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1. WO2020117740 - RECOMBINANT HIV ENV POLYPEPTIDES AND THEIR USES

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[ EN ]

What is claimed is:

1. An engineered or non-naturally occurring HIV Env polypeptide that is missing glycan sequons at N156 and N130 and has one or more basic residues at positions 168 to 171, wherein the HIV Env polypeptide binds to a Human Immunodeficiency Virus (HIV) broadly neutralizing antibody (bnAb), and wherein the HIV Env polypeptide positions correspond to the HXB2 reference (SEQ ID NO: 1).

2. An engineered or non-naturally occurring HIV Env polypeptide that is missing glycan sequons at N156 and N130 and has one or more basic residues at positions 168 to 171, wherein the HIV Env polypeptide binds to an HIV broadly neutralizing antibody (bnAb) directed to the V2 apex region of HIV envelope, and wherein the HIV Env polypeptide positions correspond to the HXB2 reference.

3. An engineered or non-naturally occurring HIV Env polypeptide that is missing glycan sequons at N156 and N130 and has one or more basic residues at positions 168 to 171, wherein the HIV Env polypeptide binds to a germline or germline reverted HIV broadly neutralizing antibody (bnAb) directed to the V2 apex region of HIV envelope, and wherein the HIV Env polypeptide positions correspond to the HXB2 reference.

4. A chimeric HIV Env polypeptide comprising an HIV Env polypeptide backbone and the V1V2 region of the ZM233 HIV Env polypeptide.

5. The chimeric HIV Env polypeptide of claim 4, wherein the V1V2 region of the ZM233 HIV Env polypeptide comprises the amino acid sequence of SEQ ID NO: 9.

6. A chimeric HIV Env polypeptide comprising an HIV Env polypeptide backbone and the amino acid residues of the ZM233 HIV Env polypeptide corresponding to positions about 131 to about 196, wherein the HIV Env polypeptide positions correspond to the HXB2 reference.

7. The chimeric HIV Env polypeptide of any one of claims 4 to 6, wherein the HIV Env polypeptide backbone comprises a BG505, ZM197, or CFR250 backbone.

8. The chimeric HIV Env polypeptide of any one of claims 4 to 7, wherein the HIV Env polypeptide backbone misses glycan sequons at N156 and N130.

9. The chimeric HIV Env polypeptide of any one of claims 4 to 8 that binds to a Human

Immunodeficiency Virus (HIV) broadly neutralizing antibody (bnAb).

10. The chimeric HIV Env polypeptide of any one of claims 4 to 8 that binds to an HIV broadly neutralizing antibody (bnAb) directed to the V2 apex region of HIV envelope.

11. The chimeric HIV Env polypeptide of any one of claims 4 to 8 that binds to a germline or

germline reverted HIV broadly neutralizing antibody (bnAb) directed to the V2 apex region of HIV envelope.

12. An engineered or non-naturally occurring ZM233 HIV Env polypeptide missing glycan sequons at N 156 and N130, wherein the HIV Env polypeptide positions correspond to the HXB2 reference.

13. The engineered or non-naturally occurring ZM233 HIV Env polypeptide of claim 12 that binds to a broadly neutralizing antibody (bnAb) directed to the V2 apex region of HIV envelope.

14. The engineered or non-naturally occurring ZM233 HIV Env polypeptide of claim 12 that binds to a germline or germline reverted HIV broadly neutralizing antibody (bnAb) directed to the V2 apex region of HIV envelope.

15. The HIV Env polypeptide of any one of claims 1 to 14, wherein the bnAb is PG9, PG16,

CAP256.08, CAP256.09, CHOI, CH04, PGT145, or PGDM1400.

16. The HIV Env polypeptide of any one of claims 1 to 14, wherein the germline or germline reverted bnAb is CAP256 UCA, PG9 iGL, CHOI iGL, or PGT145 iGL.

17. The HIV Env polypeptide any one of claims 1 to 14, wherein the germline or germline reverted bnAb is CHOI iGL.

18. The HIV Env polypeptide of any one claims 1 to 17, which comprises a complex of gpl20 and gp41.

19. The HIV Env polypeptide of any one of claims 1 to 17, which comprises a stabilized trimer.

20. The HIV Env polypeptide of claim 19, wherein the trimer is a SOSIP, NFL, or UFO trimer.

21. The HIV Env polypeptide of any one of claims 1 to 20, which comprises a V2 apex epitope of ZM233 Env.

22. The HIV Env polypeptide of claim 21, which comprises basic amino acid substitutions at

positions 168 to 171, wherein the HIV Env polypeptide positions correspond to the HXB2 reference.

23. The HIV Env polypeptide of claim 21, wherein the V2 apex region of positions 156 to 175

comprises one glycan and four consecutive basic amino acids, wherein the HIV Env polypeptide positions correspond to the HXB2 reference.

24. The HIV Env polypeptide of any one of claims 1 to 23 comprising the amino acid sequence of I- C-X1-F-N-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-V-N-V-L (SEQ ID NO: 10) at positions 156 to 175,

wherein Xi comprises S, T, N, or F;

X2 comprises I, V, T, Q, of M;

X3 comprises S or T;

X4 comprises S or T;

X5 comprises S, E, or G;

Cb comprises I, L, or V;

X7 comprises K or R;

Xg comprises G or D;

X9 comprises K, R, E, or Q;

X10 comprises K, R, E, or Q;

X11 comprises K, R, E, or Q; and

Xi2 comprises K, E, or Q.

