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

Immunol Lett. May-Jun 2014;159(1-2):1-10. doi: 10.1016/j.imlet.2014.01.017. Epub 2014 Feb 7.

Abstract

IL-2 and IL-15 are structurally relative cytokines that share two receptor subunits, CD132 (γ(c) 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 CD122(high) populations (memory CD8(+) T and NK cells) and intermediately also for CD25(high) populations (Treg and activated T cells), while IL-2/JES6-1 mAb immunocomplexes enormously expand only CD25(high) 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.

Keywords: Anti-IL-2 mAb; Biological activity; IL-15; IL-15Rα-Fc chimera; IL-2; Immunocomplexes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry
  • Antigen-Antibody Complex / genetics
  • Antigen-Antibody Complex / immunology*
  • Antigen-Antibody Complex / pharmacology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Gene Expression Regulation
  • Humans
  • Immunoglobulin Fc Fragments / chemistry
  • Interleukin Receptor Common gamma Subunit / genetics
  • Interleukin Receptor Common gamma Subunit / immunology
  • Interleukin-15 / genetics
  • Interleukin-15 / immunology*
  • Interleukin-15 / pharmacology
  • Interleukin-15 Receptor alpha Subunit / genetics
  • Interleukin-15 Receptor alpha Subunit / immunology*
  • Interleukin-2 / genetics
  • Interleukin-2 / immunology*
  • Interleukin-2 / pharmacology
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Killer Cells, Natural / cytology
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology
  • Mice
  • Signal Transduction
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*

Substances

  • Antibodies, Monoclonal
  • Antigen-Antibody Complex
  • IL15 protein, human
  • IL2RA protein, human
  • IL2RG protein, human
  • Immunoglobulin Fc Fragments
  • Interleukin Receptor Common gamma Subunit
  • Interleukin-15
  • Interleukin-15 Receptor alpha Subunit
  • Interleukin-2
  • Interleukin-2 Receptor alpha Subunit