American Association for Cancer Research
Browse
10780432ccr171628-sup-184453_2_supp_4368853_1yt9dd.docx (19.96 kB)

Legends of Figs S1 to S8 unmarked from Development of a Function-Blocking Antibody Against Fibulin-3 as a Targeted Reagent for Glioblastoma

Download (19.96 kB)
journal contribution
posted on 2023-03-31, 19:42 authored by Mohan S. Nandhu, Prajna Behera, Vivek Bhaskaran, Sharon L. Longo, Lina M. Barrera-Arenas, Sadhak Sengupta, Diego J. Rodriguez-Gil, E. Antonio Chiocca, Mariano S. Viapiano

Legends of Figs S1 to S8, unmarked version

Funding

NIH

B*Cured Foundation

History

ARTICLE 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.