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

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.

• Authors: Yawu Jing, Huarui Lu, Kailang Wu, Indira V Subramanian, S Ramakrishnan
• Journal: International journal of cancer (Int J Cancer) Vol. 129 Issue 3 Pg. 751-61 (Aug 01 2011) ISSN: 1097-0215 [Electronic] United States
• PMID: 21225621 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 UICC.

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Endostatins
• Immunoglobulin Fc Fragments
• Immunoglobulin G
• Oligopeptides
• Recombinant Fusion Proteins
• Bevacizumab
• arginyl-glycyl-aspartic acid

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Antibodies, Monoclonal (administration & dosage)
• Antibodies, Monoclonal, Humanized
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab
• Cell Line, Tumor
• Cell Movement (drug effects)
• Endostatins (therapeutic use)
• Female
• HEK293 Cells
• Half-Life
• Humans
• Immunoglobulin Fc Fragments
• Immunoglobulin G
• Mice
• Mice, Nude
• Oligopeptides
• Point Mutation
• Recombinant Fusion Proteins (therapeutic use)