Glycotargeting therapeutics
View Patent ↗Several embodiments of the present disclosure relate to therapeutic compositions configured to target the liver of a subject and that are useful in the treatment or prevention of one or more 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. In several embodiments, the compositions are configured for clearance of a circulating protein or peptide or antibody associated with one or more of the above-mentioned maladies. Methods and uses of the compositions for induction of immune tolerance are also disclosed herein.
1. A method of inducing tolerance to an antigen to which a subject develops an unwanted immune response, the method comprising administering a compound Formula 1 to the subject:
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 method of claim 1 , wherein Z comprises galactose, galactosamine, N-acetylgalactosamine, glucose, glucosamine or N-acetylglucosamine.
3. The method of claim 2 , wherein Z is the beta anomer.
4. The method of claim 2 , wherein Z is conjugated at its C1, C2 or C6 to Y.
5. The method 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 CH 2 CH 2 OH; and
Z comprises a liver-targeting moiety comprising one or more of galactose, galactosamine, N-acetylgalactosamine, glucose, glucosamine, and N-acetylglucosamine.
6. The method of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 4.
7. The method of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 5.
8. The method of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 6.
9. The method of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 7.
10. The method of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 8.
11. The method of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 9.
12. The method of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 10.
13. The method of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 11.
14. The method of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 12.
15. The method of claim 1 , wherein X comprises an antigen comprising SEQ ID NO: 13.
16. The method of claim 1 , wherein X comprises insulin or a tolerogenic portion thereof.
17. The method of claim 1 , wherein X comprises proinsulin or a tolerogenic portion thereof.
18. The method of claim 1 , wherein X comprises preproinsulin or a tolerogenic portion thereof.