Broadly neutralizing HIV-1 VRC07 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-9695230-B2
Publication Date
2017-07-04
Expiration Date
2032-12-10
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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 thereof are disclosed, including nucleic acids encoding these antibodies, vectors, and host cells. Methods for detecting HIV using these antibodies are presented, as well as the use of these antibodies, antigen binding fragments, nucleic acids, and vectors to prevent and/or treat HIV infection.
The disclosed innovation identifies the VRC07 monoclonal antibody, which specifically binds the CD4 binding site of the gp120 protein of HIV and is neutralizing. VRC07 is a VRC01-like antibody containing a novel heavy chain that can cross-complement with the light chain of VRC01. This cross-complemented antibody has increased binding affinity for gp120 and does not have significantly increased self-reactivity compared to VRC01. Variants of VRC07 heavy chain and VRC01 light chain are also disclosed, which maintain or improve binding affinity and have minimal self-reactivity or immunogenicity.
Isolated monoclonal neutralizing antibodies that specifically bind HIV-1 gp120 are provided, including fully human antibodies with optimized binding and neutralization ability. These antibodies include heavy and light chain variable domains with defined complementarity determining regions (CDRs). The antibodies and compositions can be used for detecting HIV-1 infection, diagnosing AIDS, and for treatment or prevention of HIV infection by administering therapeutically effective amounts of these antibodies or nucleic acids encoding them.
Claims Coverage
The patent includes independent claims directed to isolated monoclonal antibodies and their compositions, nucleic acids encoding them, methods for detecting HIV-1 infection, and methods for treating HIV-1 infection. The main inventive features concern the specific sequences and variable domains of the heavy and light chains, their mutations, and their functional characteristics.
Isolated monoclonal antibody with specified heavy and light chain variable domains binding HIV-1 gp120
An antibody comprising a heavy chain variable domain with HCDR1, HCDR2, and HCDR3 comprising amino acids 26-33, 51-58 and 97-114 of SEQ ID NO: 40, 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: 238, that specifically binds the CD4 binding site on HIV-1 gp120 and neutralizes HIV-1.
Heavy chain variable domain with specific amino acid substitutions
The heavy chain variable domain specifically comprises amino acids 26-33, 51-58 and 97-114 of SEQ ID NO: 40, with position X2 being G or H, including VRC07 variants such as VRC07, VRC07 G54H, and related mutations at positions I37, S58, and T93.
Light chain variable domain variants with substitutions at position F97
The light chain variable domain comprises amino acids 27-30, 48-50 and 87-91 of SEQ ID NO: 238, with variants having substitutions at position F97 (including F97D, F97K, F97S, and F97H) enhancing antibody properties.
Nucleic acids encoding the monoclonal antibody
Isolated nucleic acid molecules encoding the monoclonal antibodies consistent with the specified heavy and light chain sequences, including various disclosed sequence variants and modifications.
Methods for detection and treatment of HIV-1 using the antibodies
Methods comprising contacting a biological sample from a subject with the isolated monoclonal antibody or antigen binding fragment to detect HIV-1 gp120, and methods for treating or preventing HIV-1 infection by administering therapeutically effective amounts of the antibody or encoding nucleic acids.
The claims cover monoclonal antibodies having defined heavy and light chain variable domains with specific sequence mutations that bind the CD4 binding site of HIV-1 gp120 and neutralize HIV-1, nucleic acids encoding these antibodies, and methods of using the antibodies for HIV detection and treatment. Variants with improved binding affinity, low self-reactivity, and low immunogenicity are highlighted.
Stated Advantages
The antibodies have increased binding affinity for gp120 compared to VRC01 without significantly increased self-reactivity or immunogenicity.
VRC07 and its variants neutralize a broader and more potent range of HIV-1 strains than previously known antibodies such as b12 and VRC01.
Certain amino acid substitutions at position 54 of the heavy chain notably improve potency and breadth of neutralization.
N-terminal modifications in light chains increase neutralization potency and solubility, beneficial for therapeutic use.
Combining binding affinity-enhancing mutations with germline reversions reduces potential immunogenicity of antibodies.
Documented Applications
Detection and diagnosis of HIV-1 infection and AIDS in a subject by using antibodies that specifically bind to gp120 in biological samples.
Prevention and treatment of HIV-1 infection and AIDS by administering therapeutically effective amounts of the disclosed monoclonal antibodies or nucleic acids encoding them.
Monitoring and assessing HIV-1 viral load and treatment efficacy in a subject.
Use of the antibodies to study HIV-1 biology and possibly to test gp120-based vaccine immunogens by assessing conformation and binding properties.
Possible combination therapy with anti-retroviral drugs or other HIV-neutralizing antibodies to improve treatment effectiveness.
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