Increase of immune response and targeting by antigens and/or drug linkage
The present invention relates to compounds consisting of glycolipids covalently bound to an antigen or a drug via a linker. The said compounds are able to induce a stronger immune response than a composition comprising separated glycolipids and antigen. The said compounds are also able to target drug to CD1d restricted cells.
1. A compound having Formula (I):
wherein,
R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 6 -C 12 aralkyl, or C 1 -C 6 acyl, and R 1 is either above or below the sugar ring;
R 6 is a) —(CH 2 ) x CH 3 where x is an integer selected from 1 to 100; or
b) —(CH 2 ) x CH═CH(CH 2 ) y CH 3 or —(CH 2 ) x CH═CH(CH 2 ) y CH═CH(CH 2 ) z CH 3 wherein x, y and z are integers independently selected from 1 to 14;
R 5 is one of the following formulae (II), (III) or (IV)
wherein R 8 is hydrogen, C 1 -C 6 alkyl, C 6 -C 12 aralkyl, or C 1 -C 6 acyl, and
R 7 is a linear or branched C 3 -C 100 alkyl;
X is —O, NH or S;
Y is a cleavable or non-cleavable linker group; and
Z is an antigen derived from an infectious agent or a tumor antigen or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 and R 8 are hydrogen, R 5 is (II), R 6 is C 25 H 51 , R 7 is C 14 H 29 and X is NH.
3. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 and R 8 are hydrogen, R 5 is (II), R 6 is C 23 H 45 , R 7 is C 14 H 29 and X is NH.
4. The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 and R 8 are hydrogen, R 5 is (II), R 6 is C 23 H 47 , R 7 is C 14 H 29 and X is NH.
5. The compound according to claim 1 , wherein the linker contains a protease cleavage site.
6. The compound according to claim 1 , wherein the linker contains a lipase cleavage site.
7. The compound according to claim 1 , wherein the linker contains a protease cleavage site and/or a lipase cleavage site.
8. The compound according to claim 1 , wherein compound is capable of activating an NKT cell.
9. A vaccine composition comprising the compound of claim 1 and a physiologically acceptable vehicle.
10. A pharmaceutical composition comprising the compound of claim 1 and a physiologically acceptable vehicle.
11. A method of stimulating an immune response in a subject comprising administering to the subject an effective amount of a vaccine composition comprising a compound having Formula (I):
wherein,
R 1 , R 2 , R 3 , and R 4 are each independently hydrogen, C 1 -C 6 alkyl, C 6 -C 12 aralkyl, or C 1 -C 6 acyl, and R 1 is either above or below the sugar ring;
R 6 is a) —(CH 2 ) x CH 3 where x is an integer selected from 1 to 100; or
b) —(CH 2 ) x CH═CH(CH 2 ) y CH 3 or —(CH 2 ) x CH═CH(CH 2 ) y CH═CH(CH 2 ) z CH 3 wherein x, y and z are integers independently selected from 1 to 14;
R 5 is one of the following formulae (II), (III) or (IV)
wherein R 8 is hydrogen, C 1 -C 6 alkyl, C 6 -C 12 aralkyl, or C 1 -C 6 acyl, and
R 7 is a linear or branched C 3 -C 100 alkyl;
X is —O, NH or S;
Y is a cleavable or non-cleavable linker group; and
Z is an antigen derived from an infectious agent or a tumor antigen or a pharmaceutically acceptable salt thereof;
said composition further comprising a physiologically acceptable vehicle.
12. Method according to claim 11 , wherein the immune response is a humoral immune response.
13. Method according to claim 11 , for activating CD4+ T lymphocytes.
14. Method according to claim 11 , for activating CD8+ T lymphocytes.
15. A method of treating a subject having a tumor or an infectious disease wherein said method comprises administering to the subject an effective amount of the composition of claim 10 .