Ligands that potentiate the bioactivity of gonadotropins

1. A follicle-stimulating hormone (FSH) ligand which potentiates the bioactivity of FSH, of luteinizing hormone (LH), and of chorionic gonadotropin (CG),

wherein said ligand is an antibody or a fragment thereof, and

the heavy chain variable domain of the antibody or the fragment contains the following CDRs:

VH-CDR1, defined by the sequence

(SEQ ID NO: 5)

GFTFSSSY;

VH-CDR2, defined by the sequence

(SEQ ID NO: 6)

IYAGTGGT;

VH-CDR3, defined by the sequence

(SEQ ID NO: 7)

ARHGSYFDY;

and

the light chain variable domain of the antibody or the fragment contains the following CDRs:

VL-CDR1, defined by the sequence

(SEQ ID NO: 8)

QSVDYDGDSY;

VL-CDR2, defined by the sequence

AAS;

VL-CDR3, defined by the sequence

(SEQ ID NO: 9)

QQSNEDPYT.

2. The ligand of claim 1 , wherein the ligand is the CF12 monoclonal antibody produced by the CNCM I-4803 hybridoma.

3. The ligand of claim 1 , wherein the peptide sequence of the scFv is the sequence of SEQ ID NO: 11.

4. A ligand-gonadotropin complex chosen from:

(A) a complex of the ligand of claim 1 with FSH;

(B) a complex of a second antibody fragment with FSH;

(C) a complex of the ligand of claim 1 with LH or the chorionic gonadotropin (CG) hormone; or

(D) a complex of a second antibody fragment with LH or the chorionic gonadotropin (CG) hormone,

wherein the second antibody fragment contains a heavy chain variable domain comprising the following CDRs:

VH-CDR1, defined by the sequence

(SEQ ID NO: 5)

GFTFSSSY;

VH-CDR2, defined by the sequence

(SEQ ID NO: 6)

IYAGTGGT;

and

VH-CDR3, defined by the sequence

(SEQ ID NO: 7)

ARHGSYFDY;

or

the second antibody fragment contains a light chain variable domain comprising the following CDRs:

VL-CDR1; defined by the sequence

(SEQ ID NO: 8)

QSVDYDGDSY;

VL-CDR2, defined by the sequence

AAS;

and

VL-CDR3, defined by the sequence

(SEQ ID NO: 9)

OQSNEDRYT.

5. A method of treating infertility or hypofertility in a mammal in need thereof, the method comprising administering to the mammal an effective amount of the ligand-gonadotropin complex of claim 4 and optionally an FSH and/or an LH and/or a CG.

6. A method of stimulating procreation in a female mammal in need thereof, the method comprising administering to the female mammal an effective amount of the ligand-gonadotropin complex of claim 4 and optionally an FSH and/or an LH and/or a CG.

7. A pharmaceutical composition comprising a complex as claimed in claim 4 and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition of claim 7 further comprising an FSH and/or an LH and/or a CG.

9. A method of inducing ovulation or polyovulation in a female mammal in need thereof, the method comprising administering to the female mammal an effective amount of the complex of claim 4 and optionally an FSH and/or an LH and/or a CG.

10. A method of increasing circulating endogenous progesterone level in a female mammal in need thereof, the method comprising administering to the female mammal an effective amount of the complex of claim 4 and optionally an FSH and/or an LH and/or a CG.

11. A method of inducing ovulation or polyovulation in a female mammal in need thereof, the method comprising administering to the female mammal an effective amount of the ligand of claim 1 , or a second antibody fragment, and optionally an FSH and/or an LH and/or a CG,

wherein the second antibody fragment contains a heavy chain variable domain comprising the following CDRs:

VH-CDR1, defined by the sequence

(SEQ ID NO: 5)

GFTFSSSY;

VH-CDR2, defined by the sequence

(SEQ ID NO: 6)

IYAGTGGT;

and

VH-CDR3, defined by the sequence

(SEQ ID NO: 7)

ARHGSYFDY.

