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

项目摘要 利用单抗的分子成像方法已经显示出巨大的前景，但他们的 由于较高的辐射剂量和不方便的图像采集，将其推广到临床实践往往是困难的 间隔时间。这些问题源于长寿的放射性同位素，这些同位素是匹配生理上的 单抗本身的性质，即体内半衰期较长。几个预定位平台，旨在 通过将放射性同位素与mAb去偶联来消除剂量学问题，已经成功地利用了 在临床前模型中，在临床环境中取得的成功有限。然而，要想得到广泛的应用和 可翻译的预瞄准系统需要健壮、模块化，并与人类使用兼容，并且所有 据报道，到目前为止，平台还没有达到这些要求。从广义上讲，主要的 迄今为止报告的预靶向平台是非模块化的预靶向组件，固有的不稳定性 反应性配体，或免疫原性。因此，我们相信，利用互联网的巨大潜力 前靶向需要开发一种基于强健的配体的平台，这些配体可以服从于 模块化方法，并与人类使用兼容。我们建议开发一个满足这些要求的平台 通过使用“主：客”对Curcubit[7]uril(CB7)和金刚烷(Adma)提出了严格的要求。CB7是已知的 快速地与ADMA配体形成强烈的非共价相互作用，表现出类似的动力学和稳定性 生物素和链霉亲和素等性质。我们相信，这对主宾组合是开发 预定位平台有几个原因。首先，CB7可以很容易地功能化以连接到单抗上，而 ADMA可以很容易地功能化，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 模块化。此外，官能团既不容易外消旋，也不容易降解，这表明 他们相当健壮。最后，含有CB7和ADMA的分子都被报道为适合于 人类以各种形式使用。鉴于特殊的东道主：CB7和ADMA之间的客体化学 化合物以及它们对上述成功预靶向平台的标准的满意度，我们建议 开发和评价基于这些化合物的预靶向PET平台。建议的目标是 该项目是开发CB7结合的单抗以及含有ADMA的PET发射标记的配体 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 候选人使用体内的小鼠癌症模型。如果成功，我们的预定位系统可能是第一个 充分利用这一概念，以一种广泛适用于人类使用的方式进行预靶向PET成像。在……里面 这样做，我们可以改变基于抗体的PET成像的进程，用于精确医学。

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.