Rapid-onset clinical and mechanistic effects of anti-C5aR treatment in the mouse collagen-induced arthritis model

Christina Thulin Andersson, Carola S Wenander, Pernille A Usher, Josephine B Hebsgaard, Bodil C Sondergaard, B Rono, Charles R Mackay, Birgitte N Friedrichsen, C Chang, R Tang, L Hornum

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    17 Citations (Scopus)

    Abstract

    Preclinical evidence supports targeting the C5a receptor (C5aR) in rheumatoid arthritis (RA). To support ongoing clinical development of an anti-C5aR monoclonal antibody, we have investigated for the first time the mechanism of action and the pharmacodynamics of a blocking anti-murine C5aR (anti-mC5aR) surrogate antibody in mouse collagen-induced arthritis (CIA). First, efficacy was demonstrated in a multiple-dose treatment study. Almost complete inhibition of clinical disease progression was obtained, including reduced bone and cartilage destruction in anti-mC5aR-treated mice. Then, the mechanism of action was examined by looking for early effects of anti-mC5aR treatment in single-dose treatment studies. We found that 48 h after single-dose treatment with anti-mC5aR, the neutrophil and macrophage infiltration into the paws was already reduced. In addition, several inflammatory markers, including tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-17A were reduced locally in the paws, indicating reduction of local inflammation. Furthermore, dose-setting experiments supported a beneficial clinical effect of dosing above the C5aR saturation level. In conclusion, these preclinical data demonstrated rapid onset effects of antibody blockade of C5aR. The data have translational value in supporting the Novo Nordisk clinical trials of an anti-C5aR antibody in rheumatoid arthritis patients, by identifying potential biomarkers of treatment effects as well as by providing information on pharmacodynamics and novel insights into the mechanism of action of monoclonal antibody blockade of C5aR.
    Original languageEnglish
    Pages (from-to)219 - 233
    Number of pages15
    JournalClinical and Experimental Immunology
    Volume177
    Issue number1
    DOIs
    Publication statusPublished - 2014

    Cite this

    Andersson, C. T., Wenander, C. S., Usher, P. A., Hebsgaard, J. B., Sondergaard, B. C., Rono, B., ... Hornum, L. (2014). Rapid-onset clinical and mechanistic effects of anti-C5aR treatment in the mouse collagen-induced arthritis model. Clinical and Experimental Immunology, 177(1), 219 - 233. https://doi.org/10.1111/cei.12338
    Andersson, Christina Thulin ; Wenander, Carola S ; Usher, Pernille A ; Hebsgaard, Josephine B ; Sondergaard, Bodil C ; Rono, B ; Mackay, Charles R ; Friedrichsen, Birgitte N ; Chang, C ; Tang, R ; Hornum, L. / Rapid-onset clinical and mechanistic effects of anti-C5aR treatment in the mouse collagen-induced arthritis model. In: Clinical and Experimental Immunology. 2014 ; Vol. 177, No. 1. pp. 219 - 233.
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    abstract = "Preclinical evidence supports targeting the C5a receptor (C5aR) in rheumatoid arthritis (RA). To support ongoing clinical development of an anti-C5aR monoclonal antibody, we have investigated for the first time the mechanism of action and the pharmacodynamics of a blocking anti-murine C5aR (anti-mC5aR) surrogate antibody in mouse collagen-induced arthritis (CIA). First, efficacy was demonstrated in a multiple-dose treatment study. Almost complete inhibition of clinical disease progression was obtained, including reduced bone and cartilage destruction in anti-mC5aR-treated mice. Then, the mechanism of action was examined by looking for early effects of anti-mC5aR treatment in single-dose treatment studies. We found that 48 h after single-dose treatment with anti-mC5aR, the neutrophil and macrophage infiltration into the paws was already reduced. In addition, several inflammatory markers, including tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-17A were reduced locally in the paws, indicating reduction of local inflammation. Furthermore, dose-setting experiments supported a beneficial clinical effect of dosing above the C5aR saturation level. In conclusion, these preclinical data demonstrated rapid onset effects of antibody blockade of C5aR. The data have translational value in supporting the Novo Nordisk clinical trials of an anti-C5aR antibody in rheumatoid arthritis patients, by identifying potential biomarkers of treatment effects as well as by providing information on pharmacodynamics and novel insights into the mechanism of action of monoclonal antibody blockade of C5aR.",
    author = "Andersson, {Christina Thulin} and Wenander, {Carola S} and Usher, {Pernille A} and Hebsgaard, {Josephine B} and Sondergaard, {Bodil C} and B Rono and Mackay, {Charles R} and Friedrichsen, {Birgitte N} and C Chang and R Tang and L Hornum",
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    Andersson, CT, Wenander, CS, Usher, PA, Hebsgaard, JB, Sondergaard, BC, Rono, B, Mackay, CR, Friedrichsen, BN, Chang, C, Tang, R & Hornum, L 2014, 'Rapid-onset clinical and mechanistic effects of anti-C5aR treatment in the mouse collagen-induced arthritis model', Clinical and Experimental Immunology, vol. 177, no. 1, pp. 219 - 233. https://doi.org/10.1111/cei.12338

