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Waetzig G.H.,CONARIS Research Institute AG | Rose-John S.,University of Kiel
Expert Opinion on Therapeutic Targets | Year: 2012

Introduction: Interleukin-6 (IL-6) is a key target in inflammation and cancer. Selective inhibition of IL-6 trans-signalling could provide the same or even higher therapeutic efficacy with a better side effect profile than complete IL-6 inhibition. Animal studies with IL-6 inhibitors show that the classic IL-6 signalling pathway via the membrane-bound IL-6 receptor (IL-6R) has important physiological functions, whereas blocking the trans-signalling pathway via the soluble IL-6R (sIL-6R) is sufficient to prevent or treat IL-6-driven diseases. Due to the success of the anti-IL-6R antibody tocilizumab and difficulties of constructing selective trans-signalling inhibitors, most drug candidates in clinical development target IL-6 or IL-6R and, thus, both IL-6 pathways. By contrast, the fusion protein sgp130Fc selectively targets IL-6/sIL-6R trans-signalling by utilising the soluble gp130 receptor as the natural inhibitor of trans-signalling. Areas covered: The authors summarise recent developments in the field with a focus on animal studies highlighting the mechanistic differences between classic and trans-signalling and their therapeutic implications. Expert opinion: Characterising disease mechanisms in terms of the employed IL-6 pathways will help to select the right therapeutic IL-6 inhibitor in the future. The trans-signalling inhibitor sgp130Fc is about to enter the clinic and holds promise for a clinically different profile in comparison with complete IL-6 inhibitors. © 2012 Informa UK, Ltd. Source

Schuett H.,Hannover Medical School | Oestreich R.,Hannover Medical School | Waetzig G.H.,CONARIS Research Institute AG | Annema W.,University of Groningen | And 13 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2012

Objective-: Transsignaling of interleukin (IL)-6 is a central pathway in the pathogenesis of disorders associated with chronic inflammation, such as Crohn disease, rheumatoid arthritis, and inflammatory colon cancer. Notably, IL-6 also represents an independent risk factor for coronary artery disease (CAD) in humans and is crucially involved in vascular inflammatory processes. Methods and Results-: In the present study, we showed that treatment with a fusion protein of the natural IL-6 transsignaling inhibitor soluble glycoprotein 130 (sgp130) and IgG1-Fc (sgp130Fc) dramatically reduced atherosclerosis in hypercholesterolemic Ldlr -/- mice without affecting weight gain and serum lipid levels. Moreover, sgp130Fc treatment even led to a significant regression of advanced atherosclerosis. Mechanistically, endothelial activation and intimal smooth muscle cell infiltration were decreased in sgp130Fc-treated mice, resulting in a marked reduction of monocyte recruitment and subsequent atherosclerotic plaque progression. Of note, patients with CAD exhibited significantly lower plasma levels of endogenous sgp130, suggesting that a compromised counterbalancing of IL-6 transsignaling may contribute to atherogenesis in humans. Conclusion-: These data clarify, for the first time, the critical involvement of, in particular, the transsignaling of IL-6 in CAD and warrant further investigation of sgp130Fc as a novel therapeutic for the treatment of CAD and related diseases. © 2012 American Heart Association, Inc. Source

Holmer R.,University of Kiel | Goumas F.A.,University of Kiel | Waetzig G.H.,CONARIS Research Institute AG | Rose-John S.,University of Kiel | Kalthoff H.,University of Kiel
Hepatobiliary and Pancreatic Diseases International | Year: 2014

Background Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a poor prognosis and little treatment options. The development and progression of the disease is fostered by inflammatory cells and cytokines. One of these cytokines is interleukin-6 (IL-6), which plays an important role in a wide range of biologic activities. Data Sources A systematic search of PubMed was performed to identify relevant studies using key words such as interleukin-6, inflammatory cytokines, inflammation and pancreatic cancer or PDAC. Articles related to IL-6 and pancreatic cancer were systematically reviewed. Results IL-6 is elevated in the serum of pancreatic cancer patients and correlates with cachexia, advanced tumor stage and poor survival. Its expression is enhanced by hypoxia and proteins involved in pancreatic cancer development like Kras, mesothelin or ZIP4. IL-6 in turn contributes to the generation of a pro-tumorigenic microenvironment and is probably involved in angiogenesis and metastasis. In experimental mouse models of PDAC, IL-6 was important for the development and progression of precursor lesions. Conclusion IL-6 emerges as a key player in pancreatic cancer development and progression, and hence should be considered as a new therapeutic target. © 2014 The Editorial Board of Hepatobiliary & Pancreatic Diseases International. Source

The present invention relates to a new pharmaceutical composition containing nicotinic acid, nicotinamide, tryptophanor related compounds for positively influencing the intestinal microbiota. In certain embodiments, the pharmaceutical composition is partially or entirely released into the small intestine or large intestine.

Conaris Research Institute AG | Date: 2013-06-20

Described are soluble gp130 polypeptide monomers and dimers, wherein, in a preferred embodiment, at least one of the three amino acid residues Thr

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