Human FGF receptor and β-Klotho binding proteins
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-039/395
C07K-016/28
C07K-016/40
출원번호
US-0641041
(2011-04-13)
등록번호
US-9517264
(2016-12-13)
국제출원번호
PCT/US2011/032333
(2011-04-13)
§371/§102 date
20130201
(20130201)
국제공개번호
WO2011/130417
(2011-10-20)
발명자
/ 주소
Fachini, Roger
Foltz, Ian
Han, Seog Joon
Harris, Susie Miki
Hu, Shaw-Fen Sylvia
King, Chadwick Terence
Li, Yang
Lu, Ji
Michaels, Mark Leo
Sun, Jeonghoon
출원인 / 주소
AMGEN INC.
인용정보
피인용 횟수 :
0인용 특허 :
68
초록▼
The present invention provides compositions and methods relating to or derived from antigen binding proteins and antigen binding protein-FGF21 fusions that specifically bind to β-Klotho, or β-Klotho and one or more of FGFR1c, FGFR2c, FGFR3c, and FGFR4. In some embodiments the antigen binding protein
The present invention provides compositions and methods relating to or derived from antigen binding proteins and antigen binding protein-FGF21 fusions that specifically bind to β-Klotho, or β-Klotho and one or more of FGFR1c, FGFR2c, FGFR3c, and FGFR4. In some embodiments the antigen binding proteins and antigen binding protein-FGF21 fusions induce FGF21-like signaling. In some embodiments, an antigen binding protein or antigen binding protein-FGF21 fusion antigen binding component is a fully human, humanized, or chimeric antibody, binding fragments and derivatives of such antibodies, and polypeptides that specifically bind to β-Klotho, or β-Klotho and one or more of FGFR1c, FGFR2c, FGFR3c, and FGFR4. Other embodiments provide nucleic acids encoding such antigen binding proteins and antigen binding protein-FGF21 fusions, and fragments and derivatives thereof, and polypeptides, cells comprising such polynucleotides, methods of making such antigen binding proteins and antigen binding protein-FGF21 fusions, and fragments and derivatives thereof, and polypeptides, and methods of using such antigen binding proteins and antigen binding protein-FGF21 fusions, fragments and derivatives thereof, and polypeptides, including methods of treating or diagnosing subjects suffering from type 2 diabetes, obesity, NASH, metabolic syndrome and related disorders or conditions.
대표청구항▼
1. An antigen binding protein comprising: (a) a light chain variable domain comprising; (i) a light chain CDR1 comprising an amino acid sequence of SEQ ID NO: 107; (ii) a light chain CDR2 comprising an amino acid sequence of SEQ ID NO: 113; (iii) a light chain CDR3 comprising an amino acid sequence
1. An antigen binding protein comprising: (a) a light chain variable domain comprising; (i) a light chain CDR1 comprising an amino acid sequence of SEQ ID NO: 107; (ii) a light chain CDR2 comprising an amino acid sequence of SEQ ID NO: 113; (iii) a light chain CDR3 comprising an amino acid sequence of SEQ ID NO: 121; and(b) a heavy chain variable domain comprising: (i) a heavy chain CDR1 comprising an amino acid sequence of SEQ ID NO: 84; (ii) a heavy chain CDR2 comprising an amino acid sequence of SEQ ID NO: 90; and (iii) a heavy chain CDR3 comprising an amino acid sequence of SEQ ID NO: 99; wherein the antigen binding protein specifically binds β-Klotho. 2. The isolated antigen binding protein of claim 1, wherein the antigen binding protein comprises: (a) a light chain variable domain sequence comprising SEQ ID NO: 18; and (b) a heavy chain variable domain sequence comprising SEQ ID NO: 29; wherein the antigen binding protein specifically binds to β-Klotho. 3. The antigen binding protein of claim 2, wherein the antigen binding protein comprises: (a) the light chain constant sequence of SEQ ID NO: 13; (b) the light chain constant sequence of SEQ ID NO:15; (c) the heavy chain constant sequence of SEQ ID NO: 9; or (d) the light chain constant sequence of SEQ ID NO: 13 or SEQ ID NO: 15 and the heavy chain constant sequence of SEQ ID NO: 9. 