Programmed cell death 1 (PD-1) and programmed death-ligand 1 (PD-L1) interact to form an immune checkpoint fostering viral infection and viral oncogene-induced tumorigenesis. We generated a novel anti-human PD-1, humanized monoclonal antibody P1801 and investigated its pharmacologic, pharmacokinetic (PK), and pharmacodynamic properties. In vitro binding assays revealed that P1801 uniquely binds to human PD-1 and inhibits its interaction with PD-L1/2. It showed a minor effect on the induction of antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). P1801 significantly induced the release of IL-2 from activated T-cells but not from nonactivated T-cells. A dose-dependent linear PK profile was observed for the cynomolgus monkeys treated with repeated doses of P1801 at 5 mg/kg to 200 mg/kg once weekly. A four-week repeat-dose toxicity study revealed that P1801 given weekly was safe and well tolerated at doses ranging from 5 to 200 mg/kg/dose. No pathological abnormalities were noted. In humanized PD-1 mice harboring human PD-L1-expressing colon tumor cells, P1801 administered intraperitoneally twice per week at 12 mg/kg significantly inhibited tumor growth and prolonged mouse survival. P1801 displayed unique binding properties different from pembrolizumab and nivolumab. Therefore, it showed distinctive immunological reactions and significant antitumor activities. We are initiating a Phase 1 clinical study to test its combination use with ropeginterferon alfa-2b, which also has antiviral and antitumor activities, for the treatment of cancer.
程序性细胞死亡蛋白1（PD-1）与其配体PD-L1相互作用形成免疫检查点，促进病毒感染及病毒癌基因诱导的肿瘤发生。本研究开发了一种新型抗人PD-1人源化单克隆抗体P1801，并系统评估了其药理学、药代动力学及药效学特性。体外结合实验表明，P1801能特异性结合人PD-1并有效阻断其与PD-L1/2的相互作用。该抗体仅诱导微弱的抗体依赖性细胞介导的细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）。在激活的T细胞中，P1801显著促进白细胞介素-2（IL-2）释放，但对未激活T细胞无此效应。食蟹猴每周接受5-200 mg/kg剂量P1801重复给药后，呈现剂量依赖的线性药代动力学特征。为期四周的重复给药毒性研究显示，每周5-200 mg/kg剂量范围内的P1801安全性良好且耐受性优异，未观察到病理学异常。在携带人PD-L1表达结肠肿瘤细胞的人源化PD-1小鼠模型中，每周两次腹腔注射12 mg/kg P1801能显著抑制肿瘤生长并延长小鼠生存期。与帕博利珠单抗和纳武利尤单抗相比，P1801展现出独特的结合特性，从而产生差异化的免疫反应和显著的抗肿瘤活性。基于此，我们正启动一项Ⅰ期临床研究，探索P1801与兼具抗病毒和抗肿瘤活性的长效干扰素α-2b联合治疗癌症的潜力。
肿瘤(癌症)患者之家