Therapeutic Potential of a Monoclonal Antibody Blocking the Wnt Pathway in Diabetic Retinopathy

• Published in: Diabetes (New York, N.Y.) Vol. 61; no. 11; pp. 2948 - 2957
• Main Authors: LEE, Kyungwon, YANG HU, LEXI DING, YING CHEN, TAKAHASHI, Yusuke, MOTT, Robert, MA, Jian-Xing
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.11.2012
• Subjects: Analysis; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - pharmacology; Angiogenesis Inhibitors - therapeutic use; Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; beta Catenin - metabolism; Biological and medical sciences; Capillary Permeability - drug effects; Cattle; Cells, Cultured; Complications; Diabetes; Diabetes. Impaired glucose tolerance; Diabetic retinopathy; Diabetic Retinopathy - drug therapy; Diabetic Retinopathy - immunology; Diabetic Retinopathy - metabolism; Diabetic Retinopathy - pathology; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Endothelium, Vascular - drug effects; Endothelium, Vascular - immunology; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Genes, Reporter - drug effects; HEK293 Cells; Humans; Hyperglycemia; Hyperglycemia - metabolism; Inflammation; Intravitreal Injections; Kinases; Leukostasis - prevention & control; Ligands; Low Density Lipoprotein Receptor-Related Protein-6 - antagonists & inhibitors; Low Density Lipoprotein Receptor-Related Protein-6 - genetics; Low Density Lipoprotein Receptor-Related Protein-6 - metabolism; Low density lipoprotein receptors; Medical sciences; Molecular Targeted Therapy; Monoclonal antibodies; Ophthalmology; Physiological aspects; Proteins; Rats; Rats, Inbred BN; Receptors, Wnt - antagonists & inhibitors; Receptors, Wnt - genetics; Receptors, Wnt - metabolism; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - metabolism; Retina; Retinal Pigment Epithelium - drug effects; Retinal Pigment Epithelium - immunology; Retinal Pigment Epithelium - metabolism; Retinal Pigment Epithelium - pathology; Retinopathies; Tumor necrosis factor-TNF; Vascular endothelial growth factor; Wnt Signaling Pathway - drug effects; Endocrinopathy; Eye disease; Retinopathy; Blocking antibody; Monoclonal antibody; Diabetes mellitus
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db11-0300

Dysregulation of Wnt/β-catenin signaling contributes to the development of diabetic retinopathy by inducing retinal inflammation, vascular leakage, and neovascularization. Here, we evaluated the inhibitory effect of a monoclonal antibody (Mab) specific for the E1E2 domain of Wnt coreceptor low-density lipoprotein receptor-related protein 6, Mab2F1, on canonical Wnt signaling and its therapeutic potential for diabetic retinopathy. Mab2F1 displayed robust inhibition on Wnt signaling with a half-maximal inhibitory concentration (IC₅₀) of 20 μg/mL in retinal pigment epithelial cells. In addition, Mab2F1 also attenuated the accumulation of β-catenin and overexpression of vascular endothelial growth factor, intercellular adhesion molecule-1, and tumor necrosis factor-α induced by high-glucose medium in retinal endothelial cells. In vivo, an intravitreal injection of Mab2F1 significantly reduced retinal vascular leakage and decreased preretinal vascular cells in oxygen-induced retinopathy (OIR) rats, demonstrating its inhibitory effects on ischemia-induced retinal neovascularization. Moreover, Mab2F1 blocked the overexpression of the inflammatory/angiogenic factors, attenuated leukostasis, and reduced retinal vascular leakage in both early and late stages of streptozotocin-induced diabetes. In conclusion, Mab2F1 inhibits canonical Wnt signaling, vascular leakage, and inflammation in the retina of diabetic retinopathy models, suggesting its potential to be used as a therapeutic agent in combination with other antiangiogenic compounds.