Compounds, compositions and methods for the endocytic presentation of immunosuppressive factors

Abstract

Immunomodulating agents comprising at least one Fc receptor ligand and at least one immunosuppressive factor are provided as are methods for their manufacture and use. The immunomodulating agents may be in the form of polypeptides or chimeric antibodies and preferably incorporate an immunosuppressive factor comprising a T cell receptor antagonist. The compounds and compositions of the, invention may be used to selectively suppress the immune system to treat symptoms associated with immune disorders such as allergies, transplanted tissue rejection and autoimmune disorders including lupus, rheumatoid arthritis and multiple sclerosis.

1 . A method for treating an autoimmune disorder comprising: 
 administering to a patient suffering from an autoimmune disorder a therapeutically effective amount of an immunoglobulin or portion thereof linked to a protein fragment or peptide comprising a composition selected from the group consisting of a T cell receptor antagonist or a T cell receptor agonist, wherein said T cell receptor antagonist or T cell receptor agonist is positioned within at least one complementarity determining region, wherein the immunoglobulin or portion thereof binds to the Fc receptor of the antigen presenting cell and is internalized and processed by the antigen presenting cell so that said T cell receptor antagonist or T cell receptor agonist is presented in association with endogenous MHC Class II molecules of said antigen presenting cell, thereby preventing activation of autoreactive T cells in vivo.    
     
     
         2 . The method of  claim 1  wherein said composition is a T cell receptor antagonist.  
     
     
         3 . The method of  claim 1  wherein said composition is a T cell receptor agonist.  
     
     
         4 . The method of  claim 1  further comprising a pharmaceutically acceptable carrier.  
     
     
         5 . The method of  claim 1  wherein the protein fragment or peptide is derived from proteolipid protein.  
     
     
         6 . The method of  claim 1  wherein the protein fragment or peptide is derived from myelin basic protein.  
     
     
         7 . The method of  claim 1  wherein the T cell receptor antagonist or T cell receptor agonist is located within at least one complementarity determining and partially or fully replaces the complementarity determining region.  
     
     
         8 . The method of  claim 1  wherein the immunoglobulin molecule is human IgG molecule.  
     
     
         9 . The method of  claim 1  wherein the protein fragment or peptide comprising a T cell receptor antagonist is covalently is covalently linked to said immunoglobulin or portion thereof.  
     
     
         10 . A method for treating an autoimmune disorder comprising: 
 administering to a patient suffering from an autoimmune disorder a therapeutically effective amount of an immunomodulating agent linked to a protein fragment or peptide comprising a T cell receptor agonist, wherein the immunomodulating agent is capable of binding to an Fc receptor of an antigen presenting cell wherein the immunomodulating agent or portion thereof is internalized and processed by the antigen presenting cell so that said T cell receptor agonist is presented in association with endogenous MHC Class II molecules of said antigen presenting cell, thereby preventing activation of autoreactive T cells in vivo.    
     
     
         11 . The method of  claim 10  wherein the immunomodulating agent is an immunoglobulin or portion thereof.  
     
     
         12 . The method of  claim 10  wherein the protein fragment or peptide is derived from proteolipid protein.  
     
     
         13 . The method of  claim 10  wherein the protein fragment or peptide is derived from myelin basic protein.  
     
     
         14 . The method of  claim 10  wherein the T cell receptor agonist is located within at least one complementarity determining region and partially or fully replaces the complementarity determining region.  
     
     
         14 . The method of  claim 11  wherein the immunoglobulin molecule is human IgG molecule.  
     
     
         15 . The method of  claim 11  wherein the protein fragment or peptide comprising a T cell receptor antagonist is covalently linked to said immunoglobulin or portion thereof.