The Role of Tumor Necrosis Factor Alpha (TNF-α) in Autoimmune Disease and Current TNF-α Inhibitors in Therapeutics

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(5), P. 2719 - 2719

Published: March 8, 2021

Tumor necrosis factor alpha (TNF-α) was initially recognized as a that causes the of tumors, but it has been recently identified to have additional important functions pathological component autoimmune diseases. TNF-α binds two different receptors, which initiate signal transduction pathways. These pathways lead various cellular responses, including cell survival, differentiation, and proliferation. However, inappropriate or excessive activation signaling is associated with chronic inflammation can eventually development complications such Understanding mechanism expanded applied for treatment immune diseases, resulted in effective therapeutic tools, inhibitors. Currently, clinically approved inhibitors shown noticeable potency variety novel are being evaluated. In this review, we briefly introduce impact on diseases its inhibitors, used agents against

Language: Английский

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Cytokine-Mediated Crosstalk between Immune Cells and Epithelial Cells in the Gut

Cells, Journal Year: 2021, Volume and Issue: 10(1), P. 111 - 111

Published: Jan. 9, 2021

Cytokines are small proteins that secreted by a vast majority of cell types in the gut. They not only establish cell-to-cell interactions and facilitate cellular signaling, but also regulate both innate adaptive immune responses, thereby playing central role genetic, inflammatory, infectious diseases Both, cells gut epithelial cells, play important roles intestinal disease development. The epithelium is located between mucosal system microbiome. It establishes an efficient barrier against microbes, it signals information from lumen its composition to compartment. Communication across layer occurs other direction. Intestinal respond cytokines their response influences shapes microbial community within lumen. Thus, should be seen as translator or moderator microbiota system. Proper communication seems key homeostasis. Indeed, current genome-wide association studies for disorders have identified several susceptibility loci, which map cytokine signatures related signaling genes. A thorough understanding this tightly regulated network crucial. main objective review was shed light on how can orchestrate functions such proliferation, death, permeability, microbe interaction, maintenance, safeguarding host health. In addition, cytokine-mediated therapy inflammation cancer discussed.

Language: Английский

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Revisiting Inflammatory Bowel Disease: Pathology, Treatments, Challenges and Emerging Therapeutics Including Drug Leads from Natural Products

Journal of Clinical Medicine, Journal Year: 2020, Volume and Issue: 9(5), P. 1273 - 1273

Published: April 28, 2020

Inflammatory bowel disease (IBD) is a chronic and life-long characterized by gastrointestinal tract inflammation. It caused the interplay of host’s genetic predisposition immune responses, various environmental factors. Despite many treatment options, there no cure for IBD. The increasing incidence prevalence IBD lack effective long-term options have resulted in substantial economic burden to healthcare system worldwide. Biologics targeting inflammatory cytokines initiated shift from symptomatic control towards objective goals such as mucosal healing. There are seven monoclonal antibody therapies excluding their biosimilars approved US Food Drug Administration induction maintenance clinical remission Adverse side effects associated with almost all currently available drugs, especially biologics, main challenge management. Natural products significant potential therapeutic agents an role health care. Given that natural display great structural diversity relatively easy modify chemically, they represent ideal scaffolds upon which generate novel therapeutics. This review focuses on pathology, challenges, roles played discusses these within current biodiscovery research agenda, including applications drug discovery techniques search next-generation drugs treat plethora diseases, major focus

Language: Английский

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Autoimmune Hepatitis—Immunologically Triggered Liver Pathogenesis—Diagnostic and Therapeutic Strategies

Journal of Immunology Research, Journal Year: 2019, Volume and Issue: 2019, P. 1 - 19

Published: Nov. 25, 2019

Autoimmune hepatitis (AIH) is a severe liver disease that arises in genetically predisposed male and female individuals worldwide. Diagnosis of AIH made clinically applying diagnostic scores; however, the heterotopic phenotype often makes rapid determination challenging. responds favorably to steroids pharmacologic immunosuppression, transplantation only necessary cases with acute failure or end-stage cirrhosis. Recurrence development de novo after possible, treatment similar standard therapy. Current experimental investigations T cell-mediated autoimmune pathways analysis changes within intestinal microbiome might advance our knowledge on pathogenesis trigger spark hope for novel therapeutic strategies.

Language: Английский

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Ozoralizumab, a Humanized Anti-TNFα NANOBODY® Compound, Exhibits Efficacy Not Only at the Onset of Arthritis in a Human TNF Transgenic Mouse but Also During Secondary Failure of Administration of an Anti-TNFα IgG

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: Feb. 22, 2022

Although the introduction of tumor necrosis factor (TNF) inhibitors represented a significant advance in treatment rheumatoid arthritis (RA), traditional anti-TNFα antibodies are somewhat immunogenic, and their use results formation anti-drug (ADAs) loss efficacy (secondary failure). Ozoralizumab is trivalent, bispecific NANOBODY ® compound that differs structurally from IgGs. In this study we investigated suppressant effect ozoralizumab adalimumab, an IgG, on induction ADAs human TNF transgenic mice. markedly suppressed progression did not induce during long-term administration. We also developed animal model secondary failure by repeatedly administering adalimumab found switching to was followed superior anti-arthritis secondary-failure model. Moreover, form large immune complexes might lead ADA formation. The our studies suggest ozoralizumab, which exhibited low immunogenicity used has different antibody structure IgGs, promising candidate for RA patients only at onset but treatment.

