FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3136107264> ?p ?o ?g. }

• W3136107264 endingPage "2249" @default.
• W3136107264 startingPage "2247" @default.
• W3136107264 abstract "See “Therapeutic Interleukin-6 trans-signalling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease,” by Schreiber S, Aden K, Bernardes JP, et al, on page 2354. See “Therapeutic Interleukin-6 trans-signalling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease,” by Schreiber S, Aden K, Bernardes JP, et al, on page 2354. Delivering early, robust hints of potential efficacy is one of the most daunting challenges in drug development. No matter how good the theoretical and preclinical rationale, in the end it is only a large-scale “experiment in man,” a phase III trial, that ultimately resolves biological cause–effect relationships in a disease process, and thereby proves or disproves a new target and establishes a new therapeutic. Can high-complexity systems-level biological data, derived as close as possible to first-in-man application of an experimental drug, help de-risking development, for both company and patients alike, by selecting likely winners early on? In this issue of Gastroenterology, Schreiber et al1Schreiber S. Aden K. Bernardes J.P. et al.Therapeutic Interleukin-6 trans-signalling inhibition by olamkicept (sgp130Fc) in patients with active inflammatory bowel disease.Gastroenterology. 2021; 160: 2354-2366Abstract Full Text Full Text PDF PubMed Google Scholar demonstrate an impressive and commendable case of how such a strategy could look like in inflammatory bowel disease. The authors performed an exploratory, open-label, data-rich, duocentric phase IIa study with olamkicept in patients with moderately to severely active ulcerative colitis (UC) and Crohn’s disease (CD). Intense biosampling, including tissue biopsies obtained from the sigmoid colon at baseline and as early as 4 hours and 24 hours after first drug administration, and at weeks 2, 6 and 14, was performed, and peripheral blood and tissue analyzed by RNA sequencing and further analytic methods. Eligible patients received olamkicept every 2 weeks over a 12-week period. The primary objective was the demonstration of changes from baseline at week 14 in a composite score of a mucosal inflammatory gene signature (TNF, IL1A, REG1A, IL8, IL1B, and LILRA). Clinical and centrally read endoscopic response and remission were secondary end points. Despite the challenging protocol, the authors managed to screen 20 patients over 3 years, and to enroll 16, of whom 10 (n = 5 each CD and UC) completed the trial. Olamkicept is a recombinant soluble gp130-Fc (sgp130-Fc) fusion protein, a mechanistically intriguing therapeutic. gp130 is a subunit of all IL-6 family heteromeric receptors, where it pairs with specificity-conferring receptors for IL-6, IL-11, IL-27, ciliary neurotrophic factor, leukemia inhibitory factor, oncostatin M, cardiotrophin-1, IL-31 and IL-35.2Rose-John S. Interleukin-6 family cytokines.Cold Spring Harb Perspect Biol. 2018; 10Crossref PubMed Scopus (201) Google Scholar A soluble form of the IL-6 receptor (IL-6R), expressed as a splicing variant or cleaved from the cell surface, can bind IL-6, and this complex, by binding to cell-anchored gp130, can activate cells that do not express the IL-6R, a process referred to as trans signaling. This vastly expands the range of cells responding to IL-6, because gp130 is ubiquitously expressed while membrane-bound IL-6R is largely restricted to immune cells, hepatocytes and intestinal epithelial cells. Because sgp130-Fc does not bind IL-6, it does not affect classical (or cis) IL-6R signaling. It, however, scavenges the soluble IL-6R/IL-6 complex and thereby inhibits trans signaling (Figure 1). Rendering the biology even more complicated, forms of gp130 itself can also be released from cells, acting as decoy receptors analogously to the recombinantly engineered drug.3Wolf J. Waetzig G.H. Chalaris A. et al.Different soluble forms of the interleukin-6 family signal transducer gp130 fine-tune the blockade of interleukin-6 trans-signaling.J Biol Chem. 2016; 291: 16186-16196Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar Preclinical data predict that blocking trans signaling would not impair antimicrobial defense, glucose tolerance, or regenerative activities in the intestine, kidney, and pancreas that are the consequences of outright IL-6 blockade.2Rose-John S. Interleukin-6 family cytokines.Cold Spring Harb Perspect Biol. 2018; 10Crossref PubMed Scopus (201) Google Scholar This finding was considered a particular advantage of blocking trans signaling, because an outright blockade of IL-6 signaling in CD hinted toward efficacy, although at the possible expense of serious adverse events such as abscesses, intestinal perforation, and even death.4Ito H. Takazoe M. Fukuda Y. et al.A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease.Gastroenterology. 2004; 126 (discussion 947): 989-996Abstract Full Text Full Text PDF PubMed Scopus (525) Google Scholar,5Danese S. Vermeire S. Hellstern P. et al.Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II).Gut. 2019; 68: 40-48Crossref PubMed Scopus (64) Google Scholar Although the 6-gene expression signature, predefined as the primary end point, trended nonsignificantly lower in the 3 (2 UC and 1 CD) of 16 patients who achieved clinical and endoscopic remission, it was unaltered in patients not achieving remission. Olamkicept was clearly biologically active; it exhibited pervasive effects on gene transcription in peripheral blood cells in all patients within hours of its administration, where “neutrophil degranulation” genes were notably down-regulated. No expression signatures were identified that would predict response to therapy. These early effects in peripheral blood contrasted with only marginal changes in the mucosal tissue transcriptome at those time points. In tissue, transcriptional changes occurred only much later, at week 14, where they segregated with clinical and endoscopic remission. Similar to observations in peripheral blood, down-regulated genes were enriched for neutrophil degranulation. This finding may reflect the resolved inflammatory infiltrate, rather than an immediate pharmacodynamic effect of olamkicept. In patients achieving remission, the authors also observed a gradual decrease in phosphorylation of STAT3, a canonical IL-6–activated transcription factor, in both the intestinal epithelium and the lamina propria that harbors the immune cell infiltrate. This outcome was corroborated by demonstrating decreased tissue expression of STAT3-regulated transcripts. The authors finally compared the transcriptional signature at week 14 in patients achieving remission on olamkicept (n = 3) with those from similarly designed, separate studies with infliximab (n = 14) and vedolizumab (n = 9).6Zeissig S. Rosati E. Dowds C.M. et al.Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease.Gut. 2019; 68: 25-39Crossref PubMed Scopus (75) Google Scholar This comparison hinted toward de-enrichment for neutrophil degranulation genes in olamkicept-treated patients only. This mechanism-oriented study is as good (and intense) as it gets. The absence of early transcriptional tissue responses raises questions about sufficient dosing and drug levels at the diseased site. Regarding the molecular effects and predicting efficacy, the small number of patients remains an inherent limitation of this study type, and the insight gained needs to be balanced against a more conventional phase IIa program with control and placebo groups aimed at endoscopic and clinical end points. Such trial is currently underway for olamkicept (NCT03235752) and is expected to be reported at the upcoming international meetings later in 2021. The limitation stemming from small numbers is also vividly apparent in the immediate transcriptional response of peripheral blood to olamkicept and tocilizumab, an anti-IL-6R antibody, which is surprisingly dissimilar: does this exemplify differences in trans compared with outright IL-6 signaling inhibition or reflect interpatient variation (further complicated by these datasets stemming from separate trials)? The authors have pragmatically recruited both CD and UC patients. For many targets, it is not a priori clear which of the 2 diseases would respond better. The widely held view of “inflammatory bowel disease” as a disease “spectrum” is somehow curious, given the profound and obvious differences in clinical presentation, which necessarily need to have a biological/mechanistic equivalent. In this context, the observation of a neutrophil degranulation signature linked to olamkicept may indeed be very interesting and should be explored further. IL-6 affects neutrophil trafficking during acute inflammation.7Fielding C.A. McLoughlin R.M. McLeod L. et al.IL-6 regulates neutrophil trafficking during acute inflammation via STAT3.J Immunol. 2008; 181: 2189-2195Crossref PubMed Google Scholar Neutrophils are typically not represented in cells isolated from inflamed tissue, and their contribution to chronic inflammation is generally poorly understood and under-researched in CD and UC alike.8Fournier B.M. Parkos C.A. The role of neutrophils during intestinal inflammation.Mucosal Immunol. 2012; 5: 354-366Crossref PubMed Scopus (334) Google Scholar Therapeutic Interleukin-6 Trans-signaling Inhibition by Olamkicept (sgp130Fc) in Patients With Active Inflammatory Bowel DiseaseGastroenterologyVol. 160Issue 7PreviewA large unmet therapeutic need exists in inflammatory bowel disease (IBD). Inhibition of interleukin (IL)-6 appears to be effective, but the therapeutic benefit of a complete IL6/IL6 receptor (IL6R) blockade is limited by profound immunosuppression. Evidence has emerged that chronic proinflammatory activity of IL6 is mainly mediated by trans-signaling via a complex of IL6 bound to soluble IL6R engaging the gp130 co-receptor without the need for membrane-bound IL6R. We have developed a decoy protein, sgp130Fc, that exclusively blocks IL6 proinflammatory trans-signaling and has shown efficacy in preclinical models of IBD, without signs of immunosuppression. Full-Text PDF Open Access" @default.