4. The antigen binding protein of claim 1, wherein the antigen binding protein comprises a human antibody, a humanized antibody, chimeric antibody, a monoclonal antibody, a polyclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an F(fa′)x fragment, a domain antibody, an IgD antibody, an IgE antibody, an IgM antibody, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, an IgG4 antibody, or an IgG4 antibody having at least one mutation in the hinge region. 5. The antigen binding protein of claim 1, that, when bound to β-Klotho: (a) binds to β-Klotho with substantially the same Kd as a reference antibody; (b) induces FGF21-like signaling of 10% or greater than the signaling induced by a wild-type FGF21 standard comprising the mature form of SEQ ID NO:2 as measured in an ELK-luciferase reporter assay; (c) exhibits an EC50 of 10 nM or less of FGF21-like signaling in an assay selected from the group consisting of: (i) a FGFR1c/β-Klotho-mediated in vitro recombinant cell-based assay; (d) exhibits an EC50 of less than 10 nM of agonistic activity on FGFR1c in the presence of β-Klotho in an in vitro recombinant FGFR1c receptor mediated reporter assay; and (e) an EC50 of greater than 1 μM of agonistic activity on FGFR1c in the absence of β-Klotho in an in vitro recombinant FGFR1c receptor mediated reporter assay; and (f) competes for binding with a reference antibody to β-Klotho, wherein the reference antibody comprises one or more of the following combinations of light chain and heavy chain variable domain sequences: L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10 and L11H11. 6. The antigen binding protein of claim 5, that, when bound to β-Klotho: (a) lowers blood glucose in an animal model; (b) lowers serum lipid levels in an animal model; or (c) (a) and (b). 7. A pharmaceutical composition comprising the antigen binding protein of claim 1 in admixture with a pharmaceutically acceptable carrier thereof. 8. An isolated nucleic acid comprising a polynucleotide sequence encoding the light chain variable domain, the heavy chain variable domain, or both, of the antigen binding protein of claim 1. 9. An isolated nucleic acid comprising a polynucleotide sequence encoding, SEQ ID NO: 18, SEQ ID NO: 29, or both. 10. An expression vector comprising the nucleic acid of claim 9. 11. An isolated cell comprising the nucleic acid of claim 9. 12. The isolated cell of claim 11, comprising an expression vector comprising the nucleic acid. 13. A method of producing an antigen binding protein that specifically binds to β-Klotho comprising incubating the host cell of claim 12 under conditions that allow it to express the antigen binding protein. 14. An antigen binding protein of any of claims 1, 2, and 3-6, wherein the heavy chain comprises a peptide that specifically binds to one or more of FGFR1c, FGFR2c, FGFR3c, and FGFR4. 15. A heavy chain of the antigen binding protein of claim 14, wherein the peptide comprises one or more of: TRLWKYWV (SEQ ID NO: 184); RRLYIFWE (SEQ ID NO: 185); YKAWGYYV (SEQ ID NO: 186); YQAWGYYV (SEQ ID NO: 187); YQAWGYLV (SEQ ID NO: 188); YQAWGYFV (SEQ ID NO: 189); FTWVFWNV (SEQ ID NO: 190); YQVWGYFV (SEQ ID NO: 191); YKWLKWNL (SEQ ID NO: 192); RRLYIFEW (SEQ ID NO: 193); WAERGG (SEQ ID NO: 194); GGWAVGRI (SEQ ID NO: 195); YKYLVFWV (SEQ ID NO: 196); YKYLSYWV (SEQ ID NO: 197); YKTAWYWK (SEQ ID NO: 198); YVFHKWWV (SEQ ID NO: 199); YVFYLWWK (SEQ ID NO: 200); YRWLHWHV (SEQ ID NO: 201); YKFLFWHA (SEQ ID NO: 202); RRQWGFWV (SEQ ID NO: 203); YSAWSFWV (SEQ ID NO: 204); LARWGFWV (SEQ ID NO: 205); YDAWGYWV (SEQ ID NO: 206); WRKYYHFWVS (SEQ ID NO: 207); KRLYGLFWYD (SEQ ID NO: 208); KKHWSSLFFE (SEQ ID NO: 209); KAWPYSWEAV (SEQ ID NO: 210); EWYCGVLFNCQQ (SEQ ID NO: 211); HFGCGVIFNCVSD (SEQ ID NO: 212); WELCASGYGWCYLH (SEQ ID NO: 213); APSCKSYIGFGLYHCWDG (SEQ ID NO: 214); and or HFKCGMGLFECADP (SEQ ID NO: 215). 