Precision Antibody Imaging & Radiotherapy of Solid Tumors

项目1总结 现有的基于抗体的癌症干预依赖于循环药物的被动输送，这种药物依赖于 在穿过血管半透膜壁的大浓度梯度上进入肿瘤内部。这个 驱使药物从血流进入肿瘤的力量导致次优输送和难以接触到肿瘤 细胞，部分是因为形成血管壁的内皮细胞(EC)构成了一个重要的、限制性的屏障。我们 打算通过克服血管EC屏障来提高对原发和转移性肿瘤的精确输送 通过我们通过蛋白质组成像发现的高度精确的、活跃的运输途径，并将其命名为 洞穴抽水系统。这里提出的加强交付的方法远远超出了典型的SO- 被称为抗体的‘主动靶向’。我们的主要人源化抗体Annexin A1(HAnnA1)是一种肿瘤- 集中在EC小窝中的特异性抗体，不仅结合其预定的靶点，而且实际上是第一抗体 主动、迅速、特异地穿透实体瘤。它即使在很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。现在是时候了 在人类身上测试这种史无前例的免疫靶向。我们建议在这里开发一种放射性标记的人性化 MAnnA1用于检测和销毁原发灶和转移灶。该项目的主要目标是：1-2)评估 新型小凹靶向放射免疫结合物在难治性转移性肿瘤中的体内释放和疗效 模型和犬癌患者；3)检测人肿瘤血管空泡泵入的效果 使用PDX和新的人类IVM肿瘤模型；以及4)将hAnnA1转化为临床试验。我们会 在这里确定小窝的靶向程度，以将放射性标记的抗体泵过血管 EC将它们集中在实体肿瘤内，作为一种改善图像引导药物传递的手段，并增强 它们的功效。抗体将由核心B提供，并在核心D提供的协助下进行放射性标记 临床前工作。几种乳腺肿瘤模型将被用来评估放射性标记的hAnnA1的能力 通过Core C提供的成像服务靶向原发和转移肿瘤。我们将通过静脉研究 注射hAnnA1先进的多模式活体成像以量化和优化精确的经血管 递送和肿瘤穿透。由于小窝靶向在人类中的作用需要AnnA1在 我们将使用Core C服务来比较AnnA1在临床前肿瘤中的血管表达 模型和人体实体肿瘤。为了将我们的发现转化为临床测试，核心B将监督cGMP HAnnA1的生产。在核心D进行放射性标记后，项目3将进行首次人体成像试验， 这是我们成功地将项目1中的发现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.