Immuno-PET With Anti-PSMA 89Zr-J591 mAb For Molecular Imaging of Prostate Cancer

使用抗 PSMA 89Zr-J591 mAb 进行免疫 PET 进行前列腺癌分子成像

基本信息

批准号：
8099997
负责人：
Joseph Reginald Osborne
金额：
$ 22.05万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-19 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8099997
关键词：
Acetates Adult Affect African American American Anatomy Animals Antibodies Antibody Specificity Antigen Targeting Binding Biodistribution Cancer Model Caucasians Caucasoid Race Cell Line Cell membrane Cessation of life Characteristics Choline Clinic Clinical Clinical Trials Data Data Analyses Development Disease Disease Marker Disseminated Malignant Neoplasm Dose Drug Kinetics Evaluation Glucose Glutamate Carboxypeptidase II Goals Histologic Human Human Cell Line Image Imaging Techniques In Vitro Incidence J591 Monoclonal Antibody LNCaP Label Laboratory Markers Life Magnetic Resonance Imaging Malignant neoplasm of prostate Measures Medical center Metabolic Metastatic Prostate Cancer Metastatic to Methods Modeling Monitor Monoclonal Antibodies Mus Outcome Study PC3 cell line Patients Peptide antibodies Phase Population Positron Positron-Emission Tomography Preparation Prostate Prostate carcinoma Prostatic Diseases Prostatic Neoplasms Proteins Radiation Radioimmunoconjugate Radioimmunotherapy Radioisotopes Radiopharmaceuticals Relative (related person)Research Proposals Serum Solid Neoplasm Specificity Staging Testing Therapeutic Tissue Sample Tissues Tracer Tumor Antigens Xenograft procedure advanced disease base bone imaging cancer cell cancer diagnosis cancer imaging cancer radioimmunotherapy cancer therapy candidate selection density design experience humanized monoclonal antibodies imaging modality imaging probe improved in vivo inhibitor/antagonist male molecular imaging mortality mouse model multimodality non-invasive monitor patient population preclinical study radiotracer response small molecule tumor tumor progression uptake

项目摘要

DESCRIPTION (provided by applicant): Prostate cancer is the most common solid tumor affecting American adult males. While the disease course is well-understood, there are significant opportunities to improve non-invasive molecular imaging in prostate cancer diagnosis, staging, therapy and management. At present there is no specific radiotracer used for positron emission tomography (PET) - the most sensitive molecular imaging modality. Despite extensive experience in prostate cancer radioimmunotherapy (RIT) clinical trials at Weill Cornell Medical Center based on a humanized monoclonal antibody (huJ591), data analysis has been limited by the lack of quantitative imaging. It is only now possible to combine PET sensitivity with mAb specificity (Immuno- PET) in the clinic. We therefore propose to develop Immuno-PET using J591 mAb and 89Zr - an ideal positron (2+) emitter with physical characteristics necessary for antibody imaging - halflife (3.27 days) and positron energy (Emean = 0.395 MeV). Specifically, this research proposal will test the hypothesis that Immuno-PET based on anti-PSMA (prostate specific membrane antigen) mAb, 89Zr-J591 can enhance specificity, assess tumor progression, and monitor the relative efficacy of current Phase II and III clinical RIT trials. Preclinical studies have been designed using PSMA-positive LNCaP human cell line and non-human RM1.PGLS cell lines to measure specific 89Zr-J591 antigen targeting, internalization and biodistribution in tumor-bearing mice. The results of these studies will be compared and contrasted with another investigational radiopharmaceutical 18F labeled MIP-1224, a PSMA inhibitor. MicroPET non-invasive imaging and biodistribution studies will further determine pharmacokinetics and tumor uptake of these two tracers. To underscore the added value of ImmunoPET in RIT trials, serial PET imaging studies will be performed following 2- radiation from 177Lu-J591 mAb in PSMA (+) xenograft and metastatic cancer models. Following 177Lu-J591 RIT, correlative anatomic imaging studies using a small animal 7 Tesla MRI scanner will be performed. The expected outcome of this study is the development of 89Zr-J591 mAb as an advanced prostate cancer- specific PET radiotracer. The results of this study will have a direct impact on current RIT trials based on anti-PSMA mAb cancer therapy as well as other ongoing prostate cancer imaging trials. The long-term goal will be to improve the specificity of metastatic prostate cancer diagnosis, selection of candidates for treatment, and accuracy of therapeutic dose. Ultimately, these changes will improve management of the large population of patients living with advanced prostate disease PUBLIC HEALTH RELEVANCE: Prostate cancer is the most common solid tumor affecting American adult males. This research proposal is designed to develop an imaging technique known as Immuno-PET (positron emission tomography) based on radiolabeled antibody known as Zirconim-89-J591, which binds to a specific protein known as PSMA on prostate cancer cells. The long term goal will be to improve the specificity of metastatic prostate cancer diagnosis, selection of candidates for treatment, and accuracy of determining therapeutic dose and response.

