In vivo expansion of activated naive CD8+ T cells and NK cells driven by complexes of IL-2 and anti-IL-2 monoclonal antibody as novel approach of cancer immunotherapy.
IL-2 is potent imunostimulatory molecule that plays a key role in T and NK cell activation and expansion. IL-2 is approved by the FDA to treat metastatic renal cancer and melanoma, but its extremely short half-life and serious toxicities are significant limitations of its use. It was reported that in vivo biological activity of IL-2 can be increased by association of IL-2 with anti-IL-2 mAb (S4B6). IL-2/S4B6 mAb immunocomplexes were described to be highly stimulatory for NK and memory CD8(+) T cells and intermediately also for regulatory T cells. IL-2/JES6-1 mAb immunocomplexes are stimulatory solely for regulatory T cells. In this study we show that although both mentioned IL-2 immunocomplexes are less potent than free IL-2 in vitro, they possess extremely high stimulatory activity to expand activated naive CD8(+) T cells in vivo. IL-2 immunocomplexes expand activated naive CD8(+) T cells several hundred-fold times after four doses and more than 1000-fold times after six doses (1.5 microg/dose of IL-2), whereas free IL-2 given at the same dosage shows negligible activity. IL-2/S4B6 mAb immunocomplexes also induce massive expansion of NK cells (40% of DX5(+)NK1.1(+) cells in spleen). Importantly, activated naive CD8(+) T cells expanded by IL-2 immunocomplexes form robust population of functional memory cells. We also demonstrate in two distinct tumor models that IL-2/S4B6 mAb immunocomplexes possess considerable antitumor activity. Finally, by using radioactively labeled IL-2, we provide for first time direct evidence that IL-2 immunocomplexes have much longer half-life in circulation than free IL-2, being approximately 3 h vs <15 min, respectively.
Department of Immunology and Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Jakub
J
Tomala
Helena
H
Chmelova
Tomas
T
Mrkvan
Blanka
B
Rihova
Marek
M
Kovar
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000936:Antigen-Antibody Complex / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D006207:Half-Life; D007167:Immunotherapy; D007376:Interleukin-2 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011994:Recombinant Proteins / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D007376:Interleukin-2; D011994:Recombinant Proteins