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

• Published in: The Journal of immunology (1950) Vol. 183; no. 8; pp. 4904 - 4912
• Main Authors: Tomala, Jakub, Chmelova, Helena, Mrkvan, Tomas, Rihova, Blanka, Kovar, Marek
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 15.10.2009
• Subjects: Adoptive Transfer; Animals; Antibodies, Monoclonal - therapeutic use; Antigen-Antibody Complex - therapeutic use; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Female; Half-Life; Immunotherapy; Interleukin-2 - therapeutic use; Killer Cells, Natural - immunology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Neoplasms - immunology; Neoplasms - therapy; Recombinant Proteins - pharmacology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0900284

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.