A novel fusion protein attenuates collagen–induced arthritis by targeting interleukin 17A and tumor necrosis factor α

Liu, Zhihang; Song, Lun; Wang, Yunxin; Xu, Pengfei; Guo, Xiaochen; Yang, Jiarui; Liu, Han; Wang, Yuyang; Wu, Chao; Zhang, Teng; Yu, Dan; Opoku, Yeboah Kwaku; Khoso, Mir Hassan; Ren, Guangxin; Li, Deshan

doi:10.1016/j.ijpharm.2018.05.058

Cited by 13 publications

(7 citation statements)

References 36 publications

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“…Similarly, a variety of dual target drugs have been developed to block IL‐17 in combination with TNF, and their efficacies have been evaluated in arthritic diseases. A fusion protein targeting TNF and IL‐17A was shown to be more effective than etanercept alone in a CIA mouse model . In RA and psoriatic arthritis patients currently taking methotrexate, a dual‐variable‐domain immunoglobulin targeting human TNF and IL‐17A was shown to be safe for clinical use; however, the overall efficacy was not significantly different from that of adalimumab, a TNF‐inhibiting drug .…”

Section: Discussionmentioning

confidence: 99%

“…A fusion protein targeting TNF and IL-17A was shown to be more effective than etanercept alone in a CIA mouse model. 45 In RA and psoriatic arthritis patients currently taking methotrexate, a dual-variable-domain immunoglobulin targeting human TNF and IL-17A was shown to be safe for clinical use; however, the overall efficacy was not significantly different from that of adalimumab, a TNF-inhibiting drug. 46,47 Although IL-17 is a major pathogenic cytokine that can act on various inflammatory cells such as fibroblasts and macrophages, IL-21, which is also overproduced in Th17, Tfh, and Tph cells, may play a key role in the activity of antibody-secreting B cells and Tfh cells.…”

Section: Discussionmentioning

confidence: 99%

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A bispecific soluble receptor fusion protein that targets TNF‐α and IL‐21 for synergistic therapy in inflammatory arthritis

et al. 2019

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This study was aimed at investigating the therapeutic effects of BITRAP, a bispecific fusion protein targeting TNF-α and IL-21, on the development of autoimmune arthritis in humans and mice. To verify the effects of BITRAP in human, peripheral blood mononuclear cells were cultured with BITRAP under IL-17-producing T (Th17) cell-polarizing conditions or osteoclast differentiation conditions. BITRAP treatment inhibited the production of IL-17 and vascular endothelial growth factor but increased the production of IL-10 in CD4 + T cells, as well as directly suppressed osteoclastogenesis. Collagen-induced arthritis (CIA) and IL-1R antagonist (IL-1Ra) knockout mice were treated with BITRAP. Following injection in CIA mice, BITRAP rapidly migrated into the inflamed joints and remained there for 72 hours.Application of BITRAP attenuated the severity of autoimmune arthritis in CIA and IL-1Ra knockout mice by reducing the numbers of inflammatory cytokine-expressing cells and Th17 cells and antibody secretion. Finally, BITRAP suppressed STAT3 phosphorylation, as well as production of IL-17 and TNF-α, in murine splenic CD4 + | 249 PARK et Al.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A bispecific soluble receptor fusion protein that targets TNF‐α and IL‐21 for synergistic therapy in inflammatory arthritis

et al. 2019

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“…This was done by adding a previously identified viral chemokine-binding domain to the recombinant protein, generating a novel, bifunctional fusion construct. In a related approach, a dual inhibitor targeting simultaneously TNF and IL-17 has been tested and shown to be effective in reducing pathology in RA and psoriasis murine models [24,25]. However, in this case an IL-17 single-chain, variable fragment was fused to a soluble TNFR1 receptor, as opposed to the TNFR2 receptor of etanercept, confounding possible comparisons due to differences in binding specificity for TNF ligands of the human receptors [26].…”

