IL4-10 Fusion Protein Is a Novel Drug to Treat Persistent Inflammatory Pain

Eijkelkamp, Niels; Steen-Louws, C.; Hartgring, Sarita A. Y.; Willemen, Hanneke L.D.M.; Prado, Judith; Lafeber, Floris P. J. G.; Heijnen, Cobi J.; Hack, C. E.; Roon, Joël A G van; Kavelaars, Annemieke

doi:10.1523/jneurosci.0092-16.2016

Cited by 68 publications

(73 citation statements)

References 54 publications

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“…Recently, we developed an IL4‐10 fusion protein, retaining the biologic activity of both individual cytokines. This fusion protein has clear anti‐inflammatory, immune regulatory, analgesic and chondroprotective effects in human in vitro models and animal in vivo models . In the present study we investigated whether the IL4‐10 fusion protein protects against blood‐induced joint damage in a human in vitro model of blood‐induced cartilage damage, and joint damage upon hemarthrosis in a murine in vivo model of hemophilic arthropathy.…”

Section: Introductionmentioning

confidence: 99%

A fusion protein of interleukin‐4 and interleukin‐10 protects against blood‐induced cartilage damage in vitro and in vivo

Vulpen

Popov-Celeketic

Meegeren

et al. 2017

Journal of Thrombosis and Haemostasis

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Background Joint damage still causes significant morbidity in hemophilia. It results from synovial inflammation and direct cartilage-degenerating properties of blood components. Interleukin (IL)-4 and IL-10 have been shown to protect cartilage from blood-induced damage. Recently an IL4-10 fusion protein has been developed to combine the function of IL-4 and IL-10 and increase their bioavailability. Objectives In this study we evaluate whether this IL4-10 fusion protein protects against blood-induced joint damage. Methods In vitro, human cartilage explants were exposed to whole blood and simultaneously to a broad concentration range of the IL4-10 fusion protein. Effects on cartilage matrix turnover were compared with the individual cytokines. Moreover, the influence of the fusion protein and its individual components on IL-1β and IL-6 production was investigated. In hemophilia A mice, the effect of intra-articular treatment on synovitis and cartilage damage resulting from joint bleeding was evaluated by histochemistry. Results In vitro, the fusion protein prevented blood-induced cartilage damage in a dose-dependent manner, with equal effectiveness to the combination of the separate cytokines. In whole blood cultures 10 ng mL fusion protein completely blocked the production of IL-1β and IL-6 by monocytes/macrophages. In hemophilic mice, intra-articular injection of IL-4 and IL-10 did not influence synovitis or cartilage degeneration. In contrast, equimolar amounts of the fusion protein attenuated cartilage damage upon repeated joint bleeding, although synovial inflammation was hardly affected. Conclusions Overall, this study shows that the IL4-10 fusion protein prevents blood-induced cartilage damage in vitro and ameliorates cartilage degeneration upon joint bleeding in hemophilic mice.

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Section: Introductionmentioning

confidence: 99%

A fusion protein of interleukin‐4 and interleukin‐10 protects against blood‐induced cartilage damage in vitro and in vivo

Vulpen

Popov-Celeketic

Meegeren

et al. 2017

Journal of Thrombosis and Haemostasis

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“…To demonstrate the feasibility of IL4-10 fusion protein, we recently tested its potential in animal models for inflammatory and neuropathic chronic pain. IL4-10 FP strongly relieved hyperalgesia in all models, and inhibited pain superior to IL-4 or IL-10 mono or combination therapy [10] This emphasizes the potential of IL4-10 fusion protein to inhibit immunopathology and pain in inflammatory and degenerative diseases. IL4-10 fusion protein is a new drug that signals cells to induce immunoregulatory activity and overcomes the limitations of IL-4 and IL-10 stand-alone therapy, and therefore has therapeutic potential for inflammatory diseases such as rheumatoid arthritis.…”

