涯。该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，我将得到Jason Lewis博士的指导和David Scheinberg博士的共同指导。 Lewis 博士是一位国际公认的放射化学家和无机化学家，在用于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。 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转化方面的专家。两位博士。刘易斯和沙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。本研究计划的总体目标是让我在开发结直肠癌预靶向放射免疫治疗的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。该提案直接延伸自我之前的研究经验，因为我花了很大一部分博士后研究金来研究逆电子需求狄尔斯-阿尔德“点击”化学在正电子发射断层扫描（PET）和放射性药物合成中的应用。创建基于抗体的预靶向 PET 成像策略。这项研究表明，Diels-Alder 点击化学是一种极其有效的工具，可用于快速、简便和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用作高效预靶向 PET 成像策略的基础。该提案在两年 K99 奖励期内的具体目标是预靶向放射免疫治疗系统分子成分的合成、化学表征和体外生物学表征，特别是亲双烯体修饰的结直肠癌靶向 huA33 抗体和含四嗪、90Y 和 177Lu 标记的放射性配体（具体目标 1）。 3年R00奖励期的具体目标从这一目标延伸出来，是研究预定位系统及其各个分子成分的体内药代动力学和生物分布（具体目标2），并确定这种预定位放射免疫疗法的体内疗效结直肠癌临床前模型的策略（具体目标 3）。