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

描述(申请人提供)：胰腺癌仍然是最致命的癌症之一，由于缺乏有效的早期检测方法，复杂和侵入性的外科治疗，以及早期扩散和转移。显然，需要更好的治疗方法，同时，还需要改进检测和分期胰腺癌的手段。前列腺干细胞抗原(PSCA)最初被认为是前列腺癌和膀胱癌的标志物，也被认为在胰腺癌中高度过度表达。识别PSCA的抗体已经在前列腺癌中显示出生物活性，目前正在对胰腺癌的治疗进行临床评估。一种人源化、亲和力成熟的抗PSCA工程抗体片段(微体；单链FV-CH3融合蛋白，80 kDa)已经产生，具有快速的肿瘤靶向和快速的血液清除，优化了包括免疫PET在内的成像应用。PSCA特异性微体已经放大并在cGMP条件下生产，用于转移性前列腺癌患者的试点PET成像研究。这项Fast Track STTR赠款提案的总体目标是将PSCA特异性微体转化为胰腺癌的临床PET成像。在第一阶段，将生产和纯化人源化、亲和力成熟的PSCA微体，优化放射性碘标记并确认与重组PSCA的结合，并将在携带人胰腺癌异种移植瘤的小鼠中评估靶向、生物分布、清除和microPET成像。在第二阶段，从现有的主细胞库开始，将进行cGMP生产(&gt；350毫克)PSCA特异性微体；蛋白质将被提纯、瓶装和测试。将在临床规模上进行I-124的放射性碘试验，并准备IND申请。这些步骤将为胰腺癌患者的临床影像研究奠定基础。 公共卫生相关性：胰腺癌仍然是最致命的癌症之一，总体五年生存率(所有阶段)为5%，局部疾病的五年生存率仅为20%。该领域的挑战包括缺乏有效的早期发现，手术治疗的复杂性，以及胰腺癌的早期扩散和转移。显然，需要更好的治疗方法，同时，还需要改进检测和分期胰腺癌的手段。此外，随着胰腺癌发生发展的分子改变变得更加清晰，新的分子诊断方法的机会也随之打开。这项建议描述了一种新型的胰腺癌分子显像剂，它基于一种工程抗体片段-PSCA微体-识别在胰腺癌中特异表达的靶点。使用PSCA微体的免疫PET成像可以为胰腺癌的诊断、分期和治疗提供重要的新工具。

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. PUBLIC HEALTH RELEVANCE: Pancreatic cancer remains one of the most lethal of cancers, with an overall five-year survival rate (all stages) of 5% and only a 20% five-year survival rate for localized disease. Challenges in the field include a lack of effective early detection, complexity of surgical treatment, and early spread and metastasis of pancreatic adenocarcinomas. Clearly, better therapeutic approaches are needed, and in parallel, improved means for detecting and staging pancreatic cancer. Furthermore, as the molecular alterations that underlie the development of pancreatic cancer become more clear, opportunities for novel molecular diagnostics also open up. This proposal describes a novel molecular imaging agent for pancreatic cancer based on an engineered antibody fragment - PSCA minibody - that recognizes a target that is specifically expressed in pancreatic cancer. ImmunoPET imaging using the PSCA minibody can provide an important new tool for diagnosis, staging, and management of pancreatic cancer.