IP Library › Granted Patent US 10,035,844

Granted Patent B2

US 10,035,844 · App. 15/612,846 · Granted Jul 31, 2018

Broadly neutralizing HIV-1 VRC07 antibodies that bind to the CD4-binding site of the envelope protein

Inventors: Peter D. Kwong (Washington, DC); Gary J. Nabel (Cambridge, MA); Rebecca S. Rudicell (Silver Spring, MD); John Mascola (Rockville, MD); Mark Connors (Bethesda, MD); Ivelin Georgiev (Nashville, TN); Jiang Zhu (Ashburn, VA); Young Do Kwon (Rockville, MD); Tongqing Zhou (Boyds, MD); Yongping Yang (Potomac, MD); Baoshan Zhang (Bethesda, MD); Gwo-Yu Chuang (Rockville, MD); Xueling Wu (Potomac, MD); Zhi-yong Yang (Potomac, MD); Wei Shi (Rockville, MD)

Assignee: The United States of America, as represented by the Secretary, Department of Health and Human Services

C07K16/1063 A61K39/42 A61K45/06 G01N33/56983 G01N33/56988 C07K2317/21 C07K2317/41 C07K2317/565 C07K2317/567 C07K2317/72 C07K2317/76 C07K2317/92

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Quick Facts

Patent No.: US 10,035,844
App. No.: 15/612,846
Granted: Jul 31, 2018
Kind: B2

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Abstract

Monoclonal neutralizing antibodies that specifically bind to HIV-1 gp120 and antigen binding fragments of these antibodies are disclosed. Nucleic acids encoding these antibodies, vectors and host cells are also provided. Methods for detecting HIV using these antibodies are disclosed. In addition, the use of these antibodies, antigen binding fragment, nucleic acids and vectors to prevent and/or treat an HIV infection is disclosed.

Claims (117)

1. An isolated nucleic acid molecule encoding a monoclonal antibody or an antigen binding fragment thereof, comprising:

a heavy chain variable domain (V H ) comprising a heavy chain complementary determining region (HCDR)1, a HCDR2, and HCDR3 comprising amino acids 26-33, 51-58, and 97-114 of SEQ ID NO: 40, respectively; and

a light chain variable domain (V L ) comprising a light chain complementary determining region (LCDR)1, a LCDR2, and a LCDR3 comprising amino acids 27-30, 48-50, and 87-91 of SEQ NO: 238, respectively, wherein

the antibody or antigen binding fragment specifically binds a CD4 binding site on human immunodeficiency virus type 1 (HIV-1) gp120 and neutralizes HIV-1.

2. The nucleic acid molecule of claim 1 , wherein the V H comprises one of:

(a) amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40, wherein X 2 is G; or

(b) amino acids 26-33 (CDR1), 51-58 (CDR2) and 97-114 (CDR3) of SEQ ID NO: 40, wherein X 2 is H.

3. The nucleic acid molecule of claim 1 , wherein the V H of the antibody comprises SEQ ID NO: 40.

4. The nucleic acid molecule of claim 3 , wherein the V H comprises one of:

(a) SEQ ID NO: 40, wherein X 1 is I, X 2 is G, X 3 is S and X 4 is T (VRC07; SEQ ID NO: 2);

(b) SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is S and X 4 is T (VRC07 G54H; SEQ ID NO: 32);

(d) SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is S and X 4 is A (VRC07 I37V, G54H, T93A; SEQ ID NO: 259); or

(e) SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is N and X 4 is A (VRC07 I37V, G54H, S58N, T93A; SEQ ID NO: 260).

5. The nucleic acid molecule claim 1 , wherein the V L comprises one of:

(a) amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is F (VRC01 light chain CDRs);

(b) amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is D (VRC01 light chain CDRs with F97D);

(c) amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is K (VRC01 light chain CDRs with F97K);

(d) amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is S (VRC01 light chain CDRs with F97S); or

(e) amino acids 27-30 (CDR1), 48-50 (CDR2) and 87-91 (CDR3) of SEQ ID NO: 238, wherein X 11 is H (VRC01 light chain CDRs with F97H).

