Precision Antibody Imaging & Radiotherapy of Solid Tumors

精密抗体成像

基本信息

批准号：
9974487
负责人：
Jan Eugeniusz Schnitzer
金额：
$ 58.61万
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/9974487
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 Clinic Clinical Colon Data Detection Dose Drug Delivery Systems Effectiveness Endothelial Cells Glioma Goals Hematology Human Image Image Enhancement Injections Intravenous Kinetics Lead 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 Radio 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 Work X-Ray Computed Tomography Xenograft procedure base 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 intravital microscopy multimodality murine monoclonal antibody neoplastic cell novel pre-clinical prostate cancer model research clinical testing selective expression single photon emission computed tomography targeted agent tool tumor 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依赖于循环药物的被动输送，而循环药物取决于以大浓度梯度穿过血管半透壁进入肿瘤内部。这驱动药物从血流进入肿瘤的力量导致药物输送不理想且难以到达肿瘤细胞，部分是因为形成血管壁的内皮细胞（EC）构成了重要的限制性屏障。我们打算通过克服血管 EC 屏障来提高原发性和转移性肿瘤的精确递送通过我们通过蛋白质组成像发现的高度精确的主动运输途径，并将其命名为小凹泵送系统。这里提出的增强交付的方法远远超出了典型的方法称为抗体的“主动靶向”。我们针对膜联蛋白 A1 (hAnnA1) 的领先人源化抗体，膜联蛋白 A1 是一种肿瘤 - 集中在 EC 小凹中的特异性抗体，不仅结合其预期目标，而且实际上是第一个抗体主动、快速、特异性地穿透实体瘤。即使在非常低的剂量下也能达到这样的效果前所未有的肿瘤内浓度远远超过注射后的最高血液水平。现在是时候了在人体中测试这种前所未有的免疫靶向。我们在此建议开发一种放射性标记的人源化药物 mAnnA1 检测并破坏原发性和转移性病变。该项目的主要目标是：1-2）评估新型小窝靶向放射免疫缀合物在难以治疗的转移性肿瘤中的体内递送和疗效模型和犬类癌症患者； 3）测试人体肿瘤血管中小凹泵送的有效性使用 PDX 和新型人类 IVM 肿瘤模型； 4) 将 hAnnA1 转化为临床测试。我们将在此确定小凹可以靶向泵送放射性标记抗体穿过血管的程度 EC 将它们集中在实体瘤内，作为改善图像引导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 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用于评估放射性标记的 hAnnA1 的能力通过Core C提供的成像服务针对原发性和转移性肿瘤。我们将进行静脉研究使用先进的多模态体内成像注射 hAnnA1，以量化和优化精确的经血管递送和肿瘤渗透。由于小窝靶向在人类中的实用性需要 AnnA1 在肿瘤EC细胞小窝，我们将使用Core C服务来比较临床前肿瘤中AnnA1的血管表达模型和人类实体瘤。为了将我们的发现转化为临床测试，Core B 将监督 cGMP hAnnA1 的生产。在 Core 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 的研究成果成功转化为临床的直接结果。