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Mats Carlsson - One of the best experts on this subject based on the ideXlab platform.
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Potential Risks Related to Modulating Interleukin-13 and Interleukin-4 Signalling: A Systematic Review
Drug Safety, 2018Co-Authors: Martin Braddock, Gene Colice, Amir Sharafkhaneh, Nicola A. Hanania, Mats CarlssonAbstract:Introduction Interleukin-13 and Interleukin-4 are type-II cytokines signalling through the shared type II Interleukin-4 receptor. As a result of their structural similarity, Interleukin-13 and Interleukin-4 have overlapping functions in the mediation of type-II-driven diseases and are, therefore, promising targets of biologic drugs currently in development for the treatment of such diseases, including asthma and atopic dermatitis. Objective This systematic review was conducted to assess preclinical evidence of potential safety concerns related to blockade of Interleukin-13 alone or Interleukin-13 and Interleukin-4 in combination. Methods We specifically examined risks related to infection, malignancy and the cardiovascular system. We systematically searched the BIOSIS, MEDLINE and EMBASE databases to identify preclinical studies published between January 2006 and October 2016 that addressed the effects of Interleukin-13/Interleukin-4 blockade and modulation on the risk of infection, malignancy and cardiovascular events. To provide a clinical context, we also performed a search for clinical trials targeting the Interleukin-13/Interleukin-4 pathways. Relevant data from preclinical and clinical trials were abstracted and presented descriptively. Results Aside from expected evidence that inhibition of Interleukin-13 and Interleukin-4 impaired host responses to helminth infections, we did not identify other preclinical evidence suggesting safety risks relating to infection, malignancy or cardiovascular events. We found no evidence in clinical trials suggesting serious safety concerns, i.e. increased risk for infections, malignancy or cardiovascular events from therapeutic modulation of the Interleukin-13 pathway alone or the combined Interleukin-13/Interleukin-4 pathways. Conclusions Although our findings are reassuring, long-term safety assessments of biologics that target the Interleukin-13/Interleukin-4 pathways currently in clinical development are needed.
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Potential Risks Related to Modulating Interleukin-13 and Interleukin-4 Signalling: A Systematic Review.
Drug Safety, 2018Co-Authors: Martin Braddock, Gene Colice, Amir Sharafkhaneh, Nicola A. Hanania, Mats CarlssonAbstract:Interleukin-13 and Interleukin-4 are type-II cytokines signalling through the shared type II Interleukin-4 receptor. As a result of their structural similarity, Interleukin-13 and Interleukin-4 have overlapping functions in the mediation of type-II-driven diseases and are, therefore, promising targets of biologic drugs currently in development for the treatment of such diseases, including asthma and atopic dermatitis. This systematic review was conducted to assess preclinical evidence of potential safety concerns related to blockade of Interleukin-13 alone or Interleukin-13 and Interleukin-4 in combination. We specifically examined risks related to infection, malignancy and the cardiovascular system. We systematically searched the BIOSIS, MEDLINE and EMBASE databases to identify preclinical studies published between January 2006 and October 2016 that addressed the effects of Interleukin-13/Interleukin-4 blockade and modulation on the risk of infection, malignancy and cardiovascular events. To provide a clinical context, we also performed a search for clinical trials targeting the Interleukin-13/Interleukin-4 pathways. Relevant data from preclinical and clinical trials were abstracted and presented descriptively. Aside from expected evidence that inhibition of Interleukin-13 and Interleukin-4 impaired host responses to helminth infections, we did not identify other preclinical evidence suggesting safety risks relating to infection, malignancy or cardiovascular events. We found no evidence in clinical trials suggesting serious safety concerns, i.e. increased risk for infections, malignancy or cardiovascular events from therapeutic modulation of the Interleukin-13 pathway alone or the combined Interleukin-13/Interleukin-4 pathways. Although our findings are reassuring, long-term safety assessments of biologics that target the Interleukin-13/Interleukin-4 pathways currently in clinical development are needed.
