Dual-target fusion proteins comprising fgf21 and glp-1, connected through a fc portion of an immunoglobulin

A fusion protein comprising or consisting of:

• a) a first polypeptide, wherein the first polypeptide is glucagon-like peptide-1 (GLP-1) or an analogue thereof;
• b) a second polypeptide, wherein the second polypeptide is an IgG4 Fe portion comprising the amino acid sequence of SEQ ID NO:
• 2 or a variant thereof;
• and
• c) a third polypeptide, wherein the third polypeptide is fibroblast growth factor 21 (FGF21) comprising a variant of the amino acid sequence of SEQ ID NO:
• 15,
• wherein the first polypeptide is linked to the second polypeptide via a first linker and the third polypeptide is linked to the second polypeptide via a second linker;
• and
• wherein the variant of SEQ ID NO:
• 15 comprises one or more amino acid mutations at positions 98 and 171;
• wherein the amino acid mutation at position 98 is selected from the group consisting of L98D and L98R;
• and wherein the amino acid mutation at position 171 is selected from the group consisting of P171A and P171G;
• and
• wherein the variant of SEQ ID NO:
• 15 further comprises one or more mutations at positions including 167, 175 and 179;
• wherein the amino acid mutation at position 167 is selected from the group consisting of S167H and S167C;
• wherein the amino acid mutation at position 175 is selected from the group consisting of R175L, R175H and R175P;
• and wherein the amino acid mutation at position 179 is selected from the group consisting of Y179S and Y179F.