TREATMENT OF HYPOGLYCEMIA

• US 20150005233A1
• Filed: 02/08/2013
• Published: 01/01/2015
• Est. Priority Date: 02/08/2012
• Status: Abandoned Application

• Current Assignee: La Jolla Pharmaceutical Company (Innoviva, Inc.)
• Original Assignee: Seneb BioSciences, Inc.
• Inventors: DeFrees, Shawn
• Application Number:
  US14/377,475
• Publication Number:
  US 20150005233A1
• Time in Patent Office: Days
• US Class Current: 514/6.7
• 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 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 14/72 for hormones for neuromediators C07K14/70571
• CPC Class Codes: C07K 2319/31 fusions, other than Fc, for prolonged plasma life, e.g. albumin
• CPC Class Codes: C07K 2319/95 containing a motif/fusion for degradation (ubiquitin fusions, PEST sequence)

Abstract

This invention provides compounds, compositions, and methods for treating hypogly.

Claims

1. An isolated fusion protein, comprising an antagonist of the GLP-1 receptor (AGP) that is at least 90% identical to an amino acid sequence selected from Table 1, wherein said antagonist of the GLP-1 receptor is linked to a recombinant polypeptide (FPP), wherein the FPP is selected from Table 2

2. The isolated fusion protein of claim 1, wherein the antagonist of the GLP-1 receptor is selected from Seq ID No. 1, Seq ID No. 15 and Seq ID No. 18.

3. The isolated fusion protein of claim 1, wherein the antagonist peptide of GLP-1 receptor and the FPP are linked via a spacer, wherein the spacer sequence comprises between 1 to about 50 amino acid residues, and wherein the spacer optionally comprises a cleavage sequence.

4. The isolated fusion protein of claim 1, wherein the fusion protein binds to the same target receptor of the corresponding native antagonist of the GLP-1 receptor peptide that lacks the FPP, and wherein said fusion protein retains at least about 0.1% to about 30% or greater of the binding affinity of the corresponding antagonist peptide of the GLP-1 receptor that lacks the FPP.

5. The isolated fusion protein of claim 1, comprising an amino acid sequence that has at least 90% sequence identity to an amino acid sequence selected from Table 3.

6. A pharmaceutical composition comprising the isolated fusion protein of claim 1 and a pharmaceutically acceptable carrier.

7. The isolated protein of claim 1 that is configured according to formula I:

(FPP)x-AGP-(FPP)y wherein independently for each occurrence;

(a) x is either 0 or 1; and

(b) y is either 0 or 1, wherein x+y>

1.

8. The isolated fusion protein of claim 1, wherein the FPP is fused to an antagonist of the GLP-1 receptor peptide on an N- or C-terminus of the antagonist GLP-1 receptor peptide

9. The isolated fusion protein of claim 1, characterized in that:

(i) it has a longer terminal half-life when administered to a subject compared to the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP when administered to a subject at a comparable molar dose;

(ii) when a smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP administered to a subject under an otherwise equivalent dose regimen, the fusion protein achieves a comparable area under the curve (AUC) as the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP;

(iii) when a smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP administered to a subject under an otherwise equivalent dose regimen, the fusion protein achieves a comparable therapeutic effect as the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP;

(iv) when the fusion protein is administered to a subject less frequently in comparison to the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP administered to a subject using an otherwise equivalent molar amount, the fusion protein achieves a comparable area under the curve (AUC) as the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP;

(v) when the fusion protein is administered to a subject less frequently in comparison to the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP administered to a subject using an otherwise equivalent molar amount, the fusion protein achieves a comparable therapeutic effect as the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP;

(vi) when an accumulatively smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP administered to a subject under an otherwise equivalent dose period, the fusion protein achieves comparable area under the curve (AUC) as the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP;

or (vii) when an accumulatively smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP administered to a subject under an otherwise equivalent dose period, the fusion protein achieves comparable therapeutic effect as the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP.

10. A method of producing a fusion protein comprising a antagonist peptide of GLP-1 receptor fused to one or more recombinant polypeptides (FPP), comprising:

(a) providing host cell comprising a recombinant polynucleotide molecule encoding the fusion protein of claim 1;

(b) culturing the host cell under conditions permitting the expression of the fusion protein; and

(c) recovering the fusion protein.

