IL4-10 Fusion Protein Shows DMOAD Activity in a Rat Osteoarthritis Model

Abstract

Objective Ideally, disease-modifying osteoarthritis (OA) drugs (DMOAD) should combine chondroprotective, anti-inflammatory, and analgesic effects in a single molecule. A fusion protein of interleukin-4 (IL-4) and IL-10 (IL4-10 FP) possesses these combined effects. In this study, the DMOAD activity of rat IL4-10 FP (rIL4-10 FP) was tested in a rat model of surgically induced OA under metabolic dysregulation. Design rIL4-10 FP was produced with HEK293F cells. Bioactivity of purified rIL4-10 FP was determined in a whole blood assay. Male Wistar rats ( n = 20) were fed a high-fat diet (HFD) to induce metabolic dysregulation. After 12 weeks, OA was induced according to the Groove model. Two weeks after OA induction, rats were randomly divided into 2 groups and treated with 10 weekly, intra-articular injections of either rIL4-10 FP ( n = 10) or phosphate buffered saline (PBS; n = 10). Possible antibody formation was evaluated using ELISA, cartilage degeneration and synovial inflammation were evaluated by histology and mechanical allodynia was evaluated using the von Frey test. Results Intra-articular injections with rIL4-10 FP significantly reduced cartilage degeneration ( P = 0.042) and decreased mechanical allodynia ( P < 0.001) compared with PBS. Only mild synovial inflammation was found (nonsignificant), limiting detection of putative anti-inflammatory effects. Multiple injections of rIL4-10 FP did not induce antibodies against rIL4-10 FP. Conclusion rIL4-10 FP showed chondroprotective and analgesic activity in a rat OA model with moderate cartilage damage, mild synovial inflammation, and pain. Future studies will need to address whether less frequent intra-articular injections, for example, with formulations with increased residence time, would also lead to DMOAD activity.

The Role of Interleukin-4 and Interleukin-10 in Osteoarthritic Joint Disease: A Systematic Narrative Review

“… 19 In in vivo OA models, these effects were less clear, mainly due to the usage of noninflammatory OA models. 19 , 20 …”

“…Still, a lot of work is needed to develop the IL4-10 FP as a DMOAD, suitable for clinical practice. At present, in OA, the IL4-10 FP is envisioned to be used as intra-articular treatment, to reduce the possibility of systemic side effects, 19 , 20 and with that is not usable for OA in smaller joints or in patients with polyarthritis. A major drawback of direct intra-articular application as applied so far is the rapid clearance out of the joint cavity due to their relatively low molecular weight, leading to only relative short transient effects and the necessity of weekly injections.…”

“…The canine and rat Groove model of OA mimic early post-traumatic OA, and inflammation was too mild to evaluate anti-inflammatory effects. 19 , 20 The IL4-10 FP consists of 2 anti-inflammatory cytokines, and in that line of thought, it seems reasonable to assume that patients with an important inflammatory component as underlying mechanism for OA will most likely benefit from IL4-10 FP treatment.…”

“…IL4-10 FP has chondroprotective and anti-inflammatory effects in OA cartilage explants 7 and chondroprotective and analgesic effects in a canine OA model, as well as in a rat OA model. 19 , 20 …”

“…IL4-10 FP has chondroprotective and anti-inflammatory effects in OA cartilage explants 7 and chondroprotective and analgesic effects in a canine OA model, as well as in a rat OA model. 19,20 This systematic narrative review aims to assess the potential of IL-4, IL-10, and the combination of IL-4 and IL-10 for the treatment of OA. It describes the chondroprotective, anti-inflammatory, and analgesic effects of IL-4, IL-10, and IL4-10 FP to better understand the mechanisms behind its potential as a DMOAD.…”