Abstract
Interleukin-4 receptor α (IL-4Rα) chain is highly expressed on the surface of various human solid tumors. We designed a novel hybrid peptide termed IL-4Rα-lytic peptide that targets the IL-4Rα chain. The IL-4Rα-lytic peptide contains a target moiety to bind to IL-4Rα and a cellular toxic lytic peptide that selectively kills cancer cells. The anticancer activity of the IL-4Rα-lytic peptide was evaluated in vitro and in vivo. It was found that the IL-4Rα-lytic peptide has cytotoxic activity in cancer cell lines expressing IL-4Rα, determined by quantitative real-time PCR. The IC(50) ratios of the lytic peptide to the IL-4Rα-lytic peptide correlated well with the expression levels of IL-4Rα on cancer cells (r = 0.80). In addition, IL-4Rα-lytic peptide administered either intratumoraly or intravenously significantly inhibited tumor growth in xenograft model of human pancreatic cancer (BXPC-3) in mice. These results indicate that the IL-4Rα-lytic peptide generated in this study has a potent and selective anticancer potential against IL-4Rα-positive solid cancers.
Highlights
By increasing knowledge of unique or overexpressed cell-surface antigens or receptors on tumor cells as targets, immunotoxin, one of the form of cancer therapy drug, has been developed over the last 3 to 4 decades
Design of Interleukin-4 receptor a (IL-4Ra)–lytic peptide It is known that various solid tumor cells highly express type II interleukin-4 receptor (IL-4R) that are composed of IL-4Ra and IL-13Ra1 chains (Fig. 1A) and IL-4Ra chain binds IL-4 with high affinity (Kd 20 to 300 pmol/L)
We examined whether the enhancement of cytotoxicity of IL-4Ra–lytic peptide was correlated with the expression levels of IL-4Ra in the cells
Summary
By increasing knowledge of unique or overexpressed cell-surface antigens or receptors on tumor cells as targets, immunotoxin, one of the form of cancer therapy drug, has been developed over the last 3 to 4 decades. Immunotoxins are proteins that are composed of a target binding moiety (an antibody or growth factor that binds to target cells) and a toxin moiety There are concerns of immunogenicity and hepatotoxicity caused by the immunotoxins [7, 8]. Due to their larger molecular sizes compared with chemical compounds or fragment antibody drugs, many immunotoxins might have difficulty in penetration into
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