title: IL-2 in vivo activities and antitumor efficacy enhanced by an anti-IL-2 mAb.
abstract: IL-2 is a potent immunostimulant and has been tested for clinical use, including in immunotherapy for cancers and HIV infection. Here we show that a widely used neutralizing anti-murine IL-2 mAb (S4B6) exhibits unexpected activities that enhance the treatment effects of IL-2 in vivo. Coinjection of the anti-IL-2 mAb with a plasmid carrying murine IL-2 cDNA significantly increased the serum IL-2 levels and induced a substantial increase in the division of CD8+ T and NK1.1(high) cells in vivo. Injection of the mAb premixed with recombinant murine IL-2 showed the same enhanced effect. A 5-day treatment with the anti-IL-2 mAb alone gradually increased the CD44(high)CD8+ population, and the increased population was maintained for >300 days, suggesting that the mAb can gradually maintain and potentially enhance the bioactivity of endogenous IL-2 for extended periods. Furthermore, combined treatment with the anti-IL-2 mAb plus the IL-2 plasmid markedly enhanced Ag-specific CTL activity in vivo and partially protected mice from tumor metastasis to the lungs, compared with the anti-IL-2 mAb or IL-2 plasmid alone. These results demonstrated IL-2-enhancing effects of the anti-IL-2 mAb in vivo and suggest that combining a neutralizing anti-IL-2 Ab with IL-2 gene delivery might be used effectively to enhance IL-2 functions in clinical applications.
authors.affiliation: Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kamimura
authors.forename: Yukihisa
authors.initials: Y
authors.lastname: Sawa
authors.forename: Masae
authors.initials: M
authors.lastname: Sato
authors.forename: Eviryanti
authors.initials: E
authors.lastname: Agung
authors.forename: Toshio
authors.initials: T
authors.lastname: Hirano
authors.forename: Masaaki
authors.initials: M
authors.lastname: Murakami
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000502:physiology; D000950:Antigens, Ly; D000954:Antigens, Surface / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000819:agonists / Q000097:blood / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000097:blood / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D037181:Lectins, C-Type / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000276:immunology / Q000556:secondary / Q000628:therapy; D018655:Lymphocyte Count; D008546:Melanoma, Experimental / Q000276:immunology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055651:NK Cell Lectin-Like Receptor Subfamily B; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000819:agonists / Q000097:blood / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000950:Antigens, Ly; D000954:Antigens, Surface; D000970:Antineoplastic Agents; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018960:Hyaluronan Receptors; D007376:Interleukin-2; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D055651:NK Cell Lectin-Like Receptor Subfamily B; D011994:Recombinant Proteins