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-10273288-B2
Publication Date
2019-04-30
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 Ebola virus (EBOV) glycoprotein (GP). These antibodies and antigen binding fragments can neutralize EBOV infection and are particularly effective against the Zaire Ebola virus strain (ZEBOV). Further, nucleic acids encoding these antibodies, expression vectors comprising the nucleic acids, and host cells expressing these antibodies or fragments are also provided.
The problem addressed by the invention is the need for additional neutralizing antibodies against EBOV with varying recognition profiles and increased neutralization potency. EBOV causes severe hemorrhagic fever with high mortality and currently has no licensed vaccines or therapeutics approved for human use. The major envelope glycoprotein of EBOV, GP, which forms the envelope spike and is the target for neutralizing antibodies, presents protective mechanisms hindering humoral recognition and effective immune response. Existing neutralizing antibodies are limited, and the invention aims to provide novel monoclonal antibodies with improved efficacy for detection, prevention, and treatment of EBOV infection and disease.
Claims Coverage
The patent claims primarily relate to a monoclonal antibody comprising specific heavy and light chain variable regions derived from the EVB166 antibody and antigen binding fragments thereof, along with nucleic acid sequences, vectors, pharmaceutical compositions, and methods of detecting and treating Ebola virus infections.
Monoclonal antibody comprising specific heavy and light chain variable regions
An isolated monoclonal antibody comprising a heavy chain variable region (VH) with HCDR1, HCDR2, and HCDR3 of the VH set forth as SEQ ID NO: 5 (EVB166 VH) and a light chain variable region (VL) with LCDR1, LCDR2, and LCDR3 of the VL set forth as SEQ ID NO: 6 (EVB166 VL), which specifically binds Ebola virus glycoprotein (GP).
Amino acid sequences of complementarity determining regions (CDRs)
The HCDRs comprise amino acids 26-33, 51-58, and 97-112 of SEQ ID NO: 5, and the LCDRs comprise amino acids 27-33, 51-53, and 90-98 of SEQ ID NO: 6.
Sequence identity variants of the VH and VL
Monoclonal antibodies wherein the VH and/or VL comprise an amino acid sequence at least 80% identical to SEQ ID NOs: 5 and/or 6, respectively.
Monoclonal antibodies with exact VH and VL amino acid sequences
Monoclonal antibodies comprising the VH and VL with amino acid sequences exactly as set forth in SEQ ID NOs: 5 and 6, respectively.
Antibody variants with a light chain K104T substitution
Antibodies comprising VH and VL as in claim 1, further containing a K104T substitution according to Kabat numbering in the VL.
Human framework and constant regions
Antibodies comprising human framework regions and human constant regions, including isotypes IgG, IgM, or IgA.
Modified constant regions to enhance receptor binding and ADCC
Recombinant constant regions with one or more substitutions increasing binding to the neonatal Fc receptor and/or antibody-dependent cell cytotoxicity, such as M428L and N434S mutations.
Antigen binding fragments and multispecific antibodies
Antigen binding fragments (e.g., Fv, Fab, F(ab')2, scFv, scFv2) and bispecific antibodies incorporating the VH and VL of the monoclonal antibody.
Neutralization of Ebola virus by the antibody or fragment
The monoclonal antibody or antigen binding fragment neutralizes Ebola virus, specifically Zaire Ebola virus expressing the GP amino acid sequence as SEQ ID NO: 15.
Conjugates with effector molecules or detectable markers
The antibody or antigen binding fragment linked to an effector molecule or a detectable marker such as fluorescent, enzymatic, or radioactive labels.
Nucleic acid molecules encoding the antibodies or fragments
Isolated nucleic acid molecules encoding the VH and/or VL of the antibody or antigen binding fragment, including recombinant molecules, cDNAs, and operably linked vectors.
Pharmaceutical compositions and methods of use
Pharmaceutical compositions comprising therapeutically effective amounts of the antibody, antigen binding fragment, nucleic acid molecule, or expression vector for treating or inhibiting Ebola virus infection, and methods of detection, prevention, treatment, and production thereof.
The claims cover isolated monoclonal antibodies with specific VH and VL sequences derived from EVB166 that specifically bind to EBOV GP, antigen binding fragments, variants with high sequence identity, conjugates, nucleic acid molecules encoding such antibodies, pharmaceutical compositions, diagnostic methods, therapeutic methods for preventing or treating Ebola virus infection, and methods for producing the antibodies or fragments. The invention includes modifications to antibody constant regions to enhance efficacy.
Stated Advantages
The antibodies potently neutralize Ebola virus infection in vitro and in vivo.
The antibodies have broad recognition across multiple EBOV strains including recent variants.
Potent neutralizing antibodies showed complete protection against lethal EBOV infection in a non-human primate model.
Monotherapy with the EVB114 antibody demonstrates both neutralization and antibody-dependent cell-mediated cytotoxicity (ADCC), contributing to viral clearance.
The antibodies can be engineered for improved half-life and effector functions such as increased binding to neonatal Fc receptor (FcRn) and enhanced ADCC.
Documented Applications
Use of disclosed antibodies and antigen binding fragments to prevent and treat Ebola virus infection (EVD) in subjects at risk of or having an EBOV infection.
Use of the antibodies and antigen binding fragments for detection and diagnosis of EBOV infection or Ebola virus disease in biological samples of subjects.
Use of nucleic acids and viral vectors encoding disclosed antibodies for in vivo expression and therapy.
Compositions including antibodies, fragments, conjugates, nucleic acids, and vectors for therapeutic, diagnostic, and preventive applications against EBOV.
Use of antibodies for vaccine testing to confirm that the vaccine immunogen presents the appropriate EBOV GP conformation recognized by neutralizing antibodies.
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