HIV-1 GP140 immunogens comprising modified NHR1 regions that stabilize pre-fusion conformations

Patent metadata

Field	Value
Publication number	US-10647748-B2
Application number	US-201816176200-A
Country	US
Kind code	B2
Filing date	Oct 31, 2018
Priority date	May 2, 2016
Publication date	May 12, 2020
Grant date	May 12, 2020

Abstract

The present invention provides HIV-1 vaccine immunogens. Some of the immunogens contain a soluble gp140-derived protein that harbors a modified N-terminus of the HR1 region in gp41. Some of the immunogens contain an HIV-1 Env-derived trimer protein that is presented on a nanoparticle platform. The invention also provides methods of using the HIV-1 vaccine immunogens for eliciting an immune response or treating HIV infections.

First claim

What is claimed is:

1. A modified HIV-1 envelope gp140 protein, comprising a gp120 polypeptide and a gp41 polypeptide, wherein amino acid residues 548-568 of the N-terminus of heptad 1 region (HR1) of the gp41 polypeptide is replaced with a loop sequence of 6 to 14 amino acid residues in length that stabilizes the pre-fusion gp140 structure, wherein the numbering of the amino acid residues corresponds to HxB2 nomenclature.

2. The modified HIV-1 gp140 protein of claim 1 , wherein the gp41 polypeptide is gp41 ECTO .

3. The modified HIV-1 gp140 protein of claim 1 , wherein the gp120 and gp41 polypeptides are from different HIV-1 strains.

4. The modified HIV-1 gp140 protein of claim 1 , which is derived from HIV-1 strain BG505.

5. The modified HIV-1 gp140 protein of claim 1 , wherein the loop sequence comprises (GS)n (SEQ ID NO:23), wherein n is any integer between 3 and 7, inclusive.

6. The modified HIV-1 gp140 protein of claim 1 , wherein the loop sequence comprises (GS) 4 (SEQ ID NO:24).

7. The modified HIV-1 gp140 protein of claim 1 , wherein the loop sequence comprises 10 amino acid residues.

8. The modified HIV-1 gp140 protein of claim 7 , wherein the loop sequence comprises any one of SEQ ID NOs: 1-5.

9. The modified HIV-1 gp140 protein of claim 1 , wherein the loop sequence comprises 8 amino acid residues.

10. The modified HIV-1 gp140 protein of claim 9 , wherein the loop sequence comprises any one of SEQ ID NOs:6-10.

11. The modified HIV-1 gp140 protein of claim 1 , further comprising a flexible linker sequence that substitutes for the cleavage site sequence between gp120 and gp41.

12. The modified HIV-1 gp140 protein of claim 11 , wherein the linker sequence comprises (G4S) 2 (SEQ ID NO:22) or SGS and substitutes for residues 508-511 at the cleavage site.

13. The modified HIV-1 gp140 protein of claim 11 , wherein the linker sequence comprises 8 amino acid residues and substitutes for residues 501-518 at the cleavage site, and wherein numbering of the amino acid residues corresponds to that of HIV-1 strain BG505, SOSIP.664 gp140.

14. The modified HIV-1 gp140 protein of claim 13 , wherein the linker sequence comprises the sequence shown in any one of SEQ ID NOs: 16-20.

15. The modified HIV-1 gp140 protein of claim 1 , further comprising an engineered disulfide bond between gp120 and gp41.

16. The modified HIV-1 gp140 protein of claim 15 , wherein the engineered disulfide bond is between residues A501C and T605C.

17. The modified HIV-1 gp140 protein of claim 1 , comprising a gp140 trimer with each monomer comprising a gp120 polypeptide and a gp41 ECTO polypeptide, wherein the gp41 ECTO polypeptide is derived from HIV-1 strain BG505, and wherein the N-terminus of heptad 1 region (HR1) (SEQ ID NO:28) in the gp41 ECTO polypeptide is replaced with a loop sequence shown in SEQ ID NO:6.

18. The modified HIV-1 gp140 protein of claim 17 , further comprising (a) a linker sequence (G4S) 2 (SEQ ID NO:22) that substitutes for residues 508-511 at the cleavage site, and (b) an engineered disulfide bond between residues A501C and T605C.

Assignees

• Scripps Research Inst

Inventors

• Kong Leopold
• Wilson Ian A
• De Val Natalia
• Ward Andrew B
• Burton Dennis
• He Linling
• Zhu Jiang

Classifications

• A61K2039/6031

  Proteins · CPC title

• A61K2039/5258

  Virus-like particles · CPC title

• A61K2039/645

  Dendrimers; Multiple antigen peptides · CPC title

• C12N2740/16134

  Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein · CPC title

• A61K47/6929

  the form being a nanoparticle, e.g. an immuno-nanoparticle · CPC title