Skip to main content

Advertisement

SpringerLink
Log in

Human interleukin 10 receptor 1/IgG1-Fc fusion proteins: immunoadhesins for human IL-10 with therapeutic potential

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Interleukin 10 (IL-10) is produced by various types of human cancer, including malignant melanoma, and plays an important role in negative regulation of cell-mediated immune responses against tumors. We have developed chimeric molecules (immunoadhesins), combining the extracellular domain of human interleukin 10 receptor 1 (IL-10R1) with the Fc regions of human IgG1 heavy chain and investigated their capability of blocking the biological activities of human IL-10. Monomeric and dimeric immunoadhesins (IL-10R1/IgG1) constructs were tested for capturing human IL-10 and blocking its biological activities. Plasmid vectors that contained the IL-10 immunoadhesin constructs were directly transfected into human melanoma cell lines. Transfection of plasmid vectors into melanoma cell lines resulted in capturing of exogenously added as well as endogeneously produced IL-10. The supernatants obtained from an IL-10 non-producing melanoma cell line transfected with monomeric IL-10 immunoadhesin plasmids most efficiently captured exogenously added IL-10, compared to those obtained with the dimeric IL-10R1/IgG1 plasmid vector. Transfection of IL-10-producing melanoma cells with the monomeric IL-10 immunoadhesin plasmids totally captured endogenously produced IL-10 and enhanced T cell responses against allogeneic melanoma cells. Furthermore, purified monomeric IL-10 immunoadhesin protein showed IL-10 capturing efficacy compatible with that of IL-10-specific monoclonal antibodies. Collectively, these studies indicate that IL-10 immunoadhesins, especially in monomeric form, are potent inhibitors of biological activities of IL-10 and suggest that these molecules, alone or in conjunctions with other immunotherapeutic approaches, can be utilized for the immuno-targeting of IL-10 producing tumors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Asadullah K, Sterry W, Volk HD (2003) Interleukin-10 therapy—review of a new approach. Pharmacol Rev 55:241–269

    Article  PubMed  CAS  Google Scholar 

  2. Barrera MV, Habicheyn S, Mendiola MV, Herrera Ceballos E (2008) Etanercept in the treatment and retreatment of psoriasis in daily clinical practice. Eur J Dermatol 18:683–687

    PubMed  CAS  Google Scholar 

  3. Beckebaum S, Zhang X, Chen X, Yu Z, Frilling A, Dworacki G, Grosse-Wilde H, Broelsch CE, Gerken G, Cicinnati VR (2004) Increased levels of interleukin-10 in serum from patients with hepatocellular carcinoma correlate with profound numerical deficiencies and immature phenotype of circulating dendritic cell subsets. Clin Cancer Res 10:7260–7269

    Article  PubMed  CAS  Google Scholar 

  4. Blay JY, Burdin N, Rousset F, Lenoir G, Biron P, Philip T, Banchereau J, Favrot MC (1993) Serum interleukin-10 in non-Hodgkin’s lymphoma: a prognostic factor. Blood 82:2169–2174

    PubMed  CAS  Google Scholar 

  5. Brooks DG, Lee AM, Elsaesser H, McGavern DB, Oldstone MB (2008) IL-10 blockade facilitates DNA vaccine-induced T cell responses and enhances clearance of persistent virus infection. J Exp Med 205:533–541

    Article  PubMed  CAS  Google Scholar 

  6. Chamow SM, Ashkenazi A (1996) Immunoadhesins: principles and applications. Trends Biotechnol 14:52–60

    Article  PubMed  CAS  Google Scholar 

  7. D’Andrea A, Aste-Amezaga M, Valiante MN, Ma X, Kubin MGT (1993) Interleukine 10 (IL-10) inhibits human lymphocyte interferon γ-production by suppressing natural killter cell stimulatory factor/IL-10 synthesis in accessory cells. J Exp Med 178:1041–1048

    Article  PubMed  Google Scholar 

  8. De Vita F, Orditura M, Galizia G, Romano C, Roscigno A, Lieto E, Catalano G (2000) Serum interleukin-10 levels as a prognostic factor in advanced non-small cell lung cancer patients. Chest 117:365–373

    Article  PubMed  Google Scholar 

  9. de Waal Malefyt R, Yssel H, Roncarolo MG, Spits H, de Vries JE (1992) Interleukin-10. Curr Opin Immunol 4:314–320

  10. Denizot Y, Turlure P, Bordessoule D, Trimoreau F, Praloran V (1999) Serum IL-10 and IL-13 concentrations in patients with haematological malignancies. Cytokine 11:634–635

    Article  PubMed  CAS  Google Scholar 

  11. Donohue JH, Rosenberg SA (1983) The fate of interleukin-2 after in vivo administration. J Immunol 130:2203–2208

    PubMed  CAS  Google Scholar 

  12. Fiorentino DF, Bond MW, Mosmann TR (1989) Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 170:2081–2095

    Article  PubMed  CAS  Google Scholar 

  13. Gascoigne NR, Goodnow CC, Dudzik KI, Oi VT, Davis MM (1987) Secretion of a chimeric T-cell receptor-immunoglobulin protein. Proc Natl Acad Sci USA 84:2936–2940

