Targeting chemokine receptors in chronic inflammatory diseases: An extensive review

Koelink, Pim J.; Overbeek, Saskia A.; Braber, Saskia; Kruijf, Petra de; Folkerts, Gert; Smit, Martine J.; Kraneveld, Aletta D.

doi:10.1016/j.pharmthera.2011.06.008

Cited by 120 publications

(112 citation statements)

References 273 publications

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“…Most of the chemokine receptor targets identified for the treatment of human disease processes have been validated in animal models. 170 The majority of compounds developed targeting these receptors have shown good efficacy in animal and in vitro models, but have ultimately failed to translate into clinically effective therapeutics. There are a number of reasons to explain this frustration.…”

Section: Chemokines As Therapeutic Targetsmentioning

confidence: 99%

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

Rees¹,

Greaves²,

Baguneid

et al. 2015

Advances in Wound Care

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Section: Chemokines As Therapeutic Targetsmentioning

confidence: 99%

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

Rees¹,

Greaves²,

Baguneid

et al. 2015

Advances in Wound Care

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“…Their role is mainly to induce cellular recruitment to the inflamed organ, perpetuating the inflammatory response (8,9). Moreover, the chemokine system has also been demonstrated to be involved in tumor growth and metastasis, with chemokines potentially serving also as growth factors (10).…”

mentioning

confidence: 99%

Antibody Neutralization of CXCL10 in Vivo Is Dependent on Binding to Free and Not Endothelial-bound Chemokine

Bonvin

Gueneau

Buatois

et al. 2017

Journal of Biological Chemistry

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Edited by Gerald W. HartTo improve our understanding of properties that confer successful inhibition of chemokines in vivo, we analyzed anti-murine CXCL10 monoclonal antibodies (mAb) having different characteristics. 1B6 displayed potent inhibition of cell recruitment in vitro with an IC 50 of 0.5 nM but demonstrated little efficacy in various animal models of human disease. On the contrary, 1F11 showed efficacy in several models of inflammation yet was less potent at inhibiting chemotaxis in vitro with an IC 50 of 21 nM. Furthermore, we observed that 1B6 displayed a rapid dose-dependent clearance (t1 ⁄ 2 10 -60 h) in contrast to 1F11, which presented a dose-proportional pharmacokinetic profile and a half-life of 12 days. Moreover, 1B6 recognized glycosaminoglycan (GAG)-bound CXCL10, resulting in target-mediated clearance, which was corroborated using CXCL10-deficient mice. In contrast to 1B6, 1F11 inhibited the interaction of CXCL10 with GAGs, did not recognize GAG-bound CXCL10, and did not display target-mediated drug disposition. Confirming previous animal studies, 1B6 was poor at reversing glycemia in a model of type 1 diabetes, whereas 1F11 induced early and prolonged control of diabetes. Furthermore, when using 1A4, a subsequently generated anti-mCXCL10 mAb that shares the property with 1F11 of being unable to recognize CXCL10 immobilized on GAG, we observed a similar superior control of diabetes as compared with 1B6. We therefore concluded that targeting chemokines with antibodies such as 1B6 that recognize the more abundant GAG-bound form of the chemokine may not be the optimal strategy to achieve disease control.

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“…The reduced cellular infiltration and activation was substantiated further by a decreased level of several chemoattractants such as KC, MCP-1 and MCP-5 in paw homogenates. Together, KC, MCP-1 and MCP-5 have the potential of recruiting a panel of inflammatory cells such as neutrophils, monocytes, macrophages, dendritic cells and lymphocytes into inflammatory sites [41,42]. Reduced levels of MPO, TNF-α, IL-1β, MMP-3 and MIP-1a, MIP-2 have been demonstrated in C5aR-deficient mice in the collagen antibody-induced arthritis (CAIA) model, but our data are the first to demonstrate that this is an early therapeutic effect of C5aR blockade [21,24].…”

Section: Discussionmentioning

confidence: 99%

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

Andersson

Wenander

Usher

et al. 2014

Clinical and Experimental Immunology

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SummaryPreclinical 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 (antimC5aR) 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 antimC5aR 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)-α, 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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Targeting chemokine receptors in chronic inflammatory diseases: An extensive review

Cited by 120 publications

References 273 publications

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

Chemokines in Wound Healing and as Potential Therapeutic Targets for Reducing Cutaneous Scarring

Antibody Neutralization of CXCL10 in Vivo Is Dependent on Binding to Free and Not Endothelial-bound Chemokine

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

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