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ProtAffin Biotechnologie

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Piccinini A.M.,ProtAffin Biotechnologie | Knebl K.,ProtAffin Biotechnologie | Rek A.,ProtAffin Biotechnologie | Wildner G.,Ludwig Maximilians University of Munich | And 3 more authors.
Journal of Biological Chemistry | Year: 2010

Leukocyte recruitment from the blood into injured tissues during inflammatory diseases is the result of sequential events involving chemokines binding to their GPC receptors as well as to their glycosaminoglycan (GAG) co-receptors. The induction and the crucial role of MCP-1/CCL2 in the course of diseases that feature monocyte-rich infiltrates have been validated in many animal models, and several MCP-1/CCL2 as well as CCR2 antagonists have since been generated. However, despite some of them being shown to be efficacious in a number of animal models, many failed in clinical trials, and therapeutically interfering with the activity of this chemokine is not yet possible. We have therefore generated novel MCP-1/CCL2 mutants with increased GAG binding affinity and knocked out CCR2 activity, which were designed to interrupt the MCP-1/CCL2-related signaling cascade. We provide evidence that our lead mutant MCP-1 (Y13A/S21K/Q23R) exhibits a 4-fold higher affinity toward the natural MCP-1 GAG ligand heparan sulfate and that it shows a complete deficiency in activating CCR2 on THP-1 cells. Furthermore, a significantly longer residual time on GAG ligands was observed by surface plasmon resonance. Finally, we were able to show that MCP-1(Y13A/S21K/Q23R) had a mild ameliorating effect on experimental autoimmune uveitis and that a marginal effect on oral tolerance in the group co-fed with Met-MCP-1 (Y13A/S21K/Q23R) plus immunogenic peptide PDSAg was observed. These results suggest that disrupting wild type chemokine-GAG interactions by a chemokine-based antagonist can result in anti-inflammatory activity that could have potential therapeutic implications. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.


Patent
ProtAffin Biotechnologie | Date: 2010-01-29

Novel mutants of human monocyte chemoattractant protein 1 (MCP-1) with increased glycosaminoglycan (GAG) binding affinity and knocked-out or reduced GPCR activity compared to wild type MCP-1, and their use for therapeutic treatment of inflammatory diseases.


Patent
ProtAffin Biotechnologie | Date: 2011-09-07

A method is provided for introducing a GAG binding site into a protein comprising the steps:- identifying a region in a protein which is not essential for structure maintenance- introducing at least one basic amino acid into said site and/or deleting at least one bulky and/or acidic amino acid in said site,whereby said GAG binding site has a GAG binding affinity of Kd 10M, preferably 1M, still preferred 0.1M, as well as modified GAG binding proteins.


Patent
ProtAffin Biotechnologie | Date: 2011-01-05

A modified human GAG binding protein for use as a GAG antagonist is provided, wherein said protein is modified by substitution, insertion of at least one amino acid in order to increase the relative amount of basic amino acids in said GAG binding region, and/or deletion of at least one amino acid in order to increase the relative amount of basic amino acids, and/or reduce the amount of bulky and/or acidic amino acids in said GAG binding region, in that the GAG binding affinity of said protein is increased compared to the GAG binding affinity of a respective wild-type protein.


Patent
ProtAffin Biotechnologie | Date: 2012-12-17

Novel mutants of human monocyte chemoattractant protein 1 (MCP-1) with increased glycosaminoglycan (GAG) binding affinity and knocked-out or reduced GPCR activity compared to wild type MCP-1, and their use for therapeutic treatment of inflammatory diseases.


Patent
ProtAffin Biotechnologie | Date: 2011-04-20

A method for providing a modified GAG binding growth factor protein is provided, wherein the GAG binding region in said GAG binding growth factor protein is modified by substitution, insertion, and/or deletion of at least one amino acid in order to increase the relative amount of basic amino acids in said GAG binding region, and/or reduce the amount of bulky and/or acidic amino acids in said GAG binding region preferably at a solvent exposed position, so that the GAG binding affinity of said modified GAG binding growth factor is increased compared to the GAG binding affinity of said GAG binding wild-type growth factor.


A novel approach for inhibiting FGF2/FGFR1-mediated signalling is presented which is based on FGFR1 mutations to introduce higher affinity for the natural GAG co-receptors into the soluble part of the FGF1 receptor, preferably into the D2/D3 domains. Such recombinant drugs are expected to disrupt the natural FGF2/FGFR1/GAG triple complex by competing with the wtFGFR1 for GAG binding


Patent
ProtAffin Biotechnologie | Date: 2010-08-18

A method is provided for introducing a GAG binding site into a protein comprising the steps:


Patent
ProtAffin Biotechnologie | Date: 2010-09-13

The present invention provides a composition comprising a modified interleukin 8 (IL-8) having increased GAG binding affinity and further inhibited or down-regulated GPCR activity compared to the respective wild type IL-8 for use in preventing or treating lung inflammation with neutrophilic infiltration, for example for the prevention or treatment of chronic obstructive pulmonary disease, cystic fibrosis, severe asthma, bronchitis, broncheolitis, acute lung injury and acute respiratory distress syndrome.


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