Neutralizing antibodies to HIV-1 Env and their use
Inventors
Lusso, Paolo • Liu, Qingbo • Kwong, Peter • Mascola, John • Kwon, Young Do
Assignees
US Department of Health and Human Services
Publication Number
US-11760790-B2
Publication Date
2023-09-19
Expiration Date
2039-02-21
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Abstract
Antibodies and antigen binding fragments that specifically bind to HIV-1 Env 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 discloses monoclonal antibodies and antigen binding fragments that specifically bind to the CD4 binding site of HIV-1 Env via a quaternary interaction with multiple protomers of the HIV-1 Env trimer. A single modification to the heavy chain variable region framework region 3 (HFR3) of VRC01-class antibodies promotes the quaternary interaction and improves both HIV-1 Env binding and HIV-1 neutralization. The modification involves substitution of the amino acids of Kabat positions 72-76 of the parent VRC01-class antibody with the sequence QLSQDPDDPDWG (SEQ ID NO: 36).
HIV-1 Env is a trimer that consists of gp120 and gp41 subunits and the CD4 binding site has two parts: the classic CD4 binding site on the gp120 outer domain (CD4-BS1 domain) and a second binding site (CD4-BS2) on the inner domain of a neighboring protomer, which stabilizes CD4-Env interaction and triggers conformational changes enabling infection. Existing VRC01-class antibodies bind to the CD4-BS1 but lack interaction with CD4-BS2. The disclosed antibodies incorporate the extended HFR3 loop from VRC03 (70-03 insertion) which enables interaction with the CD4-BS2 of neighboring protomers, resulting in improved neutralization and binding compared to unmodified VRC01-class antibodies.
Claims Coverage
The patent includes multiple independent claims directed primarily to monoclonal antibodies having specific modifications in the heavy chain framework region 3 (HFR3) of VRC01-class antibodies, and nucleic acid compositions, vectors, pharmaceutical compositions, and methods involving these antibodies.
Modification in heavy chain framework region 3
A monoclonal antibody comprising a heavy chain variable region (VH) and light chain variable region (VL) from a parent VRC01-class antibody, with a substitution of the amino acids at Kabat positions 72-76 in HFR3 with the sequence QLSQDPDDPDWG (SEQ ID NO: 36), where the parent does not have an insertion at these positions, conferring specific binding and neutralization of HIV-1.
Specific VRC01-class antibody antibody embodiments
Monoclonal antibodies based on parent VRC01-class antibodies VRC01, VRC07, VRC07-523, N49P7, or VRC-PG04 with specified complementarity determining region (CDR) sequences and the HFR3 modification at Kabat positions 72-76 as described above, exhibiting specific HIV-1 Env binding and neutralization.
Antibody variants with additional substitutions and deletions
Monoclonal antibodies further comprising tryptophan, tyrosine, or phenylalanine substitution at Kabat position 54, and/or a two or three amino acid deletion at the N-terminus of the VL, enhancing antibody properties.
Sequences and identity thresholds for VH and VL
Monoclonal antibodies or antigen binding fragments wherein VH and VL sequences are at least 90% identical to specific SEQ ID NOs provided for various VRC01-class antibodies, together with the HFR3 modification.
Nucleic acid molecules, expression vectors, pharmaceutical compositions and methods
Isolated nucleic acid molecules encoding the disclosed antibodies or fragments, expression vectors (viral or non-viral), pharmaceutical compositions comprising the antibodies or encoding nucleic acids, and methods for producing antibodies, detecting HIV-1 infection, or inhibiting HIV-1 infection in a subject by administering these antibodies or encoding materials.
The claims provide broad coverage for monoclonal antibodies of the VRC01-class that include a specific HFR3 substitution promoting quaternary interactions with HIV-1 Env, along with variants, nucleic acid constructs, compositions, and methods of use for detecting and treating HIV-1 infection.
Stated Advantages
The substitution in the HFR3 loop of VRC01-class antibodies improved both HIV-1 Env binding affinity and HIV-1 neutralization potency.
Engraftment of the extended HFR3 loop stabilizes interaction between the antibody and HIV-1 Env trimer by slowing dissociation rates.
Modified antibodies demonstrate enhanced neutralization breadth and potency against diverse HIV-1 strains.
Certain modifications reduce autoreactivity of the antibodies, improving safety potential.
The modified antibodies retain favorable in vivo half-life in animal models, supporting clinical applicability.
Documented Applications
Use in methods of inhibiting or treating HIV-1 infection in subjects at risk of or infected with HIV-1.
Use for detecting HIV-1 infection in biological samples by forming detectable immune complexes with HIV-1 Env.
Use in research and diagnostics to detect HIV-1 Env or diagnose HIV-1 infection.
Use for prophylactic administration to prevent HIV-1 infection.
Use in combination with antiretroviral therapies or in antibody cocktails targeting multiple HIV-1 epitopes.
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