A potent in vivo anti-tumor efficacy of novel recombinant type I interferon
Autor: | Rong-Bing Guo, Serge Y. Fuchs, Yuliya V. Katlinskaya, Haineng Xu, Kanstantsin V. Katlinski, Xinyuan Liu, Shuai Wu, Lieyang Chen, Fang Xianlong, Kangjian Zhang, Jing Xiao, Xiao-Fei Yin, Xi Jun Liu, Da-Cheng Wang, Hui-Ling Li, Liang Chu, Yuan-Qin Yang, Guang-Wen Wei, Yan-Ni Xu, Sujing Yuan |
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Jazyk: | angličtina |
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Cancer Research Angiogenesis Immunoblotting Alpha interferon Mice Nude Antineoplastic Agents Biology Pharmacology Interferon alpha-2 Article law.invention 03 medical and health sciences Mice Interferon In vivo law medicine Animals Humans Receptor Interferon-alpha Neoplasms Experimental Surface Plasmon Resonance Flow Cytometry Xenograft Model Antitumor Assays In vitro Recombinant Proteins Mice Inbred C57BL 030104 developmental biology Oncology Recombinant DNA Female CD8 medicine.drug |
Popis: | Purpose: Antiproliferative, antiviral, and immunomodulatory activities of endogenous type I IFNs (IFN1) prompt the design of recombinant IFN1 for therapeutic purposes. However, most of the designed IFNs exhibited suboptimal therapeutic efficacies against solid tumors. Here, we report evaluation of the in vitro and in vivo antitumorigenic activities of a novel recombinant IFN termed sIFN-I. Experimental Design: We compared primary and tertiary structures of sIFN-I with its parental human IFNα-2b, as well as affinities of these ligands for IFN1 receptor chains and pharmacokinetics. These IFN1 species were also compared for their ability to induce JAK–STAT signaling and expression of the IFN1-stimulated genes and to elicit antitumorigenic effects. Effects of sIFN-I on tumor angiogenesis and immune infiltration were also tested in transplanted and genetically engineered immunocompetent mouse models. Results: sIFN-I displayed greater affinity for IFNAR1 (over IFNAR2) chain of the IFN1 receptor and elicited a greater extent of IFN1 signaling and expression of IFN-inducible genes in human cells. Unlike IFNα-2b, sIFN-I induced JAK–STAT signaling in mouse cells and exhibited an extended half-life in mice. Treatment with sIFN-I inhibited intratumoral angiogenesis, increased CD8+ T-cell infiltration, and robustly suppressed growth of transplantable and genetically engineered tumors in immunodeficient and immunocompetent mice. Conclusions: These findings define sIFN-I as a novel recombinant IFN1 with potent preclinical antitumorigenic effects against solid tumor, thereby prompting the assessment of sIFN-I clinical efficacy in humans. Clin Cancer Res; 23(8); 2038–49. ©2016 AACR. |
Databáze: | OpenAIRE |
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