Walter Sebald - One of the best experts on this subject based on the ideXlab platform.
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Enzymatic deglutathionylation to generate Interleukin-4 cysteine muteins with free thiol.
Bioconjugate chemistry, 2012Co-Authors: Viswanadham Duppatla, Maja Gjorgjevikj, Werner Schmitz, Mathias Kottmair, Thomas D. Mueller, Walter SebaldAbstract:Interleukin-4 (IL-4) is a prototypical regulator protein of the immune system that is crucial for the pathogenesis and maintenance of asthma and other atopic diseases. It, together with IL-13, uses...
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The Interleukin-4-Receptor: From Recognition Mechanism to Pharmacological Target Structure.
Angewandte Chemie (International ed. in English), 2000Co-Authors: Peter Reinemer, Walter Sebald, Albert DuschlAbstract:Organic synthesis of hormone derivatives is an established route to yield pharmacologically active agents. Until recently this has only been feasible for small organic compounds, but nowadays it is also possible to produce antagonists for larger protein hormones. In particular, the Interleukin-4-receptor was a well-suited target for this approach since it plays a pivotal role in the release and progression of allergic diseases. Accordingly, a strong interest and a high medical need is associated with the development of inhibitors. The structural elucidation of the ligand/receptor complex and an improved understanding of the mechanisms concerning receptor binding and activation allow for the rational design of variants that inhibit Interleukin-4. Since it is possible to specifically inhibit the Interleukin-4-receptor system in this way, a completely new approach to the development of new drugs against allergy and asthma has been established.
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Global and Local Determinants for the Kinetics of Interleukin‐4/Interleukin‐4 Receptor α Chain Interaction
European journal of biochemistry, 1996Co-Authors: Bojiang Shen, Thorsten Hage, Walter SebaldAbstract:An engineered Interleukin-4-binding protein (IL4-BP) representing the extracellular domain of the human Interleukin-4 (IL-4) receptor α chain was expressed in Sf9 cells. The purified IL4-BP was immobilized via a single biotinylated SH group near the carboxyl end to a biosensor matrix and analysed in real time for interaction with IL-4 and IL-4 variants. IL-4 was bound to IL4-BP at a molar ratio of approximately 1:1. The association and dissociation at pH 7.4 and 150 mM NaCl had rate constants of 1.9 ± 0.3 × 107 M−1 s−1 and 2 ± 1 × 10−3 s−1, respectively. Glycosylation and engineered amino acid substitutions of IL4-BP did not alter the kinetic constants as shown by a parallel analysis of IL4-BP variants produced in Escherichia coli or Chinese hamster ovary cells. The rate of association was only slighly affected in binding-deficient variants [E9QJIL-4 and [R88Q]IL-4 and by acidic pH down to values of 4.5, but it was reduced up to fivefold at higher ionic strength. The rate of dissociation was increased 70-fold and 150-fold with the IL-4 variants and fivefold at an acidic pH of 4.5, but it was not affected by high ionic strength. Temperatures between 6°C and 37°C yielded similar rates of IL-4 dissociation and only a marginally reduced rate of IL-4 association at 6°C. These results indicate that the high-affinity binding of IL-4 to its receptor (Kd≈100 pM) is mainly the result of an unusually high association rate. The IL-4/IL4-BP interaction appears to be dominated by charge effects. The exceedingly high rate of IL–4/IL4-BP association is augmented by the overall electrostatic potentials of both proteins (electrostatic steering). Localized charges and the formation of ion pairs may control the rate of complex dissociation.
