title: Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis.
abstract: OBJECTIVE
  Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)-GM-CSF receptor α axis (GM-CSFRα) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA). Therefore, we investigated the cellular expression of GM-CSFRα in RA synovial tissue and investigated the effects of anti-GM-CSFRα antibody treatment in vitro and in vivo in a preclinical model of RA.
  
  
  METHODS
  We compared GM-CSFRα expression on macrophages positive for CD68 or CD163 on synovial biopsy samples from patients with RA or psoriatic arthritis (PsA) to disease controls. In addition, we studied the effects of CAM-3003, an anti-GM-CSFR antibody in a collagen induced arthritis model of RA in DBA/1 mice. The pharmacokinetic profile of CAM-3003 was studied in naïve CD1(ICR) mice (see online supplement) and used to interpret the results of the pharmacodynamic studies in BALB/c mice.
  
  
  RESULTS
  GM-CSFRα was expressed by CD68 positive and CD163 positive macrophages in the synovium, and there was a significant increase in GM-CSFRα positive cells in patients in patients with RA as well as patients with PsA compared with patients with osteoarthritis and healthy controls. In the collagen induced arthritis model there was a dose dependent reduction of clinical arthritis scores and the number of F4/80 positive macrophages in the inflamed synovium after CAM-3003 treatment. In BALB/c mice CAM-3003 inhibited recombinant GM-CSF mediated margination of peripheral blood monocytes and neutrophils.
  
  
  CONCLUSIONS
  The findings support the ongoing development of therapies aimed at interfering with GM-CSF or its receptor in various forms of arthritis, such as RA and PsA.
authors.affiliation: Department of Clinical Immunology and Rheumatology, Academic Medical Center/ University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: D E A
authors.initials: DE
authors.lastname: Greven
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: E S
authors.initials: ES
authors.lastname: Cohen
authors.affiliation: Department of Clinical Immunology and Rheumatology, Academic Medical Center/ University of Amsterdam, Amsterdam, The Netherlands GlaxoSmithKline, Cambridge, UK.
authors.forename: D M
authors.initials: DM
authors.lastname: Gerlag
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: J
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: J
authors.initials: J
authors.lastname: Woods
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: N
authors.initials: N
authors.lastname: Davis
authors.affiliation: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: van Nieuwenhuijze
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Lewis
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: S
authors.initials: S
authors.lastname: Heasmen
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: M
authors.initials: M
authors.lastname: McCourt
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: D
authors.initials: D
authors.lastname: Corkill
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: A
authors.initials: A
authors.lastname: Dodd
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: J
authors.initials: J
authors.lastname: Elvin
authors.affiliation: Department of Clinical Immunology and Rheumatology, Academic Medical Center/ University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Statache
authors.affiliation: Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: I P
authors.initials: IP
authors.lastname: Wicks
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: I K
authors.initials: IK
authors.lastname: Anderson
authors.affiliation: Department of Research and Development, CSL Limited, Parkville, Victoria, Australia.
authors.forename: A
authors.initials: A
authors.lastname: Nash
authors.affiliation: Department of Respiratory, Inflammation and AutoImmunity Research, MedImmune Limited, Cambridge, UK.
authors.forename: M A
authors.initials: MA
authors.lastname: Sleeman
authors.affiliation: Department of Clinical Immunology and Rheumatology, Academic Medical Center/ University of Amsterdam, Amsterdam, The Netherlands GlaxoSmithKline, Stevenage, UK University of Cambridge, Cambridge, UK.
authors.forename: P P
authors.initials: PP
authors.lastname: Tak
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D015535:Arthritis, Psoriatic / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D016022:Case-Control Studies; D004306:Dose-Response Relationship, Immunologic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D010003:Osteoarthritis / Q000276:immunology; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013583:Synovial Membrane / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; C000603220:CAM-3003; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Pharmacokinetics; Rheumatoid Arthritis; Treatment