Novel human anti-uPAR antibodies for the treatment of pancreatic cancer

用于治疗胰腺癌的新型人类抗 uPAR 抗体

• 批准号: 7670635
• 负责人: XIAOMIN FAN
• 金额: $ 15.8万
• 依托单位: AVANTGEN, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670635
• 关键词: Affinity; Antibodies; Antigens; Binding; Biological Assay; Blocking Antibodies; Cell Line; Cell Proliferation; Cells; Development; Diagnosis; Disease; Disseminated Malignant Neoplasm; Exhibits; Extracellular Matrix; Fibrinolysis; Functional disorder; Goals; Growth; Homologous Gene; Human; Immunity; In Vitro; Individual; Lead; Libraries; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Methods; Modeling; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patients; Phase; Plasminogen; Play; Pre-Clinical Model; Prevention; Process; Radiation; Refractory; Relative (related person); Role; Screening procedure; Staging; System; Testing; Therapeutic Agents; Tissues; Urokinase; Urokinase Plasminogen Activator Receptor; Yeasts; angiogenesis; cancer therapy; chemotherapy; cross reactivity; gemcitabine; improved; in vivo; in vivo Model; inhibitor/antagonist; metastatic process; migration; mortality; novel; novel therapeutics; pancreatic neoplasm; pre-clinical; preclinical study; public health relevance; success; tumor; tumor growth

DESCRIPTION (provided by applicant): Cancers that are typically diagnosed as late-stage, metastatic disease, such as pancreatic cancer, have remained refractory to standard radiation, surgical and chemotherapy. With all the advance of newer more targeted agents, pancreatic cancer 5-year mortality rates remain a dismal 93% underscoring the urgent need to identify targets that can be used to block the metastatic process. The uPA system has shown promise as one such target. However, a major limitation of pre-clinical studies is that metastasis involves both tumor and surrounding stromal tissue-derived uPA and its receptor, uPAR. We plan to use a proprietary yeast display library and competitive screening method to try and identify antibodies that can block both human and mouse uPAR and uPA and then test each antibody in an orthotopic model of pancreatic cancer, both as individual monotherapies and in combination with gemcitabine, to evaluate their relative efficacy as inhibitors of the metastatic process. PUBLIC HEALTH RELEVANCE: Despite the progress that has been made over the past 10 to 20 years in identifying cancer treatments that are less toxic than standard chemotherapy, there has been little success in improving the outcome of patients who are diagnosed with advanced, late-stage disease that has spread throughout the body (metastatic disease). The goals of this application are to generate very potent antibodies directed against two components of a system, the so-called urokinase system, that appears to play a major role in the invasive processes underlying cancer spread and metastasis and test them in a model of pancreatic cancer. If they prove successful in these pre-clinical models, these antibodies can be directly developed into novel therapeutic agents for treatment of human pancreatic cancer.

描述（由申请人提供）：通常被诊断为后期，转移性疾病（例如胰腺癌）的癌症仍然对标准放射线，手术和化学疗法难治性。随着较新的针对性药物的所有进步，胰腺癌的5年死亡率仍然令人沮丧的93％强调了迫切需要识别可用于阻止转移过程的靶标。 UPA系统已显示为这样的目标。但是，临床前研究的主要局限性是转移涉及肿瘤和周围基质组织衍生的UPA及其受体UPAR。我们计划使用专有的酵母展示库和竞争性筛查方法来识别可以阻止人和老鼠UPAR和UPA的抗体，然后在胰腺癌正常模型中测试每种抗体，既可以作为单个单疗法，又是与gemcitabine结合使用，以评估其相对效率，以评估其抑制剂的相对效率。公共卫生相关性：尽管在过去的10到20年中取得了进展，但在鉴定毒性的毒性比标准化学疗法较小的癌症治疗方面取得了进展，但在改善被诊断出患有晚期晚期疾病的患者的结果方面却几乎没有成功。该应用的目标是生成针对系统的两个组成部分，即所谓的尿蛋白酶系统的非常有效的抗体，该抗体似乎在癌症传播和转移的侵入性过程中起主要作用，并在胰腺癌模型中对其进行测试。如果它们在这些临床前模型中获得成功，这些抗体可以直接发展为新型治疗剂，以治疗人类胰腺癌。