Targeting endosialin/CD248 through antibody-mediated internalization results in impaired pericyte maturation and dysfunctional tumor microvasculature
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Katherine Rybinski1, Hongxia Z. Imtiyaz1, Barrie Mittica1, Brian Drozdowski1, James Fulmer1, Keiji Furuuchi1, Shawn Fernando1, Marianne Henry1, Qimin Chao1, Brad Kline1, Earl Albone1, Jason Wustner1, JianMin Lin1, Nicholas C. Nicolaides1, Luigi Grasso1, Yuhong Zhou1
1Morphotek, Inc., Exton, PA 19341, USA
Yuhong Zhou, e-mail: email@example.com
Keywords: endosialin, CD248, MORAb-004, tumor microvasculature, α-SMA
Received: May 11, 2015 Accepted: June 22, 2015 Published: July 04, 2015
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.
Hongxia Z. Imtiyaz
Nicholas C. Nicolaides
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