Neutralizing antibodies to gp120 and their use
Inventors
Connors, Mark • Huang, Jinghe • Kang, Byong Ha • Mascola, John • Ishida, Elise • Zhou, Tongqing • Kwong, Peter • Zheng, Anqi
Assignees
US Department of Health and Human Services
Publication Number
US-10562960-B2
Publication Date
2020-02-18
Expiration Date
2036-03-18
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Abstract
Antibodies and antigen binding fragments that specifically bind to gp120 and neutralize HIV-1 are disclosed. Nucleic acids encoding these antibodies, vectors and host cells are also provided. Methods for detecting HIV-1 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-1 infection is disclosed.
Core Innovation
The invention provides isolated monoclonal antibodies and antigen binding fragments that specifically bind to the CD4 binding site on gp120 and neutralize HIV-1. Among these, a novel antibody termed "N6" neutralizes 98% of pseudoviruses in a panel of 181 representing diverse HIV-1 strains with high potency, characterized by a median IC50 of 0.038 μg/ml. N6 effectively neutralizes many pseudoviruses resistant to the canonical broadly neutralizing CD4 binding site antibody VRC01, indicating unique binding and neutralization properties. Variants of N6, including N17 and F8, and antibodies with similar binding specificity or variants thereof are disclosed.
The disclosed antibodies can include heavy and light chain variable regions comprising complementarity determining regions (CDRs) derived from N6, N17, or F8, specified by amino acid sequences or their variants that specifically bind to gp120 and neutralize HIV-1. Compositions comprising these antibodies and antigen binding fragments, nucleic acids encoding them, expression vectors, and host cells harboring these nucleic acids are provided. The antibodies and their fragments potently neutralize HIV-1 in vitro and can be administered therapeutically or prophylactically to subjects at risk of or infected with HIV-1.
Additionally, the antibodies, antigen binding fragments, nucleic acid molecules, vectors, and compositions disclosed can be used for detecting or diagnosing HIV-1 infection by specifically binding to gp120 in biological samples from subjects. Chimeric antigen receptors (CARs) comprising these antibodies or fragments are also provided for targeting gp120-expressing cells, offering therapeutic approaches.
The problem being solved arises from the persistent global threat of HIV-1 infection and AIDS despite extensive development of therapeutic agents. HIV-1 evades humoral immune recognition by protective mechanisms centering on its envelope proteins, notably gp120, which interacts with host cell CD4 receptors. Broadly neutralizing antibodies like VRC01 have been identified but have limitations due to resistance in certain HIV-1 strains and varying neutralization profiles. Therefore, there is a need to develop additional neutralizing antibodies with improved breadth and potency for commercial production and enhanced therapeutic and diagnostic utility.
Claims Coverage
The claims disclose multiple inventive features centered on isolated monoclonal antibodies with specified variable regions, their antigen binding fragments, nucleic acids encoding these antibodies, expression vectors, host cells, compositions, detection methods, therapeutic methods, and related kits.
Isolated monoclonal antibodies with defined heavy and light chain variable region CDRs
Antibodies comprising a heavy chain variable region (VH) including HCDR1, HCDR2, and HCDR3, and a light chain variable region (VL) including LCDR1, LCDR2, and LCDR3, as set forth in SEQ ID NOs: 1 and 2 (N6), 3 and 4 (N17), or 5 and 6 (F8) that specifically bind HIV-1 gp120 and neutralize HIV-1.
Specific CDR amino acid sequences defining antibody binding
Antibodies comprising CDRs with amino acid sequences set forth as SEQ ID NOs: 7-18, or specific combinations thereof, defining binding specificity to gp120.
Sequence variants and framework regions of therapeutic antibodies
Antibodies comprising VH and VL sequences or variants having at least 90% identity to the sequences of SEQ ID NOs: 1-6, incorporating a human framework region and enabling specific binding to gp120 and neutralization of HIV-1.
Bispecific antibodies targeting gp120 and CD3
Bispecific antibodies incorporating the VH and VL of the antibodies disclosed that specifically bind gp120 and further specifically bind to CD3, enabling immune cell targeting.
Conjugates and nucleic acids encoding antibodies
Antibodies linked to effector molecules or detectable markers (e.g., fluorescent, enzymatic, or radioactive markers), and isolated nucleic acid molecules encoding the VH and VL, operably linked to promoters and included in expression vectors, such as viral vectors, for recombinant expression.
Methods for therapeutic and diagnostic use
Methods of detecting HIV-1 infection by forming immune complexes with the antibodies and antigen binding fragments, and methods of treating HIV-1 infection in subjects by administering a therapeutically effective amount of the disclosed antibodies, fragments, nucleic acids, or vectors, optionally combined with additional anti-HIV-1 antibodies or agents.
The patent claims protect the isolated monoclonal antibodies defined by specific variable region CDR sequences derived from N6, N17, or F8 antibodies that specifically bind HIV-1 gp120 and neutralize virus, antigen binding fragments thereof, bispecific antibodies, conjugates with effector or detectable groups, nucleic acid molecules encoding these antibodies, recombinant expression vectors and host cells, kits, and methods for HIV-1 detection and treatment using these antibodies or their encoding constructs.
Stated Advantages
N6 antibody achieves both extraordinary breadth and potency in neutralizing diverse HIV-1 strains, including those resistant to other broadly neutralizing antibodies like VRC01.
N6 neutralizes 98% of tested HIV-1 pseudoviruses with a median IC50 of 0.038 µg/ml, among the most potent reported.
N6 exhibits lack of autoreactivity, suggesting improved safety and longer half-life in therapeutic applications.
Natural antibody features of N6 avoid viral resistance mechanisms, potentially limiting escape mutations due to viral fitness costs.
Documented Applications
Use of antibodies and antigen binding fragments that specifically bind to gp120 to detect and diagnose HIV-1 infection in biological samples using immunoassays.
Preventive and therapeutic administration of antibodies, antigen binding fragments, conjugates, nucleic acids, vectors, and CAR-expressing T cells to subjects with or at risk of HIV-1 infection to reduce or eliminate viral infection and viral replication.
Use of the antibodies to reduce mother-to-infant HIV-1 transmission by administering to mother and/or infant at or around childbirth or breastfeeding.
Use in combination with existing anti-retroviral therapies or other broadly neutralizing antibodies targeting different HIV-1 epitopes to treat HIV-1 infection.
Use of nucleic acids or viral vectors (including adeno-associated virus vectors) encoding the antibodies or antigen binding fragments for in vivo expression to provide durable protective or therapeutic effects against HIV-1.
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