INSULIN RECEPTOR PARTIAL AGONISTS

• US 20190177393A1
• Filed: 05/23/2017
• Published: 06/13/2019
• Est. Priority Date: 05/25/2016
• Status: Active Grant

• Current Assignee: Merck Sharp & Dohme LLC (Merck & Co., Inc.)
• Original Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Inventors: Lin, Songnian, Yan, Lin, Huo, Pei, Pissarnitski, Dmitri, Feng, Danqing, Nargund, Ravi, Madsen-Duggan, Christina, Zhu, Yuping, Kekec, Ahmet, Wu, Zhicai
• Granted Patent: US 10,689,430 B2
• Time in Patent Office: Days
• 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 38/28 Insulins
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: C07K 2319/00 Fusion polypeptide

Abstract

Insulin dimers and insulin analog dimers that act as partial agonists at the insulin receptor are disclosed.

Claims

1. An insulin dimer comprising:

a first B29 or B28 Lys of a first insulin heterodimer molecule having a first A-chain polypeptide and first B-chain polypeptide and a second B29 or B28 Lys of a second insulin heterodimer having a second A-chain polypeptide and second B-chain polypeptide conjugated together by a bifunctional linker selected from the group consisting Linker 1, Linker 2, Linker 3, Linker 4, Linker 5, Linker 6, Linker 7, Linker 8, Linker 9, Linker 10, Linker 11, Liner 12, Linker 13, Linker 14, Linker 15, Linker 16, Linker 17, Linker 18, Linker 19, Linker 20, Linker 21, Linker 22, Linker 23, Linker 24, Linker 25, Linker 26, Linker 27, Linker 28, Linker 29, Linker 30, Linker 31, Linker 32, Linker 33, Linker 34, Linker 35, Linker 36, Linker 37, Linker 38, Linker 39, Linker 40, Linker 41, Linker 42, Linker 43, Linker 44, Linker 45, Linker 46, Linker 47, Linker 48, Linker 49, Linker 50, Linker 51, Linker 52, Linker 53, Linker 54, Linker 55, Linker 56, Linker 57, Linker 58, Linker 59, Linker 60, Linker 61, Linker 62, Linker 63, Linker 64, and Linker 65.

2. The insulin dimer of claim 1, wherein at least one of the first or second A-chain or B-chain polypeptides is conjugated at its N-terminal amino acid to a substituent or at least the N-terminal amino acids of the first insulin heterodimer molecule are conjugated to a substituent or the N-terminal amino acids of both the first insulin heterodimer and second insulin heterodimer are conjugated to a substituent.

3. The insulin dimer of claim 2, wherein the substituent comprises an N-hydroxysuccinimide ester linked to a group having the general formula RC(O)—

, where R can be R′

CH₂, R′

NH, R′

O, and R′

can be H, linear alkyl chain, amino acid, peptide, polyethylene glycol (PEG), saccharides.

4. The insulin dimer of claim 2, wherein the substituent is a carbamoyl group, acetyl group, glycine, methyl group, methoxy acetyl group, dimethyl group, isobutyl group, PEG1 group, AEG group, AEG-C6 alkyl group, 3-morpholinopropionate, or PEG2 group.

5. The insulin dimer of claim 1, wherein the first insulin and the second insulin heterodimers are independently native human insulin, insulin lispro, insulin aspart, desB30 insulin, or insulin glargine.

