Human monoclonal antibodies against Hendra and Nipah viruses
Inventors
Dimitrov, Dimiter S. • Zhongyu, Zhu • Broder, Christopher C.
Assignees
Henry M Jackson Foundation for Advancedment of Military Medicine Inc • US Department of Health and Human Services
Publication Number
US-7988971-B2
Publication Date
2011-08-02
Expiration Date
2025-11-04
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Abstract
The present invention relates to monoclonal antibodies that bind or neutralize Hendra or Nipah virus. The invention provides such antibodies, fragments of such antibodies retaining Hendra or Nipah virus-binding ability, fully human antibodies retaining Hendra or Nipah virus-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 Hendra or Nipah viruses, including fragments of such antibodies retaining virus-binding ability, fully human antibodies, and pharmaceutical compositions containing these antibodies. It also offers isolated nucleic acids encoding the antibodies and host cells transformed with those nucleic acids, as well as prophylactic, therapeutic, and diagnostic methods employing the antibodies and nucleic acids.
Hendra and Nipah viruses are emerging, closely related paramyxoviruses capable of causing fatal disease in animals and humans, characterized by broad species tropisms and high infectivity. No therapeutics or vaccines currently exist for these viruses. Human monoclonal antibodies against these viruses have not been identified prior to this invention. Neutralizing antibodies are known to play a critical role in recovery and protection from viral infections, thus developing such antibodies against Hendra and Nipah viruses could provide important means for prophylaxis, passive immunotherapy, diagnosis, and serve as bases for vaccines and drugs.
Claims Coverage
The claims present one independent claim directed to an isolated antibody selectively binding a Hendra or Nipah G glycoprotein epitope, with multiple dependent claims detailing characteristics and variants of this antibody.
Antibody with specific heavy and light chain CDR regions
The antibody includes a heavy chain CDR1 region of SEQ ID NO: 307, CDR2 region of SEQ ID NO: 309, and CDR3 region of SEQ ID NO: 311, and a light chain CDR1 region of SEQ ID NO: 315, CDR2 region of SEQ ID NO: 317, and CDR3 region of SEQ ID NO: 319.
Inclusion of antibody fragments
The antibody can comprise Fd or Fab fragments, retaining selective binding to the Hendra or Nipah G glycoprotein epitope.
Presence of heavy and light chain regions
The antibody includes heavy chain Fd region of SEQ ID NO: 305 and light chain region of SEQ ID NO: 313, or VH and VL regions respectively.
Specific framework regions in heavy and light chains
The antibody includes one or more of the FR1, FR2, FR3, and FR4 regions in the heavy chain comprising SEQ ID NOs: 306, 308, 310, and 312 respectively, and similarly defined FR regions in the light chain comprising SEQ ID NOs: 314, 316, 318, and 320 respectively.
Humanized antibody with defined VH, VL, CDR and FR regions
An isolated humanized antibody selectively binding the epitope includes heavy chain VH region SEQ ID NO: 305; heavy chain FR1-4 regions SEQ ID NOs: 306, 308, 310, 312; heavy chain CDR1-3 regions SEQ ID NOs: 307, 309, 311; light chain VL region SEQ ID NO: 313; light chain FR1-4 regions SEQ ID NOs: 314, 316, 318, 320; and light chain CDR1-3 regions SEQ ID NOs: 315, 317, 319.
Pharmaceutical and diagnostic compositions
Pharmaceutical and diagnostic preparations comprising a pharmaceutically acceptable carrier and an isolated antibody as defined by any of the previous claims.
The claims cover isolated monoclonal antibodies and fragments thereof selectively binding a defined Hendra or Nipah G glycoprotein epitope characterized by specific CDR and framework sequences, including humanized versions and pharmaceutical or diagnostic compositions comprising these antibodies.
Stated Advantages
Potent neutralization of infectious Hendra virus with exceptional efficacy by the IgG1 form of antibody m101, achieving 98-100% neutralization at low microgram per milliliter concentrations.
Human monoclonal antibodies identified are fully human, reducing immunogenicity and suitable for therapeutic and prophylactic use in humans.
Fab fragments show measurable inhibitory activity and offer advantages including reduced immune complex formation, lack of Fc-mediated inflammatory responses, better tissue penetration, and easier bacterial production.
The antibodies can block virus entry by competing with the viral receptor ephrin-B2, providing a defined mechanism of neutralization.
Antibodies demonstrate cross-reactivity and neutralization of both Hendra and Nipah viruses, allowing broad utility against related Henipaviruses.
Antibodies and nucleic acid sequences provide tools for diagnosis, prophylaxis, therapy, and vaccine development against Hendra and Nipah virus infections.
Documented Applications
Use of the monoclonal antibodies for prophylactic and therapeutic treatment of Hendra Virus Disease and Nipah Virus Disease in humans and animals.
Use of antibodies in pharmaceutical compositions for immunoprophylaxis and immunotherapy against the viruses.
Diagnostic detection of Hendra or Nipah virus in vitro via immunoassays and in vivo using labeled monoclonal antibodies for imaging and monitoring infection.
Research reagents for studying virus infection mechanisms and epitope mapping.
Basis for developing candidate vaccines and drug discovery targeting the viral envelope glycoprotein G.
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