RRC ID 72001
Author Koya Y, Nara H, Yagi S, Ueno C, Kamohara M.
Title An engineered tetra-valent antibody fully activates the Tie2 receptor with comparable potency to its natural ligand angiopoietin-1.
Journal Sci Rep
Abstract Activation of the tyrosine kinase with Ig and epidermal growth factor homology domain 2 (Tie2) receptor by angiopoietin-1 (Ang1) is critical for vascular stabilization: it promotes survival signal transduction via auto-phosphorylation and reduces vascular permeability by strengthening tight junctions between endothelial cells. Thus, Tie2/Ang1 signaling is a promising therapeutic target for vascular diseases. However, in vivo use of existing Tie2 signaling modulators, such as recombinant Ang1, is restricted by limitations in manufacturability and stability. Here, we present a novel engineered tetra-valent agonistic antibody, ASP4021, which can specifically and fully activate the Tie2 receptor in an equivalent manner to Ang1. ASP4021 induced Tie2 self-phosphorylation and inhibited apoptosis in a human primary endothelial cell line. Additionally, single administration of ASP4021 significantly suppressed mustard-oil-induced vascular permeability in rats. ASP4021 may thus be a potential therapeutic candidate for diseases associated with vascular weakness such as diabetic retinopathy, diabetic macular edema and critical limb ischemia.
Volume 11(1)
Pages 14021
Published 2021-7-7
DOI 10.1038/s41598-021-93660-4
PII 10.1038/s41598-021-93660-4
PMID 34234265
PMC PMC8263585
MeSH Angiopoietin-1 / metabolism* Angiopoietin-1 / pharmacology Animals Antibodies / genetics Antibodies / pharmacology* Apoptosis / drug effects Capillary Permeability / drug effects Genetic Engineering Humans Ligands Male Mice Phosphorylation Rats Receptor, TIE-2 / agonists* Recombinant Fusion Proteins / genetics Recombinant Fusion Proteins / pharmacology*
IF 3.998
Human and Animal Cells Ba/F3(RCB0805)