Bioengineering heterodimeric cytokines: Turning promiscuous proteins into therapeutic agents

Biotechnology and Genetic Engineering Reviews

Volumn 29, Issue 2, 2013, Pages 149-174

  Belladonna, Maria Laura ^a   Grohmann, Ursula ^a  

^a UNIVERSITY OF PERUGIA   (Italy)

Author keywords

Cytokines; Fusion proteins; Heterodimers

Indexed keywords

PATHOLOGY; PROTEINS;

CONDITION; CYTOKINES; ECONOMIC MEANS; FUSION PROTEINS; HETERODIMERS; INDIVIDUAL FACTORS; INTERLEUKIN-12; MICROENVIRONMENTS; THERAPEUTIC AGENTS; VERSATILE SYSTEM;

MOLECULES;

ABATACEPT; ANGIOGENESIS INHIBITOR; ANTIINFLAMMATORY AGENT; CANCER VACCINE; CYTOKINE; HETERODIMER; HYBRID PROTEIN; INTERLEUKIN 10; INTERLEUKIN 12; INTERLEUKIN 12P35; INTERLEUKIN 12P40; INTERLEUKIN 23; INTERLEUKIN 27; INTERLEUKIN 35; INTERLEUKIN 6; P28 P40 FUSION PROTEIN; RECOMBINANT CYTOKINE; RECOMBINANT INTERLEUKIN 12; RECOMBINANT INTERLEUKIN 23; RECOMBINANT INTERLEUKIN 27; SINGLE CHAIN IL 27; SINGLE CHAIN INTERLEUKIN 23; UNCLASSIFIED DRUG; INTERLEUKIN DERIVATIVE; INTERLEUKIN-35, HUMAN;

ABSENCE OF SIDE EFFECTS; ALLERGIC ENCEPHALOMYELITIS; AMINO ACID SEQUENCE; ANTIANGIOGENIC ACTIVITY; ANTIANGIOGENIC GENE THERAPY; ANTIGEN PRESENTING CELL; ANTIINFLAMMATORY ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; BIOENGINEERING; CANCER IMMUNOTHERAPY; CANCER PROGNOSIS; CLINICAL TRIAL (TOPIC); COLITIS; COMPLEMENT DEPENDENT CYTOTOXICITY; CYTOKINE PRODUCTION; DIMERIZATION; DRUG CLEARANCE; DRUG CYTOTOXICITY; DRUG EFFECT; DRUG FATALITY; DRUG HALF LIFE; DRUG SELECTIVITY; ENZYME PHOSPHORYLATION; GENE CONSTRUCT; GENETIC TRANSFECTION; HEMORRHAGIC COLITIS; HUMAN; IMMUNOGENICITY; IMMUNOMODULATION; IMMUNOREGULATION; IMMUNOSUPPRESSIVE TREATMENT; INTERNAL RIBOSOME ENTRY SITE; LIVER CELL CARCINOMA; MELANOMA; MYCOSIS; NONHUMAN; OSMOTIC PUMP; PROTEIN ANALYSIS; PROTEIN DOMAIN; PROTEIN ENGINEERING; PROTEIN EXPRESSION; PROTEIN PURIFICATION; PROTEIN SUBUNIT; REGULATORY T LYMPHOCYTE; RHEUMATOID ARTHRITIS; SEPSIS; SIGNAL TRANSDUCTION; SOLUBILITY; TH1 CELL; TH17 CELL; TUMOR IMMUNITY; UNSPECIFIED SIDE EFFECT; CHEMISTRY; GENETICS;

AMINO ACID SEQUENCE; BIOENGINEERING; CYTOKINES; DIMERIZATION; HUMANS; INTERLEUKIN-12; INTERLEUKIN-23; INTERLEUKIN-27; INTERLEUKINS; RECOMBINANT FUSION PROTEINS;

EID: 84887447426     PISSN: 02648725     EISSN: None     Source Type: Journal    
DOI: 10.1080/02648725.2013.801228     Document Type: Article

References (106)

