Value through Innovation17 January 2013

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Scientific Publications

Boehringer Ingelheim offers an overview of scientific publications on the following pages. This overview represents all publications of the last three years (YTD) where employees of Boehringer Ingelheim worldwide were involved.

14 publications regarding Inflammation
  • Author:
    Moss N; Xiong Z; Burke M; Cogan D; Gao DA; Haverty K; Heim-Riether A; Hickey ER; Nagaraja R; Netherton M; O'Shea K; Ramsden P; Schwartz R; Shih D-T; Ward Y; Young E; Zhang Q
    Title:
    Exploration of cathepsin S inhibitors characterized by a triazole P1-P2 amide replacement.
    Source:
    Bioorg Med Chem Lett 22 (23), 7189-7193 (2012)
  • Author:
    Blech M; Peter D; Fischer P; Bauer MMT; Hafner M; Zeeb M; Nar H
    Title:
    One target - two different binding modes: Structural insights into gevokizumab and canakinumab interactions to interleukin-1beta.
    Source:
    J Mol Biol 425 (1), 94-111 (2013)
    Abstract:
    Interleukin-1beta (IL-1beta) is a key orchestrator in inflammatory and several immune responses. IL-1beta exerts its effects through interleukin-1 receptor type I (IL-1RI) and interleukin-1 receptor accessory protein (IL-1 RAcP), which together form a heterotrimeric signaling-competent complex. Canakinumab and gevokizumab are highly specific IL-1beta monoclonal antibodies. Canakinumab is known to neutralize IL-1beta by competing for binding to IL-1R and therefore blocking signaling by the antigen:antibody complex. Gevokizumab is claimed to be a regulatory therapeutic antibody that modulates IL-1beta bioactivity by reducing the affinity for its IL-1RI:IL-1RAcP signaling complex. How IL-1beta signaling is affected by both canakinumab and gevokizumab was not yet experimentally determined. We have analyzed the crystal structures of canakinumab and gevokizumab antibody binding fragment (Fab) as well as of their binary complexes with IL-1beta. Furthermore, we characterized the epitopes on IL-1beta employed by the antibodies by NMR epitope mapping studies. The direct comparison of NMR and X-ray data shows that the epitope defined by the crystal structure encompasses predominantly those residues whose NMR resonances are severely perturbed upon complex formation. The antigen:Fab co-structures confirm the previously identified key contact residues on IL-1beta and provide insight into the mechanisms leading to their distinct modulation of IL-1beta signaling. A significant steric overlap of the binding interfaces of IL-1R and canakinumab on IL-1beta causes competitive inhibition of the association of IL-1beta and its receptor. In contrast, gevokizumab occupies an allosteric site on IL-1beta and complex formation results in a minor reduction of binding affinity to IL-1RI. This suggests two different mechanisms of IL-1beta pathway attenuation.
  • Author:
    Jenh C-H; Cox MA; Cui L; Reich E-P; Sullivan L; Chen S-C; Kinsley D; Qian S; Kim SH; Rosenblum S; Kozlowski J; Fine JS; Zavodny PJ; Lundell D
    Title:
    A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection.
    Source:
    BMC Immunol 13 art.no.2 (2012)
    Abstract:
    Background: The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11) have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738.Results: In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC 50ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC 90about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment.Conclusions: SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and multiple sclerosis, and to prevent transplant rejection.
