Human monoclonal antibodies against hendra and nipah viruses
Inventors
Dimitrov, Dimiter S. • Zhu, Zhongyu • Broder, Christopher C.
Assignees
Henry M Jackson Foundation for Advancedment of Military Medicine Inc • US Department of Health and Human Services • Office of Technology Transfer
Publication Number
US-8313746-B2
Publication Date
2012-11-20
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 relates to the identification and characterization of fully human monoclonal antibodies that bind or neutralize Hendra virus (HeV) and Nipah virus (NiV). These antibodies specifically target the viral envelope G glycoprotein and have been isolated from a large naïve human phage-display library using a soluble oligomeric form of Hendra G glycoprotein as the antigen. The antibodies include full-length immunoglobulins and fragments retaining virus-binding ability, along with pharmaceutical compositions, isolated nucleic acids encoding these antibodies, and transformed host cells.
The problem addressed is that HeV and NiV are emerging paramyxoviruses with broad species tropism causing fatal diseases in humans and animals, with no currently available therapeutics or vaccines for infected individuals or livestock. These viruses are highly infectious and pose significant threats as zoonotic pathogens and potential bioterrorism agents. While antibody responses to infection exist, no human monoclonal antibodies had previously been identified against these viruses, limiting options for prophylaxis, passive immunotherapy, diagnosis, and vaccine development.
The invention solves this problem by providing potent, fully human monoclonal antibodies from a naïve human Fab library that neutralize HeV and NiV by targeting the G glycoprotein. Among these, the antibody m101 shows exceptional potency against infectious HeV, and m102 cross-neutralizes both viruses. Conversion of Fab fragments to full IgG1 molecules significantly enhances neutralizing activity. These antibodies block virus entry by competing with the virus receptor ephrin-B2 binding site on G. They have been characterized for biochemical properties, epitopic specificity, and inhibitory mechanisms, enabling their use for treatment, prevention, diagnostics, and as a research tool.
Claims Coverage
The patent includes several inventive features focusing on antibodies binding Hendra or Nipah G glycoprotein, host cells producing such antibodies, pharmaceutical and diagnostic preparations, and nucleic acid constructs encoding the antibodies.
Antibody with defined variable light chain and heavy chain CDR3 sequences
An antibody that selectively binds a Hendra or Nipah G glycoprotein epitope, comprising a variable light chain with amino acid sequence SEQ ID NO:313 and a heavy chain complementarity determining region 3 (CDR3) with amino acid sequence SEQ ID NO:311.
Inclusion of antibody fragments retaining specificity
The antibody can be present as Fd or Fab fragments while retaining binding specificity to the viral G glycoprotein.
Host cells producing the defined monoclonal antibody
Isolated host cells capable of producing the antibody with the specified variable light chain and heavy chain CDR3 sequences.
Pharmaceutical and diagnostic preparations containing the antibody
Pharmaceutical and diagnostic compositions comprising a pharmaceutically acceptable carrier and the monoclonal antibody having the specified variable light chain and heavy chain CDR3 regions.
Diagnostic method using the antibody for detection of virus
A method of detecting the presence of Hendra or Nipah virus in a biological sample by contacting the sample with the diagnostic preparation comprising the antibody and assaying for binding indicative of viral presence.
Isolated polynucleotides encoding the antibody
Nucleic acid molecules encoding the antibody with the specified variable light chain and heavy chain CDR3 sequences, optionally including vectors with regulatory sequences operably joined for expression.
The claims collectively cover isolated monoclonal antibodies with defined variable regions binding Hendra or Nipah G glycoprotein epitopes, antibody fragments, host cells producing these antibodies, pharmaceutical and diagnostic compositions containing them, methods for viral detection leveraging these antibodies, and nucleic acid constructs encoding the antibodies.
Stated Advantages
Potent neutralization of infectious Hendra and Nipah viruses by fully human monoclonal antibodies, particularly m101 and m102, with enhanced activity upon conversion to IgG1 format.
Therapeutic and prophylactic utility for prevention and treatment of Hendra Virus Disease and Nipah Virus Disease in humans and animals.
High specificity to viral G glycoprotein epitopes overlapping the receptor binding site, thereby blocking virus entry mechanism.
Use for in vitro and in vivo diagnostic applications to detect presence of Hendra or Nipah virus.
Suitability as research reagents and as a basis for vaccine development.
Advantages of Fab fragments include reduced immune complex formation, better tissue penetration, and easier bacterial production compared to full-length antibodies.
Documented Applications
Prophylactic administration to high-risk subjects to prevent or lessen severity of Hendra or Nipah virus infection.
Therapeutic administration to subjects already infected with Hendra or Nipah viruses for treatment of active disease.
In vitro diagnostic assays such as radioimmunoassay, sandwich assays, immunohistochemical assays to detect viral antigens in biological fluids, tissues, or samples.
In vivo diagnostic imaging by administration of detectably labeled antibodies to identify sites of infection.
Research reagents for understanding virus neutralization mechanisms, epitope mapping, and antibody characterization.
Basis for development of vaccines and drugs by characterizing epitopes of neutralizing antibodies.
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