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Design of human Interleukin-4 antagonists inhibiting Interleukin-4-dependent and Interleukin-13-dependent responses in T-cells and B-cells with high efficiency
European journal of biochemistry, 1994Co-Authors: Hans Peter Tony, Bojiang Shen, Petra Reusch, Walter SebaldAbstract:Human Interleukin-4 possesses two distinct sites for receptor activation. A signalling site, comprising residues near the C-terminus on helix D, determines the efficacy of Interleukin-4 signal transduction without affecting the binding to the Interleukin-4 receptor alpha subunit. A complete antagonist and a series of low-efficacy agonist variants of human Interleukin-4 could be generated by introducing combinations of two or three negatively charged aspartic acid residues in this site at positions 121, 124, and 125. One of the double variants, designated [R121D,Y124D]Interleukin-4, with replacements of both Arg121 and Tyr124 by aspartic acid residues was completely inactive in all analysed cellular responses. The loss of efficacy in [R121D,Y124D]Interleukin-4 is estimated to be larger than 2000-fold. Variant [R121D,Y124D]Interleukin-4 was also a perfect antagonist for inhibition of Interleukin-13-dependent responses in B-cells and the TF-1 cell line with a Ki value of approximately 100 pM. In addition, inhibition of both Interleukin-4-induced and Interleukin-13-induced responses could be obtained by monoclonal antibody X2/45 raised against Interleukin-4Rex, the extracellular domain of the Interleukin-4 receptor alpha subunit. These results indicate that efficient Interleukin-4 antagonists can be designed on the basis of a sequential two-step activation model. In addition, the experiments indicate the functional participation of the Interleukin-4 receptor alpha subunit in the Interleukin-13 receptor system.
Martin Braddock - One of the best experts on this subject based on the ideXlab platform.
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Potential Risks Related to Modulating Interleukin-13 and Interleukin-4 Signalling: A Systematic Review
Drug Safety, 2018Co-Authors: Martin Braddock, Gene Colice, Amir Sharafkhaneh, Nicola A. Hanania, Mats CarlssonAbstract:Introduction Interleukin-13 and Interleukin-4 are type-II cytokines signalling through the shared type II Interleukin-4 receptor. As a result of their structural similarity, Interleukin-13 and Interleukin-4 have overlapping functions in the mediation of type-II-driven diseases and are, therefore, promising targets of biologic drugs currently in development for the treatment of such diseases, including asthma and atopic dermatitis. Objective This systematic review was conducted to assess preclinical evidence of potential safety concerns related to blockade of Interleukin-13 alone or Interleukin-13 and Interleukin-4 in combination. Methods We specifically examined risks related to infection, malignancy and the cardiovascular system. We systematically searched the BIOSIS, MEDLINE and EMBASE databases to identify preclinical studies published between January 2006 and October 2016 that addressed the effects of Interleukin-13/Interleukin-4 blockade and modulation on the risk of infection, malignancy and cardiovascular events. To provide a clinical context, we also performed a search for clinical trials targeting the Interleukin-13/Interleukin-4 pathways. Relevant data from preclinical and clinical trials were abstracted and presented descriptively. Results Aside from expected evidence that inhibition of Interleukin-13 and Interleukin-4 impaired host responses to helminth infections, we did not identify other preclinical evidence suggesting safety risks relating to infection, malignancy or cardiovascular events. We found no evidence in clinical trials suggesting serious safety concerns, i.e. increased risk for infections, malignancy or cardiovascular events from therapeutic modulation of the Interleukin-13 pathway alone or the combined Interleukin-13/Interleukin-4 pathways. Conclusions Although our findings are reassuring, long-term safety assessments of biologics that target the Interleukin-13/Interleukin-4 pathways currently in clinical development are needed.
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Potential Risks Related to Modulating Interleukin-13 and Interleukin-4 Signalling: A Systematic Review.
