Monoclonal antibodies against orthopoxviruses
Inventors
Chen, Zhaochun • Earl, Patricia • Moss, Bernard • Emerson, Suzanne U. • Purcell, Robert H.
Assignees
US Department of Health and Human Services
Publication Number
US-7914788-B2
Publication Date
2011-03-29
Expiration Date
2026-12-22
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Abstract
The present invention relates to monoclonal antibodies that bind or neutralize Orthopoxviruses. The invention provides such antibodies, fragments of such antibodies retaining B5 or A33 binding ability, fully human antibodies retaining B5 or A33 binding ability, and pharmaceutical compositions including such antibodies. The invention further provides for isolated nucleic acids encoding the antibodies of the invention and host cells transformed therewith. Additionally, the invention provides for prophylactic, therapeutic, and diagnostic methods employing the antibodies and nucleic acids of the invention.
Core Innovation
The invention relates to monoclonal antibodies that bind or neutralize Orthopoxviruses, specifically targeting the B5 and A33 proteins. It provides purified monoclonal antibodies, fragments retaining binding ability to B5 or A33, fully human or humanized antibodies, pharmaceutical compositions including these antibodies, isolated nucleic acids encoding them, host cells transformed with such nucleic acids, and methods for prophylactic, therapeutic, and diagnostic use employing these antibodies and nucleic acids.
The problem addressed arises from the adverse reactions and limitations of current treatments for Orthopoxvirus infections and vaccination complications. Vaccinia immune globulin (VIG), historically used for treating adverse reactions from vaccinia virus vaccination, has potential variability in potency and risk of transmitting other viral agents. There is a need for safer, more effective monoclonal antibodies to neutralize Orthopoxviruses such as variola and vaccinia viruses, which would provide better prophylaxis, therapy, and diagnostics.
Claims Coverage
The claims include one independent claim directed to a purified monoclonal antibody binding a conformational epitope of B5 antigen, and additional dependent claims on antibody fragments, pharmaceutical and diagnostic preparations, and methods of treating and detecting Orthopoxvirus infection using these antibodies.
Purified monoclonal antibody binding to B5 conformational epitope
A fully humanized or humanized chimpanzee monoclonal antibody comprising a heavy chain variable region of SEQ ID NO:1 and a light chain variable region of SEQ ID NO:9 that binds to a conformational epitope of the B5 antigen.
Antibody with specific B5 CDR regions
A purified monoclonal antibody binding the conformational epitope of B5 antigen recognized by anti-B5 8AH8AL, comprising the specified heavy chain CDR1 (SEQ ID NO:3), CDR2 (SEQ ID NO:5), CDR3 (SEQ ID NO:7), and light chain CDR1 (SEQ ID NO:11), CDR2 (SEQ ID NO:13), CDR3 (SEQ ID NO:15) regions.
Fab fragment of the purified monoclonal antibody
The antibody may comprise an Fab fragment of the described monoclonal antibody.
Pharmaceutical and diagnostic preparations containing the antibodies
Pharmaceutical or diagnostic compositions comprising the monoclonal antibodies as described, suitable for prophylactic, therapeutic or diagnostic use against Orthopoxvirus infections.
Methods of treating Orthopoxvirus infection
Therapeutic methods involving administration of a therapeutically effective amount of the monoclonal antibody pharmaceutical preparations to inhibit Orthopoxvirus infection post exposure.
Methods of passive immunization
Passive immunization by administering an effective amount of the pharmaceutical compositions comprising the monoclonal antibodies prior to Orthopoxvirus infection for protection.
Methods of detecting Orthopoxvirus infection
Diagnostic methods involving contacting a biological sample with the diagnostic preparation containing the monoclonal antibodies and assaying binding to Orthopoxvirus, where antibodies can be immobilized on solid support or labeled with detectable markers.
The independent claims focus on purified monoclonal antibodies binding B5 antigen epitopes with defined variable regions and CDRs. Dependent claims cover antibody fragments, pharmaceutical and diagnostic compositions, and methods of treating, protecting against, and detecting Orthopoxvirus infections using these antibodies.
Stated Advantages
The monoclonal antibodies provide superior protection with a lower dose and higher safety profile than vaccinia immune globulin (VIG).
The antibodies neutralize both vaccinia virus and variola virus, the agent of smallpox, including prevention and post-exposure therapeutic efficacy.
Chimpanzee/human monoclonal antibodies have higher binding affinity and slower off-rates than previously available rat monoclonal antibodies, contributing to enhanced protective efficacy.
The antibodies specifically neutralize extracellular enveloped virus forms essential for virus dissemination, reducing disease severity and virus spread.
Fab fragments can be produced inexpensively in bacteria, avoid immune complex formation, and have better tissue penetration compared to full-length antibodies.
Documented Applications
Prophylactic use in passive immunization to protect against Orthopoxvirus infections, including smallpox and vaccinia-related complications.
Therapeutic use for treatment of Orthopoxvirus infections post exposure, including treatment of complications arising from vaccinia virus vaccination.
Diagnostic use in detecting Orthopoxvirus infection in biological samples via immunoassays utilizing labeled or immobilized monoclonal antibodies.
Use of isolated nucleic acids and host cells transformed therewith for production of monoclonal antibodies.
Use in pharmaceutical preparations for immunoprophylaxis and immunotherapy against Orthopoxvirus infection.
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