title: 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.affiliation: Department of Pharmacology, University of Minnesota, Minneapolis, MN55455, USA.
authors.forename: Yawu
authors.initials: Y
authors.lastname: Jing
authors.forename: Huarui
authors.initials: H
authors.lastname: Lu
authors.forename: Kailang
authors.initials: K
authors.lastname: Wu
authors.forename: Indira V
authors.initials: IV
authors.lastname: Subramanian
authors.forename: S
authors.initials: S
authors.lastname: Ramakrishnan
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D043169:Endostatins / Q000627:therapeutic use*; D005260:Female; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D051379:Mice; D008819:Mice, Nude; D009842:Oligopeptides; D017354:Point Mutation; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D043169:Endostatins; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D009842:Oligopeptides; D011993:Recombinant Fusion Proteins; D000068258:Bevacizumab; C047981:arginyl-glycyl-aspartic acid