Anti-PTK7 Monoclonal Antibodies Inhibit Angiogenesis by Suppressing PTK7 Function

• Published in: Cancers Vol. 14; no. 18; p. 4463
• Main Authors: Oh, Si Won, Shin, Won-Sik, Lee, Seung-Taek
• Format: Journal Article
• Language: English
• Published: Basel MDPI AG 01.09.2022; MDPI
• Subjects: Analysis; Angiogenesis; Aorta; Cell activation; Cytotoxicity; Deletion mutant; Dosage and administration; Endothelial cells; Endothelium; Ethylenediaminetetraacetic acid; Health aspects; Immunoglobulins; Kinases; Metastases; Metastasis; Monoclonal antibodies; Mutagenesis; Neovascularization; Oligomerization; Oligomers; Phenotypes; Phosphotransferases; Prevention; Protein-tyrosine kinase; Proteins; Signal transduction; Tyrosine; Vascular endothelial growth factor; Wound healing; South Korea; United States > US
• ISSN: 2072-6694; 2072-6694
• DOI: 10.3390/cancers14184463

PTK7, a catalytically defective receptor protein tyrosine kinase, promotes angiogenesis by activating KDR through direct interaction and induction of KDR oligomerization. This study developed anti-PTK7 monoclonal antibodies (mAbs) to regulate angiogenesis by inhibiting PTK7 function. The effect of anti-PTK7 mAbs on vascular endothelial growth factor (VEGF)-induced angiogenic phenotypes in human umbilical vascular endothelial cells (HUVECs) was examined. Analysis of mAb binding with PTK7 deletion mutants revealed that mAb-43 and mAb-52 recognize immunoglobulin (Ig) domain 2 of PTK7, whereas mAb-32 and mAb-50 recognize Ig domains 6–7. Anti-PTK7 mAbs inhibited VEGF-induced adhesion and wound healing in HUVECs. mAb-32, mAb-43, and mAb-52 dose-dependently mitigated VEGF-induced migration and invasion in HUVECs without exerting cytotoxic effects. Additionally, mAb-32, mAb-43, and mAb-52 inhibited capillary-like tube formation in HUVECs, and mAb-32 and mAb-43 suppressed angiogenesis ex vivo (aortic ring assay) and in vivo (Matrigel plug assay). Furthermore, mAb-32 and mAb-43 downregulated VEGF-induced KDR activation and downstream signaling and inhibited PTK7–KDR interaction in PTK7-overexpressing and KDR-overexpressing HEK293 cells. Thus, anti-PTK7 mAbs inhibit angiogenic phenotypes by blocking PTK7–KDR interaction. These findings indicate that anti-PTK7 mAbs that neutralize PTK7 function can alleviate impaired angiogenesis-associated pathological conditions, such as cancer metastasis.