Long-acting FGF21 fusion protein and pharmaceutical composition containing the same

Abstract

To provide a fusion protein containing an FGF21 mutant protein which has improved in vivo duration, protein stability and pharmacological effectiveness.SOLUTION: Provided is a fusion protein containing an FGF21 mutant protein and an Fc region of immunoglobulin. The fusion protein shows improved pharmacological effectiveness, in vivo duration and protein stability, and a pharmaceutical composition containing the fusion protein as an active ingredient can be effectively used as a therapeutic agent for diabetes mellitus, obesity, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease or non-alcoholic steatohepatitis.SELECTED DRAWING: Figure 5

Claims

1. A fusion protein comprising a fibroblast growth factor 21 (FGF21) mutant protein and the Fc region of an immunoglobulin, The FGF21 mutant protein is (1) Amino acid substitution of the EIRP amino acid sequence (SEQ ID NO: 42) at positions 98-101 from the N-terminus of the wild-type FGF21 protein; and (6) Amino acid substitution of amino acid E at position 180 from the N-terminus of the wild-type FGF21 protein. Includes, One of the following mutations (2) Amino acid substitution in the TGLEAV amino acid sequence (SEQ ID NO: 43) at positions 170-174 from the N-terminus of the wild-type FGF21 protein; (3) Amino acid substitutions in the TGLEAN amino acid sequence (SEQ ID NO: 44) at positions 170-174 from the N-terminus of the wild-type FGF21 protein; and (4) Amino acid substitution at amino acid N at position 170 from the N-terminus of the wild-type FGF21 protein It further includes, The wild-type FGF21 protein has the amino acid sequence shown by SEQ ID NO: 1, and the amino acid residue N of the FGF21 mutant protein introduced by mutation is glycosylated. The FGF21 mutant protein is linked to the Fc region of immunoglobulin via a linker. The Fc region of immunoglobulins is a hybrid Fc containing one or a combination thereof of the Fc regions of IgG1, IgG2, IgG3, IgG4, and IgGD. Fusion protein.

2. The fusion protein according to claim 1, wherein a linker is ligated to the C-terminus of the Fc region of the immunoglobulin and to the N-terminus of the FGF21 mutant protein.

3. The fusion protein according to claim 1 or 2, wherein the linker is a peptide consisting of 10 to 30 amino acid residues.

4. The fusion protein according to claim 3, wherein the linker has an amino acid sequence indicated by any one of sequence numbers 2 to 5.

5. The fusion protein according to claim 1, wherein the hybrid Fc comprises an IgG4 region and an IgD region.

6. The fusion protein according to claim 1, wherein the fusion protein has an amino acid sequence indicated by SEQ ID NO: 36, SEQ ID NO: 37, or SEQ ID NO:

39.

7. A pharmaceutical composition comprising a fusion protein according to any one of claims 1 to 6 for treating diabetes, obesity, dyslipidemia, metabolic syndrome, non-alcoholic fatty liver disease, or non-alcoholic steatohepatitis.

8. An isolated nucleic acid molecule encoding the fusion protein according to any one of claims 1 to 6.

9. An expression vector comprising the nucleic acid molecule described in claim 8.

10. A host cell comprising the expression vector described in claim 9.

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