  • Author:
    Chen L; Klein T; Leung P S
    Title:
    Effects of combining linagliptin treatment with BI-38335, a novel SGLT2 inhibitor, on pancreatic islet function and inflammation in db/db mice
    Source:
    Curr Mol Med 12 (8), 995-1004 (2012)
    Abstract:
    Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance incretin actions and beta-cell function. Concurrently, sodium-glucose co-transporter 2 (SGLT2) inhibitors block renal glucose reabsorption promoting excretion. In this study, we investigated the effects of linagliptin (a DPP-4 inhibitor) and BI-38335 (an SGLT2 inhibitor), individually and in combination, on glucose homeostasis, islet function, and pancreatic islet morphology in db/db mice. Diabetic and non-diabetic mice received linagliptin (3 mg/kg), BI-38335 (1 mg/kg), the two drugs in combination or control once daily for 8 weeks. Blood glucose homeostasis and insulin sensitivity were assessed. Pancreatic islet function and morphology as well as inflammatory factors and tolllike receptor 2 (TLR2) pathways involved in islet inflammation were investigated. Active treatments markedly reduced blood glucose and glycated hemoglobin A1c (HbA 1c) levels, with the combined treatment showing the greater effects. Insulin resistance was improved in the BI-38335 and combination groups with the enhancement of insulin sensitivity and significant increase of serum adiponectin levels. The combined treatment exhibited greater effects on enhanced islet glucose-stimulated insulin secretion and improved glucose tolerance. Moreover, the combination restored the islet beta-/alpha-cell ratio, reduced beta-cell apoptosis, decreased expression of islet immune cell markers, and suppressed factors related to the TLR2 pathway. In addition, all active treatments reduced serum lipid profiles, though the combination produced more robust effects. Collectively, our data show that combined treatment with BI-38335 and linagliptin work, at least in part, synergistically to benefit islet cell function/architecture and insulin resistance, thus improving glycemic control. © 2012 Bentham Science Publishers.
  • Author:
    Wagner C L; Visvanathan S; Elashoff M; Mcinnes I B; Mease P J; Krueger G G; Murphy F T; Papp K; Gomez-Reino JJ; Mack M; Beutler A; Gladman D; Kavanaugh A
    Title:
    Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab
    Source:
    Ann Rheum Dis 72 (1), 83-88 (2013)
    Abstract:
    Objective: To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA). Methods: GO-REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14. Results: Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1?) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor ?). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone. Conclusions: This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment. Copyright Article author (or their employer) 2012.
  • Author:
    Teunissen M B M; Zheng L; De Groot M; De Rie M A; Fine J S; Chen S C
    Title:
    Rise in dermal CD11c + dendritic cells associates with early-stage development of psoriatic lesions
    Source:
    Arch Dermatol Res 304 (6), 443-449 (2012)
    Abstract:
    There is limited information available regarding the phenotype and function of leukocytes involved in the earliest stages of psoriatic lesion development. In this study, we examined the presence of different types of leukocytes in psoriatic point lesions collected at three 1-week interval time points from a recent and simultaneously formed group of point lesions. The cells were quantified and compared with K16 expression and epidermal thickness, both typically increased in this disease and considered as hallmarks. We found a significant correlation between K16 + cell increment and the increase in epidermal thickness in the timeframe of 14 days. The change in CD3 +, CD4 +, and CD8 + T-cell numbers in the dermis showed a significant association with these two features from d7 to d14, whereas in the epidermis only CD8 + T cells demonstrated a significant correlation. Remarkably, the relationship between T cells and disease progression was preceded by a significant correlation of CD11c + dendritic cells (DCs) with K16 expression and epidermal thickness from baseline onwards. Interestingly, there was also a numeric correlation of CD11c + DCs with the CD3 + T-cell shifts from d7 to d14. A significant correlation was also found between dermal CD14 + cells and K16 expression from d7 to d14. BDCA-2 + plasmacytoid DCs were absent in nonlesional skin, but found at low numbers in most lesions. The change in plasmacytoid DC or neutrophil numbers did not correlate with lesion development. In conclusion, our study suggests a relevant role for T cells, and in particular dermal CD11c + DCs, in the earliest stage of psoriatic lesion development. © The Author(s) 2012.
  • Author:
    Teunissen MBM; Zheng L; de Groot M; de Rie MA; Fine JS; Chen S-C
    Title:
    Rise in dermal CD11c + dendritic cells associated with early-stage development of psoriatic lesions.
    Source:
    Arch Dermatol Res, 1-7 (2012)
  • Author:
    Nozaki S; Doi H; Wada Y; Suzuki M; Watanabe Y; Ozaki N; Encinas J
    Title:
    Development of early diagnostic techniques for rheumatoid arthritis using carbone eleven labeled PK11195 and carbone eleven labeled ketoprofen.
    Source:
    Arthritis Rheum 63 (10) (Supp.[S]), S74-S75 (2011)
  • Author:
    Mechtcheriakova D; Sobanov Y; Bajna E; Svoboda M; Jensen-Jarolim E; Holtappels G; Bachert C; Jaritz M
    Title:
    Activation-induced cytidine deaminase (AID)-associated multigene signature to assess impact of AID in etiology of diseases withh inflammatory component.
