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

Kasper Almholt; Josephine B Hebsgaard; Anneline Nansen; Christina Andersson; Jesper Pass; Birgitte Rønø; Peter Thygesen; Hermann Pelzer; Mette Loftager; Ida K Lund; Gunilla Høyer-Hansen; Thomas Frisch; Claus H Jensen; Kristian S Otte; Niels H Søe; Else M Bartels; Martin Andersen; Henning Bliddal; Pernille A Usher

doi:10.4049/jimmunol.1701317

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

Kasper Almholt, Josephine B Hebsgaard, Anneline Nansen, Christina Andersson, Jesper Pass, Birgitte Rønø, Peter Thygesen, Hermann Pelzer, Mette Loftager, Ida K Lund, Gunilla Høyer-Hansen, Thomas Frisch, Claus H Jensen, Kristian S Otte, Niels H Søe, Else M Bartels, Martin Andersen, Henning Bliddal, Pernille A Usher

Department of Clinical Medicine

13 Citations (Scopus)

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-a 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.

Original language	English
Journal	The Journal of Immunology
Volume	200
Issue number	3
Pages (from-to)	957-965
ISSN	0022-1767
DOIs	https://doi.org/10.4049/jimmunol.1701317
Publication status	Published - 1 Feb 2018

Keywords

Animals
Antibodies, Monoclonal/immunology
Arthritis, Experimental/pathology
Arthritis, Rheumatoid/pathology
Disease Models, Animal
Disease Progression
Endothelial Cells/immunology
Etanercept/pharmacology
Female
Humans
Hypersensitivity, Delayed/immunology
Macrophages/immunology
Male
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Neutrophils/immunology
Receptors, Urokinase Plasminogen Activator/metabolism
Synovial Membrane/immunology
Tumor Necrosis Factor-alpha/antagonists & inhibitors
Urokinase-Type Plasminogen Activator/antagonists & inhibitors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Almholt, K., Hebsgaard, J. B., Nansen, A., Andersson, C., Pass, J., Rønø, B., Thygesen, P., Pelzer, H., Loftager, M., Lund, I. K., Høyer-Hansen, G., Frisch, T., Jensen, C. H., Otte, K. S., Søe, N. H., Bartels, E. M., Andersen, M., Bliddal, H., & Usher, P. A. (2018). Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models. The Journal of Immunology, 200(3), 957-965. https://doi.org/10.4049/jimmunol.1701317

Almholt, K, Hebsgaard, JB, Nansen, A, Andersson, C, Pass, J, Rønø, B, Thygesen, P, Pelzer, H, Loftager, M, Lund, IK, Høyer-Hansen, G, Frisch, T, Jensen, CH, Otte, KS, Søe, NH, Bartels, EM, Andersen, M, Bliddal, H & Usher, PA 2018, 'Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models', The Journal of Immunology, vol. 200, no. 3, pp. 957-965. https://doi.org/10.4049/jimmunol.1701317

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title = "Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models",

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-a 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.",

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author = "Kasper Almholt and Hebsgaard, {Josephine B} and Anneline Nansen and Christina Andersson and Jesper Pass and Birgitte R{\o}n{\o} and Peter Thygesen and Hermann Pelzer and Mette Loftager and Lund, {Ida K} and Gunilla H{\o}yer-Hansen and Thomas Frisch and Jensen, {Claus H} and Otte, {Kristian S} and S{\o}e, {Niels H} and Bartels, {Else M} and Martin Andersen and Henning Bliddal and Usher, {Pernille A}",

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language = "English",

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T1 - Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models

AU - Almholt, Kasper

AU - Hebsgaard, Josephine B

AU - Nansen, Anneline

AU - Andersson, Christina

AU - Pass, Jesper

AU - Rønø, Birgitte

AU - Thygesen, Peter

AU - Pelzer, Hermann

AU - Loftager, Mette

AU - Lund, Ida K

AU - Høyer-Hansen, Gunilla

AU - Frisch, Thomas

AU - Jensen, Claus H

AU - Otte, Kristian S

AU - Søe, Niels H

AU - Bartels, Else M

AU - Andersen, Martin

AU - Bliddal, Henning

AU - Usher, Pernille A

PY - 2018/2/1

Y1 - 2018/2/1

N2 - 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-a 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.

AB - 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-a 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.

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KW - Antibodies, Monoclonal/immunology

KW - Arthritis, Experimental/pathology

KW - Arthritis, Rheumatoid/pathology

KW - Disease Models, Animal

KW - Disease Progression

KW - Endothelial Cells/immunology

KW - Etanercept/pharmacology

KW - Female

KW - Humans

KW - Hypersensitivity, Delayed/immunology

KW - Macrophages/immunology

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Inbred DBA

KW - Neutrophils/immunology

KW - Receptors, Urokinase Plasminogen Activator/metabolism

KW - Synovial Membrane/immunology

KW - Tumor Necrosis Factor-alpha/antagonists & inhibitors

KW - Urokinase-Type Plasminogen Activator/antagonists & inhibitors

U2 - 10.4049/jimmunol.1701317

DO - 10.4049/jimmunol.1701317

M3 - Journal article

C2 - 29282305

SN - 0022-1767

VL - 200

SP - 957

EP - 965

JO - The Journal of Immunology

JF - The Journal of Immunology

IS - 3

ER -

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

Abstract

Keywords

UN SDGs

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