Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

Abstract

Background New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. Methods We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Results Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-dependent manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Conclusion Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.

Dasatinib, a selective tyrosine kinase inhibitor, prevents joint destruction in rheumatoid arthritis animal model

“…Another study demonstrated combination therapy of dasatinib and subtherapeutic dose of TNF inhibitor showed a synergistic anti‐arthritic effect on a Tg197 arthritis mouse model 30 . In the present study, the inhibition of osteoclastogenesis by dasatinib administration was significantly inhibited in the dasatinib pretreatment group, and this was not evaluated in the previous studies 12,30 . The suppression of immunoglobulin and pro‐inflammatory cytokines presented in the previous study 12 was also confirmed in the present study (data not shown).…”

“…We aimed to compare which effect (preventive versus therapeutic) would be more prominent in the CIA model, and conclude that the preventive role of dasatinib was more evident and was exerted earlier than the therapeutic effects. Another study demonstrated combination therapy of dasatinib and subtherapeutic dose of TNF inhibitor showed a synergistic anti‐arthritic effect on a Tg197 arthritis mouse model 30 . In the present study, the inhibition of osteoclastogenesis by dasatinib administration was significantly inhibited in the dasatinib pretreatment group, and this was not evaluated in the previous studies 12,30 .…”

In Silico Identification and Evaluation of Natural Products as Potential Tumor Necrosis Factor Function Inhibitors Using Advanced Enalos Asclepios KNIME Nodes

“…Notably, the new two best NPs identified, although ~5-fold less effective than SPD304, presented much less toxicity on the cells (in the range of two orders of magnitude). Additionally, mostly Nepalensinol B, and to a lesser extent, Miyabenol A, were able to downregulate chemokine ligand 5 (CCL5), which was found to be, among others, a pathogenic chemokine, being used for drug testing, both in human RA [ 88 ] and mouse chronic polyarthritis [ 89 ]. Both Nepalensinol B and Miyabenol A reduced CCL5 in both hTNFtg SFs, which spontaneously secrete high levels of chemokines, and wild-type (WT) SFs exogenously stimulated with human TNF in order to increase their pro-inflammatory potential.…”

The second decade of anti-TNF-a therapy in clinical practice: new lessons and future directions in the COVID-19 era

“…Combination therapies carry the advantage of synergic action of both drugs, usually allowing lower doses to be administered. In a recent experimental study, the tyrosine kinase inhibitor dasatinib was co-administered with sub-therapeutic doses (only 10% of the standard dose) of infliximab, adalimumab, golimumab or etanercept in the human TNF-dependent Tg197 arthritis mouse model [ 202 ]. The combination therapy led to amelioration of clinical and histopathological findings of arthritis, which was more profound with the combination of low-dose infliximab and dasatinib, to a degree similar to the therapeutic infliximab dose.…”