    Article  PubMed  CAS  Google Scholar 

  14. Howard M, O’Garra A (1992) Biological properties of interleukin 10. Immunol Today 13:198–200

    Article  PubMed  CAS  Google Scholar 

  15. Jones BC, Logsdon NJ, Josephson K, Cook J, Barry PA, Walter MR (2002) Crystal structure of human cytomegalovirus IL-10 bound to soluble human IL-10R1. Proc Natl Acad Sci USA 99:9404–9409

    Article  PubMed  CAS  Google Scholar 

  16. Josephson K, Logsdon NJ, Walter MR (2001) Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site. Immunity 15:35–46

    Article  PubMed  CAS  Google Scholar 

  17. Kim J, Modlin RL, Moy RL, Dubinett SM, McHugh T, Nickoloff BJ, Uyemura K (1995) IL-10 production in cutaneous basal and squamous cell carcinomas. A mechanism for evading the local T cell immune response. J Immunol 155:2240–2247

    PubMed  CAS  Google Scholar 

  18. Kohno T, Tam LT, Stevens SR, Louie JS (2007) Binding characteristics of tumor necrosis factor receptor (TNFR)-Fc fusion proteins vs anti-tumor necrosis factor mAbs. J Investig Dermatol Symp Proc 12:5–8

    Article  PubMed  CAS  Google Scholar 

  19. Kotenko SV, Krause CD, Izotova LS, Pollack BP, Wu W, Pestka S (1997) Identification and functional characterization of a second chain of the interleukin-10 receptor complex. EMBO J 16:5894–5903

    Article  PubMed  CAS  Google Scholar 

  20. Kotenko SV, Pestka S (2000) Jak-Stat signal transduction pathway through the eyes of cytokine class II receptor complexes. Oncogene 19:2557–2565

    Article  PubMed  CAS  Google Scholar 

  21. Liossis SN, Tsokos GC (2005) Monoclonal antibodies and fusion proteins in medicine. J Allergy Clin Immunol 116:721–729 quiz 30

    Article  PubMed  CAS  Google Scholar 

  22. Liu Y, Wei SH, Ho AS, l Malefyt R, Moore KW (1994) Expression cloning and characterization of a human IL-10 receptor. J Immunol 152:1821–1829

    PubMed  CAS  Google Scholar 

  23. Lutfalla G, Gardiner K, Uze G (1993) A new member of the cytokine receptor gene family maps on chromosome 21 at less than 35 kb from IFNAR. Genomics 16:366–373

    Article  PubMed  CAS  Google Scholar 

  24. Matsuda M, Salazar F, Petersson M, Masucci G, Hansson J, Pisa P, Zhang QJ, Masucci G, Kiessling R (1994) Interleukin 10 pretreatment protects target cells from tumor- and allo-specific cytotoxic T cells and downregulates HLA class I expression. J Exp Med 180:2371–2376

    Article  PubMed  CAS  Google Scholar 

  25. McBride JM, Jung T, de Vries JE, Aversa G (2002) IL-10 alters DC function via modulation of cell surface molecules resulting in impaired T-cell responses. Cell Immunol 215:162–172

    Article  PubMed  CAS  Google Scholar 

  26. Mocellin S, Panelli M, Wang E, Rossi CR, Pilati P, Nitti D, Lise M, Marincola FM (2004) IL-10 stimulatory effects on human NK cells explored by gene profile analysis. Genes Immun 5:621–630

    Article  PubMed  CAS  Google Scholar 

  27. Moore KW, O’Garra A, l Malefyt R, Vieira P, Mosmann TR (1993) Interleukin-10. Annu Rev Immunol 11:165–190

    Article  PubMed  CAS  Google Scholar 

  28. Nadeau RW, Satoh H, Scheide S, Crowl R, Conroy R, Garland WA, Liberato DJ (1995) A comparison of mass balance, pharmacokinetics and disposition of [14C(U)]- and [125I] recombinant human interleukin-2 in cynomolgus monkeys. Drug Metab Dispos 23:904–909

    PubMed  CAS  Google Scholar 

  29. Novak L, Igoucheva O, Cho S, Alexeev V (2007) Characterization of the CCL21-mediated melanoma-specific immune responses and in situ melanoma eradication. Mol Cancer Ther 6:1755–1764

    Article  PubMed  CAS  Google Scholar 

  30. Ordemann J, Jacobi CA, Braumann C, Schwenk W, Volk HD, Muller JM (2002) Immunomodulatory changes in patients with colorectal cancer. Int J Colorectal Dis 17:37–41

    Article  PubMed  CAS  Google Scholar 

  31. Patel KB, Berd D, Mastrangelo MJ, Terai M, Sato T (2002) Prognostic importance of interleukin-10 (IL-10) production by metastatic melanoma tissues from patients receiving autologous vaccine therapy. Proc of ASCO 21:432a

