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

Oncotarget
Katherine RybinskiYuhong Zhou

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.

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Citations

Feb 26, 2016·Oncotarget·Sara E S LangeBrian A Van Tine
Aug 6, 2016·Oncotarget·Daniel J O'ShannessyNicholas C Nicolaides
Nov 12, 2017·Investigational New Drugs·Sandra P D'AngeloRichard D Carvajal
Apr 5, 2017·EMBO Molecular Medicine·Carolin MoglerHellmut G Augustin
Feb 2, 2018·Frontiers in Immunology·Carlos Cuesta-MateosCecilia Muñoz-Calleja
Jan 30, 2020·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Francesco CiconeJohn O Prior
Jul 10, 2019·The FEBS Journal·Kabir A KhanRoy Bicknell
Mar 9, 2019·Oncotarget·Beverly A Teicher
Sep 17, 2016·Cancer Research·Carmen ViskiHellmut G Augustin
Jun 29, 2021·Frontiers in Cell and Developmental Biology·Ruipu SunPing-Pui Wong

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Methods Mentioned

BETA
xenograft
X-ray
xenografts
FACS
PCR
electrophoresis
dissection
transfection

Software Mentioned

Integrated Morphometry Analysis ( IMA )
MetaMorph
Numira
Altaview

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