Cell-type–restricted anti-cytokine therapy: TNF inhibition from one pathogenic source

Efimov, Grigory A.; Kruglov, Andrey; Хлопчатникова, З.В.; Rozov, F. N.; Mokhonov, Vladislav V.; Rose-John, Stefan; Scheller, Jürgen; Gordon, Siamon; Stacey, Martin; Drutskaya, Marina S.; Тиллиб, С. В.; Nedospasov, Sergei A.

doi:10.1073/pnas.1520175113

Cited by 67 publications

(57 citation statements)

References 45 publications

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“…Thus, biologics like the chimeric-IL-1Ra that might reduce the inflammatory process in the tumor site without reducing the patient's ability to fight infection is a desirable approach. In order to inhibit cell surface TNF, in a cell-type restricted manner, Efimov et al constructed bispecific antibody that recognizes both the F4/80 macrophage marker and the membranal TNF- α [154]. In this manner, the antibody favors binding of TNF- α on myeloid cells rather than free TNF- α or T lymphocytes derived TNF- α .…”

Section: Reducing Infections In Anti-inflammatory Biologicsmentioning

confidence: 99%

Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations

Rider

Carmi

Bar‐Sela

2016

International Journal of Cell Biology

161

111

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Proinflammatory cytokines are potent mediators of numerous biological processes and are tightly regulated in the body. Chronic uncontrolled levels of such cytokines can initiate and derive many pathologies, including incidences of autoimmunity and cancer. Therefore, therapies that regulate the activity of inflammatory cytokines, either by supplementation of anti-inflammatory recombinant cytokines or by neutralizing them by using blocking antibodies, have been extensively used over the past decades. Over the past few years, new innovative biological agents for blocking and regulating cytokine activities have emerged. Here, we review some of the most recent approaches of cytokine targeting, focusing on anti-TNF antibodies or recombinant TNF decoy receptor, recombinant IL-1 receptor antagonist (IL-1Ra) and anti-IL-1 antibodies, anti-IL-6 receptor antibodies, and TH17 targeting antibodies. We discuss their effects as biologic drugs, as evaluated in numerous clinical trials, and highlight their therapeutic potential as well as emphasize their inherent limitations and clinical risks. We suggest that while systemic blocking of proinflammatory cytokines using biological agents can ameliorate disease pathogenesis and progression, it may also abrogate the hosts defense against infections. Moreover, we outline the rational need to develop new therapies, which block inflammatory cytokines only at sites of inflammation, while enabling their function systemically.

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Section: Reducing Infections In Anti-inflammatory Biologicsmentioning

confidence: 99%

Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations

Rider

Carmi

Bar‐Sela

2016

International Journal of Cell Biology

161

111

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“…Our study demonstrated that A20 expression on the CD56 bright subset, the key source of proinflammatory cytokines in patients with AS, was negatively correlated with IFN-γ and TNFα, indicating that the decreased A20 might increase the severity of disease, at least partly. Furthermore, monocytes or macrophages were demonstrated to be the predominant source of the proinflammatory cytokines, preferentially producing TNF-α [38][39][40]. A previous study also illustrated that NK cells, particularly the CD56 bright subset, can stimulate monocytes to produce abundant amounts of TNF-α [21].…”

Section: Discussionmentioning

confidence: 94%

“…Furthermore, monocytes or macrophages were demonstrated to be the predominant source of the proinflammatory cytokines, preferentially producing TNF-α [38][39][40]. Furthermore, monocytes or macrophages were demonstrated to be the predominant source of the proinflammatory cytokines, preferentially producing TNF-α [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

Decreased A20 expression on circulating CD56bright NK cells contributes to a worse disease status in patients with ankylosing spondylitis

Yang

Zhou

Liu

et al. 2019

Clinical &Amp; Experimental Immunology

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A20, a pivotal anti-inflammatory protein, preserves immune homeostasis and regulates prolonged inflammation. A previous study has shown that A20 expression levels are down-regulated in peripheral blood mononuclear cells (PBMCs) from patients with ankylosing spondylitis (AS). However, the precise role of A20 in reducing autoimmune disorders needs to be further elucidated. In this study, A20 expression was found to be preferentially reduced on circulating CD56 bright natural killer (NK) cells in patients with AS, and its level was negatively correlated with that of proinflammatory cytokines. Further investigation demonstrated that A20 reduces interferon (IFN)-γ and tumour necrosis factor (TNF)-α production in CD56 bright NK cells after stimulation with monokines or phorbol myristate acetate (PMA)/ionomycin(P/I). Furthermore, CD56 bright NK cells isolated from AS patients promote TNF-α secretion by autologous monocytes, and increasing the A20 expression level partially attenuates this process. More importantly, decreased A20 expression on circulating CD-56 bright NK cells is associated with worse disease status in patients with AS. Our findings reveal that A20 participates in the pathogenesis of AS by negatively regulating CD56 bright NK cells and that its reduced expression contributes to a worsened disease status in patients with AS. Fig. 5. A20 on the circulating CD56 bright subset is negatively associated with disease activity. (a) Negative correlations between A20 expression on the CD56 bright subset and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in ankylosing spondylitis (AS) patients. (b) Significant negative correlations between A20 expression on the CD56 bright subset and AS Disease Activity Score (ASDAS) in patients with AS. A P-value <0·05 was considered statistically significant for the test.

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“…Several MYSTIs, based on recombinant antibodies with dual specificity, were engineered and evaluated. In particular, the surface molecules F4/80 and CD11b expressed by myeloid cells were tested as the targets for the second specificity to direct anti-TNF moiety specifically to myeloid cells [84,85]. Instead of using conventional antibodies and their conjugates, we used small antigen-binding domains, called VHH, coming from a unique class of single heavy-chain antibodies in camelids [86,87].…”

Section: Toward Selective Cytokine Targetingmentioning

confidence: 99%

Can we design a better anti-cytokine therapy?

Drutskaya

Efimov

Kruglov

et al. 2017

Journal of Leukocyte Biology

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Cytokine neutralization is successfully used for treatment of various autoimmune diseases and chronic inflammatory conditions. The complex biology of the two well-characterized proinflammatory cytokines TNF and IL-6 implicates unavoidable consequences when it comes to their global blockade. Because systemic cytokine ablation may result in unwanted side effects, efforts have been made to develop more specific cytokine inhibitors, which would spare the protective immunoregulatory functions of a given cytokine. In this article, we review current research and summarize new strategies for improved anti-TNF and anti-IL-6 biologics, which specifically target only selected parts of the signaling cascades mediated by these ligands.

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Cell-type–restricted anti-cytokine therapy: TNF inhibition from one pathogenic source

Cited by 67 publications

References 45 publications

Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations

Biologics for Targeting Inflammatory Cytokines, Clinical Uses, and Limitations

Decreased A20 expression on circulating CD56bright NK cells contributes to a worse disease status in patients with ankylosing spondylitis

Can we design a better anti-cytokine therapy?

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