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-10047148-B2
Publication Date
2018-08-14
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
The invention provides isolated human monoclonal neutralizing antibodies that specifically bind to the HIV-1 gp41 membrane-proximal external region (MPER). These antibodies include the 10E8 antibody and antibodies similar thereto that bind a previously uncharacterized epitope of gp41 designated herein as the 10E8 epitope. The antibodies specifically contact conserved residues in the gp41 MPER and are neutralizing with broad activity against diverse HIV-1 strains. The antibodies do not exhibit self-reactivity, in contrast to prior MPER-specific antibodies such as 2F5 and 4E10, and possess enhanced accessibility to the gp41 epitope on the cell and virion surfaces. Crystallographic studies of 10E8 in complex with a gp41 MPER peptide reveal detailed structural features explaining their mode of binding, interaction with conserved residues, and broad neutralization activity.
The problem being solved is the limited ability of current HIV-1 vaccines to induce potent and broadly reactive neutralizing antibodies (NAbs) capable of blocking most circulating HIV-1 strains. Prior known neutralizing monoclonal antibodies that bind gp41, such as 2F5, 4E10, and Z13E1, exhibit limited strain cross-reactivity or potency and are associated with self-reactivity, reducing their therapeutic viability. There is a need for methods to prepare monoclonal broadly neutralizing antibodies that are potent, broad, and non-autoreactive, suitable for protection and treatment against HIV infection. The disclosed antibodies address this need by targeting a highly conserved gp41 MPER epitope with broad and potent neutralizing activity and lack of autoreactivity.
Claims Coverage
The patent claims cover multiple inventive features relating to monoclonal antibodies and antigen binding fragments that specifically bind HIV-1 gp41 and neutralize HIV-1. Key inventive features involve the antibody sequences and structural features conferring neutralization breadth and potency, methods of treatment, and embodiments of antibody variants.
Monoclonal antibody with defined CDR regions specifically binds gp41 and neutralizes HIV-1
A monoclonal antibody comprising a heavy chain variable region including complementarity determining regions (CDRs) at amino acids 26-33 (HCDR1), 51-60 (HCDR2), and 99-120 (HCDR3) of SEQ ID NO: 1, and a light chain variable region including CDRs at amino acids 26-31 (LCDR1), 49-51 (LCDR2), and 88-99 (LCDR3) of SEQ ID NO: 2, wherein the antibody specifically binds gp41 and neutralizes HIV-1 infection.
Heavy chain variable region sequence variants with limited framework substitutions
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 sequence defined by specific residues with positional variation
The heavy chain variable region comprises the amino acid sequence set forth as SEQ ID NO: 11, with positions X1 being Q or R, X2 being V or A, X3 being S or Y, and X4 being T or I.
Light chain variable region sequence variants with limited framework substitutions
The light chain variable region includes amino acid 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.
Combinations of specified heavy and light chain variable region sequences
The antibody comprises a heavy chain variable region selected from SEQ ID NOs: 1, 3, 5, 149, 154, 189-192, 200-201, or 204 paired with a light chain variable region selected from SEQ ID NOs: 2, 4, 150-152, or 164-168.
Specific heavy and light chain pairs for antibodies neutralizing HIV-1
Specific embodiments include the heavy chain variable region of SEQ ID NO: 154 paired with light chain variable region of SEQ ID NO: 152, or heavy chain variable region of SEQ ID NO: 192 paired with light chain variable region of SEQ ID NO: 152.
Methods of inhibiting HIV-1 by administering monoclonal antibody of specified variable regions
Methods of inhibiting HIV-1 infection by administering an effective amount of antibodies as described with the above heavy and light chain variable region sequences.
Methods employing antigen binding fragments of monoclonal antibodies specific for gp41
Administration of antigen binding fragments such as Fab, Fab', F(ab')2, scFv, or dsFv comprising heavy and light chain variable regions as defined above to bind gp41 and neutralize HIV-1.
Methods of treatment including administration of antibodies to subjects with HIV infection or AIDS
Methods for treating subjects with HIV infection or AIDS by administering the disclosed antibodies or fragments thereof.
Methods combining disclosed antibodies with additional anti-viral agents or antibodies
Combination therapies comprising the disclosed antibodies plus anti-viral agents such as reverse-transcriptase inhibitors or other antibodies specific to gp120 or gp41.
In conclusion, the claims cover monoclonal antibodies and antigen binding fragments comprising sequences of heavy and light chain variable regions that specifically bind HIV-1 gp41 MPER and neutralize HIV-1; variants with limited substitutions; specific sequence pairs; and therapeutic methods involving administering such antibodies alone or in combination with other therapies to inhibit or treat HIV-1 infection.
Stated Advantages
The disclosed antibodies exhibit broad and potent neutralization of diverse HIV-1 strains, neutralizing approximately 98% of tested isolates at low IC50 values.
The antibodies do not exhibit self-reactivity, unlike prior gp41 MPER antibodies, making them safer for therapeutic use and more suitable for vaccine design.
They possess enhanced accessibility to the native MPER epitope on virions and infected cells, improving neutralization efficacy.
The disclosed monoclonal antibodies target a highly conserved gp41 epitope, which is critical for HIV-1 entry, thus overcoming obstacles of viral diversity.
Documented Applications
Use of the disclosed monoclonal antibodies to detect the presence of HIV-1 in biological samples or diagnose HIV-1 infection and AIDS.
Therapeutic use of the disclosed antibodies or antigen binding fragments to treat or prevent HIV-1 infection in subjects, including subjects with AIDS.
Use of the antibodies for neutralization assays to evaluate vaccine responses or screen for neutralizing activity in sera.
Application in combination therapies with anti-retroviral agents or other antibodies for improved HIV treatment.
Interested in licensing this patent?