Precision Delivery and Imaging to Enhance Solid Tumor Therapy

项目1概要 针对癌症的现有基于抗体的干预依赖于循环的被动递送。 药物依赖于穿过半渗透壁的大浓度梯度， 血管进入肿瘤内部。驱使药物从血液中进入 肿瘤导致次优递送和对肿瘤细胞的不良接近，部分原因是 形成血管壁的内皮细胞（EC）构成重要的限制性屏障。 我们打算通过克服以下问题来提高对原发性和转移性肿瘤的精确递送 血管EC屏障通过一个高度精确的主动转运途径， 通过蛋白质组成像发现并命名为小窝泵系统。的 这里提出的提高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（hAnnA 1）的领先人源化抗体， 肿瘤特异性抗体集中在EC小窝中，不仅结合其预期靶点， 但实际上是第一种主动、快速和特异性穿透实体瘤的抗体。 它甚至在非常低的剂量下也能做到这一点，并达到前所未有的肿瘤内 浓度远远超过注射后的最高血液水平。现在是时候测试 这种前所未有的免疫靶向作用。我们建议在此制定一个 放射性标记的人源化mAnnA 1，以检测和破坏原发性和转移性病变。 该项目的主要目的是：1-2）评价新的药物的体内递送和功效。 在难以治疗的转移性肿瘤模型中的靶向小窝的放射性免疫缀合物 乳腺癌; 3）测试在人类肿瘤血液中的小窝泵送的有效性 使用PDX和新的人IVM肿瘤模型的血管;并将hAnnA 1翻译为 临床试验我们将在这里确定小窝可以被瞄准的程度 将放射性标记的抗体泵入血管EC， 肿瘤作为改善图像引导的药物递送和增强 他们的功效。抗体将由Core B提供，并在辅助下进行放射性标记 由核心D提供用于临床前工作。几种乳腺肿瘤模型将用于 评估放射性标记的hAnnA 1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hAnnA 1与 先进的多模态体内成像，可量化和优化精确的经血管 递送和肿瘤穿透。由于在人类中靶向小窝的效用需要 AnnA 1在肿瘤EC小窝中的表达，我们将使用Core C成像服务进行比较 AnnA 1在临床前肿瘤模型和人肿瘤中的血管表达。翻译 我们的临床测试结果，我们将测试hAnnA 1，如果需要的话进一步人性化， 与NCI的NExT计划合作，用于cGMP生产，质量控制和毒理学 hAnnA1.对于核心D，项目3将优化进行必要的hAnnA 1放射性标记， 首次人体成像试验是我们的发现成功转化的直接结果 从项目1到诊所

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.