1. Awasthi, A., Carrier, Y., Peron, J. P., Bettelli, E., Kamanaka, M., Flavell, R. A., ... Weiner, H. L. (2007). A dominant function for interleukin 27 in generating interleukin 10-producing anti-inflammatory T cells. Nature Immunology, 8, 1380-1389.
2. Banchereau, J., Pascual, V., & O'Garra, A. (2012). From IL-2 to IL-37: The expanding spectrum of anti-inflammatory cytokines. Nature Immunology, 13, 925-931.
3. Belladonna, M. L., Renauld, J. C., Bianchi, R., Vacca, C., Fallarino, F., Orabona, C., ... Puccetti, P. (2002). IL-23 and IL-12 have overlapping, but distinct, effects on murine dendritic cells. Journal of Immunology, 168, 5448-5454.
4. Bettini, M., Castellaw, A. H., Lennon, G. P., Burton, A. R., & Vignali, D. A. (2012). Prevention of autoimmune diabetes by ectopic pancreatic beta-cell expression of interleukin-35. Diabetes, 61, 1519-1526.
5. Boniface, K., Blom, B., Liu, Y. J., & de Waal Malefyt, R. (2008). From interleukin-23 to T-helper 17 cells: Human T-helper cell differentiation revisited. Immunological Reviews, 226, 132-146.
6. Borsellino, G., Kleinewietfeld, M., Di Mitri, D., Sternjak, A., Diamantini, A., Giometto, R., ... Falk, K. (2007). Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood, 110, 1225-1232.
7. Brahmachari, S., & Pahan, K. (2009). Suppression of regulatory T cells by IL-12p40 homodimer via nitric oxide. Journal of Immunology, 183, 2045-2058.
8. Car, B. D., Eng, V. M., Lipman, J. M., & Anderson, T. D. (1999). The toxicology of interleukin-12: A review. Toxicologic Pathology, 27, 58-63.
9. Chaturvedi, V., Collison, L. W., Guy, C. S., Workman, C. J., & Vignali, D. A. (2011). Cutting edge: Human regulatory T cells require IL-35 to mediate suppression and infectious tolerance. Journal of Immunology, 186, 6661-6666.
10. Chen, X., Zaro, J.L., & Shen, W.C. (2012). Fusion protein linkers: Property, design and functionality. Advanced Drug Delivery Reviews. Retrieved from http://dx.doi.org/10.1016/j.addr.2012.09.039.
11. Cocco, C., Canale, S., Frasson, C., Di Carlo, E., Ognio, E., Ribatti, D., ... Airoldi, I. (2010). Interleukin-23 acts as antitumor agent on childhood B-acute lymphoblastic leukemia cells. Blood, 116, 3887-3898.
12. Cohen, J. (1995). IL-12 deaths: Explanation and a puzzle. Science, 270, 908.
13. Collison, L. W., Chaturvedi, V., Henderson, A. L., Giacomin, P. R., Guy, C., Bankoti, J., ... Vignali, D. A. (2010). IL-35-mediated induction of a potent regulatory T cell population. Nature Immunology, 11, 1093-1101.
14. Collison, L. W., Delgoffe, G. M., Guy, C. S., Vignali, K. M., Chaturvedi, V., Fairweather, D., ... Vignali, D. A. (2012). The composition and signaling of the IL-35 receptor are unconventional. Nature Immunology, 13, 290-299.
15. Collison, L. W., & Vignali, D. A. (2008). Interleukin-35: Odd one out or part of the family? Immunological Reviews, 226, 248-262.
16. Collison, L. W., Workman, C. J., Kuo, T. T., Boyd, K., Wang, Y., Vignali, K. M., ... Vignali, D. A. (2007). The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature, 450, 566-569.
17. Colombo, M. P., Vagliani, M., Spreafico, F., Parenza, M., Chiodoni, C., Melani, C., & Stoppacciaro, A. (1996). Amount of interleukin 12 available at the tumor site is critical for tumor regression. Cancer Research, 56, 2531-2534.
18. D'Andrea, A., Rengaraju, M., Valiante, N. M., Chehimi, J., Kubin, M., Aste, M., ... Trinchieri, G. (1992). Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. Journal of Experimental Medicine, 176, 1387-1398.
