Increasing the biological activity of IL-2 and IL-15 through complexing with anti-IL-2 mAbs and IL-15Rα-Fc chimera

• The in vivo biological activity of IL-2 can be increased by anti-IL-2 mAbs.
• The in vivo biological activity of IL-15 can be increased by IL-15Rα-Fc chimera.
• IL-15/IL-15Rα-Fc complexes are more potent than IL-15 both in vitro and in vivo.
• IL-2/anti-IL-2 mAb immunocomplexes are more potent than IL-2 only in vivo.
• IL-2/anti-IL-2 mAb immunocomplexes show selectivity in the stimulation of immune cells.

IL-2 and IL-15 are structurally relative cytokines that share two receptor subunits, CD132 (γc chain) and CD122 (β chain). However, the expression pattern and physiological role of IL-2 and IL-15 private receptor α chains CD25 and IL-15Rα, respectively, are strikingly different. CD25, together with CD122 and CD132, forms a trimeric high affinity IL-2 receptor that is expressed and functions on cells acquiring an IL-2 signal. Conversely, IL-15Rα is expressed and binds IL-15 with high affinity per se already in the endoplasmic reticulum of the IL-15 producing cells and it presents IL-15 to cells expressing CD122/CD132 dimeric receptor in trans. Thus, while IL-2 is secreted almost exclusively by activated T cells and acts as a free molecule, IL-15 is expressed mostly by myeloid cells and works as a cell surface-associated cytokine. Interestingly, the in vivo biological activity of IL-2 can be dramatically increased through complexing with certain anti-IL-2 mAbs; such IL-2/anti-IL-2 mAbs immunocomplexes selectively stimulate the proliferation of a distinct population of immune cells, depending on the clone of the anti-IL-2 mAb used. IL-2/S4B6 mAb immunocomplexes are highly stimulatory for CD122high populations (memory CD8+ T and NK cells) and intermediately also for CD25high populations (Treg and activated T cells), while IL-2/JES6-1 mAb immunocomplexes enormously expand only CD25high cells. Although IL-2 immunocomplexes are much more potent than IL-2 in vivo, they show comparable to slightly lower activity in vitro. The in vivo biological activity of IL-15 can be dramatically increased through complexing with recombinant IL-15Rα-Fc chimera; however, IL-15/IL-15Rα-Fc complexes are significantly more potent than IL-15 both in vivo and in vitro. In this review we summarize and discuss the features and biological relevance of IL-2/anti-IL-2 mAbs and IL-15/IL-15Rα-Fc complexes, and try to foreshadow their potential in immunological research and immunotherapy.