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1. (WO2018083087) BINDING PROTEINS
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Claims

1. A binding protein, which comprises an antibody specific for human LAG-3 attached by a linker to one or more epitope binding domains specific to human PD-1,

wherein the antibody specific for human LAG-3 comprises one or more of CDRHl, CDRH2 and CDRH3, wherein CDRHl is selected from the group consisting of: CDRHl as present in SEQ ID NO:l and CDRHl that differs from the CDRHl present in SEQ ID NO:l by the addition or deletion or substitution of 1, 2 or 3 amino acids, wherein CDRH2 is selected from the group consisting of: CDRH2 as present in SEQ ID NO:l and CDRH2 that differs from the CDRH2 present in SEQ ID NO:l by the addition or deletion or substitution of 1, 2 or 3 amino acids, and wherein CDRH3 is selected from the group consisting of: CDRH3 as present in SEQ ID NO: 1 and CDRH3 that differs from the CDRH3 present in SEQ ID NO:l by the addition or deletion or substitution of 1, 2 or 3 amino acids;

wherein the antibody specific for human LAG-3 comprises one or more of CDRL1, CDRL2 and CDRL3, wherein CDRL1 is selected from the group consisting of: CDRL1 as present in SEQ ID NO:2 and CDRL1 that differs from the CDRL1 present in SEQ ID NO:2 by the addition or deletion or substitution of 1, 2 or 3 amino acids, wherein CDRL2 is selected from the group consisting of: CDRL2 as present in SEQ ID NO:2 and CDRL2 that differs from the CDRL2 present in SEQ ID NO:2 by the addition or deletion or substitution of 1, 2 or 3 amino acids, and wherein CDRL3 is selected from the group consisting of: CDRL3 as present in SEQ ID NO: 2 and CDRL3 that differs from the CDRL3 present in SEQ ID NO:2 by the addition or deletion or substitution of 1, 2 or 3 amino acids;

wherein the one or more epitope binding domains specific to human PD-1 comprise one or more of CDRHl, CDRH2 and CDRH3, wherein CDRHl is selected from the group consisting of: CDRHl as present in SEQ ID NO:3 and CDRHl that differs from the CDRHl present in SEQ ID NO:3 by the addition or deletion or substitution of 1, 2 or 3 amino acids, wherein CDRH2 is selected from the group consisting of: CDRH2 as present in SEQ ID NO:3 and CDRH2 that differs from the CDRH2 present in SEQ ID NO:3 by the addition or deletion or substitution of 1, 2 or 3 amino acids, and wherein CDRH3 is selected from the group consisting of: CDRH3 as present in SEQ ID NO: 3 and CDRH3 that differs from the CDRH3 present in SEQ ID NO:3 by the addition or deletion or substitution of 1, 2 or 3 amino acids; and

wherein the linker is selected from the group consisting of a bond or a peptide linker.

2. A binding protein according to claim 1, wherein the antibody specific for human LAG-3 comprises CDRHl, CDRH2 and CDRH3, wherein CDRHl is selected from the group consisting of: CDRHl as present in SEQ ID NO:l and CDRHl that differs from the CDRHl present in SEQ ID NO:l by the addition or deletion or substitution of 1, 2 or 3 amino acids, wherein CDRH2 is selected from the group consisting of: CDRH2 as present in SEQ ID NO:l and CDRH2 that differs from the CDRH2 present in SEQ ID NO:l by the addition or deletion or substitution of 1, 2 or 3 amino acids, and wherein CDRH3 is selected from the group consisting of: CDRH3 as present in SEQ ID NO: 1 and CDRH3 that differs from the CDRH3 present in SEQ ID NO:l by the addition or deletion or substitution of 1, 2 or 3 amino acids;

wherein the antibody specific for human LAG-3 comprises CDRL1 and CDRL2, wherein CDRL1 is selected from the group consisting of: CDRL1 as present in SEQ ID NO:2 and CDRL1 that differs from the CDRL1 present in SEQ ID NO:2 by the addition or deletion or substitution of 1, 2 or 3 amino acids, and wherein CDRL2 is selected from the group consisting of: CDRL2 as present in SEQ ID NO:2 and CDRL2 that differs from the CDRL2 present in SEQ ID NO:2 by the addition or deletion or substitution of 1, 2 or 3 amino acids; and

wherein the one or more epitope binding domains specific to human PD-1 have CDRHl, CDRH2 and CDRH3, wherein CDRHl is selected from the group consisting of: CDRHl as present in SEQ ID NO:3 and CDRHl that differs from the CDRHl present in SEQ ID NO:3 by the addition or deletion or substitution of 1, 2 or 3 amino acids, wherein CDRH2 is selected from the group consisting of: CDRH2 as present in SEQ ID NO:3 and CDRH2 that differs from the CDRH2 present in SEQ ID NO:3 by the addition or deletion or substitution of 1, 2 or 3 amino acids, and wherein CDRH3 is selected from the group consisting of: CDRH3 as present in SEQ ID NO: 3 and CDRH3 that differs from the CDRH3 present in SEQ ID NO:3 by the addition or deletion or substitution of 1, 2 or 3 amino acids.

