Hyperglycosylated polypeptide variants and methods of use

• US 7,597,884 B2
• Filed: 02/08/2006
• Issued: 10/06/2009
• Est. Priority Date: 08/09/2004
• Status: Active Grant

• Current Assignee: Alios Biopharma, Inc. (Johnson & Johnson)
• Original Assignee: Alios Biopharma, Inc. (Johnson & Johnson)
• Inventors: Seiwert, Scott D., Hong, Jin, Blatt, Lawrence M.
• Primary Examiner(s): Tsang; Cecilia
• Assistant Examiner(s): Ha; Julie
• Application Number:
  US11/351,163
• Publication Number:
  US 20060204473A1
• Time in Patent Office: 1,336 Days
• Field of Search: None
• US Class Current: 424/85.4
• 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: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 14/555 Interferons [IFN]
• CPC Class Codes: C07K 14/56 IFN-alpha
• CPC Class Codes: C07K 14/565 IFN-beta
• CPC Class Codes: C07K 14/57 IFN-gamma
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides synthetic Type I interferon receptor polypeptide agonists comprising consensus or hybrid Type I interferon receptor polypeptide agonists, containing one or more native or non-native glycosylation sites. The present invention provides synthetic Type I interferon receptor polypeptide agonists comprising consensus or hybrid Type I interferon receptor polypeptide agonists, containing one or more native or non-native glycosylation sites, as well as erythropoietin and darbepoetin alfa, each of which are linked to a penetrating peptide that facilitates translocation of a substance across a biological barrier as well as pharmaceutical compositions, including oral formulations, of the same. The present invention further provides oral formulations of hyperglycosylated or protease-resistant, hyperglycosylated polypeptide variants, which polypeptide variants lack at least one protease cleavage site found in a parent polypeptide, and thus exhibit increased protease resistance compared to the parent polypeptide, which polypeptide variants further include (1) a carbohydrate moiety covalently linked to at least one non-native glycosylation site not found in the parent protein therapeutic or (2) a carbohydrate moiety covalently linked to at least one native glycosylation site found but not glycosylated in the parent protein therapeutic. The present invention further provides compositions, including oral pharmaceutical compositions, comprising the synthetic Type I interferon receptor polypeptide agonist, the hyperglycosylated polypeptide variant, or the hyperglycosylated, protease-resistant polypeptide variant. The present invention further provides containers, devices, and kits comprising the synthetic Type I interferon receptor polypeptide agonist, the hyperglycosylated polypeptide variant, or the hyperglycosylated, protease-resistant polypeptide variant. The present invention further provides therapeutic methods involving administering an effective amount of an oral pharmaceutical composition comprising a synthetic Type I interferon receptor polypeptide agonist, a hyperglycosylated polypeptide variant, or a hyperglycosylated, protease-resistant polypeptide variant to an individual in need thereof.

Claims

1. A hyperglycosylated Type 1 interferon variant of a parent Type 1 interferon, wherein the parent Type 1 interferon is selected from the group consisting of interferon alfacon-1 and interferon α

14, wherein the hyperglycosylated Type 1 interferon variant is the parent Type 1 interferon that has been modified to include at least three additional glycosylation sites, wherein at least one of the additional glycosylation sites is introduced by an amino acid substitution selected from the group consisting of D31N, D102N, D108N, and E138T.

2. The hyperglycosylated Type 1 interferon variant of claim 1, wherein the parent Type 1 interferon is interferon alfacon-1.

3. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitution D102N.

4. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitution D108N.

5. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitution E138T.

6. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitutions D102N and D108N.

7. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitutions D102N and E138T.

8. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitutions D108N and E138T.

9. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitutions D102N, D108N, and E138T.

10. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is selected from the group consisting of an amino acid sequence set forth in SEQ ID NOS:

1769-1773.

11. The hyperglycosylated Type 1 interferon variant of claim 1, wherein the parent Type 1 interferon is interferon α

14.

12. The hyperglycosylated Type 1 interferon variant of claim 11, wherein the hyperglycosylated Type 1 interferon variant is interferon α

14 comprising at least the amino acid substitution D108N.

13. The hyperglycosylated Type 1 interferon variant of claim 11, wherein the hyperglycosylated Type 1 interferon variant is interferon α

14 comprising at least the amino acid substitution E138T.

14. The hyperglycosylated Type 1 interferon variant of claim 11, wherein the hyperglycosylated Type 1 interferon variant is interferon α

14 comprising at least the amino acid substitution D108N and E138T.

15. A pharmaceutical composition comprising the hyperglycosylated Type 1 interferon variant of claim 1;

and a pharmaceutically acceptable excipient.

16. The composition of claim 15, wherein the pharmaceutically-acceptable excipient is suitable for oral delivery.

17. The composition of claim 15, wherein the pharmaceutically-acceptable excipient is suitable for parenteral delivery.

18. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitutions D31N and D102N.

19. The hyperglycosylated Type 1 interferon variant of claim 3, further comprising the amino acid substitution S104T.

20. The hyperglycosylated Type 1 interferon variant of claim 1, further comprising the amino acid substitution S104T.

21. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitution D31N.

22. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitutions D31N and D108N.

23. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitutions D31N and E138T.

24. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitutions D31N, D102N, and D108N.

25. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitutions D31N, D102N, and E138T.

26. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitutions D31N, D108N, and E138T.

27. The hyperglycosylated Type 1 interferon variant of claim 2, wherein the hyperglycosylated Type 1 interferon variant is interferon alfacon-1 comprising at least the amino acid substitutions D31N, D102N, D108N, and E138T.