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J Immunol. 2018 Feb 1;200(3):957-965. doi: 10.4049/jimmunol.1701317. Epub 2017 Dec 27.

Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models.

Author information

1
Global Research, Novo Nordisk A/S, DK-2760 Måløv, Denmark; KAHL@novonordisk.com.
2
Global Research, Novo Nordisk A/S, DK-2760 Måløv, Denmark.
3
The Finsen Laboratory, Rigshospitalet, DK-2200 Copenhagen, Denmark.
4
Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Rigshospitalet, DK-2100 Copenhagen, Denmark.
5
Aleris-Hamlet Hospital, DK-2000 Frederiksberg, Denmark.
6
Department of Orthopaedic Surgery, Hvidovre Hospital, DK-2650 Hvidovre, Denmark.
7
Section of Hand Surgery, Herlev and Gentofte Hospital, DK-2900 Hellerup, Denmark; and.
8
Parker Institute, Bispebjerg and Frederiksberg Hospital, DK-2000 Frederiksberg, Denmark.

Abstract

Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis. A mAb that neutralizes mouse uPA significantly reduced arthritis progression in the CIA and delayed-type hypersensitivity arthritis models. In the CIA model, the impact of anti-uPA treatment was on par with the effect of blocking TNF-α by etanercept. A pharmacokinetics evaluation of the therapeutic Ab revealed target-mediated drug disposition consistent with a high turnover of endogenous uPA. The cellular expression patterns of uPA and uPAR were characterized by double immunofluorescence in the inflamed synovium from patients with rheumatoid arthritis and compared with synovium from healthy donors. The arthritic synovium showed expression of uPA and uPAR in neutrophils, macrophages, and a fraction of endothelial cells, whereas there was little or no expression in synovium from healthy donors. The data from animal models and human material provide preclinical proof-of-principle that validates uPA as a novel therapeutic target in rheumatic diseases.

PMID:
29282305
DOI:
10.4049/jimmunol.1701317
[Indexed for MEDLINE]
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