Precision Delivery and Imaging to Enhance Solid Tumor Therapy

项目1总结 现有的基于抗体的癌症干预依赖于循环的被动递送 这种药物依赖于穿过半透膜壁的大浓度梯度 血管进入肿瘤内部。驱使药物从血液进入体内的力量 肿瘤导致次优输送和很难接触到肿瘤细胞，部分原因是 形成血管壁的内皮细胞(EC)构成了一个重要的、有限的屏障。 我们打算通过克服以下问题来提高对原发和转移肿瘤的精确度 血管内皮细胞屏障通过一条高度精确、活跃的运输途径，我们 通过蛋白质组成像发现，并命名为小窝抽水系统。这个 这里提出的加强交付的方法远远超出了典型的所谓主动 以抗体为靶点。我们的主要人源化抗体Annexin A1(HAnnA1)， 集中在EC小窝中的肿瘤特异性抗体不仅能结合其预定的靶点 但实际上是第一个主动、快速和特异地穿透实体瘤的抗体。 即使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。 注射后的浓度远远超过最高血液水平。现在是测试的时候了 这种史无前例的免疫靶向作用于人类。我们在此建议开发一种 放射性标记人源化mAnnA1，用于检测和销毁原发和转移灶。 该项目的主要目的是：1-2)评价新药的体内释放和疗效 小凹靶向放射免疫结合物在难治性脑转移瘤模型中的应用 乳腺癌；3)检测肿瘤血液中空泡泵入的效果 使用PDX和新的人类IVM肿瘤模型的血管；并将hAnnA1翻译为 临床测试。我们将在这里确定凹陷的目标程度 将放射性标记的抗体注入血管内皮细胞，使其在固体内浓缩 肿瘤作为改善图像引导药物递送和增强 它们的功效。抗体将由Core B提供，并在辅助下进行放射性标记 由Core D提供，用于临床前工作。几种乳腺肿瘤模型将用于 评价放射性标记hAnnA1靶向原发和转移肿瘤的能力 核心C提供成像服务。我们将通过静脉注射hAnnA1 先进的多模活体成像技术，用于量化和优化精确度的经血管 递送和肿瘤穿透。因为小窝靶向在人类中的效用需要 AnnA1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 AnnA1在临床前肿瘤模型和人类肿瘤中的血管表达。翻译 我们的发现用于临床测试，我们将测试hAnnA1，如果需要进一步人性化和 与NCI的下一个cGMP生产、质量控制和毒理学项目合作 HAnnA1。对于核心D，项目3将优化进行以下操作所需的hAnnA1放射性标记 作为成功翻译我们的发现的直接结果的第一次人体成像试验 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.