12. A method of increasing circulating endogenous progesterone level in a female mammal in need thereof, the method comprising administering to the female mammal an effective amount of the ligand of claim 1 , or a second antibody fragment, and optionally an FSH and/or an LH and/or a CG,

wherein the second antibody fragment contains a heavy chain variable domain comprising the following CDRs:

VH-CDR1, defined by the sequence

(SEQ ID NO: 5)

GFTFSSSY;

VH-CDR2, defined by the sequence

(SEQ ID NO: 6)

IYAGTGGT;

and

VH-CDR3, defined by the sequence

(SEQ ID NO: 7)

ARHGSYFDY.

13. A pharmaceutical composition comprising the ligand of claim 1 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition as claimed in claim 13 , wherein it also comprises an FSH and/or an LH and/or a CG.

15. A method of treating infertility hypofertility in a mammal in need thereof, the method comprising administering to the mammal an effective amount of the ligand of claim 1 or a second antibody fragment, and optionally an FSH and/or an LH and/or a CG,

wherein the second antibody fragment contains a heavy chain variable domain comprising the following CDRs:

VH-CDR1, defined by the sequence

(SEQ ID NO: 5)

GFTFSSSY;

VH-CDR2, defined by the sequence

(SEQ ID NO: 6) 

IYAGTGGT;

and

VH-CDR3, defined by the sequence

(SEQ ID NO: 7)

ARHGSYFDY.

16. A method of stimulating procreation in a female mammal in need thereof, the method comprising administering to the female mammal an effective amount of the ligand of claim 1 or a second antibody fragment, and optionally an FSH and/or an LH and/or a CG,

wherein the second antibody fragment contains a heavy chain variable domain comprising the following CDRs:

VH-CDR1, defined by the sequence

(SEQ ID NO: 5)

GFTFSSSY;

VH-CDR2, defined by the sequence

(SEQ ID NO: 6)

IYAGTGGT;

and

VH-CDR3, defined by the sequence

(SEQ ID NO: 7)

ARHGSYFDY.

17. The ligand of claim 1 , wherein the ligand is selected from the group consisting of: Fab, Fab′, F(ab′)2, Fv, dsFv, scFv, diabodies, triabodies, and tetrabodies.

18. A method for increasing circulating endogenous progesterone level in a female mammal in need thereof, comprising administering to the female mammal an effective amount of the ligand as claimed in claim 1 .

19. The method of claim 18 , further comprising administering an FSH and/or an LH and/or a CG.

20. A method for treating infertility or hypofertility in a mammal in need thereof, comprising administering to the mammal an effective amount of the ligand as claimed in claim 1 .

21. The method of claim 20 , further comprising administering an FSH and/or an LH and/or a CG.

22. A method for stimulating procreation in a female mammal in need thereof, comprising administering to the mammal an effective amount of the ligand as claimed in claim 1 .

23. The method of claim 22 , further comprising administering an FSH and/or an LH and/or a CG.

24. A method of inducing ovulation or polyovulation in a female mammal in need thereof, comprising administering to the female mammal an effective amount of the ligand as claimed in claim 1 .

25. The method of claim 24 further comprising administering an FSH and/or an LH and/or a CG.

26. A follicle-stimulating hormone (FSH) ligand which potentiates the bioactivity of FSH, of luteinizing hormone (LH), and of chorionic gonadotropin (CG),

wherein said ligand is an antibody or a fragment thereof, and

the heavy chain variable domain of the antibody or the fragment contains the sequence of SEQ ID NO: 2 or 30; and

the light chain variable domain of the antibody or the fragment contains the sequence SEQ ID NO:4 or 28.

27. A pharmaceutical composition comprising the ligand claimed in claim 26 and a pharmaceutically acceptable carrier,

and optionally an FSH and/or an LH and/or a CG.

28. A method for increasing circulating endogenous progesterone level in a female mammal in need thereof, comprising administering to the female mammal an effective amount of the ligand as claimed in claim 26 and optionally an FSH and/or an LH and/or a CG.

