Methods and compositions for inducing oral tolerance in mammals

• US 6,391,303 B1
• Filed: 05/03/1999
• Issued: 05/21/2002
• Est. Priority Date: 11/18/1996
• Status: Expired due to Term

• Current Assignee: NOVO Nordisk North America Operations A/S (Novo Nordisk A/S)
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Milstein, Sam J., Haas, Susan
• Primary Examiner(s): Jones, Dwayne C.
• Application Number:
  US09/101,921
• Time in Patent Office: 1,114 Days
• Field of Search: 514/54, 514/617, 424/183.1
• US Class Current: 424/185.1
• CPC Class Codes: A61K 2039/542 oral/gastrointestinal
• CPC Class Codes: A61K 2239/31 characterized by the route of administration
• CPC Class Codes: A61K 2239/38 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 39/00 Medicinal preparations containing antigens or antibodies materials for immunoassay G01N33/53
• CPC Class Codes: A61K 39/0008 Antigens related to auto-immune diseases; Preparations to induce self-tolerance
• CPC Class Codes: A61K 39/35 Allergens
• CPC Class Codes: A61K 39/461 characterised by the cell type used
• CPC Class Codes: A61K 39/4621 immunosuppressive or immunotolerising
• CPC Class Codes: A61K 39/46433 Antigens related to auto-immune diseases; Preparations to induce self-tolerance
• CPC Class Codes: A61K 39/46434 Antigens related to induction of tolerance to non-self
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame

Abstract

The present invention relates to methods and pharmaceutical formulations for orally delivering an antigen to induce tolerance. The antigen is combined with derivatized amino acids or salts thereof. The induction of oral tolerance may be applied clinically for the prevention or treatment of auto-immune diseases and clinical allergic hypersensitivities, and for the prevention of allograft rejection.

Claims

1. A method of inducing oral tolerance in an animal, comprising orally administering to said animal a pharmaceutical formulation comprising an antigen and a delivery agent comprising at least one derivatized amino acid or a salt thereof in an amount sufficient to induce tolerance to said antigen.

2. The method of claim 1, wherein the derivatized amino acid is an acylated amino acid compound of the formula

wherein:

Ar is a substituted or unsubstituted phenyl,

R¹ is C₁ to C₁₀ alkyl, C₁ to C₁₀ alkenyl, phenyl, naphthyl, (C₁ to C₁₀ alkyl)phenyl, (C₁ to C₁₀ alkenyl)phenyl, (C₁ to C₁₀ alkyl)naphthyl, (C₁ to C₁₀ alkenyl)naphthyl;

R¹ is optionally substituted with C₁ to C₄ alkyl, C₁ to C₄ alkenyl, C₁ to C₄ alkoxy, —

OH, —

SH and —

CO₂R², cycloalkyl, cycloalkenyl, heteroalkyl, alkaryl, heteroaryl, heteroalkaryl, or any combination thereof; and

R² is hydrogen, C₁ to C₄ alkyl or C₁ to C₄ alkenyl.

3. The method of claim 1, wherein the derivatized amino acid is a sulphonated amino acid compound of the formula

4. The method of claim 1, wherein the antigen is selected from the group consisting of synthetic proteins, naturally produced proteins, synthetic peptides, naturally produced peptides, carbohydrates and lipopolysaccharides.

5. The method of claim 1, wherein the antigen is associated with the induction of auto-immune diseases, clinical (allergic) hypersensitivities or allograft rejection, and subunits or extracts therefrom.

6. The method of claim 1, wherein the formulation incorporates the derivatized amino acid at a dose of 100-1000 mg per kg of body weight.

7. The method of claim 6, wherein the formulation incorporates the derivatized amino acid at a dose of 250-750 mg per kg of body weight.

8. The method of claim 1, wherein the formulation additionally incorporates an enzyme inhibitor.

9. The method of claim 1, wherein the formulation additionally incorporates an adjuvant.

19. The method of claim 2, wherein the derivatized amino acid is an acylated amino acid compound of the formula

20. The method of claim 2, wherein the derivatized amino acid is an acylated amino acid compound of the formula

21. The method of claim 2, wherein the derivatized amino acid is an acylated amino acid compound of the formula

22. The method of claim 2, wherein the derivatized amino acid is an acylated amino acid compound of the formula

23. The method of claim 2, wherein the derivatized amino acid is an acylated amino acid compound of the formula

24. The method of claim 2, wherein the derivatized amino acid is an acylated amino acid compound of the formula

25. The method of claim 2, wherein the derivatized amino acid is an acylated amino acid compound of the formula

26. The method of claim 2, wherein the derivatized amino acid is an acylated amino acid compound of the formula

27. The method of claim 2, wherein the derivatized amino acid is an acylated amino acid compound of the formula

10. A pharmaceutical formulation for inducing oral tolerance in a mammal, comprising an antigen and a delivery agent comprising at least one derivatized amino acid or a salt thereof in an amount sufficient to induce oral tolerance.

11. The pharmaceutical formulation of claim 10, wherein the derivatized amino acid is an acylated amino acid compound of the formula

wherein:

Ar is a substituted or unsubstituted phenyl

R¹ is C₁ to C₁₀ alkyl, C₁ to C₁₀ alkenyl, phenyl, naphthyl, (C₁ to C₁₀ alkyl)phenyl, (C₁ to C₁₀ alkenyl)phenyl, (C₁ to C₁₀ alkyl)napthyl, (C₁ to C₁₀ alkenyl)naphthyl;

R¹ is optionally substituted with C₁ to C₄ alkyl, C₁ to C₄ alkenyl,C₁ to C₄ alkoxy, —

OH, —

SH and —

CO₂R², cycloalkyl, cycloalkenyl, heteroalkyl, alkaryl, heteroaryl, heteroalkaryl, or any combination thereof; and

R² is hydrogen, C₁ to C₄ alkyl or C₁ to C₄ alkenyl.

12. The pharmaceutical formulation of claim 10, wherein the derivatized amino acid is a sulphonated amino acid compound of the formula

13. The pharmaceutical formulation claim 10, wherein the derivatized amino acid is administered at a dose of about 100-1000 mg per kg of body weight.

14. The pharmaceutical formulation claim 10, wherein the derivatized amino acid is administered at a dose of about 250-750 mg per kg of body weight.

15. The pharmaceutical formulation of claim 10, wherein the antigen is selected from the group consisting of synthetic proteins, naturally produced proteins, synthetic peptides, naturally produced peptides, carbohydrates and lipopolysaccharides.

16. The pharmaceutical formulation of claim 10, wherein the antigen is associated with the induction of auto-immune diseases, clinical (allergic) hypersensitivities or allograft rejection, and subunits or extracts therefrom.

17. The pharmaceutical formulation of claim 10, wherein the formulation additionally incorporates an adjuvant.

18. The pharmaceutical formulation of claim 10, wherein the formulation additionally incorporates an enzyme inhibitor.