描述（由申请人提供）：前列腺癌是影响美国成年男性的最常见的实体瘤。尽管该疾病的病程已得到充分理解，但在前列腺癌诊断，分期，治疗和管理中有很大的机会来改善非侵入性分子成像。目前，尚无用于正电子发射断层扫描（PET）的特异性放射性示踪剂 - 最敏感的分子成像方式。尽管基于人源化的单克隆抗体（HUJ591）的Weill Cornell医疗中心的前列腺癌免疫疗法（RIT）临床试验丰富的经验，但由于缺乏定量成像，数据分析受到限制。直到现在，才有可能在诊所中将PET灵敏度与MAB特异性（免疫PET）相结合。因此，我们建议使用J591 MAB和89ZR开发免疫-PET-理想的正电子（2+）发射极具有抗体成像所需的物理特征 - 半衰期（3.27天）和正电子能量（EMEAN = 0.395 MEV）。具体而言，该研究建议将检验以下假设：基于抗PSMA（前列腺特异性膜抗原）MAB的免疫PET，89ZR-J591可以提高特异性，评估肿瘤进展，并监测当前II期II期和III期临床RIT试验的相对功效。已经使用PSMA阳性LNCAP人细胞系和非人类RM1.PGLS细胞系设计了临床前研究，以测量含有肿瘤的小鼠中特定的89ZR-J591抗原靶向，内在化和生物分布。这些研究的结果将与另一项标记为MIP-1224（PSMA抑制剂）标记的放射性射击18F进行比较并形成鲜明对比。 MicroPET非侵入性成像和生物分布研究将进一步确定这两个示踪剂的药代动力学和肿瘤吸收。为了强调RIT试验中免疫集的附加值，将在PSMA（+）异种移植物和转移性癌症模型中的177LU-J591 MAB 2-辐射后进行连环PET成像研究。在177LU-J591 RIT之后，将进行使用小动物7 Tesla MRI扫描仪的相关解剖成像研究。这项研究的预期结果是将89ZR-J591 MAB作为晚期前列腺癌 - 特异性PET放射性示踪剂的发展。这项研究的结果将对基于抗PSMA MAB癌症治疗以及其他正在进行的前列腺癌成像试验的当前RIT试验产生直接影响。长期目标是提高转移性前列腺癌诊断的特异性，治疗候选者的选择以及治疗剂量的准确性。最终，这些变化将改善患有晚期前列腺疾病的大量患者的管理公共卫生相关性：前列腺癌是影响美国成年男性的最常见的实体瘤。该研究建议旨在开发一种基于辐射标记的抗体，称为氧化锆89-J591的成像技术（正电子发射断层扫描），该抗体与前列腺癌细胞上称为PSMA的特定蛋白质结合。长期目标是提高转移性前列腺癌诊断的特异性，选择治疗的候选物以及确定治疗剂量和反应的准确性。