药理学
生物利用度
癌症免疫疗法
肽
化学
CD8型
单克隆抗体
免疫疗法
外周血单个核细胞
癌症研究
体外
医学
免疫系统
抗体
免疫学
生物化学
作者
Wanqiong Li,Xueqiong Zhu,Xiaoxi Zhou,Xiaoxi Wang,Wenjie Zhai,Bingyu Li,Jiangfeng Du,Guodong Li,Xinghua Sui,Yahong Wu,Mingxia Zhai,Yuanming Qi,Guanyu Chen,Yanfeng Gao
标识
DOI:10.1016/j.jconrel.2021.04.036
摘要
Blockade of the immune checkpoint PD-1/PD-L1 with monoclonal antibodies demonstrated unprecedented clinical efficacies in many cancers. But the orally available low molecular weight inhibitors remain infancy. Compared to small molecules, peptide exhibits better selectivity and fewer side effects, but poor half-life and a big challenge to be orally administrated. Here, we developed a proteolysis-resistant D peptide OPBP-1 (Oral PD-L1 Binding Peptide 1) which could selectively bind PD-L1, significantly block PD-1/PD-L1 interaction and enhance IFN-γ (interferon γ) secretion from CD8+ T cells in human PBMCs (Peripheral blood mononuclear cells). OPBP-1 could significantly inhibit tumor growth in murine colorectal CT26 and melanoma B16-OVA models at a relatively low dose of 0.5 mg/kg, with enhancing the infiltration and function of CD8+ T cells. More interestingly, oral delivery of OPBP-1 loaded TMC (N, N, N-trimethyl chitosan) hydrogel ([email protected]) showed promising OPBP-1 oral bioavailability (52.8%) and prolonged half-life (14.55 h) in rats, and also significantly inhibited tumor growth in CT26 model. In conclusion, we discovered and optimized a PD-1/PD-L1 blocking peptide OPBP-1, and subsequently loaded into a TMC based hydrogel oral delivery system, in order to maximally elevate the oral bioavailability of the peptide drug and effectively inhibit tumor growth. These results opened up a new prospect for oral drug development in cancer immunotherapy.
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