Neutralizing antibodies to HIV-1 GP41 and their use
Inventors
Kwong, Peter • Kwon, Young Do • Georgiev, Ivelin • Ofek, Gilad • Zhang, Baoshan • McKee, Krisha • Mascola, John • Connors, Mark • Chuang, Gwo-Yu • O'Dell, Sijy • Bailer, Robert • Louder, Mark • ASOKAN, Mangaiarkarasi • Schwartz, Richard • Cooper, Jonathan • Carlton, Kevin • Bender, Michael • PEGU, Amarendra • Shapiro, Lawrence • Gindin, Tatyana • Kueltzo, Lisa
Assignees
United States, Represented By Sectetary Department Of Health And Human Services AS • Columbia University in the City of New York • US Department of Health and Human Services
Publication Number
US-11236152-B2
Publication Date
2022-02-01
Expiration Date
2036-11-03
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Abstract
Neutralizing antibodies that specifically bind to HIV-1 Env 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-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.
Core Innovation
The invention provides isolated antibodies and antigen binding fragments that specifically bind to the HIV-1 gp41 envelope protein and neutralize HIV-1. These include antibodies comprising heavy and light chain variable regions with particular amino acid substitutions compared to the 10E8 antibody, resulting in an improved balance of neutralization potency, solubility, and autoreactivity properties. Various variants such as 10E8v4, 10E8v5, and further substitutions like S100cF and V5R S100cF are described, which specifically bind to gp41 and neutralize HIV-1 effectively.
The problem addressed arises from the challenges posed by HIV-1's envelope protein structure and the limited solubility and autoreactivity profiles of existing neutralizing antibodies such as the parent 10E8 antibody. Although 10E8 neutralizes a large percentage of HIV-1 strains, its solubility is suboptimal for commercial production, and modifications made in prior art to improve solubility led to increased autoreactivity. There is a need for novel antibodies with varying recognition and neutralization profiles that combine high potency, improved solubility, and low autoreactivity, suitable for therapeutic and diagnostic use.
Claims Coverage
The patent contains multiple independent claims focusing on isolated antibodies or antigen binding fragments comprising specified heavy and light chain variable regions with particular complementarity determining regions (CDRs) and framework residues, and their specific binding to gp41 and neutralization of HIV-1.
Antibody comprising specific VH and VL CDRs with defined amino acid residues at kabat positions
An isolated antibody having a heavy chain variable region with HCDR1, HCDR2, and HCDR3 as SEQ ID NO: 75, and a light chain variable region with LCDR1, LCDR2, and LCDR3 as SEQ ID NO: 6, with the HCDRs and LCDRs comprising amino acid sequences set forth in SEQ ID NOs: 7, 8, 77, 10, 11, and 12 respectively, wherein the VH includes specified amino acid residues at kabat positions 3, 61, 62, 64, 72, 74, 75, 77, 82c, 84, 87, 89, 105, and 110, and the VL includes specified amino acid residues at kabat positions 1, 2, 7, 8, 9, 16, 17, 45, 58, 76, 83, and 85, and wherein the antibody specifically binds gp41 and neutralizes HIV-1.
Antibody with VH and VL comprising amino acid sequences at least 90% identical to 10E8v4 S100cF or 10E8v4 V5R S100cF
An isolated antibody comprising a VH having HCDR1, HCDR2, and HCDR3 as SEQ ID NO: 75 and VL comprising LCDR1, LCDR2, and LCDR3 as SEQ ID NO: 6, where the VH and VL framework regions further comprise amino acid sequences at least 90% identical to SEQ ID NOs: 75 and 6 (10E8v4 S100cF) or SEQ ID NOs: 76 and 6 (10E8v4 V5R S100cF), wherein the antibody specifically binds to gp41 and neutralizes HIV-1.
Antibody solubility and humanized features
The antibody dissolves to at least 5 mg/ml in phosphate buffered saline, pH 7.4, at 20°C, includes human framework regions, a human constant region, and can be an IgG, IgM, or IgA with modifications enhancing binding to the neonatal Fc receptor such as M428L and N434S substitutions, while specifically binding gp41 and neutralizing HIV-1.
Antigen binding fragment and conjugates
Antigen binding fragments of the antibodies are included such as Fv, Fab, F(ab′)2, scFv, or scFv2. Further, antibodies or antigen binding fragments linked to effector molecules or detectable markers, including fluorescent, enzymatic, or radioactive markers, are claimed.
Methods for detection and treatment of HIV-1 infection
Methods of detecting HIV-1 infection by contacting a biological sample with the antibody or antigen binding fragments to form and detect an immune complex are claimed. Methods of inhibiting or treating HIV-1 infection by administering a therapeutically effective amount of the antibody or antigen binding fragment to a subject at risk of or having HIV-1 infection are claimed, optionally with additional neutralizing antibodies such as VRC01-class antibodies.
The claims cover isolated antibodies and antigen binding fragments with specific heavy and light chain variable region sequences and CDRs that specifically bind gp41 and neutralize HIV-1, with particular amino acid residue patterns, including variants of 10E8 with improved solubility and neutralization properties. They also cover related compositions, diagnostic and therapeutic methods using these antibodies, antigen binding fragments, conjugates with effector or detectable markers, as well as nucleic acids encoding these antibodies and their expression vectors and host cells.
Stated Advantages
The disclosed antibodies and antigen binding fragments exhibit an improved combination of HIV-1 neutralization breadth and potency, solubility, and low autoreactivity compared to the parent 10E8 antibody.
Modifications to 10E8 variants result in antibodies that do not aggregate in solution and remain monodisperse, improving manufacturability.
Certain 10E8 variants have substantially increased half-life in serum compared to the parent 10E8 antibody.
The 10E8v4 S100cF and 10E8v4 V5R S100cF variants possess an optimal combination of neutralization potency, solubility, and low autoreactivity, with enhanced stability and ability to be concentrated at high levels.
Documented Applications
Use of isolated antibodies and antigen binding fragments to prevent and treat HIV-1 infections in subjects, including both prophylactic and therapeutic applications.
Use of antibodies, antigen binding fragments, nucleic acids, and vectors for detecting HIV-1 infection by binding to gp41 in biological samples, aiding diagnosis of HIV-1 infection.
Use of antibodies and antigen binding fragments in combination with other anti-retroviral agents or other HIV-1 neutralizing antibodies to treat HIV-1 infection.
Use of nucleic acids encoding these antibodies for expression in vitro or in vivo, including gene delivery via viral vectors such as AAV to generate therapeutic antibodies in subjects.
Use in monitoring or testing vaccine compositions containing HIV-1 Env immunogens that include the 10E8 epitope conformation.
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