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，以推动我在靶向癌症靶向放射疗法策略发展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，这一时期将用于扩大我的科学知识和指导能力。在K99奖项期间，我将由Jason Lewis博士指导，并由David Scheinberg博士合作。刘易斯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，发育和临床翻译方面具有丰富的经验。 Scheinberg博士是纪念斯隆 - 凯特林癌症中心分子药理学和化学计划的主席，是针对性放射免疫治疗药的开发和翻译专家。两个博士。刘易斯（Lewis）和舍因堡（Scheinberg）指导了许多科学家和临床研究员，其中一些人已转移到成功的学术职业。纪念斯隆 - 凯特林癌症中心（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，以促进我实现目标所需的互动。这项研究建议的总体目标是让我学习有针对性放射免疫疗法的基本理论和实验室实践，这是为了制定有预定于结直肠癌的放射疗法的新策略。该提案直接从我以前的研究经验中延伸，因为我花了很大一部分的博士后奖学金，这些奖学金调查了逆电子需求diels-alder-alder-alder“单击”化学的应用，这两者都可以综合放射性武器来构成正电子发射术（PET）（PET），并在基于抗体基于基于抗体的基于基于抗体的宠物宠物图像的策略中的创建。这项研究已经确定，Diels-Alder Click Chemistry是一种非常有效的工具，用于快速，易于模块化的放射性药物。此外，这项工作表明，这种生物正交的点击化学可以用作高效有效的宠物成像策略的基础。该提案在2年K99奖励期间的具体目的是对有限的放射免疫疗法系统的分子成分的合成，化学表征和体外生物学表征，特别是Dienophile-Modified的结直肠癌，靶向HuA33抗体的结直肠癌和甲氮齐氮的特定目的，特定于90y-andecerigy randiol and rand rabior and rabior）rabiol（1777777777777777）。 3年R00奖励期的具体目的是从这个目标延伸，并且是研究预先靶标系统及其个体分子成分的体内药代动力学和生物分布（具体目的2），并确定这种预处理的良好的放射疗法策略的体内效率（特定于良性的良好模型）。