Targeted immunostimulation with bispecific reagents

Abstract

Disclosed are methods of stimulating in a subject an immune response to an antigen to which the immune response is targeted. This method includes the step of administering to the subject a binding agent which binds a surface receptor of an antigen-presenting cell, in some instances without being blocked substantially by the natural ligand for the surface receptor, and an antigen to which the immune response is targeted, in a physiologically acceptable medium to the subject. Also disclosed are molecular complexes including the binding agent coupled to an antigen.

1 . A method of stimulating an immune response in a subject to an antigen, comprising the step of administering a binding agent, which binds a surface receptor of an antigen-presenting cell, and an antigen, to which the immune response is targeted, in a pharmacologically acceptable medium to the subject, whereby the antigen is targeted to the receptor of the antigen-presenting cell.  
     
     
         2 . The method of  claim 1  wherein the binding agent binds the surface receptor of the antigen-presenting cell without being blocked substantially by the natural ligand for the surface receptor.  
     
     
         3 . The method of  claim 1 , wherein the antigen is coupled to the binding agent.  
     
     
         4 . The method of  claim 1 , wherein the binding agent is an antibody, or fragment thereof comprising at least one complementarity determining region.  
     
     
         5 . The method of  claim 1 , wherein the binding agent is bispecific, having a binding affinity for the receptor and for the antigen.  
     
     
         6 . The method of  claim 4 , wherein the bispecific binding agent is selected from the group consisting of heteroantibodies, bispecific antibodies, and bispecific molecules.  
     
     
         7 . The method of  claim 1 , wherein the antigen is selected from the group consisting of viral, bacterial, parasite, allergen, venom, and tumor-associated antigens.  
     
     
         8 . The method of  claim 7 , wherein the antigen is derived from hepatitis virus.  
     
     
         9 . The method of  claim 7 , wherein the antigen is an HIV antigen.  
     
     
         10 . The method of  claim 1 , wherein the surface receptor is selected from the group consisting of FcγRI, FcγRII, and FcγRIII.  
     
     
         11 . The method of  claim 1 , wherein the antigen-presenting cell is a macrophage.  
     
     
         12 . The method of  claim 1  wherein the administering step comprises administering the binding agent and the antigen as a molecular complex, 
 the binding agent being a bispecific antibody, heteroantibody, or bispecific molecule including: 
 (i) a first antibody, or fragment thereof, which specifically binds the Fc receptor for immunoglobulin G (IgG) on the macrophage surface without being blocked substantially by IgG; and  
 (ii) a second antibody, or fragment thereof, which specifically binds the antigen.  
 
 
     
     
         13 . The method of  claim 12 , wherein the heteroantibody comprises an Fab-Fab conjugate.  
     
     
         14 . A method of treating hepatitis B infection comprising administering to an individual infected with the virus a molecular complex comprising: 
 (a) a hepatitis B surface antigen, or surface-exposed portion thereof; and    (b) an Fab-Fab heteroantibody, wherein the first Fab binds the high affinity Fc receptor for immunoglobulin G without being blocked substantially by IgG, and the second Fab binds the antigen.    
     
     
         15 . A molecular complex comprising: 
 (a) an antigen; complexed to    (b) a binding agent which binds a surface receptor of an antigen-presenting cell.    
     
     
         16 . The molecular complex of  claim 15  wherein the binding agent binds a surface receptor of an antigen-presenting cell without being blocked substantially by the natural ligand for the receptor.  
     
     
         17 . The molecular complex of  claim 15 , wherein the binding agent is selected from the group consisting of a monoclonal antibody, a heteroantibody, a bispecific antibody, and a bispecific molecule.  
     
     
         18 . The molecular complex of  claim 15  wherein the binding agent is chemically coupled to the antigen.  
     
     
         19 . The molecular complex of  claim 15  wherein the binding agent is peptide-linked to the antigen, the molecular complex produced by recombinant DNA techniques.  
     
     
         20 . The molecular complex of  claim 15 , wherein the antigen is selected from the group consisting of viral, bacterial, parasite, allergen, venom, and tumor-associated antigens.  
     
     
         21 . The molecular complex of  claim 20 , wherein the antigen is a hepatitis antigen.  
     
     
         22 . The molecular complex of  claim 20 , wherein the antigen is an HIV antigen.  
     
     
         23 . The molecular complex of  claim 20 , wherein the antigen is selected from the group consisting of bee venom, pollen, and dust mite antigen.  
     
     
         24 . The molecular complex of  claim 15 , wherein the antigen-presenting cell is a macrophage.  
     
     
         25 . The molecular complex of  claim 15 , wherein the surface receptor is a receptor on a macrophage selected from the group consisting of FcγRI, FcγRII, and FcγRIII.  
     
     
         26 . The molecular complex of  claim 25 , wherein the surface receptor is the high affinity FcγRI for immunoglobulin G on a macrophage.  
     
     
         27 . The molecular complex of  claim 20  wherein the antigen comprises an allergen which binds to IgE on mast cells and basophils, thereby causing a type I hypersensitivity reaction, and the bispecific binding agent is a heteroantibody that binds the high affinity Fc receptor without being blocked by IgG binding to the receptor.  
     
     
         28 . The molecular complex of  claim 15  wherein the binding agent comprises an antibody fragment including at least one complementarity determining region  
     
     
         29 . The method of  claim 28  wherein the antibody fragment is selected from the group consisting of Fab, Fab′, and Fv fragments.  
     
     
         30 . The molecular complex of  claim 28  wherein the binding agent comprises an Fab-Fab heteroantibody, the first Fab binding the Fcγ receptor for immunoglobulin G (IgG) without being blocked by IgG, and the second Fab binding the antigen.  
     
     
         31 . The molecular complex of  claim 30  wherein the first Fab binds the FcγRI.  
     
     
         32 . A vaccine composition comprising the molecular complex of  claim 15  in a pharmaceutically acceptable medium.  
     
     
         33 . A binding agent specific for an Fcγ receptor, incorporated into a carrier for targeting antigen to an FcγR-expressing cell, the carrier including the antigen.  
     
     
         34 . The binding agent of  claim 33 , wherein the carrier is a liposome having an inner layer and an outer layer and containing an antigen within the liposome, the binding agent being incorporated into the outer layer of the liposome.  
     
     
         35 . The binding agent of  claim 33  which is an anti-Fc receptor antibody selected from the group consisting of an anti-FcγRI antibody, an FcγRII antibody, and an FcγRIII antibody.  
     
     
         36 . The binding agent of  claim 35  comprising an anti-FcγRI antibody.  
     
     
         37 . The binding agent of  claim 33  wherein the carrier contains an antigen selected from the group consisting of viral, bacterial, parasite, allergen, venom, and tumor-associated antigens.  
     
     
         38 . A bispecific antibody that is reactive with a surface receptor selected from the group consisting of FcγRI, FcγRII, and FcγRIII.  
     
     
         39 . A method of depleting antigen in the circulation of a subject comprising the step of administering to the subject the bispecific antibody of  claim 38  in a pharmacologically acceptable medium.  
     
     
         40 . A method of decreasing hypersensitivity in a subject comprising the step of administering a molecular complex in a pharmacologically acceptable medium to the circulation of a patient in an amount sufficient to induce an immune response in the subject, the complex comprising: 
 (i) an allergen which binds to IgE on mast cells and basophils, thereby causing a type I hypersensitivity reactions; complexed to    (ii) a binding agent selected from the group consisting of a heteroantibody, bispecific antibody, and monoclonal antibody, the binding agent binding the high affinity Fc receptor without being blocked by IgG binding to the receptor.