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Open Access Research article

Human epidermal growth factor receptor bispecific ligand trap RB200: abrogation of collagen-induced arthritis in combination with tumour necrosis factor blockade

Luke L Gompels1, Nasser M Malik12, Leigh Madden13, Pei Jin45, Marc Feldmann13, H Michael Shepard46 and Ewa M Paleolog13*

Author Affiliations

1 Faculty of Medicine, Kennedy Institute of Rheumatology, 65 Aspenlea Road, London, W6 8LH, Imperial College London, London, UK

2 William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK

3 Kennedy Institute of Rheumatology, University of Oxford, 65 Aspenlea Road, London, W6 8LH, UK

4 Receptor BioLogix Inc, 3350 West Bayshore Road, Suite 150, Palo Alto, CA 94303, USA

5 Novartis Institutes for Biomedical Research, 350 Massachusetts Avenue #1, Cambridge, MA 02139, USA

6 Halozyme Therapeutics Inc, 11588 Sorrento Valley Road, Suite 17, San Diego, CA 92121, USA

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Arthritis Research & Therapy 2011, 13:R161  doi:10.1186/ar3480

Published: 7 October 2011

Abstract

Introduction

Rheumatoid arthritis (RA) is a chronic disease associated with inflammation and destruction of bone and cartilage. Although inhibition of TNFα is widely used to treat RA, a significant number of patients do not respond to TNFα blockade, and therefore there is a compelling need to continue to identify alternative therapeutic strategies for treating chronic inflammatory diseases such as RA. The anti-epidermal growth factor (anti-EGF) receptor antibody trastuzumab has revolutionised the treatment of patients with EGF receptor-positive breast cancer. Expression of EGF ligands and receptors (known as HER) has also been documented in RA. The highly unique compound RB200 is a bispecific ligand trap that is composed of full-length extracellular domains of HER1 and HER3 EGF receptors. Because of its pan-HER specificity, RB200 inhibits responses mediated by HER1, HER2 and HER3 in vitro and in vivo. The objective of this study was to assess the effect of RB200 combined with TNF blockade in a murine collagen-induced arthritis (CIA) model of RA.

Methods

Arthritic mice were treated with RB200 alone or in combination with the TNF receptor fusion protein etanercept. We performed immunohistochemistry to assess CD31 and in vivo fluorescent imaging using anti-E-selectin antibody labelled with fluorescent dye to elucidate the effect of RB200 on the vasculature in CIA.

Results

RB200 significantly abrogated CIA by reducing paw swelling and clinical scores. Importantly, low-dose RB200 combined with a suboptimal dose of etanercept led to complete abrogation of arthritis. Moreover, the combination of RB200 with etanercept abrogated the intensity of the E-selectin-targeted signal to the level seen in control animals not immunised to CIA.

Conclusions

The human pan-EGF receptor bispecific ligand trap RB200, when combined with low-dose etanercept, abrogates CIA, suggesting that inhibition of events downstream of EGF receptor activation, in combination with TNFα inhibitors, may hold promise as a future therapy for patients with RA.