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：
10265375
负责人：
Jacob Houghton
金额：
$ 19.94万
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/10265375
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.

项目概要利用单克隆抗体 (mAb) 的分子成像方法已显示出巨大的前景，但其由于高辐射剂量和不方便的图像采集，扩展到临床实践通常很困难这些问题源于与生理学相匹配所必需的长寿命放射性同位素。 mAb 本身的特性，即体内半衰期长，旨在实现多种预定位平台的作用。通过将放射性同位素与单克隆抗体分离来消除剂量测定问题，已成功使用然而，在临床前模型中并在临床环境中取得了有限的成功，但仍需广泛应用和使用。可翻译的预定位系统需要稳健、模块化且兼容人类使用，并且所有迄今为止报告的平台尚未满足这些要求。迄今为止报道的预定位平台的预定位组件是非模块化的，内在不稳定性因此，我们相信利用反应性配体的巨大潜力。预靶向需要开发一个基于强大配体的平台，该配体适合我们建议开发一个满足这些要求的模块化方法并与人类使用兼容。通过使用“主：客”对葫芦[7]乌里尔（CB7）和金刚烷（Adma）的严格要求是已知的。与 Adma 配体快速形成强的非共价相互作用，表现出相似的动力学和稳定性我们相信这种宿主：客体对非常适合开发一种生物素和链霉亲和素。首先，CB7 可以很容易地功能化以连接到 mAb，同时。 Adma 可以轻松地功能化，用于使用任何 PET 放射性同位素进行放射性标记，从而提供必要的此外，这两种功能都不易外消旋或容易退化，这表明最后，据报道，含 CB7 和 Adma 的分子都适用于。鉴于 CB7 和基于 Adma 之间的特殊宿主：客体化学，人类以各种形式使用。化合物以及它们对成功预定位平台的上述标准的满意度，我们建议开发和评估基于这些化合物的预定位 PET 平台。项目是开发 CB7 结合的 mAb 以及用 PET 发射标记的含 Adma 的配体我们将对预定位组件进行严格的优化并测试我们的领先优势。如果成功的话，我们的预靶向系统可能是第一个使用体内癌症小鼠模型的候选者。以广泛适用于人类的方式充分利用预靶向 PET 成像的概念。这样做，我们可以改变基于抗体的 PET 成像的精准医疗过程。