A Potent In Vivo Antitumor Efficacy of Novel Recombinant Type I Interferon.

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.

[Effect of Recombinant Super-compound Interferon (rSIFN-co) on Proliferation and Apoptosis of Human Pulmonary Adenocarcinoma Cell A549].

OBJECTIVE: To investigate the effect of recombinant super-compound interferon (rSIFN-co) on the proliferation and apoptosis of pulmonary adenocarcinoma cell line A549. METHODS: Screening tests were conducted to determine the concentrations of rSIFN-co that have a significant impact on A549 and the optimal concentration and duration for the test of rSIFN-co combined with Cisplatin. A549 cells were treated with rSIFN-co, Infergen, rSIFN- co+ Cisplatin, Infergen + Cisplatin, and Cisplatin, respectively, and compared with those cultured in normal medium. The viable A549 cells from Day 1 to Day 7 were detected by MTT assay. Cell apoptosis was detected by flow cytometry (FCM). Apoptosis-associated proteins, Fas and Bcl-2 were detected by immunofluoroscence at 48 h. RESULTS: Effective concentrations of rSIFN-co ranged from 1 to 64 µg/mL, and a minimal of 2 µg/mL Cisplatin was needed. The optimal test condition was set at 5 µg/mL rSIFN-co combined with 2 µg/mL Cisplatin for a duration of 48 h. rSIFN-co demonstrated a stronger inhibiting effect on cell proliferation than Infergen. The inhibiting efficiency of rSIFN-co+Cisplatin was also stronger than that of Infergen+Cisplatin. Apoptosis of A549 cells induced by rSIFN-co was also more significant than that of Infergen (P = 0.000). Cells treated with rSIFN- co+ Cisplatin has a higher apoptosis rate than those treated with rSIFN-co (P = 0.004) or Cisplatin (P = 0.023). rSIFN-co increased the expression of Fas and decreased the expression of Bcl-2. Cells treated with rSIFN-co showed lower fluoroscence intensity of Bcl-2 than those treated with Infergen (P < 0.05). CONCLUSION: rSIFN-co inhibits the proliferation of A549 and its effect is stronger than that of Infergen. Cisplatin can further enhance the inhibiting effect of rSIFN-co. The inhibiting efficiency may be associated with the expression of apoptosis-related genes.