Drug Safety, 2018Co-Authors: Martin Braddock, Gene Colice, Amir Sharafkhaneh, Nicola A. Hanania, Mats CarlssonAbstract:Interleukin-13 and Interleukin-4 are type-II cytokines signalling through the shared type II Interleukin-4 receptor. As a result of their structural similarity, Interleukin-13 and Interleukin-4 have overlapping functions in the mediation of type-II-driven diseases and are, therefore, promising targets of biologic drugs currently in development for the treatment of such diseases, including asthma and atopic dermatitis. This systematic review was conducted to assess preclinical evidence of potential safety concerns related to blockade of Interleukin-13 alone or Interleukin-13 and Interleukin-4 in combination. We specifically examined risks related to infection, malignancy and the cardiovascular system. We systematically searched the BIOSIS, MEDLINE and EMBASE databases to identify preclinical studies published between January 2006 and October 2016 that addressed the effects of Interleukin-13/Interleukin-4 blockade and modulation on the risk of infection, malignancy and cardiovascular events. To provide a clinical context, we also performed a search for clinical trials targeting the Interleukin-13/Interleukin-4 pathways. Relevant data from preclinical and clinical trials were abstracted and presented descriptively. Aside from expected evidence that inhibition of Interleukin-13 and Interleukin-4 impaired host responses to helminth infections, we did not identify other preclinical evidence suggesting safety risks relating to infection, malignancy or cardiovascular events. We found no evidence in clinical trials suggesting serious safety concerns, i.e. increased risk for infections, malignancy or cardiovascular events from therapeutic modulation of the Interleukin-13 pathway alone or the combined Interleukin-13/Interleukin-4 pathways. Although our findings are reassuring, long-term safety assessments of biologics that target the Interleukin-13/Interleukin-4 pathways currently in clinical development are needed.
Susan R. Ross - One of the best experts on this subject based on the ideXlab platform.
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Interleukin-4 Up-Regulates Mouse Mammary Tumor Virus Expression yet Is Not Required for In Vivo Virus Spread
Journal of virology, 2001Co-Authors: Jennifer Czarneski, Jennifer L. Meyers, Tao Peng, Valsamma Abraham, Rosemarie Mick, Susan R. RossAbstract:The mouse mammary tumor virus (MMTV) superantigen induces T-cell production of cytokines, such as Interleukin-4, which in turn increase MMTV transcription. However, Interleukin-4 is not required for in vivo virus spread, because mice lacking Interleukin-4 or the STAT6 transcription factor showed wild-type infection of lymphoid and mammary tissue. In spite of this, mammary tumor incidence was decreased in STAT6 null mice.
Jürgen Kraus - One of the best experts on this subject based on the ideXlab platform.
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μ opioid receptor agonist-selective regulation of Interleukin-4 in T lymphocytes.
Journal of neuroimmunology, 2013Co-Authors: Christine Börner, Sara Lanciotti, Thomas Koch, Volker Höllt, Jürgen KrausAbstract:Opioids are irreplaceable for the treatment of severe pain. However, opioid-induced immunomodulation affects therapies. Here we report that treatment of human T lymphocytes with the opioids fentanyl, methadone, loperamide and beta-endorphin resulted in a strong induction of the cytokine Interleukin-4. In contrast, morphine and buprenorphine induced markedly and significantly lower levels of Interleukin-4 mRNA and protein. These findings suggest agonist-biased μ opioid receptor signaling in T cells. In the future, better knowledge about agonist-specific immunomodulatory effects of opioids offers the possibility to select drugs for a therapy with more favorable and/or less detrimental side effects in immune cells.
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Mu opioid receptor agonist-selective regulation of Interleukin-4 in T lymphocytes
Journal of Neuroimmunology, 2013Co-Authors: Christine Börner, Sara Lanciotti, Thomas Koch, Volker Höllt, Jürgen KrausAbstract:Opioids are irreplaceable for the treatment of severe pain. However, opioid-induced immunomodulation affects therapies. Here we report that treatment of human T lymphocytes with the opioids fentanyl, methadone, loperamide and beta-endorphin resulted in a strong induction of the cytokine Interleukin-4. In contrast, morphine and buprenorphine induced markedly and significantly lower levels of Interleukin-4 mRNA and protein. These findings suggest agonist-biased μ opioid receptor signaling in T cells. In the future, better knowledge about agonist-specific immunomodulatory effects of opioids offers the possibility to select drugs for a therapy with more favorable and/or less detrimental side effects in immune cells.