Precision Antibody Imaging & Radiotherapy of Solid Tumors

精密抗体成像

基本信息

批准号：
10655400
负责人：
Jan Eugeniusz Schnitzer
金额：
$ 29.7万
依托单位：
PROTEOGENOMICS RESEARCH INSTIT/SYS/ MED
依托单位国家：
美国
项目类别：
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/10655400
关键词：
Active Biological Transport Affinity Annexin A1 Antibodies Binding Biodistribution Blood Blood Circulation Blood Vessels Bone Marrow Breast Breast Cancer Model Cancer Intervention Cancer Model Cancer Patient Canis familiaris Caveolae Cell surface Circulation Classification Clinic Clinical Colon Data Detection Dose Drug Delivery Systems Effectiveness Endothelial Cells Glioma Goals Hematologic Neoplasms Human Image Image Enhancement Injections Intravenous Kinetics Lead Leptomeninges Lung Lung Neoplasms Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Mediating Metastatic Neoplasm to the Lung Metastatic breast cancer Modeling Monitor Monoclonal Antibodies Multi-Drug Resistance Names Neoplasm Metastasis Neoplasms in Vascular Tissue Normal tissue morphology Organ Pathway interactions Patients Penetration Permeability Pharmaceutical Preparations Primary Lesion Primary Neoplasm Prostate Proteomics Publishing Pump Radiation Radiation Tolerance Radiation therapy Radioimmunoconjugate Radioimmunotherapy Radioisotopes Radiolabeled Radionuclide therapy Radiopharmaceuticals Rattus Research Rodent Safety Services Solid Solid Neoplasm Surface System Testing Therapeutic Therapeutic Agents Time Tissues Toxic effect Translating Translations Treatment Efficacy Tumor Burden Vascular Endothelial Cell Vascular Endothelium Visualization Work X-Ray Computed Tomography cGMP production cancer imaging clinical translation design dosage driving force effectiveness testing first-in-human human imaging humanized antibody humanized monoclonal antibodies image guided image-guided drug delivery imaging agent improved in vivo in vivo imaging intravenous injection intravital microscopy multimodality murine monoclonal antibody neoplastic cell novel patient derived xenograft model pre-clinical prostate cancer model research clinical testing selective expression single photon emission computed tomography targeted agent tool tumor tumor eradication uptake

项目摘要

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.

项目1摘要现有的基于抗体的癌症干预措施取决于循环药物的被动输送在半渗透的血管壁上浓度较大的梯度，以进入肿瘤。这将药物从血液中驱动到肿瘤的力导致次优的递送和进入肿瘤的不良通道细胞，部分原因是形成血管壁的内皮细胞（EC）构成了一个重要的限制性障碍。我们打算通过克服血管EC屏障来提高精确递送到原发性和转移性肿瘤通过我们通过蛋白质组学成像发现的高度精确，主动的运输途径小窝抽水系统。这里提出的以增强交付的方法远远超出了典型的So- 称为抗体的“主动靶向”。我们对膜联蛋白A1（Hanna1）的人性化抗体，一种肿瘤 - 集中在Ec Caveolae中的特定抗体，不仅结合其预期靶标，而且实际上是第一抗体积极，快速，具体地渗透实体瘤。它即使在非常低的剂量和达到注射后，空前的肿瘤内浓度远远超出了最高的血液水平。现在是时候了在人类中测试这种前所未有的免疫靶向。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）评估新颖的小窝靶向放射免疫共轭物在难以治疗的转移性肿瘤中的体内递送和功效模型和犬类癌患者； 3）测试口腔泵送在人类肿瘤血管中的有效性使用PDX和新型人IVM肿瘤模型； 4）将Hanna1转换为临床测试。我们将在此确定可以将口腔靶向泵送放射性标记抗体的程度 EC将它们集中在实体瘤中，以改善图像引导的药物输送并增强他们的功效。抗体将由核心B提供，并在核心D提供的帮助下提供抗体临床前工作。几种乳腺肿瘤模型将用于评估放射标记的Hanna1的能力通过CoreC提供的成像服务目标原发性和转移性肿瘤。我们将静脉内研究注入带有高级多模态的Hanna在体内成像中，以量化和优化精度经过血管分娩和肿瘤穿透。由于人类中的小窝靶向的实用性需要Anna1的表达肿瘤EC Caveolae，我们将使用核心C服务比较临床前肿瘤中ANNA1的血管表达模型和人类实体瘤。为了翻译我们的临床测试发现，Core B将监督CGMP Hanna1的生产。核心D中的放射性标记后，项目3将进行首次人类成像试验作为成功翻译我们发现从项目1转化为诊所的直接结果。