Soluble cd33 for treating myelodysplastic syndromes (mds)

Abstract

Disclosed are compositions and methods for treating disease or condition caused or exacerbated by S100A9 activity, such as myelodysplastic syndromes (MDS) using a composition comprising an effective amount of a CD33/S100A9 inhibitor.

What is claimed is: 
     
         1 . A recombinant fusion protein, comprising:
 (a) at least two S100A9-binding moieties selected from the group consisting of an extracellular domain of human CD33, an extracellular domain of toll like receptor 4 (TLR4), and an extracellular domain of Receptor for Advanced Glycation End Products (RAGE); and   (b) an immunoglobulin Fc region.   
     
     
         2 . The fusion protein of  claim 1 , comprising a formula selected from the group consisting of:
 eCD33-eTLR4-Fc,   eCD33-eRAGE-Fc,   eTLR4-eRAGE-Fc,   eRAGE-eTLR4-Fe,   eCD33-eTLR4-eRAGE-Fe,   eCD33-eRAGE-eTLR4-Fe,   eTLR4-eCD33-eRAGE-Fe,   eRAGE-eCD33-eTLR4-Fc,   eTLR4-eRAGE-eCD33-Fc, and   eRAGE-eTLR4-eCD33-Fc,   wherein “eCD33” comprises the extracellular domain of human CD33,   wherein “eTLR4” comprises the extracellular domain of TLR4,   wherein “eRAGE” comprises the extracellular domain of RAGE,   wherein “Fe” comprises the immunoglobulin Fe region, and   wherein “−” consists of a peptide linker or a peptide bond.   
     
     
         3 . The fusion protein of  claim 1  or  2 , further comprising a biotin acceptor peptide that can be biotinylated with biotin ligase (BirA) in the presence of biotin and ATP. 
     
     
         4 . A recombinant fusion protein, comprising:
 (a) an S100A9-binding moiety selected from the group consisting of an extracellular domain of human CD33, an extracellular domain of toll like receptor 4 (TLR4), and an extracellular domain of Receptor for Advanced Glycation End Products (RAGE);   (b) a biotin acceptor peptide that can be biotinylated with biotin ligase (BirA) in the presence of biotin and ATP; and   (c) an immunoglobulin Fc region.   
     
     
         5 . The fusion protein of  claim 4 , comprising a formula selected from the group consisting of:
 eCD33-Fc-Avi,   eTLR4-Fc-Avi,   eRAGE-Fc-Avi,   eCD33-eTLR4-Fc-Avi,   eCD33-eRAGE-Fc-Avi,   eTLR4-eRAGE-Fc-Avi,   eRAGE-eTLR4-Fc-Avi,   eCD33-eTLR4-eRAGE-Fc-Avi,   eCD33-eRAGE-eTLR4-Fc-Avi,   eTLR4-eCD33-eRAGE-Fc-Avi,   eRAGE-eCD33-eTLR4-Fc-Avi,   eTLR4-eRAGE-eCD33-Fe-Avi, and   eRAGE-eTLR4-eCD33-Fc-Avi   wherein “eCD33” comprises the extracellular domain of human CD33,   wherein “eTLR4” comprises the extracellular domain of TLR4,   wherein “eRAGE” comprises the extracellular domain of RAGE,   wherein “Fe” comprises the immunoglobulin Fe region,   wherein “Avi” comprises an optional biotin acceptor peptide that can be biotinylated with biotin ligase (BirA) in the presence of biotin and ATP, and   wherein “−” consists of a peptide linker or a peptide bond.   
     
     
         6 . The fusion protein of any one of  claims 3  to  5 , wherein the biotin acceptor peptide comprises the amino acid sequence SEQ ID NO:7, or an amino acid sequence having at least 90% identity to SEQ ID NO:7. 
     
     
         7 . The fusion protein of any one of  claims 1  to  6 , wherein the extracellular domain of human CD33 comprises only the variable region. 
     
     
         8 . A recombinant fusion protein, consisting essentially of:
 (a) the variable extracellular domain of human CD33; and   (b) an immunoglobulin Fc region.   
     
     
         9 . The fusion protein of any one of  claims 1  to  8 , wherein the extracellular domain of human CD33 comprises the amino acid sequence SEQ ID NO:1, or an amino acid sequence having at least 90% identity to SEQ ID NO:1. 
     
     
         10 . The fusion protein of  claim 9 , wherein the extracellular domain of human CD33 comprises the amino acid sequence SEQ ID NO:2. 
     
     
         11 . The fusion protein of any one of  claims 7  to  8 , wherein the variable region of human CD33 comprises the amino acid sequence SEQ ID NO:3, or an amino acid sequence having at least 90% identity to SEQ ID NO:3. 
     
     
         12 . The fusion protein of  claim 11 , wherein the variable region of human CD33 comprises the amino acid sequence SEQ ID NO:4. 
     
     
         13 . The fusion protein of any one of  claims 1  to  12 , wherein the extracellular domain of human TLR4 comprises the amino acid sequence SEQ ID NO:5, or an amino acid sequence having at least 90% identity to SEQ ID NO:5. 
     
     
         14 . The fusion protein of any one of  claims 1  to  13 , wherein the extracellular domain of RAGE comprises the amino acid sequence SEQ ID NO:6, or an amino acid sequence having at least 90% identity to SEQ ID NO:6. 
     
     
         15 . A multimeric complex comprising two or more fusion proteins of any one of  claims 1  to  14  conjugated to a core molecule or particle. 
     
     
         16 . The multimeric complex of  claim 15 , wherein the core molecule is streptavidin, wherein the two or more fusion proteins are biotinylated. 
     
     
         17 . The multimeric complex of  claim 15 , wherein the core molecule is a liposome comprising antibodies that specifically bind the two or more fusion proteins. 
     
     
         18 . The multimeric complex of  claim 17 , wherein the antibodies specifically bind the biotin acceptor peptide. 
     
     
         19 . The multimeric complex of any one of  claims 15  to  18 , comprising from 2 to 5 fusion proteins conjugated to the core molecule or particle. 
     
     
         20 . A method for treating a disease or condition caused or exacerbated by S100A9 activity, comprising administering to a subject in need thereof a composition comprising the fusion protein of any one of  claims 1  to  18  or the multimeric complex of any one of  claims 15  to  19 . 
     
     
         21 . The method of  claim 20 , wherein the method comprises treating an infection, sepsis, or a combination thereof in the patient. 
     
     
         22 . The method of  claim 20 , wherein the method comprises treating an autoimmune disease in the patient. 
     
     
         23 . The method of  claim 20 , wherein the method comprises treating rheumatoid arthritis in the patient. 
     
     
         24 . The method of  claim 20 , wherein the method comprises treating a cancer in the patient. 
     
     
         25 . The method of  claim 20 , wherein the method comprises treating a myelodysplastic syndrome (MDS) in the subject. 
     
     
         26 . A method for treating myelodysplastic syndrome (MDS) in a subject, comprising administering to the subject a therapeutically effective amount of a composition comprising a soluble CD33 fusion protein that binds and sequesters S100A9. 
     
     
         27 . A method for identifying an agent for treating myelodysplastic syndromes (MDS), comprising screening candidate agents for the ability to prevent S100A9 binding to CD33.