3. A binding protein according to claim 1 or claim 2, wherein the antibody specific to LAG-3 is of the IgA or IgG class.

4. A binding protein according to claim 3, wherein the antibody specific to LAG-3 is of the IgG class.

5. A binding protein according to any preceding claim, wherein the one or more epitope binding domains specific to human PD-1 is single variable domain of an antibody (wherein optionally the single variable domain is a VH domain).

6. A binding protein according to any preceding claim, wherein the one or more epitope binding domains are attached by a linker to the C terminus of the heavy chain of the antibody specific to human LAG-3.

7. A binding protein according to claim 6, wherein there are two epitope binding domains, one attached to the C-terminus of each of the two heavy chains of the antibody specific to LAG-3.

8. A binding protein having the general formula (I):

L (LAG-3)

VH(PD-1) - A - H '(LAG-3)

( 4 )n

VH(PD-1) - A -H (LAG-3)

L '(LAG-3)

(I)

wherein:

H(LAG-3) is an antibody heavy chain of the IgG class comprising CDRHl, CDRH2 and CDRH3, wherein said CDRHl is selected from : CDRHl present in SEQ I D NO:l, and CDRHl that differs from the CDRHl present in SEQ I D NO:l by the addition or deletion or substitution of 1, 2 or 3 amino acids; wherein CDRH2 is selected from : CDRH2 present in SEQ I D NO:l and CDRH2 that differs from the CDRH2 present in SEQ I D NO:l by the addition or deletion or substitution of 1, 2 or 3 amino acids; and wherein CDRH3 is selected from : CDRH3 as present in SEQ I D NO: 1 and CDRH3 that differs from the CDRH3 present in SEQ ID NO:l by the addition or deletion or substitution of 1, 2 or 3 amino acids;

L(LAG-3) is an antibody light chain of the IgG class comprising CDRL1 and CDRL2, wherein said CDRL1 is selected from : CDRL1 present in SEQ ID NO :2 and CDRL1 that differs from the CDRL1 present in SEQ ID NO :2 by the addition or deletion or substitution of 1, 2 or 3 amino acids; and wherein CDRL2 is selected from : CDRL2 present in SEQ ID NO:2 and CDRL2 that differs from the CDRL2 present in SEQ I D NO:2 by the addition or deletion or substitution of 1, 2 or 3 amino acids;

n is an integer selected from 2, 4 and 11;

A is a bond or a peptide linker; and

VH(PD-I) is an antibody heavy chain variable domain having CDRHl, CDRH2 and CDRH3, wherein said CDRHl is selected from: CDRHl present in SEQ I D NO:3, and CDRHl that differs from the CDRHl present in SEQ I D NO:3 by the addition or deletion or substitution of 1, 2 or 3 amino acids; wherein CDRH2 is selected from : CDRH2 present in SEQ ID NO:3 and CDRH2 that differs from the CDRH2 present in SEQ I D NO:3 by the addition or deletion or substitution of 1, 2 or 3 amino acids; and wherein CDRH3 is selected from : CDRH3 as present in SEQ I D NO: 3 and CDRH3 that differs from the CDRH3 present in SEQ I D NO:3 by the addition or deletion or substitution of 1, 2 or 3 amino acids.

9. A binding protein according to any preceding claim, wherein CDRHl of VH(PD-I) is THYMX4, wherein X4 is V or A; wherein CDRH2 of VH(PD-1) is FIGPAGDX5TYYADSVX6G wherein X5 is T, F or S and e is K or E; and wherein CDRH3 of VH(PD-I) is

YTX7TSX8X9DX10YDV, wherein X7 is A or E, X8 is G, S or D, X9 is V, F or Y, and Χω is T or S.

10. A binding protein according to any preceding claim, wherein CDRL1 of the antibody specific for LAG -3 or L is RASQX1ISSX2LX3, wherein Xi is G or S, X2 is W, F or Y, and X3 is A or N.