Section: Discussionmentioning

confidence: 69%

“…To demonstrate the feasibility of IL4‐10 fusion protein, we recently tested its potential in animal models for inflammatory and neuropathic chronic pain. IL4‐10 FP strongly relieved hyperalgesia in all models, and inhibited pain superior to IL‐4 or IL‐10 mono or combination therapy This emphasizes the potential of IL4‐10 fusion protein to inhibit immunopathology and pain in inflammatory and degenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

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IL4-10 fusion protein: a novel immunoregulatory drug combining activities of interleukin 4 and interleukin 10

Steen-Louws

Hartgring

Popov-Celeketic

et al. 2018

Clinical &Amp; Experimental Immunology

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SummaryThe objective of this study was to test the capacity of a newly developed fusion protein of interleukin 4 (IL‐4) and IL‐10 [IL4‐10 fusion protein (FP)] to shift multiple pro‐inflammatory pathways towards immune regulation, and to inhibit pro‐inflammatory activity in arthritis models. The effects of IL4‐10 FP in comparison with IL‐4, IL‐10 and IL‐4 plus IL‐10 on pro‐ and anti‐inflammatory mediators, T cells and immunoglobulin (Ig) receptors in favour of immunoregulatory activity were studied. In addition, the capacity of IL4‐10 FP to inhibit pro‐inflammatory activity in ex‐vivo and in‐vivo arthritis models was investigated. IL4‐10 FP robustly inhibited pro‐inflammatory cytokine [IL‐1β, tumour necrosis factor (TNF)‐α, IL‐6 and IL‐8] production in whole blood cultures, mediated by both the IL‐10 and the IL‐4 moiety. IL4‐10 fusion protein induced IL‐1 receptor antagonist (IL‐1RA) production and preserved soluble TNF receptor (sTNFR) levels, strongly increasing IL‐1RA/IL‐1β and sTNFR/TNF‐α ratios. In addition, IL4‐10 FP strongly inhibited T helper (Th) type 1 and 17 cytokine secretion, while maintaining FoxP3 expression and up‐regulating Th2 activity. In addition, while largely leaving expression of activating Fc gamma receptor (FcγR)I, III and Fc epsilon receptor (FcεR) unaffected, it significantly shifted the FcγRIIa/FcγRIIb ratio in favour of the inhibitory FcγRIIb. Moreover, IL4–10 FP robustly inhibited secretion of pro‐inflammatory cytokines by rheumatoid arthritis synovial tissue and suppressed experimental arthritis in mice, without inducing B cell hyperactivity. IL4‐10 fusion protein is a novel drug, signalling cells to induce immunoregulatory activity that overcomes limitations of IL‐4 and IL‐10 stand‐alone therapy, and therefore has therapeutic potential for inflammatory diseases such as rheumatoid arthritis.

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“…276–278 An interesting variation is the intrathecal transfection of an IL4/IL10 fusion protein leading to a potent and persistent antihyperalgesia. 279 …”

Section: Survey Of Current Targets Of Pain Therapeuticsmentioning

confidence: 99%

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Knezevic

Yekkirala

Yaksh

2017

Anesthesia &Amp; Analgesia

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Opioids Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management, has limitations and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of re-enforcing activity in the absence of a pain state. The present work provides a non-exclusive overview of current drug targets and potential future directions of research and development. We discuss channels activators and blockers, including: sodium channel blockers, potassium channel activators and calcium channel blockers; glutamate receptor targeted agents, including: NMDA, AMPA and metabotropic receptors). Further, we discuss therapeutics targeted at GABA, alpha2 adrenergic and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors, and agonists/antagonists of adenosine, purine receptors. And cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of drugable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising pre-clinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans’ targets, which should assist in developing non-addictive analgesics.

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IL4-10 Fusion Protein Is a Novel Drug to Treat Persistent Inflammatory Pain

Cited by 68 publications

References 54 publications

A fusion protein of interleukin‐4 and interleukin‐10 protects against blood‐induced cartilage damage in vitro and in vivo

A fusion protein of interleukin‐4 and interleukin‐10 protects against blood‐induced cartilage damage in vitro and in vivo

IL4-10 fusion protein: a novel immunoregulatory drug combining activities of interleukin 4 and interleukin 10

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

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