Insulin immunoglobulin fusion proteins
Disclosed herein are immunoglobulin fusion proteins comprising an insulin therapeutic peptide and an immunoglobulin region that targets the insulin therapeutic peptide to the liver of an individual in need thereof. Further disclosed herein are compositions comprising the immunoglobulin fusion proteins and methods for using the immunoglobulin fusion proteins for the treatment or prevention of a disease or condition in a subject, for example, diabetes and diabetes related conditions.
1. A composition comprising a molecule of Formula XVII:
I-L-G (Formula XVII)
wherein:
I has the formula B-C-A or A-C-B; wherein B comprises an insulin B chain; A comprises an insulin A chain; C comprises a connecting peptide connecting B and A;
L comprises a linker; and
G comprises an immunoglobulin or immunoglobulin fragment that specifically binds to an asialoglycoprotein receptor (ASGPR).
2. The composition of claim 1 , wherein A and B are linked by a disulfide bond.
3. The composition of claim 1 , wherein the insulin B chain comprises an amino acid sequence having no more than 1, 2, 3 or 4 amino acid differences from SEQ ID NO: 160 (FVNQHLCGSHLVEALYLVCGERGFFYT).
4. The composition of claim 1 , wherein the insulin A chain comprises an amino acid sequence having no more than 1, 2, 3 or 4 amino acid differences from SEQ ID NO: 161 (GIVEQCCTSICSLYQLENYC).
5. The composition of claim 1 , wherein the linker comprises a linker peptide.
6. The composition of claim 5 , wherein the linker peptide comprises an amino acid sequence selected from: (a) an amino acid sequence having at least 50% glycine, serine, or glycine and serine amino acids; and (b) an amino acid sequence having at least 50% glycine, alanine, or glycine and alanine amino acids.
7. A method of treating a disease or condition associated with glucose metabolism in a subject in need thereof, the method comprising administering an effective amount of the composition of claim 1 .
8. The composition of claim 1 , wherein the insulin therapeutic peptide comprises SEQ ID NOS: 160 and 161.
9. The composition of claim 1 , wherein the connecting peptide comprises SEQ ID NO: 159 (GGGX 1 X 2 ), wherein X 1 and X 2 are independently a naturally or a non-naturally occurring amino acid.
10. The composition of claim 9 , wherein X 1 is P, G, or S.
11. The composition of claim 9 , wherein X 2 is R, S, G, or K.
12. The composition of claim 1 , wherein C comprises a protease cleavage site.
13. The composition of claim 1 , wherein the insulin B chain comprises SEQ ID NO: 157 (FVNQHLCGSX A LVEALYLVCGERGFFYTX B X C T); and X A , X B , and X C are independently a naturally or a non-naturally occurring amino acid.
14. The composition of claim 13 , wherein the X A is D or H; the X B is D or P; or the X C is P or K.
15. The composition of claim 1 , wherein the insulin A chain comprises SEQ ID NO: 158 (GIVEQCCX D SICSLYQLENYCN), and X D is a naturally or a non-naturally occurring amino acid.
16. The composition of claim 15 , wherein X D is selected from H and T.