10E8 neutralizing antibody variants that bind to the MPER region of 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
Columbia University in the City of New York • US Department of Health and Human Services
Publication Number
US-12043660-B2
Publication Date
2024-07-23
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 relates to isolated antibodies and antigen binding fragments that specifically bind to the Human Immunodeficiency Virus type 1 (HIV-1) gp41 and neutralize HIV-1. These include antibodies comprising heavy and light chain variable regions with amino acid substitutions compared to the 10E8 antibody sequence, which impart an improved combination of neutralization, solubility, and auto-reactivity properties relative to the 10E8 antibody. The invention also provides nucleic acids encoding these antibodies, expression vectors comprising the nucleic acids, isolated host cells, and compositions including these molecules.
The innovation addresses the challenge of HIV-1 evading humoral recognition by protective mechanisms, with the envelope spike composed of gp120 and gp41 being a prime target for neutralizing antibodies. Although the 10E8 antibody was known to specifically bind the membrane proximal external region (MPER) of gp41 and neutralize a high percentage of HIV-1 strains, there was a need to develop additional neutralizing antibodies for HIV-1 with improved properties over 10E8, particularly regarding solubility and auto-reactivity for commercial production.
The antibodies disclosed include variants of the 10E8 antibody featuring amino acid substitutions in heavy and light chain variable regions, including complementary determining regions (CDRs) and framework regions. For example, antibodies comprising heavy chain variable region sequences such as SEQ ID NO: 5 (10E8v4) paired with a light chain variable region sequence such as SEQ ID NO: 6 (rL3-6mut) specifically bind gp41 and neutralize HIV-1. Such variants demonstrate broad and potent neutralization with improved solubility and minimal auto-reactivity compared to the parent 10E8 antibody.
Claims Coverage
The claims include several independent claims covering isolated antibodies or antigen binding fragments with defined variable regions and amino acid substitutions, nucleic acids encoding these antibodies, expression vectors, host cells, pharmaceutical compositions, methods of treatment and detection, and conjugates.
Antibody variable region substitutions for enhanced neutralization and solubility
An isolated antibody comprising a heavy chain variable region (VH) with defined complementarity determining regions (CDRs) and framework amino acid substitutions at specified kabat positions, paired with a light chain variable region (VL) with specified LCDRs and framework substitutions, wherein the antibody specifically binds HIV-1 gp41 and neutralizes HIV-1.
Inclusion of V5R mutation in the heavy chain variable region
An isolated antibody or antigen binding fragment comprising a VH with a V5R mutation along with the specified VH and VL amino acid sequences, providing improved HIV-1 neutralization properties.
Use of human framework regions and constant regions
Antibodies comprising human framework regions and human constant regions, including IgG, IgM or IgA isotypes, optionally containing substitutions that increase binding to the neonatal Fc receptor to enhance half-life.
Pharmaceutical compositions containing the antibodies
Therapeutic compositions comprising a therapeutically effective amount of the disclosed antibodies or antigen binding fragments and a pharmaceutically acceptable carrier for treating HIV-1 infection.
Methods of inhibiting or treating HIV-1 infection
Methods comprising administering to a subject a therapeutically effective amount of the disclosed antibodies or antigen binding fragments, thereby preventing or treating HIV-1 infection, including co-administration with other HIV-1 neutralizing antibodies such as VRC01-class antibodies.
Methods for detecting HIV-1 infection using antibodies
Methods involving contacting a biological sample from a subject with the disclosed antibodies or antigen binding fragments under conditions sufficient to form an immune complex and detecting the complex to indicate the presence of HIV-1 infection.
The claims collectively cover antibodies and antigen binding fragments with specific heavy and light chain variable region sequences and mutations, their nucleic acid sequences, expression systems, pharmaceutical compositions, and methods for treatment and diagnosis of HIV-1 infection, highlighting improvements in solubility, neutralization breadth and potency, and reduced auto-reactivity.
Stated Advantages
Modified 10E8 antibodies have an improved combination of HIV-1 neutralization breadth and potency.
These antibodies possess enhanced solubility compared to the parental 10E8 antibody, facilitating commercial production.
The modified antibodies exhibit reduced or minimal auto-reactivity relative to the original 10E8, enhancing safety for therapeutic use.
Incorporation of specific amino acid substitutions increases antibody half-life in serum.
Documented Applications
The antibodies and antigen binding fragments can be used for treating or inhibiting HIV-1 infection in subjects at risk or those infected with HIV-1.
The antibodies and antigen binding fragments can be used for detecting or diagnosing HIV-1 infection by detecting gp41 in biological samples.
The disclosed antibodies can be used in combination with other anti-retroviral agents and antibodies to provide enhanced therapeutic effectiveness.
Antibodies and antigen binding fragments can be conjugated with detectable markers for use in diagnostic immunoassays.
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