• W3136107264 created "2021-03-29" @default.
• W3136107264 creator A5050963621 @default.
• W3136107264 creator A5054264568 @default.
• W3136107264 date "2021-06-01" @default.
• W3136107264 modified "2023-09-25" @default.
• W3136107264 title "Is IL-6 Back in trans Signaling for Inflammatory Bowel Disease?" @default.
• W3136107264 cites W2069931076 @default.
• W3136107264 cites W2118877038 @default.
• W3136107264 cites W2140500533 @default.
• W3136107264 cites W2404703682 @default.
• W3136107264 cites W2626842659 @default.
• W3136107264 cites W2772378626 @default.
• W3136107264 cites W2801753207 @default.
• W3136107264 cites W3133637024 @default.
• W3136107264 doi "https://doi.org/10.1053/j.gastro.2021.03.030" @default.
• W3136107264 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/33753099" @default.
• W3136107264 hasPublicationYear "2021" @default.
• W3136107264 type Work @default.
• W3136107264 sameAs 3136107264 @default.
• W3136107264 citedByCount "0" @default.
• W3136107264 crossrefType "journal-article" @default.
• W3136107264 hasAuthorship W3136107264A5050963621 @default.
• W3136107264 hasAuthorship W3136107264A5054264568 @default.
• W3136107264 hasBestOaLocation W31361072641 @default.
• W3136107264 hasConcept C126322002 @default.
• W3136107264 hasConcept C203014093 @default.
• W3136107264 hasConcept C2777572184 @default.
• W3136107264 hasConcept C2778260677 @default.
• W3136107264 hasConcept C2779134260 @default.
• W3136107264 hasConcept C71924100 @default.
• W3136107264 hasConcept C90924648 @default.
• W3136107264 hasConceptScore W3136107264C126322002 @default.
• W3136107264 hasConceptScore W3136107264C203014093 @default.
• W3136107264 hasConceptScore W3136107264C2777572184 @default.
• W3136107264 hasConceptScore W3136107264C2778260677 @default.
• W3136107264 hasConceptScore W3136107264C2779134260 @default.
• W3136107264 hasConceptScore W3136107264C71924100 @default.
• W3136107264 hasConceptScore W3136107264C90924648 @default.
• W3136107264 hasIssue "7" @default.
• W3136107264 hasLocation W31361072641 @default.
• W3136107264 hasLocation W31361072642 @default.
• W3136107264 hasLocation W31361072643 @default.
• W3136107264 hasOpenAccess W3136107264 @default.
• W3136107264 hasPrimaryLocation W31361072641 @default.
• W3136107264 hasRelatedWork W154415141 @default.
• W3136107264 hasRelatedWork W1989568804 @default.
• W3136107264 hasRelatedWork W2052065748 @default.
• W3136107264 hasRelatedWork W2075334414 @default.
• W3136107264 hasRelatedWork W2156758733 @default.
• W3136107264 hasRelatedWork W2314098491 @default.
• W3136107264 hasRelatedWork W2408939568 @default.
• W3136107264 hasRelatedWork W3134857862 @default.
• W3136107264 hasRelatedWork W3209514756 @default.
• W3136107264 hasRelatedWork W4232531751 @default.
• W3136107264 hasVolume "160" @default.
• W3136107264 isParatext "false" @default.
• W3136107264 isRetracted "false" @default.
• W3136107264 magId "3136107264" @default.
• W3136107264 workType "article" @default.