title: Immunoglobulin Fc domain fusion to apolipoprotein(a) kringle V significantly prolongs plasma half-life without affecting its anti-angiogenic activity.
abstract: Angiogenesis is crucial for tumor growth and metastasis. Blocking this process is, therefore, a potentially powerful approach for the treatment of cancer. Human apolipoprotein(a) kringle V (rhLK8) is an angiogenesis inhibitor and is currently under development as an anti-cancer therapeutic. However, a relatively short in vivo half-life limits its widespread clinical use. This study was performed to evaluate whether fusion of an Fc domain to rhLK8 can extend plasma half-life. RhLK8-Fc fusion protein was expressed in CHO DG44 cells as a dimer and was readily purified by protein G affinity chromatography. The anti-angiogenic activity of rhLK8-Fc was similar to that of rhLK8, as determined by migration and tube formation assays with endothelial cells in vitro and a chorioallantoic membrane assay in vivo. Pharmacokinetic profiles in mice after single intravenous administration of rhLK8 or rhLK8-Fc showed that Fc fusion significantly increased the elimination half-life (t(½)) and the systemic exposure (AUC(inf)) of the protein, in parallel with a significant decrease in total clearance (CL). These data suggest that Fc fusion to rhLK8 is a powerful strategy for extending the plasma half-life of rhLK8 without affecting its anti-angiogenic activity, and could thus improve the clinical applicability of rhLK8.
authors.affiliation: Cancer Therapeutics Team, Mogam Biotechnology Research Institute, 341 Bojeong-dong, Giheung-gu, Yongin 449-910, Republic of Korea.
authors.forename: Hyun-Kyung
authors.initials: HK
authors.lastname: Yu
authors.forename: Ho-Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Jin-Hyung
authors.initials: JH
authors.lastname: Ahn
authors.forename: In-Hwan
authors.initials: IH
authors.lastname: Lim
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Moon
authors.forename: Yeup
authors.initials: Y
authors.lastname: Yoon
authors.forename: Lee S H
authors.initials: LS
authors.lastname: Yi
authors.forename: Sun Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Jang-Seong
authors.initials: JS
authors.lastname: Kim
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D000818:Animals; D001054:Apolipoproteins A / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D016466:CHO Cells; D002465:Cell Movement / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D006207:Half-Life; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000097:blood* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D001054:Apolipoproteins A; D007141:Immunoglobulin Fc Fragments; C574732:LK8 peptide; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins
keywords: Fc fusion proteins; angiogenesis inhibitors; apolipoprotein (a); kringle; pharmacokinetics