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: 10449304
• 负责人: Jan Eugeniusz Schnitzer
• 金额: $ 253.44万
• 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/10449304
• 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; diagnostic tool; 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; 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取决于循环的被动输送 依赖于跨半渗透壁的大浓度梯度的药物 血管进入肿瘤。将药物从血液驱动到的力 肿瘤会导致亚次最佳分娩和对肿瘤细胞的不良接入，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障碍。 我们打算通过克服将精度递送到原发性和转移性肿瘤中 我们的血管EC屏障通过我们的高度精确，主动的运输途径 通过蛋白质组学成像发现并命名为小窝泵送系统。这 这里提出的以增强交付的方法远远超出了典型的So-so Active 靶向抗体。我们对膜联蛋白A1（Hanna1）的铅人性化抗体，一个 肿瘤 - 特异性抗体集中在Ec Caveolae中，不仅结合其预期靶标 但实际上是第一种积极，快速，具体地渗透实体瘤的抗体。 它即使在非常低的剂量下也可以达到前所未有的肿瘤内 注射后的浓度远远超出了最高的血液水平。现在该测试了 这种空前的免疫靶向在人类中。我们在这里建议开发一个 放射性标记的人源化manna1检测并破坏原发性和转移性病变。 该项目的主要目的是：1-2）评估新颖的体内递送和功效 难以治疗的转移性肿瘤模型中的小窝靶向放射免疫偶联物 乳腺癌; 3）测试口腔泵送人类肿瘤血液的有效性 使用PDX和新型人IVM肿瘤模型的血管；并将Hanna1转换为 临床测试。我们将4）在此确定可以针对Caveolae的程度 泵送横跨血管EC的放射性标记抗体以将其集中在固体中 肿瘤是改善图像引导的药物输送并增强的手段 他们的功效。抗体将由核心B提供，并在辅助方面进行放射性标记 由核心D提供的临床前工作。几种乳腺肿瘤模型将用于 评估放射标记的Hanna1通过 CoreC中提供的成像服务。我们将通过静脉注射Hanna1的研究 体内成像中的高级多模式性，以量化和优化精度经过血管 分娩和肿瘤穿透。由于人类目标的小洞的实用性需要 Anna1表达在肿瘤ec Caveolae中，我们将使用核心C成像服务进行比较 临床前肿瘤模型和人类肿瘤中ANNA1的血管表达。翻译 我们对临床测试的发现，我们将测试Hanna1，在需要时进一步人性化，并且 与NCI的下一个CGMP生产，质量控制和毒理学的合作伙伴合作 Hanna1。使用核心D，项目3将优化执行所需的Hanna1 radiolabeling 成功翻译我们的发现的直接结果，这是一个人类成像试验 从项目1到诊所。