6. The nucleic acid molecule of claim 1 , wherein the V L comprises SEQ ID NO: 238.

7. The nucleic acid molecule claim 6 , wherein the V L comprises one of:

(a) SEQ ID NO: 238, wherein X 1 is E; X 2 is I; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01 light chain; SEQ ID NO: 9);

(b) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is E; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; and X 13 is I (VRC01L E1/I2del-V3E; SEQ ID NO: 219);

(c) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is K; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; and X 13 is I (VRC01L V3K light chain; SEQ ID NO: 220);

(d) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; and X 13 is I (VRC01L E1/I2del V3S light chain; SEQ ID NO: 221);

(e) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is D; X 12 is V; and X 13 is I (VRC01L E1/I2del F97D; SEQ ID NO: 222);

(f) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is K; X 12 is V; and X 13 is I (VRC01L E1/I2del F97K; SEQ ID NO: 223);

(g) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is S; X 12 is V; and X 13 is I (VRC01L E1/I2del F97S; SEQ ID NO: 224);

(h) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is H; X 12 is V; and X 13 is I (VRC01L E1/I2del F97H; SEQ ID NO: 225);

(i) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is E; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is S; X 12 is V; and X 13 is I (VRC01L E1/I2del V3E/F97S; SEQ ID NO: 226);

(j) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is E; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is H; X 12 is V; and X 13 is I (VRC01L E1/I2del V3E/F97H; SEQ ID NO: 227);

(k) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is S; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; and X 13 is I (VRC01hpL03; SEQ ID NO: 228);

(l) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is Q; X 5 is S; X 6 is S; X 7 is N; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; and X 13 is I (VRC01hpL04; SEQ ID NO: 229);

(m) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is Q; X 5 is S; X 6 is S; X 7 is N; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is Q; and X 13 is N (VRC01hpL05; SEQ ID NO: 230);

(n) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is E; X 5 is K; X 6 is E; X 7 is E; X 8 is E; X 9 is R; X 10 is R; X 11 is F; X 12 is Q; and X 13 is N (VRC01hpL06; SEQ ID NO: 231);

(o) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is T; X 5 is S; X 6 is S; X 7 is S; X8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is Q; and X 13 is N (VRC01hpL02 E1/I2 deletion/V3S; SEQ ID NO: 232);

(p) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is I; X 5 is S; X 6 is S; X 7 is S; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; and X 13 is I (VRC01hpL03 E1/I2 deletion/V3S; SEQ ID NO: 233);

(q) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is Q; X 5 is S; X 6 is S; X 7 is N; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; and X 13 is I (VRC01hpL04 E1/I2 deletion/V3S; SEQ ID NO: 234);

(r) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is Q; X 5 is S; X 6 is S; X 7 is N; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is Q; and X 13 is N (VRC01hpL05 E1/I2 deletion/V3S; SEQ ID NO: 235);

(s) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is S; X 4 is E; X 5 is K; X 6 is E; X 7 is E; X 8 is E; X 9 is R; X 10 is R; X 11 is F; X 12 is Q; and X 13 is N (VRC01hpL06 E1/I2 deletion/V3S; SEQ ID NO: 236);

(t) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is E; X 4 is Q; X 5 is S; X 6 is S; X 7 is N; X 8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is V; and X 13 is I (VRC01hpL04 E1/I2 deletion/V3E; SEQ ID NO: 237);

(u) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; and X 13 is I (VRC01 E1/I2 deletion; SEQ ID NO: 53); or

(v) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is T; X 5 is S; X 6 is S; X 7 is S; X8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is Q; and X 13 is N (VRC01hpL02; SEQ ID NO: 50).

8. The nucleic acid molecule of claim 1 , wherein:

the HCDR1, the HCDR2, and the HCDR3 comprise amino acids 26-33, 51-58, and 97-114 of SEQ ID NO: 2, respectively; and

the LCDR1, the LCDR2, and the LCDR3 comprise amino acids 27-30, 48-50, and 87-91 of SEQ NO: 9, respectively.

9. The nucleic acid molecule of claim 8 , wherein the V H comprises the amino acid sequence set forth as SEQ ID NO: 2, and the V L comprises the amino acid sequence set forth as SEQ NO: 9.

