Broadly neutralizing HIV-1 antibodies that bind to the CD4-binding site of the envelope protein
Inventors
Kwong, Peter D. • Nabel, Gary J. • Rudicell, Rebecca S. • Mascola, John • Connors, Mark • Georgiev, Ivelin • Zhu, Jiang • Kwon, Young Do • Zhou, Tongqing • Yang, YongPing • Zhang, Baoshan • Chuang, Gwo-Yu • Wu, Xueling • Yang, Zhi-Yong • Shi, Wei
Assignees
US Department of Health and Human Services
Publication Number
US-10815295-B2
Publication Date
2020-10-27
Expiration Date
2032-12-10
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Monoclonal neutralizing antibodies that specifically bind to HIV-1 gp120 and antigen binding fragments of these antibodies are disclosed. Nucleic acids encoding these antibodies, vectors and host cells are also provided. Methods for detecting HIV using these antibodies are disclosed. In addition, the use of these antibodies, antigen binding fragment, nucleic acids and vectors to prevent and/or treat an HIV infection is disclosed.
Core Innovation
Monoclonal neutralizing antibodies that specifically bind to HIV-1 gp120 and antigen binding fragments of these antibodies are disclosed. The invention includes nucleic acids encoding these antibodies, vectors, and host cells expressing these nucleic acids. Methods for detecting HIV infection using these antibodies are also described. Furthermore, the use of these antibodies, their antigen binding fragments, nucleic acids and vectors to prevent and/or treat an HIV infection is disclosed.
The invention identifies the VRC07 monoclonal antibody, which specifically binds to the CD4 binding site of the gp120 protein of HIV and is neutralizing. VRC07 is a VRC01-like monoclonal antibody and includes a novel heavy chain ("VRC07 heavy chain") that can be cross-complemented with the light chain of the VRC01 monoclonal antibody. This combination has increased binding affinity for gp120 without significantly increased self-reactivity compared to VRC01. Variants of VRC07 heavy chain and VRC01 light chain, and cross-complemented monoclonal antibodies including such variants with increased binding affinity for gp120 and low or no self-reactivity are also disclosed.
The antibodies disclosed include those with framework region amino acid substitutions but limited CDR substitutions, resulting in a class of monoclonal antibodies with increased gp120 binding affinity and low immunogenicity or self-reactivity. They can be used therapeutically for treatment and prevention of HIV infection. The antibodies and their fragments may be fully human and include heavy and light chain variable domains. Compositions including these antibodies and their encoding nucleic acids and vectors are also provided.
Claims Coverage
The patent includes one independent claim directed to a method for inhibiting HIV-1 infection by administering a therapeutically effective amount of specific monoclonal antibodies or their antigen binding fragments.
Monoclonal antibody with specific variable domain sequences
The method employs an isolated monoclonal antibody comprising: (a) a heavy chain variable domain with HCDR1, HCDR2, and HCDR3 comprising amino acids 26-33, 51-58, and 97-114 of SEQ ID NO: 32, and a light chain variable domain with LCDR1, LCDR2, and LCDR3 comprising amino acids 27-30, 48-50, and 87-91 of SEQ ID NO: 9; or (b) a heavy chain variable domain with HCDRs comprising amino acids 26-33, 51-58, and 97-114 of SEQ ID NO: 259, and a light chain variable domain comprising LCDRs 27-30, 48-50, 87-91 of SEQ ID NO: 9; or (c) a heavy chain variable domain with HCDRs 26-33, 51-58, and 97-114 of SEQ ID NO: 2, and a light chain variable domain comprising LCDRs 27-30, 48-50, 87-91 of SEQ ID NO: 9.
IgG antibody specificity
The antibody is of IgG isotype and specifically binds the CD4 binding site on HIV-1 gp120.
Use of antigen binding fragments
The method encompasses use of antigen binding fragments of the antibody, including Fab, Fab′, F(ab)′2, scFv, or dsFv fragments.
The claims cover a method for treating HIV-1 infection by administering antibodies or antigen binding fragments with specified heavy and light chain variable domain sequences that bind the CD4 binding site on gp120, including IgG antibodies and their fragments.
Stated Advantages
The disclosed antibodies have increased binding affinity for gp120 compared to VRC01, resulting in increased neutralization potency and breadth.
These antibodies do not have significantly increased self-reactivity compared to VRC01, supporting safety for therapeutic use.
Variants show low immunogenicity, which is advantageous for clinical applications.
Increased half-life in vivo can be achieved by introduction of LS mutations in the Fc region, enhancing therapeutic efficacy.
Documented Applications
Use of monoclonal antibodies for detecting HIV-1 infection or diagnosing AIDS in a subject by detecting gp120 binding in biological samples.
Use of monoclonal antibodies and binding fragments to treat or prevent HIV-1 infection, including administration to subjects with HIV-1 or AIDS or at risk of infection.
Use in combination with other anti-retroviral therapies for improved treatment outcomes.
Potential application in passive immunization and for reducing viral reservoirs in infected subjects.
Interested in licensing this patent?