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

• 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
• 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

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实体瘤。虽然疾病的病程已被充分了解，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，还没有特定的放射性示踪剂用于正电子发射断层扫描（PET）——最灵敏的分子成像方式。尽管威尔康奈尔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）临床试验方面拥有丰富的经验，但由于缺乏定量成像，数据分析受到限制。现在才可能在临床上将 PET 敏感性与 mAb 特异性 (Immuno-PET) 结合起来。因此，我们建议使用 J591 mAb 和 89Zr 开发免疫 PET，89Zr 是一种理想的正电子 (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）。具体来说，该研究计划将测试基于抗 PSMA（前列腺特异性膜抗原）单克隆抗体 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 试验的相对疗效的假设。使用 PSMA 阳性 LNCaP 人类细胞系和非人类 RM1.PGLS 细胞系设计了临床前研究，以测量荷瘤小鼠中特异性 89Zr-J591 抗原的靶向、内化和生物分布。这些研究的结果将与另一种研究性放射性药物 18F 标记的 MIP-1224（一种 PSMA 抑制剂）进行比较和对比。 MicroPET 非侵入性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 ImmunoPET 在 RIT 试验中的附加价值，将在 PSMA (+) 异种移植物和转移性癌症模型中使用 177Lu-J591 mAb 进行 2-辐射后进行系列 PET 成像研究。 177Lu-J591 RIT 之后，将使用小型动物 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当前基于抗 PSMA 单克隆抗体癌症治疗的 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，这些变化将改善对大量晚期前列腺疾病患者的管理 公共卫生相关性：前列腺癌是影响美国成年男性的最常见实体瘤。该研究计划旨在开发一种称为免疫 PET（正电子发射断层扫描）的成像技术，该技术基于称为 Zirconim-89-J591 的放射性标记抗体，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、治疗候选者的选择以及确定治疗剂量和反应的准确性。