Precision Delivery and Imaging to Enhance Solid Tumor Therapy

精准输送和成像增强实体瘤治疗

• 批准号: 9974485
• 负责人: Jan Eugeniusz Schnitzer
• 金额: $ 266.71万
• 依托单位: PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-08 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9974485
• 关键词: Active Biological Transport; Annexin A1; Antibodies; Antibody-drug conjugates; Antineoplastic Agents; Binding; Biodistribution; Blood Vessels; Bypass; Cancer Patient; Caveolae; Cells; Cisplatin; Clinic; Clinical; Clinical Trials; Cyclic GMP; Cytotoxic agent; Development; Diagnostic; Disease; Disseminated Malignant Neoplasm; Dose; Drug Delivery Systems; Drug resistance; Endothelial Cells; Endothelium; Environment; Exhibits; Genes; Goals; Grant; Hematologic Neoplasms; Human; Image; Immunoconjugates; Lesion; Life Style; Lung; Malignant Neoplasms; Mammary Neoplasms; Mediating; Modeling; Molecular; Multi-Drug Resistance; Neoplasm Metastasis; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase I Clinical Trials; Platinum; Pre-Clinical Model; Preclinical Testing; Prevention; Primary Neoplasm; Program Research Project Grants; Pump; Radiation therapy; Radiolabeled; Safety; Solid; Solid Neoplasm; Surface; System; Testing; Therapeutic; Therapeutic Agents; Therapeutic Index; Tissues; Toxic effect; Toxicology; Translating; Treatment Efficacy; Tumor Tissue; Vascular Endothelium; War; Work; antibody conjugate; base; cancer imaging; cancer therapy; chemoradiation; chemotherapy; cytotoxic; disease diagnosis; dosage; drug efficacy; drug sensitivity; expectation; first-in-human; imaging agent; imaging study; improved; in vivo; individual patient; intravenous injection; molecular targeted therapies; novel; novel therapeutics; patient variability; pre-clinical; precision drugs; precision medicine; precision oncology; programs; research clinical testing; targeted imaging; targeted treatment; tool; treatment optimization; tumor

PROJECT 1 SUMMARY Existing antibody-based interventions for cancer rely on passive delivery of the circulating drug that depends on a large concentration gradient across the semi-permeable wall of blood vessels to get inside tumors. The forces driving the drug from the bloodstream into tumors result in sub-optimal delivery and poor access to tumor cells, in part because endothelial cells (EC) forming the vascular wall constitute a significant, limiting barrier. We intend to boost precision delivery into primary and metastatic tumors by overcoming the vascular EC barrier through a highly precise, active transport pathway that we discovered through proteomic imaging and named the caveolae pumping system. The approach proposed here to enhance delivery goes well beyond typical so- called 'active targeting' of antibodies. Our lead humanized antibody against Annexin A1 (hAnnA1), a tumor- specific antibody concentrated in EC caveolae, not only binds its intended target but is actually the first antibody to penetrate solid tumors actively, rapidly and specifically. It does so even at very low dosages and reaches unprecedented intra-tumoral concentrations well beyond the highest blood levels after injection. It is now time to test this unprecedented immunotargeting in humans. We propose here to develop a radiolabeled humanized mAnnA1 to detect and destroy primary and metastatic lesions. Major aims of this project are to: 1-2) evaluate in vivo delivery and efficacy of novel caveolae-targeting radioimmunoconjugates in hard-to-treat metastatic tumor models of breast cancer; 3) test the effectiveness of caveolae pumping in human tumor blood vessels using PDX and novel human IVM tumor models; and translate hAnnA1 towards clinical testing. We will 4) determine here the degree to which caveolae can be targeted to pump radiolabeled antibodies across vascular EC to concentrate them inside solid tumors as means to improve image-guided drug delivery and enhance their efficacy. Antibodies will be provided by Core B and radiolabeled with assistance provided by Core D for preclinical work. Several mammary tumor models will be used to assess the ability of radiolabeled hAnnA1 to target primary and metastatic tumors via imaging services provided in Core C. We will study by intravenously injected hAnnA1 with advanced multimodality in vivo imaging to quantify and optimize precision transvascular delivery and tumor penetration. As the utility of caveolae targeting in humans requires AnnA1 expression in tumor EC caveolae, we will use Core C imaging services to compare vascular expression of AnnA1 in preclinical tumor models and human tumors. To translate our findings for clinical testing, we will test hAnnA1, humanize further if needed and partner with NCI's NExT program for cGMP production, quality control and toxicology of hAnnA1. With Core D, Project 3 will optimize hAnnA1 radiolabeling necessary to conduct a first-in-human imaging trial as a direct result of successful translation of our findings from Project 1 into the clinic.

项目 1 摘要 现有的基于抗体的癌症干预措施依赖于循环抗体的被动传递 药物依赖于半透壁上的大浓度梯度 进入肿瘤内部的血管。推动药物从血液进入的力量 肿瘤导致递送不理想并且难以接近肿瘤细胞，部分原因是 形成血管壁的内皮细胞（EC）构成了重要的限制性屏障。 我们打算通过克服以下问题来提高原发性和转移性肿瘤的精准递送： 通过高度精确的主动运输途径，我们可以突破血管 EC 屏障 通过蛋白质组成像发现并命名为小凹泵系统。这 这里提出的增强交付的方法远远超出了典型的所谓“主动” 抗体的“靶向”。我们针对膜联蛋白 A1 (hAnnA1) 的领先人源化抗体， 肿瘤特异性抗体集中在 EC 小凹中，不仅结合其预期靶点 但实际上是第一个主动、快速、特异性地穿透实体瘤的抗体。 即使在非常低的剂量下它也能达到前所未有的肿瘤内效果 浓度远远超过注射后的最高血液浓度。现在是测试的时候了 这种对人类前所未有的免疫靶向作用。我们在此建议开发一个 放射性标记的人源化 mAnnA1 可检测并破坏原发性和转移性病变。 该项目的主要目标是：1-2）评估新型药物的体内递送和功效 难以治疗的转移性肿瘤模型中的小窝靶向放射免疫缀合物 乳腺癌; 3) 测试小窝泵入人体肿瘤血液的有效性 使用 PDX 和新型人类 IVM 肿瘤模型的血管；并将 hAnnA1 翻译为 临床测试。我们将 4) 在此确定可以针对小窝的程度 将放射性标记抗体泵入血管内皮细胞，将其浓缩在固体内 肿瘤作为改善图像引导药物输送和增强 他们的功效。抗体将由 Core B 提供并在协助下进行放射性标记 由 Core D 提供用于临床前工作。多种乳腺肿瘤模型将用于 通过评估放射性标记的 hAnnA1 靶向原发性和转移性肿瘤的能力 核心 C 中提供的成像服务。我们将通过静脉注射 hAnnA1 进行研究 先进的多模态体内成像，用于量化和优化精确的经血管 递送和肿瘤渗透。由于小窝靶向人类的效用需要 AnnA1在肿瘤EC小凹中的表达，我们将使用Core C成像服务来比较 AnnA1 在临床前肿瘤模型和人类肿瘤中的血管表达。翻译 我们的临床测试结果，我们将测试 hAnnA1，如果需要的话进一步人性化， 与 NCI 的 NExT 计划合作，进行 cGMP 生产、质量控制和毒理学 hAnnA1。借助 Core D，项目 3 将优化进行必要的 hAnnA1 放射性标记 首次人体成像试验是我们研究结果成功转化的直接结果 从项目1进入临床。