Spatially precise radio-chemo-immunotherapy using antibody conjugates

项目摘要/摘要 局部晚期癌症仍然是一个需要根除的治疗挑战。最成功的治疗方法是 这类患者继续将数十年前的经典细胞毒化疗与放射治疗相结合。而当 化疗-放射治疗改善肿瘤控制，使用非靶向药物增加正常组织损伤 照射野和全身毒性排除了进一步强化治疗的可能性。定向投放 通过限制高效放射增敏剂的方法可以改善化疗-放射治疗的范例 特别是在激活抗肿瘤免疫反应的同时照射的肿瘤靶点 避免使用正常组织。为了验证这一假设，我们利用抗体药物结合物(ADC)技术 受体限制性放射增敏。ADC将肿瘤靶向和杀伤的作用分为两个截然不同的角色 分子任务。靶向是通过抗体部分优先识别细胞表面受体来实现的 在肿瘤细胞上发现。在细胞表面受体结合后，ADC被内吞并附着在药物上 有效载荷弹头专门在目标单元内释放。ADC一直是由 将细胞毒药物与肿瘤靶向抗体联系起来。强效抗微管蛋白药物单甲基金雀异黄素E (MMAE)是最常见的ADC弹头。我们发现MMAE也具有放射增敏作用。前进到 使用我们的新型药物输送工具建立同基因小鼠模型，我们现在已经提供了第一个演示 MMAE产生依赖于CD8 T细胞的持久的辐射肿瘤控制，并通过 免疫检查点抑制。当抗体偶联时，MMAE受到靶向性限制。然而，一旦获释， MMAE具有剂量限制性毒性。为了实现日益精确的肿瘤放射增敏，我们使用 正交化策略和合理构造一流的辐射增敏模数转换器 损伤修复。作为概念证明，我们将抗EGFR抗体西妥昔单抗连接到ATM抑制剂AZD0156 (CETUX-AZD0156)。CETUX-AZD0156与EGFR+肿瘤特异性结合并递送药物，同时避免 癌旁正常组织。此外，CETUX-AZD0156对放射增敏和增加照射的肿瘤 控制力。基于这些发现，我们假设偶联到辐射增敏弹头上的抗ErbB ADC 提高放射增敏的空间精度，参与肿瘤免疫微环境(时间)。这个 这项建议的目标是通过评估放射增敏ADC弹头来系统地检验这一假设 使用我们创新的肿瘤靶向放射增敏ADC弹头工具箱建立小鼠肿瘤模型。在目标1中， 我们将测试Auristatins塑造照射时间和促进免疫原性肿瘤控制的能力。在……里面 目的2，我们将测试免疫疗法是否能增强放射增敏金黄色葡萄糖素以实现持久的肿瘤控制。 在目标3中，我们将测试一流的带有ATM抑制弹头的ADC，用于组织选择性放射增敏。 在先进的小鼠模型中严格测试辐射增敏ADC将为撤除 从非靶向放化疗转向分子导向的精确放化疗免疫疗法。

PROJECT SUMMARY/ABSTRACT Locally advanced cancers remain a therapeutic challenge to eradicate. The most successful treatments for such patients continue to combine decades old classical cytotoxic chemotherapies with radiotherapy. While chemo-radiotherapy improves tumor control, using non-targeted drugs increases normal tissue damage in the irradiated field along with systemic toxicities precluding further treatment intensification. Targeted delivery approaches can improve the chemo-radiotherapy paradigm by restricting highly potent radiosensitizers specifically to irradiated tumor targets that activate anti-tumor immune responses while simultaneously avoiding normal tissues. To test this hypothesis, we leveraged antibody drug conjugate (ADC) technology for receptor-restricted radiosensitization. ADCs split the roles of tumor targeting and killing into two distinct molecular tasks. Targeting is achieved by the antibody portion recognizing cell surface receptors preferentially found on tumor cells. Following cell surface receptor binding, ADCs are endocytosed and the attached drug payload warhead intracellularly released specifically within target cells. ADCs have been exclusively built by linking cytotoxic drugs to tumor targeting antibodies. The potent anti-tubulin drug monomethyl auristatin E (MMAE) is the most common ADC warhead. We discovered MMAE could also radiosensitize. Advancing to syngeneic murine models using our novel drug delivery vehicles, we have now provided the first demonstration that MMAE produces durable irradiated tumor control which is dependent on CD8 T cells and is enhanced by immune checkpoint inhibition. While antibody coupled, MMAE is target restricted. However once released, MMAE has dose limiting toxicities. To achieve increasingly precise tumor radiosensitization, we used orthogonal strategies and rationally constructed a first-in-class radiosensitizing ADC designed to inhibit DNA damage repair. As proof of concept, we conjugated anti-EGFR antibody cetuximab to ATM inhibitor AZD0156 (cetux-AZD0156). Cetux-AZD0156 specifically bound and delivered drug to EGFR+ tumors while avoiding adjacent peri-tumoral normal tissue. Moreover, cetux-AZD0156 radiosensitized and increased irradiated tumor control. Based on these findings, we hypothesize that anti-ErbB ADCs coupled to radiosensitizing warheads improve spatial precision of radiosensitization and engage the tumor immune microenvironment (TIME). The goals of this proposal are to methodically test this hypothesis by evaluating radiosensitizing ADC warheads in murine tumor models using our innovative toolbox of tumor-targeted radiosensitizing ADC warheads. In Aim 1, we will test the ability of auristatins to sculpt the irradiated TIME and promote immunogenic tumor control. In Aim 2, we will test if immunotherapies potentiate radiosensitizing auristatins to achieve durable tumor control. In Aim 3, we will test first-in-class ADCs with ATM inhibitor warheads for tissue selective radiosensitization. Rigorously testing radiosensitizing ADCs in advanced murine models will provide rationale for moving away from non-targeted chemo-radiotherapy toward molecularly guided precision radio-chemo-immunotherapies.