Protozoan variant-specific surface proteins (VSP) as carriers for oral drug delivery

Patent metadata

Field	Value
Publication number	US-9457096-B2
Application number	US-201313843766-A
Country	US
Kind code	B2
Filing date	Mar 15, 2013
Priority date	Jul 6, 2012
Publication date	Oct 4, 2016
Grant date	Oct 4, 2016

Abstract

The invention provides compositions for oral delivery and methods of treatment using VSP carriers, such as Giardia sp. variable surface proteins (VSP), to deliver therapeutic agents. VSP drug carriers can be combined with bioactive peptides, e.g., insulin, glucagon, or hGH, and be administered orally or mucosally. VSP carriers are resistant to acidic pHs and to proteolytic degradation and protect therapeutic agents from degradation in the gastrointestinal tract.

First claim

What is claimed is:

1. A therapeutic composition comprising a VSP (Variant-specific Surface Protein) carrier and a bioactive peptide, wherein
(i) the VSP carrier can bind to the bioactive peptide;
(ii) the VSP carrier is not covalently bound to the bioactive peptide via a peptidic bond;
(iii) the bioactive peptide is therapeutically effective after binding to the VSP carrier;
(iv) the binding of the VSP carrier to the bioactive peptide increases the resistance of the bioactive peptide to pH-mediated and/or enzymatic degradation compared to the resistance of the same bioactive peptide not bound to said VSP carrier;
(v) the bioactive peptide is selected from the group consisting of insulin, human growth hormone, and glucagon;
(vi) the bioactive peptide is not a vaccine immunogen, and
(vii) the VSP carrier has at least 70% amino acid sequence identity with the sequence of the extracellular domain of a VSP from Giardia selected from VSP1267 (SEQ ID NO: 490), VSP9B10 (SEQ ID NO: 572), and VSPH7 (SEQ ID NO:504).

2. The composition of claim 1 , formulated for oral administration.

3. The composition of claim 1 , formulated for mucosal administration.

4. The composition of claim 1 , wherein the VSP carrier further comprise a protein purification tag sequence.

5. The composition of claim 4 , wherein the protein purification tag sequence is a His6 tag.

6. The composition of claim 1 , wherein the VSP carrier consists of the sequence of SEQ ID NO:1.

7. The composition of claim 1 , wherein the insulin is a natural insulin.

8. The composition of claim 1 , wherein the insulin is a recombinant insulin.

9. The composition of claim 1 , wherein the insulin is an insulin analog.

10. The composition of claim 9 , wherein the insulin analog is a fast-acting insulin.

11. The composition of claim 9 , wherein the insulin analog is a long-acting insulin.

12. The composition of claim 10 , wherein the fast-acting insulin is insulin aspart.

13. The composition of claim 11 , wherein the long-acting insulin is insulin glargine.

14. The composition of claim 1 , wherein the molecule to molecule ratio of VSP carrier to the bioactive peptide ranges from about 10:1 to about 1:10.

15. The composition of claim 14 , wherein the molecule to molecule ratio of VSP carrier to the bioactive peptide ranges from about 3:1 to about 1:3.

16. The composition of claim 15 , wherein the molecule to molecule ratio of VSP carrier to the bioactive peptide is 3:1.

17. The composition of claim 15 , wherein the molecule to molecule ratio of VSP carrier to the bioactive peptide is 1:1.

18. The composition of claim 1 , further comprising a pharmaceutically acceptable excipient.

19. A method of delivering a bioactive peptide to a target location in a subject comprising administering the therapeutic composition of claim 1 to a subject in need thereof.

20. A method of treating a disease or condition in a subject comprising administering an effective amount of the therapeutic composition of claim 1 to a subject in need thereof, wherein the disease or condition is a hormone deficiency.

