Imaging Prostate Cancer with Engineered PSCA Antibodies

前列腺干细胞抗原(PSCA)是一种在大多数前列腺癌中表达的细胞表面蛋白。 在过去的4年里，我们已经(1)确认PSCA是前列腺癌治疗的靶点(2)表明 PSCA可能是PTEN缺失型前列腺癌的标志物(3)证明了一种单抗 靶向PSCA在体内抑制前列腺癌的进展和转移(4)表明抗PSCA抗体 PSCA通过Fc非依赖机制诱导细胞死亡和(5)人源化PSCA抗体 保持活力并可用于临床的药物。同时，一种完全人源性抗PSCA抗体 与业界合作开发，并成功转化为转移性男性患者的I期试验 前列腺癌。在目前的应用中，我们建议开发和测试一种放射性标记的PSCA抗体 用SPECT和PET扫描对前列腺癌进行分子成像。一种PSCA靶向分子 成像探头有可能提高对晚期和转移性前列腺癌的检测能力。它 可用于基于PSCA表达的水平和程度在分子水平上对肿瘤进行分类， 这可能识别出PTEN突变的肿瘤或对PSCA抗体治疗有反应的肿瘤。最后，PSCA- 靶向分子成像探针可用于监测治疗反应(例如。PSCA抗体治疗 或靶向PIS激酶-PTEN-Akt通路的药物)。人性化的PSCA微型车身已经 构建了PSCA阳性异种移植物的显着图像，具有良好的药代动力学(即高 肿瘤从正常组织摄取和快速清除)。本研究的目的是(1)开发和测试 受控生物系统中的工程抗体片段(2)评估PSCA抗体片段以 前列腺癌的图像转基因模型，以及(3)在转移性男性患者中进行初步成像试验 前列腺癌。这些研究有可能推动前列腺癌成像在靶向时代的发展。 并将这种疾病的诊断和治疗更紧密地联系在一起。外行人声明：这是 应用建议开发一种新的测试来识别转移性前列腺癌并对肿瘤进行分类 分子水平通过一种非侵入性的手段。我们将开发一种放射性标记的抗体并与之结合 前列腺癌细胞表面的PSCA蛋白。小鼠和人类注射这种抗体将 用SPECT扫描进行成像，以检测局限性或转移性前列腺癌。

Prostate Stem Cell Antigen (PSCA) is a cell surface protein expressed by a majority of prostate cancers. Over the past 4 years, we have (1) validated PSCA as a target for prostate cancer therapy (2) shown that PSCA may be a marker of PTEN null prostate cancers (3) demonstrated that a monoclonal antibody targeting PSCA inhibits prostate cancer progression and metastasis in vivo (4) shown that antibody against PSCA induces cell death by an Fc-independent mechanism and (5) developed humanized PSCA antibodies that retain activity and may be used in the clinic. In parallel, a fully human anti-PSCA antibody was developed in collaboration with industry and successfully translated into Phase I trials in men with metastatic prostate cancer. In the current application, we propose to develop and test a radiolabeled PSCA antibody fragment to molecularly image prostate cancer with SPECT and PET scans. A PSCA-targeted molecular imaging probe has the potential to improve the ability to detect advanced and metastatic prostate cancer. It may be used to classify tumors at the molecular level based on the level and extent of PSCA expression, which may identify tumors with PTEN mutation or that respond to PSCA antibody therapy. Finally, a PSCA- targeted molecular imaging probe might be used to monitor response to therapy (eg. PSCA antibody therapy or drugs that target the PIS kinase-PTEN-Akt pathway). A humanized PSCA minibody has already been constructed and yields striking images of PSCA-positive xenografts with excellent pharmacokinetics (i.e high tumor uptake and rapid clearance from normal tissues). The Aims of this study are (1) to develop and test engineered antibody fragments in contolled biological systems (2) to assess PSCA antibody fragments to image transgenic models of prostate cancer, and (3) to perform a pilot imaging trial in men with metastatic prostate cancer. These studies have the potential to advance prostate cancer imaging in the age of targeted therapies and to link more closely the diagnosis and treatment of this disease. Layman statement: This application proposes to develop a new test to identify metastatic prostate cancer and to classify tumors at the molecular level by a noninvasive means. We will develop an antibody that is radiolabeled and binds to the protein PSCA on the surface of prostate cancer cells. Mice and then men administered this antibody will be imaged with SPECT scans in order to detect localized or metastatic prostate cancer.