Anti-FGFR1c antibody-FGF21 fusion proteins
The present invention provides agonists of FGF21 signaling. In particular, the present invention provides FGF21 receptor (FGF21R) agonists that are capable of simultaneously binding βKlotho (KLB) and/or FGFR1c to mimic the signaling activity of FGF21. The present invention also provides anti-FGF21 and anti-KLB/FGFR1c antibodies and antigen-binding fragments thereof. Also provided are methods of treating various metabolic disorders by administering the FGF21R agonists and/or anti-FGF21 antibodies to a subject in need thereof.
1. 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 C H 2 domain, an immunoglobulin C H 3 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.
2. A pharmaceutical composition comprising an FGF21R agonist of claim 1 , and a pharmaceutically acceptable carrier or diluent.
3. The FGF21R agonist of claim 1 , wherein the antigen-binding portion of the anti-FGFR1c antibody is a Fab.
4. The FGF21R agonist of claim 1 , wherein the antigen-binding portion of the anti-FGFR1c antibody is an scFv.
5. The FGF21R agonist of claim 1 , wherein the antigen-binding portion of the anti-FGFR1c antibody comprises an HCVR/LCVR amino acid sequence pair of SEQ ID NOs: 306/314.
6. The FGF21R agonist of claim 1 , wherein M1 and M2 are each an Fc domain of an immunoglobulin.
7. The FGF21R agonist of claim 1 , wherein K1, K2, F1 and/or F2 are attached to M1 and/or M2 via a linker component (L).
8. The FGF21R agonist of claim 7 , wherein L is an amino acid sequence having the formula (G 4 S) n , wherein n is an integer from 1 to 10.
9. The FGF21R agonist of claim 1 that is a homodimer, wherein each monomer of the homodimer comprises the amino acid sequence of SEQ ID NO: 462.
10. A pharmaceutical composition comprising an FGF21R agonist of claim 9 , and a pharmaceutically acceptable carrier or diluent.