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 compound comprising Formula 1:
X Y-Z] m Formula 1
where:
m is an integer from 1 to 100;
X comprises an antigen comprising one or more of SEQ ID NOs: 4 to 13, or
X is selected from the group consisting of insulin, proinsulin, preproinsulin or a tolerogenic portion of any of insulin, proinsulin, or preproinsulin;
Y comprises
where:
the left bracket “(” indicates the bond between X and Y;
the 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;
R 8 is —CH 2 —CH 2 —C(CH 3 )(CN)—; and
W is a copolymer or a random copolymer of the W 1 and W 2 having p repeat units, where:
where:
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; and
R 10 is an aliphatic group, an alcohol or an aliphatic alcohol; and
Z comprises one or more liver-targeting moieties.
2. The compound of claim 1 , wherein Z comprises galactose, galactosamine, N-acetylgalactosamine, glucose, glucosamine or N-acetylglucosamine.
3. The compound of claim 2 , wherein Z is the beta anomer.
4. The compound of claim 2 , wherein Z is conjugated at its C1, C2 or C6 to Y.
5. The compound of claim 1 , wherein:
m is 1 to 3;
R 9 is —C(O)—NH—(CH 2 —CH 2 —O—) t —CH 2 —CH 2 —;
t is 1;
R 10 is CH2CH2OH; and
Z comprises a liver-targeting moiety comprising one or more of galactose, galactosamine, N-acetylgalactosamine, glucose, glucosamine, and N-acetylglucosamine.
6. The compound of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 4.
7. The compound of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 5.
8. The compound of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 6.
9. The compound of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 7.
10. The compound of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 8.
11. The compound of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 9.
12. The compound of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 10.
13. The compound of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 11.
14. The compound of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 12.
15. The compound of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 13.
16. The compound of claim 1 , wherein X comprises insulin or a tolerogenic portion thereof.
17. The compound of claim 1 , wherein X comprises proinsulin or a tolerogenic portion thereof.
18. The compound of claim 1 , wherein X comprises preproinsulin or a tolerogenic portion thereof.