NEUTRALIZING ANTIBODIES TO GP120 AND THEIR USE
Antibodies and antigen binding fragments that specifically bind to gp120 and neutralize HIV-1 are disclosed. Nucleic acids encoding these antibodies, vectors and host cells are also provided. Methods for detecting HIV-1 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-1 infection is disclosed.
1 . An isolated monoclonal antibody, comprising
a heavy chain variable region (V H ) comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3 set forth as SEQ ID NOs: 7, 8, and 9, respectively;
a light chain variable region (V L ) comprising a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3 set forth as SEQ ID NOs: 10, 11, and 12, respectively; and
a recombinant constant domain comprising M428L and N434S mutations,
wherein the antibody specifically binds to HIV-1 gp120 and neutralizes HIV-1.
2 . The isolated monoclonal antibody of claim 1 , wherein the V H comprises the amino acid sequence of SEQ ID NO: 1.
3 . The isolated monoclonal antibody of claim 1 , wherein the V L comprises the amino acid sequence of SEQ ID NO: 2.
4 . The isolated monoclonal antibody of claim 1 , wherein the V H comprises the amino acid sequence of SEQ ID NO: 1 and the V L comprises the amino acid sequence of SEQ ID NO: 2.
5 . A multi-specific antibody comprising the V H and the V L of the monoclonal antibody of claim 1 , wherein the multi-specific antibody specifically binds to gp120 and neutralizes HIV-1.
6 . An antigen binding fragment comprising the V H and the V L of the isolated monoclonal antibody of claim 1 .
7 . The antigen binding fragment of claim 6 , wherein the antigen binding fragment is a Fv, Fab, F(ab′) 2 , scFV or a scFV 2 fragment.
8 . The isolated monoclonal antibody of claim 1 , wherein the antibody is an IgG, IgA or IgM antibody.
9 . The isolated monoclonal antibody of claim 1 , wherein the antibody neutralizes at least 50% of the following HIV-1 isolates: 6540.v4.c1, 620345.c1, T278-50, 6322.V4.C1, DU422.01, X2088.c9, 6545.V4.C1, 242-14, T250-4, 7165.18, BL01.DG, H086.8, 6471.V1.C16, 6631.V3.C10, TVI.29, TZA125.17, CAP210.E8, DU172.17 with an inhibitory concentration (IC 50 ) of <50 μg/ml.
10 . The isolated monoclonal antibody of claim 1 , linked to an effector molecule or a detectable marker.
11 . The isolated monoclonal antibody of claim 14 , wherein the detectable marker is a fluorescent, enzymatic, or radioactive marker.
12 . A pharmaceutical composition for use in treating an HIV-1 infection, comprising: a therapeutically effective amount of the antibody of claim 1 , or an antigen binding fragment of the antibody and a pharmaceutically acceptable carrier.
13 . The pharmaceutical composition of claim 12 , wherein the composition is sterile and/or is in unit dosage form or a multiple thereof.
14 . A method of treating an HIV-1 infection in a subject, comprising administering to the subject a therapeutically effective amount of the antibody of claim 1 or an antigen binding fragment of the antibody, thereby treating the HIV-1 infection.
15 . The method of claim 18 , further comprising administering to the subject an additional antibody, antigen binding fragment, or nucleic acid encoding the additional antibody or antigen binding fragment, wherein the additional antibody or antigen binding fragment specifically binds to HIV-1 Env and neutralizes HIV-1 infection.
16 . The method of claim 14 , wherein the subject is a human subject.
17 . The method of claim 16 , wherein the subject is a pregnant female.
18 . The method of claim 17 , further comprising administering to the subject an effective amount of an anti-retroviral therapy.
19 . The method of claim 19 , wherein the anti-retroviral therapy is a nucleoside analog reverse-transcriptase inhibitor, a nucleotide reverse transcriptase inhibitors, a non-nucleoside reverse transcriptase inhibitor, a protease inhibitor, a viral entry or fusion inhibitor, a maturation inhibitor, or IL-15.