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

基本信息

批准号：
8641677
负责人：
ROBERT E REITER
金额：
$ 40.26万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8641677
关键词：
Address Adopted Affinity Antibodies Antigen Targeting Behavior Biodistribution Biological Markers Biopsy Bladder Diseases Cell Surface Proteins Cell surface Classification Clinic Clinical Clinical Management Combined Modality Therapy Detection Diagnosis Disease Disease Progression Disease model Drug Kinetics Drug or chemical Tissue Distribution Engineering Evaluation Future Gene Expression Genes Genetic Engineering Genetically Engineered Mouse Goals Hand Human Image Immune system Immunoglobulin Fragments Indolent Kinetics Knock-in Mouse Label Laboratories Lead Malignant Bone Neoplasm Malignant Lymph Node Neoplasm Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Molecular Molecular Target Monitor Newly Diagnosed Normal tissue morphology Operative Surgical Procedures Pancreatic Ductal Adenocarcinoma Patient Monitoring Patients Phase Positron Positron-Emission Tomography Prognostic Factor Prostate Protein Engineering Radioimmunoconjugate Radioisotopes Radiolabeled Randomized Recurrence Recurrent disease Relative (related person)Resistance Route Selection for Treatments Site Staging Stomach Therapeutic Time Tracer Translating Xenograft procedure advanced disease antibody engineering arm base gemcitabine high risk human monoclonal antibodies imaging modality improved in vivo lymph nodes men molecular imaging mouse model novel outcome forecast phase 2 study prostate cancer model prostate stem cell antigen public health relevance radiotracer response soft tissue therapeutic target tool treatment response tumor uptake

项目摘要

DESCRIPTION (provided by applicant): 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 guide patient management. Antibodies can provide highly specific probes for molecular targets, and can be combined with positron emission tomography (PET) to provide sensitive and quantitative detection. Novel immunoPET imaging agents will be 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, will be evaluated to explore their different kinetics and clearance routes in vivo and identify the optimal format(s) for imaging prostate and pancreatic cancer. Protein engineering will be employed to generate multifunctional fragments that can be radiolabeled with positron-emitting radionuclides 124I, 89Zr, or 18F using a variety of conjugation strategies. Promising PSCA-targeted antibody agents will be evaluated by immunoPET in mouse models of prostate cancer disease progression and in genetically engineered mouse models of prostate cancer. Candidate engineered fragments will also be used to image pancreatic ductal adenocarcinoma in xenograft and genetically engineered mouse models of pancreatic cancer. 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; quantification of PSCA expression in vivo to improve selection and classification of patients for PSCA-targeted therapy; and monitoring disease response to therapy, particularly in sites such as bone where cancer-specific imaging is difficult (e.g. prostate cancer).

描述（由申请人提供）：前列腺和胰腺癌是最常见且难以治疗的癌症之一。前列腺癌管理中的主要困境包括难以区分侵略性和懒惰形式的疾病，以及需要改善高风险和castrate抗性转移性疾病的治疗。在胰腺癌的情况下，主要问题是晚期诊断和高致死性。两种疾病的进步和未满足需求的一个主要障碍是相对缺乏有效的分子成像示踪剂/工具可以指导患者管理。抗体可以为分子靶标提供高度特异性的探针，并且可以与正电子发射断层扫描（PET）结合使用，以提供敏感和定量检测。新型免疫集成像剂将基于针对前列腺干细胞抗原（PSCA）的工程抗体片段开发，这是由大多数前列腺和胰腺癌表达的细胞表面生物标志物，也是一个有前途的治疗靶标。将评估两种碎片格式，即cys-Diabody和Cys-sinibopy，以探索其体内不同的动力学和清除路线，并确定用于成像前列腺和胰腺癌的最佳格式。蛋白质工程将用于生成多功能片段，这些片段可以使用多种共轭策略使用正电子发射放射性核素124i，89zr或18F进行放射性标记。在前列腺癌疾病进展的小鼠模型和前列腺癌的基因工程小鼠模型中，将评估具有PSCA靶向PSCA的抗体剂。候选工程碎片还将用于对异种移植物中的胰腺导管腺癌和胰腺癌的基因工程小鼠模型进行成像。这些充分人性化的免疫集探针可以很容易地转化为诊所，以解决临床管理中的紧迫问题，包括分阶段的新诊断，复发和转移性前列腺和胰腺癌的分期；对体内PSCA表达的定量，以改善针对PSCA靶向治疗的患者的选择和分类；并监测疾病对治疗的反应，特别是在癌症特异性成像困难的骨骼（例如前列腺癌）中。