Caixing Wu1, Xiaofei Xiang2, Yang Yue2, Lin Li2, Yesen Li1, Chong Zhang2, Yuhong Xu3. 1. Zhejiang-California International NanoSystems Institute, Zhejiang University, Hangzhou, China. 2. School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China. 3. College of Pharmacy and Chemistry, Dali University, Dali, China. yhxu@sjtu.edu.cn.
Abstract
PURPOSE: Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs were found to be able to target cells that express Toll-like receptor 9 to modulate innate and adaptive immune reactions. But their in vivo application in immunotherapy against cancer has not been successful. We attempted in this study to examine polyethylene-glycol (PEG) conjugated CpG ODNs and investigated their mechanism of immune modulation in anti-cancer therapy. METHODS: CpG-PEG conjugates with different PEG lengths were synthesized. In vitro activity as well as in vivo pharmacokinetics and pharmacodynamics properties were evaluated. RESULTS: CpG-PEG20Ks were found to be able to persist longer in circulation and activate various downstream effector cells. After intravenous injection, they resulted in higher levels of IL-12p70 in the circulation and lower M-MDSC infiltrates in the tumor microenvironment. Such activities were different from those of CpG ODNs without PEGylation, suggesting different PK-PD profiles systemically and locally. CONCLUSIONS: Our data support the development of CpG-PEGs as a new therapeutic agent that can be systemically administered to modulate immune responses and the microenvironment in tumor tissues.
PURPOSE: Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs were found to be able to target cells that express Toll-like receptor 9 to modulate innate and adaptive immune reactions. But their in vivo application in immunotherapy against cancer has not been successful. We attempted in this study to examine polyethylene-glycol (PEG) conjugated CpG ODNs and investigated their mechanism of immune modulation in anti-cancer therapy. METHODS:CpG-PEG conjugates with different PEG lengths were synthesized. In vitro activity as well as in vivo pharmacokinetics and pharmacodynamics properties were evaluated. RESULTS: CpG-PEG20Ks were found to be able to persist longer in circulation and activate various downstream effector cells. After intravenous injection, they resulted in higher levels of IL-12p70 in the circulation and lower M-MDSC infiltrates in the tumor microenvironment. Such activities were different from those of CpG ODNs without PEGylation, suggesting different PK-PD profiles systemically and locally. CONCLUSIONS: Our data support the development of CpG-PEGs as a new therapeutic agent that can be systemically administered to modulate immune responses and the microenvironment in tumor tissues.
Authors: Yanyan Lou; Chengwen Liu; Gregory Lizée; Weiyi Peng; Chunyu Xu; Yang Ye; Brian A Rabinovich; Yared Hailemichael; Alexander Gelbard; Dapeng Zhou; Willem W Overwijk; Patrick Hwu Journal: J Immunother Date: 2011-04 Impact factor: 4.456
Authors: Stefan Nierkens; Martijn H den Brok; Thijs Roelofsen; Jori A L Wagenaars; Carl G Figdor; Theo J Ruers; Gosse J Adema Journal: PLoS One Date: 2009-12-18 Impact factor: 3.240