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1. WO2018061004 - THERAPEUTIC MULTI-TARGETING CONSTRUCTS AND USES THEREOF

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CLAIMS

I. A construct comprising at least two different peptides binding to at least two different extracellular tumor antigens, and at least one toxin, wherein the peptides and the toxin are covalently bound directly or through a carrier.

2. The construct of claim 1 , wherein at least one of the peptides binds specifically to an extracellular tumor antigen selected from human epidermal growth factor receptor (EGFR) and human Programmed death- ligand 1 (PD-L1).

3. The construct of claim 2, wherein the another one of the at least two peptides binds specifically to an extracellular tumor antigen selected from the group consisting of EGFR, PD-L1, HER2, androgen receptor, benzodiazepine receptor, Cadherin, CXCR4, CTLA- 4, CD2, CD19, endothelin receptor, ERBB4, FGFR, folate receptor, HER4, HGFR, Mucin 1, OGFR, PD-1 , PD-L2, PDGFR, and VEGFR.

4. The construct of any one of claims 1 to 3, wherein each one of the peptides consists of from 5 to 30 or from 10 to 25 amino acid residues.

5. The construct of any one of claims 1 to 4, wherein the construct comprises from 3 to 10 different peptides.

6. The construct of any one of claims 1 to 5, wherein at least one of the peptides binds specifically to EGFR.

7. The construct of claim 6, wherein the peptide comprises the amino acid sequence set forth in SEQ ID NO: 1 or an analog thereof.

8. The construct of claim 7, wherein the analog has at least 70% identity to SEQ ID NO: 1.

9. The construct of any one of claims 1 to 5, wherein at least one of the peptides binds specifically to PD-L1.

10. The construct of claim 9, wherein the peptide comprises the amino acid sequence set forth in SEQ ID NO: 2 or an analog thereof.

I I. The construct of claim 10, wherein the analog has at least 70% identity to SEQ ID NO: 2.

12. The construct of any one of claims 1 to 5, wherein one of the peptides binds specifically to EGFR and one of the peptides binds specifically to PD-L1.

13. The construct of claim 12, wherein the peptide that binds specifically to EGFR is a peptide having SEQ ID NO: 1 or an analog thereof, and the peptide that binds specifically to PD-L1 is a peptide having SEQ ID NO: 2 or an analog thereof.

14. The construct of any one of claims 1 to 13, wherein the construct comprises multiple copies of at least one of the peptides.

15. The construct of claim 14, wherein the construct comprises from 2 to 50 copies of at least one of the peptides.

16. The construct of any one of claims 1 to 15, wherein the toxin is a peptide, polypeptide or protein toxin.

17. The construct of claim 16, wherein the toxin is selected from the group consisting of a toxin specifically binding to a eukaryotic elongation factor 2, BIM-BH3 of SEQ ID NO: 5, Diphtheria toxin, Pseudomonas exotoxin, Anthrax toxin, botulinum toxin, Ricin, PAP, Saporin, Gelonin, Momordin, ProTx-I ProTx-II, Conus californicus toxin, snake- venom toxin, and cyanotoxin.

18. The construct of claim 17, wherein the toxin binding to eukaryotic elongation factor 2 is a toxin comprising the amino acid sequence selected from SEQ ID NO: 3, 4, or an analog thereof.

19. The construct of claim 17 or 18, wherein the toxin comprises amino acid sequence selected from SEQ ID NO: 3, 4 and 5.

20. The construct of any one of claim 16 to 19, wherein the construct comprises 2 to 10 different toxins.

21. The construct of claim 20, wherein the construct comprises a toxin having SEQ ID NO: 3 and a toxin having SEQ ID NO: 4.

22. The construct of any one of claim 16 to 21 , wherein the construct comprises multiple copies of at least one of the toxins.

23. The construct of claim 22, wherein the construct comprises from 2 to 50 copies of the at least one of the toxins.

24. The construct of claim 23, wherein the construct comprises 2 to 50 copies of a toxin having SEQ ID NO: 3 and 2 to 50 copies of a toxin having SEQ ID NO: 4.

25. The construct of claims 1 , wherein one of the peptides binds specifically to EGFR and one of the peptides binds specifically to PD-Ll and the toxin is selected from a toxin binding to eukaryotic elongation factor 2 and a toxin having SEQ ID NO: 5.

26. The construct of claim 25, comprising a peptide having SEQ ID NO: 1 or an analog thereof, a peptide having SEQ ID NO: 2 or an analog thereof, and at least one toxin having amino acid sequence selected from SEQ ID NO: 3, 4, and 5.

27. The construct of claim 26, comprising a peptide comprising SEQ ID NO: 1 or an analog thereof, a peptide comprising SEQ ID NO: 2 or an analog thereof, a toxin comprising SEQ ID NO: 3, and a toxin comprising SEQ ID NO: 4.

28. The construct of claim of any one of claims 25 to 27, comprising multiple copies of each one of the peptides and the toxin(s).

29. The construct of any one of claims 1 to 28, wherein at least one of the peptides and/or at least one toxin are covalently bound through a carrier, wherein the carrier is an organic scaffold.

30. The construct of any one of claims 1 to 29, wherein each one of the peptides and the toxin(s) are bound to a carrier and wherein the carrier is an organic scaffold.

31. The construct of claim 29 or 30, wherein the organic scaffold comprises a polyethylene glycol (PEG) molecule or a modified PEG molecule.

32. The construct of claim 31 , wherein the PEG molecule comprises 8 to 56 sites available to bind the peptides and the toxin(s).