19. Del Vecchio, M., Bajetta, E., Canova, S., Lotze, M. T., Wesa, A., Parmiani, G., & Anichini, A. (2007). Interleukin-12: Biological properties and clinical application. Clinical Cancer Research, 13, 4677-4685.
20. Delgoffe, G. M., Murray, P. J., & Vignali, D. A. (2011). Interpreting mixed signals: The cell's cytokine conundrum. Current Opinion in Immunology, 23, 632-638.
21. di Guan, C., Li, P., Riggs, P. D., & Inouye, H. (1988). Vectors that facilitate the expression and purification of foreign peptides in Escherichia coli by fusion to maltose-binding protein. Gene, 67, 21-30.
22. Diveu, C., McGeachy, M. J., Boniface, K., Stumhofer, J. S., Sathe, M., Joyce-Shaikh, B., ... Kastelein, R. A. (2009). IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells. Journal of Immunology, 182, 5748-5756.
23. Ehigiator, H. N., McNair, N., & Mead, J. R. (2007). Cryptosporidium parvum: The contribution of Th1-inducing pathways to the resolution of infection in mice. Experimental Parasitology, 115, 107-113.
24. Einhauer, A., Schuster, M., Wasserbauer, E., & Jungbauer, A. (2002). Expression and purification of homogenous proteins in Saccharomyces cerevisiae based on ubiquitin-FLAG fusion. Protein Expression and Purification, 24, 497-504.
25. Esposito, D., & Chatterjee, D. K. (2006). Enhancement of soluble protein expression through the use of fusion tags. Current Opinion in Biotechnology, 17, 353-358.
26. Fiocco, U., Sfriso, P., Oliviero, F., Pagnin, E., Scagliori, E., Campana, C., ... Punzi, L. (2008). Co-stimulatory modulation in rheumatoid arthritis: The role of (CTLA4-Ig) abatacept. Autoimmunity Reviews, 8, 76-82.
27. Fitzgerald, D. C., Ciric, B., Touil, T., Harle, H., Grammatikopolou, J., Das Sarma, J., ... Rostami, A. (2007a). Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. Journal of Immunology, 179, 3268-3275.
28. Fitzgerald, D. C., Zhang, G. X., El-Behi, M., Fonseca-Kelly, Z., Li, H., Yu, S., ... Rostami, A. (2007b). Suppression of autoimmune inflammation of the central nervous system by interleukin 10 secreted by interleukin 27-stimulated T cells. Nature Immunology, 8, 1372-1379.
29. Gaberc-Porekar, V., & Menart, V. (2001). Perspectives of immobilized-metal affinity chromatography. Journal of Biochemical and Biophysical Methods, 49, 335-360.
30. Garbers, C., Hermanns, H. M., Schaper, F., Muller-Newen, G., Grotzinger, J., Rose-John, S., & Scheller, J. (2012). Plasticity and cross-talk of interleukin 6-type cytokines. Cytokine and Growth Factor Reviews, 23, 85-97.
31. Germann, T., Rude, E., Mattner, F., & Gately, M. K. (1995). The IL-12 p40 homodimer as a specific antagonist of the IL-12 heterodimer. Immunology Today, 16, 500-501.
32. Gillessen, S., Carvajal, D., Ling, P., Podlaski, F. J., Stremlo, D. L., Familletti, P. C., ... Gately, M. K. (1995). Mouse interleukin-12 (IL-12) p40 homodimer: A potent IL-12 antagonist. European Journal of Immunology, 25, 200-206.
33. Grohmann, U., Bianchi, R., Belladonna, M. L., Vacca, C., Silla, S., Ayroldi, E., ... Puccetti, P. (1999). IL-12 acts selectively on CD8 alpha-dendritic cells to enhance presentation of a tumor peptide in vivo. Journal of Immunology, 163, 3100-3105.
34. Ha, S. J., Kim, D. J., Baek, K. H., Yun, Y. D., & Sung, Y. C. (2004). IL-23 induces stronger sustained CTL and Th1 immune responses than IL-12 in hepatitis C virus envelope protein 2 DNA immunization. Journal of Immunology, 172, 525-531.
35. Heinzel, F. P., Hujer, A. M., Ahmed, F. N., & Rerko, R. M. (1997). in vivo production and function of IL-12 p40 homodimers. Journal of Immunology, 158, 4381-4388.
