Anti-FGFR1c antibody-FGF21 fusion proteins

An FGF21 receptor (FGF21R) agonist that is capable of simultaneously binding βKlotho (KLB) and FGFR1c, wherein the FGF21R agonist comprises:

• a first KLB-interacting domain (K1) and a second KLB-interacting domain (K2), wherein each of K1 and K2 comprise an N-terminally truncated FGF21 fragment (ΔN-FGF21) comprising the amino acid sequence of SEQ ID NO:
• 448;
• a first FGFR1c-interacting domain (F1) and a second FGFR1-c-interacting domain (F2), wherein each of F1 and F2 comprise an antigen-binding portion of an anti-FGFR1c antibody, wherein the antigen-binding portion comprises three complementarity determining regions (CDRs) of a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO:
• 306 and three CDRs of a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO:
• 314;
• and
• a first multimerizing domain (M1), and a second multimerizing domain, wherein each of M1 and M2 is selected from an immunoglobulin CH2 domain, an immunoglobulin CH3 domain, and an Fc domain of an immunoglobulin;
• wherein K1 is attached to the C-terminus of M1, K2 is attached to the C-terminus of M2, F1 is attached to the N-terminus of M1, and F2 is attached to the N-terminus of M2.