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-10035844-B2
Publication Date
2018-07-31
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 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 fragments, nucleic acids and vectors to prevent and/or treat an HIV infection is disclosed.
Human Immunodeficiency Virus (HIV) infection, and the resulting Acquired Immunodeficiency Syndrome (AIDS) remain threats to global public health, despite extensive efforts to develop anti-HIV therapeutic agents. Some HIV-infected individuals eventually develop broadly neutralizing antibodies (bNAbs), which neutralize a large panel of HIV viruses. These individuals show delayed development of AIDS, even in the absence of any treatment for HIV infection. One previously characterized HIV-1 neutralizing mAb, called b12, can bind to a site on gp120 that is required for viral attachment to its primary cellular receptor, CD4. b12 can neutralize about 75% of clade B strains of HIV-1 but less than 50% of other strains of HIV-1 worldwide. Therefore, there is a need to develop additional neutralizing antibodies for HIV-1.
Disclosed herein is the identification of 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”) cross complemented with the light chain of the VRC01 monoclonal antibody. VRC07 heavy chain is a clonal variant of the VRC01 heavy chain. An antibody including the VRC07 heavy chain cross complemented with the VRC01 light chain has increased binding affinity for gp120 and does not have significantly increased self-reactivity compared to VRC01. Further disclosed are variants of the VRC07 heavy chain and the VRC01 light chain, and cross-complemented monoclonal antibodies including such variants that have increased binding affinity for gp120 and are not self-reactive, or have only low self reactivity, compared to VRC01. Some of these variants include framework region amino acid substitutions but have up to two amino acid substitutions in the complementarity determining regions (CDRs) compared to VRC07 heavy chain or VRC01 light chain. The disclosed class of monoclonal antibodies have increased binding affinity for gp120 and are not self-reactive or have low self reactivity. In some embodiments, the antibodies are not immunogenic or have low immunogenicity.
The antibodies and compositions disclosed herein can be used for various purposes such as detecting an HIV-1 infection or diagnosing AIDS in a subject by contacting a sample from the subject with a monoclonal antibody that specifically binds gp120 and detecting binding of the antibody to the sample. The antibodies can also be used for the prevention and/or treatment of HIV infection, including administration of therapeutically effective amounts of the monoclonal antibodies, antigen binding fragments, or nucleic acids encoding the antibodies.
Claims Coverage
The patent includes 6 main independent claims focusing on specific nucleic acid molecules encoding monoclonal antibodies or antigen-binding fragments thereof with defined heavy and light chain variable domains that specifically bind and neutralize HIV-1 gp120 at the CD4 binding site.
Isolated nucleic acid encoding specific antibody variable domains
An isolated nucleic acid molecule encoding a monoclonal antibody or antigen binding fragment thereof, where the heavy chain variable domain (VH) has HCDR1, HCDR2, and HCDR3 comprising amino acids 26-33, 51-58, and 97-114 of SEQ ID NO: 40 respectively; and the light chain variable domain (VL) has LCDR1, LCDR2, and LCDR3 comprising amino acids 27-30, 48-50, and 87-91 of SEQ ID NO: 238 respectively. The encoded antibody specifically binds the CD4 binding site on HIV-1 gp120 and neutralizes HIV-1.
Variants of the heavy chain variable domain
The VH comprises one of: (a) amino acids 26-33 (CDR1), 51-58 (CDR2), and 97-114 (CDR3) of SEQ ID NO: 40, where X2 is G; or (b) amino acids 26-33 (CDR1), 51-58 (CDR2), and 97-114 (CDR3) of SEQ ID NO: 40, where X2 is H.
Specific heavy chain amino acid sequences
VH of the antibody comprises SEQ ID NO: 40 or specific forms thereof including variants with substitutions at positions X1, X2, X3, and X4, as defined, including VRC07 and specific mutants such as VRC07 G54H, S58N, I37V, and combinations thereof.
Specific light chain variants
VL comprises one of: (a) amino acids 27-30 (CDR1), 48-50 (CDR2), and 87-91 (CDR3) of SEQ ID NO: 238, with variations at position X11 (F, D, K, S, or H); or (b) VL comprising SEQ ID NO: 238 including specific variations of amino acids X1 through X13 as detailed.
Specific combined VH and VL sequences
The antibody includes combinations of the VH variable domain (such as SEQ ID NO: 2 or variants thereof) and VL variable domain (such as SEQ ID NO: 9 or variants thereof) that specifically bind gp120, are neutralizing, and include specific CDR regions as defined in the claims.
Vectors and host cells expressing nucleic acids
Vectors comprising the nucleic acid molecules encoding the monoclonal antibody or antigen binding fragment are covered, as well as isolated host cells transformed with such vectors.
The claims cover isolated nucleic acid molecules encoding monoclonal antibodies or antigen binding fragments with defined complementarity determining regions of heavy and light chains targeting the CD4 binding site of HIV-1 gp120, including specific variants increasing potency and specificity, as well as their expression vectors and host cells.
Stated Advantages
The disclosed antibodies have increased binding affinity for gp120 compared to VRC01.
The antibodies do not have significantly increased self-reactivity compared to VRC01, some having low or no autoreactivity.
Certain mutations increase neutralization potency, breadth, and solubility while maintaining low immunogenicity.
N-terminal deletions and specific amino acid substitutions increase potency up to 10-fold over parental antibodies.
Optimization increases in vivo half-life by 2-3 fold without affecting breadth or potency.
Documented Applications
Use of the monoclonal antibodies for detecting HIV-1 infection or diagnosing AIDS by binding to gp120 in samples.
Use of the antibodies or nucleic acids encoding them to prevent or treat HIV-1 infection in subjects.
Use in combination with anti-retroviral agents or other antibodies for enhanced treatment.
Use in vaccine testing to detect immunogens adopting conformations that bind the antibodies.
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