36. Hisada, M., Kamiya, S., Fujita, K., Belladonna, M. L., Aoki, T., Koyanagi, Y., ... Yoshimoto, T. (2004). Potent antitumor activity of interleukin-27. Cancer Research, 64, 1152-1156.
37. Ho, M. Y., Leu, S. J., Sun, G. H., Tao, M. H., Tang, S. J., & Sun, K. H. (2009). IL-27 directly restrains lung tumorigenicity by suppressing cyclooxygenase-2-mediated activities. Journal of Immunology, 183, 6217-6226.
38. Hopkins, A. L. (2008). Network pharmacology: the next paradigm in drug discovery. Nature Chemical Biology, 4, 682-690.
39. Hu, J., Yuan, X., Belladonna, M. L., Ong, J. M., Wachsmann-Hogiu, S., Farkas, D. L., ... Yu, J. S. (2006). Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells. Cancer Research, 66, 8887-8896.
40. Hu, P., Hu, H. D., Chen, M., Peng, M. L., Tang, L., Tang, K. F., ... Ren, H. (2009). Expression of interleukins-23 and 27 leads to successful gene therapy of hepatocellular carcinoma. Molecular Immunology, 46, 1654-1662.
41. Hunter, C. A. (2005). New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions. Nature Reviews. Immunology, 5, 521-531.
42. Jana, M., Dasgupta, S., Saha, R. N., Liu, X., & Pahan, K. (2003). Induction of tumor necrosis factor-alpha (TNF-alpha) by interleukin-12 p40 monomer and homodimer in microglia and macrophages. Journal of Neurochemistry, 86, 519-528.
43. Jana, M., & Pahan, K. (2009). IL-12 p40 homodimer, but not IL-12 p70, induces the expression of IL-16 in microglia and macrophages. Molecular Immunology, 46, 773-783.
44. Jazayeri, J. A., & Carroll, G. J. (2008). Fc-based cytokines: prospects for engineering superior therapeutics. Bio Drugs, 22, 11-26.
45. Jones, L. L., Chaturvedi, V., Uyttenhove, C., Van Snick, J., & Vignali, D. A. (2012). Distinct subunit pairing criteria within the heterodimeric IL-12 cytokine family. Molecular Immunology, 51, 234-244.
46. Kaplan, W., Husler, P., Klump, H., Erhardt, J., Sluis-Cremer, N., & Dirr, H. (1997). Conformational stability of pGEX-expressed Schistosoma japonicum glutathione Stransferase: A detoxification enzyme and fusion-protein affinity tag. Protein Science, 6, 399-406.
47. Kerkar, S. P., Muranski, P., Kaiser, A., Boni, A., Sanchez-Perez, L., Yu, Z., ... Restifo, N. P. (2010). Tumor-specific CD8+ T cells expressing interleukin-12 eradicate established cancers in lymphodepleted hosts. Cancer Research, 70, 6725-6734.
48. Kleinschek, M. A., Muller, U., Brodie, S. J., Stenzel, W., Kohler, G., Blumenschein, W. M., & Alber, G. (2006). IL-23 enhances the inflammatory cell response in Cryptococcus neoformans infection and induces a cytokine pattern distinct from IL-12. Journal of Immunology, 176, 1098-1106.
49. Kobayashi, M., Fitz, L., Ryan, M., Hewick, R. M., Clark, S. C., Chan, S., ... Trinchieri, G. (1989). Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. Journal of Experimental Medicine, 170, 827-845.
50. Kochetkova, I., Golden, S., Holderness, K., Callis, G., & Pascual, D. W. (2010). IL-35 stimulation of CD39+ regulatory T cells confers protection against collagen II-induced arthritis via the production of IL-10. Journal of Immunology, 184, 7144-7153.
51. Kuo, T. T., & Aveson, V. G. (2011). Neonatal Fc receptor and IgG-based therapeutics. MAbs, 3, 422-430.
52. Kuramoto, T., Fujii, R., Nagai, H., Belladonna, M. L., Yoshimoto, T., Kohjimoto, Y., ... Hara, I. (2011). IL-23 gene therapy for mouse bladder tumour cell lines. BJU International, 108, 914-921.
53. Langrish, C. L., McKenzie, B. S., Wilson, N. J., de Waal Malefyt, R., Kastelein, R. A., & Cua, D. J. (2004). IL-12 and IL-23: Master regulators of innate and adaptive immunity. Immunological Reviews, 202, 96-105.
