Multifunctional immunoPET tracers for pancreatic and prostate cancer

描述（由申请人提供）：前列腺癌和胰腺癌是最常见和最难治疗的癌症。前列腺癌治疗的主要难题包括难以区分侵袭性和惰性形式的疾病，以及需要改进对高风险和去势抵抗转移性疾病的治疗。就胰腺癌而言，主要问题是诊断晚和死亡率高。这两种疾病进展的一个主要障碍和未满足的需求是相对缺乏有效的分子成像示踪剂/工具来指导患者管理。抗体可以为分子靶点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）相结合，提供敏感和定量的检测。新的免疫pet显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，PSCA是大多数前列腺癌和胰腺癌表达的细胞表面生物标志物，也是一个有前景的治疗靶点。将评估两种片段格式，cys- diabody和cys-minibody，以探索它们在体内不同的动力学和清除途径，并确定前列腺癌和胰腺癌成像的最佳格式。蛋白质工程将用于生成多功能片段，这些片段可以使用各种共轭策略用正电子发射的放射性核素124I， 89Zr或18F进行放射性标记。有希望的psca靶向抗体将通过免疫pet在前列腺癌疾病进展的小鼠模型和前列腺癌基因工程小鼠模型中进行评估。候选工程片段也将用于胰腺导管腺癌的异种移植和基因工程小鼠胰腺癌模型的成像。这些完全人源化的免疫pet探针可以很容易地转化为临床，以解决临床管理中的紧迫问题，包括新诊断、复发和转移性前列腺癌和胰腺癌的分期；定量PSCA在体内的表达，以改善PSCA靶向治疗患者的选择和分类；监测疾病对治疗的反应，特别是在骨骼等难以进行癌症特异性成像的部位（例如前列腺癌）。

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).