IL4-10 fusion protein has chondroprotective, anti-inflammatory and potentially analgesic effects in the treatment of osteoarthritis

Steen-Louws, C.; Popov-Celeketic, J.; Mastbergen, S.C.; Coeleveld, K.; Hack, C. E.; Eijkelkamp, Niels; Tryfonidou, Marianna A.; Spruijt, S.; Roon, Joël A G van; Lafeber, Floris P. J. G.

doi:10.1016/j.joca.2018.05.005

Cited by 27 publications

(43 citation statements)

References 48 publications

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“…IL4 and IL10 do have overlapping and complementary activities[24] and combined administration showed promising effects in experimental models of arthritis[25, 26]. Recently, we developed a human fusion protein of IL4 and IL10 (hIL4-10 FP)[27] that has DMOAD properties in multiple models of osteoarthritis[28]. Human OA cartilage tissue explants were demonstrated to express elevated levels of IL4R and IL10R, rendering OA cartilage more sensitive to the IL4-10 FP.…”

Section: Introductionmentioning

confidence: 99%

Canine IL4-10 fusion protein provides disease modifying activity in a canine model of OA; an exploratory study

et al. 2019

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Objective An ideal disease modifying osteoarthritis drug (DMOAD) has chondroprotective, anti-inflammatory, and analgesic effects. This study describes the production and characterization of a canine IL4-10 fusion protein (IL4-10 FP) and evaluates its in vivo DMOAD activity in a canine model of osteoarthritis (OA). Design The canine Groove model was used as an in vivo model of degenerative knee OA. Six weeks after OA induction dogs were intra-articularly injected weekly, for ten weeks, with either IL4-10 FP or phosphate buffered saline (PBS). In addition to the use of human IL4-10 FP, canine IL4-10 FP was developed and characterized in vitro , and tested in vivo . Force plate analysis (FPA) was performed to analyze joint loading as a proxy measure for pain. After ten weeks dogs were euthanized and cartilage and synovial tissue samples were analyzed by histochemistry (OARSI scores) and biochemistry (cartilage proteoglycan turnover). Results Repetitive intra-articular injections with human IL4-10 FP led to antibody formation, that blocked its functional activity. Therefore, a canine IL4-10 FP was developed, which completely inhibited LPS-induced TNFα production by canine blood cells, and increased proteoglycan synthesis of canine cartilage in vitro (p = 0.043). In vivo , canine IL4-10 FP restored the, by OA impaired, joint loading (p = 0.002) and increased cartilage proteoglycan content (p = 0.029). Conclusions This first study on the potential DMOAD activity upon prolonged repeated treatment with IL4-10 FP demonstrates that a species-specific variant has anti-inflammatory and chondroprotective effects in vitro and chondroprotective and analgesic effects in vivo . These data warrant further research on the DMOAD potential of the IL4-10 FP.

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Section: Introductionmentioning

confidence: 99%

Canine IL4-10 fusion protein provides disease modifying activity in a canine model of OA; an exploratory study

et al. 2019

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“…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. Recent data suggest an even broader potential as, next to prevention of pain , IL4‐10 FP suppresses articular cartilage damage in models for osteoarthritis .…”

Section: Discussionmentioning

confidence: 99%

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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“…In addition, animal studies indicate protective effects of JAK/STAT inhibition in experimental OA [ 103 , 105 ]. However, targeting of JAK/STAT signalling also results in inhibition of multiple cytokines including IL-10, IL-4 and IGF-1, which have a beneficial role in joint biology and OA development [ 14 , 132 , 133 ]. As OA is a very heterogeneous disease with large differences in severity of inflammation and cytokine profile [ 53 ], it will be difficult to predict outcome of JAK/STAT inhibition in OA patients.…”

Section: Under Construction: Il-6 Targeted Therapy In Oamentioning

confidence: 99%

A roadmap to target interleukin-6 in osteoarthritis

2020

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Joint inflammation is present in the majority of OA patients and pro-inflammatory mediators, such as IL-6, are actively involved in disease progression. Increased levels of IL-6 in serum or synovial fluid from OA patients correlate with disease incidence and severity, with IL-6 playing a pivotal role in the development of cartilage pathology, e.g. via induction of matrix-degrading enzymes. However, IL-6 also increases expression of anti-catabolic factors, suggesting a protective role. Until now, this dual role of IL-6 is incompletely understood and may be caused by differential effects of IL-6 classic vs trans-signalling. Here, we review current evidence regarding the role of IL-6 classic- and trans-signalling in local joint pathology of cartilage, synovium and bone. Furthermore, we discuss targeting of IL-6 in experimental OA models and provide future perspective for OA treatment by evaluating currently available IL-6 targeting strategies.

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IL4-10 fusion protein has chondroprotective, anti-inflammatory and potentially analgesic effects in the treatment of osteoarthritis

Abstract: The results of current preliminary study suggest that IL4-10 FP has DMOAD potentials since it shows chondroprotective and anti-inflammatory effects in vitro, as well as potentially analgesic effect in a canine in vivo model of osteoarthritis.

Cited by 27 publications

References 48 publications

Canine IL4-10 fusion protein provides disease modifying activity in a canine model of OA; an exploratory study

Canine IL4-10 fusion protein provides disease modifying activity in a canine model of OA; an exploratory study

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

A roadmap to target interleukin-6 in osteoarthritis

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