54. Leader, B., Baca, Q., & Golan, D. E. (2008). Protein therapeutics: A summary and pharmacological classification. Nature Reviews. Drug Discovery, 7, 21-39.
55. Li, X., Mai, J., Virtue, A., Yin, Y., Gong, R., Sha, X., ... Yang, X. F. (2012). IL-35 is a novel responsive anti-inflammatory cytokine-A new system of categorizing anti-inflammatory cytokines. PLoS One, 7, e33628.
56. Lieschke, G. J., Rao, P. K., Gately, M. K., & Mulligan, R. C. (1997). Bioactive murine and human interleukin-12 fusion proteins which retain antitumor activity in vivo. Nature Biotechnology, 15, 35-40.
57. Lyakh, L., Trinchieri, G., Provezza, L., Carra, G., & Gerosa, F. (2008). Regulation of interleukin-12/interleukin-23 production and the T-helper 17 response in humans. Immunological Reviews, 226, 112-131.
58. Manoukian, G., & Hagemeister, F. (2009). Denileukin diftitox: A novel immunotoxin. Expert Opinion on Biological Therapy, 9, 1445-1451.
59. Marblestone, J. G., Edavettal, S. C., Lim, Y., Lim, P., Zuo, X., & Butt, T. R. (2006). Comparison of SUMO fusion technology with traditional gene fusion systems: Enhanced expression and solubility with SUMO. Protein Science, 15, 182-189.
60. Matsui, M., Moriya, O., Belladonna, M. L., Kamiya, S., Lemonnier, F. A., Yoshimoto, T., & Akatsuka, T. (2004). Adjuvant activities of novel cytokines, interleukin-23 (IL-23) and IL-27, for induction of hepatitis C virus-specific cytotoxic T lymphocytes in HLA-A/0201 transgenic mice. Journal of Virology, 78, 9093-9104.
61. Mazzolini, G., Alfaro, C., Sangro, B., Feijoo, E., Ruiz, J., Benito, A., ... Melero, I. (2005). Intratumoral injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas. Journal of Clinical Oncology, 23, 999-1010.
62. Mondal, S., Roy, A., & Pahan, K. (2009). Functional blocking monoclonal antibodies against IL-12p40 homodimer inhibit adoptive transfer of experimental allergic encephalomyelitis. Journal of Immunology, 182, 5013-5023.
63. Nagai, H., Oniki, S., Fujiwara, S., Xu, M., Mizoguchi, I., Yoshimoto, T., & Nishigori, C. (2010). Antitumor activities of interleukin-27 on melanoma. Endocrine. Metabolic and Immune Disorders. Drug Targets, 10, 41-46.
64. Niedbala, W., Wei, X. Q., Cai, B., Hueber, A. J., Leung, B. P., McInnes, I. B., & Liew, F. Y. (2007). IL-35 is a novel cytokine with therapeutic effects against collagen-induced arthritis through the expansion of regulatory T cells and suppression of Th17 cells. European Journal of Immunology, 37, 3021-3029.
65. Nilsson, B., Moks, T., Jansson, B., Abrahmsen, L., Elmblad, A., Holmgren, E., ... Uhlen, M. (1987). A synthetic IgG-binding domain based on staphylococcal protein A. Protein Engineering, 1, 107-113.
66. Oniki, S., Nagai, H., Horikawa, T., Furukawa, J., Belladonna, M. L., Yoshimoto, T., ... Nishigori, C. (2006). Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma. Cancer Research, 66, 6395-6404.
67. Oppmann, B., Lesley, R., Blom, B., Timans, J. C., Xu, Y., Hunte, B., ... Kastelein, R. A. (2000). Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity, 13, 715-725.
68. O'Shea, J. J., & Paul, W. E. (2002). Regulation of T(H)1 differentiation-Controlling the controllers. Nature Immunology, 3, 506-508.
69. Owaki, T., Asakawa, M., Morishima, N., Hata, K., Fukai, F., Matsui, M., ... Yoshimoto, T. (2005). A role for IL-27 in early regulation of Th1 differentiation. Journal of Immunology, 175, 2191-2200.
70. Pahan, K., Sheikh, F. G., Liu, X., Hilger, S., McKinney, M., & Petro, T. M. (2001). Induction of nitric-oxide synthase and activation of NF-kappaB by interleukin-12 p40 in microglial cells. Journal of Biological Chemistry, 276, 7899-7905.
