Targeting endosialin/CD248 through antibody-mediated internalization results in impaired pericyte maturation and
Katherine Rybinski1, Hongxia Z Imtiyaz1, Barrie Mittica1
1Morphotek, Inc., Exton, PA 19341, USA.
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.
Insights
The anti-cancer antibody MORAb-004 targets endosialin/CD248, reducing tumor blood vessel growth and dysfunction. This antibody treatment suppressed tumor development and metastasis in preclinical models.
Area of Science:
- Oncology
- Immunology
- Vascular Biology
Background:
- Endosialin/CD248 is overexpressed in tumor microvasculature, making it a potential anti-angiogenic target.
- Targeting tumor vasculature is a key strategy in cancer therapy.
Purpose of the Study:
- To investigate the efficacy of MORAb-004, a humanized anti-CD248 antibody, in targeting tumor angiogenesis and growth.
- To evaluate the impact of MORAb-004 on tumor microvasculature and pericyte function.
Main Methods:
- Generation of a human CD248 knock-in mouse model.
- Treatment of mice with MORAb-004 antibody.
- Analysis of tumor growth, metastasis, and microvasculature using immunofluorescence staining.
Main Results:
- MORAb-004 treatment significantly suppressed syngeneic tumor growth and metastasis.
- Tumors treated with MORAb-004 exhibited shortened, distorted, and dysfunctional blood vessels.
- CD248 internalization on pericytes led to reduced α-SMA expression, pericyte depolarization, and impaired microvessel maturation.
Conclusions:
- MORAb-004 effectively targets CD248 on tumor pericytes, disrupting tumor microvasculature development.
- This disruption of tumor angiogenesis ultimately suppresses tumor growth and metastasis.
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