16. The antigen binding protein heavy chain of claim 15, wherein the heavy chain comprises a CH2 loop, a CH3 loop or both a CH2 and a CH3 loop. 17. The heavy chain of claim 16, wherein the heavy chain comprises a CH3 loop. 18. The heavy chain of claim 17, wherein the CH3 loop comprises the peptide. 19. The heavy chain of claim 16, wherein the heavy chain comprises a CH2 loop. 20. The heavy chain of claim 19, wherein the CH2 loop comprises the peptide. 21. An antigen binding protein comprising the heavy chain of claim 15, 18 or 20. 22. A pharmaceutical composition comprising the antigen binding protein of claim 14 in admixture with a pharmaceutically acceptable carrier thereof. 23. An isolated nucleic acid comprising a polynucleotide sequence encoding the light chain variable domain, the heavy chain variable domain, or both, of the antigen binding protein of claim 14. 24. The isolated nucleic acid of claim 23, comprising a polynucleotide sequence encoding SEQ ID NO: 18, SEQ ID NO: 29, or both. 25. An expression vector comprising the nucleic acid of claim 24. 26. An isolated cell comprising the nucleic acid of claim 24. 27. The isolated cell of claim 26, comprising an expression vector comprising the nucleic acid. 28. A method of producing an antigen binding protein that specifically binds to β-Klotho comprising incubating the host cell of claim 27 under conditions that allow it to express the antigen binding protein. 29. An antigen binding protein-FGF21 fusion comprising: (a) an antigen binding component, wherein the antigen binding component comprises an antigen binding protein of claim 1; and (b) an FGF21 component. 30. The antigen binding protein-FGF21 fusion of claim 29, wherein the FGF21 component comprises at least 25 consecutive residues of SEQ ID NO:341. 31. The antigen binding protein-FGF21 fusion of claim 30, wherein the FGF21 component comprises (a) SEQ ID NO:342 or (b) SEQ ID NO:343. 32. The antigen binding protein-FGF21 fusion of claim 29, further comprising a linker. 33. The antigen binding protein-FGF21 fusion of claim 29 or claim 31, wherein the antigen binding component comprises SEQ ID NOS:18 and 29. 34. The antigen binding protein-FGF21 fusion of claim 32, wherein the linker is selected from the group consisting of (G4S)3, (SEQ ID NO: 336) (G4S)6 (SEQ ID NO: 337), (G4S)9 (SEQ ID NO: 338), (G4S)12 (SEQ ID NO: 339) and (G4S)15 (SEQ ID NO: 340). 35. The antigen binding protein-FGF21 fusion of claim 29, wherein the FGF21 component is joined to the heavy chain of the antigen binding component. 36. The antigen binding protein-FGF21 fusion of claim 35, wherein the heavy chain comprises one or more of: SEQ ID NOs:316, 320, 322, 324, 326, 318, 328, 330, 332 and 334. 37. The antigen binding protein-FGF21 fusion of claim 29, wherein the FGF21 component is joined to the light chain of the antigen binding component. 38. The antigen binding protein of claim 29, that, when bound to β-Klotho, β-Klotho and one or more of FGFR1c, FGFR2c, FGFR3c, and FGFR4: (a) lowers blood glucose in an animal model; (b) lowers serum lipid levels in an animal model; or (c) (a) and (b). 39. A pharmaceutical composition comprising an antigen binding protein-FGF21 fusion of claim 29, further comprising a pharmaceutically acceptable carrier. 40. A method of treating a condition in a subject in need of such treatment comprising administering a therapeutically effective amount of the composition of claim 7, 22, or 39 to the subject, wherein the condition is treatable by lowering blood glucose. 41. The method of claim 40, wherein the condition is selected from type 2 diabetes, obesity, dyslipidemia, NASH, cardiovascular disease, and metabolic syndrome.
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이 특허에 인용된 특허 (68)
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