Polymer conjugates of box-a of hmgb1 and box-a variants of hmgb1

Abstract

The present invention relates to novel polymer conjugates of polypeptide variants of the HMGB1 high affinity binding domain Box-A (HMGB1 Box-A) or of a biologically active fragment of HMGB1 Box-A. Further, the invention relates to novel polymer conjugates of polypeptide variants of the HMGB1 high affinity binding domain Box-A (HMGB1 Box-A). Moreover, the present invention concerns the use of said polymer conjugates of polypeptide molecules of HMGB1 Box-A to diagnose, prevent, alleviate and/or treat pathologies associated with extracellular HMGB1 and/or associated with an increased expression of RAGE.

1 . A method of alleviating, and/or treating a pathology selected from the group consisting of HMGB-1 associated pathologies, RAGE-related pathologies, auto immune disease, systemic inflammatory response syndrome, cardiovascular affection, dermatological disease, and neurological disease comprising administering to a patient an effective amount of a polymer conjugate of the human and/or non human wild type HMGB-1 high affinity binding domain Box-A (HMGB1 Box-A), a polypeptide variant of the human and/or non human HMGB-1 Box-A, or of a biologically active fragment of HMGB-1 Box-A, whereby the amino acid sequence of said polypeptide variant differs from the amino acid sequence of the wild type HMGB-1 Box-A by the mutation of one or more single amino acid. 
     
     
         2 . The method of  claim 1 , wherein said cardiovascular affection is ischemia. 
     
     
         3 . The method of  claim 1 , wherein said dermatological disease is psoriasis. 
     
     
         4 . The method of  claim 1 , wherein said HMGB-1 associated pathology is a neurological disease. 
     
     
         5 . The method of  claim 1 , wherein said RAGE-related pathology is diabetes of type I and/or type II. 
     
     
         6 . The method of  claim 1 , wherein said polymer is administered in combination with a further agent capable of inhibiting an early mediator of the inflammatory cytokine cascade, wherein said further agent is an antagonist or inhibitor of a cytokine, an antibody to RAGE, a nucleic acid or nucleic acid analogue capable of inhibiting RAGE expression, a small synthetic molecule antagonist of the HMGB-1 interaction with RAGE or soluble RAGE (sRAGE), the N-terminal lectin-like domain (D1) of native or mutated thrombomodulin, a synthetic double-stranded nucleic acid or nucleic acid analogue molecule with a bent, shape structure, K-252a, a salt or derivative of K-252a, a polymer conjugate of K252a, a derivative of K-252a polymer conjugate, or an inhibitor of the interaction HMGB-1 with at least one Toll-like receptor (TLR). 
     
     
         7 . The method of  claim 6 , wherein said nucleic acid or nucleic acid analogue capable of inhibiting RAGE expression is selected from the group consisting of an antisense molecule, a ribozyme and a RNA interference molecule. 
     
     
         8 . The method of  claim 6 , wherein said synthetic double-stranded nucleic acid or nucleic acid analogue molecule with a bent shape structure is selected from the group consisting of bent and cruciform DNA and PNA.