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Apolipoprotein A-I (Apo A-I) is a major component of high density lipoproteins (HDL) that transport cholesterol in circulation. We have constructed an expression plasmid encoding a chimeric molecule encompassing interleukin-15 (IL-15) and Apo A-I (pApo-hIL15) that was tested by hydrodynamic injections into mice and was co-administered with a plasmid encoding the sushi domain of IL-15Rα (pSushi) in order to enhance IL-15 trans-presentation and thereby bioactivity. The pharmacokinetics of the Apo A-I chimeric protein were much longer than non-stabilized IL-15 and its bioactivity was enhanced in combination with IL-15Rα Sushi. Importantly, the APO-IL-15 fusion protein was incorporated in part into circulating HDL. Liver gene transfer of these constructs increased NK and memory-phenotype CD8 lymphocyte numbers in peripheral blood, spleen and liver as a result of proliferation documented by CFSE dilution and BrdU incorporation. Moreover, the gene transfer procedure partly rescued the NK and memory T-cell deficiency observed in IL-15Rα(-/-) mice. pApo-hIL15+ pSushi gene transfer to the liver showed a modest therapeutic activity against subcutaneously transplanted MC38 colon carcinoma tumors, that was more evident when tumors were set up as liver metastases. The improved pharmacokinetic profile and the strong biological activity of APO-IL-15 fusion protein holds promise for further development in combination with other immunotherapies.

Original publication

DOI

10.1371/journal.pone.0052370

Type

Journal article

Journal

PloS one

Publication Date

01/2012

Volume

7

Addresses

Center for Applied Medical Research, University of Navarra, Pamplona, Spain.

Keywords

Liver, Spleen, Killer Cells, Natural, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Animals, Mice, Inbred C57BL, Humans, Mice, Neoplasm Metastasis, Lipoproteins, HDL, Apolipoprotein A-I, Recombinant Proteins, Interleukin-15, Blotting, Western, Immunotherapy, Cell Count, Injections, Subcutaneous, Gene Transfer Techniques, Cell Proliferation, Immunologic Memory, Protein Structure, Tertiary, Phenotype, Interleukin-15 Receptor alpha Subunit, Genetic Therapy