11. A binding protein according to any preceding claim, wherein the antibody specific for LAG -3 or H(LAG-3) has CDRHl, CDRH2 and CDRH3 as present in SEQ ID NO. 1.

12. A binding protein according to any preceding claim, wherein the antibody specific for LAG or L(LAG-3) has CDRL1 and CDRL2 as present in SEQ ID NO. 2.

13. A binding protein according to claim 11 or claim 12, wherein the antibody specific for LAG -3 or L(LAG-3) has CDRL1, CDRL2 and CDRL3 as present in SEQ ID NO. 2.

14. A binding protein according to any preceding claim, wherein the one or more epitope binding domains specific to PD-1 or VH(PD-1) has CDRHl, CDRH2 and CDRH3 as present in SEQ I D NO. 3.

15. A binding protein according to claim 11, wherein, in the antibody specific for LAG-3 or H(LAG-3), CDRHl has the sequence defined as SEQ ID NO: 4, CDRH2 has the sequence defined as SEQ I D NO: 5 and CDRH3 has the sequence defined as SEQ ID NO: 6.

16. A binding protein according to claim 13 or claim 15, wherein in the antibody specific for LAG-3 or L( LAG-3), CDRL1 has the sequence defined as SEQJ D NO: 7, CDRL2 has the sequence defined as SEQ. ID NO: 8 and CDRL3 has the sequence defined as SEQ ID NO: 9.

17. A binding protein according to claim 14, claim 15 or claim 16, wherein, in the one or more epitope binding domains specific to PD-1 or VH(PD-I), CDRHl has the sequence defined as SEQ ID NO: 10, CDRH2 has the sequence defined as SEQ ID NO: 11 and CDRH3 has the sequence defined as SEQ ID NO: 12.

18. A binding protein according to any preceding claim, wherein the heavy chains of the antibody specific for human LAG-3 or H(LAG-3) comprises the sequence defined as SEQ ID NO.l or a variant of SEQ ID NO. 1 that differs in having up to 10 amino acid additions, deletions or substitutions.

19. A binding protein according to claim 18, wherein the up to 10 amino acid additions, deletions or substitutions are not within the CDR regions.

20. A binding protein according to any preceding claim, wherein the light chains of the antibody specific for human LAG-3 or L( LAG-3) comprises the sequence defined as SEQ ID NO. 2 or a variant of SEQ ID NO. 2 that differs in having up to 10 amino acid additions, deletions or substitutions.

21. A binding protein according to claim 20, wherein the up to 10 amino acid additions, deletions or substitutions are not within the CDR regions.

22. A binding protein according to any preceding claim, wherein the one or more epitope binding domains specific to human PDl or VH(PD-I) comprise the sequence defined as SEQ ID NO.3 or a variant of SEQ ID NO. 3 that differs in having up to 10 amino acid additions, deletions or substitutions.

23. A binding protein according to claim 22, wherein the up to 10 amino acid additions, deletions or substitutions are not within the CDR regions.

24. A binding protein according to any one of claims 1 to 17, wherein the heavy chains of the antibody specific for human LAG-3 or H(LAG-3) comprises the sequence defined as SEQ ID NO.l or a sequence that has at least 90% sequence identity to the sequence of SEQ ID NO. 1.

25. A binding protein according to claim 24, wherein variation occurs outside of the CDR regions.

26. A binding protein according to any one of claims 1 to 17 or 24 to 25, wherein the light chains of the antibody specific for human LAG-3 or L(LAG-3) comprises the sequence defined as SEQ ID NO.2 or a sequence that has at least 90% sequence identity to the sequence of SEQ. ID NO. 2.

27. A binding protein according to claim 26, wherein variation occurs outside of the CDR regions.

28. A binding protein according to any one of claims 1 to 17 or 24 to 27, wherein the one or more epitope binding domains specific to human PDl or VH(PD-I) comprise the sequence defined as SEQ ID NO.3 or a sequence that has at least 90% sequence identity to the sequence of SEQ ID NO. 3.

29. A binding protein according to claim 28, wherein variation occurs outside of the CDR regions.

30. A binding protein according to any preceding claim, wherein the heavy chains of the antibody specific for human LAG-3 or H(LAG-3) comprises the sequence defined as SEQ ID NO.l.

31. A binding protein according to any preceding claim, wherein the light chains of the antibody specific for human LAG-3 or L( LAG-3) comprises the sequence defined as SEQ ID NO.2.

32. A binding protein according to any preceding claim, wherein the one or more epitope binding domains specific to human PDl or VH(PD-I) comprises the sequence defined as SEQ ID NO.3.

