Glycotargeting therapeutics
Several embodiments of the present disclosure relate to glycotargeting therapeutics that are useful in the treatment of transplant rejection, autoimmune disease, food allergy, and immune response against a therapeutic agent. In several embodiments, the compositions are configured to target the liver and deliver antigens to which tolerance is desired. Methods and uses of the compositions for induction of immune tolerance are also disclosed herein.
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 liver targeting moiety; and
a polymeric linker comprising:
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 a liver targeting moiety;
W is a copolymer or a random copolymer of the W 1 and W 2 having p repeat units, where:
where:
p is an integer from 2 to 150;
R 9 is a direct bond, —C(O)—NH—CH 2 —CH 2 —, or —C(O)—NH—(CH 2 —CH 2 —O—) t —CH 2 —CH 2 —;
t is an integer from 1 to 5;
R 10 is an aliphatic group, an alcohol or an aliphatic alcohol;
Y′ comprises:
where
n is an integer from 1 to 100;
the left bracket “(” of Y′ indicates the bond between the antigen and linker;
the right bracket “)” of Y′ indicates a bond between Y′ and the remainder of the polymeric linker;
wherein the polymeric linker is bonded 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 cleave after administration of the composition to the subject and to release the antigen to which tolerance is desired from the polymeric linker.
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 or Type I Diabetes.
3. The composition of claim 1 , wherein the antigen which tolerance is desired is associated with multiple sclerosis and comprises one or more of SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 8, or SEQ ID NO: 9.
4. The composition of claim 1 , wherein the antigen to which tolerance is desired is associated with Type I diabetes and comprises a portion of SEQ ID NO: 1.
5. The composition of claim 1 , further comprising one or more additional antigens.
6. The composition claim 5 , wherein composition further comprises an additional antigen to which tolerance is desired, wherein the additional antigen is derived from insulinoma-associated protein 2 (IA-2).
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 liver-targeting moiety; and
a polymeric linker comprising:
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 a liver targeting moiety;
W is a copolymer or a random copolymer of the W 1 and W 2 having p repeat units, where:
where:
p is an integer from 2 to 150;
R 9 is a direct bond, —C(O)—NH—CH 2 —CH 2 —, or —C(O)—NH—(CH 2 —CH 2 —O—) t —CH 2 —CH 2 —;
t is an integer from 1 to 5;
R 10 is an aliphatic alcohol;
Y′ comprises:
where
n is an integer from 1 to 100;
the left bracket “(” of Y′ indicates the bond between the antigen and linker;
the right bracket “)” of Y′ indicates a bond between Y′ and the remainder of the polymeric linker;
wherein the polymeric linker is bonded 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 cleave after administration of the composition to the subject and to release the antigen to which tolerance is desired from 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 self-antigen.
10. The composition of claim 9 , 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 myelin oligodendrocyte glycoprotein.
12. The composition of claim 7 , wherein the antigen to which tolerance is desired comprises one or more amino acid sequences of SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 8, or SEQ ID NO: 9.
13. The composition of claim 8 , wherein the antigen to which tolerance is desired is associated with Type I diabetes.
14. The composition of claim 7 , wherein the antigen to which tolerance is desired comprises a portion of SEQ ID NO: 1.
15. The composition claim 14 , wherein the antigen to which tolerance is desired comprises an amino acid sequence comprising a portion of SEQ ID NO: 1 and one or more of IA-2, and a tolerogenic fragment thereof.
16. 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;
wherein the one or more antigens to which tolerance is desired comprises:
one or more antigens associated with multiple sclerosis, or
one or more antigens associated with Type I Diabetes;
a liver targeting moiety, wherein the liver targeting moiety comprises N acetylgalactosamine;
a polymeric linker comprising:
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 a liver targeting moiety;
W is a copolymer or a random copolymer of the W 1 and W 2 having p repeat units, where:
where:
p is an integer from 2 to 150;
R 9 is a direct bond, —C(O)—NH—CH 2 —CH 2 —, or —C(O)—NH—(CH 2 —CH 2 —O—) t —CH 2 —CH 2 —;
t is an integer from 1 to 5;
R 10 is an aliphatic group, an alcohol or an aliphatic alcohol;
Y′ comprises:
where
n is an integer from 1 to 100;
the left bracket “(” of Y′ indicates the bond between the antigen and linker;
the right bracket “)” of Y′ indicates a bond between Y′ and the remainder of the 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 cleave after administration of the composition to the subject and to release the one or more antigens from the polymeric linker.
17. The composition of claim 16 , wherein the one or more antigens to which tolerance is desired is associated with Type I diabetes and comprises a portion of SEQ ID NO: 1.
18. The composition of claim 17 , further comprising one or more of IA-2 and a tolerogenic fragment thereof.
19. The composition of claim 16 , wherein the one or more antigens to which tolerance is desired comprises one or more amino acid sequences of SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 8, or SEQ ID NO: 9.
20. The composition of claim 19 , further comprising one or more of proteolipid protein (PLP) and a tolerogenic fragment thereof.