Molecular complexes which modify immune responses

Abstract

Extracellular domains of transmembrane heterodimeric proteins, particularly T cell receptor and major histocompatibility complex proteins, can be covalently linked to the heavy and light chains of immunoglobulin molecules to provide soluble multivalent molecular complexes with high affinity for their cognate ligands. The molecular complexes can be used, inter alia, to detect and regulate antigen-specific T cells and as therapeutic agents for treating disorders involving immune system regulation, such as allergies, autoimmune diseases, tumors, infections, and transplant rejection.

1 . A method for treating a patient, comprising
 administering to the patient a molecular complex, wherein the molecular complex comprises at least four fusion proteins, wherein:
 (a) two first fusion proteins comprise
 (i) an immunoglobulin heavy chain, wherein the immunoglobulin heavy chain comprises a variable region, and 
 (ii) an extracellular domain of a first transmembrane polypeptide; and 
 
 (b) two second fusion proteins comprise
 (i) an immunoglobulin light chain and 
 (ii) an extracellular domain of a second transmembrane polypeptide, 
 
   
       wherein the fusion proteins associate to form the molecular complex, wherein the molecular complex comprises two ligand binding sites, each ligand binding site formed by the extracellular domains of the first and second transmembrane polypeptides, wherein each ligand binding site is bound to an antigenic peptide, wherein the patient is selected from the group consisting of:
 (1) a patient suffering from an allergy, wherein the antigenic peptide is an antigen to which the patient has an allergic response; 
 (2) a patient who has received or will receive an organ transplant, wherein the antigenic peptide is an alloantigen; 
 (3) a patient suffering from an autoimmune disease, wherein the antigenic peptide is an antigen to which the patient expresses an autoimmune response; and 
 (4) a patient having an infection caused by an infectious agent, wherein the antigenic peptide is a peptide of the infectious agent. 
 
     
     
         2 . A method of labeling antigen-specific T cells, comprising:
 contacting a sample which comprises antigen-specific T cells with a molecular complex, wherein the molecular complex comprises at least four fusion proteins, wherein:   (a) two first fusion proteins comprise
 (i) an immunoglobulin heavy chain, wherein the immunoglobulin heavy chain comprises a variable region, and 
 (ii) an extracellular domain of a first transmembrane polypeptide; and 
   (b) two second fusion proteins comprise
 (i) an immunoglobulin light chain and 
 (ii) an extracellular domain of a second transmembrane polypeptide, 
   
       wherein the fusion proteins associate to form the molecular complex, wherein the molecular complex comprises two ligand binding sites, each ligand binding site formed by the extracellular domains of the first and second transmembrane polypeptides, wherein each ligand binding site is bound to an identical antigenic peptide, whereby the antigenic peptide specifically binds to the antigen-specific T cells, thereby labeling the cells with the molecular complex. 
     
     
         3 . A method of activating antigen-specific T cells, comprising:
 contacting a sample which comprises antigen-specific T cells with a molecular complex, wherein the molecular complex comprises at least four fusion proteins, wherein:   (a) two first fusion proteins comprise
 (i) an immunoglobulin heavy chain, wherein the immunoglobulin heavy chain comprises a variable region, and 
 (ii) an extracellular domain of a first transmembrane polypeptide; and 
   (b) two second fusion proteins comprise
 (i) an immunoglobulin light chain and 
 (ii) an extracellular domain of a second transmembrane polypeptide, 
   
       wherein the fusion proteins associate to form the molecular complex, wherein the molecular complex comprises two ligand binding sites, each ligand binding site formed by the extracellular domains of the first and second transmembrane polypeptides, wherein each ligand binding site is bound to an antigenic peptide, whereby the antigenic peptide specifically binds to and activates the antigen-specific T cells.