Spatially precise radio-chemo-immunotherapy using antibody conjugates

使用抗体偶联物进行空间精确的放射化学免疫治疗

• 批准号: 10585803
• 负责人: Sunil J Advani
• 金额: $ 53.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-01 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585803
• 关键词: Antibodies; Antibody-drug conjugates; Binding; CD8-Positive T-Lymphocytes; Cancer Model; Cancer Patient; Carcinogens; Cell Surface Receptors; Cell membrane; Cells; Cetuximab; Clinical; Coupled; Cytotoxic Chemotherapy; Cytotoxic agent; Cytotoxin; DNA Damage; DNA Repair; Data; Dose Limiting; ERBB2 gene; Epidermal Growth Factor Receptor; Goals; Grant; Immune; Immune checkpoint inhibitor; Immune response; Immuno-Chemotherapy; Immunocompetent; Immunotherapy; Implant; Ionizing radiation; Irradiated tumor; Link; Locally Advanced Malignant Neoplasm; Modeling; Molecular; Morbidity - disease rate; Mus; Normal tissue morphology; Organ; Pathway interactions; Patients; Pharmaceutical Preparations; Quality of life; Radiation induced damage; Radiation therapy; Radiation-Sensitizing Agents; Radio; Radiosensitization; Role; Schedule; Systemic Therapy; Techniques; Technology; Testing; Therapeutic; Therapeutic Index; Time; Tissues; Toxic effect; Trastuzumab; Treatment-related toxicity; Tubulin; adaptive immune response; anti-tumor immune response; antibody conjugate; carcinogenesis; checkpoint inhibition; chemoradiation; chemotherapy; clinically relevant; curative treatments; cytotoxic; cytotoxicity; delivery vehicle; design; drug development; efficacy testing; immune cell infiltrate; immunogenic; improved; improved outcome; inhibitor; innovation; interest; mouse model; neoplastic cell; novel therapeutics; pre-clinical; precision medicine; programmed cell death protein 1; receptor; receptor binding; response; success; systemic toxicity; targeted delivery; tool; tumor; tumor specificity; tumor xenograft; tumor-immune system interactions

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.

项目总结/摘要 局部晚期癌症仍然是根除的治疗挑战。最成功的治疗方法 这些患者继续将联合收割机与几十年前的经典细胞毒性化疗相结合。而 化疗-放疗改善了肿瘤控制，使用非靶向药物增加了正常组织损伤， 照射野沿着全身毒性，妨碍进一步强化治疗。靶向递送 方法可以通过限制高效放射增敏剂来改善化学-放射疗法范例 特异性地针对激活抗肿瘤免疫应答同时 避开正常组织为了验证这一假设，我们利用抗体药物偶联物（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种不同的作用， 分子任务通过抗体部分优先识别细胞表面受体实现靶向 在肿瘤细胞上发现的。在细胞表面受体结合后，ADC被内吞，并且附着的药物 有效载荷弹头在靶细胞内特异性释放。ADC由以下公司独家构建： 将细胞毒性药物与肿瘤靶向抗体连接起来。强效抗微管蛋白药物monomethyl auristatin E （MMAE）是最常见的ADC弹头。我们发现MMAE也有放射增敏作用。前进到 使用我们的新型药物递送载体的同基因小鼠模型，我们现在已经提供了第一个演示 MMAE产生持久的辐射肿瘤控制，其依赖于CD 8 T细胞，并通过以下方式增强： 免疫检查点抑制。当抗体偶联时，MMAE是靶标限制性的。但是一旦被释放， MMAE具有剂量限制性毒性。为了实现越来越精确的肿瘤放射增敏，我们使用 正交策略，并合理构建了一流的放射增敏ADC，旨在抑制DNA 损伤修复作为概念证明，我们将抗EGFR抗体西妥昔单抗与ATM抑制剂AZD 0156偶联， （cetux-AZD 0156）。Cetux-AZD 0156特异性结合并递送药物至EGFR+肿瘤，同时避免 邻近肿瘤周围正常组织。此外，cetux-AZD 0156放射增敏并增加了照射的肿瘤 控制基于这些发现，我们假设抗ErbB ADC与放射增敏弹头偶联， 提高放射增敏的空间精度并参与肿瘤免疫微环境（TIME）。的 这项建议的目标是通过评估ADC弹头的辐射增敏性，系统地检验这一假设， 小鼠肿瘤模型使用我们的创新工具箱肿瘤靶向放射增敏ADC弹头。在目标1中， 我们将测试澳瑞他汀塑造辐射TIME和促进免疫原性肿瘤控制的能力。在 目的2，我们将测试免疫疗法是否增强放射增敏奥瑞他汀以实现持久的肿瘤控制。 在目标3中，我们将测试具有ATM抑制剂弹头的一流ADC用于组织选择性放射增敏。 在高级小鼠模型中严格测试放射增敏ADC将为放弃提供依据 从非靶向的化学-放射疗法到分子引导的精确放射-化学-免疫疗法。