Multifunctional immunoPET tracers for pancreatic and prostate cancer

用于胰腺癌和前列腺癌的多功能免疫PET示踪剂

• 批准号: 9769635
• 负责人: ROBERT E REITER
• 金额: $ 34.81万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769635
• 关键词: Ablation; Address; Androgens; Animal Model; Antibodies; Antigen Targeting; Area; Biodistribution; Biological Markers; Castration; Cell Surface Proteins; Cell surface; Classification; Clinic; Clinical; Clinical Management; Diagnosis; Disease; Dose; Engineering; Excision; Extraprostatic; Future; Goals; Human; Image; Imagery; ImmunoPET; Immunoglobulin Fragments; Impotence; Incontinence; Indolent; Label; Laboratories; Lead; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of pancreas; Malignant neoplasm of prostate; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Probes; Molecular Target; Monitor; Morbidity - disease rate; Mus; Neoplasm Metastasis; Newly Diagnosed; Operative Surgical Procedures; Optics; Outcome; PARP inhibition; PET/CT scan; Patients; Positron; Positron-Emission Tomography; Pre-Clinical Model; Primary Neoplasm; Progress Reports; Public Health; Radiation; Radiation therapy; Radioimmunotherapy; Radioisotopes; Radiolabeled; Randomized; Recurrence; Recurrent Malignant Neoplasm; Residual state; Resistance; Site; Staging; Surgeon; Surgical Management; Surgical margins; Targeted Radiotherapy; Testing; Therapeutic; Time; Tracer; Translating; Work; accurate diagnosis; advanced disease; antibody engineering; base; bone; cancer imaging; dosimetry; high risk; hormone therapy; human monoclonal antibodies; imaging agent; imaging approach; imaging probe; imaging study; improved; innovation; interest; lymph nodes; men; molecular imaging; novel; optical imaging; patient stratification; phase 2 study; prostate cancer risk; prostate stem cell antigen; response; scaffold; targeted imaging; targeted treatment; theranostics; therapeutic target; tool; traditional therapy; tumor; whole body imaging

PROJECT SUMMARY Prostate and pancreatic cancers are among the most common and difficult to treat cancers. Major dilemmas in the management of prostate cancer include the difficulty of discriminating between aggressive and indolent forms of the disease and the need for improved treatment of high-risk and castrate resistant metastatic disease. In the case of pancreatic cancer, the major problems are late diagnosis and high lethality. One major barrier to progress and an unmet need in both diseases is the relative absence of effective molecular imaging tracers/tools that can be used at the whole-body or intraoperative level, to guide patient management. Antibodies can provide highly specific probes for molecular targets, and can be engineered to optimize their utility as imaging agents for clinical use. During the previous project period, novel immunoPET imaging agents have been developed based on engineered antibody fragments directed towards Prostate Stem Cell Antigen (PSCA), a cell surface biomarker expressed by a majority of prostate and pancreatic cancers which is also a promising therapeutic target. Two fragment formats, cys-diabody and cys-minibody, which enable site-specific conjugation and labeling, have been produced with the goal of providing multifunctional fragments that can be radiolabeled with positron-emitting radionuclides 124I, 89Zr, or 18F, and/or conjugation with fluorescent labels for optical imaging. In the proposed work, fluorescently labeled PSCA cys-diabodies and cys-minibodies will be developed as intraoperative molecular imaging probes and their utility assessed in preclinical models. Dually labeled probes (PET/optical) will also be produced such that the same probe can be used for whole-body imaging followed by intraoperative visualization of local/regional spread. Finally, based on promising biodistribution and imaging studies of minibodies in patients, the therapeutic potential of radiolabeled anti-PSCA cys-minibodies will be explored, comparing non-residualizing (131I) and residualizing (177Lu) therapeutic radionuclides. Full biodistributions will be performed for dose estimations (mouse and human dosimetry), followed by radioimmunotherapy studies in preclinical models. Furthermore, the efficiacy of PSCA-targeted radioimmunotherapy in combination with androgen ablation or PARP inhibition will be evaluated. These fully humanized immunoPET probes can be readily translated to the clinic to address pressing questions in clinical management, including staging of newly diagnosed, recurrent and metastatic prostate and pancreatic cancers; improved selection and classification of patients for PSCA-targeted therapy; and monitoring disease response to therapy, and ultimately could serve as an efficacious delivery vehicle for tumor-targeted radiotherapy.

项目概要 前列腺癌和胰腺癌是最常见且最难治疗的癌症之一。主要困境 前列腺癌的治疗包括难以区分侵袭性和惰性形式 该疾病的进展以及改进高风险和去势抵抗性转移性疾病治疗的需要。在 胰腺癌的主要问题是诊断晚、致死率高。进步的一大障碍 这两种疾病的未满足需求是相对缺乏有效的分子成像示踪剂/工具 可用于全身或术中水平，以指导患者管理。抗体可以提供高度 针对分子靶点的特异性探针，并且可以进行设计以优化其作为临床显像剂的效用 使用。在上一个项目期间，基于 针对细胞表面生物标志物前列腺干细胞抗原 (PSCA) 的工程化抗体片段 大多数前列腺癌和胰腺癌都表达，这也是一个有前途的治疗靶点。二 片段格式，cys-diabody 和 cys-minibody，可实现位点特异性缀合和标记。 生产的目的是提供可以用正电子发射进行放射性标记的多功能片段 放射性核素 124I、89Zr 或 18F，和/或与荧光标记结合用于光学成像。在提议的 工作中，荧光标记的 PSCA cys-双抗体和 cys-微型抗体将在术中开发 分子成像探针及其在临床前模型中评估的效用。双标记探针（PET/光学） 还将生产相同的探头，用于全身成像，然后进行术中 局部/区域传播的可视化。最后，基于有前途的生物分布和成像研究 患者体内的微型抗体，将探索放射性标记的抗 PSCA cys-微型抗体的治疗潜力， 比较非残留 (131I) 和残留 (177Lu) 治疗放射性核素。完整的生物分布将是 进行剂量估计（小鼠和人体剂量测定），然后进行放射免疫治疗研究 临床前模型。此外，PSCA 靶向放射免疫治疗与联合治疗的疗效 将评估雄激素消除或 PARP 抑制。这些完全人源化的免疫PET探针可以 很容易转化为临床，以解决临床管理中的紧迫问题，包括新的分期 确诊的、复发性和转移性前列腺癌和胰腺癌；改进的选择和分类 接受 PSCA 靶向治疗的患者；并监测疾病对治疗的反应，最终可以作为 一种有效的肿瘤靶向放射治疗递送载体。