33. A binding protein according to any preceding claim, wherein the linker or A is a peptide linker

34. A binding protein according to claim 33, wherein the linker or A has the sequence of SEQ ID NO. 30.

35. A binding protein according to any preceding claim, which binding protein exhibits >50% inhibition of LAG3-MHCII interaction in competition flow cytometry assay, and an IC50 of less than or equal to 5 nM in the PD-l/PDL-1 competition assay.

36. An isolated nucleic acid encoding the heavy chain of the binding protein defined in any one of claims 1 to 7.

37. An isolated nucleic acid encoding the light chain of the binding protein defined in any one of claims 1 to 7.

38. An isolated nucleic acid encoding H(LAG-3)-A- VH(PD-1), wherein H(LAG-3), A and VH(PD-1) are as defined in any one of claims 8 to 35.

39. An isolated nucleic acid encoding L(LAG-3), wherein L(LAG-3) is as defined in any one of claims 8 to 35.

40. A vector comprising a nucleic acid as defined in any one of claims 36 to 39.

41. A vector according to claim 40, which is an expression vector.

42. A host cell comprising a vector according to claim 41.

43. A method of producing a binding protein as defined in any one of claims 1 to 7, comprising culturing a host cell according to claim 42 under conditions suitable for protein expression, and isolating the binding protein, wherein the host cell contains the nucleic acids defined in claim 36 and claim 37 in one or more expression vectors.

44. A method of producing a binding protein as defined in any one of claims 8 to 35, comprising culturing a host cell according to claim 42 under conditions suitable for protein expression, and isolating the binding protein, wherein the host cell contains the nucleic acids defined in claim 38 and claim 39 in one or more expression vectors.

45. A pharmaceutical composition comprising a binding protein according to any one of claims 1 to 35 and a pharmaceutically acceptable excipient.

46. A method of treating cancer which comprises administering to a human in need thereof a therapeutically effective amount of a binding protein as defined in any one of claims 1 to 35.

47. A method of treating an infectious disease which comprises administering to a human in need thereof a therapeutically effective amount of a binding protein as defined in any one of claims 1 to 35.

48. A method of treating an infectious disease according to claim 47, wherein the infectious disease is a bacterial infection, a parasitic infection, a viral infection or sepsis.

49. A method of treating HIV which comprises administering to a human in need thereof a therapeutically effective amount of a binding protein as defined in any one of claims 1 to 35.

50. A method of treating HIV according to claim 49 which further comprises administering one or more antiretroviral agents.

51. A method of curing HIV which comprises administering to a human in need thereof a therapeutically effective amount of a binding protein as defined in any one of claims 1 to 35.

52. A method of curing HIV according to claim 51 which further comprises administering one or more antiretroviral agents.

53. A binding protein as defined in any one of claims 1 to 35 for use in medicine.

54. A binding protein as defined in any one of claims 1 to 35 for use in the treatment of cancer.

55. A binding protein as defined in any one of claims 1 to 35 for use in the treatment of infectious diseases.

56. A binding protein for use according to claim 55, wherein the infectious disease is a bacterial infection, a parasitic infection, a viral infection or sepsis.

57. A binding protein as defined in any one of claims 1 to 35 for use in the treatment of HIV.

58. A binding protein as defined in any one of claims 1 to 35 for use in curing HIV.

59. A binding protein as defined in any one of claims 1 to 35 and one or more antiretroviral agents for separate simultaneous or sequential use in treating HIV.

60. A binding protein as defined in any one of claims 1 to 35 and one or more antiretroviral agents for separate simultaneous or sequential use in curing HIV.

61. Use of a binding protein as defined in any one of claims 1 to 35 in the manufacture of a medicament for the treatment of cancer.

62. Use of a binding protein as defined in any one of claims 1 to 35 in the manufacture of a medicament for the treatment of infectious diseases.

63. Use of a binding protein according to claim 62, wherein the infectious disease is a bacterial infection, a parasitic infection, a viral infection or sepsis.

64. Use of a binding protein as defined in any one of claims 1 to 35 in the manufacture of a medicament for the treatment of HIV.

65. Use of a binding protein as defined in any one of claims 1 to 35 in the manufacture of a medicament for curing HIV.

66. Use of a binding protein as defined in any one of claims 1 to 35 and one or more anti-retroviral agents in the manufacture of medicaments for separate simultaneous or sequential use in treating HIV.

67. Use of a binding protein as defined in any one of claims 1 to 35 and one or more anti-retroviral agents for use in the manufacture of medicaments for separate simultaneous or sequential use in curing HIV.