Non-invasive Quantification of Dose-Exposure-Response of PD-L1 Therapeutics at the Tumor

项目摘要。 药物-靶点结合的完整性和适当解决细胞异质性对于药物治疗是至关重要的。 抗癌治疗的成功。免疫检查点疗法也不例外，因为它 了解为什么大多数患者（70%）没有反应。当前免疫检查点治疗患者 分层（肿瘤免疫组织化学）使得结果的预测对于确定 个别患者的合适候选人。总PD-L1目标水平及其与治疗的关系 肿瘤中的抗体（mAb）对于生物活性至关重要。然而，非侵入性测量技术 这些级别是不可用的。我们提出了一种新的方法，可用于预测疗效在每一个可识别的 通过实时测量靶点表达水平和药物-靶点结合来治疗肿瘤。我们将执行这些 评价治疗性mAb与程序性死亡配体-1（PD-L1）（一种免疫检查点）结合的研究 这种蛋白质构成了当今免疫肿瘤学治疗工作的支柱。所有获批的PD-L1 治疗剂是mAb。mAb治疗对药效学测量提出了独特的挑战， 它们的大小和对肿瘤的有限渗透。外周血中基于T细胞的药效学测量 血液用于免疫检查点治疗剂的剂量确定。然而，病变占用水平并没有 使用mAb在体内计算，部分原因是其循环时间延长，这可以通过以下方法解决： 使用肽代替。此外，mAb的肿瘤浓度受动态变化的显著影响。 靶点表达的变化以及肿瘤固有的参数，如间质压，和外源性 与其复杂PK相关的参数。这些发现强调了开发非侵入性工具的必要性， 评估所有可识别病变处的总PD-L1水平、PD-L1 mAb的递送、保留和接合。正电子 发射断层摄影术（PET）越来越多地用于指导癌症免疫治疗。精密PET放射性示踪剂 可以提供PD-L1表达的动态体内评估，并可以改善PD-L1治疗的反应和结果。 这些疗法。然而，它们尚未用于PD-L1治疗剂的评价。我们最近 开发了一种高亲和力的人PD-L1特异性PET成像肽，可提供高图像对比度， 免疫检查点疗法本提案的目标是确定我们的PD-L1 PET示踪剂性能， 测量总肿瘤PD-L1水平，评价不同mAb在肿瘤处的药物递送和PD-L1结合， 并确定mAb的剂量-暴露-反应，以增强和加速免疫检查点治疗 管理这项新技术能够提供一种经验手段，以确定谁将受益于 免疫检查点疗法、辅助/使能/推进剂量选择和优化、辅助药物开发和 评估和识别脱靶负债，以减少在患者中观察到的不良反应 接受免疫检查点治疗。

Project Summary. Completeness of drug-target engagement and appropriately addressing cellular heterogeneity are critical for the success of anti-cancer therapeutics. Immune checkpoint therapeutics are no exception, for it is poorly understood why the majority of patients (70%) do not respond. Current immune checkpoint therapy patient stratification (tumor immunohistochemistry) makes projection of results highly unpredictable for determining suitable candidacy of individual patients. Total PD-L1 target levels and their engagement by therapeutic antibodies (mAbs) at the tumor are crucial for biological activity. However, technology to non-invasively measure these levels is unavailable. We propose a novel method that can be used to predict efficacy at every identifiable tumor by measuring target expression levels and drug-target engagement in real-time. We will perform these studies to evaluate binding of therapeutic mAbs to programmed death ligand-1 (PD-L1), an immune checkpoint protein that forms the backbone of therapeutic efforts in immuno-oncology today. All the approved PD-L1 therapeutics are mAbs. mAb therapeutics pose unique challenges to pharmacodynamics measurements due to their size and limited penetration into tumors. T cell-based pharmacodynamic measurements from peripheral blood are used in dose-finding of immune checkpoint therapeutics. However, lesion occupancy levels have not been calculated in vivo using mAbs, in part due to their prolonged circulation time, which could be addressed by using a peptide instead. Moreover, tumor concentrations of mAbs are significantly influenced by dynamic changes in target expression, as well as parameters intrinsic to tumor, such as interstitial pressure, and extrinsic parameters related to their complex PK. These findings underscore the need to develop non-invasive tools to assess total PD-L1 levels, delivery, retention and engagement of PD-L1 mAbs at all identifiable lesions. Positron emission tomography (PET) is increasingly used to guide cancer immunotherapy. Precision PET radiotracers can provide dynamic in vivo assessment of PD-L1 expression, and can improve responses and outcomes of these therapies. However, they have not been used for the evaluation of PD-L1 therapeutics. We recently developed a high-affinity human PD-L1-specific PET imaging peptide that provides high image contrast to guide immune checkpoint therapy. The goals of this proposal are to establish our PD-L1 PET tracer performance to measure total tumor PD-L1 levels, evaluate drug delivery and PD-L1 engagement at the tumor by different mAbs, and determine dose-exposure-response of mAbs to enhance and accelerate immune checkpoint therapy management. This new technology enables provision of an empirical means to determine who will benefit from immune checkpoint therapy, aid/enable/advance dose selection and optimization, assist drug development and evaluation, and identification of off-target liabilities to reduce adverse effects that are observed in patients receiving immune checkpoint therapeutics.