Development and Validation of a Robust and Modular Host: Guest-based Pretargeting Platform

强大的模块化主机的开发和验证：基于访客的预定位平台

基本信息

批准号：
9896402
负责人：
Jacob Houghton
金额：
$ 23.93万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-17 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896402
关键词：
3-Dimensional Adamantane Alder plant Amantadine Anti-CEA Antibody Antibodies Antibody Therapy Antigen Targeting Binding Biodistribution Biotin Bispecific Antibodies Cancer Model Chelating Agents Chemicals Chemistry Clinical Development Drug Kinetics Drug or chemical Tissue Distribution Effectiveness Electrons Equilibrium Exhibits Face Future Goals Growth Half-Life Human Image In Situ Injections Investigation Isotopes Kinetics Label Lead Length Ligands Low Dose Radiation Masks Monoclonal Antibodies Mus Patients Physiological Polyethylene Glycols Positron-Emission Tomography Pre-Clinical Model Property Radiation Dose Unit Radioconjugate Radioimmunotherapy Radioisotopes Radiolabeled Reporting Series Side Streptavidin System Temperature Testing Time Tracer Tumor Tissue Validation Xenograft procedure base clinical practice design dosimetry imaging approach imaging platform imaging probe immunogenicity immunoreactivity in vivo in vivo evaluation lead candidate molecular imaging mouse model novel precision medicine prevent racemization radioligand satisfaction stem success tumor uptake vector

项目摘要

Project Summary Molecular imaging approaches that utilize monoclonal antibodies (mAbs) have shown great promise, but their extension into clinical practice is often difficult due to high radiation doses and inconvenient image acquisition intervals. These problems stem from the long-lived radioisotopes that are necessary to match the physiological properties of the mAbs themselves, namely a long in vivo half-life. Several pretargeting platforms, which aim to eliminate the dosimetry concerns by decoupling the radioisotope from the mAb, have been utilized successfully in preclinical models and with limited success in a clinical setting. However, to be widely applicable and translatable, pretargeting systems need to be robust, modular, and compatible for human use, and all of the platforms reported to date have not met those requirements. Broadly, the limitations of the predominant pretargeting platforms reported to date are non-modularity of the pretargeting components, intrinsic instability of the reactive ligands, or immunogenicity. Thus, we believe that taking advantage of the immense potential of pretargeting necessitates the development of a platform that is based on robust ligands that are amenable to a modular approach and are compatible with human use. We propose to develop a platform that meets these rigorous demands by utilizing the “host:guest” pair curcubit[7]uril (CB7) and adamantane (Adma). CB7 is known to rapidly form a strong, noncovalent interaction with Adma ligands, exhibiting similar kinetic and stability properties as biotin and streptavidin. We believe that this host:guest pair is ideal for development of a pretargeting platform for several reasons. First, CB7 may be easily functionalized for attachment to mAbs while Adma can be easily functionalized for radiolabeling with essentially any PET radioisotope, providing the requisite modularity. Additionally, neither functionality susceptible to racemization or prone to degradation, suggesting they are suitably robust. Finally, both CB7- and Adma-containing molecules have been reported as suitable for human use in various forms. Given the exceptional host:guest chemistry between CB7 and Adma-based compounds as well as their satisfaction of the above criteria for successful pretargeting platforms, we propose to develop and evaluate a pretargeted PET platform based on these compounds. The goal of the proposed project is to develop CB7-conjugated mAbs as well as Adma-containing ligands labeled with PET emitting radioisotopes. We will carry out a rigorous optimization of the pretargeting components and test our lead candidates using in vivo murine models of cancer. If successful, our pretargeting system could be the first to fully seize upon this concept of pretargeted PET imaging in a way that is widely applicable for human use. In doing so, we could alter the course of antibody-based PET imaging for precision medicine.

项目摘要利用单克隆抗体（mAb）的分子成像方法表现出巨大的希望，但是它们由于高辐射剂量和不便的图像获取，通常很难扩展到临床实践间隔。这些问题源于与生理相匹配的长期放射性同位素 mabs本身的特性，即体内半衰期。几个有限的平台，旨在通过将放射性同位素与mAb解耦消除剂量测定问题，已成功使用在临床前模型中，在临床环境中成功有限。但是，要广泛适用，可翻译的预定系统必须是强大的，模块化的，并且可以兼容人类的使用，以及所有迄今为止报告的平台尚未满足这些要求。广泛地，主要的局限性迄今为止报告的有预量平台是预先构成组件的非模块化，固有的不稳定性反应性配体或免疫原性。那就是我们相信，利用有预定的需要开发基于适合一个适合的强大配体的平台模块化方法，与人类使用兼容。我们建议开发一个符合这些的平台使用“主机：客人” curcubit [7] uril（CB7）和Adamantane（ADMA）提出严格的要求。 CB7是已知的快速与ADMA配体形成强，非共价的相互作用，表现出相似的动力学和稳定性作为生物素和链霉亲和素的特性。我们认为，这位主人：来宾对是开发的理想选择有限的平台有几个原因。首先，CB7很容易函数化以固定在mab上时 ADMA可以很容易地使用任何PET放射性同位素来进行放射性标记，从而提供必要的模块化。此外，既不容易受到种族化或容易降解的功能，这表明他们很健壮。最后，据报道，含CB7的分子都适合人类使用各种形式。鉴于出色的主机：CB7和基于ADMA之间的访客化学反应我们提出了化合物以及对成功预定平台的上述标准的满意基于这些化合物开发和评估一个有预量的宠物平台。提议的目标项目将开发与宠物排放的标记的CB7偶联的单元和含ADMA的配体放射性同位素。我们将对有限的组件进行严格的优化，并测试我们的铅候选人使用体内鼠模型的癌症模型。如果成功的话，我们的预定系统可能是第一个充分抓住了这种有限的宠物成像的概念，该概念广泛适用于人类使用。在这样做，我们可以改变基于抗体的PET成像的精确药物的过程。