29. A method for treating infertility or hypofertility in a mammal in need thereof, comprising administering to the mammal an effective amount of the ligand as claimed in claim 26 and optionally an FSH and/or an LH and/or a CG.

30. A method for stimulating procreation in a female mammal in need thereof, comprising administering to the mammal an effective amount of the ligand as claimed in claim 26 and optionally an FSH and/or an LH and/or a CG.

31. A method of inducing ovulation or polyovulation in a female mammal in need thereof, comprising administering to the female mammal an effective amount of the ligand as claimed in claim 26 and optionally an FSH and/or an LH and/or a CG.

32. A follicle-stimulating hormone (FSH) ligand which potentiates the bioactivity of FSH, of luteinizing hormone (LH), and of chorionic gonadotropin (CG),

wherein said ligand is an antibody fragment, and

wherein the antibody fragment contains the following CDRs:

VH-CDR1, defined by the sequence

(SEQ ID NO: 5)

GFTFSSSY;

VH-CDR2, defined by the sequence

(SEQ ID NO: 6)

IYAGTGGT;

and

VH-CDR3, defined by the sequence

(SEQ ID NO: 7)

ARHGSYFDY.

33. The ligand of claim 32 , wherein the antibody fragment is a domain V H H or a heavy chain variable domain.

34. A method for treating infertility or hypofertility in a mammal in need thereof, comprising administering to the mammal an effective amount of the ligand as claimed in claim 32 .

35. The method as claimed in claim 34 , further comprising an FSH and/or an LH and/or a CG.

36. A method for stimulating procreation in a female mammal in need thereof, comprising administering to the female mammal an effective amount of the ligand as claimed in claim 32 .

37. The method as claimed in claim 36 , further comprising administering an FSH and/or an LH and/or a CG.

38. A pharmaceutical composition comprising a ligand as claimed in claim 32 and a pharmaceutically acceptable carrier.

39. The pharmaceutical composition as claimed in claim 38 , wherein it also comprises an FSH and/or an LH and/or a CG.

40. A method for inducing ovulation or polyovulation in a female mammal in need thereof, comprising administering to the female mammal an effective amount of the ligand of claim 32 .

41. The method as claimed in claim 40 , further comprising administering to the female mammal an FSH and/or an LH and/or a CG.

42. A method for increasing circulating endogenous progesterone level in a female mammal in need thereof, comprising administering to the female mammal an effective amount of the ligand as claimed in claim 32 .

43. The method as claimed in claim 42 , further comprising administering to the female mammal an FSH and/or an LH and/or a CG.

44. A follicle-stimulating hormone (FSH) ligand which potentiates the bioactivity of FSH, of luteinizing hormone (LH), and of chorionic gonadotropin (CG),

wherein said ligand is an antibody fragment, and

the heavy chain variable domain of the antibody fragment contains the sequence of SEQ ID NO: 2 or 30; or

the light chain variable domain of the antibody fragment contains the sequence SEQ ID NO: 28.

45. A pharmaceutical composition comprising the ligand as claimed in claim 44 and a pharmaceutically acceptable carrier,

and optionally an FSH and/or an LH and/or a CG.

46. A method for increasing circulating endogenous progesterone level in a female mammal in need thereof, comprising administering to the female mammal an effective amount of the ligand as claimed in claim 44 and optionally an FSH and/or an LH and/or a CG.

47. A method for treating infertility or hypofertility in a mammal in need thereof, comprising administering to the mammal an effective amount of the ligand as claimed in claim 44 and optionally an FSH and/or an LH and/or a CG.

48. A method for stimulating procreation in a female mammal in need thereof, comprising administering to the mammal an effective amount of the ligand as claimed in claim 44 and optionally an FSH and/or an LH and/or a CG.

49. A method of inducing ovulation or polyovulation in a female mammal in need thereof, comprising administering to the female mammal an effective amount of the ligand as claimed in claim 44 and optionally an FSH and/or an LH and/or a CG.