Abstract
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.
Highlights
There is much interest in the development of interleukin-15 for immunotherapy [1,2]
Fusion Proteins Encompassing IL-15 and Apolipoprotein A-I (Apo A-I) are more Stable in Plasma and Partly become Complexed with high density lipoproteins (HDL)
The sushi domain of IL-15Ra was cloned in a similar expression cassette
Summary
There is much interest in the development of interleukin-15 for immunotherapy [1,2]. This is because it inhibits activation induced T cell death [3], homeostaticaly increases lymphocyte numbers [4,5], and up-regulates the function of NK cells [6,7,8,9] and IKDC (interferon-producing killer dendritic cells) [10]. IL-15 is more a costimulatory molecule than a soluble cytokine in the sense that it is physiologically trans-presented [11] as a cell surface complex which is non-covalently attached with high affinity to IL15Ra [8,9,11,12]. The binding of IL-15 to the sushi domain of IL15Ra is believed to orient the molecule and improves the interaction with the IL-2Rb/IL-2Rc signaling receptors [13,15].
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