Neutralizing antibodies to Ebola virus glycoprotein and their use
Inventors
Sullivan, Nancy • Mulangu, Sabue • Corti, Davide • Lanzavecchia, Antonio • Graham, Barney • Muyembe-Tamfun, Jean-Jacques • Trefry, John • Ledgerwood, Julie • Stanley, Daphne
Assignees
Institute for Research in Biomedicine IRB • Humabs Biomed SA • US Department of Health and Human Services • United States Department of the Army
Publication Number
US-10160795-B2
Publication Date
2018-12-25
Expiration Date
2035-11-13
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Abstract
Neutralizing antibodies and antigen binding fragments that specifically bind to Ebola virus glycoprotein are disclosed. Nucleic acids encoding these antibodies, vectors and host cells are also provided. Methods for detecting Ebola virus using the antibodies and antigen binding fragments are disclosed. The antibodies, antigen binding fragments, nucleic acids, and vectors, can be used, for example, to prevent and/or treat Ebola virus infection in a subject.
Core Innovation
The invention provides isolated monoclonal antibodies and antigen binding fragments that specifically bind to an epitope on the Ebola virus glycoprotein (EBOV GP). These antibodies and fragments can neutralize EBOV infection. Nucleic acids encoding these antibodies, vectors for their expression, and host cells containing the nucleic acids are also provided. The compositions including these antibodies and fragments can be used for detecting EBOV infection, diagnosing Ebola virus disease (EVD), and for preventing or treating EBOV infection in a subject.
Ebola virus disease is a severe hemorrhagic fever caused by infection with Ebola virus (EBOV), with high mortality rates and no currently licensed vaccines or therapeutics approved for human use. EBOV employs protective mechanisms to evade humoral recognition, particularly via its envelope glycoprotein (GP), composed of GP1 and GP2 subunits that form the envelope spike and are targets for neutralizing antibodies. Although some neutralizing antibodies against EBOV GP are known, there is a need for additional neutralizing antibodies with varying recognition profiles and enhanced neutralization potency.
The invention addresses this need by providing novel monoclonal antibodies including EVB114, EVB100, EVB165, EVB166, and EVB167, their antigen binding fragments, and variants comprising specific heavy and light chain variable regions and complementarity determining regions (CDRs). These antibodies exhibit potent neutralization of EBOV infection both in vitro and in vivo. The glycosylation and sequence of these antibodies can be modified to improve properties such as half-life, antibody-dependent cell-mediated cytotoxicity, and neutralization activity. Methods using these antibodies for detecting the presence of EBOV GP or diagnosing EVD, as well as methods of treating or preventing EBOV infection by administering therapeutically effective amounts of these antibodies, are disclosed.
Claims Coverage
The claims include several independent claims covering isolated monoclonal antibodies, antigen binding fragments, nucleic acid molecules encoding these antibodies, vectors for expression, pharmaceutical compositions for treatment, and methods for detection and treatment of Ebola virus infection using these antibodies or fragments.
Antibodies with specific heavy and light chain variable regions binding to Ebola virus glycoprotein
Antibodies or antigen binding fragments comprising heavy chain variable regions (VH) including HCDR1, HCDR2, and HCDR3 of SEQ ID NO: 1 (EVB114 VH) or SEQ ID NO: 3 (EVB100 VH) and light chain variable regions (VL) including LCDR1, LCDR2, and LCDR3 of SEQ ID NO: 2 (EVB114 VL) or SEQ ID NO: 4 (EVB100 VL), that specifically bind Ebola virus glycoprotein (GP).
Antigen binding fragments specific to EBOV GP
Antigen binding fragments such as Fv, Fab, F(ab′)2, scFv, or scFv2 comprising the VH and VL of the disclosed antibodies which specifically bind the extracellular domain of Ebola virus GP.
Nucleic acid molecules and expression vectors encoding the antibodies or antigen binding fragments
Nucleic acid molecules, including cDNA molecules, encoding the VH and/or VL of the disclosed antibodies or antigen binding fragments, operably linked to promoters, and vectors containing these nucleic acids for expression of the antibodies or fragments.
Pharmaceutical compositions comprising the antibodies, antigen binding fragments, nucleic acids, or vectors
Pharmaceutical compositions containing therapeutically effective amounts of the disclosed antibodies, antigen binding fragments, nucleic acids encoding them, or expression vectors, with pharmaceutically acceptable carriers, formulated for treatment of Ebola virus infection.
Methods of detecting Ebola virus infection using the antibodies or fragments
Methods including contacting a biological sample from a subject with the disclosed antibodies or antigen binding fragments under conditions sufficient to form an immune complex, and detecting said complex to diagnose Ebola virus infection.
Methods of preventing or treating Ebola virus infection by administration of the disclosed antibodies or fragments
Administration of a therapeutically effective amount of the disclosed monoclonal antibodies, antigen binding fragments, nucleic acids encoding them, or expression vectors to prevent or treat Ebola virus infection in a subject.
Antibodies with modified constant regions to enhance half-life or ADCC
Antibodies comprising recombinant constant regions with mutations such as M428L and N434S that increase binding to neonatal Fc receptor and/or modifications that increase antibody-dependent cell-mediated cytotoxicity.
The independent claims cover isolated monoclonal antibodies and antigen binding fragments with specific VH and VL regions targeting EBOV GP, nucleic acid encoding these antibodies and fragments, pharmaceutical compositions for treatment, methods of detection and treatment of Ebola virus infection, and antibody modifications enhancing therapeutic properties.
Stated Advantages
The disclosed antibodies potently neutralize Ebola virus infection in vitro and in vivo.
The antibodies exhibit binding to distinct epitopes on Ebola virus glycoprotein, allowing combination therapies to improve efficacy and reduce viral escape.
Some antibodies mediate antibody-dependent cell-mediated cytotoxicity (ADCC), contributing to viral clearance.
Certain antibodies can neutralize multiple strains of Ebola virus, including the Zaire and Makona variants.
These antibodies retain potent neutralizing activity in the absence of complement and can protect non-human primates from lethal Ebola virus challenge as monotherapy or in combination.
Documented Applications
Treatment or prevention of Ebola virus infection (including Zaire Ebola virus infection) in subjects at risk or infected with EBOV by administering therapeutically effective amounts of the disclosed antibodies, antigen binding fragments, nucleic acids encoding them, or expression vectors.
Detection and diagnosis of Ebola virus infection or Ebola virus disease in subjects by contacting biological samples with the disclosed antibodies or antigen binding fragments to detect immune complex formation indicative of EBOV presence.
Research use to study Ebola virus glycoprotein and immune responses, including vaccine evaluation to confirm presence of epitopes on EBOV GP.
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