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

Patent metadata

Field	Value
Publication number	US-9695230-B2
Application number	US-201214363740-A
Country	US
Kind code	B2
Filing date	Dec 10, 2012
Priority date	Dec 8, 2011
Publication date	Jul 4, 2017
Grant date	Jul 4, 2017

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.

First claim

We claim:

1. An isolated monoclonal antibody comprising:
a heavy chain variable domain 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 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 specifically binds a CD4 binding site on human immunodeficiency virus type 1 (HIV-1) gp120 and neutralizes HIV-1.

2. The isolated monoclonal antibody of claim 1 , wherein the heavy chain variable domain 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 isolated monoclonal antibody of claim 1 , wherein the heavy chain variable domain of the antibody comprises SEQ ID NO: 40.

4. The isolated monoclonal antibody of claim 1 , wherein the heavy chain variable domain of the antibody 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);
(c) SEQ ID NO: 40, wherein X 1 is I, X 2 is H, X 3 is N and X 4 is T (VRC07 G54H, S58N; SEQ ID NO: 258);
(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 isolated monoclonal antibody claim 1 , wherein the light chain variable domain 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 isolated monoclonal antibody of claim 1 , wherein the light chain variable domain of the antibody comprises SEQ ID NO: 238.

7. The isolated monoclonal antibody claim 6 , wherein the light chain variable domain of the antibody 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 5; X 6 is 5; X 7 is W; X 8 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 5; X 6 is 5; X 7 is W; X 8 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 5; X 6 is 5; X 7 is W; X 8 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 5; X 4 is I; X 5 is S; X 6 is S; X 7 is W; X 8 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; X 8 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; X 8 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; X 8 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; X 8 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; X 8 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; X 8 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 5; X 4 is T; X 5 is 5; X 6 is 5; X 7 is S; 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 (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 5; X 4 is I; X 5 is 5; X 6 is 5; X 7 is 5; 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 5; X 4 is Q; X 5 is 5; X 6 is 5; 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 5; X 4 is Q; X 5 is 5; X 6 is 5; 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 5; 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 5; X 6 is 5; 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 5; X 6 is 5; X 7 is W; X 8 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

Assignees

• Us Health

Inventors

• 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

Classifications

• C07K2317/41

  Glycosylation, sialylation, or fucosylation · CPC title

• G01N33/56988

  HIV or HTLV · CPC title

• C07K2317/565

  Complementarity determining region [CDR] · CPC title

• C07K2317/72

  Increased effector function due to an Fc-modification · CPC title

• C07K2317/567

  Framework region [FR] · CPC title