21. The method of claim 20 , wherein the hormone deficiency is an insulin deficiency.

22. The method of claim 21 , wherein the insulin deficiency is type 1 diabetes.

23. A method of treating a disease or condition in a subject comprising (a) combining a VSP carrier and a bioactive peptide, wherein the VSP carrier can bind to the bioactive peptide, wherein the bioactive peptide is not a vaccine immunogen, therein the VSP carrier is not covalently bound to the bioactive peptide via peptidic bonds, wherein the bioactive peptide is therapeutically effective after binding to the VSP carrier, the binding of the VSP carrier to the bioactive peptide increases the resistance of the bioactive peptide to pH-mediated and/or enzymatic degradation compared to the resistance of the same bioactive peptide not bound to said VSP carrier, wherein the bioactive peptide is selected from the group consisting of insulin, human growth hormone, and glucagon, and wherein the VSP carrier has at least 70% amino acid sequence identity with the sequence of the extracellular domain of a VSP from Giardia selected from VSP1267 (SEQ ID NO:490), VSP9B10 (SEQ ID NO:572), and VSPH7 (SEQ ID NO:504); and wherein administering an effective amount of the combination of said VSP carrier and bioactive peptide treats the disease or condition in the subject, wherein the disease or condition is a hormone deficiency.

24. A method of making an orally deliverable composition, comprising combining a VSP carrier and a bioactive peptide, wherein the VSP carrier can bind to the bioactive peptide, wherein the bioactive peptide is not a vaccine immunogen, therein the VSP carrier is not covalently bound to the bioactive peptide via peptidic bonds, the binding of the VSP carrier to the bioactive peptide increases the resistance of the bioactive peptide to pH-mediated and/or enzymatic degradation compared to the resistance of the same bioactive peptide not bound to said VSP carrier, wherein the bioactive peptide is therapeutically effective after binding to the VSP carrier, wherein the bioactive peptide is selected from the group consisting of insulin, human growth hormone, and glucagon, and the VSP carrier has at least 70% amino acid sequence identity with the sequence of the extracellular domain of a VSP from Giardia selected from VSP1267 (SEQ ID NO:490), VSP9B10 (SEQ ID NO:572), and VSPH7 (SEQ ID NO:504).

25. A method of making an injectable composition suitable for oral administration comprising combining a VSP carrier and a bioactive peptide, wherein the VSP carrier can bind to the bioactive peptide, wherein the bioactive peptide is not a vaccine immunogen, wherein the VSP carrier is not covalently bound to the bioactive peptide via peptidic bonds, the binding of the VSP carrier to the bioactive peptide increases the resistance of the bioactive peptide to pH-mediated and/or enzymatic degradation compared to the resistance of the same bioactive peptide not bound to said VSP carrier, thereby making the injectable composition suitable for oral administration, wherein the bioactive peptide is therapeutically effective after binding to the VSP carrier, wherein the bioactive peptide is selected from the group consisting of insulin, human growth hormone, and glucagon, and the VSP carrier has at least 70% amino acid sequence identity with the sequence of the extracellular domain of a VSP from Giardia selected from VSP1267 (SEQ ID NO:490), VSP9B10 (SEQ ID NO: 572), and VSPH7 (SEQ ID NO: 504).

26. (Withdrawn-previously presented) The method of claim 25 , wherein the VSP carrier further comprises a protein purification tag sequence.

27. The method of claim 26 , wherein the protein purification tag sequence is a His6 tag.

28. The method of claim 25 , wherein the VSP carrier consists of the sequence of SEQ ID NO:1.

29. The method of claim 28 , wherein the insulin is a natural insulin.

30. The method of claim 28 , wherein the insulin is a recombinant insulin.

31. The method of claim 28 , wherein the insulin is an insulin analog.

32. The method of claim 31 , wherein the insulin analog is a fast-acting insulin.

33. The method of claims 31 , wherein the insulin analog is a long-acting insulin.

Assignees

• Consejo Nac De Investig Cientificas Y Tecn (Conicet)
• Inserm (Institut Nat De La Sante Et De La Rech Medicale)
• Consejo Nac De Investig Cientificas Y Tecn (Concet)
• Univ Catolica De Cordoba
• Assist Pubuque Hopitaux De Paris
• Univ Pierre Et Marie Curie (Paris 8)

Inventors

• Klatzmann David
• Piaggio Eliane
• Lujan Hugo

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K47/64

  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 title

• A61K38/26

  Glucagons · CPC title

• A61K38/29

  Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides · CPC title

• A61K38/27

  Growth hormone [GH], i.e. somatotropin · CPC title