Section: Discussionmentioning

confidence: 99%

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

Alejo

Sánchez

Amu

et al. 2019

JCM

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The inhibition of tumor necrosis factor (TNF) through the use of either antibodies or soluble receptors is a highly effective strategy for the clinical control of chronic inflammatory conditions such as rheumatoid arthritis. Different viruses have similarly exploited this concept by expressing a set of specifically tailored secreted TNF decoy receptors to block host inflammatory responses. Poxviruses have been shown to encode at least two distinct molecules, termed Cytokine response modifier D (CrmD) and CrmB, in which a TNF inhibitor is combined with a chemokine inhibitor on the same molecule. The ectromelia virus CrmD protein was found to be a critical determinant of virulence in vivo, being able to control local inflammation to allow further viral spread and the establishment of a lethal infection. Strikingly, both the TNF and the chemokine inhibitory domains are required for the full activity of CrmD, suggesting a model in which inhibition of TNF is supported by the concomitant blockade of a reduced set of chemokines. Inspired by this model, we reasoned that a similar strategy could be applied to modify the clinically used human TNF receptor (etanercept), producing a generation of novel, more effective therapeutic agents. Here we show the analysis of a set of fusion proteins derived from etanercept by addition of a viral chemokine-binding protein.A bifunctional inhibitor capable of binding to and blocking the activity of TNF as well as a set of chemokines is generated that is active in the prevention of arthritis in a murine disease model.

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“…However, according to the results of clinical trials, almost 50% of RA patients treated with TNF-α inhibitors do not achieve efficient response. Moreover, some RA patients treated with cytokine inhibitors lose their sensitivity over the time and need to switch to other agents [6].Therefore, there are still a high medical requirement and also alternative strategies to fight against inflammatory and autoimmune illnesses and to further improve patients' lives.…”

Section: Introductionmentioning

confidence: 99%

Designing a new bi-specific tandem single-chain variable fragment antibody against tumor necrosis factor-α and interleukin-23 via in silico studies for the treatment of Rheumatoid arthritis

Barkhordaria

Mahnam

Sadeghi

2020

Preprint

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Background: Rheumatoid arthritis disease is a chronic autoimmune inflammatory disease that mainly causes synovial joint inflammation and cartilage destruction. Tumor necrosis factor-α (TNF-α) is a pivotal cytokine that plays an important role in rheumatoid arthritis. The treatments focusing on a single cytokine' inhibition, are able to clinically produce meaningful responses in only about half of the treated patients due to multiple cytokines involved in this disease. In the present study, a bi-specific tandem single-chain variable fragment was designed in order to suppress both human tumor necrosis factor-α and interleukin-23 (IL23) as a potential therapeutic drug candidate for this disease. To do so, at first, eight bi-specific tandem single-chain variable fragment models were built against tumor necrosis factor-α and interleukin-23 cytokines with different domain orders and then 50 ns molecular dynamics simulation was performed for each one and thereafter structural properties were exploited. Results: MD simulation results indicate that the domains' order strongly affects tandem single-chain variable fragment properties and in overall, the fragment VLIL23+Linker+VHIL23+linker+VLTNF+Linker+VHTNF +His6 (VL is variable light and VH is variable heavy fragments and His6 is six histidine) not only separated antibody domains but also had better stability and solvation energy. Conclusions: Hence, this structure can be considered as a potential drug for rheumatoid arthritis. It is hoped that this research could shed a light for the treatment of Rheumatoid arthritis disease.

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A novel fusion protein attenuates collagen–induced arthritis by targeting interleukin 17A and tumor necrosis factor α

Cited by 13 publications

References 36 publications

A bispecific soluble receptor fusion protein that targets TNF‐α and IL‐21 for synergistic therapy in inflammatory arthritis

A bispecific soluble receptor fusion protein that targets TNF‐α and IL‐21 for synergistic therapy in inflammatory arthritis

Addition of a Viral Immunomodulatory Domain to Etanercept Generates a Bifunctional Chemokine and TNF Inhibitor

Designing a new bi-specific tandem single-chain variable fragment antibody against tumor necrosis factor-α and interleukin-23 via in silico studies for the treatment of Rheumatoid arthritis

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