Patent ID: 9593156
Date: 2017-03-14
CPC Classifications: A61K,A61P,C07K

Claim:
1. An insulin analog dimer, said dimer comprising i) a first insulin polypeptide and a second insulin polypeptide, wherein said first insulin and second insulin polypeptide are both single chain insulin analogs each comprising a first and second set of an A chain, a B chain and a linking moiety, wherein for each set of A chain, B chain and linking moiety a first end of said linking moiety is covalently bound to the carboxy terminus of the B chain and a second end of said linking moiety is covalently bound to the amino terminus of the A chain, further wherein the first and second insulin polypeptides are linked to one another via a PEG, or disulfide bearing, dimerization linker covalently linking the side chain of a lysine of the linking moiety of the respective first and second insulin polypeptides, said A chain of the first and second insulin polypeptide comprising a sequence independently selected from GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1), GIVDECCFRSCDLRRLENYCN (SEQ ID NO: 11), GIVDECCFRSCDLRRLEMYCA (SEQ ID NO: 5) and GIVEECCFRSCDLALLETYCA (SEQ ID NO: 7) said B chain of the first and second insulin polypeptide comprising a sequence independently selected from FVNQHLCGSHLVEALYLVCGERGFF (SEQ ID NO: 23), GPETLCGAELVDALYLVCGDRGFY (SEQ ID NO: 77), GPETLCGAELVDALQFVCGDRGFY (SEQ ID NO: 89), GPEHLCGAELVDALYLVCGDRGFY (SEQ ID NO: 14); AYRPSETLCGGELVDTLQFVCGDRGFY (SEQ ID NO: 90) and AYRPSETLCGGELVDTLYLVCGDRGFY (SEQ ID NO: 92) said linking moiety of the first and second insulin polypeptide comprising a sequence independently selected from GYGSSSRX ii) a first insulin polypeptide and a second insulin polypeptide, wherein said first insulin polypeptide is a two chain insulin analog comprising a first A chain, and a first B chain, wherein said first A chain and first B chain are linked to one another through interchain disulfide bonds; said second insulin polypeptide is a single chain insulin analog comprising a second A chain, a second B chain and a linking moiety, wherein a first end of said linking moiety is covalently bound to the carboxy terminus of the second B chain and a second end of said linking moiety is covalently bound to the amino terminus of the second A chain, wherein the first and second insulin polypeptides are linked to one another via a disulfide bearing, dimerization linker, wherein a first end of the dimerization linker is covalently linked to the side chain of the N-terminal amino acid of the B chain of said first insulin polypeptide and a second end of the dimerization linker is covalently linked to the side chain of a lysine of the linking moiety of the second insulin polypeptide, said A chain of the first and second insulin polypeptide comprising a sequence independently selected from GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1), GIVDECCFRSCDLRRLENYCN (SEQ ID NO: 11), GIVDECCFRSCDLRRLEMYCA (SEQ ID NO: 5) and GIVEECCFRSCDLALLETYCA (SEQ ID NO: 7) said B chain of the first insulin polypeptide comprising a sequence independently selected from CFVNQHLCGSHLVEALYLVCGERGFFYTPKT (SEQ ID NO: 94), CGPETLCGAELVDALYLVCGDRGFYFNKPT (SEQ ID NO: 95), CGPETLCGAELVDALQFVCGDRGFYFNKPT (SEQ ID NO: 96), CGPEHLCGAELVDALYLVCGDRGFYNKPT (SEQ ID NO: 97); CAYRPSETLCGGELVDTLQFVCGDRGFY (SEQ ID NO: 91) and CAYRPSETLCGGELVDTLYLVCGDRGFY (SEQ ID NO: 93); said B chain of the second insulin polypeptide comprising a sequence independently selected from FVNQHLCGSHLVEALYLVCGERGFF (SEQ ID NO: 23), GPETLCGAELVDALYLVCGDRGFY (SEQ ID NO: 77), GPETLCGAELVDALQFVCGDRGFY (SEQ ID NO: 89), GPEHLCGAELVDALYLVCGDRGFY (SEQ ID NO: 14); AYRPSETLCGGELVDTLQFVCGDRGFY (SEQ ID NO: 90) and AYRPSETLCGGELVDTLYLVCGDRGFY (SEQ ID NO: 92) said linking moiety of the second insulin polypeptide comprising a sequence independently selected from GYGSSSRX iii) a first insulin polypeptide and a second insulin polypeptide, wherein said first insulin and second insulin polypeptide are both two chain insulin analogs comprising a first and second set of A chain and a B chain, respectively, wherein the A chain and B chain of each set are linked to one another through interchain disulfide bonds, further wherein the first and second insulin polypeptides are linked to one another via a dimerization linker joining the side chain of a carboxy terminal amino acid of the respective two B chains, wherein said A chain of the first and second insulin polypeptide comprise a sequence independently selected from the group consisting of GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1), GIVDECCFRSCDLRRLENYCN (SEQ ID NO: 11), GIVDECCFRSCDLRRLEMYCA (SEQ ID NO: 5) and GIVEECCFRSCDLALLETYCA (SEQ ID NO: 7) said B chain of the first and second insulin comprise a sequence independently selected from the group consisting of FVNQHLCGSHLVEALYLVCGERGFFYTPX iv. a first insulin polypeptide and a second insulin polypeptide, wherein said first insulin and second insulin polypeptide are both single chain insulin analogs each comprising a first and second set of an A chain, a B chain and a linking moiety, wherein for each set of A chain, B chain and linking moiety, a first end of said linking moiety is covalently bound to the carboxy terminus of the B chain and a second end of said linking moiety is covalently bound to the amino terminus of the A chain, further wherein the first and second insulin polypeptides are linked to one another via a PEG, or disulfide bearing, dimerization linker, wherein a first end of the dimerization linker is covalently linked to the side chain of a lysine of the linking moiety of one of the first or second insulin polypeptides and a second end of the dimerization linker is covalently linked to the N-terminal amine of the B chain of the other first or second insulin polypeptide, said A chain of the first insulin polypeptide comprising the sequence TPAKSEGIVEECCFRSCDLALLETYCA (SEQ ID NO: 103); said B chain of the first insulin polypeptide comprising the sequence AYRPSETLCGGELVDTLQFVCGDRGFY (SEQ ID NO: 90) or AYRPSETLCGGELVDTLYLVCGDRGFY (SEQ ID NO: 92); said A chain of the second insulin polypeptide comprising the sequence GIVEQCCTSICSLYQLENYCN (SEQ ID NO: 1); said B chain of the second insulin polypeptide comprising a sequence independently selected from FVNQHLCGSHLVEALYLVCGERGFF (SEQ ID NO: 23), and GPEHLCGAELVDALYLVCGDRGFY (SEQ ID NO: 14), said linking moiety of the first and second insulin polypeptides comprising a sequence independently selected from GYGSSSRX