Language: Английский

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Efficacy and Safety of Elective Switching from Intravenous to Subcutaneous Infliximab [CT-P13]: A Multicentre Cohort Study

Journal of Crohn s and Colitis, Journal Year: 2022, Volume and Issue: 16(9), P. 1436 - 1446

Published: April 7, 2022

Abstract Background Intravenous [IV] infliximab is a well-established therapy for inflammatory bowel diseases [IBD] patients. A subcutaneous [SC] formulation of [CT-P13] has recently been shown to be as effective IV after two doses induction in randomised trial, but there are no data support elective switching patients on maintenance therapy. We aimed assess the effectiveness an programme SC CT-P13 treated with infliximab. Methods Patients established infliximab, who switched CT-P13, were included this retrospective multicentre cohort study. Disease activity was monitored serially Harvey-Bradshaw Index [HBI] Crohn’s disease [CD] and Simple Clinical Colitis Activity [SCCAI] ulcerative colitis (UC) up 12 months at 3, 6, 12. Faecal calprotectin [FC] C-reactive protein [CRP] recorded baseline follow-up, if available. Infliximab trough levels measured prior switch following switch. The primary outcome measure treatment persistence latest follow-up. Secondary measures pharmacokinetics [PK], safety, need corticosteroid rescue therapy, surgery. Results 181 patients, whom 115 [63.5%] had CD. majority [72.4%] 8-weekly dosing intravenous switching, more than half [59.1%] concomitant immunomodulatory (CD: 106, 92.2%; UC: 46, 76.7%; IBD unclassified [IBD-U]: 5, 83.3%) clinical remission. Treatment rate high [n = 167, 92.3%] only 14 [7.7%] stopped during follow-up period. There significant difference between repeat measurements or HBI, SCCAI, CRP, FC. Of total cohort, 25 (13.8%) perianal these, [8%] worsening CD required antibiotic further examination under anaesthesia [EUA]. Both these also back Median level increased from 8.9 µg/dl [range 0.4-16] 16.0 2.3-16, p <0.001] 3 months. Serum stayed stable 6 [median 16 µg/dl, range 0.3-17.2] 0.3-19.1, both <0.001 compared baseline]. Among variables examined, antibodies [ATI] associated (odds ratio [OR] -13.369, 95% CI -15.405, -11.333, <0.001]. developed ATI; nine [64.3%] Immunomodulatory not significantly development ATI [p 0.15]. In subset receiving escalated frequency observed weekly versus alternate CT-P13. Patient acceptance satisfaction rates very high. Conclusions we low immunogenicity, change indices biomarkers. serum levels.

Language: Английский

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Sequential immunotherapy: towards cures for autoimmunity

Nature Reviews Drug Discovery, Journal Year: 2024, Volume and Issue: 23(7), P. 501 - 524

Published: June 5, 2024

Language: Английский

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Emerging strategies for nanomedicine in autoimmunity

Advanced Drug Delivery Reviews, Journal Year: 2024, Volume and Issue: 207, P. 115194 - 115194

Published: Feb. 10, 2024

Language: Английский

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Phage Display Technology as a Powerful Platform for Antibody Drug Discovery

Viruses, Journal Year: 2021, Volume and Issue: 13(2), P. 178 - 178

Published: Jan. 25, 2021

Antibody drugs with a high affinity and specificity are effective safe for intractable diseases, such as cancers autoimmune diseases. Furthermore, they have played central role in drug discovery, currently accounting eight of the top 20 pharmaceutical products worldwide by sales. Forty years ago, clinical trials on antibody that were thought to be magic bullet failed, partly due immunogenicity monoclonal antibodies produced mice. The recent breakthrough is largely because contribution phage display technology. Here, we reviewed importance technology powerful platform discovery from various perspectives, development human antibodies, enhancement identification therapeutic targets drugs.

Language: Английский

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Efficacy and pharmacokinetics of ozoralizumab, an anti-TNFα NANOBODY® compound, in patients with rheumatoid arthritis: 52-week results from the OHZORA and NATSUZORA trials

Arthritis Research & Therapy, Journal Year: 2023, Volume and Issue: 25(1)

Published: April 13, 2023

Abstract Introduction Ozoralizumab (OZR), a tumor necrosis factor alpha (TNFα) inhibitor, is NANOBODY ® compound that binds to TNFα and human serum albumin. The main objective of this study was analyze the pharmacokinetics (PK) drug its correlation with clinical efficacy in patients rheumatoid arthritis (RA). Methods Efficacy data were analyzed from OHZORA trial, which OZR 30 or 80 mg administered Japanese RA at 4-week intervals for 52 weeks combination methotrexate (MTX; n = 381), NATSUZORA without concomitant MTX ( 140). Effects patient baseline characteristics anti-drug antibodies (ADAs) on PK investigated, post hoc analysis effects performed. Results maximum plasma concentration (C max ) reached 6 days both groups, an elimination half-life 18 days. C area under concentration–time curve increased dose-dependent manner, trough steady state by week 16. exposure correlated negatively body weight not affected other characteristics. ADAs limited trials. However, neutralize binding had some effect trial. receiver operating characteristic American College Rheumatology 20% 50% improvement rates retrospectively performed, cutoff approximately 1 μg/mL 16 obtained indicators subgroup ≥ higher than those < 16, while no clear Conclusions showed long favorable properties. A suggested sustained independent subcutaneous administration weeks. Trial registration JapicCTI, trial: JapicCTI-184029, date July 9, 2018; JapicCTI-184031, 2018.

Language: Английский

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