Glycotargeting therapeutics
Glycotargeting therapeutics are useful in the treatment of transplant rejection, autoimmune disease, food allergy, and immune response against a therapeutic agent.
1. A composition comprising a compound of Formula 1:
where:
m is an integer from 1 to 100;
X comprises a self-antigen which induces an unwanted immune response;
Y comprises one or more structures represented by one or more of the following Formulae:
where:
the left bracket “(” indicates the bond between X and Y;
the right or bottom bracket and “)” indicates the bond between Y and Z;
n, where present, is an integer from 1 to 100;
p, where present, is an integer from 2 to 150;
q, where present, is an integer from 1 to 44;
R 8 , where present, is —CH 2 — or —CH 2 —CH 2 —C(CH 3 )(CN)—; and
R 9 , where present, is a direct bond or —C(O)—NH—CH 2 —CH 2 —; and
Z comprises one or more liver-targeting moieties, wherein Z is selected from the group consisting of glucose, glucosamine or N-acetylglucosamine.
2. The composition of claim 1 comprising Z conjugated at its C1, C2 or C6 to Y.
3. The composition of claim 1 where Y is produced using N-hydroxysuccinamidyl linkers, malaemide linkers, vinylsulfone linkers, pyridyl di-thiol-poly(ethylene glycol) linkers, pyridyl di-thiol linkers, n-nitrophenyl carbonate linkers, NHS-ester linkers, or nitrophenoxy poly(ethylene glycol)ester linkers.
4. The composition of claim 1 where:
n, where present, is 40 to 80;
p, where present, is 10 to 100;
q, where present, is 3 to 20;
R 8 , where present, is —CH 2 —CH 2 —C(CH 3 )(CN)—; and
R 9 , where present, is —C(O)—NH—CH 2 —CH 2 -, Z is glucose or N-acetylglucosamine conjugated at its C1.
5. The composition of claim 4 where Y comprises Formula Ya, Formula Yb, Formula Ym or Formula Yn.
6. The composition of claim 1 where Y comprises Formula Ya, Formula Yb, Formula Yh, Formula Yi, Formula Yk, Formula Ym or Formula Yn.
7. The composition of claim 6 , wherein X is selected from the group consisting of insulin, proinsulin, preproinsulin, glutamic acid decarboxylase-65 (GAD-65), GAD-67, glucose-6 phosphatase 2, insulinoma-associated protein 2, and insulinoma-associated protein 2β.
8. The composition of claim 1 where Y comprises Formula Ym.
9. The composition of claim 8 , wherein X is selected from the group consisting of insulin, proinsulin, preproinsulin, glutamic acid decarboxylase-65 (GAD-65), GAD-67, glucose-6 phosphatase 2, insulinoma-associated protein 2, and insulinoma-associated protein 2β.
10. The composition of claim 1 wherein X comprises a synthetic self-antigen.
11. The composition of claim 1 where Y comprises Formula Ym, Formula Yn, or Formula Yp.
12. The composition of claim 1 where Y comprises Formula Yp.
13. The composition of claim 1 where Y further comprises the following:
14. The composition of claim 1 , wherein X is selected from the group consisting of insulin, proinsulin, preproinsulin, glutamic acid decarboxylase-65 (GAD-65), GAD-67, glucose-6 phosphatase 2, insulinoma-associated protein 2, and insulinoma-associated protein 2β.
15. The composition of claim 1 , wherein X is selected from the group consisting of myelin basic protein, myelin oligodendrocyte glycoprotein, myelin proteolipid protein, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13.
16. The composition of claim 1 , wherein X is transglutaminase.
17. A compound comprising a compound of Formula 1:
where:
m is an integer from 1 to 100;
X is selected from the group consisting of insulin, proinsulin, preproinsulin, glutamic acid decarboxylase-65 (GAD-65), GAD-67, glucose-6 phosphatase 2, insulinoma-associated protein 2, and insulinoma-associated protein 20, myelin basic protein, myelin oligodendrocyte glycoprotein, myelin proteolipid protein, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, and SEQ ID NO:13;
Y comprises one or more
structures represented by one or more of the following Formulae:
where:
the left bracket “(” indicates the bond between X and Y;
the right or bottom bracket and “)” indicates the bond between Y and Z;
n, where present, is an integer from 1 to 100;
p, where present, is an integer from 2 to 150;
q, where present, is an integer from 1 to 44;
R 8 , where present, is —CH 2 — or —CH 2 —CH 2 —C(CH 3 )(CN)—; and
R 9 , where present, is a direct bond or —C(O)—NH—CH 2 —CH 2 —; and
Z comprises one or more liver-targeting moieties.
18. The compound of claim 17 , wherein Z is selected from the group consisting of galactose, galactosamine, N-acetylgalactosamine, glucose, glucosamine or N-acetylglucosamine.
19. The compound of claim 17 where Y comprises one or more of Ym, Yn, and Yp.
20. The compound of claim 17 where Y comprises Formula Yp.
21. The compound of claim 17 where Y further comprises the following:
22. The compound of claim 17 where Y comprises Formula Ym.
23. A composition comprising a compound of Formula 1:
where:
m is an integer from 1 to 100;
X comprises a synthetic self-antigen;
Y comprises a structure represented by one or more of the following Formulae:
where:
the left bracket “(” indicates the bond between X and Y;
the right or bottom bracket and “)” indicates the bond between Y and Z;
n is an integer from 1 to 100;
p is an integer from 2 to 150;
q is an integer from 1 to 44;
R 8 is —CH 2 — or —CH 2 —CH 2 —C(CH 3 )(CN)—; and
R 9 is a direct bond or —C(O)—NH—CH 2 —CH 2 —; and
Z comprises one or more liver-targeting moieties, wherein Z is selected from the group consisting of glucose, glucosamine or N-acetylglucosamine.
24. The composition of claim 23 , wherein the synthetic self-antigen is a of an antigen selected from the group consisting of insulin, proinsulin, preproinsulin, glutamic acid decarboxylase-65 (GAD-65), GAD-67, glucose-6 phosphatase 2, insulinoma-associated protein 2, and insulinoma-associated protein 2β.
25. The composition of claim 24 , for use in treating Type I diabetes.