Neutralizing GP41 antibodies and their use
Inventors
Connors, Mark • Huang, Jinghe • Laub, Leo B. • Kwong, Peter • Nabel, Gary • Mascola, John R. • Zhang, Baoshan • Rudicell, Rebecca S. • Georgiev, Ivelin • Yang, YongPing • Zhu, Jiang • Ofek, Gilad
Assignees
US Department of Health and Human Services
Publication Number
US-9475862-B2
Publication Date
2016-10-25
Expiration Date
2032-11-07
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Monoclonal neutralizing antibodies are disclosed that specifically bind to the HIV-1 gp41 membrane-proximal external region (MPER). Also disclosed are compositions including the disclosed antibodies that specifically bind gp41, nucleic acids encoding these antibodies, expression vectors including the nucleic acids, and isolated host cells that express the nucleic acids. The antibodies and compositions disclosed herein can be used for detecting the presence of HIV-1 in a biological sample, or detecting an HIV-1 infection or diagnosing AIDS in a subject. In additional, the broad neutralization breadth of the disclosed antibodies makes them ideal for treating a subject with an HIV infection. Thus, disclosed are methods of treating and/or preventing HIV infection.
Core Innovation
Monoclonal neutralizing antibodies that specifically bind to the HIV-1 gp41 membrane-proximal external region (MPER) are disclosed. These isolated human monoclonal antibodies, including epitopes designated as the 10E8 epitope, bind to a previously uncharacterized epitope within the MPER, extending C-terminal to the 2F5 epitope and distinct from the 4E10 and Z13E1 epitopes. The antibodies may be optimized for binding and neutralization, and compositions including these antibodies, nucleic acids encoding them, expression vectors and host cells expressing the nucleic acids are also provided. These antibodies demonstrate broad neutralization breadth and do not exhibit self-reactivity, distinguishing them from known neutralizing antibodies 2F5 and 4E10.
The antibodies and compositions may be used for detecting the presence of HIV-1 in biological samples or diagnosing AIDS. Methods of treating and preventing HIV infection by administering these antibodies to subjects are disclosed. The problem addressed is the inability of current HIV-1 vaccines to induce potent, broadly neutralizing antibodies, partly due to limited understanding of the envelope glycoprotein regions recognized by neutralizing antibodies and the limitations of known gp41 neutralizing antibodies in strain cross-reactivity and potency.
Claims Coverage
The patent claims cover several inventive features centered around isolated human monoclonal antibodies specific for HIV-1 gp41 with defined heavy and light chain variable regions, their variants, compositions containing these antibodies, and related methods and kits.
Monoclonal antibodies with specific heavy and light chain CDRs that bind gp41 and neutralize HIV-1
Isolated human monoclonal antibodies comprising heavy chain variable regions with HCDR1, HCDR2, and HCDR3 comprising amino acids 26-33, 51-60, and 99-120 of SEQ ID NO: 1, and light chain variable regions with LCDR1, LCDR2, and LCDR3 comprising amino acids 26-31, 49-51, and 88-99 of SEQ ID NO: 2, respectively, that specifically bind gp41 and neutralize HIV-1 infection.
Variants of the heavy chain variable region with specific amino acid sequences and limited framework substitutions
Antibodies wherein the heavy chain variable region comprises sequences set forth as one of SEQ ID NOs: 1, 3, 5, 149, 154, 189-192, 200-201, or 204, with at most ten amino acid substitutions in framework regions.
Heavy chain variable region with defined amino acid sequence variations
Antibodies with heavy chain variable region amino acid sequence set forth as SEQ ID NO: 11 with variable residues X1, X2, X3, and X4 defined as Q or R, V or A, S or Y, and T or I, respectively.
Light chain variable region with defined amino acid sequences and variants
Antibodies wherein the light chain variable region comprises sequences set forth as one of SEQ ID NOs: 2, 4, 150-152, or 164-168, with at most ten amino acid substitutions in framework regions.
Specific heavy and light chain pairings forming neutralizing antibodies
Antibodies with heavy chain variable regions comprising SEQ ID NO: 1 or 154 or 192 paired with light chain variable regions comprising SEQ ID NO: 2 or 152, which specifically bind gp41 and neutralize HIV-1.
Antibody isotype variations including IgG, IgM or IgA types
The antibodies can be of IgG, IgM or IgA isotypes.
Neutralization breadth of antibodies
Antibodies that neutralize at least 98% of HIV-1 isolates listed in FIGS. 17C-17F with IC50 less than 50 μg/ml, or neutralize at least 72% with IC50 less than 1 μg/ml.
Bispecific and antigen-binding fragment antibodies derived from the monoclonal antibodies
Inclusion of bispecific antibodies containing the described monoclonal antibodies and isolated antigen-binding fragments such as Fab, Fab’, F(ab)’2, scFv or dsFv maintaining gp41 binding and HIV-1 neutralization.
Antibodies and fragments linked to effector moieties or Fc fusion proteins
The antibodies or antigen-binding fragments may be linked to Fc domains, IL-15, or effector moieties such as toxins or detectable labels.
Pharmaceutical compositions and diagnostic kits containing the antibodies
Compositions comprising the antibodies and pharmaceutically acceptable carriers, kits including the antibodies and instructions for use in diagnosis or treatment of HIV-1.
The claims comprehensively cover isolated human monoclonal antibodies that specifically bind gp41 with defined CDR sequences and variable region sequences including variants, compositions containing these antibodies, methods using these antibodies for neutralization and diagnosis of HIV-1, and various functional or structural antibody formats and uses.
Stated Advantages
The disclosed 10E8 and 10E8-like antibodies exhibit broad and potent neutralization against diverse HIV-1 isolates, neutralizing 98% of tested viruses with high potency.
Unlike previously known MPER antibodies such as 2F5 and 4E10, these antibodies are not autoreactive and do not bind anionic phospholipids, reducing concerns about autoreactivity and improving therapeutic potential.
The 10E8 antibodies have greater access to the MPER epitope on native virus and infected cell surfaces compared to known MPER antibodies.
The antibodies specifically target a highly conserved and structurally defined site-of-vulnerability on gp41, offering a promising target for vaccine design and therapeutic intervention.
Documented Applications
Using the disclosed antibodies and compositions for detecting the presence of HIV-1 in biological samples and diagnosing AIDS.
Using the antibodies for treating and preventing HIV-1 infection, including administration to infected subjects.
Using the antibodies in methods for post-exposure prophylaxis and to eliminate the viral reservoir in patients receiving anti-viral therapy.
Use of the antibodies in vaccine research to test whether vaccine immunogens assume a conformation capable of binding the 10E8 epitope on gp41.
Interested in licensing this patent?