Targeting endosialin/CD248 through antibody-mediated internalization results in impaired pericyte maturation and dysfunctional tumor microvasculature.
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.
Morphotek, Inc., Exton, PA 19341, USA.
Katherine
K
Rybinski
Morphotek, Inc., Exton, PA 19341, USA.
Hongxia Z
HZ
Imtiyaz
Morphotek, Inc., Exton, PA 19341, USA.
Barrie
B
Mittica
Morphotek, Inc., Exton, PA 19341, USA.
Brian
B
Drozdowski
Morphotek, Inc., Exton, PA 19341, USA.
James
J
Fulmer
Morphotek, Inc., Exton, PA 19341, USA.
Keiji
K
Furuuchi
Morphotek, Inc., Exton, PA 19341, USA.
Shawn
S
Fernando
Morphotek, Inc., Exton, PA 19341, USA.
Marianne
M
Henry
Morphotek, Inc., Exton, PA 19341, USA.
Qimin
Q
Chao
Morphotek, Inc., Exton, PA 19341, USA.
Brad
B
Kline
Morphotek, Inc., Exton, PA 19341, USA.
Earl
E
Albone
Morphotek, Inc., Exton, PA 19341, USA.
Jason
J
Wustner
Morphotek, Inc., Exton, PA 19341, USA.
JianMin
J
Lin
Morphotek, Inc., Exton, PA 19341, USA.
Nicholas C
NC
Nicolaides
Morphotek, Inc., Exton, PA 19341, USA.
Luigi
L
Grasso
Morphotek, Inc., Exton, PA 19341, USA.
Yuhong
Y
Zhou
D000199:Actins / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000378:metabolism / Q000494:pharmacology*; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D001692:Biological Transport; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055806:Microvessels / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D020286:Pericytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects
C558396:Acta2 protein, mouse; D000199:Actins; D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D000951:Antigens, Neoplasm; C078203:CD248 protein, human; C000604563:ontuxizumab
CD248; MORAb-004; endosialin; tumor microvasculature; α-SMA