Neutralizing antibodies to ebola virus glycoprotein and their use
Inventors
Sullivan, Nancy • Leigh, Kendra • Misasi, John • Cagigi, Alberto
Assignees
US Department of Health and Human Services
Publication Number
US-11976109-B2
Publication Date
2024-05-07
Expiration Date
2038-12-31
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Abstract
Antibodies and antigen binding fragments that specifically bind to ebolavirus glycoprotein and neutralize ebolavirus infection are disclosed. Nucleic acids encoding these antibodies, vectors, and host cells are also provided. The disclosed antibodies, antigen binding fragments, nucleic acids and vectors can be used, for example, to inhibit an ebolavirus infection in a subject.
Core Innovation
The invention provides isolated monoclonal antibodies and antigen binding fragments that specifically bind to ebolavirus glycoprotein (GP) and neutralize ebolavirus infection. These antibodies include heavy and light chain variable regions, comprising complementarity determining regions (CDRs) exemplified by the S1-4-A09 antibody sequences (SEQ ID NOs: 1 and 2). The antibodies and fragments can be formulated for administration and are useful for inhibiting ebolavirus infection or for diagnostic purposes by detecting ebolavirus in biological samples.
Ebolavirus disease (EVD) causes severe hemorrhagic fever with high mortality, up to 90% for Zaire ebolavirus, and poses a global health threat exacerbated by international travel. Existing neutralizing antibodies have limitations in recognition profiles and potency. The invention addresses the urgent need for additional potent neutralizing antibodies that specifically target ebolavirus GP to inhibit infection and disease progression, thereby contributing to therapeutic and diagnostic strategies against ebolavirus.
Claims Coverage
The claims of the patent cover one independent inventive feature regarding an isolated monoclonal antibody with specific sequence and functional properties related to ebolavirus GP binding and neutralization.
Antibody specificity and neutralization
An isolated monoclonal antibody comprising heavy chain variable region (VH) with HCDR1, HCDR2, and HCDR3 from SEQ ID NO: 1 and light chain variable region (VL) with LCDR1, LCDR2, and LCDR3 from SEQ ID NO: 2, specifically binding ebolavirus glycoprotein (GP) and neutralizing ebolavirus.
N-linked glycan sequon removal in VH
The VH region of the antibody lacks an N-linked glycan sequon beginning at any of Kabat residues 58-60, including through amino acid substitutions such as A61P to remove the glycan sequon at position 60.
Sequence variants and framework composition
The VH and VL sequences can be at least 90% identical to specified sequences (SEQ ID NO: 1 or 3 for VH and SEQ ID NO: 2 for VL) with human framework regions, including full-length amino acid sequences as specified, comprising a human constant domain, and existing as human IgG, especially IgG1.
Antigen binding fragments and conjugates
Isolated antigen binding fragments comprising the VH and VL of the antibody that specifically bind ebolavirus GP and neutralize ebolavirus, including Fab, Fv, scFv, and scFv2 fragments, and antibodies conjugated to effector molecules or detectable markers.
Nucleic acid molecules and expression vectors
Isolated nucleic acid molecules encoding the VH, VL, or both, with specific sequences (SEQ ID NOs: 13, 14, 15) operably linked to promoters, and expression vectors comprising these nucleic acids.
Therapeutic and diagnostic methods
Methods of inhibiting ebolavirus infection in a subject by administering effective amounts of the antibody, alone or in combination with other antibodies; and methods of detecting ebolavirus presence in biological samples by forming immune complexes with the antibody.
The claims comprehensively cover isolated monoclonal antibodies and antigen binding fragments defined by specific VH and VL sequences that bind and neutralize ebolavirus GP, especially Zaire ebolavirus, including sequence variants and glycan sequon modifications, their genetic encoding, pharmaceutical compositions, conjugates, and methods for treatment and detection of ebolavirus infection.
Stated Advantages
Disclosed antibodies potently neutralize ebolavirus and inhibit infection in accepted in vitro and in vivo models.
Removal of N-linked glycan sequon at Kabat position 60 improves antibody characteristics such as solubility, autoreactivity, and neutralization potency.
S1-4-A09 antibody has favorable manufacturability and biophysical properties suitable for product development.
S1-4-A09 shows low or no autoreactivity, enhancing its safety profile.
S1-4-A09, alone or combined with mAb114, improves survival in lethal Zaire ebolavirus challenge models in macaques.
Documented Applications
Inhibition of ebolavirus infection in a subject by administration of an effective amount of the disclosed antibodies, antigen binding fragments, conjugates, or nucleic acid molecules encoding such molecules.
Diagnostic detection of ebolavirus infection in a subject by detecting ebolavirus GP presence in biological samples using the disclosed antibodies or antigen binding fragments.
Use of the antibodies for confirming diagnosis of Zaire ebolavirus infection in biological samples, including blood.
Testing vaccine compositions by evaluating binding of the disclosed antibodies to ebolavirus GP immunogens.
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