Neutralizing antibodies to HIV-1 and their use
Inventors
Mascola, John R. • Wyatt, Richard T. • Wu, Xueling • Li, Yuxing • Hogerkorp, Carl-Magnus • Roederer, Mario • Yang, Zhi-Yong • Nabel, Gary J. • Kwong, Peter D. • Zhou, Tongqing • Connors, Mark • Schief, William R.
Assignees
University of Washington • US Department of Health and Human Services
Publication Number
US-9175070-B2
Publication Date
2015-11-03
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
Isolated human monoclonal neutralizing antibodies that specifically bind to the HIV-1 gp120 or gp41 envelope glycoproteins are disclosed. These antibodies include heavy and light chains with specific complementarity-determining regions (CDRs) sequences as set forth, such as those of SEQ ID NO: 1 and 2 for gp120 binding antibodies (VRC01 and variants), and SEQ ID NO: 5 for gp41 binding antibodies (2F5 and its variants). The antibodies have high affinity and broad neutralization activities against diverse HIV-1 strains. Methods for their use include detection and diagnosis of HIV-1 infection or AIDS, as well as treatment by administration of therapeutically effective amounts to subjects with HIV-1 infection.
The problem addressed is the difficulty in inducing broadly neutralizing antibodies (NAbs) against HIV-1 with existing vaccines, especially targeting conserved regions on gp120 and gp41. Prior neutralizing monoclonal antibodies such as b12 target the CD4 binding site on gp120 but are limited in breadth and potency. There is a need to identify and isolate human monoclonal antibodies with potent and broad neutralizing activity against most circulating HIV-1 strains for effective diagnosis and treatment.
The invention also includes methods for isolating such antibodies by using structurally resurfaced and epitope-focused antigen probes: proteins engineered to preserve the neutralizing epitope, such as the CD4 binding site, while masking other antigenic surfaces. These epitope scaffolds are used to identify and sort rare memory B cells expressing antibodies specific to the desired vulnerable epitope. Structural studies of antibodies like VRC01 bound to gp120 reveal their modes of precise binding to conserved outer domain epitopes, partially mimicking CD4 interaction, which underpins their broad neutralizing capabilities.
Claims Coverage
The claims include one independent claim directed to an isolated human monoclonal antibody with defined CDR sequences and specific binding to a gp120 epitope, with varying Fc regions.
Monoclonal antibody with specific CDR sequences binding gp120
An isolated human monoclonal antibody comprising a heavy chain variable region with HCDR1, HCDR2, and HCDR3 comprising amino acids 26-33, 51-58, and 97-110 of SEQ ID NO: 1 respectively, and a light chain variable region with LCDR1, LCDR2, and LCDR3 comprising amino acids 27-30, 48-50, and 87-91 of SEQ ID NO: 2 respectively, which specifically binds to an epitope on a gp120 protein.
Inclusion of specific variable region sequences
The antibody variable regions comprise amino acid sequences set forth as SEQ ID NO: 1 for heavy chain, and SEQ ID NO: 2 or SEQ ID NO: 4 for light chain.
Antibody with different antibody isotypes
The antibody can be IgG, IgM, or IgA isotypes.
Labeled antibody
The antibody can be labeled with fluorescent, enzymatic, or radioactive labels.
Pharmaceutical composition comprising the antibody
A composition comprising the claimed antibody in a pharmaceutically acceptable carrier.
The claims cover isolated human monoclonal antibodies with defined CDR sequences that specifically bind the CD4 binding site epitope on HIV-1 gp120, spanning various antibody isotypes and including labeled forms, as well as pharmaceutical compositions containing these antibodies.
Stated Advantages
The antibodies VRC01 and VRC02 neutralize over 90% of tested HIV-1 isolates with high potency, including across diverse genetic subtypes.
The antibodies partially mimic the interaction of CD4, recognizing a highly conserved site of vulnerability on gp120, enabling broad neutralization.
The use of epitope-scaffold probes enables selective isolation of B cells producing highly specific broadly neutralizing antibodies.
Mutational analysis allows enhancement of binding and neutralizing capacity of antibodies such as 2F5 via changes to its CDR H3 hydrophobicity.
Multimeric forms of VRC01 IgM display increased neutralizing activity compared to IgG1 format.
Documented Applications
Use of isolated monoclonal antibodies specific for gp120 or gp41 for diagnosing HIV-1 infection or AIDS in a subject by detecting antibody binding to samples.
Therapeutic methods for treating HIV-1 infection or AIDS in a subject by administering a therapeutically effective amount of human monoclonal gp120- or gp41-specific antibodies.
Using epitope scaffold probes for isolating and enhancing antibodies with desired binding and neutralizing activity.
Use of antibodies or their labeled forms in immunoassays for detecting HIV-1 envelope proteins.
Prevention of mother-to-child HIV transmission by administration of therapeutically effective antibody amounts to mother and/or infant.
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