Glycotargeting therapeutics

• US 10,046,056 B2
• Filed: 06/17/2016
• Issued: 08/14/2018
• 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
• Primary Examiner(s): Ahmed, Hasan
• Assistant Examiner(s): D' Ambrosio, Thea
• Application Number:
  US15/185,564
• Publication Number:
  US 20170007708A1
• Time in Patent Office: 788 Days
• Field of Search: None
• CPC Class Codes: A61K 2039/577 tolerising response
• CPC Class Codes: A61K 2039/60 characteristics by the carrier linked to the antigen
• CPC Class Codes: A61K 2039/6087 Polysaccharides; Lipopolysaccharides [LPS]
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/164 from bacteria
• CPC Class Codes: A61K 38/1709 from mammals
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/37 Factors VIII
• CPC Class Codes: A61K 38/38 Albumins
• CPC Class Codes: A61K 39/0002 Fungal antigens, e.g. Trichophyton, Aspergillus, Candida
• CPC Class Codes: A61K 39/0005 Vertebrate antigens from snakes A61K39/38
• CPC Class Codes: A61K 39/0008 Antigens related to auto-immune diseases; Preparations to induce self-tolerance
• 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 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: C07K 14/07 Vaccinia virus; Variola virus
• CPC Class Codes: C07K 14/77 Ovalbumin
• CPC Class Codes: C07K 16/241 : Tumor Necrosis Factors
• CPC Class Codes: C07K 16/2848 : against integrin beta3-subunit-containing molecules, e.g. CD41, CD51, CD61
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• CPC Class Codes: C07K 2319/01 : containing a localisation/targetting motif

Abstract

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.

Claims

1. A composition comprising a compound of Formula 1:

XY—

Z]L 

 

Formula 1

where;

m is an integer from about 1 to 100;

X comprises an antigen against which a patient develops an unwanted immune response;

Y comprises

2. The composition of claim 1 where Z comprises galactose, galactosamine, N-acetylgalactosamine, glucose, glucosamine or N-acetylglucosamine.

3. The composition of claim 2, wherein Z is the beta anomer.

4. The composition of claim 2 comprising Z conjugated at its C1, C2 or C6 to Y.

5. The composition of claim 1 where Y is prepared using a linker precursor selected from N-hydroxysuccinamidyl-based linkers, malaemide-based linkers, vinylsulfone-based linkers, pyridyl di-thiol-poly(ethylene glycol)-based linkers, pyridyl di-thiol-based linkers, n-nitrophenyl carbonate-based linkers, NHS-ester-based linkers, and nitrophenoxy poly(ethylene glycol)ester-based linkers.

6. The composition of claim 1, wherein X is a synthetic self-antigen and the unwanted immune response is an autoimmune response.

7. The composition of claim 1, wherein X is selected from the group consisting of myelin oligodendrocyte glycoprotein, myelin proteolipid protein, and myelin basic protein and wherein the unwanted immune response is associated with multiple sclerosis.

8. The composition of claim 1, wherein X is selected from the group consisting of insulin, proinsulin, and preproinsulin and wherein the unwanted immune response is associated with type 1 diabetes mellitus.

9. The composition of claim 1, wherein X is a therapeutic agent selected from the group consisting of Factor VIII and Factor IX.

10. The composition of claim 1, wherein X is a therapeutic agent selected from the group consisting of asparaginase and uricase.

11. The composition of claim 1, wherein X is a is a food antigen selected from the group consisting of:

conarachin (Ara h

     1), allergen II (Ara h

     2), arachis agglutinin, conglutin (Ara h

     6), a-lactalbumin (ALA), lactotransferrin, Pen a 1 allergen (Pen a

     1), allergen Pen m 2 (Pen m

     2), tropomyosin fast isoform, high molecular weight glutenin, low molecular weight glutenin, alpha-gliadin, gamma-gliadin, omega-gliadin, hordein, secalin, and avenin.

12. The composition of claim 1, wherein administration of the composition to the subject results in a greater degree of proliferation of antigen-specific T cells as compared to proliferation of antigen-specific T cells resulting from administration of the antigen alone.

13. The composition of claim 3, wherein administration of the composition to the subject results in a greater expression of exhaustion markers or markers of apoptosis on antigen-specific T cells as compared to expression of exhaustion markers or markers of apoptosis on antigen-specific T cells resulting from administration of the antigen alone.

18. The composition of claim 1, wherein m is 1 to 3;

R⁸ is —

CH₂—

CH₂—

C(CH₃)(CN)—

;

R⁹ is —

C(O)—

NH—

(CH₂—

CH₂—

O—

)_t—

CH₂—

CH₂—

;

t is 1;

R¹⁰ is CH₂CH₂OH; and

Z comprises a liver-targeting moiety comprising one or more of galactose, galactosamine, N-acetylgalactosamine, glucose, glucosamine, and N-acetylglucosamine.

14. A composition for inducing tolerance to an antigen to which a subject develops an unwanted immune response, the composition comprising a compound of Formula 1:

XY—

Z]L 

 

Formula 1

where;

m is an integer from about 1 to 10;

X comprises an antigen to which patients develop an unwanted immune response, wherein the antigen is a food antigen, a therapeutic agent, or a self-antigen;

Y is;

15. The composition of claim 14, wherein m is 1 to 3.

16. The composition of claim 14, wherein X is selected from the group consisting of myelin oligodendrocyte glycoprotein, myelin proteolipid protein, and myelin basic protein and wherein the unwanted immune response is associated with multiple sclerosis.

17. The composition of claim 14, wherein X is a is a food antigen selected from the group consisting of:

conarachin (Ara h

     1), allergen II (Ara h

     2), arachis agglutinin, conglutin (Ara h

     6), a-lactalbumin (ALA), lactotransferrin, Pen a 1 allergen (Pen a

     1), allergen Pen m 2 (Pen m

     2), tropomyosin fast isoform, high molecular weight glutenin, low molecular weight glutenin, alpha-gliadin, gamma-gliadin, omega-gliadin, hordein, secalin, and avenin.

19. The composition of claim 14, wherein X is selected from the group consisting of insulin, proinsulin, and preproinsulin and wherein the unwanted immune response is associated with type 1 diabetes mellitus.

20. The composition of claim 14, wherein X is a self-antigen and the unwanted immune response is an autoimmune response.

21. The composition of claim 14, wherein Z is the beta anomer.

22. The composition of claim 14 comprising Z conjugated at its C1, C2 or C6 to Y.

23. The composition of claim 14, wherein X is a therapeutic agent selected from the group consisting of Factor VIII and Factor IX.

24. The composition of claim 14, wherein X is a therapeutic agent selected from the group consisting of asparaginase and uricase.

25. The composition of claim 14, wherein m is 1 to 3;

R⁹ is —

CH₂—

CH₂—

(O—

CH₂—

CH₂)_t—

NH—

C(O)—

;

t is 1; and

R¹⁹ is CH₂CH₂OH.