Preclinical characterisation of the GM-CSF receptor as a therapeutic target in rheumatoid arthritis
Details
Publication Year 2015-10, Volume 74, Issue #10, Page 1824-30
Journal Title
Annals of the Rheumatic Diseases
Publication Type
Journal Article
Abstract
OBJECTIVE: Previous work has suggested that the granulocyte macrophage colony stimulating factor (GM-CSF)-GM-CSF receptor alpha axis (GM-CSFRalpha) may provide a new therapeutic target for the treatment of rheumatoid arthritis (RA). Therefore, we investigated the cellular expression of GM-CSFRalpha in RA synovial tissue and investigated the effects of anti-GM-CSFRalpha antibody treatment in vitro and in vivo in a preclinical model of RA. METHODS: We compared GM-CSFRalpha 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 naive CD1(ICR) mice (see online supplement) and used to interpret the results of the pharmacodynamic studies in BALB/c mice. RESULTS: GM-CSFRalpha was expressed by CD68 positive and CD163 positive macrophages in the synovium, and there was a significant increase in GM-CSFRalpha 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.
Publisher
BMJ
WEHI Research Division(s)
Inflammation
PubMed ID
24936585
Rights Notice
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/


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