Immunotherapeutic and toxic effects of a triple fusion protein encompassing apolipoprotein A-I, IL-15 and IL-15Rα sushi domain
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1
Fundation for medical applied research, Spain
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2
University Hospital of Navarra, Spain
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3
Austral university, Argentina
Interleukin 15 (IL-15) effects on CD8 T and NK lymphocytes hold promise to treat cancer. Fusion proteins have been engineered to provide IL-15 receptor alpha (IL-15Rα) mediated trans-presentation to lymphocytes and extend the plasma half-life of the cytokine. In this study, we report on a triple fusion protein combining apolipoprotein A-I, IL-15 and IL-15Rα’s sushi domain. Apolipoprotein A-I conveys IL-15 to high-density lipoproteins (HDL), from which the cytokine is trans-presented by the IL-15Rα´s sushi domain. Such a construction was tested by hydrodynamic gene transfer to the liver of mice. Lethal toxicity was observed upon injection of 10μg of the expression plasmid. Mice died from an acute lymphocytic pneumonitis in which T and NK cells dominate a severe inflammatory infiltrate. Importantly, mice devoid of NK cells were not susceptible to such toxicity and mice lacking granzymes A and B also survived the otherwise lethal gene transfer. Lower plasmid doses (<2.5μg) were tolerated and dramatically increased the numbers of NK and memory CD8 T lymphocytes in the liver, spleen and lungs, to the point of rescuing the deficiency of such lymphocyte subsets in IL-15Rα-/- mice. Doses of plasmid within the therapeutic window successfully treated metastatic tumor models, including B16OVA lung metastasis of melanoma and MC38 colon cancer liver metastasis. Sushi-IL15-Apo as a recombinant protein was also bioactive in vivo, became conjugated to HDL and displayed immuno-therapeutic effects against metastatic disease.
Acknowledgements
Financial support was from MEC/MICINN (SAF2005-03131 and SAF2008-03294 SAF2011-22831), Departamento de Salud del Gobierno de Navarra, European Commission 7th Framework Program (ENCITE) SUDOE-IMMUNONET, Fundacion Mutua Madrileña, Fondo de Investigacion Sanitaria (FIS PI10/00264) and “UTE for project FIMA”. MCO and PB received contracts from Fondo de Investigación Sanitaria. SH-S received contract from Ministerio de Educacion y Ciencia.
Keywords:
Interleukin-15,
interleukin-15 alpha subunit,
Apolipoprotein A-I,
cancer immunotherapy,
Natural Killer cells
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Translational immunology and immune intervention
Citation:
Ochoa
MC,
Fioravanti
J,
Rodriguez
I,
Hervas-Stubbs
S,
Mazzolini
G,
Prieto
J,
Berraondo
P and
Melero
I
(2013). Immunotherapeutic and toxic effects of a triple fusion protein encompassing apolipoprotein A-I, IL-15 and IL-15Rα sushi domain.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00766
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Received:
13 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. María C Ochoa, Fundation for medical applied research, Pamplona, Spain, mochnie@unav.es