Glycotargeting therapeutics

Patent metadata

Field	Value
Publication number	US-11801305-B2
Application number	US-201916724067-A
Country	US
Kind code	B2
Filing date	Dec 20, 2019
Priority date	Feb 21, 2014
Publication date	Oct 31, 2023
Grant date	Oct 31, 2023

Abstract

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.

First claim

What is claimed is:

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 the 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; and
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; and
wherein the liver-targeting moiety comprises a galactosylating 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 Celiac disease.

3. The composition of claim 1 , wherein the antigen which tolerance is desired is associated with Celiac disease and comprises one or more of SEQ ID NO: 21, SEQ ID NO: 20, SEQ ID NO: 22, or SEQ ID NO: 23.

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 Celiac disease and comprises at least a portion of SEQ ID NO: 21.

6. The composition claim 4 , wherein compound further comprises an additional antigen to which tolerance is desired, wherein the additional antigen is a food antigen.

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;
wherein the liver-targeting moiety comprises a galactosylating or glucosylating moiety;

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; and
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 compound 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 food antigen.

10. The composition of claim 7 , wherein the antigen to which tolerance is desired comprises one or more portions of deamidated alpha gliadin, native alpha gliadin and omega gliadin.

11. The composition of claim 7 , wherein the antigen to which tolerance is desired comprises at least one tolerogenic portion of alpha gliadin.

12. The composition of claim 7 , wherein the antigen to which tolerance is desired comprises an amino acid sequence of SEQ ID NO: 21, SEQ ID NO: 20, SEQ ID NO: 22, or SEQ ID NO: 23.

13. The composition of claim 7 , wherein the antigen to which tolerance is desired is associated with Celiac disease.

14. The composition of claim 13 , wherein the antigen to which tolerance is desired comprises SEQ ID NO: 21.

15. The composition claim 14 , further comprising SEQ ID NO: 20.

16. The composition of claim 7 , wherein the antigen to which tolerance is desired is a food antigen selected from portions of one or more of high molecular weight glutenin, low molecular weight glutenin, alpha-, gamma- and omega-gliadin, hordein, secalin and/or avenin.

17. 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 liver targeting moiety, wherein the liver targeting moiety comprises N-acetylgalactosamine;
a polymeric linker:

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

Assignees

• Ecole Polytechnique Fed Lausanne Epfl

Inventors

• Hubbell Jeffrey A
• Wilson David Scott

Classifications

• A61K47/549 Primary

  Sugars, nucleosides, nucleotides or nucleic acids · CPC title

• A61K38/28

  Insulins · CPC title

• A61K38/38

  Albumins · CPC title

• A61K39/001

  Preparations to induce tolerance to non-self, e.g. prior to transplantation · CPC title

• A61K39/35

  Allergens · CPC title