    Source:
    Plos One 6 (10) (2011)
  • Author:
    Giblin P; Boxhammer K; Desai S; Kroe-Barrett R; Hansen G; Ksiazek J; Panzenbeck M; Ralph K; Schwartz R; Zimmitti C; Pracht C; Miller S; Magram J; Litzenburger T
    Title:
    Fully human antibodies against the protease-activated receptor-2 (PAR-2) with anti-inflammatory activity.
    Source:
    Hum Antibodies 20 (3), 83-94 (2011)
    Abstract:
    PAR-2 belongs to a family of G-protein coupled Protease-Activated Receptors (PAR) which are activated by specific proteolytic cleavage in the extracellular N-terminal region. PAR-2 is activated by proteases such as trypsin, tryptase, proteinase 3, factor VIIa, factor Xa and is thought to be a mediator of inflammation and tissue injury, where elevated levels of proteases are found. Utilizing the HuCAL GOLD.RTM. phage display library we generated fully human antibodies specifically blocking the protease cleavage site in the N-terminal domain. In vitro affinity optimization resulted in antibodies with up to 1000-fold improved affinities relative to the original parental antibodies with dissociation constants as low as 100 pM. Corresponding increases in potency were observed in a mechanistic protease cleavage assay. The antibodies effectively inhibited PAR-2 mediated intracellular calcium release and cytokine secretion in various cell types stimulated with trypsin. In addition, the antibodies demonstrated potent inhibition of trypsin induced relaxation of isolated rat aortic rings ex vivo. In a short term mouse model of inflammation, the trans vivo DTH model, anti-PAR-2 antibodies showed inhibition of the inflammatory swelling response. In summary, potent inhibitors of PAR-2 were generated which allow further assessment of the role of this receptor in inflammation and evaluation of their potential as therapeutic agents.
  • Author:
    Jones NR; Pegues MA; McCrory MA; Szalai AJ; Kerr StW; Jiang H; Sellati R; Berger V; Villalona J; Parikh R; McFarland M; Pantages L; Madwed JB
    Title:
    Collagen-induced arthritis is exacerbated in C-reactive protein-deficient mice.
    Source:
    Arthritis Rheum 63 (9), 2641-2650 (2011)
    Abstract:
    Objective Blood C-reactive protein (CRP) is routinely measured to gauge inflammation. In rheumatoid arthritis (RA), a heightened CRP level is predictive of a poor outcome, while a lowered CRP level is indicative of a positive response to therapy. CRP interacts with the innate and adaptive immune systems in ways that suggest it may be causal in RA and, although this is not proven, it is widely assumed that CRP makes a detrimental contribution to the disease process. Paradoxically, results from animal studies have indicated that CRP might be beneficial in RA. This study was undertaken to study the role of CRP in a mouse model of RA, the collagen-induced arthritis (CIA) model. Methods We compared the impact of CRP deficiency with that of transgenic overexpression of CRP on inflammatory and immune responses in mice, using CRP-deficient (Crp -/-) and human CRP-transgenic (CRP-Tg) mice, respectively. Susceptibility to CIA, a disease that resembles RA in humans, was compared between wild-type, Crp-/-, and CRP-Tg mice. Results CRP deficiency significantly altered the inflammatory cytokine response evoked by challenge with endotoxin or anti-CD3 antibody, and heightened some immune responses. Compared to that in wild-type mice, CIA in Crp-/- mice progressed more rapidly and was more severe, whereas CIA in CRP-Tg mice was dramatically attenuated. Despite these disparate clinical outcomes, anticollagen autoantibody responses during CIA did not differ among the genotypes. Conclusion CRP exerts an early and beneficial effect in mice with CIA. The mechanism of this effect remains unknown but does not involve improvement of the autoantibody profile. In humans, the presumed detrimental role of a heightened blood CRP level during active RA might be balanced by a beneficial effect of the baseline CRP (i.e., levels manifest during the preclinical stages of disease).
  • Author:
    Guinea-Viniegra J; Bakiri L; Schonthaler HB; Wagner EF; Zenz R; Scheuch H; Hnisz D; Holcmann M; Sibilia M
    Title:
    TNF alpha shedding and epidermal inflammation is controlled by Jun/AP-1.
