Our paper in Journal of Translational Medicine shows that combination of dasatinib and other kinase inhibitors with a subtherapeutic anti‐hTNF dose effectively treats arthritis pathology.

 

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.

 

With a new publication in Arthritis Research and Therapy, entitled “Ectopic bone formation and systemic bone loss in a transmembrane TNF-driven model of human spondyloarthritis”, Biomedcode in collaboration with George Kollias Lab at BSRC Al. Fleming, introduce the TgA86 transmembrane TNF transgenic mouse as a novel model of human spondyloarthritis (SpA).

The authors show that the TgA86 mouse model develops spontaneously peripheral arthritis and axial pathologies that closely reproduce key pathogenic features of human SpA, including distinct stages of inflammation and ectopic new bone formation. This is a chronic and complex disease model that similar to human patients also develops extraarticular comorbidities such as heart valve pathology and systemic bone loss. As with human patients in the clinic, all the pathologies of the TgA86 mouse model are reversed following early treatment with anti-hTNF therapeutics.

This novel model of SpA that captures not only specific features, but also the complexity of human disease, can prove to be an invaluable translational tool in the study of SpA pathogenesis as well as in the evaluation of human therapeutics. Read More

Biomedcode is excited to participate as one of the 63 European companies that have been selected to join the EUGATEWAY Healthcare and Medical Technologies Business Mission to Singapore on 8-11 December 2020. Due to the COVID-19 pandemic this will be a virtual event and we look forward to discussing with potential new partners and clients about future collaborations!

 

 

During rheumatoid arthritis (RA) treatment, long-term injection of antitumor necrosis factor α antibodies (anti-TNFα Abs) may induce on-target toxicities, including severe infections (tuberculosis [TB] or septic arthritis) and malignancy. Here, we used an immunoglobulin
G1 (IgG1) hinge as an Ab lock to cover the TNFα-binding site of Infliximab by linking it with matrix metalloproteinase (MMP) -2/9 substrate to generate pro-Infliximab that can be specif- ically activated in the RA region to enhance the selectivity and safety of treatment. The Ab lock significantly inhibits the TNFα binding and reduces the anti-idiotypic (anti-Id) Ab binding to pro-Infliximab by 395-fold, 108-fold compared with Infliximab, respectively, and MMP-2/9 can completely restore the TNFα neutralizing ability of pro-Infliximab to block TNFα down- stream signaling. Pro-Infliximab was only selectively activated in the disease site (mouse paws) and presented similar pharmacokinetics (PKs) and bio-distribution to Infliximab. Fur- thermore, pro-Infliximab not only provided equivalent therapeutic efficacy to Infliximab but also maintained mouse immunity against Listeria infection in the RA mouse model, leading to a significantly higher survival rate (71%) than that of the Infliximab treatment group (0%). The high-selectivity pro-Infliximab maintains host immunity and keeps the original therapeu- tic efficiency, providing a novel strategy for RA therapy.

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In response to the current outbreak of coronavirus disease (COVID-19), Biomedcode has implemented measures to help ensure the health and safety of our employees as well as their families but to also ensure the welfare of the mice under our care as well as the uninterrupted provision of services under the same high standards of quality.

Greece is currently implementing a “Stay At Home” order, intended to minimize the spread of the disease. In this context Biomedcode has adjusted its operation so that personnel that can work from home are doing so, while personnel essential for the proper operation of our animal facilities as well as the execution of contracted research activities, are provided with the necessary documentation to ensure their on-site presence. 

With a long-standing mission to support biomedical research and drug development, Biomedcode is closely monitoring the scientific findings of this pandemic and is open to contributing with its  preclinical mouse models in the global effort to fight this pandemic.

We will continue to take all necessary precautions and we will be happy to address any questions or concerns you may at info@biomedcode.com.

 

 

Targeting TNF-α as a treatment modality has shown tremendous success, however there are several limitations associated with the current anti-TNF-α biologic drugs including: immunogenicity, life-threatening infections, resistance to treatment, complexity of manufacture and cost of treatment. Ubah et al.  report the in vivo efficacy of novel anti-TNF-α formats generated from molecular engineering of variable new antigen receptors (VNARs), originally derived from the immune system of an immunized nurse shark.

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