71. Pardridge, W. M. (2010). Biopharmaceutical drug targeting to the brain. Journal of Drug Targeting, 18, 157-167.
72. Parham, C., Chirica, M., Timans, J., Vaisberg, E., Travis, M., Cheung, J., ... Moore, K. W. (2002). A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. Journal of Immunology, 168, 5699-5708.
73. Peng, L. S., Penichet, M. L., & Morrison, S. L. (1999). A single-chain IL-12 IgG3 antibody fusion protein retains antibody specificity and IL-12 bioactivity and demonstrates antitumor activity. Journal of Immunology, 163, 250-258.
74. Pflanz, S., Hibbert, L., Mattson, J., Rosales, R., Vaisberg, E., Bazan, J.F., ... Kastelein, R. A. (2004). WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. Journal of Immunology, 172, 2225-2231.
75. Pflanz, S., Timans, J. C., Cheung, J., Rosales, R., Kanzler, H., Gilbert, J., ... Kastelein, R. A. (2002). IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity, 16, 779-790.
76. Presky, D. H., Yang, H., Minetti, L. J., Chua, A. O., Nabavi, N., Wu, C. Y., ... Gubler, U. (1996). A functional interleukin 12 receptor complex is composed of two beta-type cytokine receptor subunits. Proceedings of the National Academy of Sciences of the United States of America, 93, 14002-14007.
77. Puccetti, P., Belladonna, M. L., & Grohmann, U. (2002). Effects of IL-12 and IL-23 on antigenpresenting cells at the interface between innate and adaptive immunity. Critical Reviews in Immunology, 22, 373-390.
78. Riggs, P. (2000). Expression and purification of recombinant proteins by fusion to maltose-binding protein. Molecular Biotechnology, 15, 51-63.
79. Rizzo, H. L., Kagami, S., Phillips, K. G., Kurtz, S. E., Jacques, S. L., & Blauvelt, A. (2011). IL-23-mediated psoriasis-like epidermal hyperplasia is dependent on IL-17A. Journal of Immunology, 186, 1495-1502.
80. Salcedo, R., Stauffer, J. K., Lincoln, E., Back, T. C., Hixon, J. A., Hahn, C., ... Wigginton, J. M. (2004). IL-27 mediates complete regression of orthotopic primary and metastatic murine neuroblastoma tumors: Role for CD8+ T cells. Journal of Immunology, 173, 7170-7182.
81. Sasaoka, T., Ito, M., Yamashita, J., Nakajima, K., Tanaka, I., Narita, M., ... Kaneko, K. (2011). Treatment with IL-27 attenuates experimental colitis through the suppression of the development of IL-17-producing T helper cells. American Journal of Physiology. Gastrointestinal and Liver Physiology, 300, G568-576.
82. Shimizu, M., Shimamura, M., Owaki, T., Asakawa, M., Fujita, K., Kudo, M.,...Yoshimoto, T. (2006). Antiangiogenic and antitumor activities of IL-27. Journal of Immunology, 176, 7317-7324.
83. Smith, D. B., & Johnson, K. S. (1988). Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene, 67, 31-40.
84. Stern, A. S., Podlaski, F. J., Hulmes, J. D., Pan, Y. C., Quinn, P. M., Wolitzky, A. G., ... Gately, M. K. (1990). Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proceedings of the National Academy of Sciences of the United States of America, 87, 6808-6812.
85. Stumhofer, J. S., Tait, E. D., Quinn, W. J.3rd, Hosken, N., Spudy, B., Goenka, R., ... Hunter, C. A. (2010). A role for IL-27p28 as an antagonist of gp130-mediated signaling. Nature Immunology, 11, 1119-1126.
86. Tahara, H., & Lotze, M. T. (1995). Antitumor effects of interleukin-12 (IL-12): Applications for the immunotherapy and gene therapy of cancer. Gene therapy, 2, 96-106.
87. Thierfelder, W. E., van Deursen, J. M., Yamamoto, K., Tripp, R. A., Sarawar, S. R., Carson, R. T., ... Ihle, J. N. (1996). Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature, 382, 171-174.
