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

描述（由申请人提供）：前列腺癌是影响美国成年男性最常见的实体肿瘤。虽然我们对前列腺癌的病程了解得很清楚，但在前列腺癌的诊断、分期、治疗和管理方面，仍有很大的机会来改进非侵入性分子成像。目前还没有特定的放射性示踪剂用于正电子发射断层扫描(PET) -最敏感的分子成像方式。尽管Weill Cornell医学中心在基于人源化单克隆抗体（huJ591）的前列腺癌放射免疫治疗（RIT）临床试验中有丰富的经验，但由于缺乏定量成像，数据分析受到限制。直到现在，临床上才有可能将PET敏感性与mAb特异性（免疫- PET）结合起来。因此，我们建议使用J591 mAb和89Zr(一种理想的正电子（2+）发射器，具有抗体成像所需的物理特性-半衰期（3.27天）和正电子能量（Emean = 0.395 MeV）来开发免疫pet。具体而言，本研究计划将验证基于抗psma（前列腺特异性膜抗原）mAb， 89Zr-J591的免疫pet可以增强特异性，评估肿瘤进展，并监测当前II期和III期临床RIT试验的相对疗效。临床前研究使用psma阳性LNCaP人类细胞系和非人类RM1进行设计。PGLS细胞系测定89Zr-J591抗原在荷瘤小鼠中的特异性靶向、内化和生物分布。这些研究的结果将与另一种放射性药物18F标记的MIP-1224进行比较和对比，MIP-1224是一种PSMA抑制剂。MicroPET无创成像和生物分布研究将进一步确定这两种示踪剂的药代动力学和肿瘤摄取。为了强调免疫PET在RIT试验中的附加价值，将在PSMA（+）异种移植和转移癌模型中使用177Lu-J591 mAb进行2-辐射后进行一系列PET成像研究。在177Lu-J591 RIT之后，将使用小动物7特斯拉MRI扫描仪进行相关解剖成像研究。本研究的预期结果是开发89Zr-J591 mAb作为晚期前列腺癌特异性PET放射性示踪剂。这项研究的结果将对目前基于抗psma单抗癌症治疗的RIT试验以及其他正在进行的前列腺癌成像试验产生直接影响。长期目标将是提高转移性前列腺癌诊断的特异性，治疗候选人的选择和治疗剂量的准确性。最终，这些改变将改善对大量晚期前列腺疾病患者的管理

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.