    Google Scholar 

  32. Reuben JM, Lee BN, Li C, Gomez-Navarro J, Bozon VA, Parker CA, Hernandez IM, Gutierrez C, Lopez-Berestein G, Camacho LH (2006) Biologic and immunomodulatory events after CTLA-4 blockade with ticilimumab in patients with advanced malignant melanoma. Cancer 106:2437–2444

    Article  PubMed  CAS  Google Scholar 

  33. Rudge JS, Thurston G, Davis S, Papadopoulos N, Gale N, Wiegand SJ, Yancopoulos GD (2005) VEGF trap as a novel antiangiogenic treatment currently in clinical trials for cancer and eye diseases, and VelociGene-based discovery of the next generation of angiogenesis targets. Cold Spring Harb Symp Quant Biol 70:411–418

    Article  PubMed  CAS  Google Scholar 

  34. Salazar-Onfray F, Charo J, Petersson M, Freland S, Noffz G, Qin Z, Blankenstein T, Ljunggren HG, Kiessling R (1997) Down-regulation of the expression and function of the transporter associated with antigen processing in murine tumor cell lines expressing IL-10. J Immunol 159:3195–3202

    PubMed  CAS  Google Scholar 

  35. Sato T, McCue P, Masuoka K, Salwen S, Lattime EC, Mastrangelo MJ, Berd D (1996) Interleukin 10 production by human melanoma. Clin Cancer Res 2:1383–1390

    PubMed  CAS  Google Scholar 

  36. Spencer SD, Di Marco F, Hooley J, Pitts-Meek S, Bauer M, Ryan AM, Sordat B, Gibbs VC, Aguet M (1998) The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor. J Exp Med 187:571–578

    Article  PubMed  CAS  Google Scholar 

  37. Stearns ME, Garcia FU, Fudge K, Rhim J, Wang M (1999) Role of interleukin 10 and transforming growth factor beta 1 in the angiogenesis and metastasis of human prostate primary tumor lines from orthotopic implants in severe combined immunodeficiency mice. Clin Cancer Res 5:711–720

    PubMed  CAS  Google Scholar 

  38. Stearns ME, Rhim J, Wang M (1999) Interleukin 10 (IL-10) inhibition of primary human prostate cell-induced angiogenesis: IL-10 stimulation of tissue inhibitor of metalloproteinase-1 and inhibition of matrix metalloproteinase (MMP)-2/MMP-9 secretion. Clin Cancer Res 5:189–196

    PubMed  CAS  Google Scholar 

  39. Steinbrink K, Graulich E, Kubsch S, Knop J, Enk A (2002) CD4(+) and CD8(+) anergic T cells induced by interleukin-10-treated human dendritic cells display antigen-specific suppressor activity. Blood 99:2468–2476

    Article  PubMed  CAS  Google Scholar 

  40. Touraine JL, Sanhadji K, Sembeil R (2003) Gene therapy for human immunodeficiency virus infection in the humanized SCID mouse model. Isr Med Assoc J 5:863–867

    PubMed  CAS  Google Scholar 

  41. Uwatoko N, Tokunaga T, Hatanaka H, Osada H, Kawakami T, Yamazaki H, Abe Y, Kijima H, Ueyama Y, Nakamura M (2002) Expression of IL-10 is inversely correlated with distant metastasis of renal cell carcinoma. Int J Oncol 20:729–733

    PubMed  CAS  Google Scholar 

  42. Yue FY, Dummer R, Geertsen R, Hofbauer G, Laine E, Manolio S, Burg G (1997) Interleukin-10 is a growth factor for human melanoma cells and down-regulates HLA class-I, HLA class-II and ICAM-1 molecules. Int J Cancer 71:630–637

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the Bonnie Kroll Research Fund, the Siobhan McDonald Research Fund, and the Eye Melanoma Research Fund.

Author information

Authors and Affiliations

  1. Jefferson Medical College of Thomas Jefferson University, 1015 Walnut Street, Suite 1024, Philadelphia, PA, 19107-5099, USA

    Mizue Terai, Vitali Alexeev, David Berd, Michael J. Mastrangelo & Takami Sato

  2. Chiba University, Chiba, Japan

    Mizue Terai & Yutaka Tamura

  3. Hokkaido University, Sapporo, Japan

    Eiko Ohtsuka

Authors
  1. Mizue Terai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yutaka Tamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vitali Alexeev
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eiko Ohtsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. David Berd
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael J. Mastrangelo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Takami Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takami Sato.

Additional information

M. Terai and Y. Tamura contributed equally to this work. Yutaka Tamura and Eiko Otsuka are listed as inventors in the pending patent application for IL-10 Immunoadhesins (PCT/JP2004/013090).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Terai, M., Tamura, Y., Alexeev, V. et al. Human interleukin 10 receptor 1/IgG1-Fc fusion proteins: immunoadhesins for human IL-10 with therapeutic potential. Cancer Immunol Immunother 58, 1307–1317 (2009). https://doi.org/10.1007/s00262-008-0644-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-008-0644-9

Keywords

Search

Navigation