GLYCOTARGETING THERAPEUTICS

• US 20200129625A1
• Filed: 12/20/2019
• Published: 04/30/2020
• Est. Priority Date: 02/21/2014
• Status: Active Grant

• Current Assignee: Ecole polytechnique fãdãrale de lausanne epfl (Schweizerische Eidgenossenschaft)
• Original Assignee: Ecole polytechnique fãdãrale de lausanne epfl (Schweizerische Eidgenossenschaft)
• Inventors: Hubbell, Jeffrey A., Wilson, David Scott
• Granted Patent: US 11,801,305 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/38 Albumins
• CPC Class Codes: A61K 39/001 Preparations to induce tolerance to non-self, e.g. prior to transplantation
• CPC Class Codes: A61K 39/35 Allergens
• CPC Class Codes: A61K 39/385 Haptens or antigens, bound to carriers
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/555 pre-targeting systems involving an organic compound, other than a peptide, protein or antibody, for targeting specific cells
• CPC Class Codes: A61K 47/58 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol

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.

Claims

1. (canceled)

2. 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 polymeric linker comprising;

a copolymer or a random copolymer, wherein the copolymer or random copolymer comprises a first methacrylic unit and a second methacrylic unit, the first methacrylic unit comprising a first ethylacetamido functionality and the second methacrylic unit comprising a second ethylacetamido functionality;

wherein the second ethylacetamido functionality is conjugated to an aliphatic group, an alcohol, or an aliphatic alcohol;

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

a liver-targeting moiety;

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

wherein the liver-targeting moiety is bonded to the polymeric linker through the first ethylacetamido functionality.

3. The composition of claim 2, 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.

4. The composition of claim 2, 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.

5. The composition of claim 2, further comprising one or more additional antigens.

6. The composition of claim 2, wherein the antigen to which tolerance is desired is associated with Celiac disease and comprises at least a portion of SEQ. ID. NO. 21.

7. The composition claim 5, wherein compound further comprises an additional antigen to which tolerance is desired, wherein the additional antigen is a food antigen.

8. 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;

a copolymer or a random copolymer, wherein the copolymer or random copolymer comprises a first unit and a second unit, the first unit comprising a first functionality that bonds the first unit to the liver-targeting moiety and the second unit comprising a second functionality conjugated to an aliphatic group, an alcohol, or an aliphatic alcohol;

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.

9. The composition of claim 8, further comprising one or more additional antigens.

10. The composition of claim 8, wherein the antigen to which tolerance is desired is a food antigen.

11. The composition of claim 8, wherein the antigen to which tolerance is desired comprises one or more portions of deamidated alpha gliadin, native alpha gliadin and omega gliadin.

12. The composition of claim 8, wherein the antigen to which tolerance is desired comprises at least one tolerogenic portion of alpha gliadin.

13. The composition of claim 8, 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.

14. The composition of claim 8, wherein the antigen to which tolerance is desired is associated with Celiac disease.

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

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

20.

17. The composition of claim 8, 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.

18. 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;

wherein the polymeric linker comprises a copolymer or a random copolymer, wherein the copolymer or random copolymer comprises a first unit and a second unit, the first unit comprising a first functionality that bonds the first unit to the liver-targeting moiety and the second unit comprising a second functionality conjugated to an aliphatic group, an alcohol, or an aliphatic alcohol;

wherein the polymeric linker is bonded to the antigen via a disulfide bond or a disulfanyl ethyl ester, and

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 from the polymeric linker.

19. The composition of claim 18, wherein the one or more antigens to which tolerance is desired comprises one or more of amino acids of SEQ ID NO:

21 or SEQ ID NO;

20.

20. The composition of claim 18, wherein the one or more antigens to which tolerance is desired is associated with Celiac disease.

21. The composition of claim 18, wherein the one or more antigens to which tolerance is desired comprises an amino acid sequence of SEQ ID NO:

21.