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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 Immunotherapy¹

Department of Immunology and Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i., Prague, Czech Republic

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 µg/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 3 h vs <15 min, respectively.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grants IAA500200712 and KAN200200651 from Grant Agency of Academy of Sciences of the Czech Republic, Grant 310/08/H077 from Grant Agency of the Czech Republic, and by Grant AV0250200510 from the Institutional Research Concept.

² Address correspondence and reprint requests to Dr. Marek Kovar, Department of Immunology and Gnotobiology, Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i., Videnska 1083, Prague 4-Krc 14220, Czech Republic. E-mail address: makovar{at}biomed.cas.cz

³ Abbreviation used in this paper: poly(I:C), polyinosinic-polycytidylic acid.

⁴ The online version of this article contains supplemental material.