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 for the induction of antigen-specific immune tolerance in a subject, the composition comprising:
an antigen to which tolerance is desired;
wherein the antigen to which tolerance is desired is capable of inducing an unwanted immune response in the subject;
a polymeric linker;
wherein the polymeric linker is coupled to the antigen to which tolerance is desired via a disulfide bond or a disulfanyl ethyl ester;
wherein the disulfide bond or the disulfanyl ethyl ester are each configured to be cleaved after administration of the composition to the subject and to release the antigen to which tolerance is desired from the polymeric linker;
a liver-targeting moiety;
wherein the polymeric linker comprises the following structure:
where
the right bracket “)” indicates a bond between the linker and a corresponding reversible addition-fragmentation chain transfer (RAFT) polymerization agent;
p is an integer from 2 to 150;
R 9 comprises —C(O)—NH—CH 2 —CH 2 —; and
the bottom bracket “)” indicates a bond between the linker and the liver targeting moiety;
Y′ comprises:
where
n is an integer from 1 to 100;
the left bracket “(” indicates the bond between the antigen and linker; and
the right bracket “)” of Y′ indicates a bond between Y′ and the remainder of the polymeric linker;
wherein the liver-targeting moiety comprises a galactosylating moiety.
2. The composition of claim 1 , wherein the liver targeting moiety is a beta anomer, wherein the liver targeting moiety comprises N-acetylgalactosamine, wherein the N-acetylgalactosamine is conjugated at its C1, C2 or C6 carbon to the polymeric linker, and wherein the antigen is associated with Celiac Disease.
3. The composition of claim 1 , wherein the antigen to which tolerance is desired is associated with Celiac Disease and comprises one or more of SEQ ID NO: 25, SEQ ID NO: 24, SEQ ID NO: 26, or SEQ ID NO: 27.
4. The composition of claim 1 , further comprising one or more additional antigens.
5. The composition of claim 4 , wherein the composition further comprises an additional antigen to which tolerance is desired, wherein the additional antigen a food antigen.
6. The composition of claim 1 , wherein the antigen to which tolerance is desired is associated with Celiac Disease and comprises at least a portion of SEQ ID NO. 25.
7. A composition for the induction of antigen-specific immune tolerance in a subject, the composition comprising:
an antigen to which tolerance is desired,
wherein the antigen to which tolerance is desired is capable of inducing an unwanted immune response in the subject;
a polymeric linker:
wherein the polymeric linker is bonded to the antigen via a disulfide bond or a disulfanyl ethyl ester;
wherein the disulfide bond or the disulfanyl ethyl ester are each configured to be cleaved after administration of the composition to the subject and to release the antigen from the polymeric linker;
a liver targeting moiety;
wherein the polymeric linker comprises the following structure:
where
the right bracket “)” indicates a bond between the linker and a corresponding reversible addition-fragmentation chain transfer (RAFT) polymerization agent;
p is an integer from 2 to 150;
R 9 comprises —C(O)—NH—CH 2 —CH 2 —; and
the bottom bracket “)” indicates a bond between the linker and the liver targeting moiety;
Y′ comprises:
where
n is an integer from 1 to 100;
the left bracket “(” indicates the bond between the antigen and linker; and
the right bracket “)” of Y′ indicates a bond between Y′ and the remainder of the polymeric linker.
8. The composition of claim 7 , further comprising one or more additional antigens.
9. The composition of claim 7 , wherein the antigen to which tolerance is desired is a food antigen.
10. The composition of claim 7 , wherein the antigen to which tolerance is desired comprises one or more of portions of deamidated alpha gliadin, native alpha gliadin and omega gliadin.
11. The composition of claim 7 , wherein the antigen to which tolerance is desired comprises at least one tolerogenic portion of alpha gliadin.
12. The composition of claim 7 , wherein the antigen to which tolerance is desired comprises an amino acid sequence of SEQ ID NO: 25, SEQ ID NO: 24, SEQ ID NO: 26, or SEQ ID NO: 27.
13. The composition of claim 7 , wherein the antigen to which tolerance is desired is associated with Celiac disease.
14. The composition of claim 13 , wherein the antigen to which tolerance is desired comprises SEQ ID NO: 25.
15. The composition of claim 13 , further comprising SEQ ID NO: 24.
16. The composition of claim 7 , wherein the antigen to which tolerance is desired is a food antigen selected from portions of one or more of high molecular weight glutenin, low molecular weight glutenin, alpha-, gamma- and omega-gliadin, hordein, secalin and/or avenin.
17. The composition of claim 16 , wherein the one or more antigens to which tolerance is desired comprises an amino acid sequence of SEQ ID NO: 25.
18. A composition for the induction of antigen-specific immune tolerance in a subject, the composition comprising:
one or more antigens to which tolerance is desired,
wherein the one or more antigens, to which tolerance is desired is capable of inducing an unwanted immune response in the subject;
a polymeric linker:
wherein the polymeric linker is bonded to the one or more antigens via a disulfide bond or a disulfanyl ethyl ester,
wherein the disulfide bond or the disulfanyl ethyl ester are each configured to be cleaved after administration of the compound to the subject and to release the one or more antigens from the polymeric linker, and
a liver targeting moiety, wherein the liver targeting moiety comprises N acetylgalactosamine;
wherein the polymeric linker comprises the following structure:
where
the right bracket “)” indicates a bond between the linker and a corresponding reversible addition-fragmentation chain transfer (RAFT) polymerization agent;
p is an integer from 2 to 150;
R 9 comprises —C(O)—NH—CH 2 —CH 2 —; and
the bottom bracket “)” indicates a bond between the linker and the liver targeting moiety;
Y′ comprises:
where
n is an integer from 1 to 100;
the left bracket “(” indicates the bond between the antigen and linker; and
the right bracket “)” of Y′ indicates a bond between Y′ and the remainder of the polymeric linker.
19. The composition of claim 18 , wherein the one or more antigens to which tolerance is desired comprises one or more of SEQ ID NO: 24 or SEQ ID NO: 25.
20. The composition of claim 18 , wherein the one or more antigens to which tolerance is desired is associated with Celiac disease.