Human monoclonal antibodies against the middle east respiratory syndrome coronavirus (MERS-CoV) and engineered bispecific fusions with inhibitory peptides
Inventors
Dimitrov, Dimiter S. • Ying, Tianlei • Ju, Tina W. • Yuen, Kwok Yung
Assignees
Veritech Ltd • Versitech Ltd • US Department of Health and Human Services
Publication Number
US-10421802-B2
Publication Date
2019-09-24
Expiration Date
2034-10-16
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Abstract
The invention provides polypeptides (e.g., antibodies) and fusion proteins that target a epitope in the receptor binding domain (RBD) of the spike (S) glycoprotein of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). The polypeptides and fusion proteins can be used to treat and prevent MERS-CoV infection in mammals.
Core Innovation
The invention provides polypeptides, specifically antibodies, and fusion proteins that target an epitope in the receptor binding domain (RBD) of the spike (S) glycoprotein of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). These polypeptides and fusion proteins can be used to treat and prevent MERS-CoV infection in mammals by inhibiting viral entry into cells. The invention also includes nucleic acids encoding these polypeptides, as well as methods of administering them to inhibit MERS-CoV infection.
Emerging viruses like MERS-CoV pose a significant threat to public health due to their severity, high mortality rates, and capacity for human-to-human transmission. Specifically, MERS-CoV uses its spike glycoprotein to attach to the host cell receptor DPP4, enabling viral entry and infection. Currently, no effective targeted therapeutics or vaccines exist for MERS-CoV, and existing treatments such as IFN-α2b and ribavirin have limited efficacy, especially in severe cases. There is a pressing need for new therapeutics that specifically target viral mechanisms to prevent and treat MERS-CoV infections.
Claims Coverage
The patent includes one independent claim covering multiple embodiments of polypeptides comprising specific complementarity determining regions (CDRs) of antibodies against MERS-CoV, along with related features such as fusion with inhibitory peptides and dimerization domains.
Polypeptides comprising defined antibody variable regions against MERS-CoV
The polypeptide comprises immunoglobulin heavy chain and light chain variable regions containing specific complementarity determining regions (CDRs) defined by SEQ ID NOs: 3-8, or combinations from SEQ ID NOs: 4, 11-15, and 11, 18-22, targeting the MERS-CoV spike glycoprotein receptor binding domain (RBD).
Monoclonal antibody formats and fragments
The polypeptide can be a monoclonal antibody or fragments such as Fab, Fab', F(ab')2, scFv, di-scFv, fusion proteins, or conjugates thereof, retaining binding and inhibitory activities against MERS-CoV.
Fusion with inhibitory peptides and dimerization domains
The polypeptide may further comprise a MERS-CoV inhibitory peptide including SEQ ID NO: 26 and/or a CH3 antibody dimerization domain sequence, allowing for enhanced potency and stability, such as in bispecific fusion protein constructs.
Pharmaceutical compositions and combination therapies
Pharmaceutical compositions comprising the polypeptide with pharmaceutically acceptable carriers and combinations with additional active agents like interleukins (IL-2, IL-7, IL-12), Cyclosporin A, inactivated virus, CD40 ligand with IL-12, ribavirin, or interferons.
Dimers of fusion polypeptides
Dimers formed by two polypeptides comprising the inhibitory peptide and CH3 antibody dimerization domain sequences for increased binding strength and neutralization potency.
The claims cover antibodies and antibody fragments with specific variable regions targeting MERS-CoV RBD, including fusion proteins with inhibitory peptides and dimerization domains. They also encompass pharmaceutical compositions with these polypeptides alone or in combination with other therapeutic agents, and multimeric forms to enhance efficacy.
Stated Advantages
The antibodies bind with very high avidity (subnanomolar) and neutralize MERS-CoV in vitro with exceptional potency.
Fusion proteins combining antibodies with inhibitory peptides provide increased potency and breadth of neutralization against viral entry.
The use of human or humanized antibodies reduces the likelihood of undesirable immune responses in treated humans.
Documented Applications
The polypeptides and fusion proteins are used to inhibit, treat, and prevent MERS-CoV infection in mammalian hosts, including therapeutic and prophylactic applications.
Animal models, such as mouse and monkey models infected with live MERS-CoV, are used to confirm efficacy, safety, and pharmacokinetics of the antibodies and fusion proteins.
The compositions can be administered via various routes including topical, oral, inhalation, or parenteral delivery to humans or other mammals at risk or infected with MERS-CoV.
The polypeptides and fusion proteins can be combined with existing antiviral agents such as ribavirin and interferons for enhanced treatment of MERS-CoV infection.
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