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-9708392-B2
Publication Date
2017-07-18
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 provides monoclonal antibodies that bind or neutralize Orthopoxviruses, specifically targeting the B5 and A33 antigens. These include full-length humanized antibodies, fragments retaining B5 or A33 binding ability, isolated nucleic acids encoding these antibodies, and host cells transformed with such nucleic acids. Additionally, pharmaceutical compositions containing these antibodies and methods for prophylactic, therapeutic, and diagnostic use are disclosed.
The invention addresses the need for safer, more potent treatments against Orthopoxvirus infections, including complications arising from smallpox vaccination. Existing vaccinia immune globulin (VIG) treatments vary in potency and pose risks of transmitting infectious agents. The invention solves this by generating high-affinity, human-like monoclonal antibodies derived from chimpanzees, which closely resemble human IgG and exhibit superior binding characteristics to vaccinia virus B5 and A33 proteins. These antibodies effectively neutralize extracellular enveloped virus forms, protect mice in challenge models, and provide better protection than rat antibodies or VIG.
Claims Coverage
The claims include several inventive features focused on chimeric chimpanzee monoclonal antibodies binding B5 antigen, their fragments, pharmaceutical and diagnostic preparations, and methods of use against Orthopoxvirus infection.
Chimeric chimpanzee monoclonal antibody binding B5 antigen
A substantially pure polypeptide comprising a chimeric chimpanzee monoclonal antibody that binds B5 antigen, characterized by heavy chain CDR1, CDR2, CDR3 (SEQ ID NO:19, 21, 23) and light chain CDR1, CDR2, CDR3 (SEQ ID NO:27, 29, 31) amino acid sequences.
Antibody fragments retaining B5 binding
Antibodies comprising Fd or Fab fragments based on the chimeric chimpanzee monoclonal antibody that retains B5 antigen binding ability.
Pharmaceutical and diagnostic preparations
Formulations comprising the monoclonal antibody for therapeutic or diagnostic application against Orthopoxvirus infections.
Fully characterized VH and VL regions
Monoclonal antibodies comprising VH and VL regions having the amino acid sequences of SEQ ID NO:17 and SEQ ID NO:25, respectively.
Humanized chimpanzee monoclonal antibodies
Chimeric antibodies that are humanized chimpanzee monoclonal antibodies based on the sequences described above.
Variants with conservative variations
Monoclonal antibodies variant of the primary antibody with conservative amino acid substitutions in the CDR regions that maintain binding to the conformational epitope of B5.
Methods for inhibiting infection
Methods for inhibiting Orthopoxvirus infection by administering an effective amount of the pharmaceutical preparation including the described monoclonal antibodies.
Diagnostic methods using monoclonal antibodies
Methods for diagnosis of Orthopoxvirus infection by administering the diagnostic preparation comprising the monoclonal antibody and detecting binding to B5 antigen.
Detection of Orthopoxvirus in biological samples
Methods of detecting Orthopoxvirus presence by contacting a biological sample with the diagnostic preparation and assaying for antibody binding to B5 antigen.
The claims collectively cover chimeric chimpanzee monoclonal antibodies targeting B5 antigen, their fragments, pharmaceutical and diagnostic uses, variants with conservative changes, and methods for prevention, treatment, and detection of Orthopoxvirus infection.
Stated Advantages
Provides monoclonal antibodies with higher potency and affinity than existing rat antibodies or vaccinia immune globulin (VIG).
Offers superior prophylactic and therapeutic protection against Orthopoxvirus infections, including smallpox, in animal models.
Reduces variability and risk of infectious agent transmission compared to VIG treatment.
Fully humanized or human-like antibodies reduce immunogenicity upon administration.
Antibody fragments such as Fabs provide better tissue penetration, reduce immune complex formation, and can be produced more economically in bacteria.
Documented Applications
Use of monoclonal antibodies and fragments for prophylactic and therapeutic treatment of Orthopoxvirus infections and complications of smallpox vaccination.
Diagnostic use in vitro and in vivo to detect Orthopoxvirus infection by binding B5 or A33 antigens in biological samples or infected tissues.
Pharmaceutical compositions containing monoclonal antibodies for administration by injection or infusion routes for prevention or treatment of Orthopoxvirus infection.
Use of nucleic acids encoding antibodies for recombinant expression in host cells or gene therapy.
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