Multifunctional immunoPET tracers for pancreatic and prostate cancer

项目摘要 前列腺癌和胰腺癌是最常见和最难治疗的癌症之一。主要困境 前列腺癌的治疗包括区分侵袭性和惰性形式的困难 以及需要改善高风险和去势抵抗性转移性疾病的治疗。在 在胰腺癌的病例中，主要问题是诊断晚和高致死率。进步的一个主要障碍 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， 用于全身或术中水平，以指导患者管理。抗体可以提供高度 分子靶点的特异性探针，并且可以被工程化以优化它们作为临床成像剂的效用。 使用.在上一个项目期间，已经开发了基于以下的新型免疫PET成像剂： 针对前列腺干细胞抗原（PSCA）（细胞表面生物标志物）的工程化抗体片段 由大多数前列腺癌和胰腺癌表达，这也是一个有前途的治疗靶点。两 能够实现位点特异性缀合和标记的片段形式，cys-双抗体和cys-微抗体， 产生的目的是提供可以用正电子发射的放射性标记的多功能片段， 放射性核素124 I、89 Zr或18F，和/或与荧光标记物缀合用于光学成像。拟议 在这项工作中，荧光标记的PSCA cys-双抗体和cys-微抗体将被开发为术中 分子成像探针及其在临床前模型中的效用评估。双标记探针（PET/光学） 同样的探头可用于全身成像， 本地/区域传播的可视化。最后，基于有希望的生物分布和成像研究， 为了在患者中检测微抗体，将探索放射性标记的抗PSCA cys-微抗体的治疗潜力， 比较非残留（131 I）和残留（177 Lu）治疗性放射性核素。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，靶向PSCA的放射免疫疗法与 将评价雄激素消除或PARP抑制。这些完全人源化的免疫PET探针可以是 容易翻译到诊所，以解决临床管理中的紧迫问题，包括新的分期 诊断，复发和转移性前列腺癌和胰腺癌;改善的选择和分类 患者进行PSCA靶向治疗;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载体。

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.