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

描述(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肿瘤。虽然人们对前列腺癌的病程已有了很好的了解，但在前列腺癌的诊断、分期、治疗和管理方面，仍有很大的机会改进非侵入性分子成像。目前，正电子发射断层扫描(PET)--最灵敏的分子成像手段--还没有特效的放射性示踪剂。尽管威尔·康奈尔医学中心基于人源化单抗(HuJ591)的前列腺癌放射免疫治疗(RIT)临床试验经验丰富，但由于缺乏定量成像，数据分析一直受到限制。现在才有可能在临床上结合PET的敏感性和mAb的特异性(免疫-PET)。因此，我们建议使用J591mAb和89Zr-一个理想的正电子(2+)发射体，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(平均为0.395 MeV)来开发免疫正电子发射计算机断层扫描。具体地说，这项研究提案将检验基于抗PSMA(前列腺特异性膜抗原)单抗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试验的相对有效性的假设。利用PSMA阳性的人LNCaP细胞系和非人RM1.PGLS细胞系进行了临床前研究，以检测特异性89Zr-J591抗原在荷瘤小鼠体内的靶向性、内化和生物分布。这些研究的结果将与另一种标记PSMA抑制剂MIP-1224的研究放射性药物18F进行比较和对比。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进行177Lu-J591单抗2次照射后进行系列PET成像研究。在177Lu-J591RIT之后，将使用小型动物7Tesla磁共振扫描仪进行相关的解剖成像研究。这项研究的预期结果是开发出89Zr-J591 mAb作为一种先进的前列腺癌特异性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、治疗候选者的选择和治疗剂量的准确性。最终，这些变化将改善对大量晚期前列腺癌患者的管理。

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