Middle east respiratory syndrome coronavirus immunogens, antibodies, and their use
Inventors
Graham, Barney • Kong, Wing-pui • Modjarrad, Kayvon • Wang, Lingshu • Shi, Wei • Joyce, Michael Gordon • Kanekiyo, Masaru • Mascola, John
Assignees
US Department of Health and Human Services
Publication Number
US-10301377-B2
Publication Date
2019-05-28
Expiration Date
2036-02-24
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Abstract
Methods of inducing an immune response in a subject to the Middle East respiratory syndrome coronavirus (MERS-CoV) are provided. In several embodiments, the immune response is a protective immune response that inhibits or prevents MERS-CoV infection in the subject. Recombinant MERS-CoV polypeptides and nucleic acid molecules encoding same are also provided. Additionally, neutralizing antibodies that specifically bind to MERS-CoV S protein and antigen binding fragments thereof are disclosed. The antibodies and antigen binding fragments are useful, for example, in methods of detecting MERS-CoV S protein in a sample or in a subject, as well as methods of preventing and treating a MERS-CoV infection in a subject.
Core Innovation
Middle East respiratory syndrome coronavirus (MERS-CoV) has emerged as a highly fatal cause of severe acute respiratory infection with a high case fatality rate, vaguely defined epidemiology, and absence of prophylactic or therapeutic measures, creating an urgent need for an effective vaccine and related therapeutic agents. Prior coronavirus vaccine efforts have used various approaches, but there remains a need for an immunization strategy that induces a broad and potent immune response against MERS-CoV.
This disclosure provides new methods for inducing an immune response to MERS-CoV spike (S) protein, which are effective for generating neutralizing antibody responses capable of preventing or treating MERS-CoV infection. The methods include single or multiple administrations of recombinant MERS-CoV S proteins or immunogenic fragments thereof (such as the S1 subunit or the receptor binding domain) alone or in combination with nucleic acid molecules encoding the S protein. Specifically, a prime-boost vaccination protocol is described wherein a nucleic acid molecule encoding full-length MERS-CoV S protein is administered as a prime, followed by boosts that include nucleic acid molecules encoding S protein and/or administration of MERS-CoV S1 protein. In some embodiments, this immunization induces potent and cross-neutralizing antibodies targeting multiple epitopes of MERS-CoV S protein, with Th1-biased immune responses and diverse mechanisms of neutralization.
Additionally, isolated monoclonal antibodies and antigen binding fragments specifically binding to MERS-CoV S protein epitopes are disclosed. These antibodies neutralize MERS-CoV infection and can be used for detecting MERS-CoV S protein in samples as well as for preventing and treating MERS-CoV infection in subjects. Methods for producing immunogens including MERS-CoV S protein fragments linked to nanoparticle subunits such as ferritin, encapsulin, or lumazine synthase are also described, facilitating their use in vaccines generating robust immune responses.
Claims Coverage
The patent includes multiple independent claims focusing on isolated monoclonal antibodies that specifically bind to MERS-CoV S protein, encompassing various antibody variable region sequences and their antigen-binding fragments.
Isolated monoclonal antibody comprising specific heavy and light chain variable regions
An isolated monoclonal antibody comprising heavy and light chain variable regions including a heavy chain complementarity determining region (HCDR)1, HCDR2, HCDR3, and a light chain complementarity determining region (LCDR)1, LCDR2, LCDR3, where the VH and VL are selected from specific sequences listed as SEQ ID NOs: 2 and 4 (JC57-13), 6 and 8 (JC57-11), 10 and 12 (JC57-14), 36 and 38 (C2), 40 and 42 (C5), 44 and 46 (A2), 48 and 50 (A10), 52 and 54 (FIB_B2), 56 and 58 (FIB_H1), 36 and 110 (C2 LCDR1 NG-NS), 36 and 111 (C2 LCDR1 NG-NA), 115 and 117 (G2), 119 and 121 (G4), 123 and 125 (D12), or 127 and 129 (F11), and wherein the antibody specifically binds to MERS-CoV S protein.
Antibody with defined complementarity determining region sequences
An isolated monoclonal antibody with HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 sequences corresponding to those set forth for JC57-13, JC57-11, JC57-14, C2, C5, A2, A10, FIB_B2, FIB_H1, C2 LCDR1 NG-NS, C2 LCDR1 NG-NA, G2, G4, D12, or F11 antibodies.
Antibody with specified VH and VL amino acid sequences
An isolated monoclonal antibody with VH and VL comprising amino acid sequences as set forth for JC57-13, JC57-11, JC57-14, C2, C5, A2, A10, FIB_B2, FIB_H1, C2 LCDR1 NG-NS, C2 LCDR1 NG-NA, G2, G4, D12, or F11 antibodies.
Antibody comprising human framework or being humanized
An isolated monoclonal antibody comprising a human framework region or humanized with a human constant domain, optionally including a human IgG1 constant domain comprising specific mutations (e.g., M428L and N434S) to increase half-life or effector function.
Antigen binding fragments and conjugates
Antigen binding fragments (such as Fv, Fab, F(ab')2, scFv, scFv2) of the isolated monoclonal antibodies; and antibodies conjugated to an effector molecule or detectable marker.
Pharmaceutical compositions and methods of use
Pharmaceutical compositions comprising the isolated monoclonal antibodies or antigen binding fragments, nucleic acids encoding them, or vectors, for preventing or treating MERS-CoV infection in subjects, along with methods of detecting MERS-CoV in samples using said antibodies, or treating subjects by administering a therapeutically effective amount of these antibodies or compositions.
The claims cover a broad range of isolated monoclonal antibodies and antigen binding fragments specifically binding MERS-CoV S protein, defined by selected heavy and light chain variable regions and complementarity determining regions from specified sequences. The claims also cover humanized and conjugated antibodies, pharmaceutical compositions comprising such antibodies, and methods for treating, detecting, and preventing MERS-CoV infection using these antibodies and compositions.
Stated Advantages
The immunization strategy induces broad neutralizing antibodies effective against multiple MERS-CoV strains.
The prime-boost vaccination with DNA prime and protein boost yields functionally diverse neutralizing antibodies and Th1-biased immune responses.
Monoclonal antibodies isolated recognize epitopes both within and outside the receptor binding domain, providing diverse mechanisms of virus neutralization.
Structural insights from antibody-antigen complexes elucidate mechanisms of neutralization and potential escape mutations.
Vaccine regimens confer protective immunity in non-human primates, reducing pulmonary disease upon MERS-CoV challenge.
Documented Applications
Use of recombinant MERS-CoV S proteins or fragments, nucleic acids encoding them, and related immunogens to induce neutralizing immune responses against MERS-CoV in subjects for prevention or treatment.
Utilization of isolated monoclonal antibodies and antigen binding fragments specific for MERS-CoV S protein for detection of MERS-CoV infection in biological samples.
Therapeutic administration of MERS-CoV S protein specific monoclonal antibodies or antigen binding fragments to subjects for prevention or treatment of MERS-CoV infection.
Development of vaccine compositions including MERS-CoV S protein or immunogenic fragments, protein nanoparticles, or viral-like particles for immunization against MERS-CoV.
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