Virus-like particles for the induction of autoantibodies

Abstract

The invention described herein relates to compositions and methods for stimulating immune responses in vivo against a tolerogen. Novel biotechnological tools, pharmaceuticals, therapeutics and prophylactics, which concern chimeric or conjugated virus-like particles, and methods of use of the foregoing are provided for the study of B cell tolerance and the treatment or prevention of human diseases, which involve the onset of B cell tolerance, such as chronic viral infection, chronic inflammatory disease, and neoplasia.

What is claimed:  
     
         1 . A composition comprising: 
 a support having an ordered assembly of subunits; and    at least one B cell epitope of a tolerogen joined to the support so as to form a tolerogen-presenting immunogen, wherein the tolerogen-presenting immunogen displays the tolerogen in a regular, repetitive array.    
     
     
         2 . The composition of  claim 1 , wherein the support is a virus-like particle, a capsomeric structure, or a bead.  
     
     
         3 . The composition of  claim 2 , wherein the virus-like particle, the capsomeric structure, or the bead comprises a virus capsid protein.  
     
     
         4 . The composition of  claim 3 , wherein the virus-like particle, the capsomeric structure, or the bead comprises a virus capsid protein of an icosohedral virus.  
     
     
         5 . The composition of  claim 4 , wherein the icosohedral virus is one with T=7 symmetry.  
     
     
         6 . The composition of  claim 5 , wherein the icosohedral virus is a papillomavirus.  
     
     
         7 . A composition comprising: 
 a capsomeric structure having a symmetrical assembly of capsid proteins; and    at least one B cell epitope of a tolerogen joined to the capsomeric structure so as to form a tolerogen presenting virus-like particle (VLP), wherein the tolerogen presenting VLP displays the tolerogen in an ordered, repetitive array.    
     
     
         8 . The composition of  claim 7 , wherein the capsid protein is a capsid protein from a virus selected from the group consisting of papillomavirinae, polyomavirinae, and parvoviridae.  
     
     
         9 . The composition of  claim 7 , wherein the capsid protein is a papillomavirus L1 protein.  
     
     
         10 . The composition of  claim 7 , wherein the capsomeric structure is icosohedral.  
     
     
         11 . The composition of  claim 1  or  claim 7 , wherein the tolerogen is joined to the support by a linker.  
     
     
         12 . The composition of  claim 11 , wherein the linker comprises biotin.  
     
     
         13 . The composition of  claim 1  or  claim 7 , wherein the tolerogen is selected from the group consisting of a peptide, nucleic acid, carbohydrate, and lipid.  
     
     
         14 . The composition of  claim 1  or  claim 7 , wherein the tolerogen is a self antigen.  
     
     
         15 . The composition of  claim 1  or  claim 7 , wherein the tolerogen comprises a protein expressed on the surface of a cell.  
     
     
         16 . The composition of  claim 1  or  claim 7 , wherein the tolerogen is a protein associated with angiogenesis.  
     
     
         17 . The composition of  claim 1  or  claim 7 , wherein the tolerogen is CCR5.  
     
     
         18 . The composition of  claim 1  or  claim 7 , wherein the tolerogen is Tumor Necrosis Factor a (TNF-α).  
     
     
         19 . An isolated complex comprising the composition of  claim 1  or  claim 7  joined to a cell of the immune system.  
     
     
         20 . A pharmaceutical comprising the composition of  claim 1  or  claim 7 .  
     
     
         21 . A method of generating antibodies to a tolerogen comprising; 
 identifying a subject in need of antibodies to a tolerogen; and    providing to the subject a sufficient amount of the composition of  claim 1  or  claim 7  to generate antibodies to the tolerogen.    
     
     
         22 . The method of  claim 21 , wherein the tolerogen is a self antigen.  
     
     
         23 . A method of identifying agents that generate auto-antibodies comprising: 
 (a) providing the composition of  claim 1  or  claim 7  to a subject;    (b) isolating antibodies from the subject;    (c) determining the titer of the antibodies isolated in step (b) that bind to the tolerogen; and    (d) identifying the agent by the ability to generate high titer antibodies.    
     
     
         24 . A method of inhibiting HIV infection comprising the step of administering the pharmaceutical of  claim 20 .  
     
     
         25 . A method of reducing inflammation comprising administering the pharmaceutical of  claim 20 .  
     
     
         26 . A method of treating chronic viral infection comprising administering the pharmaceutical of  claim 20 .  
     
     
         27 . A method of generating high titer antibodies comprising administering the agent identified by the method of  claim 23  to a subject in need thereof.  
     
     
         28 . A method of generating monoclonal antibodies to a tolerogen comprising: 
 providing the composition of  claim 1  or  claim 7  to a subject; and    making a hybridoma with a B cell from the subject.    
     
     
         29 . A method of enhancing the production of antibodies to a normally immunogenic compound comprising: 
 selecting an antigen that generates a low titer antibody response in a subject;    joining this antigen to a modified VLP so as to form a conjugated VLP, wherein the conjugated VLP displays the antigen in a regular repetitive array; and    providing the conjugated VLP to a subject and thereby generating high titer antibodies.    
     
     
         30 . The method of  claim 29  wherein the spacing between the antigens is above 50 angstroms.  
     
     
         31 . The method of  claim 29  wherein the modified VLP is joined to the antigen by way of a biotin molecule.