25. The HIV Env polypeptide of claim 24, wherein at least three of X9, X10, Xu, and X12 comprise basic amino acid residues.

26. The HIV Env polypeptide of claim 24, wherein all of X9, X10, Xn, and X12 comprise basic amino acid residues.

27. The HIV Env polypeptide of claim 24, wherein X9, X10, Xn, and X12 comprise K.

28. The HIV Env polypeptide of claim 21 comprising the amino acid sequence of

IC SFNMTTELRDKKRKVNVL (SEQ ID NO: 11) at positions 156 to 175.

29. An HIV Env polypeptide comprising the amino acid sequence of SEQ ID NO: 6, 7, or 8.

30. The HIV Env polypeptide of any one of claims 1 to 17, which comprises gpl40.

31. The HIV Env polypeptide of claim 19, wherein the trimer comprises gpl20-gp41 heterodimers.

32. The HIV Env polypeptide of claim 31, wherein the heterodimers are covalently linked.

33. The HIV Env polypeptide of claim 31, wherein the heterodimers comprise gpl20-gp41 fusions proteins.

34. A nucleic acid molecule encoding the HIV Env polypeptide of any one of claims 1-33.

35. A vector comprising a regulatory element operable in a eukaryotic cell operably linked to the nucleic acid molecule of claim 34.

36. The vector of claim 35, wherein the vector comprises a viral vector.

37. The vector of claim 36, wherein the vector comprise AAV.

38. A method of eliciting an immune response in a mammal comprising administering the HIV Env polypeptide of any one of claims 1 to 33, the nucleic acid of claim 34, or the vector of any one of claims 35 to 37.

39. The method of stimulating of a broadly neutralizing HIV antibody (bnAb) in a mammal

comprising administering the HIV Env polypeptide of any one of claims 1 to 33, the nucleic acid of claim 34, or the vector of any one of claims 35 to 37.

40. The method of claim 39, which comprises stimulating a germline precursor of a bnAb.

41. The method of any one of claims 38 to 40, wherein the mammal is a human.

42. The method of any one of claims 38 to 40, wherein the mammal is a non-human primate.

43. The method of any one of claims 38 to 40, wherein the mammal is a mouse.

44. The method of claim 43, wherein the mammal comprises elements of a human immune system.

45. The method of any one of claims 38 to 44, wherein the method comprises administering two or more of the HIV Env polypeptide of any one of claims 1 to 33.

46. The method of any one of claims 38 to 44, wherein the method comprises administering two or more of the HIV Env polypeptide of any one of claims 1 to 33, each of which comprises a V2 apex epitope of ZM233 trimer.

47. The method of claim 45 or claim 46, wherein two or more different HIV Env polypeptide are administered.

48. The method of any one of claims 45 to 47, wherein the HIV Env polypeptides are administered sequentially.

49. The method of any one of claims 45 to 48, wherein the HIV Env polypeptides are administered together.

50. The method of claim 38 to 49, wherein the HIV Env polypeptide is administered with an

adjuvant.

51. The method of claim 50, wherein the adjuvant comprises a lecithin.

52. The method of claim 51, wherein the lecithin is (a) combined with an acrylic polymer, (b) in a coated oil droplet in an oil-in-water emulsion or (c) in an acrylic polymer in an oil-in-water emulsion.

53. The method of claim 52, wherein the adjuvant is ISCOMATRIX or Adjuplex.

54. The method of claim 50, wherein the adjuvant comprises alum.

55. The method of any one of claims 38 to 54, wherein the trimer is administered in a liposome or in a nanoparticle.

56. The method of any one of claims 38 to 54, wherein the trimer is fixed.

57. The method of claim 56, wherein the trimer is fixed in glutaraldehyde.

58. The method of any one of claims 38 to 57, wherein the trimer is quenched with glycine.

59. The method of any one of claims 38 to 44, wherein the method comprises administering two or more of the nucleic acid molecule of claim 34 or two or more of the vector of any one of claims 35 to 37.

60. A method of engineering an immunogen capable of eliciting a broadly neutralizing antibody (bnAb) against a V2 epitope of an immunodeficiency virus which comprises a) identifying a V2 epitope conserved across two different HIV viruses, b) selecting or designing an antibody that binds to the epitope, and c) designing an immunogen that comprises the V2 epitope and binds to the germline or germline reverted antibody.

61. The method of claim 60, wherein the antibody is a germline antibody.

62. The method of claim 60, which comprises engineering the V2 epitope to improve binding of the V2 epitope to the germline or germline reverted antibody.

63. The method of claim 60, wherein designing the immunogen comprises substituting an amino acid in the immunogen.

64. A method of identifying an HIV binder which comprises contacting a candidate binder with an HIV Env polypeptide of any one of claims 1 to 33 and identifying a candidate binder that binds to the HIV Env polypeptide.

65. A method of identifying a broadly neutralizing antibody (bnAb) against HIV which comprises contacting a candidate antibody with an HIV Env polypeptide of any one of claims 1 to 33 and identifying an antibody that binds to the HIV Env polypeptide as a bnAb.

66. The method of claim 65, wherein the bnAb is a germline or germline reverted bnAb.