Protein Engineering & Pharmacology, ProtAffin Biotechnologie AG, Graz
Glycosaminoglycans (GAGs) are a class of highly negatively charged, unbranched, O-linked polysaccharides which are involved in many diseases. Their role as protein binding matrix on cell surfaces has long been recognized but therapeutic approaches to interfere with protein-GAG interactions have been limited due to the complex chemistry of GAGs on the one hand and due to the lack of specific antibodies against GAGs on the other hand. We have developed a protein engineering platform (the so-called CellJammer® technology) which enables us to introduce higher GAG binding affinity into natural GAG-binding proteins. In combination with impaired biological, receptor binding function we obtained the first high-affinity and selective GAG antagonists. Chemokines are amongst the prototypic GAG-binding proteins and here we present selected results of our CellJammer® technology applied to several of these pro-inflammatory proteins. An overview is given on our lead decoy protein PA401 which is a CXCL8-based mutant protein with increased GAG-binding affinity and knocked-out CXCR1/2 binding and activation. Major results from our CCL2 and CCL5 programs are also summarized and an outlook to potential future application is made.
