Inhibition of ovarian cancer by RGD-P125A-endostatin-Fc fusion proteins

Yawu Jing, Huarui Lu, Kailang Wu, Indira V. Subramanian, Sundaram Ramakrishnan

Research output: Contribution to journalArticlepeer-review

13 Scopus citations

Abstract

Previous studies have shown that a single point mutation in endostatin at position 125 (P125A) can improve the biological activity of endostatin. Addition of an integrin-targeting moiety, R-G-D, resulted in better localization to tumor vasculature and improved the antiangiogenic activity of endostatin. Because endostatin has relatively shorter serum half-life, frequent dosing was required for inhibiting tumor growth. In our study, we have genetically fused RGD-P125A-endostatin to Fc of IgG4 isotype and evaluated its antiangiogenic and antitumor effects in athymic mice. Two genetic constructs were made, RGD-P125A-endostatin-Fc (RE-Fc) and P125A-endostatin-RGD-Fc (ER-Fc). Both constructs were cloned and expressed in mammalian cells. Purified fusion proteins inhibited endothelial cell migration and proliferation better than yeast-derived P125A-endostatin. Both RE-Fc and ER-Fc inhibited ovarian cancer growth and were found to be as effective as Bevacizumab treatment. Fusion protein showed marked increased half-life. Combination treatment with Bevacizumab and ER-Fc showed additive inhibition of ovarian cancer growth. These studies demonstrate that genetic fusion with human IgG4-Fc increases the half-life of P125A-endostatin and can be used along with Bevacizumab to improve antiangiogenic and antitumor activities.

Original languageEnglish (US)
Pages (from-to)751-761
Number of pages11
JournalInternational Journal of Cancer
Volume129
Issue number3
DOIs
StatePublished - Aug 1 2011

Keywords

  • Bevacizumab
  • Fc-fusion protein
  • mutant endostatin
  • ovarian cancer
  • tumor angiogenesis

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