Clinical Production and IND enabling Studies for PSCA Minibody Imaging in Pancrea

描述（由申请人提供）：由于缺乏有效的早期检测方法、复杂和侵入性的手术治疗以及早期扩散和转移，胰腺癌仍然是最致命的癌症之一。显然，需要更好的治疗方法，同时需要改进胰腺癌的检测和分期方法。前列腺干细胞抗原（PSCA）最初被鉴定为前列腺癌和膀胱癌的标志物，也被认为在胰腺癌中高度过表达。识别PSCA的抗体已在前列腺癌中表现出生物活性，目前正在对胰腺癌的治疗进行临床评价。已经产生了人源化的亲和力成熟的抗PSCA工程化抗体片段（微抗体;单链Fv-CH 3融合蛋白，80 kDa），其具有快速肿瘤靶向和快速血液清除，优化用于成像应用，包括免疫PET。PSCA特异性微抗体已在cGMP条件下按比例放大和生产，用于转移性前列腺癌患者的试点PET成像研究。这项快速通道STTR拨款提案的总体目标是将PSCA特异性微抗体用于胰腺癌的临床PET成像。在I期，将生产和纯化人源化的亲和力成熟的PSCA微抗体，放射性碘标记优化并确认与重组PSCA的结合，并将在携带人胰腺肿瘤异种移植物的小鼠中评价靶向、生物分布、清除和microPET成像。在II期，从现有的主细胞库开始，将进行PSCA特异性微抗体的cGMP生产运行（>350 mg）;将纯化蛋白质，将其装入小瓶并进行测试。将以临床规模进行I-124放射性碘化试验，并准备IND申请。这些步骤将为胰腺癌患者的临床影像学研究奠定基础。

DESCRIPTION (provided by applicant): Pancreatic cancer remains one of the most lethal of cancers, due to a lack of effective early detection methods, complex and invasive surgical treatments, and early spread and metastasis. Clearly, better therapeutic approaches are needed, and in parallel, improved means for detecting and staging pancreatic cancer. Prostate stem cell antigen (PSCA), originally identified as a marker in prostate and bladder cancer, and has also been recognized as highly over expressed in pancreatic adenocarcinoma. Antibodies recognizing PSCA have demonstrated biological activity in prostate cancer and are currently in clinical evaluation for treatment of pancreatic cancer. A humanized, affinity-matured anti-PSCA engineered antibody fragment (minibody; single- chain Fv-CH3 fusion protein, 80 kDa) has been generated with rapid tumor targeting and fast blood clearance optimize for imaging applications, including immunoPET. The PSCA-specific minibody has been scaled up and produced under cGMP conditions for a pilot PET imaging study in patients with metastatic prostate cancer. The overall goal of this Fast Track STTR grant proposal is to translate PSCA-specific minibodies for clinical PET imaging of pancreatic cancer. In Phase I, humanized, affinity-matured PSCA minibody will be produced and purified, radioiodination optimized and binding to recombinant PSCA confirmed, and targeting, biodistribution, clearance, and microPET imaging will be evaluated in mice bearing human pancreatic tumor xenografts. In Phase II, starting with an existing Master Cell Bank, a cGMP production run (>350 mg) of PSCA-specific minibody will be conducted; protein will be purified, vialed and tested. Test radioiodinations withI-124 will be conducted at clinical scale, and an IND application will be prepared. These steps will set the stage for a clinical imaging study in patients with pancreatic adenocarcinoma.