10. The nucleic acid molecule of claim 1 , wherein the V H comprises SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is S and X 4 is T (VRC07 G54H; SEQ ID NO: 32), and the light chain of the antibody comprises:

(a) SEQ ID NO: 238, wherein X 1 is E; X 2 is I; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01 light chain; SEQ ID NO: 9);

11. The nucleic acid molecule of claim 1 , wherein the V H of the antibody comprises SEQ ID NO: 40, wherein X 1 is V, X 2 is H, X 3 is S and X 4 is A (VRC07 I37V, G54H, T93A; SEQ ID NO: 259), and the light chain of the antibody comprises:

(a) SEQ ID NO: 238, wherein X 1 is E; X 2 is I; X 3 is V; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X8 is D; X 9 is N; X 10 is T; X 11 is F; X 12 is V; X 13 is I (VRC01 light chain; SEQ ID NO: 9);

(v) SEQ ID NO: 238, wherein X 1 is no amino acid; X 2 is no amino acid; X 3 is V; X 4 is T; X 5 is; X 6 is S; X 7 is S; X8 is D; X 9 is T; X 10 is T; X 11 is F; X 12 is Q; and X 13 is N (VRC01hpL02; SEQ ID NO: 50).

12. The nucleic acid molecule of claim 1 , encoding the antibody.

13. The nucleic acid molecule of claim 12 , wherein the antibody is an IgG, IgM or IgA.

14. The nucleic acid molecule of claim 1 , encoding the antigen binding fragment of the antibody.

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

16. A vector comprising the nucleic acid molecule of claim 15 .

17. The vector of claim 16 , wherein the vector is a viral vector.

18. The viral vector of claim 17 , wherein the viral vector is adeno-associated viral vector.

19. A pharmaceutical composition comprising the nucleic acid molecule of claim 1 .

20. A method for inhibiting human immunodeficiency virus type 1 (HIV-1) replication in a subject, comprising administering to the subject a therapeutically effective amount of the nucleic acid molecule of claim 1 , thereby inhibiting HIV-1 replication in the subject.

21. The nucleic acid molecule of claim 1 , wherein:

the HCDR1, the HCDR2, and the HCDR3 comprising amino acids 26-33, 51-58, and 97-114 of SEQ ID NO: 32, respectively; and

the LCDR1, the LCDR2, and the LCDR3 comprising amino acids 27-30, 48-50, and 87-91 of SEQ NO: 9, respectively.

22. The nucleic acid molecule of claim 21 , wherein the V H comprises the amino acid sequence set forth as SEQ ID NO: 32, and the V L comprises the amino acid sequence set forth as SEQ NO: 221.

23. The nucleic acid molecule of claim 21 , wherein the V H comprises the amino acid sequence set forth as SEQ ID NO: 259, and the V L comprises the amino acid sequence set forth as SEQ NO: 221.

24. The nucleic acid molecule of claim 21 , encoding the antibody.

25. The nucleic acid molecule of claim 24 , wherein the antibody is an IgG, IgM or IgA.

26. The nucleic acid molecule of claim 21 , encoding the antigen binding fragment of the antibody.

27. The nucleic acid molecule of claim 21 , operably linked to a promoter.

28. A vector comprising the nucleic acid molecule of claim 27 .

29. The vector of claim 28 , wherein the vector is a viral vector.

30. The viral vector of claim 29 , wherein the viral vector is adeno-associated viral vector.

31. A pharmaceutical composition comprising the nucleic acid molecule of claim 21 .

32. A method for inhibiting human immunodeficiency virus type 1 (HIV-1) replication in a subject, comprising administering to the subject a therapeutically effective amount of the nucleic acid molecule of claim 21 , thereby inhibiting HIV-1 replication in the subject.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 26, 2020

From: KWONG, PETER D.; NABEL, GARY J.; RUDICELL, REBECCA S.; MASCOLA, JOHN; CONNORS, MARK; GEORGIEV, IVELIN; ZHU, JIANG; KWON, YOUNG DO; ZHOU, TONGQING; YANG, YONGPING; ZHANG, BAOSHAN; CHUANG, GWO-YU; WU, XUELING; YANG, ZHI-YONG; SHI, WEI

To: THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES

Reel/Frame 053044/0812 →

Continuity (5)

Division 14363740

Provisional Application 61698452 · Sep 7, 2012

Provisional Application 61613431 · Mar 20, 2012

Provisional Application 61568520 · Dec 8, 2011

Related Publication 20170267748A1 · Sep 21, 2017

Cited By (1)

US 12,428,472