Precision Antibody Imaging & Radiotherapy of Solid Tumors

项目1概要 现有的基于抗体的癌症干预措施依赖于循环药物的被动递送， 在一个大的浓度梯度上穿过半透性的血管壁进入肿瘤内部。的 驱使药物从血流进入肿瘤的力导致次优递送和到达肿瘤的不良途径 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 旨在通过克服血管EC屏障来提高原发性和转移性肿瘤的精确递送 我们通过蛋白质组成像发现了一种高度精确的主动转运途径， 洞穴泵送系统这里提出的加强交付的方法远远超出了典型的，因此- 称为抗体的“主动靶向”。我们针对膜联蛋白A1（hAnnA 1）的领先人源化抗体， 浓缩在EC小窝中的特异性抗体，不仅结合其预期靶标，而且实际上是第一抗体 主动、快速、特异地穿透实体瘤。即使在非常低的剂量下也会这样， 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 在人体中测试这种前所未有的免疫靶向。我们在这里建议开发放射性标记的人源化 mAnnA 1检测和破坏原发性和转移性病变。该项目的主要目标是：1-2）评估 新型靶向小窝的放射免疫缀合物在难治转移性肿瘤中的体内递送和功效 模型和犬癌症患者; 3）测试人肿瘤血管中的小窝泵送的有效性 使用PDX和新的人IVM肿瘤模型;和4）将hAnnA 1翻译用于临床测试。我们将 在这里确定小窝可以靶向泵送放射性标记抗体穿过血管的程度， EC将它们集中在实体肿瘤内，作为改善图像引导药物递送和增强 他们的功效。抗体将由核心B提供，并在核心D的协助下进行放射性标记， 临床前工作。将使用几种乳腺肿瘤模型来评估放射性标记的hAnnA 1的能力， 通过Core C提供的成像服务瞄准原发性和转移性肿瘤。我们将研究静脉注射 注射hAnnA 1与先进的多模态体内成像，以量化和优化精确的经血管 递送和肿瘤穿透。由于靶向小窝在人体中的效用需要AnnA 1在细胞中的表达， 肿瘤EC caveolae，我们将使用Core C服务比较AnnA 1在临床前肿瘤中的血管表达 模型和人实体瘤。为了将我们的发现转化为临床试验，核心B将监督cGMP hAnnA 1的产生。在核心D中进行放射性标记后，项目3将进行首次人体成像试验， 这是我们将项目1的发现成功转化为临床的直接结果。

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 actually is 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 and canine cancer patients; 3) test the effectiveness of caveolae pumping in human tumor blood vessels using PDX and novel human IVM tumor models; and 4) translate hAnnA1 towards clinical testing. We will determine here the degree to which caveolae can be targeted to pump radiolabeled antibodies across vascular EC to concentrate them inside solid tumors as a 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 by Core C. We will study 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 services to compare vascular expression of AnnA1 in preclinical tumor models and human solid tumors. To translate our findings for clinical testing, Core B will oversee cGMP production of hAnnA1. Following radiolabeling in Core D, Project 3 will conduct a first-in-human imaging trial as a direct result of successful translation of our findings from Project 1 into the clinic.