Fibroblast growth factor-21-Fc fusion proteins
The invention relates to the identification of fusion proteins comprising polypeptide and protein variants of fibroblast growth factor 21 (FGF21) with improved pharmaceutical properties. Also disclosed are methods for treating FGF21-associated disorders, including metabolic conditions.
1. A fusion protein comprising an FGF21 variant and an Fc region, wherein the FGF21 variant comprises the following mutations relative to the full length hFGF21 sequence SEQ ID NO:1: Q55C, R105K, G148C, K150R, P158S, S195A, P199G, and G202A.
2. The fusion protein of claim 1 , wherein the FGF21 variant comprises the amino acid sequence of SEQ ID NO:11.
3. The fusion protein of claim 1 , wherein the FGF21 variant is fused to said Fc region by a GS linker.
4. The fusion protein of claim 1 , wherein the Fc region is a modified Fc fragment with a LALA mutation.
5. The fusion protein of claim 1 , comprising at least one disulfide bond engineered between Gln55Cys and a cysteine residue at one of Cys103, Cys 121, Gly148Cys, Asn149Cys, Lys150Cys, Ser141Cys, Pro152Cys, His153Cys, Arg154Cys, Asp155Cys, Pro156Cys, Ala157Cys, Pro158Cys, Arg159Cys, Gly160Cys, Pro161Cus, Ala162Cys, and Arg163Cys.
6. The fusion protein of claim 1 , comprising at least one disulfide bond engineered between Gly148Cys and a cysteine residue at one of Cys103, Cys 121, Arg47Cys, Tyr48Cys, Leu49Cys, Tyr50Cys, Thr51Cys, Asp52Cys, Asp53Cys, Ala54Cys, Gln55Cys, Gln56Cys, Thr57Cys, Glu58Cys, Gly160Cys, Pro161Cys, Ala162Cys, Arg163Cys, and Phe164Cys.
7. The fusion protein of claim 6 , further enhanced with engineered disulfide bond Gln55Cys-Gly148Cys.