6. The insulin dimer of claim 1, wherein each A-chain polypeptide independently comprises the amino acid sequence GX₂X₃EQCCX₈SICSLYQLX₁₇NX₁₉CX₂₃ (SEQ ID NO:

3) and each B-chain polypeptide independently comprises the amino acid sequence X₂₅LCGX₂₉X₃₀LVEALYLVCGERGFX₂₇YTX₃₁X₃₂ (SEQ ID NO;

4) or X₂₂VNQX₂₅X₂₆CGX₂₉X₃₀LVEALYLVCGERGFX₂₇YTX₃₁X₃₂X₃₃X₃₄X₃₅ (SEQ ID NO;

5) wherein X₂ is isoleucine or threonine;

X₃ is valine, glycine, or leucine;

X₈ is threonine or histidine;

X₁₇ is glutamic acid or glutamine;

X₁₉ is tyrosine, 4-methoxy-phenylalanine, alanine, or 4-amino phenylalanine;

X₂₃ is asparagine or glycine;

X₂₂ is or phenylalanine and desamino-phenylalanine;

X₂₅ is histidine or threonine;

X₂₆ is leucine or glycine;

X₂₇ is phenylalanine or aspartic acid;

X₂₉ is alanine, glycine, or serine;

X₃₀ is histidine, aspartic acid, glutamic acid, homocysteic acid, or cysteic acid;

X₃₁ is aspartic acid, proline, or lysine;

X₃₂ is lysine or proline;

X₃₃ is threonine, alanine, or absent;

X₃₄ is arginine or absent; and

X₃₅ is arginine or absent;

with the proviso at least one of X₃₁ or X₃₂ is lysine.

7. A composition comprising:

a first insulin or insulin analog heterodimer and a second insulin or insulin analog heterodimer each heterodimer including an A-chain polypeptide and a B-chain polypeptide, wherein the A-chain polypeptide and the B-chain polypeptide are linked together through interchain disulfide bonds;

wherein the first and second insulin or insulin analog heterodimers are covalently linked together through a linking moiety joining the side chain of an amino acid at or near the carboxy terminus of the two respective B-chain polypeptides;

wherein the linking moiety is selected from the group consisting of Linking moiety 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36,37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64 and 65;

wherein the insulin analog is selected from insulin lispro, insulin aspart, and insulin glargine; and

wherein the amino terminus of at least one of the A-chain polypeptides and the B-chain polypeptides of the first insulin polypeptide or second insulin polypeptide is covalently linked to a substituent.

8. The composition of claim 7, wherein the first and second insulin or insulin analog heterodimers are the same or wherein the first and second insulin or insulin analog heterodimers are different.

9. The composition of claim 7, wherein the linking moiety covalently links the first insulin or insulin analog heterodimer and the second insulin or insulin analog heterodimer via the epsilon amino group of a lysine residue at or near the carboxy terminus of their respective B-chain polypeptides.

10. The composition of claim 7, wherein the substituent has a general formula RC(O)—

, where R can be R′

CH2, R′

NH, R′

O, and R′

can be H, linear alkyl chain, amino acid, peptide, PEG, saccharides, which in particular aspects RC(O)—

may be acetyl, phenylacetyl, carbamoyl, N-alkyl carbamoyl, or alkoxycarbonyl. In particular aspects, the substituent is selected from the group consisting of acetyl, phenylacetyl, carbamoyl, N-alkyl carbamoyl, isobutyl, methoxy acetyl, glycine, aminoethylglucose (AEG), AEG-C6, PEG1, PEG2, N-dimethyl, and alkoxycarbonyl.

11. (canceled)

12. The composition of claim 11, wherein the composition further comprises a pharmaceutically acceptable carrier.

13. The composition of claim 11, wherein the composition further comprises a GLP-1 receptor agonist.

14. A method for treating diabetes comprising administering to an individual with diabetes a therapeutically effective amount of a composition comprising the insulin receptor partial agonist of claim 11.

15. The method of claim 14, wherein the diabetes is Type 1 diabetes, Type 2 diabetes, or gestational diabetes.

16. A composition for the treatment of diabetes comprising the insulin receptor partial agonist of claim 11.

17. The composition of claim 16, wherein the diabetes is Type 1 diabetes, Type 2 diabetes, or gestational diabetes.

18-19. -19. (canceled)

20. A composition comprising an insulin dimer selected from the group consisting of: