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-8637036-B2
Publication Date
2014-01-28
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
The invention provides isolated human monoclonal neutralizing antibodies that specifically bind to the CD4 binding site of HIV-1 gp120 or to HIV-1 gp41, their identification, and their use. It includes compositions comprising these antibodies, nucleic acids encoding the antibodies, expression vectors, and host cells expressing the nucleic acids. The antibodies can be used for detecting HIV-1 infection and diagnosing AIDS by contacting a sample from the subject with the antibody and detecting binding, wherein increased binding relative to a control confirms infection.
The problem solved by the invention is the inability of current HIV-1 vaccines to induce potent and broadly reactive neutralizing antibodies active against most circulating HIV-1 strains. Limited understanding exists regarding the envelope glycoprotein regions recognized by neutralizing antibodies, and prior neutralizing antibodies such as b12 neutralize only a portion of circulating strains. Therefore, there is a need to develop neutralizing antibodies for HIV-1 that can broadly and potently neutralize diverse strains.
Claims Coverage
The patent claims cover an isolated human monoclonal antibody comprising specific CDR sequences of heavy and light chains that specifically bind the CD4 binding site of gp120 and neutralize HIV-1, along with functional fragments, labeled variants, compositions including the antibodies, and methods for detecting HIV-1 in a subject's biological sample.
Isolated human monoclonal antibody specific for CD4 binding site of gp120 with defined CDR regions
An antibody having heavy chain CDR1, CDR2, and CDR3 comprising amino acids 26-33, 51-58, and 97-110 of SEQ ID NO: 1, respectively, and light chain CDR1, CDR2, and CDR3 comprising amino acids 27-30, 48-50, and 87-91 of SEQ ID NO: 2, respectively, that specifically binds the CD4 binding site on gp120 and neutralizes HIV-1.
Binding affinity to resurfaced stabilized core protein RSC3
The antibody binds the resurfaced stabilized core 3 (RSC3) protein with a KD of 10−8 M or less, indicating high affinity binding.
Epitope specificity to defined gp120 residues
The antibody specifically binds residues 276, 278-283, 365-368, 371, 455-459, 461, 469, and 472-474 of gp120 according to HXB2 numbering.
Broad neutralization breadth
The antibody neutralizes over 90% of HIV-1 isolates listed in FIGS. 16-24 with an IC50 less than 50 μg/ml.
Defined heavy and light chain sequences
The heavy chain variable region comprises SEQ ID NO: 1, and the light chain comprises SEQ ID NO: 2 or SEQ ID NO: 4; the antibody can be IgG, IgM, or IgA isotypes.
Functional antibody fragments and labeling
Functional fragments such as Fab, Fab′, F(ab′)2, scFv, or dsFv that specifically bind the CD4 binding site and neutralize HIV-1, and labeled forms of these antibodies or fragments are claimed.
Diagnostic and therapeutic uses
Methods of detecting HIV-1 in a biological sample using the antibody or functional fragment and detecting bound antibody, indicating infection; and compositions comprising the antibody or fragment in a pharmaceutically acceptable carrier are claimed.
The claims encompass isolated human monoclonal antibodies with defined CDR sequences targeting the CD4 binding site of gp120 that neutralize HIV-1 broadly and potently, functional fragments thereof, labeled variants, compositions for therapeutic use, and diagnostic methods employing these antibodies to detect HIV-1 infection.
Stated Advantages
The antibodies VRC01 and VRC02 neutralize over 90% of tested circulating HIV-1 isolates across all major genetic subtypes, demonstrating remarkable neutralization breadth and potency.
VRC01 and VRC02 antibodies mimic the CD4 receptor interaction with gp120, allowing them to bind both CD4-bound and non-CD4-bound conformations of gp120, overcoming conformational masking by HIV-1.
Use of resurfaced stabilized core proteins greatly improves identification and isolation of broadly neutralizing antibodies targeting the CD4 binding site.
2F5 antibody variants with increased hydrophobicity in the CDR H3 loop show enhanced HIV-1 neutralization, indicating a novel mechanism to augment antibody potency.
Documented Applications
Detection and diagnosis of HIV-1 infection in a subject via immunoassays using the isolated monoclonal antibodies or functional fragments to detect gp120 or gp41 in biological samples.
Therapeutic treatment of HIV-1 infection or AIDS in subjects by administering a therapeutically effective amount of the isolated monoclonal antibodies specific for gp120 or gp41.
Screening for HIV-1 in subjects by use of monoclonal antibodies to test vaccines or biological samples, confirming infection.
Identification and isolation of additional neutralizing antibodies through use of epitope scaffolds and next generation sequencing combined with structural analysis (454 sequencing, epitope scaffolds).
Development of monoclonal antibodies as microbicides, passive immunotherapies, or components of vaccine formulations.
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