A PotentIn VivoAntitumor 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 thein vitroandin vivoantitumorigenic 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.
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania.|Sichuan Huiyang Life Science and Technology Corp., Chengdu, Sichuan, China.
Kang-Jian
KJ
Zhang
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Xiao-Fei
XF
Yin
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, China.
Yuan-Qin
YQ
Yang
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Hui-Ling
HL
Li
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Yan-Ni
YN
Xu
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Lie-Yang
LY
Chen
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Xi-Jun
XJ
Liu
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Su-Jing
SJ
Yuan
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Xian-Long
XL
Fang
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Jing
J
Xiao
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Shuai
S
Wu
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.|Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
Hai-Neng
HN
Xu
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Liang
L
Chu
Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania.
Kanstantsin V
KV
Katlinski
Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania.
Yuliya V
YV
Katlinskaya
Sichuan Huiyang Life Science and Technology Corp., Chengdu, Sichuan, China.
Rong-Bing
RB
Guo
Sichuan Huiyang Life Science and Technology Corp., Chengdu, Sichuan, China.
Guang-Wen
GW
Wei
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Da-Cheng
DC
Wang
State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. xyliu@sibcb.ac.cn syfuchs@upenn.edu.|Xinyuan Institute of Medicine and Biotechnology, Zhejiang Sci-Tech University, Hangzhou, China.
Xin-Yuan
XY
Liu
Department of Biomedical Sciences, University of Pennsylvania, Philadelphia, Pennsylvania. xyliu@sibcb.ac.cn syfuchs@upenn.edu.
Serge Y
SY
Fuchs
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D020349:Surface Plasmon Resonance; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins
Cancer Biol Ther. 2007 Sep;6(9):1437-41
17873516
J Cell Biochem. 2014 Jan;115(1):8-16
23959845
Cell. 2014 Feb 27;156(5):986-1001
24581497
J Neuroimmunol. 2000 Aug 1;108(1-2):64-7
10900338
Nat Rev Immunol. 2015 Jul;15(7):405-14
26027717
Structure. 1996 Dec 15;4(12):1453-63
8994971
J Biol Chem. 2008 Nov 21;283(47):32925-36
18801736
Semin Cancer Biol. 2000 Apr;10(2):125-44
10936063
Clin Cancer Res. 2000 Jul;6(7):2881-90
10914738
J Biol Chem. 2007 Apr 13;282(15):11602-11
17310065
Cell Host Microbe. 2009 Jan 22;5(1):72-83
19154989
J Interferon Cytokine Res. 2013 Apr;33(4):211-25
23570388
J Cell Biol. 2007 Dec 3;179(5):935-50
18056411
Nat Rev Immunol. 2005 May;5(5):375-86
15864272
Blood. 2011 Oct 6;118(14):4003-6
21832278
Chin Med J (Engl). 2011 Feb;124(3):396-400
21362340
Immunol Rev. 2004 Dec;202:8-32
15546383
Cell Rep. 2016 Apr 5;15(1):171-80
27052162
Mol Cell Biol. 2009 Sep;29(17):4778-87
19564411
Neurochem Int. 2000 Mar;36(3):193-6
10676852
J Mol Biol. 2007 Feb 16;366(2):525-39
17174979
Nat Genet. 2009 May;41(5):544-52
19282848
Oncol Rep. 1999 Jan-Feb;6(1):149-53
9864419
J Biotechnol. 2010 Mar;146(1-2):74-83
20067809
Mol Cell Biol. 2011 Aug;31(16):3252-66
21690295
Ann Surg. 2007 Aug;246(2):259-68
17667505
Pigment Cell Melanoma Res. 2010 Dec;23(6):838-40
21644263
Genes Cancer. 2010 Jul;1(7):725-34
21127735
Oncogene. 2012 Jan 12;31(2):161-72
21666722
Oncogene. 2013 Sep 5;32(36):4214-21
23045272
Eur J Cancer. 2010 Jan;46(2):284-97
19906524
Nat Rev Drug Discov. 2007 Dec;6(12):975-90
18049472
PLoS One. 2014 Jan 09;9(1):e84259
24416207
Cancer Cell. 2014 Jan 13;25(1):37-48
24434209
J Biol Chem. 2004 Nov 5;279(45):46614-20
15337770
Cytokine. 2011 Nov;56(2):282-9
21856167
Trends Immunol. 2015 Mar;36(3):139-49
25687684
Science. 2014 Jan 3;343 (6166):84-7
24336571
Nat Biotechnol. 2007 Dec;25(12 ):1411-9
18066038
Mol Cell Biol. 2006 Mar;26(5):1888-97
16479007
Cell. 1995 May 19;81(4):551-60
7758109
EMBO J. 2003 Oct 15;22(20):5480-90
14532120
Cell. 2011 Aug 19;146(4):621-32
21854986
Growth Factors. 2012 Jun;30(3):141-8
22394219
Curr Top Microbiol Immunol. 2007;316:71-95
17969444
Nat Rev Drug Discov. 2008 Jan;7(1):84-99
18079757
Pharmacol Rep. 2015 Jun;67(3):542-4
25933967
J Neuroimmunol. 2004 Nov;156(1-2):107-12
15465601
Immunol Rev. 2012 Nov;250(1):317-34
23046138
J Clin Oncol. 1984 Apr;2(4):336-52
6323641