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

描述(申请人提供)：通常被诊断为晚期转移性疾病的癌症，如胰腺癌，仍然对标准的放射、手术和化疗无效。随着更新的更有针对性的药物的进步，胰腺癌的5年死亡率仍然是令人沮丧的93%，这突显了确定可以用于阻断转移过程的靶点的迫切需要。UPA系统已经显示出作为这样一个目标的前景。然而，临床前研究的一个主要局限性是转移涉及肿瘤和周围间质组织来源的uPA及其受体uPAR。我们计划使用专有的酵母展示文库和竞争性筛选方法来尝试和鉴定可以阻断人和鼠的uPAR和uPA的抗体，然后在胰腺癌的原位模型中测试每种抗体，无论是作为单独的单一疗法还是与吉西他滨联合使用，以评估它们作为转移过程抑制剂的相对有效性。与公共卫生相关：尽管在过去10到20年中，在确定毒性低于标准化疗的癌症治疗方面取得了进展，但在改善被诊断为晚期、已扩散到全身的疾病(转移性疾病)的患者的结果方面收效甚微。这项应用的目标是产生非常有效的抗体，针对一个系统的两个组件，即所谓的尿激酶系统，该系统似乎在癌症扩散和转移的潜在侵袭过程中发挥重要作用，并在胰腺癌模型中对它们进行测试。如果他们在这些临床前模型中被证明是成功的，这些抗体可以直接开发成治疗人类胰腺癌的新型治疗剂。

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.