Abstract
ObjectiveAn 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).DesignThe 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).ResultsRepetitive 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).ConclusionsThis 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.
Highlights
Osteoarthritis (OA) is characterized by changes in allarticular tissues, such as cartilage, bone, synovial tissue, ligaments, and muscles[1, 2]
JP, NE, and CEH are shareholders of Synerkine Pharma BV, a spin-off of the UMC Utrecht licensing the patents on the Interleukin 4 (IL4)-10 fusion protein. This first study on the potential disease modifying OA drug (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
Human IL4-10 FP was immunogenic in dogs upon repeated i.a. injections, leading to the formation of antibodies after only three repetitive i.a. injections (Fig 2B)
Summary
Osteoarthritis (OA) is characterized by changes in all (peri-)articular tissues, such as cartilage, (subchondral) bone, synovial tissue, ligaments, and muscles[1, 2]. There is still a great need for joint preserving conservative drug treatments Such treatments should ideally be chondroprotective (regenerative), anti-inflammatory, and analgesic, and should be preferably combined in one drug. At present such treatments do not exist, multiple drugs are studied as potential disease modifying OA drug (DMOAD). SM04690, a Wnt pathway inhibitor, induced chondrocyte differentiation, reduced cartilage catabolism in vitro, and showed chondroprotective activity in a rat model of OA[14], and in humans[15]. None of these studies demonstrated chondroprotective, anti-inflammatory, and analgesic effects in combination
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