11. The method of claim 10, wherein the antagonist peptide of GLP-1 receptor of the fusion protein has at least 90% sequence identity to:

(a) human antagonist peptide of GLP-1 receptor;

or (b) a sequence selected from Table 1.

12. The method of claim 10, wherein the one or more FPP of the expressed fusion protein has at least 90%>

sequence identity to a sequence selected from Table 2.

13. The method of claim 10, wherein the polynucleotide molecule encoding the fusion protein comprises a nucleic acid sequence exhibiting at least 90%>

sequence identity of a nucleic acid of the peptides listed in Table 3.

14. The method of claim 13, wherein the polynucleotide is codon optimized for enhanced expression of said fusion protein in the host cell.

15. The method of claim 10, wherein the host cell is a prokaryotic cell.

16. The method of claim 10, wherein the isolated fusion protein is recovered from the host cell cytoplasm in substantially soluble form.

17. An isolated nucleic acid comprising a nucleotide sequence encoding the fusion protein of claim 1 or the complement thereof.

18. A method of treating a glucose regulating peptide related condition in a subject, comprising administering to the subject a therapeutically effective amount of a fusion protein of claim 1.

19. The method of claim 18, wherein the glucose regulating peptide related condition is selected from neonatal hyperinsulinism, congential hyperinsulinism, acute hypoglycemia, nocturnal hypoglycemia, chronic hypoglycemia, Beckwith-Wiedemann syndrome, congenital disorders of glycosylation, hypoglycemia resulting from dialysis, glucagonomas, secretory disorders of the airway, arthritis, neuroendocrine tumors, osteoporosis, central nervous system disease, restenosis, neurodegenerative disease, renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, hypertension, and disorders wherein the reduction of food intake is desired, stroke, irritable bowel syndrome, myocardial infarction (e.g., reducing the morbidity and/or mortality associated therewith), stroke, acute coronary syndrome (e.g., characterized by an absence of Q-wave) myocardial infarction, post-surgical catabolic changes, hibernating myocardium or diabetic cardiomyopathy, post-prandial hypoglycemia, insufficient urinary sodium excretion, excessive urinary potassium concentration, conditions or disorders associated with toxic hypervolemia, (e.g., renal failure, congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary edema, and hypertension), polycystic ovary syndrome, respiratory distress, nephropathy, left ventricular systolic dysfunction, (e.g., with abnormal left ventricular ejection fraction), gastrointestinal disorders such as diarrhea, postoperative dumping syndrome and irritable bowel syndrome, (i.e., via inhibition of antro-duodenal motility), critical illness polyneuropathy (CIPN), dyslipidemia, organ tissue injury caused by reperfusion of blood flow following ischemia, and coronary heart disease risk factor (CHDRF) syndrome.

20. The method of claim 18, wherein the therapeutically effective amount results in maintaining blood concentrations of the fusion protein within a therapeutic window for the fusion protein at least three-fold longer compared to the corresponding native antagonist peptide of GLP-1 receptor that lacks the FPP administered at a comparable amount to a subject.

21. The method of claim 20, wherein administration of two or more consecutive doses of the fusion protein administered using a therapeutically effective dose regimen to a subject results in a gain in time between consecutive Cmax peaks and/or Cmin troughs for blood levels of the fusion protein compared to the corresponding antagonist peptide of GLP-1 receptor not linked to the fusion protein and administered using a therapeutically dose regimen established for the AGP.

22. The method of claim 21, wherein (i) a smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP administered to a subject under an otherwise equivalent dose regimen, and the fusion protein achieves a comparable therapeutic effect as the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP;

(ii) the fusion protein is administered less frequently to a subject in comparison to the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP administered to a subject using an otherwise equivalent molar dose, and the fusion protein achieves a comparable therapeutic effect as the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP;

or (iii) an accumulatively smaller molar amount of the fusion protein is administered to a subject in comparison to the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP administered to a subject under the otherwise equivalent dose period, the fusion protein achieves a comparable therapeutic effect as the corresponding antagonist peptide of GLP-1 receptor that lacks the FPP.

23. The method of claim 19, wherein the therapeutic effect is a measured parameter selected from HbAlc concentrations, insulin concentrations, stimulated C peptide, fasting plasma glucose (FPG), serum cytokine levels, CRP levels, insulin secretion and Insulin-sensitivity index derived from an oral glucose tolerance test (OGTT), body weight, and food consumption.