88. Trinchieri, G. (1994). Interleukin-12: A cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood, 84, 4008-4027.
89. Trinchieri, G. (2003). Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Reviews. Immunology, 3, 133-146.
90. Trinchieri, G., Pflanz, S., & Kastelein, R. A. (2003). The IL-12 family of heterodimeric cytokines: New players in the regulation of T cell responses. Immunity, 19, 641-644.
91. Uhlen, M., Nilsson, B., Guss, B., Lindberg, M., Gatenbeck, S., & Philipson, L. (1983). Gene fusion vectors based on the gene for staphylococcal protein A. Gene, 23, 369-378.
92. Vignali, D. A., Collison, L. W., & Workman, C. J. (2008). How regulatory T cells work. Nature Reviews. Immunology, 8, 523-532.
93. Vignali, D. A., & Kuchroo, V. K. (2012). IL-12 family cytokines: Immunological playmakers. Nature Immunology, 13, 722-728.
94. Wang, R. X., Yu, C. R., Mahdi, R. M., & Egwuagu, C. E. (2012). Novel IL27p28/IL12p40 cytokine suppressed experimental autoimmune uveitis by inhibiting autoreactive Th1/Th17 cells and promoting expansion of regulatory T cells. Journal of Biological Chemistry, 287, 36012-36021.
95. Wang, X., Wilkinson, V. L., Podlaski, F. J., Wu, C., Stern, A. S., Presky, D. H., & Magram, J. (1999). Characterization of mouse interleukin-12 p40 homodimer binding to the interleukin-12 receptor subunits. European Journal of Immunology, 29, 2007-2013.
96. Waugh, D. S. (2005). Making the most of affinity tags. Trends in Biotechnology, 23, 316-320.
97. Weaver, C. T., & Hatton, R. D. (2009). Interplay between the TH17 and TReg cell lineages: A (co-)evolutionary perspective. Nature Reviews. Immunology, 9, 883-889.
98. Weiss, J. M., Subleski, J. J., Wigginton, J. M., & Wiltrout, R. H. (2007). Immunotherapy of cancer by IL-12-based cytokine combinations. Expert Opinion on Biological Therapy, 7, 1705-1721.
99. Wojno, E. D., & Hunter, C. A. (2012). New directions in the basic and translational biology of interleukin-27. Trends in Immunology, 33, 91-97.
100. Wulff, H., Krieger, T., Kruger, K., Stahmer, I., Thaiss, F., Schafer, H., & Block, A. (2007). Cloning and characterization of an adenoviral vector for highly efficient and doxycycline-suppressible expression of bioactive human single-chain interleukin 12 in colon cancer. BMC Biotechnology, 7, 35-43.
101. Yoshida, H., & Miyazaki, Y. (2008). Regulation of immune responses by interleukin-27. Immunological Reviews, 226, 234-247.
102. Yoshimoto, T., Morishima, N., Mizoguchi, I., Shimizu, M., Nagai, H., Oniki, S., ... Mizuguchi, J. (2008). Antiproliferative activity of IL-27 on melanoma. Journal of Immunology, 180, 6527-6535.
103. Yoshimoto, T., Okada, K., Morishima, N., Kamiya, S., Owaki, T., Asakawa, M., ... Mizuguchi, J. (2004). Induction of IgG2a class switching in B cells by IL-27. Journal of Immunology, 173, 2479-2485.
104. Yuan, X., Hu, J., Belladonna, M. L., Black, K. L., & Yu, J. S. (2006). Interleukin-23-expressing bone marrow-derived neural stem-like cells exhibit antitumor activity against intracranial glioma. Cancer Research, 66, 2630-2638.
105. Zhang, C., Yang, X. L., Yuan, Y. H., Pu, J., & Liao, F. (2012). Site-specific PEGylation of therapeutic proteins via optimization of both accessible reactive amino acid residues and PEG derivatives. Bio Drugs, 26, 209-215.
106. Zitvogel, L., Tahara, H., Cai, Q., Storkus, W. J., Muller, G., Wolf, S. F., ... Lotze, M. T. (1994). Construction and characterization of retroviral vectors expressing biologically active human interleukin-12. Human Gene Therapy, 5, 1493-1506.