    Rapid-onset clinical and mechanistic effects of anti-C5aR treatment in the mouse collagen-induced arthritis model. / Andersson, Christina Thulin; Wenander, Carola S; Usher, Pernille A; Hebsgaard, Josephine B; Sondergaard, Bodil C; Rono, B; Mackay, Charles R; Friedrichsen, Birgitte N; Chang, C; Tang, R; Hornum, L.

    In: Clinical and Experimental Immunology, Vol. 177, No. 1, 2014, p. 219 - 233.

    Research output: Contribution to journalArticleResearchpeer-review

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    T1 - Rapid-onset clinical and mechanistic effects of anti-C5aR treatment in the mouse collagen-induced arthritis model

    AU - Andersson, Christina Thulin

    AU - Wenander, Carola S

    AU - Usher, Pernille A

    AU - Hebsgaard, Josephine B

    AU - Sondergaard, Bodil C

    AU - Rono, B

    AU - Mackay, Charles R

    AU - Friedrichsen, Birgitte N

    AU - Chang, C

    AU - Tang, R

    AU - Hornum, L

    PY - 2014

    Y1 - 2014

    N2 - Preclinical evidence supports targeting the C5a receptor (C5aR) in rheumatoid arthritis (RA). To support ongoing clinical development of an anti-C5aR monoclonal antibody, we have investigated for the first time the mechanism of action and the pharmacodynamics of a blocking anti-murine C5aR (anti-mC5aR) surrogate antibody in mouse collagen-induced arthritis (CIA). First, efficacy was demonstrated in a multiple-dose treatment study. Almost complete inhibition of clinical disease progression was obtained, including reduced bone and cartilage destruction in anti-mC5aR-treated mice. Then, the mechanism of action was examined by looking for early effects of anti-mC5aR treatment in single-dose treatment studies. We found that 48 h after single-dose treatment with anti-mC5aR, the neutrophil and macrophage infiltration into the paws was already reduced. In addition, several inflammatory markers, including tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-17A were reduced locally in the paws, indicating reduction of local inflammation. Furthermore, dose-setting experiments supported a beneficial clinical effect of dosing above the C5aR saturation level. In conclusion, these preclinical data demonstrated rapid onset effects of antibody blockade of C5aR. The data have translational value in supporting the Novo Nordisk clinical trials of an anti-C5aR antibody in rheumatoid arthritis patients, by identifying potential biomarkers of treatment effects as well as by providing information on pharmacodynamics and novel insights into the mechanism of action of monoclonal antibody blockade of C5aR.

    AB - Preclinical evidence supports targeting the C5a receptor (C5aR) in rheumatoid arthritis (RA). To support ongoing clinical development of an anti-C5aR monoclonal antibody, we have investigated for the first time the mechanism of action and the pharmacodynamics of a blocking anti-murine C5aR (anti-mC5aR) surrogate antibody in mouse collagen-induced arthritis (CIA). First, efficacy was demonstrated in a multiple-dose treatment study. Almost complete inhibition of clinical disease progression was obtained, including reduced bone and cartilage destruction in anti-mC5aR-treated mice. Then, the mechanism of action was examined by looking for early effects of anti-mC5aR treatment in single-dose treatment studies. We found that 48 h after single-dose treatment with anti-mC5aR, the neutrophil and macrophage infiltration into the paws was already reduced. In addition, several inflammatory markers, including tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-17A were reduced locally in the paws, indicating reduction of local inflammation. Furthermore, dose-setting experiments supported a beneficial clinical effect of dosing above the C5aR saturation level. In conclusion, these preclinical data demonstrated rapid onset effects of antibody blockade of C5aR. The data have translational value in supporting the Novo Nordisk clinical trials of an anti-C5aR antibody in rheumatoid arthritis patients, by identifying potential biomarkers of treatment effects as well as by providing information on pharmacodynamics and novel insights into the mechanism of action of monoclonal antibody blockade of C5aR.

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