Neutralizing antibodies to HIV-1 and their use
Inventors
Mascola, John • Wyatt, Richard • Wu, Xueling • Li, Yuxing • Hogerkorp, Carl-Magnus • Roederer, Mario • Yang, Zhi-Yong • Nabel, Gary • Kwong, Peter • Zhou, Tongqing • Connors, Mark • Schief, William
Assignees
University of Washington • US Department of Health and Human Services
Publication Number
US-10035845-B2
Publication Date
2018-07-31
Expiration Date
2030-09-24
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Abstract
Monoclonal neutralizing antibodies are disclosed that specifically bind to the CD4 binding site of HIV-1 gp120. Monoclonal neutralizing antibodies also are disclosed that specifically bind to HIV-1 gp41. The identification of these antibodies, and the use of these antibodies are also disclosed. Methods are also provided for enhancing the binding and neutralizing activity of any antibody using epitope scaffold probes.
Core Innovation
Monoclonal neutralizing antibodies specifically binding to the CD4 binding site of HIV-1 gp120 or to HIV-1 gp41 have been isolated and disclosed, including compositions comprising these antibodies, nucleic acids encoding them, expression vectors, and host cells expressing the nucleic acids. These antibodies include variants with specific complementarity-determining region sequences (CDRs) from SEQ ID NOs: 1, 2, 3, 4, 27, 28 and others in the range of SEQ ID NOs: 760-1459. They exhibit specificity and neutralization of HIV-1 by targeting vulnerable epitopes on gp120 or gp41.
The antibodies described can be used diagnostically to detect HIV-1 infection or AIDS by contacting a sample from a subject with the monoclonal antibodies and detecting binding relative to control samples. They can also be used therapeutically by administering a therapeutically effective amount to a subject with HIV infection, including AIDS. Additionally, methods for enhancing antibody binding and neutralizing activity using epitope scaffold probes are provided.
The problem solved by these inventions is the difficulty in inducing potent and broadly reactive neutralizing antibodies (NAbs) by vaccines against HIV-1. One major obstacle has been the limited understanding of the regions on HIV-1 envelope glycoproteins gp120 and gp41 that are recognized by effective NAbs. Previously identified antibodies such as b12 and 2F5 have limited neutralization breadth and their elicitation by vaccines has been unsuccessful. This invention identifies new monoclonal neutralizing antibodies with broader activity and provides methods for their use in prevention, diagnosis, and treatment of HIV-1 infection.
Claims Coverage
The patent includes multiple independent claims focused on nucleic acids encoding antibodies with specific CDR sequences and antibodies that specifically bind gp120.
Antibody variable region encoding sequences
An isolated nucleic acid molecule encoding an antibody heavy chain variable region comprising CDR1, CDR2, and CDR3 corresponding to amino acids 26-33, 51-58, and 97-110 of SEQ ID NO: 1, respectively, and a light chain variable region comprising CDR1, CDR2, and CDR3 corresponding to amino acids 27-30, 48-50, and 87-91 of SEQ ID NO: 2, respectively.
Antibodies with specified CDR amino acid sequences that specifically bind gp120
An antibody comprising a heavy chain variable region including CDR1, CDR2, and CDR3 of SEQ ID NO: 1 and a light chain variable region including CDR1, CDR2, and CDR3 of SEQ ID NO: 2 that specifically binds gp120.
Nucleic acid molecules encoding antibodies with sequences at least 90% identical to SEQ ID NOs: 1 and 2
Nucleic acid molecules encoding heavy and light chain variable regions comprising the respective CDRs and amino acid sequences at least 90% identical to SEQ ID NO: 1 for heavy chain and SEQ ID NO: 2 for light chain.
Expression vectors and host cells for producing gp120-specific antibodies
Expression vectors incorporating the nucleic acid molecules encoding the described antibodies and isolated host cells transformed with these nucleic acids for expression.
Methods of producing antibodies that specifically bind gp120
Expressing in a host cell the nucleic acids encoding heavy and light chain variable regions with the defined CDR sequences corresponding to SEQ ID NO: 1 and SEQ ID NO: 2, respectively, followed by purification of the antibody.
The claims cover isolated nucleic acids encoding heavy and light chain variable regions with defined CDR sequences from SEQ ID NO: 1 and SEQ ID NO: 2, antibodies comprising these sequences that specifically bind gp120, expression vectors and host cells for producing such antibodies, and methods of antibody production. These claims define the molecular features of broadly neutralizing antibodies targeting the HIV-1 gp120 CD4 binding site.
Stated Advantages
The antibodies described have remarkable broad and potent neutralization of HIV-1 strains from all genetic subtypes.
The antibody VRC01 neutralizes over 90% of HIV-1 isolates with high potency.
Some antibodies partially mimic the CD4 receptor interaction, allowing recognition of multiple gp120 conformations, contributing to neutralization breadth.
Mutational analysis and structural characterization provide insight to design antibodies with enhanced binding and neutralization activities.
Variants of antibodies with altered hydrophobic CDR H3 loops enhance neutralization potency without compromising antigen affinity.
Documented Applications
Screening for HIV-1 infection in a subject by detecting the binding of monoclonal antibodies specific to gp120 or gp41 to biological samples from the subject.
Treatment of HIV-1 infection and AIDS in a subject by administering therapeutically effective amounts of monoclonal antibodies specific to gp120 or gp41.
Use of epitope scaffold probes for isolation, enhancement, and identification of antibodies with desired binding properties against specific epitopes.
Use of antibodies to study HIV-1 biology and to develop vaccines targeting the CD4 binding site of gp120.
Production and therapeutic use of oligomeric forms of antibodies (e.g., pentameric IgM with VRC01 variable regions) with enhanced neutralizing activity.
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