Human interleukin 10 receptor 1/IgG1-Fc fusion proteins: immunoadhesins for human IL-10 with therapeutic potential.
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.
Terai
Mizue
M
Jefferson Medical College of Thomas Jefferson University, 1015 Walnut Street, Philadelphia, PA 19107-5099, USA.
Tamura
Yutaka
Y
Alexeev
Vitali
V
Ohtsuka
Eiko
E
Berd
David
D
Mastrangelo
Michael J
MJ
Sato
Takami
T
D045744:Cell Line, Tumor; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology; D053709:Interleukin-10 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology*; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology*; D014162:Transfection
D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D053709:Interleukin-10 Receptor alpha Subunit; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10