title: Human epidermal growth factor receptor bispecific ligand trap RB200: abrogation of collagen-induced arthritis in combination with tumour necrosis factor blockade.
abstract: BACKGROUND
  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.
authors: Faculty of Medicine, Kennedy Institute of Rheumatology, 65 Aspenlea Road, London, W6 8LH, Imperial College London, London, UK.
authors: Luke L
authors: LL
authors: Gompels
authors: Nasser M
authors: NM
authors: Malik
authors: Leigh
authors: L
authors: Madden
authors: Pei
authors: P
authors: Jin
authors: Marc
authors: M
authors: Feldmann
authors: H Michael
authors: HM
authors: Shepard
authors: Ewa M
authors: EM
authors: Paleolog
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism*; D002417:Cattle; D066246:ErbB Receptors / Q000378:metabolism*; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008024:Ligands; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D007074:Immunoglobulin G; D008024:Ligands; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; C512478:EGFR protein, human; D066246:ErbB Receptors; D020893:Receptor, ErbB-3; D000068800:Etanercept