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.

项目摘要 前列腺和胰腺癌是最常见和难以治疗的癌症之一。重大困境 前列腺癌的管理包括歧视侵略性和懒惰形式的困难 该疾病以及需要改善高风险和castate抗性转移性疾病的需要。在 胰腺癌的病例，主要问题是晚期诊断和高致死性。进步的主要障碍 两种疾病的需求都不满足，这是相对没有有效的分子成像示踪剂/工具 在全身或术中用于指导患者管理。抗体可以高度提供 分子靶标的特定探针，可以设计以优化其作为临床成像剂的实用性 使用。在上一个项目期间，基于 针对前列腺干细胞抗原（PSCA）的工程抗体片段，一种细胞表面生物标志物 由大多数前列腺和胰腺癌表示，这也是一个有前途的治疗靶标。二 片段格式，cys-diabody和cys-sinibody，可以实现特定地点的共轭和标签 生产的目的是提供可以用正电子发射来放射标记的多功能片段 放射性核素124i，89zR或18f，以及与荧光标签共轭用于光学成像。在提议中 荧光标记为PSCA CYS-果糖和CYS-INIBODIES的工作将开发为术中 在临床前模型中评估了分子成像探针及其效用。双重标记的探针（PET/光学） 还将产生以使得相同的探针可用于全身成像，然后进行术中。 可视化局部/区域差异。最后，基于有希望的生物分布和成像研究 在患者中，将探索放射性标记的抗PSCA CYS微蛋白的治疗潜力，探索 比较非残疾（131i）和剩余（177LU）治疗放射性核素。完整的生物分布将是 进行剂量估计（小鼠和人剂量法），然后进行放射免疫疗法研究 临床前模型。此外，PSCA靶向的放射免疫疗法的效力与 将评估雄激素消融或PAR抑制。这些完全人性化的免疫集探针可以是 容易转化为诊所，以解决临床管理中的紧迫问题，包括新的 被诊断，反复和转移性前列腺和胰腺癌；改进的选择和分类 靶向PSCA的患者；并监测疾病对治疗的反应，并最终可以作为 靶向肿瘤的放射疗法的有效输送工具。