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Myositis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Immunoproteasome inhibitors selectively target proteasome found in immune effector cells and lead to decreased cytokine release.111 Data showed that the selective subunit inhibition of the immunoproteasome by KZR-616 resulted in a favorable anti-inflammatory profile.112, 113 Therefore, the therapeutic benefit of KZR-616 is being studied in multiple trials. One of these studies is the PRESIDIO trial, a phase 2 randomized, placebo-controlled study on active PM and DM patients, which was completed and is currently pending publication of results.
Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Modulation of CD8 T-cell responses with HDAC inhibitors is another important aspect in controlling tumor growth. Tumor-oriented cytolytic CD8 effector T cells, which produce IFN-γ and TNF-α, cytokines that activate APCs can make the tumor cells more immunogenic by enhancing MHC expression, activating the immunoproteasome and promoting tumor cytotoxicity (de Charette et al., 2016; Jorgovanovic et al., 2020). For example, a combination of entinostat and IL-2 elicits dramatic increases in IFN-γ production and CD8 T-cell cytotoxicity in a mouse model of renal cancer (Shen et al., 2012).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Onyx Pharmaceuticals has also developed a second-generation, orally available proteasome inhibitor, oprozomib (ONX 0912), which selectively inhibits the chymotrypsin-like activity of both the constitutive proteasome (PSMB5) and the immunoproteasome (LMP7). It was granted orphan drug status by the FDA for the treatment of Waldenström’s macroglobulinaemia and multiple myeloma in 2014 and has been in a number of hematological clinical trials, although it has not yet reached the approval stage.
Suppression of prostate cancer and amelioration of the immunosuppressive tumor microenvironment through selective immunoproteasome inhibition
Published in OncoImmunology, 2023
Julia Koerner, Dennis Horvath, Franziska Oliveri, Jun Li, Michael Basler
Immunoproteasome inhibitors suppress the development and progression of autoimmune diseases in numerous preclinical mouse models and are currently investigated in phase II trials of autoimmune diseases.33,34 Given that chronic inflammation is a risk factor for cancer development, we and others have previously investigated whether immunoproteasome inhibition can also suppress the development and progression of colon cancer that is known to be promoted by inflammatory cytokines which are suppressed by immunoproteasome inhibition in autoimmune diseases. In fact, immunoproteasome inhibition with ONX 0914 markedly slowed down colon carcinoma progression in genetic and mutagen-induced models in therapeutic settings.17,18 These results encouraged us to investigate a potential therapeutic effect of ONX 0914 in TRAMP mice building on the insight that PC progression is promoted by the same pro-inflammatory cytokines IL-6, TNF, IL-17, and IL-23.9,19
Drug development and novel therapeutics to ensure a personalized approach in the treatment of systemic sclerosis
Published in Expert Review of Clinical Immunology, 2023
N Farina, C Campochiaro, A Lescoat, G Benanti, G De Luca, D Khanna, L Dagna, M Matucci-Cerinic
Proteasomes are multi-subunit proteases that remove damaged proteins to prevent their accumulation, and they are essential to cell homeostasis [126]. An alternative type of proteasome, the immunoproteasome, can be induced by pro-inflammatory cytokines in immune cells [127]. The prototypical function of immunoproteasome is the cleavage of proteins to generate antigen peptides that are then complexed to MHC-I [128]. Inhibition of the immunoproteasome has shown a potentially beneficial role in many autoimmune conditions, including psoriasis, inflammatory bowel diseases, immune thrombocytopenia, and rheumatoid arthritis [129–131]. Ixazomib is an orally available proteasome inhibitor, which has been successfully trialed in the treatment of patients with multiple myeloma [132]. This molecule is currently being studied for the treatment of SSc-ILD in a phase II trial (NCT04837131).
Combination strategies for lupus nephritis: facts and controversies
Published in Expert Review of Clinical Immunology, 2023
Ianalumab is a dual-action biologic that targets the BAFF receptor and mediates depletion of BAFF-receptor expressing B cells through direct antibody-dependent cell-mediated cytotoxicity (ADCC) [74]. A phase IIb RCT showed efficacy of ianalumab in primary Sjogren’s syndrome [75] and a phase III RCT in LN has started patient recruitment (SIRIUS-LN) (NCT05126277). Other targeted small molecules such as Janus kinase (JAK) inhibitors, Bruton tyrosine kinase (BTK) inhibitors, cereblon E3 ligase modulators, immunoproteasome inhibitors, and sphingosine 1-phosphate (S1P)/S1P receptor-1 (S1PR1) modulators are being tested in non-renal SLE patients. Of note is zetomipzomib, a selective immunoproteasome inhibitor with an improved safety profile, is undergoing trials in SLE and LN [76].