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

项目摘要。 药物靶向结合的完整性和适当地处理细胞异质性对于 抗癌治疗的成功。免疫检查点疗法也不例外，因为它很差 理解为什么大多数患者(70%)没有反应。目前的免疫检查点治疗患者 分层(肿瘤免疫组织化学)使结果的投影高度不可预测以确定 个别病人的合适候选人资格。PD-L1总靶点水平及其在治疗中的作用 肿瘤上的抗体(MAbb)对生物活性至关重要。然而，技术要非侵入性地测量 这些级别不可用。我们提出了一种新的方法，可以用来预测在每个可识别的 通过实时测量靶点表达水平和药物靶点接合来检测肿瘤。我们将执行这些 评价治疗性单抗与免疫检查点程序死亡配体-1(PD-L1)结合的研究 构成当今免疫肿瘤学治疗努力的支柱的蛋白质。所有批准的PD-L1 治疗学是单抗。单抗疗法对药效学测量构成了独特的挑战，因为 它们的大小和对肿瘤的穿透有限。基于T细胞的外周血药效学测量 血液被用于免疫检查点疗法的剂量发现。然而，病变的占有率并没有 在体内使用单抗计算，部分原因是它们延长了循环时间，这可以通过以下方法解决 取而代之的是使用多肽。此外，肿瘤中单抗的浓度受到动态变化的显著影响。 靶基因表达的变化，以及肿瘤的内在参数，如间质压力和外在的 与其复数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PD-L1总水平、PD-L1单抗在所有可识别病变处的传递、保留和接合。正电子 发射断层扫描(PET)越来越多地被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表达的体内动态评估，并可以改善对 这些疗法。然而，它们还没有被用于PD-L1疗法的评估。我们最近 开发高亲和力的人PD-L1特异性PET成像肽，提供高图像对比度以指导 免疫检查点疗法。这项提案的目标是建立我们的PD-L1 PET示踪剂性能，以 测量肿瘤总PD-L1水平，评价不同单抗对肿瘤的药物传递和PD-L1结合， 并确定单抗的剂量-暴露-反应，以加强和加速免疫检查点治疗 管理层。这项新技术提供了一种经验方法，以确定谁将受益于 免疫检查点疗法，协助/启用/推进剂量选择和优化，协助药物开发和 评估和确定偏离目标的责任，以减少患者观察到的不良反应 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.