EphA3 Pay-Loaded Antibody Therapeutics for the Treatment of Glioblastoma.

Carolin Offenhäuser,Paul Jamieson,Brett Stringer,Craig Bell,Simon Puttick,Fares Al-Ejeh,Benjamin Carrington,Bryan Day,Stephen Rose,Andrew Boyd,Rosalind Jeffree,Kristofer Thurecht,Zara Bruce,Kathleen Ensbey,Fiona Smith,Adrian Fuchs

doi:10.3390/cancers10120519

Abstract

The EphA3 receptor has recently emerged as a functional tumour-specific therapeutic target in glioblastoma (GBM). EphA3 is significantly elevated in recurrent disease, is most highly expressed on glioma stem cells (GSCs), and has a functional role in maintaining self-renewal and tumourigenesis. An unlabelled EphA3-targeting therapeutic antibody is currently under clinical assessment in recurrent GBM patients. In this study, we assessed the efficacy of EphA3 antibody drug conjugate (ADC) and radioimmunotherapy (RIT) approaches using orthotopic animal xenograft models. Brain uptake studies, using positron emission tomography/computed tomography (PET/CT) imaging, show EphA3 antibodies are effectively delivered across the blood-tumour barrier and accumulate at the tumour site with no observed normal brain reactivity. A robust anti-tumour response, with no toxicity, was observed using EphA3, ADC, and RIT approaches, leading to a significant increase in overall survival. Our current research provides evidence that GBM patients may benefit from pay-loaded EphA3 antibody therapies.

Highlights

Glioblastoma (GBM) is the most common and aggressive adult malignant brain cancer.Despite surgical resection, radiation, and temozolomide chemotherapy, median survival is Cancers 2018, 10, 519; doi:10.3390/cancers10120519 www.mdpi.com/journal/cancersCancers 2018, 10, 519 approximately 15 months [1,2]
The IIIA4 antibody was deemed to be an excellent candidate for antibody drug conjugate (ADC) therapy, as previous studies have shown that the IIIA4 antibody-ephrin type-A receptor 3 (EphA3) interaction induces rapid internalisation [17]
We prepared an EphA3-ADC by conjugating the IIIA4 antibody to the cytotoxic microtubule-targeting agent maytansine (USAN), using a non-cleavable succinimidyl

Summary

Introduction

Glioblastoma (GBM) is the most common and aggressive adult malignant brain cancer.Despite surgical resection, radiation, and temozolomide chemotherapy, median survival is Cancers 2018, 10, 519; doi:10.3390/cancers10120519 www.mdpi.com/journal/cancersCancers 2018, 10, 519 approximately 15 months [1,2]. Glioblastoma (GBM) is the most common and aggressive adult malignant brain cancer. Brain cancer sufferers have not seen meaningful increases in overall survival for decades. This is, in large part, due to the highly infiltrative and heterogeneous nature of these aggressive tumours [3]. Eph receptors are the largest family of receptor tyrosine kinases (RTKs). Whilst they have critical functions during embryonic development, they are typically expressed at low levels in normal adult tissues [4]. It is established that numerous Eph receptors are re-expressed and functional in human cancers, making them attractive, relatively tumour-specific targets [5,6]. EphA3 has been widely implicated in a number of developmental processes involving cell adhesion, cell migration, and tissue boundary formation

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Results

Conclusion