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-9738703-B2
Publication Date
2017-08-22
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 are disclosed that specifically bind to the CD4 binding site of HIV-1 gp120 or to HIV-1 gp41, their identification, and their use. The antibodies have defined heavy and light chain complementarity-determining regions (CDRs) and exhibit neutralizing activity against HIV-1. Methods for enhancing the binding and neutralizing activity of any antibody using epitope scaffold probes are also provided.
The problem being solved is the difficulty in developing an effective HIV-1 vaccine that induces potent and broadly reactive neutralizing antibodies (NAbs) against most circulating strains of HIV-1. Current vaccines fail to induce such antibodies, partly because of limited understanding of the regions of HIV-1 envelope glycoproteins gp120 and gp41 recognized by NAbs. Existing neutralizing monoclonal antibodies such as b12 and 2F5 have limitations in neutralization breadth and natural occurrence, thus there is a need to develop new NAbs for HIV-1.
Claims Coverage
The patent presents 2 main independent inventive features focused on antibody-mediated treatment of HIV-1 infections using antibodies with specified complementarity determining regions.
Therapeutic use of gp120-specific antibodies with defined CDR sequences
The method involves administering an antibody or functional fragment specifically binding gp120, wherein the antibody has a heavy chain variable region comprising HCDR1, HCDR2, and HCDR3 consisting of amino acids 26-33, 51-58, and 97-110 of SEQ ID NO: 1, and a light chain variable region comprising LCDR1, LCDR2, and LCDR3 consisting of amino acids 27-30, 48-50, and 87-91 of SEQ ID NO: 2. This treatment effectively treats or inhibits HIV-1 infection in a subject.
Gene therapy approach using expression vectors encoding gp120-specific antibodies
Administering an expression vector encoding an antibody or functional fragment that specifically binds gp120, characterized by 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 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, such that expression of the antibody treats the HIV-1 infection or inhibits infection in the subject.
The claimed invention covers methods of treating or preventing HIV-1 infection by administration of antibodies or expression vectors encoding antibodies with specified CDR sequences binding HIV-1 gp120, emphasizing the importance of the particular variable region sequences and their complementarity determining regions.
Stated Advantages
Broad and potent neutralization capacity against a wide range of HIV-1 strains due to targeting the conserved CD4 binding site on gp120, achievable in naturally occurring antibodies such as VRC01 and VRC03.
Use of epitope scaffold design allows isolation and enhancement of antibodies with focused specificity, improving the likelihood of inducing broadly neutralizing antibodies.
Some antibodies, such as VRC01 and VRC02, act as partial CD4 agonists, inducing conformational changes in gp120 that facilitate broader neutralization.
Engineering of antibody variants, such as 2F5 CDR H3 loop modifications, enhances neutralization potency by increasing hydrophobic interactions critical for function without compromising antigen affinity.
Documented Applications
Use of isolated human monoclonal neutralizing antibodies binding gp120 or gp41 for diagnostic purposes, including detecting HIV-1 infection or confirming AIDS diagnosis by antibody binding assays.
Therapeutic treatment of subjects infected with HIV-1 or at risk of infection by administering effective amounts of the monoclonal neutralizing antibodies or nucleic acids encoding them to reduce or inhibit infection and HIV replication.
Methods for enhancing the binding affinity and neutralizing activity of antibodies through use of epitope scaffold probes.
Use of isolated antibodies in vaccine design, including testing vaccine immunogens for conformations capable of binding the neutralizing antibodies.
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