Compositions and methods for inducing immune tolerance
Several embodiments provided in the present disclosure relate to compositions that carry an antigen to which tolerance is desired, the antigen being coupled, bound, or otherwise joined to a targeting moiety, the targeting moiety configured to direct the composition to the liver of a subject. In several embodiments, the antigen in coupled to the targeting moiety by way of a polymeric linker. In several embodiments, the polymeric linker is configured to liberate the antigen in vivo. Methods of using the compositions to reduce and/or prevent unwanted immune responses against an antigen of interest are also provided.
1. A compound comprising Formula 1:
where:
m is an integer from 1;
X comprises an antigen or a tolerogenic portion thereof;
Y is of a linker moiety having Formula Yj′:
wherein:
n is 43;
q is 3;
v is 2;
R 1 is —(CH 2 ) 2 —C(CH 3 )(CN)—; and
Y′ is a random copolymer or block copolymer of W 1 and W 2 , where W 1 and W 2 are as depicted below:
wherein the number of repeat units of W 1 is denoted as p and wherein p is an integer of at least 1;
wherein the number of repeat units of W 2 is denoted as r and wherein r is an integer of at least 1;
where, R 9 is —C(O)—NH—(CH 2 ) 2 —(O—CH 2 —CH 2 ) t —;
t is 1;
where, R 10 is —CH 2 —CH 2 —OH; and
R 2 is:
where Ar is an unsubstituted aromatic group; and
Z is N-acetylgalactosamine.
2. The compound of claim 1 , where Z is conjugated at its C1, C2 or C6 to Y.
3. The compound of claim 1 , wherein the ratio of p to r is 1:1.
4. The compound of claim 1 , wherein the ratio of p to r is 4:1.
5. The compound of claim 1 , where Y is prepared using N-hydroxysuccinamidyl linkers, maleimide linkers, vinylsulfone linkers, pyridyl di-thiol-poly(ethylene glycol) linkers, pyridyl di-thiol linkers, n-nitrophenyl carbonate linkers, NHS-ester linkers, and nitrophenoxy poly(ethylene glycol)ester linkers.
6. The compound of claim 1 , where X induces an unwanted immune response in a subject.
7. The compound of claim 1 , wherein X comprises a self antigen.
8. The compound of claim 7 , wherein the self antigen is selected from myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), proteolipid protein (PLP), a portion of any of said antigens, and a mimetic of any of said antigens.
9. The compound of claim 7 , wherein the self antigen is selected from insulin, proinsulin, preproinsulin, glutamic acid decarboxylase-65 (GAD-65), GAD-67, insulinomaassociated protein 2 (IA-2), a portion of any of said antigens, and a mimetic of any of said antigens.
10. The compound of claim 1 , wherein X comprises a food antigen.
11. The compound of claim 10 , wherein the food antigen is selected from the group consisting of high molecular weight glutenin, low molecular weight glutenin, alpha-, gamma- and omega-gliadin, hordein, secalin, avenin, a portion of any of said antigens, and a mimetic of any of said antigens.
12. A compound comprising Formula 1:
where:
m is an integer from 1 to 100;
X comprises an antigen or a tolerogenic portion thereof;
Y is of a linker moiety having Formula Yj′:
where
n is an integer from 1 to 100;
q is an integer from 1 to 100;
v is an integer from 1 to 4;
R 1 is —(CH 2 ) 2 —C(CH 3 )(CN); and
Y′ is a random copolymer or block copolymer of W 1 and W 2 , where W 1 and W 2 are as depicted below:
wherein the number of repeat units of W 1 is denoted as p and wherein p is an integer of at least 1;
wherein the number of repeat units of W 2 is denoted as r and wherein r is an integer of at least 1;
where, R 9 is C(O)—NH—(CH 2 ) 2 —(O—CH 2 —CH 2 ) t —;
t is an integer from 1 to 5; and
R 10 is —CH 2 —CH 2 —OH;
R 2 is selected:
when Ar is an unsubstituted aromatic group;
and
Z comprises a liver-targeting moiety.
13. The compound of claim 12 , where Z is galactose, glucose, galactosamine, glucosamine, N-acetylgalactosamine, or N-acetylglucosamine.
14. The compound of claim 12 , wherein X comprises a self antigen.
15. The compound of claim 14 , wherein the self antigen is selected from myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP), proteolipid protein (PLP), a portion of any of said antigens, and a mimetic of any of said antigens.
16. The compound of claim 14 , wherein the self antigen is selected from insulin, proinsulin, preproinsulin, glutamic acid decarboxylase-65 (GAD-65), GAD-67, insulinoma associated protein 2 (IA-2), a portion of any of said antigens, and a mimetic of any of said antigens.
17. The compound of claim 12 , wherein X comprises a food antigen.
18. The compound of claim 17 , wherein the food antigen is selected from the group consisting of high molecular weight glutenin, low molecular weight glutenin, alpha-, gamma- and omega-gliadin, hordein, secalin, avenin, a portion of any of said antigens, and a mimetic of any of said antigens.