Neutralizing antibodies to HIV-1 and their use

Patent metadata

Field	Value
Publication number	US-10035845-B2
Application number	US-201715661867-A
Country	US
Kind code	B2
Filing date	Jul 27, 2017
Priority date	Sep 25, 2009
Publication date	Jul 31, 2018
Grant date	Jul 31, 2018

Abstract

Monoclonal neutralizing antibodies are disclosed that specifically bind to the CD4 binding site of HIV-1 gp120. Monoclonal neutralizing antibodies also are disclosed that specifically bind to HIV-1 gp41. The identification of these antibodies, and the use of these antibodies are also disclosed. Methods are also provided for enhancing the binding and neutralizing activity of any antibody using epitope scaffold probes.

First claim

We claim:

1. An isolated nucleic acid molecule, comprising:
a nucleotide sequence encoding:
an antibody heavy chain variable region comprising a heavy chain complementarity determining region (HCDR) 1, a HCDR2, and a HCDR3, comprising amino acids 26-33, 51-58, and 97-110, of SEQ ID NO: 1, respectively;
an antibody light chain variable region comprising a light chain complementarity determining region (LCDR) 1, a LCDR2, and a LCDR3, comprising amino acids 27-30, 48-50, and 87-91, of SEQ ID NO: 2, respectively; or
an antibody comprising a heavy chain variable region comprising a HCDR1, a HCDR2, and a HCDR3, comprising amino acids 26-33, 51-58, and 97-110, of SEQ ID NO: 1, respectively, and an antibody light chain variable region comprising a LCDR1, a LCDR2, and a LCDR3, comprising amino acids 27-30, 48-50, and 87-91, of SEQ ID NO: 2, respectively, wherein the antibody specifically binds to gp120.

2. The isolated nucleic acid molecule of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1.

3. The isolated nucleic acid molecule of claim 1 , wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2.

4. The isolated nucleic acid molecule of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 3.

5. The isolated nucleic acid molecule of claim 1 , wherein the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 4.

6. The isolated nucleic acid molecule of claim 1 , wherein the heavy chain variable region comprises the HCDR1, the HCDR2, and the HCDR3, and an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 1.

7. The isolated nucleic acid molecule of claim 1 , wherein the light chain variable region comprises the LCDR1, the LCDR2, and the LCDR3, and an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 2.

8. The isolated nucleic acid molecule of claim 1 , comprising:
the nucleotide sequence encoding the antibody comprising
the heavy chain variable region comprising a HCDR1, a HCDR2, and a HCDR3, comprising amino acids 26-33, 51-58, and 97-110, of SEQ ID NO: 1, respectively, and
the antibody light chain variable region comprising a LCDR1, a LCDR2, and a LCDR3, comprising amino acids 27-30, 48-50, and 87-91, of SEQ ID NO: 2, respectively; and
wherein the antibody specifically binds to gp120.

9. The isolated nucleic acid molecule of claim 1 , wherein
the heavy chain variable region comprises the HCDR1, the HCDR2, and the HCDR3, and an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 1; and
the light chain variable region comprises the LCDR1, the LCDR2, and the LCDR3, and an amino acid sequence at least 90% identical to the amino acid sequence set forth as SEQ ID NO: 2.

10. The isolated nucleic acid molecule of claim 1 , wherein the heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 1, and the light chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 2.

11. The isolated nucleic acid molecule of claim 10 , wherein the antibody is an IgG, an IgM, or an IgA.

12. The isolated nucleic acid molecule of claim 11 , wherein the antibody is an IgG 1.

13. An isolated nucleic acid molecule, comprising a nucleotide sequence encoding an antigen binding fragment of the antibody encoded by the nucleic acid molecule of claim 8 .

14. The isolated nucleic acid molecule of claim 13 , wherein the antigen binding fragment is a Fab fragment, a Fab′ fragment, a F(ab)′ 2 fragment, a single chain Fv protein (scFv), or a disulfide stabilized Fv protein (dsFv).

15. The isolated nucleic acid molecule of claim 1 , wherein the nucleic acid sequence comprises at least one of one of the nucleic acid sequences set forth as SEQ ID NOs: 29-32.

16. The isolated nucleic acid molecule of claim 1 , operably linked to a promoter.

17. An expression vector comprising the isolated nucleic acid molecule of claim 1 .

18. The expression vector of claim 17 , wherein the expression vector is a viral vector.

19. The expression vector of claim 18 , wherein the viral vector is an adeno-associated viral vector.

20. An isolated host cell transformed with the nucleic acid molecule of claim 1 .

21. A method of making an antibody that specifically binds to gp120, comprising:
expressing in a host cell one or more nucleic acid molecules encoding:
an antibody heavy chain variable region comprising a heavy chain complementarity determining region (HCDR) 1, a HCDR2, and a HCDR3, comprising amino acids 26-33, 51-58, and 97-110, of SEQ ID NO: 1, respectively; and
an antibody light chain variable region comprising a light chain complementarity determining region (LCDR) 1, a LCDR2, and a LCDR3, comprising amino acids 27-30, 48-50, and 87-91, of SEQ ID NO: 2, respectively; and
purifying the antibody.

Assignees

• Us Health
• Univ Washington

Inventors

• Mascola John
• Wyatt Richard
• Wu Xueling
• Li Yuxing
• Hogerkorp Carl-Magnus
• Roederer Mario
• Yang Zhi-Yong
• Nabel Gary
• Kwong Peter
• Zhou Tongqing
• Connors Mark
• Schief William

Classifications

• A61P31/18

  for HIV · CPC title

• C12N2740/16111

  concerning HIV env · CPC title

• C12N2740/16011

  Human Immunodeficiency Virus, HIV · CPC title

• C12N2740/10011

  Retroviridae · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title