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.
Highlights
Angiogenesis plays an essential role in embryonic development and wound healing, and in cancer development [1, 2]
The CD248 levels on cell surfaces of neovasculature pericytes were significantly reduced due to its internalization. This reduction of CD248 was accompanied by reduced α-SMA expression, depolarization of pericytes and endothelium, and dysfunctional microvessels. These results suggest that MORAb-004 reduced CD248 on pericytes, impaired tumor microvasculature maturation and suppressed tumor development
To examine whether MORAb-004 treatment would directly cause reduction of CD248 levels on the cell surface, pericytes were cultured in the presence of MORAb-004 for up to 18 hours and stained with a labeled anti-CD248 monoclonal IgG, 9G5, which recognizes a different epitope from that of MORAb-004 (Figure S1C)
Summary
Angiogenesis plays an essential role in embryonic development and wound healing, and in cancer development [1, 2]. The first of such targets, VEGFR, is expressed on vascular endothelial cells [4] Intensive studies of this gene have led to the successful launch of an antiVEGFR antibody and a VEGF-trap, the first two antiangiogenesis therapeutic agents for metastatic cancers and age-related macular degeneration (AMD) [5]. An anti-PDFGR antibody (Fovista®) has been advanced to the clinical stage and recently had a successful Phase 2b clinical trial in combination with an anti-VEGF agent for the treatment of patients newly diagnosed with wet AMD [7] These successes have stimulated the search for more angiogenesis targets expressed directly on endothelial cells as well as stromal cells that support vessel formation. CD248, is expressed on tumor associated pericytes and tumor stromal fibroblasts and was identified as a potential anti-tumor vasculature target due to its tight association with tumor neovasculature [3]
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