Neutralizing GP41 antibodies and their use
Inventors
Connors, Mark • Huang, Jinghe • Laub, Leo B. • Kwong, Peter • Nabel, Gary • Mascola, John R. • Zhang, Baoshan • Rudicell, Rebecca S. • Georgiev, Ivelin • Yang, YongPing • Zhu, Jiang • Ofek, Gilad
Assignees
US Department of Health and Human Services
Publication Number
US-9783595-B2
Publication Date
2017-10-10
Expiration Date
2032-11-07
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Abstract
Monoclonal neutralizing antibodies are disclosed that specifically bind to the HIV-1 gp41 membrane-proximal external region (MPER). Also disclosed are compositions including the disclosed antibodies that specifically bind gp41, nucleic acids encoding these antibodies, expression vectors including the nucleic acids, and isolated host cells that express the nucleic acids. The antibodies and compositions disclosed herein can be used for detecting the presence of HIV-1 in a biological sample, or detecting an HIV-1 infection or diagnosing AIDS in a subject. In additional, the broad neutralization breadth of the disclosed antibodies makes them ideal for treating a subject with an HIV infection. Thus, disclosed are methods of treating and/or preventing HIV infection.
Core Innovation
Isolated human monoclonal neutralizing antibodies specifically binding to the HIV-1 gp41 membrane-proximal external region (MPER) are disclosed. These antibodies include variants with optimized binding and neutralization abilities, and compositions comprising these antibodies, nucleic acids encoding them, expression vectors, and host cells expressing such nucleic acids are provided. The antibodies bind a novel epitope on gp41, referred to as the 10E8 epitope, which overlaps but differs from previously known epitopes, allowing broad and potent neutralization of diverse HIV-1 isolates.
The problem addressed arises from the limited ability of current HIV-1 vaccines to induce potent and broadly reactive neutralizing antibodies (NAbs) due to gaps in understanding the vulnerable regions of HIV-1 envelope proteins such as gp41. Prior neutralizing monoclonal antibodies to gp41, including 2F5, 4E10, and Z13E1, have limited strain cross-reactivity and potency, rendering them ineffective therapeutically. Therefore, there exists a need for broadly neutralizing monoclonal antibodies against conserved gp41 regions to provide protection or treatment against HIV.
The disclosed antibodies exhibit broad neutralization breadth, are not autoreactive unlike previously characterized MPER antibodies, and bind to a highly conserved gp41 helical region including residues previously thought inaccessible. The antibodies can be used for various purposes such as detecting HIV-1 presence in biological samples or diagnosing AIDS, and are suited for treating and/or preventing HIV infection due to their broad and potent neutralizing capabilities.
Claims Coverage
The patent includes multiple independent claims directed to isolated nucleic acid molecules encoding human monoclonal antibodies or antigen-binding fragments thereof that specifically bind gp41 and neutralize HIV-1. The claims cover variants of heavy and light chain variable regions with defined complementarity determining regions (CDRs), expression vectors, compositions, and kits.
Isolated nucleic acid encoding a broadly neutralizing antibody specific for gp41
An isolated nucleic acid molecule encoding a human monoclonal antibody comprising a heavy chain variable region with HCDR1, HCDR2, and HCDR3 from amino acids 26-33, 51-60, and 99-120 of SEQ ID NO: 1 and a light chain variable region with LCDR1, LCDR2 and LCDR3 from amino acids 26-31, 49-51, and 88-99 of SEQ ID NO: 2, wherein the antibody specifically binds gp41 and neutralizes HIV-1.
Heavy chain variable region variants with framework mutations
The heavy chain variable region comprises an amino acid sequence from SEQ ID NOs: 1, 3, 5, 149, 154, 189-192, 200-201, or 204 and includes at most ten amino acid substitutions in framework regions.
Heavy chain variable region comprising specific sequence variants
The heavy chain variable region comprises amino acid sequences as set forth in SEQ ID NO: 11 with defined amino acid variable positions, or as set forth in SEQ ID NOs: 1, 3, 5, 149, 154, 189-192, 200-201, or 204.
Light chain variable region variants with framework mutations
The light chain variable region comprises an amino acid sequence from SEQ ID NOs: 2, 4, 150-152, or 164-168 and includes at most ten amino acid substitutions in framework regions.
Light chain variable region comprising specific sequences
The light chain variable region comprises an amino acid sequence as set forth in SEQ ID NOs: 2, 4, 150-152, or 164-168.
Combination of specific heavy and light chain sequences
The antibody includes a heavy chain variable region comprising an amino acid sequence as set forth in SEQ ID NOs: 1, 3, 5, 149, 154, 189-192, 200-201, or 204 and a light chain variable region comprising an amino acid sequence as set forth in SEQ ID NOs: 2, 4, 150-152, or 164-168.
Specific exemplary heavy and light chain combinations
The heavy chain variable region comprises SEQ ID NO: 154 paired with the light chain variable region of SEQ ID NO: 152; or the heavy chain variable region of SEQ ID NO: 192 paired with the light chain variable region of SEQ ID NO: 152.
Antibody isotype coverage
The antibody can be an IgG, IgM or IgA antibody, specifically including IgG1.
Antigen binding fragment variants
Nucleic acid molecules encoding antigen binding fragments of the antibody comprising the defined heavy and light chain CDR regions, including Fab, Fab′, F(ab)′2, scFv, or dsFv fragments specifically binding gp41 and neutralizing HIV-1.
Expression vectors and compositions
Expression vectors comprising the nucleic acid molecules encoding the antibody or antigen binding fragments are claimed, including those for adeno-associated viral vectors and pharmaceutical compositions including the nucleic acids and carriers.
Kits comprising nucleic acids
Kits include nucleic acid molecules encoding the antibody or antibody binding fragments and instructions for use in detection or treatment.
The claims cover isolated nucleic acid molecules encoding human monoclonal antibodies or antigen binding fragments thereof that specifically bind the gp41 MPER and neutralize HIV-1. Covered embodiments include variants of heavy and light chain variable regions with defined CDRs and allowable framework substitutions, expression vectors for these antibodies, compositions, and diagnostic or therapeutic kits. The antibodies include multiple sequence variants exemplified by SEQ ID NOs and are of varying isotypes including IgG1.
Stated Advantages
The disclosed 10E8-like antibodies neutralize a broad spectrum of diverse HIV-1 isolates with high potency, neutralizing approximately 98% of viruses at low IC50 concentrations.
Unlike previously characterized MPER antibodies, these antibodies lack lipid binding and autoreactivity, which makes them more suitable for therapeutic or vaccine use.
The antibodies bind a structurally conserved and highly conserved epitope on gp41, including residues previously believed inaccessible, enhancing their neutralization breadth and potency.
Their accessibility to cell-surface and virion-associated Env is greater than other MPER antibodies, contributing to improved neutralization performance.
The antibodies and compositions can be used for the detection of HIV-1 infection and diagnosis of AIDS with high specificity.
Documented Applications
Use of the disclosed antibodies and compositions for detecting the presence of HIV-1 in a biological sample or diagnosing AIDS in a subject.
Use of the disclosed broad and potent neutralizing antibodies for treating or preventing HIV infection, including post-exposure prophylaxis and potentially clearing viral reservoirs.
Use of the antibodies in characterizing B cell repertoires and isolating broadly neutralizing antibodies from infected subjects.
Diagnostic methods and kits employing the antibodies to detect gp41 antigen in biological samples.
Screening and evaluation of vaccine candidates by testing their ability to assume conformations that bind the disclosed antibodies.
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