Fusion protein of exendin-4 to a transferrin (Tf) polypeptide
View Patent ↗The invention provides fusion proteins comprising an exendin-4 fused to a transferrin (Tf) via a polypeptide linker, as well as corresponding nucleic acid molecules, vectors, host cells, and pharmaceutical compositions. The invention also provides the use of the exendin-4/Tf fusion proteins for treatment of Type II diabetes, obesity, and to reduce body weight.
1. A fusion protein comprising an exendin-4 fused to a transferrin (Tf) via a polypeptide linker, wherein said Tf is modified to exhibit reduced glycosylation as compared to a native transferrin molecule, and further wherein said Tf has the amino acid sequence as shown in SEQ ID NO: 17.
2. The fusion protein of claim 1 , wherein the linker is a nonhelical polypeptide.
3. The fusion protein of claim 1 , wherein the linker is selected from the group consisting of PEAPTD (SEQ ID NO: 6), (PEAPTD) 2 (SEQ ID NO: 5), PEAPTD (SEQ ID NO: 6) in combination with an IgG hinge linker, and (PEAPTD) 2 (SEQ ID NO: 5) in combination with an IgG hinge linker.
4. The fusion protein of claim 1 , wherein said exendin-4 has the amino acid sequence as shown in SEQ ID NO: 4.
5. The fusion protein of claim 1 , wherein the exendin-4 molecule is fused at the N-terminal end of the fusion protein, at the C-terminal end of the fusion protein or at both the N- and C-terminal ends of the fusion protein.
6. The fusion protein of claim 1 , wherein the N-terminus of the fusion protein further comprises a secretion signal sequence.
7. The fusion protein of claim 6 , wherein the signal sequence is a signal sequence from serum transferrin, lactoferrin, melanotransferrin, or a variant thereof.
8. The fusion protein of claim 6 , wherein the signal sequence is a human scrum albumin (HS,A)/MFα-1 hybrid leader sequence, a modified PISA/MFα-1 hybrid leader sequence, or a Tf signal sequence.
9. The fusion protein of claim 6 , wherein the signal sequence is the human Tf signal sequence as shown in SEQ ID NO: 1.8.
10. A pharmaceutical composition comprising the fusion protein of claim 1 and a pharmaceutically acceptable carrier.
11. The pharmaceutical composition of claim 10 , wherein the composition is adapted to be administered via inhalation.