Targeting endosialin/CD248 through antibody-mediated internalization results in impaired pericyte maturation and dysfunctional tumor microvasculature.

Abstract

Over-expression of endosialin/CD248 (herein referred to as CD248) has been associated with increased tumor microvasculature in various tissue origins which makes it an attractive anti-angiogenic target. In an effort to target CD248, we have generated a human CD248 knock-in mouse line and MORAb-004, the humanized version of the mouse anti-human CD248 antibody Fb5. Here, we report that MORAb-004 treatment significantly impacted syngeneic tumor growth and tumor metastasis in the human CD248 knock-in mice. In comparison with untreated tumors, MORAb-004 treated tumors displayed overall shortened and distorted blood vessels. Immunofluorescent staining of tumor sections revealed drastically more small and dysfunctional vessels in the treated tumors. The CD248 levels on cell surfaces of neovasculature pericytes were significantly reduced due to its internalization. This reduction of CD248 was also accompanied by reduced α-SMA expression, depolarization of pericytes and endothelium, and ultimately dysfunctional microvessels. These results suggest that MORAb-004 reduced CD248 on pericytes, impaired tumor microvasculature maturation and ultimately suppressed tumor development.

• Authors: Katherine Rybinski, Hongxia Z Imtiyaz, Barrie Mittica, Brian Drozdowski, James Fulmer, Keiji Furuuchi, Shawn Fernando, Marianne Henry, Qimin Chao, Brad Kline, Earl Albone, Jason Wustner, JianMin Lin, Nicholas C Nicolaides, Luigi Grasso, Yuhong Zhou
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 28 Pg. 25429-40 (Sep 22 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26327620 (Publication Type: Journal Article)

Chemical References

• Acta2 protein, mouse
• Actins
• Angiogenesis Inhibitors
• Antibodies, Monoclonal, Humanized
• Antigens, CD
• Antigens, Neoplasm
• CD248 protein, human
• ontuxizumab

Topics

• Actins (metabolism)
• Angiogenesis Inhibitors (metabolism, pharmacology)
• Animals
• Antibodies, Monoclonal, Humanized (metabolism, pharmacology)
• Antigens, CD (genetics, immunology, metabolism)
• Antigens, Neoplasm (genetics, immunology, metabolism)
• Biological Transport
• Carcinoma, Lewis Lung (blood supply, drug therapy, genetics, immunology, metabolism, pathology)
• Cell Movement (drug effects)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Endothelial Cells (drug effects, immunology, metabolism)
• Female
• Humans
• Male
• Melanoma, Experimental (blood supply, drug therapy, genetics, immunology, metabolism, pathology)
• Mice, Inbred C57BL
• Mice, Transgenic
• Microvessels (drug effects, immunology, metabolism, pathology)
• Neoplasm Metastasis
• Neovascularization, Pathologic
• Pericytes (drug effects, immunology, metabolism, pathology)
• RNA Interference
• Time Factors
• Transfection
• Tumor Burden (drug effects)