Compositions comprising a b subunit of shiga toxin and a means stimulating nkt cells

Abstract

The present invention relates to a composition comprising a) a B subunit of Shiga toxin or a functional equivalent thereof which is able to bind the Gb3 receptor, complexed with an antigen and b) at least one ligand of CDl capable of stimulating NK T cells; and to a pharmaceutical composition and a medicament comprising said composition.

1 . A method of breaking tolerance against a self antigens said method comprising administering to a mammal in need of such treatment a composition comprising
 a) a B subunit of Shiga toxin or a functional equivalent thereof which binds to the Gb3 receptor, complexed with an antigen and   b) at least one ligand of CD1 that stimulates NK T cells, wherein said ligand is a glycolipid, a phospholipid, a glycosphingolipid, a derivative or an analogue thereof, wherein said composition breaks tolerance against self antigens and stimulates dendritic cells and wherein there is synergy between said B subunit of Shiga toxin or a functional equivalent thereof which binds to the Gb3 receptor, complexed with an antigen and said at least one ligand of CD1 that stimulates NK T cells.   
     
     
         2 . The method according to  claim 1 , wherein the functional equivalent of the B subunit of Shiga toxin is administered which binds to the Gb3 receptor has at least 60% amino acid sequence identity to the B subunit of Shiga toxin. 
     
     
         3 . The method according to  claim 1 , wherein said ligand of CD1 is a ligand of CD1d is administered. 
     
     
         4 . The method according to  claim 1 , wherein said ligand that is administered is chosen from disialogamgloside (GD3), phosphotidylethanolamine (PE) or phosphatidylinositol (P1). 
     
     
         5 . The method according to  claim 1 , wherein said ligand that is administered is a glycosylceramide or an analog or a derivative thereof. 
     
     
         6 . The method according to  claim 5 , wherein said glycosylceramide that is administered is selected from the group consisting of α-GalCer, α-GlcCer, Galα1-6Galα1-1′Cer, Galα1-6Glcα1-1′Cer, Galα1-2Galα1-1′Cer, Galα1-3Galα1-1′Cer and a derivative thereof. 
     
     
         7 . The method according to  claim 6 , wherein the glycosylceramide α-GalCer that is administered is (2S,3S,4S)-1-O-(α-D-galactopyranosyl)-2-(N-hexacosanoylamino)-1,3,4,-octadecanetriol. 
     
     
         8 . The method according to  claim 6 , wherein the glycosylceramide that is administered is α-GalCer is (2S,3S,4S)-1-O-(α-D-galactopyranoxy)-2-(N-hexacosanoylamino)-3,4,-octadecanetriol (KRN7000). 
     
     
         9 . The method according to  claim 5 , wherein said ligand that is administered is selected from the group consisting of 3-O-sulfo-α-GalCer, α-GalCer, and OCH compound and α-C-GalCer. 
     
     
         10 . The method according to  claim 5 , wherein said glycosylceramide that is administered is α-C-GalCer. 
     
     
         11 . The method according to  claim 6 , wherein said glycosylceramide that is administered is PBA-57. 
     
     
         12 . The method according to  claim 1 , wherein said ligand that is administered is a microbe derived glycolipid. 
     
     
         13 . The method according to  claim 1 , wherein said ligand that is administered is
 a  Sphingomonas  species-derived glycosphingolipid selected from the group consisting of GSL-1 and GSL′1 or   a  Borrelia  species derived glycolipid selected from the group consisting of BbGL-I and BgGL-II or   a  Mycobacteria  species derived phosphoglycolipid PIM.   
     
     
         14 . The method according to  claim 1 , wherein said composition is administered mucosally, transdermally, subcutaneously or intramuscularly. 
     
     
         15 . The method according to  claim 1 , wherein said at least one ligand that stimulates NK T cells is administered before, simultaneously or after the B subunit of Shiga toxin or functional equivalent thereof which is able to bind Gb3 receptor cells which is complexed to an antigen. 
     
     
         16 . The method according to  claim 1 , wherein said composition is administered in a therapeutically effective amount for stimulating an immune response against an antigen in said mammal. 
     
     
         17 . The method according to  claim 16 , wherein said antigen is administered at a dose of 0.1 to 1,000 μg. 
     
     
         18 . The method according to  claim 1 , wherein said mammal is a human. 
     
     
         19 . The method according to  claim 1 , wherein said antigen is a tumor antigen, a viral antigen or a bacterial antigen. 
     
     
         20 . The method according to  claim 1 , further comprising a pharmaceutically acceptable carrier. 
     
     
         21 . The method according to  claim 1 , wherein said composition is administered as a vaccine. 
     
     
         22 . The method according to  claim 21 , wherein said vaccine is initially administered followed by one or more booster administrations.