    Source:
    Adv TNF Fam Res 691, 788 (2011)
  • Author:
    Venkatesh J; Yoshifuji H; Kawabata D; Chinnasamy P; Stanevsky A; Grimaldi ChM; Cohen-Solal J; Diamond B
    Title:
    Antigen is required for maturation and acivation of pathogenic anti-DNA antibodies and systemic inflammation.
    Source:
    J Immunol 186 (9), 5304-5312 (2011)
    Abstract:
    Systemic lupus erythematosus is an autoimmune disease characterized by autoantibodies and systemic inflammation that results in part from dendritic cell activation by nucleic acid containing immune complexes. There are many mouse models of lupus, some spontaneous and some induced. We have been interested in an induced model in which estrogen is the trigger for development of a lupus-like serology. The R4A transgenic mouse expresses a transgene-encoded H chain of an anti-DNA Ab. This mouse maintains normal B cell tolerance with deletion of high-affinity DNA-reactive B cells and maturation to immunocompetence of B cells making nonglomerulotropic, low-affinity DNA-reactive Abs. When this mouse is given estradiol, normal tolerance mechanisms are altered; high-affinity DNA-reactive B cells mature to a marginal zone phenotype, and the mice are induced to make high titers of anti-DNA Abs.We now show that estradiol administration also leads to systemic inflammation with increased B cell-activating factor and IFN levels and induction of an IFN signature. DNA must be accessible to B cells for both the production of high-affinity anti-DNA Abs and the generation of the proinflammatory milieu. When DNase is delivered to the mice at the same time as estradiol, there is no evidence for an abrogation of tolerance, no increased B cell-activating factor and IFN, and no IFN signature. Thus, the presence of autoantigen is required for positive selection of autoreactive B cells and for the subsequent positive feedback loop that occurs secondary to dendritic cell activation by DNA-containing immune complexes.
  • Author:
    Duechs MJ; Hahn C; Benediktus E; Werner-Klein M; Braun A; Hoymann HG; Gantner F; Erb KJ
    Title:
    TLR-agonist mediated suppression of allergic responses is associated with increased innate inflammation in the aiways.
    Source:
    Pulm Pharmacol Ther 24 (2), 203-214 (2011)
    Abstract:
    Toll-like receptor (TLR) mediated signaling induces pro-inflammatory responses and can both suppress and exacerbate allergic responses in the airways. The aim of our study was to directly compare the efficacy of different TLR agonists in inhibiting or exacerbating the development of Th2-mediated responses in the airways and investigate if the suppressive effects were associated with increased pro-inflammatory responses. Mice were immunized on day 0, 14 and 21 by intraperitoneal injection of ovalbumin/alum and exposed to ovalbumin aerosol on day 26 and 27. TLR2, TLR3, TLR4, TLR7 and TLR9 agonists (0.001, 0.01, 0.1, or 1 mg/kg) were administered intratracheally 1 h before each allergen exposure. Both the TLR7 and TLR9 agonists dose dependently reduced airway eosinophilia, while the TLR3 agonist only reduced airway eosinophilia at a dose of 1.0 mg/kg. The TLR2 and TLR4 agonists potentiated eosinophilia. All TLR agonists enhanced neutrophil numbers at doses as low as 0.01 mg/kg, in particular TLR2 and TLR4 agonists. TLR7 and TLR9 agonists also significantly reduced IL-4 and IL-5 levels and all TLR agonists, with the exception of TLR7, enhanced the amount IL-1?, IL-6, and TNF-? detected in the whole lung lavage. Only application of TLR9 agonist induced detectable levels of IL-10 in the lung. Suppressive effects of the TLR agonists were not dependent upon IFN-? and IL-10 or associated with increased numbers of Foxp3<sup>+</sup>CD4<sup>+</sup> Tr cells in the lavage fluid. Airway resistance was reduced significantly only when TLR7 agonist was administered. When applied therapeutically 2 days after allergen exposure, all TLR agonists, except TLR2, similarly reduced airway eosinophilia and IL-4 levels. Taken together our results show that TLR7 agonists had the strongest anti-asthmatic effects with the lowest pro-inflammatory potential, suggesting that activating TLR7 may have the greatest potential to treat allergic disorders in humans.
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