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;
the bottom bracket “ ” indicates a bond between the linker and the liver targeting moiety;
Y′ comprises a remaining portion of the polymeric linker:
n is an integer from 1 to 100;
p is an integer from 2 to 150;
R 9 comprises —C(O)—NH—CH 2 —CH 2 —;
the left bracket “(” indicates the bond between the antigen and linker;
the bottom bracket “ ” indicates the bond between the linker and the liver targeting moiety; and
wherein the liver-targeting moiety comprises a galactosylating moiety or glucosylating 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 multiple sclerosis.
3. The composition of claim 1 , wherein the antigen to which tolerance is desired is associated with multiple sclerosis and comprises one or more of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 12, or SEQ ID NO: 13.
4. The composition of claim 1 , further comprising one or more additional antigens.
5. The composition of claim 1 , wherein the antigen to which tolerance is desired is associated with multiple sclerosis and comprises SEQ ID NO: 15.
6. The composition of claim 5 , wherein the composition further comprises an additional antigen to which tolerance is desired, wherein the additional antigen is derived from myelin basic protein (MBP).
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 prepared by methacrylating a galactosylating moiety to provide a methacrylate and polymerizing the methacrylate:
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; and
a liver targeting moiety.
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 self-antigen.
10. The composition of claim 7 , wherein the antigen to which tolerance is desired comprises one or more of myelin oligodendrocyte glycoprotein, myelin basic protein, proteolipid protein, and a tolerogenic portion of any of said antigens.
11. The composition of claim 7 , wherein the antigen to which tolerance is desired comprises at least one tolerogenic portion of myelin oligodendrocyte glycoprotein.
12. The composition of claim 7 , wherein the antigen to which tolerance is desired comprises an amino acid sequence of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 12, or SEQ ID NO: 13.
13. The composition of claim 7 , wherein the antigen to which tolerance is desired is associated with Multiple Sclerosis.
14. The composition of claim 13 , wherein the antigen to which tolerance is desired comprises SEQ ID NO: 15.
15. The composition claim 13 , wherein the antigen to which tolerance is desired comprises SEQ ID NO: 15 and a tolerogenic fragment of myelin basic protein (MBP).
16. The composition of claim 13 , wherein the antigen to which tolerance is desired comprises SEQ ID NO: 16 and a tolerogenic fragment of proteolipid protein (PLP).
17. The composition of claim 13 , wherein the antigen to which tolerance is desired comprises SEQ ID NO: 15 and a tolerogenic fragment of MBP or a tolerogenic fragment of PLP.
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 poly(galactose methacrylate) or poly(glucose methacrylate) 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 composition 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.
19. The composition of claim 18 , wherein the antigen to which tolerance is desired comprises one or more of SEQ ID NO: 15 and SEQ ID NO: 16.
20. The composition of claim 18 , wherein the antigen to which tolerance is desired comprises an amino acid sequence of SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 12, or SEQ ID NO: 13.