Novel Platform to achieve high avidity of heterodimers for targeted cancer imaging

 描述(申请人提供)：靶向癌症成像对于从根本上改善癌症患者的护理至关重要，目前的成像质量和诊断准确性在很大程度上依赖于靶向生物标记物和靶向配体(小分子、多肽和抗体)之间的亲和力/特异性。异二聚体配体同时将两个连接的配体与两个不同的靶向生物标记物结合，提供了一种广泛适用的方法，将低亲和力的配体(Kd亲和力~mm-µM)转换为高亲和力/特异性的配体(Kdavidity~NM)。这种高亲和力的杂二聚体通常是通过：1)合成多个具有不同连接基的杂二聚体；以及2)单独测量它们的体外亲和力。然而，不同实验室的癌细胞类型可能会有所不同，因此受体密度和距离也会相应地变化，因此亲和力测量和异源二聚体文库合成(如果实验室没有这样的文库)需要再次单独进行。更令人失望的是，一旦感兴趣的受体发生变化，就需要重复整个过程(包括新的异源二聚体文库合成和亲和力测量)。因此，缺乏通用的快速优化平台被认为是异二聚体配体在临床前和/或临床研究中广泛和常规使用的主要障碍之一。为了克服这一问题，我们提出了第一个高通量平台，可以方便地制备高亲和力的异源二聚体，可以广泛应用于各种双生物标记物组合和不同的肿瘤。这种广泛应用的技术将显著加速和/或增强使用异二聚体的靶向肿瘤成像，特别是在以下情况下：1)低丰度表达的靶向生物标记物(S)；以及2)没有高亲和力(和/或特异性)的单价配体的情况。

 DESCRIPTION (provided by applicant): Targeted cancer imaging is critical for fundamental improvements in cancer patient care and current imaging quality and diagnosis accuracy rely heavily on the affinity/specificity between the targeted biomarker and targeting ligand (small molecules, peptides and antibodies). A heterodimeric ligand that simultaneously associates two linked ligands with two different targeting biomarkers provides a broadly applicable approach to convert low affinity ligands (Kdaffinity ~ mM - µM) to the one with high avidity/specificity (Kdavidity ~ nM). Such high avidity heterodimers are usually pursued by: 1) synthesizing a number of heterodimers with different linkers; and 2) measuring their in vitro avidities individually. However the type of cancer cells may vary in different labs and then the receptors density and distance varies accordingly, so that avidity measurements and heterodimer library synthesis (if such a library is not available in the lab) need to be conducted individually again. Even more disappointing is the fact that, once the receptor of interest changes, repeating the entire procedure (including new heterodimer library synthesis and avidity measurement) is required. Therefore, a lack of a generic and rapid optimization platform has been considered as one of the major barriers for the widespread and routine utilization of heterodimeric ligand for preclinical and/or clinical studies. In order to overcome this problem, we propose the first, high-throughput platform for the easy preparation of high avidity heterodimers, which can be broadly applied to various dual-biomarker combinations and different tumors. Such widespread applicable technology will significantly accelerate and/or enhance targeted cancer imaging using heterodimers, particularly in the following situations: 1) targeted biomarker(s) which are expressed in low abundance; and 2) situations where no high affinity (and/or specificity) monovalent ligands are available.