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Clin Cancer Res. 2018 Feb 15;24(4):821-833. doi: 10.1158/1078-0432.CCR-17-1628. Epub 2017 Nov 16.

Development of a Function-Blocking Antibody Against Fibulin-3 as a Targeted Reagent for Glioblastoma.

Author information

1
Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
2
Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York.
3
Department of Neurosurgery, SUNY Upstate Medical University, Syracuse, New York.
4
Brain Tumor Laboratory, Roger Williams Medical Center, Providence, Rhode Island.
5
Department of Biomedical Sciences, East Tennessee State University, Johnson City, Tennessee.
6
Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts. viapianm@upstate.edu.

Abstract

Purpose: We sought a novel approach against glioblastomas (GBM) focused on targeting signaling molecules localized in the tumor extracellular matrix (ECM). We investigated fibulin-3, a glycoprotein that forms the ECM scaffold of GBMs and promotes tumor progression by driving Notch and NFκB signaling.Experimental Design: We used deletion constructs to identify a key signaling motif of fibulin-3. An mAb (mAb428.2) was generated against this epitope and extensively validated for specific detection of human fibulin-3. mAb428.2 was tested in cultures to measure its inhibitory effect on fibulin-3 signaling. Nude mice carrying subcutaneous and intracranial GBM xenografts were treated with the maximum achievable dose of mAb428.2 to measure target engagement and antitumor efficacy.Results: We identified a critical 23-amino acid sequence of fibulin-3 that activates its signaling mechanisms. mAb428.2 binds to that epitope with nanomolar affinity and blocks the ability of fibulin-3 to activate ADAM17, Notch, and NFκB signaling in GBM cells. mAb428.2 treatment of subcutaneous GBM xenografts inhibited fibulin-3, increased tumor cell apoptosis, and enhanced the infiltration of inflammatory macrophages. The antibody reduced tumor growth and extended survival of mice carrying GBMs as well as other fibulin-3-expressing tumors. Locally infused mAb428.2 showed efficacy against intracranial GBMs, increasing tumor apoptosis and reducing tumor invasion and vascularization, which are enhanced by fibulin-3.Conclusions: To our knowledge, this is the first rationally developed, function-blocking antibody against an ECM target in GBM. Our results offer a proof of principle for using "anti-ECM" strategies toward more efficient targeted therapies for malignant glioma. Clin Cancer Res; 24(4); 821-33. ©2017 AACR.

PMID:
29146721
PMCID:
PMC5815892
DOI:
10.1158/1078-0432.CCR-17-1628
[Indexed for MEDLINE]
Free PMC Article

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