FIELD OF THE DISCLOSURE

This relates to antibodies and antigen binding fragments that specifically bind to Human Immunodeficiency Virus type 1 (HIV-1) gp41 and their use, for example, in methods of treating a subject with HIV-1 infection.

BACKGROUND

HIV-1 infection, and the resulting Acquired Immunodeficiency Syndrome (AIDS), remain threats to global public health, despite extensive efforts to develop anti-HIV-1 therapeutic agents. An enveloped virus, HIV-1 hides from humoral recognition behind a wide array of protective mechanisms. The major HIV-1 envelope protein (HIV-1 Env) is a glycoprotein of approximately 160 kD (gp160). During infection, proteases of the host cell cleave gp160 into gp120 and gp41. gp41 is an integral membrane protein, while gp120 protrudes from the mature virus. Together gp120 and gp41 make up the HIV-1 envelope spike, which is a target for neutralizing antibodies. Broadly neutralizing antibodies that bind to HIV-1 Env have been identified, including the 10E8 antibody, which specifically binds to the membrane proximal external region (MPER) of gp41 and can neutralize a high percentage of HIV-1 strains. However, there is a need to develop additional neutralizing antibodies for HIV-1 with varying recognition and neutralization profiles for commercial production.

SUMMARY

Disclosed herein are isolated antibodies and antigen binding fragments that specifically bind to HIV-1 gp41 and neutralize HIV-1. In some embodiments, the isolated antibody or antigen binding fragment comprises heavy and light chain variable regions comprising one or more amino acid substitutions (for example in the complementarity determining regions (CDRs) and/or the framework regions) compared to the 10E8 antibody sequence that impart an improved combination of neutralization, solubility, and auto-reactivity properties relative to the 10E8 antibody.

In some embodiments, the isolated antibody or antigen binding fragment comprises a heavy chain variable region (VH) comprising a heavy chain complementarity determining region (HCDR)1, a HCDR2, and a HCDR3 of the VHset forth as SEQ ID NO: 75 (10E8v4 S100cF), and a light chain variable region (VL) comprising a light chain complementarity determining region (LCDR)1, a LCDR2, and a LCDR3 of the VLset forth as SEQ ID NO: 6 (rL3-6mut), wherein the antibody or antigen binding fragment specifically binds to gp41 and neutralizes HIV-1. In some embodiments, the HCDR1, the HCDR2, the HCDR3, the LCDR1, the LCDR2, and the LCDR3 comprise the amino acid sequences set forth as SEQ ID NOs: 7, 8, 77, 10, 11, and 12, respectively (10E8v4 S100cF IMGT CDRs). In some embodiments, the VHand VLof the isolated antibody or antigen binding fragment comprise the amino acid sequences set forth as SEQ ID NOs: 75 and 6, respectively (10E8v4 S100cF), or SEQ ID NOs: 76 and 6, respectively (10E8v4 V5R S100cF), wherein the antibody or antigen binding fragment specifically binds to gp41 and neutralizes HIV-1.

In additional embodiments, the isolated antibody comprises a VHcomprising a HCDR1, a HCDR2, and a HCDR3 of the VHset forth as SEQ ID NO: 5, and a VLcomprising a light chain LCDR1, a LCDR2, and a LCDR3 of the VLset forth as SEQ ID NO: 6, wherein the VHcomprises arginine, glutamate, serine, lysine, aspartate, threonine, lysine, threonine, valine, threonine, threonine, tyrosine, glutamine, and isoleucine residues at kabat positions 3, 61, 62, 64, 72, 74, 75, 77, 82C, 84, 87, 89, 105, and 110, respectively, and the VLcomprises alanine, serine, aspartate, proline, alanine, lysine, glutamine, valine, isoleucine, threonine, glutamate, and aspartate residues at kabat positions 1, 2, 7, 8, 9, 16, 17, 45, 58, 76, 83, and 85, respectively, and wherein the antibody or antigen binding fragment specifically binds to gp41 and neutralizes HIV-1.

Also disclosed are compositions including the antibodies and antigen binding fragments, nucleic acids encoding the antibodies and antigen binding fragments, expression vectors comprising the nucleic acids, and isolated host cells that comprise the nucleic acids. In some embodiments, the nucleic acid molecule can be a bicistronic expression construct encoding the VHand VLof the antibody or antigen binding fragment.

The disclosed antibodies and antigen binding fragments potently neutralize HIV-1 in an accepted in vitro model of HIV-1 infection. Accordingly, a method is disclosed for treating or inhibiting an HIV-1 infection in a subject. The methods include administering a therapeutically effective amount of one or more of the disclosed antibodies, antigen binding fragments, nucleic acid molecules, vectors, or compositions, to the subject, for example to a subject at risk of or having an HIV-1 infection.

The antibodies, antigen binding fragments, nucleic acid molecules, vectors, and compositions disclosed herein can be used for a variety of additional purposes, such as for detecting an HIV-1 infection or diagnosing HIV-1 infection in a subject, or detecting HIV-1 in a sample.

The foregoing and other features and advantages of this disclosure will become more apparent from the following detailed description of several embodiments which proceeds with reference to the accompanying figures.

