The major accomplishments for this year are summarized below. 1) Previously, we reported the isolation of henipavirus-neutralizing recombinant hmAbs including one, m102.4, which exhibited exceptionally potent and cross-reactive inhibitory activity against both HeV and NiV, and was administered to humans exposed to HeV. HeV is a recently emerged zoonotic paramyxovirus that can cause a severe and often fatal disease in horses and humans. HeV is categorized as a biosafety level 4 agent, which has made the development of animal models and testing of potential therapeutics and vaccines challenging. Animal studies with this antibody continue and more are planned with GMP produced m102.4. Large quantities of the antibody were produced in both Australia and USA for human clinical trials. 2) Combinatory antibody library display technologies have been invented and successfully implemented for the selection and engineering of therapeutic antibodies. Precise targeting of important epitopes on the protein of interest is essential for such isolated antibodies to serve as effective modulators of molecular interactions. We developed a strategy to efficiently isolate antibodies against a specific epitope on a target protein from a yeast display antibody library using dengue virus envelope protein domain III as a target. Two unique clones were identified and showed cross-reactive binding to envelope protein domain IIIs from different serotypes. Epitope mapping of one of the antibodies confirmed that its epitope overlapped with the neutralizing epitope. This novel approach has implications for many areas of research where the isolation of epitope-specific antibodies is desired, such as selecting antibodies against conserved epitope(s) of viral envelope proteins from a library containing high titer, high affinity non-neutralizing antibodies, and targeting unique epitopes on cancer-related proteins. 3) Identification of human neutralizing antibodies against influenza H7N9 was initiated and the first antibodies were tested, and their characterization and improvement continues.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011156-05
Application #
8763371
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$252,767
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Zhu, Zhongyu; Prabakaran, Ponraj; Chen, Weizao et al. (2013) Human monoclonal antibodies as candidate therapeutics against emerging viruses and HIV-1. Virol Sin 28:71-80
Chen, Weizao; Zhu, Zhongyu; Xiao, Xiaodong et al. (2009) Construction of a human antibody domain (VH) library. Methods Mol Biol 525:81-99, xiii
Bishop, Kimberly A; Hickey, Andrew C; Khetawat, Dimple et al. (2008) Residues in the stalk domain of the hendra virus g glycoprotein modulate conformational changes associated with receptor binding. J Virol 82:11398-409