Enhancement of the antiangiogenic activity of interleukin-12 by peptide targeted delivery of the cytokine to α vβ 3 integrin

Erin B. Dickerson, Nasim Akhtar, Howard Steinberg, Zun Yi Wang, Mary J. Lindstrom, Marcia L. Padilla, Robert Auerbach, Stuart C. Helfand

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Abstract

We engineered a fusion protein, mrIL-12vp [mouse recombinant interleukin (IL)-12 linked to vascular peptide], linking the vascular homing peptide CDCRGDCFC (RGD-4C), a ligand for α vβ 3 integrin, to mrIL-12 to target IL-12 directly to tumor neovasculature. The fusion protein stimulated IFN-γ production in vitro and in vivo, indicating its biological activity was consistent with mrIL-12. Immunofluorescence techniques showed mrIL-12vp specifically bound to α vβ 3 integrin-positive cells but not to α vβ 3 integrin-negative cells. In corneal angiogenesis assays using BALB/c mice treated with either 0.5 μg/mouse/d of mrIL-12vp or mrIL-12 delivered by subcutaneous continuous infusion, mrIL-12vp inhibited corneal neovascularization by 67% compared with only a slight reduction (13%) in angiogenesis in the mrIL-12-treated animals (P = 0.008). IL-12 receptor knockout mice given mrIL-12vp showed a marked decrease in the area of corneal neovascularization compared with mice treated with mrIL-12. These results indicate that mrIL-12vp inhibits angiogenesis through IL-12-dependent and IL-12-independent mechanisms, and its augmented antiangiogenic activity may be due to suppression of endothelial cell signaling pathways by the RGD-4C portion of the fusion protein. Mice injected with NXS2 neuroblastoma cells and treated with mrIL-12vp showed significant suppression of tumor growth compared with mice treated with mrIL-12 (P = 0.03). Mice did not show signs of IL-12 toxicity when treated with mrIL-12vp, although hepatic necrosis was present in mrIL-12-treated mice. Localization of IL-12 to neovasculature significantly enhances the antiangiogenic effect, augments antitumor activity, and decreases toxicity of IL-12, offering a promising strategy for expanding development of IL-12 for treatment of cancer patients.

Original languageEnglish (US)
Pages (from-to)663-673
Number of pages11
JournalMolecular Cancer Research
Volume2
Issue number12
StatePublished - Dec 1 2004

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    Dickerson, E. B., Akhtar, N., Steinberg, H., Wang, Z. Y., Lindstrom, M. J., Padilla, M. L., Auerbach, R., & Helfand, S. C. (2004). Enhancement of the antiangiogenic activity of interleukin-12 by peptide targeted delivery of the cytokine to α vβ 3 integrin. Molecular Cancer Research, 2(12), 663-673.