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

临床生产和 IND 使胰腺 PSCA 微型体成像研究成为可能

基本信息

批准号：
8199036
负责人：
DAVID MORRIS COLCHER
金额：
$ 7.14万
依托单位：
IMAGINAB, INC.
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-27 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8199036
关键词：
Affinity Antibodies Applications Grants Binding Biodistribution Biological Blood Cancer Patient Cell Line Cell surface Chimeric Proteins Clinical Clinical Protocols Complex Cyclic GMP Detection Development Diagnosis Diagnostic Early Diagnosis Early treatment Engineering Evaluation Flow Cytometry Goals High Pressure Liquid Chromatography Human I125 isotope Image Imagery Immunoglobulin Fragments In Vitro Localized Disease Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Metastatic Prostate Cancer Methods Molecular Mus Neoplasm Metastasis Operative Surgical Procedures Pancreas Pancreatic Adenocarcinoma Patients Phase Phenotype Positron Positron-Emission Tomography Preparation Production Property Proteins Radioactivity Radioisotopes Radiolabeled Recombinants Running Small Business Technology Transfer Research Soft Tissue Neoplasms Staging Survival Rate Testing Therapeutic Tracer Translating Work Xenograft procedure antibody engineering base cGMP production cancer imaging cell bank immunoreactivity improved in vivo meetings molecular imaging mouse model novel overexpression pancreatic cancer cells pancreatic neoplasm preclinical study prostate stem cell antigen radiotracer research clinical testing scale up tool tumor tumor xenograft uptake

项目摘要

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.

描述（申请人提供）：由于缺乏有效的早期检测方法、复杂且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）最初被确定为前列腺癌和膀胱癌的标志物，并且也被认为在胰腺癌中高度过度表达。识别 PSCA 的抗体已在前列腺癌中表现出生物活性，目前正在进行胰腺癌治疗的临床评估。已生成人源化、亲和力成熟的抗 PSCA 工程抗体片段（微型抗体；单链 Fv-CH3 融合蛋白，80 kDa），并针对成像应用（包括免疫 PET）进行快速肿瘤靶向和快速血液清除优化。 PSCA 特异性微型抗体已在 cGMP 条件下进行放大和生产，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 特异性微型抗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 微型抗体，优化放射性碘标记并确认与重组 PSCA 的结合，并将在携带人胰腺肿瘤异种移植物的小鼠中评估靶向、生物分布、清除和 microPET 成像。在第二阶段，将从现有的主细胞库开始，进行 PSCA 特异性微型抗体的 cGMP 生产运行（> 350 毫克）；蛋白质将被纯化、装瓶并进行测试。 I-124 放射性碘标记试验将在临床规模上进行，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。公共健康相关性：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%。该领域面临的挑战包括缺乏有效的早期检测、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，同时需要改进胰腺癌的检测和分期方法。此外，随着胰腺癌发展背后的分子改变变得更加清晰，新型分子诊断的机会也随之出现。该提案描述了一种基于工程化抗体片段（PSCA 微型抗体）的新型胰腺癌分子成像剂，该片段可识别胰腺癌中特异性表达的靶点。使用 PSCA 微型抗体的免疫 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。