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

• 批准号: 10456858
• 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
• 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/10456858
• 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; translational potential; tumor; uptake; vector

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）的分子成像方法已经显示出很大的前景，但是其 由于高辐射剂量和不方便的图像获取 的间隔这些问题源于长寿命的放射性同位素，这些同位素是与生理上的 mAb本身的特性，即长的体内半衰期。几个预定位平台，旨在 通过将放射性同位素与mAb解耦来消除剂量测定问题，已成功使用 在临床前模型中，并且在临床环境中的成功有限。然而，为了广泛适用， 可翻译的预定位系统需要是健壮的、模块化的，并且与人类使用兼容， 迄今报告的平台没有达到这些要求。一般来说，占主导地位的 迄今为止报道的预靶向平台是预靶向组件的非模块化，固有的不稳定性 或者免疫原性。因此，我们认为，利用 预靶向需要开发一种基于稳健配体的平台， 模块化的方法，并与人类使用兼容。我们建议开发一个平台，以满足这些 严格的要求，利用“主：客”对curcubit[7]脲（CB7）和金刚烷（Adma）。CB7已知 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 生物素和链霉亲和素的性质。我们相信，这种主宾配对是发展一个 预定位平台有几个原因。首先，CB 7可以容易地被官能化以连接到mAb， Adma可以很容易地官能化，用于基本上任何PET放射性同位素的放射性标记，提供必要的放射性标记。 模块化此外，对外消旋化敏感或易于降解的官能团都不存在，这表明 它们是适当坚固的。最后，已报道含CB7和Adma的分子都适合于 人类以各种形式使用。考虑到CB7和基于Adma的特殊宿主：客体化学 化合物以及它们满足成功的预靶向平台的上述标准，我们建议 开发和评估基于这些化合物的预靶向PET平台。建议的目标 项目是开发CB7缀合的mAb以及用PET发射标记的含Adma的配体。 放射性同位素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 使用癌症的体内鼠模型的候选物。如果成功的话，我们的预定位系统可能是第一个 以广泛适用于人类使用的方式完全抓住这种预先靶向PET成像的概念。在 这样做，我们可以改变基于抗体的PET成像的过程，用于精确医学。