GLUCAGON/GLP-1 RECEPTOR CO-AGONISTS

• US 20150376256A1
• Filed: 09/08/2015
• Published: 12/31/2015
• Est. Priority Date: 06/22/2011
• Status: Active Grant

• Current Assignee: Indiana University Research & Technology Corporation (Indiana University)
• Original Assignee: Indiana University Research & Technology Corporation (Indiana University)
• Inventors: DiMARCHI, Richard D., SMILEY, David L.
• Granted Patent: US 9,758,562 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• 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 38/26 Glucagons
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61K 49/00 Preparations for testing in vivo
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• 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: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/605 Glucagons
• CPC Class Codes: C07K 16/283 against Fc-receptors, e.g. CD16, CD32, CD64 CD23 C07K16/2851
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: C07K 2319/33 : fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
• CPC Class Codes: G01N 2333/605 : Glucagons
• CPC Class Codes: G01N 2800/042 : Disorders of carbohydrate metabolism, e.g. diabetes, glucose metabolism
• CPC Class Codes: G01N 2800/085 : Liver diseases, e.g. portal hypertension, fibrosis, cirrhosis, bilirubin
• CPC Class Codes: G01N 2800/2821 : Alzheimer
• CPC Class Codes: G01N 2800/2835 : Movement disorders, e.g. Parkinson, Huntington, Tourette
• CPC Class Codes: G01N 33/74 : involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors

Abstract

Provided herein are peptides and variant peptides that exhibit enhanced activity at the GLP-1 receptor, as compared to native glucagon.

Claims

1. A peptide comprising the amino acid sequence of:

a) SEQ ID NO;

12;

b) SEQ ID NO;

13;

c) SEQ ID NO;

14;

d) SEQ ID NO;

15, or

e) SEQ ID NO;

16;

or a pharmaceutically acceptable salt thereof.

2. A peptide of claim 1 comprising the amino acid sequence of SEQ ID NO:

12, or a pharmaceutically acceptable salt thereof.

3. A variant peptide comprising an amino acid sequence that is at least 85%, 90%, or 95% identical to the amino acid sequence of the peptide of claim 1, said variant peptide differing from the amino acid sequence of the peptide of claim 1 in that the variant peptide comprises one or more of the following features:

a) an acylated amino acid or an alkylated amino acid at position 10;

b) an amino acid covalently attached to a hydrophilic moiety at position 24;

d) the C-terminal amino acid of the variant peptide comprises a C-terminal amide in place of a C-terminal alpha carboxylate;

f) an amino acid at any of positions 1 through 29 is replaced with the corresponding amino acid of native glucagon (SEQ ID NO;

     1) at that position;

g) or any combinations thereof;

or a pharmaceuticallyacceptable salt thereof,

wherein the variant peptide exhibits enhanced activity at the GLP-1 receptor, as compared to native glucagon, and exhibits at least 100-fold greater selectivity for the human GLP-1 receptor versus the GIP receptor, or a pharmaceutically acceptable salt thereof.

4. The variant peptide of claim 3, comprising (i) a hydrophilic moiety covalently attached to an amino acid at position 16, 17, 21, 24, 29, a position within a C-terminal extension, or at the C-terminus, or a pharmaceutically acceptable salt thereof, or (ii) a Cys, Lys, Orn, homocysteine, and Ac-Phe covalently attached to a hydrophilic moiety, optionally, wherein the Cys, Lys, Orn, homocysteine, and Ac-Phe is located at position 16, 17, 21, 24, 29, a position within a C-terminal extension, or at the C-terminus of the variant peptide, or a pharmaceutically acceptable salt thereof.

5. The variant peptide of claim 4, wherein the hydrophilic moiety is a polyethylene glycol, optionally, a PEG of molecular weight between 10 kDa and 40 kDa, or a pharmaceutically acceptable salt thereof.

6. The variant peptide of claim 3, comprising (i) an acylated or alkylated amino acid which comprises a C8 to C20 alkyl chain, a C12 to C18 alkyl chain, or a C14 or C16 alkyl chain, or a pharmaceutically acceptable salt thereof, (ii) an acylated or alkylated amino acid which an acylated or alkylated amino acid of Formula I, Formula II, or Formula III, optionally, wherein the amino acid of Formula I is Lys, or a pharmaceutically acceptable salt thereof, (iii) an acylated or alkylated amino acid, wherein the acyl group or alkyl group is covalently attached to the amino acid via a spacer, optionally, wherein the spacer is an amino acid or a dipeptide, or a pharmaceutically acceptable salt thereof, (iv) or a combination thereof.

7. The variant peptide of claim 6, wherein the spacer comprises one or two acidic residues, or a pharmaceutically acceptable salt thereof.

8. The peptide of claim 1, wherein the

9. A conjugate comprising a peptide of claim 1 conjugated to a heterologous moiety, or a pharmaceutically acceptable salt thereof, wherein the conjugate exhibits enhanced activity at the GLP-1 receptor, as compared to native glucagon, and exhibits at least 100-fold greater selectivity for the human GLP-1 receptor versus the GIP receptor.

10. The conjugate of claim 9, wherein the heterologous moiety comprises one or more of:

a peptide, a polypeptide, a nucleic acid molecule, an antibody or fragment thereof, a polymer, a quantum dot, a small molecule, a toxin, a diagonostic agent, or a pharmaceutically acceptable salt thereof.

11. The conjugate of claim 10, comprising an extension of 1-21 amino acids C-terminal to the amino acid at position 31 of the peptide or variant peptide, or a pharmaceutically acceptable salt thereof.

12. The conjugate of claim 11, wherein the extension is selected from the group consisting of:

Gly, Glu, Cys, Gly-Gly, Gly-Glu, GPSSGAPPPS (SEQ ID NO;

     9) or GGPSSGAPPPS (SEQ ID NO;

     10), or a pharmaceutically acceptable salt thereof.

13. A dimer or multimer comprising a peptide of claim 1, or a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising the peptide of claim 1, or a pharmaceutically acceptable salt thereof.

15. The pharmaceutical composition of claim 14, comprising an anti-diabetic or anti-obesity agent.

16. A method of treating a disease or medical condition in a patient, wherein the disease or medical condition is selected from the group consisting of:

metabolic syndrome, diabetes, obesity, liver steatosis, and a neurodegenerative disease, comprising administering to the patient the pharmaceutical composition of claim 14 in an amount effective to treat the disease or medical condition.

17. A conjugate comprising a variant peptide of claim 3 conjugated to a heterologous moiety, or a pharmaceutically acceptable salt thereof, wherein the conjugate exhibits enhanced activity at the GLP-1 receptor, as compared to native glucagon, and exhibits at least 100-fold greater selectivity for the human GLP-1 receptor versus the GIP receptor.

18. The conjugate of claim 17, wherein the heterologous moiety comprises one or more of:

a peptide, a polypeptide, a nucleic acid molecule, an antibody or fragment thereof, a polymer, a quantum dot, a small molecule, a toxin, a diagonostic agent, or a pharmaceutically acceptable salt thereof.

19. The conjugate of claim 18, comprising an extension of 1-21 amino acids C-terminal to the amino acid at position 31 of the peptide or variant peptide, or a pharmaceutically acceptable salt thereof.

20. The conjugate of claim 19, wherein the extension is selected from the group consisting of:

Gly, Glu, Cys, Gly-Gly, Gly-Glu, GPSSGAPPPS (SEQ ID NO;

     9) or GGPSSGAPPPS (SEQ ID NO;

     10), or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising the variant peptide of claim 3, or a pharmaceutically acceptable salt thereof.