Safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the monoclonal antibody ASK8007 blocking osteopontin in patients with rheumatoid arthritis: a randomised, placebo controlled, proof-of-concept study

Boumans, Maria J H; Houbiers, J. G. A.; Verschueren, Patrick; Ishikura, Hiroaki; Westhovens, René; Brouwer, Elisabeth; Rojkovich, Bernadette; Kelly, Stephen; Adel, Mona; Isaacs, John D.; Jacobs, H. S.; Gómez-Reino, Juan J.; Holtkamp, Gertjan M.; Hastings, Alex; Gerlag, Daniëlle M.; Tak, Paul P.

doi:10.1136/annrheumdis-2011-200298

Cited by 45 publications

(29 citation statements)

References 34 publications

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“…Several studies have reported an association of the rs9138 A risk allele with low serum levels of soluble OPN 3 17. However, to date, the exact role of OPN in RA joint damage is controversial: distinct murine models of RA have shown conflicting results on the relevance of OPN in bone erosion pathogenesis,18 19 and, more importantly, OPN blockade was found to be unlikely to induce robust clinical improvement in patients with RA 20…”

Section: Discussionmentioning

confidence: 99%

SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis

Juge

Steenbergen

Constantin

et al. 2014

Annals of the Rheumatic Diseases

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Section: Discussionmentioning

confidence: 99%

SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis

Juge

Steenbergen

Constantin

et al. 2014

Annals of the Rheumatic Diseases

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“…These studies highlight that the influence of inflammation on bone is specific to the site of inflammation and dependent on the cytokines present within the local bone microenvironment. It has also been shown that OPN has implications for inflammation involving osteoclasts, monocytes, lymphocytes, and neutrophils (37), and in fact, cumulative evidence suggests that OPN is involved in the pathogenesis of RA because it is important in both joint inflammation and destruction (38). The physiologic concentration of OPN is 20-35 ng/ml (39,40); however, high concentrations of OPN have been detected in RASFs and have even been known to induce chondrosarcoma cell migration (41,42).…”

Section: Discussionmentioning

confidence: 99%

Osteopontin Promotes Oncostatin M Production in Human Osteoblasts: Implication of Rheumatoid Arthritis Therapy

Chiang

Huang

et al. 2015

The Journal of Immunology

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Accumulating evidence indicates that subchondral bone might play an essential role in rheumatoid arthritis (RA). Osteopontin (OPN) induces the production of an important proinflammatory cytokine involved in the pathogenesis of RA. This study evaluated the activation of oncostatin M (OSM) by OPN in human primary osteoblasts to understand RA pathogenesis and characterized the intracellular signaling pathways involved in this activation. Quantitative PCR, ELISA, and Western blot results indicated that stimulation of human primary osteoblasts with OPN induces OSM expression through αvβ3 integrin/c-Src/platelet-derived growth factor receptor transactivation/MEK/ERK. Treatment of osteoblasts with OPN also increased c-Jun phosphorylation, AP-1 luciferase activity, and c-Jun binding to the AP-1 element on the OSM promoter, as demonstrated using chromatin immunoprecipitation assay. Moreover, inhibition of OPN expression using lentiviral-OPN short hairpin RNA resulted in the amelioration of articular swelling, cartilage erosion, and OSM expression in the ankle joint of mice with collagen-induced arthritis as shown using microcomputed tomography and immunohistochemistry staining. Our results imply that OSM expression in osteoblasts increases in response to OPN-induced inflammation in vitro. Finally, lentiviral-OPN short hairpin RNA ameliorates the inflammatory response and bone destruction in mice with collagen-induced arthritis. Therefore, OPN may be a potential therapeutic target for RA.

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“…OPN is a Hh-target, and a matricellular protein that is highly upregulated in fibrotic skin, lungs, kidneys, and joints (27–30). Mice genetically-deficient in OPN develop less fibrosis after certain injuries, suggesting that OPN may be a direct effector of the fibrotic process.…”

Section: Introductionmentioning

confidence: 99%

“…Despite prevailing data giving credence to OPN being an attractive anti-fibrotic target, and humanized antibodies to OPN being developed for inflammatory-joint diseases (30), no study has yet evaluated the impact of OPN neutralization in the treatment of fibrosis complicating CLD. Therefore, to evaluate these hypotheses, we studied the direct effects of OPN in cultures of liver progenitors, examined the effects of OPN-neutralization (by OPN-specific aptamers or OPN-neutralizing antibodies) in three murine models of liver fibrosis, and corroborated findings with analysis of liver tissues from patients with CLD.…”

Section: Introductionmentioning

confidence: 99%

Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice

Coombes

Swiderska‐Syn

Dollé

et al. 2014

Gut

111

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Background Chronic liver injury triggers a progenitor-cell repair-response, and liver fibrosis occurs when repair becomes de-regulated. Previously, we reported that reactivation of the Hedgehog (Hh) pathway promotes fibrogenic liver-repair. Osteopontin (OPN) is a Hh-target, and a cytokine that is highly upregulated in fibrotic tissues, and regulates stem-cell fate. Thus, we hypothesized that OPN may modulate liver progenitor-cell response, and thereby, modulate fibrotic outcomes. We further evaluated the impact of OPN-neutralization on murine liver fibrosis. Methods Liver progenitors (603B and BMOL) were treated with OPN-neutralizing aptamers in the presence or absence of TGF–β, to determine if (and how) OPN modulates liver progenitor function. Effects of OPN-neutralization (using OPN-aptamers or OPN-neutralizing antibodies) on liver progenitor-cell response and fibrogenesis were assessed in three models of liver fibrosis (carbon tetrachloride, methionine-choline deficient diet, 3, 5,-diethoxycarbonyl-1,4-dihydrocollidine diet) by qRTPCR, Sirius-Red staining, hydroxyproline assay, and semi-quantitative double-immunohistochemistry. Finally, OPN expression and liver progenitor response were corroborated in liver tissues obtained from patients with chronic liver disease. Results OPN is over-expressed by liver progenitors in humans and mice. In cultured progenitors, OPN enhances viability and wound-healing by modulating TGF-β signaling. In vivo, OPN-neutralization attenuates the liver progenitor-cell response, reverses epithelial-mesenchymal-transition in Sox9+ cells, and abrogates liver fibrogenesis. Conclusions OPN upregulation during liver injury is a conserved repair-response, and influences liver progenitor-cell function. OPN-neutralization abrogates the liver progenitor-cell response and fibrogenesis in mouse models of liver fibrosis.

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Safety, tolerability, pharmacokinetics, pharmacodynamics and efficacy of the monoclonal antibody ASK8007 blocking osteopontin in patients with rheumatoid arthritis: a randomised, placebo controlled, proof-of-concept study

Abstract: Osteopontin blockade is well tolerated and not related to safety concerns. These results consistently show that osteopontin blockade is unlikely to induce robust clinical improvement in RA patients.

Cited by 45 publications

References 34 publications

SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis

SPP1 rs9138 variant contributes to the severity of radiological damage in anti-citrullinated protein autoantibody-negative rheumatoid arthritis

Osteopontin Promotes Oncostatin M Production in Human Osteoblasts: Implication of Rheumatoid Arthritis Therapy

Osteopontin neutralisation abrogates the liver progenitor cell response and fibrogenesis in mice

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