Compositions comprising a B subunit of Shiga toxin and a means stimulating NKT cells
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 CDI capable of stimulating NK T cells; and to a pharmaceutical composition and a medicament comprising said composition.
1. 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 analog 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 composition according to claim 1 , wherein the functional equivalent of the B subunit of Shiga toxin which binds to the Gb3 receptor has at least 60% amino acid sequence identity to the B subunit of Shiga toxin.
3. The composition according to claim 1 , wherein said ligand of CD1 is a ligand of CD1d.
4. The composition according to claim 1 , wherein said ligand is chosen from disialogangloside (GD3), phosphotidylethanolamine (PEI) or phosphatidylinositol (PI).
5. The composition according to claim 1 , wherein said ligand is a glycosylceramide or an analog or a derivative thereof.
6. The composition according to claim 5 , wherein said glycosylceramide 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 composition according to claim 5 , wherein the glycosylceramide α-GalCer is (2S,3S,4S)-1-O-(α-D-galactopyranosyl)-2-(N-hexacosanoylamino)-1,3,4,-octadecanetriol.
8. The composition according to claim 5 , wherein the glycosylceramide α-GalCer is (2S,3S,4S)-1-O-(α-D-galactopyranoxy)-2-(N-hexacosanoylamino)-3,4,-octadecanetriol (KRN7000).
9. The composition according to claim 5 , wherein said ligand is selected from the group consisting of 3-O-sulfo-α-GalCer, α-GalCer, and OCR compound and α-C-GalCer.
10. The composition according to claim 5 , wherein said glycosylceramide is α-C-GalCer.
11. The composition according to claim 5 , wherein said glycosylceramide is PBA-57.
12. The composition according to claim 1 , wherein said ligand is a microbe derived glycolipid.
13. The composition according to claim 1 , wherein said ligand is
a Sphingomonas species-derived glycosphingolipid selected from the group consisting of GSL-1 and GaL′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 composition according to claim 1 , wherein the B subunit of Shiga toxin or the functional equivalent thereof is present in a universal polypeptidic carrier having the formula STxB-Z(n)-Cys, wherein
StxB is the Shiga Toxin B subunit or a functional equivalent thereof which binds to the Gb3 receptor,
Z is an amino acid devoid of a sulfhydryl group, n being 0.1 or a polypeptide,
Cys is the amino acid Cysteine.
15. The composition according to claim 14 , wherein n is 0.
16. The composition according to claim 14 , wherein the antigen is covalently linked to the —S residue of the universal carrier by a —S—S, or —S—CO or —S—CH 2 , or —S—NH linkage.
17. The composition according to claim 14 , wherein the universal carrier is covalently linked to an oligopeptide or a polypeptide by a —S—S, or —S—CO or —S—CH 2 , or —S—NH linkage, and the antigen to be targeted is operably linked to said oligopeptide or polypeptide.
18. The composition according to claim 14 , wherein the universal carrier is covalently linked to a poly-lysine oligopeptide moiety and the antigen to be targeted is operably linked to said poly-lysine moiety.
19. The composition according to claim 1 , wherein the antigen is a tumor antigen, a viral antigen or a bacterial antigen.
20. The composition according to claim 1 , further comprising a pharmaceutically acceptable carrier.
21. A medicament comprising a composition according to claim 1 .
22. A pharmaceutical kit comprising:
a first container comprising a B subunit of Shiga toxin or a functional equivalent thereof which binds to the Gb3 receptor, complexed with an antigen and
a) at least a second container comprising 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 analog thereof.
23. The composition according to claim 6 , wherein said derivative is a C glycoside derivative or a C glycoside derivative of a α-GalCer.
24. A composition comprising
a) a B subunit of Shiga toxin or a functional equivalent which binds to the Gb3 receptor thereof which is able to bind the Gb3 receptor, complexed with an antigen and
b) α-GalCer that stimulates NK T cells, wherein said composition breaks tolerance against self antigens, stimulates dendritic cells and elicits antiviral immunity, 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 α-GalCer that stimulates NK T cells.