OPN neutralization monoclonal antibody 100G2 for human pancreatic cancer immunotherapy

项目摘要 根据美国癌症协会的数据，胰腺癌患者的5年总生存率为 约9%。吉西他滨是胰腺癌的标准疗法，但它只会增加患者的死亡率。 存活约5周。尽管免疫检查点抑制剂（ICI）免疫治疗在许多疾病中取得了突破， 人类癌症的类型。胰腺癌是为数不多的人类癌症之一， ICI免疫疗法。因此，胰腺癌迫切需要新的治疗方法。底层 胰腺癌对ICI免疫疗法无应答的机制目前尚不清楚。一种观点认为， 胰腺癌是一种缺乏细胞毒性T淋巴细胞（CTL）肿瘤的"冷或非免疫原性"癌症 浸润我们最近发现，CTL浸润存在于人胰腺癌中， 人胰腺肿瘤细胞表达丰富的PD-L1。此外，文献表明，髓系- 衍生的抑制细胞（MDSC）在胰腺癌中很丰富，我们和其他人已经确定 MDSC通过PD-L1依赖性和PD-L1非依赖性机制抑制CTL。因此 CTL也可能被PD-L1非依赖性机制抑制，该机制补偿PD-L1功能 在胰腺肿瘤微环境中。我们在小鼠肿瘤模型和人类癌症患者中发现， 骨桥蛋白（OPN）作为另一个免疫检查点，负调节T细胞活化。我们 已发表的数据和未发表的初步研究表明，将OPN靶向 抑制胰腺癌免疫逃避。与这一提议高度相关，我们开发了一流的 OPN中和单克隆抗体，其在逆转OPN介导的T细胞抑制中是有效的 activation.我们的中心假设是OPN在抑制CTL活化中补偿PD-L1功能 OPN mAb对胰腺癌ICI免疫治疗有效。为了验证这一 假设，我们将追求以下两个具体目标：1）测试假设，中和OPN功能 增加抗PD-1免疫疗法在体内抑制胰腺癌中的功效;和2）人源化 OPN mAb用于人胰腺癌免疫治疗。成功完成拟议的研究， 开发用于人胰腺癌免疫治疗的人源化OPN单克隆抗体的潜力。

Project Summary According to the American Cancer Society, the 5-year overall survival rate of pancreatic cancer patients is approximately 9%. Gemcitabine is the standard therapy for pancreatic cancer, but it only increases patient survival by about 5 weeks. Despite breakthroughs in immune checkpoint inhibitors (ICI) immunotherapy in many types of human cancer. Pancreatic cancer stands out as one of the few human cancers that does not respond to ICI immunotherapy. New therapies therefore are in urgent need for pancreatic cancer. The underlying mechanism of pancreatic cancer non-response to ICI immunotherapy is currently unknown. One notion is that pancreatic cancer is a type of “cold or nonimmunogenic” cancer that lacks cytotoxic T lymphocyte (CTL) tumor infiltration. We have recently shown that CTL infiltrates are present in the human pancreatic carcinoma and human pancreatic tumor cells express abundant PD-L1. Furthermore, literatures have shown that myeloid- derived suppressor cells (MDSCs) are abundant in the pancreatic cancer, and we and others have determined that MDSCs suppress CTLs through both PD-L1-dependent and PD-L1-independent mechanisms. It is therefore likely that CTLs are also suppressed by a PD-L1-independent mechanism that compensates for PD-L1 function in the pancreatic tumor microenvironment. We discovered in mouse tumor models and human cancer patients that osteopontin (OPN) acts as another immune checkpoint that negatively regulates T cell activation. Our published data and unpublished preliminary studies demonstrated strong scientific promise to target OPN to suppress pancreatic cancer immune evasion. Highly relevant to this proposal, we have developed a first-in-class OPN neutralization monoclonal antibody that is potent in reversing OPN-mediated suppression of T cell activation. Our central hypothesis is that OPN compensates for PD-L1 function in suppression of CTL activation and OPN mAb is effective in rendering pancreatic cancer response to ICI immunotherapy. To test this hypothesis, we will pursue the following two specific aims: 1) test the hypothesis that neutralizing OPN function increases the efficacy of anti-PD-1 immunotherapy in suppression of pancreatic cancer in vivo; and 2) humanize OPN mAb for human pancreatic cancer immunotherapy. Successful completion of the proposed studies has the potential to develop a humanized OPN monoclonal antibody for human pancreatic cancer immunotherapy.