权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

实现异二聚体高亲合力的新平台，用于靶向癌症成像

基本信息

批准号：
9719581
负责人：
Dexing Zeng
金额：
$ 5.49万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9719581
关键词：
Novel Platform achieve avidity heterodimers

项目摘要

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.

描述（由申请人提供）：靶向癌症成像对于癌症患者护理的根本改善至关重要，目前的成像质量和诊断准确性严重依赖于靶向生物标志物和靶向配体（小分子、肽和抗体）之间的亲和力/特异性。同时将两个连接的配体与两个不同的靶向生物标志物结合的异二聚体配体提供了一种广泛适用的方法，将低亲和力配体（Kd亲和力~ mM - μM）转化为具有高亲合力/特异性的配体（Kd亲和力~ nM）。这种高亲合力异二聚体通常通过以下方式来实现：1）合成许多具有不同接头的异二聚体;和2）单独测量它们的体外亲合力。然而，癌细胞的类型在不同的实验室中可能会有所不同，然后受体密度和距离也会相应变化，因此需要再次单独进行亲合力测量和异源二聚体文库合成（如果实验室中没有这种文库）。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合力测量）。因此，缺乏通用和快速优化平台已被认为是广泛和常规利用异二聚体配体进行临床前和/或临床研究的主要障碍之一。为了克服这个问题，我们提出了第一个高通量平台，用于容易地制备高亲合力异二聚体，其可以广泛地应用于各种双生物标志物组合和不同的肿瘤。这种广泛适用的技术将显著加速和/或增强使用异二聚体的靶向癌症成像，特别是在以下情况下：1）以低丰度表达的靶向生物标志物;和2）没有高亲和力（和/或特异性）单价配体可用的情况。