33. The construct of any one of claims 29 to 32, wherein the multiple copies of each one of the peptides and the multiple copies of at least one toxin are bound to the carrier and wherein at least one of the peptides binds specifically to EGFR or PD-Ll.

34. The construct of claim 33, wherein one of the peptides binds specifically to EGFR and one of the peptides binds specifically to PD-L1.

35. The construct of claim 34, wherein the peptide that binds specifically to EGFR is a peptide having SEQ ID NO: 1 or an analog thereof, and the peptide that binds specifically to PD-L1 is a peptide having SEQ ID NO: 2 or an analog thereof.

36. The construct of claim 34 or 35, wherein the toxin comprises the amino acid sequence selected from SEQ ID NO: 3, 4 and 5, or an analog thereof.

37. The construct of claim 33, wherein the construct comprises multiple copies of: (i) a peptide having SEQ ID NO: 1 , (ii) a peptide having SEQ ID NO: 2, (iii) a toxin having SEQ ID NO: 3 and (iv) a toxin having SEQ ID NO: 4, wherein each one of the peptides and the toxins is bound to the scaffold.

38. The construct of claim 33, wherein the construct comprises multiple copies of: (i) a peptide consisting of SEQ ID NO: 1 (ii) a peptide consisting of SEQ ID NO: 2, and (iii) a toxin consisting of SEQ ID NO: 3, and (iv) a toxin consisting of SEQ ID NO: 4, wherein each one of the peptides and the toxins is bound to the scaffold.

39. The construct of claim 37 or 38, wherein the stoichiometric molar ratio between the peptide having or consisting of SEQ ID NO: 1 , the peptide having or consisting of SEQ ID NO: 2, the toxin having or consisting of SEQ ID NO: 3 and the toxin having or consisting of SEQ ID NO: 4 is 1 :1 :3:3.

40. The construct of any one of claims 1 to 39, wherein at least one of the peptides or of the toxins is connected to the scaffold through a linker or spacer.

41. The construct of any one of claims 1 to 40, further comprising a permeability-enhancing moiety.

42. A pharmaceutical composition comprising a construct according to any one of claims 1 to 41, and a pharmaceutically acceptable excipient.

43. The pharmaceutical composition of claim 42, for use in treating cancer.

44. A method of treating cancer in a subject in need thereof comprising administering to said subject a pharmaceutical composition according to claim 42.

45. The method of claim 44 wherein the pharmaceutical composition is administered as part of a treatment regimen in combination with at least one anti-cancer agent.

46. A peptide binding specifically to human eukaryotic Elongation Factor 2 (eEF2), wherein the peptide comprises the amino acid sequence selected from SEQ ID NO:3, SEQ ID NO: 4 or an analog thereof.

47. The peptide of claim 46, wherein the analog has a sequence identity of at least 70%, at least 80%, or at least 90% to said peptide.

48. The peptide of claims 46 or 47, wherein said peptide or analog thereof is cyclic.

49. The peptide of any one of claims 46 to 48, wherein said peptide enhances eEF2 activity.

50. The peptide of any one of claims 46 to 49, for use in inducing cell death.

51. The peptide of claim 50, wherein the cells are cancer cell.

52. The peptide of any one of claims 46 to 50, wherein said peptide consists of the amino acid sequence selected from SEQ ID NO: 3 and SEQ ID NO: 4.

53. A peptide comprising the amino acids sequence set forth in SEQ ID NO: 1 or an analog thereof.

54. The peptide of claim 53, wherein said peptide, is an antagonist of a human Epidermal Growth Factor Receptor (EGFR).

55. The peptide of claim 53 or 54, wherein said analog has a sequence identity of at least 70%, at least 80%, or at least 90% to SEQ ID NO: 1.

56. The peptide of any one of claims 53 to 55, wherein said peptide or analog thereof is cyclic.

57. The peptide of any one of claims 53 to 56, wherein the peptide consists of the amino acid sequence set forth in SEQ ID NO: 1.

58. A peptide comprising the amino acids sequence set forth in SEQ ID NO: 2 or an analog thereof.

59. The peptide of claim 58, wherein said peptide or analog thereof is an antagonist of a human Programmed death-ligand 1 (PD-L1).

60. The peptide claim 58 or 59, wherein said analog has a sequence identity of at least 70%, at least 80%, or at least 90% to SEQ ID NO: 2.

61. The peptide of any one of claims 58 to 60, wherein said peptide is cyclic.

62. The peptide of any one of claims 58 to 61 , wherein said peptide consists of the amino acid sequence set forth in SEQ ID NO: 2.

63. The peptide of any one of claims 58 to 62, for use in targeting to cancer cells.

64. A conjugate comprising at least one peptide of any one of claims 46 to 63.

65. A pharmaceutical composition comprising the peptide of any one of claims 46 to 63 or the conjugate of claim 64, and a pharmaceutically acceptable carrier.

66. The pharmaceutical composition of claim 65, wherein said composition comprises a plurality of said peptides or of said conjugates.

67. The pharmaceutical composition of claim 65 or 66, for use in treating cancer.

68. A method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of the peptides of any one of claims 46 to 63 or of the conjugates of claim 64.

69. An isolated polynucleotide comprising a sequence encoding the peptide or analog thereof according to any one of claims 46 to 63.

70. An isolated polynucleotide comprising a sequence encoding for a polypeptide comprising (i) at least one copy of SEQ ID NO:l ; (ii) at least one copy of SEQ ID NO: 2; (iii) at least one copy of SEQ ID NO: 3, and/or at least one copy of SEQ ID NO: 4.

71. A nucleic acid construct, comprising the polynucleotide of claim 69 or 70, operably linked to a promoter.

72. A vector comprising at least one polynucleotide according to claim 70.