Neutralizing antibodies to GP120 and their use
Inventors
Connors, Mark • Huang, Jinghe • Kang, Byong Ha • Mascola, John • Ishida, Elise • Zhou, Tongqing • Kwong, Peter • Zheng, Anqi
Assignees
US Department of Health and Human Services
Publication Number
US-12202886-B2
Publication Date
2025-01-21
Expiration Date
2036-03-18
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Abstract
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.
Core Innovation
Human Immunodeficiency Virus type 1 (HIV-1) infection remains a major public health threat worldwide, despite extensive efforts to develop therapeutic agents. HIV-1 evades humoral immunity through various protective mechanisms. The viral envelope protein, gp160, is cleaved into gp120 and gp41; gp120 is exposed on the surface and is a key target for neutralizing antibodies.
Broadly neutralizing antibodies that target HIV-1 Env, such as VRC01 which binds the CD4 binding site on gp120, have been identified but additional antibodies with diverse recognition and neutralization profiles are needed for commercial production and therapeutic use.
This invention discloses isolated monoclonal antibodies and antigen-binding fragments that specifically bind the CD4 binding site on gp120 and potently neutralize HIV-1. A novel antibody, termed N6, neutralized 98% of a panel of 181 pseudoviruses representing diverse HIV-1 strains with an IC50 under 50 μg/ml and 96% with an IC50 under 1 μg/ml, demonstrating superior breadth and potency compared to existing antibodies like VRC01. N6 neutralized most VRC01-resistant viruses, indicating a unique and effective mode of gp120 recognition.
The invention includes antibodies and antigen binding fragments with the binding specificity of N6 and related variants (N17, F8), compositions including these antibodies and binding fragments, nucleic acid molecules encoding them, expression vectors, and host cells. Methods for treating or inhibiting HIV-1 infection using these antibodies or molecules, as well as for detecting HIV-1 infection, are disclosed.
Claims Coverage
The claims include one independent antibody claim and independent method and composition claims relating to the antibodies and their therapeutic use.
Monoclonal antibody with defined variable regions and IgG constant region mutations
An isolated monoclonal antibody comprising a heavy chain variable region with the amino acid sequence of SEQ ID NO: 1, a light chain variable region with SEQ ID NO: 2, and an IgG constant domain containing M428L and N434S mutations, which binds the CD4 binding site on HIV-1 gp120.
Specific binding and neutralization of HIV-1
The monoclonal antibody specifically binds HIV-1 gp120 and neutralizes HIV-1, including neutralization of at least 50% of certain listed HIV-1 isolates with an IC50 less than 50 μg/ml.
Therapeutic method of treating HIV-1 infection
A method of treating HIV-1 infection by administering a therapeutically effective amount of the described monoclonal antibody to a subject, including human subjects and pregnant females, optionally with additional antibodies or antigen binding fragments and in conjunction with antiretroviral therapies.
Pharmaceutical composition comprising the monoclonal antibody
A pharmaceutical composition containing a therapeutically effective amount of the isolated monoclonal antibody and a pharmaceutically acceptable carrier, suitable for treating HIV-1 infection.
The claims protect a broadly neutralizing human monoclonal antibody with specific variable domain sequences and constant region mutations, methods of treating HIV-1 infection with this antibody including combination therapies, and pharmaceutical compositions thereof.
Stated Advantages
N6 antibody displays both remarkable breadth and potency against diverse HIV-1 strains including VRC01-resistant isolates.
N6 shows minimal autoreactivity, suggesting favorable safety and pharmacokinetics profiles for therapeutic use.
N6’s unique mode of gp120 recognition enables neutralization of viruses resistant to other members of the VRC01-class.
The antibody’s potency and breadth may reduce viral escape and improve therapeutic durability.
Documented Applications
Therapeutic treatment of HIV-1 infection in subjects, including prevention, inhibition, and reduction of viral replication and disease progression.
Use in combination with other antibodies or antiretroviral therapies for enhanced treatment efficacy.
Prophylactic administration to subjects at risk of HIV-1 infection, including prevention of mother-to-infant transmission.
Use as diagnostic agents to detect gp120 and HIV-1 infection in biological samples or subjects.
Expression of antibodies by nucleic acid molecules or viral vectors including adeno-associated virus for in vivo antibody production.
Incorporation of antibody binding fragments into chimeric antigen receptors for cellular immunotherapy targeting HIV-1 infected cells.
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