Il-37 variants

Abstract

This invention relates to polypeptides, including variants of interleukin-37 (IL-37), and related therapeutics and compositions. The invention also relates to the use of the polypeptides and compositions in methods of treating inflammatory diseases or conditions. The present invention provides a monomeric anti-inflammatory polypeptide comprising an amino acid sequence of an IL-37 monomer, the amino acid sequence having a mutation or modification for preventing the anti-inflammatory peptide from forming a homodimer.

1 - 35 . (canceled) 
     
     
         36 . A method of inhibiting or preventing inflammation in a subject in need thereof, the method comprising administering to the subject, a therapeutically effective amount of a polypeptide comprising the amino acid sequence of an IL-37 polypeptide,
 wherein the polypeptide comprises an amino acid sequence having a mutation or modification that reduces the capacity of the polypeptide to form a dimer compared to a polypeptide comprising the amino acid sequence of SEQ ID NO: 1 or compared to a polypeptide comprising the amino acid sequence of SEQ ID NO: 1 and a truncation of residues 1 to 20 or 1 to 45 thereof;   wherein the amino acid sequence of the polypeptide has at least 70% identity with the amino acid sequence of SEQ ID NO: 1 and the mutation or modification is at any one or more residues, or residues equivalent to, 71 to 74, 78, 80, 83 to 88 and 184 in SEQ ID NO: 1;   thereby inhibiting or preventing inflammation in the subject.   
     
     
         37 . The method of  claim 36 , wherein the inflammation is associated with an inflammatory disease or condition, and the method thereby treats or prevents an inflammatory disease or condition in the subject. 
     
     
         38 . The method of  claim 36 , wherein the mutation prevents the anti-inflammatory polypeptide from forming a dimerization interface that enables dimerization of IL-37 monomers. 
     
     
         39 . The method of  claim 36 , wherein the mutation is located in a region of the anti-inflammatory polypeptide that has the same amino acid sequence as the amino acid sequence that forms the dimerization interface of an IL-37 monomer. 
     
     
         40 . The method of  claim 36 , wherein the mutation is located in the loop between the β3 and β4 strands that form the dimerization interface of an IL-37 monomer. 
     
     
         41 . The method of  claim 36 , wherein the mutation or modification occurs at a residue at a position, or at a position equivalent to, D73, K83, N84, Y85, I86, R87 or P88 in SEQ ID NO: 1. 
     
     
         42 . The method of  claim 36 , wherein the amino acid residue at, or equivalent to:
 position 71 in SEQ ID NO: 1 is not a Val;   position 72 in SEQ ID NO: 1 is not an Leu;   position 73 in SEQ ID NO: 1 is not a Asp;   position 74 in SEQ ID NO: 1 is not a Ser;   position 78 in SEQ ID NO: 1 is not an Ile;   position 80 in SEQ ID NO: 1 is not a Val;   position 83 in SEQ ID NO: 1 is not a Lys;   position 84 in SEQ ID NO: 1 is not an Asn;   position 85 in SEQ ID NO: 1 is not a Tyr;   position 86 in SEQ ID NO: 1 is not an Ile;   position 87 in SEQ ID NO: 1 is not an Arg;   position 88 in SEQ ID NO: 1 is not a Pro; and/or   position 184 in SEQ ID NO: 1 is not an Asn.   
     
     
         43 . The method of  claim 36 , wherein the mutation is a replacement with a non-conservative amino acid or wherein the mutation is a replacement with alanine or an amino acid with an opposite charge. 
     
     
         44 . The method of  claim 36 , wherein the polypeptide has an amino acid sequence having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence of SEQ ID NO: 1. 
     
     
         45 . The method of  claim 36 , wherein the mutation is D73A. 
     
     
         46 . The method of  claim 36 , wherein the mutation is D73K. 
     
     
         47 . The method of  claim 36 , wherein the mutation is K83E. 
     
     
         48 . The method of  claim 36 , wherein the mutation is Y85A. 
     
     
         49 . The method of  claim 36 , wherein one or more residues at a position, or position equivalent to, residues 83 to 88 of SEQ ID NO: 1 is deleted. 
     
     
         50 . The method of  claim 36 , wherein the polypeptide has an N terminal truncation of, or equivalent to, residues 1 to 20 or 1 to 45. 
     
     
         51 . The method of  claim 36 , wherein the inflammation is associated with or caused by an inflammatory disease predominantly mediated by activation of TLR2 or TLR4. 
     
     
         52 . The method of  claim 36 , wherein the inflammation is associated with or caused by an inflammatory disease predominantly mediated by activation of TLR7, 8 or 9. 
     
     
         53 . The method of  claim 36 , wherein the inflammation is associated with or caused by an inflammatory disease that is an autoimmune disease. 
     
     
         54 . The method of  claim 36 , wherein the inflammation is associated with or caused by endotoxic shock. 
     
     
         55 . The method of  claim 36 , wherein the inflammation is associated or caused by endotoxic shock caused by bacteria.