Peptide-based PET quantifies target engagement of PD-L1 therapeutics
Peptide-based PET quantifies target engagement of PD-L1 therapeutics
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DOI：
10.1172/jci122216
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发表时间：
2019-02-01
影响因子：
15.9
通讯作者：
Nimmagadda, Sridhar
中科院分区：
文献类型：
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作者：
Kumar, Dhiraj;Lisok, Ala;Nimmagadda, Sridhar
免疫检查点疗法在癌症治疗中显示出巨大的前景。然而，一直缺乏评估其目标参与的工具，因此也缺乏预测其功效的能力。在这里，我们表明，靶向程序性死亡配体-1（PD-L1）的抗体治疗剂的靶向接合和肿瘤驻留动力学可以非侵入性地定量。在计算对接研究中，我们观察到PD-L1靶向单克隆抗体（atezolizumab、avelumab和durvalumab）和高亲和力PD-L1结合肽WL 12在PD-L1上具有共同的相互作用位点。在体内使用肽放射性示踪剂[Cu-64] WL 12，我们在多种异种移植模型中采用正电子发射断层扫描（PET）成像和生物分布研究，并证明了可变PD-L1表达及其通过atezolizumab、avelumab和durvalumab的饱和度可以独立于抗体的生物物理特性和药代动力学进行定量。接下来，我们使用[Cu-64] WL 12来评价治疗期间时间和剂量对肿瘤PD-L1未占用分数的影响。通过数学建模，这些定量测量使得能够预测实现治疗有效占用（定义为>90%）所需的抗体剂量。因此，我们表明，基于肽的PET是一种很有前途的工具，可用于优化使用PD-L1检查点抗体的剂量和治疗方案，并可用于提高治疗效果。
Immune checkpoint therapies have shown tremendous promise in cancer therapy. However, tools to assess their target engagement, and hence the ability to predict their efficacy, have been lacking. Here, we show that target engagement and tumor-residence kinetics of antibody therapeutics targeting programmed death ligand-1 (PD-L1) can be quantified noninvasively. In computational docking studies, we observed that PD-L1-targeted monoclonal antibodies (atezolizumab, avelumab, and durvalumab) and a high-affinity PD-L1-binding peptide, WL12, have common interaction sites on PD-L1. Using the peptide radiotracer [Cu-64]WL12 in vivo, we employed positron emission tomography (PET) imaging and biodistribution studies in multiple xenograft models and demonstrated that variable PD-L1 expression and its saturation by atezolizumab, avelumab, and durvalumab can be quantified independently of biophysical properties and pharmacokinetics of antibodies. Next, we used [Cu-64]WL12 to evaluate the impact of time and dose on the unoccupied fraction of tumor PD-L1 during treatment. These quantitative measures enabled, by mathematical modeling, prediction of antibody doses needed to achieve therapeutically effective occupancy (defined as >90%). Thus, we show that peptide-based PET is a promising tool for optimizing dose and therapeutic regimens employing PD-L1 checkpoint antibodies, and can be used for improving therapeutic efficacy.