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-8999336-B2
Publication Date
2015-04-07
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 providing such antibodies, fragments retaining B5 or A33 binding ability, fully human antibodies retaining B5 or A33 binding ability, and pharmaceutical compositions including these antibodies. It further includes isolated nucleic acids encoding the antibodies and host cells transformed with such nucleic acids. The invention also provides prophylactic, therapeutic, and diagnostic methods employing these antibodies and nucleic acids.
The problem addressed is that existing treatments for complications arising from vaccinia virus immunization, such as vaccinia immune globulin (VIG), have variability in potency and carry risks of transmitting other viral agents. There is a need for more potent, safer monoclonal antibodies that can neutralize Orthopoxviruses like vaccinia and variola viruses effectively and provide superior protection compared to current treatments.
Claims Coverage
The patent contains 13 main inventive features derived from independent claims focusing on monoclonal antibodies binding A33 antigen of Orthopoxviruses and related methods and compositions.
Monoclonal antibody binding A33 antigen
A substantially pure polypeptide comprising a fully human or humanized chimpanzee monoclonal antibody that binds the A33 antigen, comprising heavy chain CDR1, CDR2, and CDR3 with amino acid sequences of SEQ ID NO:67, 69, and 71 respectively, and light chain CDR1, CDR2, and CDR3 with amino acid sequences of SEQ ID NO:75, 77, and 79 respectively.
Monoclonal antibody binding conformational epitope of A33
A substantially pure monoclonal antibody that binds the conformational epitope targeted by the anti-vaccinia virus A33 12F protein Fab fragment deposited as ATCC Accession No. PTA-7324.
Inclusion of Fd fragment
The monoclonal antibody may include an Fd fragment.
Inclusion of Fab fragment
The monoclonal antibody may include a Fab fragment.
Deposited anti-vaccinia virus A33 12F antibody
The anti-vaccinia virus A33 12F monoclonal antibody deposited under ATCC Accession No. PTA-7324.
Pharmaceutical preparation comprising the monoclonal antibody
A pharmaceutical preparation including the monoclonal antibody that binds A33 antigen as defined.
Diagnostic preparation comprising the monoclonal antibody
A diagnostic preparation comprising the monoclonal antibody binding A33 antigen as defined.
Method for inhibiting Orthopoxvirus infection
Administering to a patient an effective amount of the pharmaceutical preparation containing the monoclonal antibody to inhibit Orthopoxvirus infection.
Method for diagnosis of Orthopoxvirus infection
Obtaining and administering the diagnostic preparation containing the monoclonal antibody to a patient and detecting binding as a determination of Orthopoxvirus presence.
Method of detecting Orthopoxvirus in biological sample
Contacting a biological sample with the diagnostic preparation and assaying binding of the antibody to determine the presence of Orthopoxvirus.
VH region amino acid sequence inclusion
The monoclonal antibody comprising a VH region having the amino acid sequence of SEQ ID NO:65.
VL region amino acid sequence inclusion
The monoclonal antibody comprising a VL region having the amino acid sequence of SEQ ID NO:73.
Variant monoclonal antibodies with conservative variations
A substantially pure monoclonal antibody variant comprising conservative variations in one or more of the CDR amino acid sequences defined by SEQ ID NOs: 67, 69, 71, 75, 77, or 79 that binds the conformational epitope of A33 antigen.
The claims cover fully human or humanized chimpanzee monoclonal antibodies specific to the A33 antigen of Orthopoxviruses, their fragments, pharmaceutical and diagnostic compositions including these antibodies, and methods for inhibiting infection, diagnosing, and detecting Orthopoxvirus using these antibodies or compositions.
Stated Advantages
Chimpanzee/human monoclonal antibodies provide superior protection with higher safety profiles and efficacy than vaccinia immune globulin (VIG) or rat monoclonal antibodies.
These monoclonal antibodies neutralize extracellular enveloped virus forms of both vaccinia and variola viruses, indicating broad orthopoxvirus activity.
Monoclonal antibodies bind conformational epitopes with high affinity and slow dissociation rates, contributing to prolonged protective efficacy.
The antibodies can be manufactured as fully human or humanized forms, reducing the risk of immune reactions upon administration.
Fab fragments and smaller antibody fragments offer advantages such as better tissue penetration, reduced immune complex formation, and easier production in bacterial systems.
Documented Applications
Prophylactic and therapeutic administration of monoclonal antibodies for prevention and treatment of Orthopoxvirus infections such as vaccinia virus and smallpox (variola virus).
Use of monoclonal antibodies and their fragments as diagnostic tools in immunoassays to detect Orthopoxvirus antigens in biological fluids, tissues, or in vivo.
Development of pharmaceutical and diagnostic compositions comprising the antibodies or nucleic acids encoding them for immunoprophylaxis, immunotherapy, and diagnosis of Orthopoxvirus infection.
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