Therapeutic potential of TNFα inhibitors in chronic inflammatory disorders: Past and future

Zhang, Hongtao; Shi, Nelson; Diao, Zhuo; Chen, Youhai; Zhang, Yejia

doi:10.1016/j.gendis.2020.02.004

Cited by 29 publications

(18 citation statements)

References 57 publications

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“…Similar to the targeting of IL-6, anti-TNFα mAbs are used to treat inflammatory conditions, such as rheumatoid arthritis, juvenile arthritis, inflammatory bowel diseases, and psoriasis (reviewed in Refs. [ 55 , 56 ]). In light of their joint pro-inflammatory activities, the reduction in both IL-6 and TNFα, along with other cytokines through the inhibition of the central transcription factor NF-κB, as demonstrated for our compounds, might be even more effective in the treatment of the chronic inflammatory diseases for which either IL-6- and TNFα-mAbs are currently used.…”

Section: Discussionmentioning

confidence: 99%

Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors

et al. 2022

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For many inflammatory diseases, new effective drugs with fewer side effects are needed. While it appears promising to target the activation of the central pro-inflammatory transcription factor NF-κB, many previously discovered agents suffered from cytotoxicity. In this study, new alkylthiourea quinazoline derivatives were developed that selectively inhibit the activation of NF-κB in macrophage-like THP−1 cells while showing low general cytotoxicity. One of the best compounds, 19, strongly inhibited the production of IL-6 (IC50 = 0.84 µM) and, less potently, of TNFα (IC50 = 4.0 µM); in comparison, the reference compound, caffeic acid phenethyl ester (CAPE), showed IC50s of 1.1 and 11.4 µM, respectively. Interestingly, 19 was found to block the translocation of the NF-κB dimer to the nucleus, although its release from the IκB complex was unaffected. Furthermore, 19 suppressed the phosphorylation of NF-κB-p65 at Ser468 but not at Ser536; however, 19 did not inhibit any kinase involved in NF-κB activation. The only partial suppression of p65 phosphorylation might be associated with fewer side effects. Since several compounds selectively induced cell death in activated macrophage-like THP−1 cells, they might be particularly effective in various inflammatory diseases that are exacerbated by excess activated macrophages, such as arteriosclerosis and autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors

et al. 2022

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“…Anti-TNF-a agents have demonstrated efficacy both in monotherapy and in combination with disease-modifying antirheumatic drugs (DMARDs) in the treatment of chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA), Crohn's disease (CD), PsO, and PsA (32). However, the immunogenicity of these drugs plays a significant role in the variability of clinical responses among patients with these types of diseases.…”

Section: Anti-tnfmentioning

confidence: 99%

Immunogenicity to biological drugs in psoriasis and psoriatic arthritis

Valenzuela

Flores

2021

Clinics

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Monoclonal antibodies or fusion proteins, defined as biological drugs, have modified the natural history of numerous immune-mediated disorders, allowing the development of therapies aimed at blocking the pathophysiological pathways of the disease, providing greater efficacy and safety than conventional treatment strategies. Virtually all therapeutic proteins elicit an immune response, producing anti-drug antibodies (ADAs) against hypervariable regions of immunoglobulins. Immunogenicity against biological drugs can alter their pharmacokinetic and pharmacodynamic properties, thereby reducing the efficacy of these drugs. In more severe cases, ADAs can neutralize the therapeutic effects of the drug or cause serious adverse effects, mainly hypersensitivity reactions. The prevalence of ADAs varies widely depending on the type of test used, occurrence of false-negative results, and non-specific binding to the drug, making it difficult to accurately assess their clinical impact. Concomitant use of immunosuppressors efficiently reduces the immunogenicity in a dosedependent manner, either by decreasing the frequency of detectable ADAs or by delaying their appearance, thereby enhancing the effectiveness of biological therapies. Among the new therapeutic strategies for the management of psoriasis, biological agents have gained increasing importance in recent years as they interrupt key inflammation pathways involved in the physiopathology of the disease. Reports regarding ADA in new biologics are still scarce, but the most recent evidence tends to show little impact on the clinical response to the drug, even with prolonged treatment. It is therefore essential to standardize laboratory tests to determine the presence and titles of ADAs to establish their administration and management guidelines that allow the determination of the real clinical impact of these drugs.

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“…1 H, 13 C{ 1 H} (JMOD), and 31 P{ 1 H} NMR spectra were recorded using AV300PAS, AV400PAS, and AV400LIQ spectrometers (Bruker, Germany). To assign the 13 C NMR signals, JMOD, heteronuclear multiple-bond coherence, and heteronuclear multiple quantum correlation NMR experiments were carried out when necessary. Protonated dendrimers were characterized only by 31 P{ 1 H} NMR to ensure the integrity of the structures.…”

Section: ■ Introductionmentioning

confidence: 99%

Amphiphilic Phosphorus Dendrons Associated with Anti-inflammatory siRNA Reduce Symptoms in Murine Collagen-Induced Arthritis

Tsapis

Fay

et al. 2023

Biomacromolecules

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Small interfering RNA (siRNA) holds promise for treating rheumatoid arthritis by inhibiting major cytokines such as tumor necrosis factor-α (TNF-α). We developed original cationic amphiphilic phosphorus dendrons to produce dendriplexes associated with TNF-α siRNA. The dendrons were made of 10 pyrrolidinium end groups and a C17 aliphatic chain. The dendriplexes demonstrated the ability to protect siRNA from nuclease degradation and to promote macrophage uptake. Moreover, they led to potent inhibition of TNF-α expression in the lipopolysaccharide-activated mouse macrophage cell line RAW264.7 in vitro model. A significant anti-inflammatory effect in the murine collagen-induced arthritis model was observed through arthritis scoring and histological observations. These results open up essential perspectives in using this original amphiphilic dendron to reduce the disease burden and improve outcomes in chronic inflammatory diseases.

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Therapeutic potential of TNFα inhibitors in chronic inflammatory disorders: Past and future

Cited by 29 publications

References 57 publications

Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors

Development of (4-Phenylamino)quinazoline Alkylthiourea Derivatives as Novel NF-κB Inhibitors

Immunogenicity to biological drugs in psoriasis and psoriatic arthritis

Amphiphilic Phosphorus Dendrons Associated with Anti-inflammatory siRNA Reduce Symptoms in Murine Collagen-Induced Arthritis

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