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US 2025/0051416 A1Published application
Insulin receptor partial agonists
AssigneeMerck Sharp & Dohme Corp.
InventorsDanqing Feng, Pei Huo, Ahmet Kekec, Songnian Lin, Dmitri A. Pissarnitski, Lin Yan
Life of this patent
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Abstract
Insulin dimers and insulin analog dimers that act as partial agonists at the insulin receptor are disclosed.
Claims22
An insulin dimer comprising:
- a first B29 Lys of a first insulin heterodimer molecule having a first A-chain polypeptide and first B-chain polypeptide and a second B29 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, Linker 12, Linker 13, Linker 14, Linker 15, and Linker 16, wherein at least one of the B-chain polypeptides is conjugated at its N-terminal amino acid to a capping group, or at least one of the N-terminal amino acids of the first insulin heterodimer molecule are conjugated to a capping group or at least one of N-terminal amino acids of the first insulin heterodimer and/or second insulin heterodimer are conjugated to a capping group.
A composition comprising:
- a first insulin or insulin analog heterodimer and a second insulin or insulin analog heterodimer each heterodimer having 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 Linker 1, Linker 2, Linker 3, Linker 4, Linker 5, Linker 6, Linker 7, Linker 8, Linker 9, Linker 10, Linker 11, Linker 12, Linker 13, Linker 14, Linker 15, and Linker 16;
- wherein the insulin is human insulin and the insulin analog is selected from insulin lispro, insulin aspart, and insulin glargine;
- and
- wherein at least one amino terminus of the B-chain polypeptides of the first insulin polypeptide and/or second insulin polypeptide is covalently linked to a capping group.
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A composition comprising an insulin dimer selected from the group consisting of
- Dimer
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- Structure
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- wherein the disulfide linkages are located between the Cys6 and Cys11 residues of the A-chain polypeptide and between the Cys7 and Cys20 of the A-chain to the Cys7 and Cys19 of the B-chain polypeptide, respectively;
- wherein the linking moieties are covalently linked to the epsilon amino acid of the lysine residue wherein the A-chain polypeptide for Dimers 1-43 has the amino acid sequence shown in SEQ ID NO:1;
- the B-chain polypeptide Dimers 1-43 has the amino acid sequence shown in SEQ ID NO:2, wherein SEQ ID NO:1 and SEQ ID NO:
- 2 as depicted by Formula I:
47 more elements
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Dependencies are inferred from the claim text.