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.

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Houser, Katherine V; Gretebeck, Lisa; Ying, Tianlei et al. (2016) Prophylaxis With a Middle East Respiratory Syndrome Coronavirus (MERS-CoV)-Specific Human Monoclonal Antibody Protects Rabbits From MERS-CoV Infection. J Infect Dis 213:1557-61
Ying, Tianlei; Li, Wei; Dimitrov, Dimiter S (2016) Discovery of T-Cell Infection and Apoptosis by Middle East Respiratory Syndrome Coronavirus. J Infect Dis 213:877-9
Ying, Tianlei; Prabakaran, Ponraj; Du, Lanying et al. (2015) Junctional and allele-specific residues are critical for MERS-CoV neutralization by an exceptionally potent germline-like antibody. Nat Commun 6:8223
Dimitrov, Dimiter S; Jiang, Shibo; Ying, Tianlei et al. (2015) No evidence for a superior platform to develop therapeutic antibodies rapidly in response to MERS-CoV and other emerging viruses. Proc Natl Acad Sci U S A 112:E5115
Ying, Tianlei; Li, Haoyang; Lu, Lu et al. (2015) Development of human neutralizing monoclonal antibodies for prevention and therapy of MERS-CoV infections. Microbes Infect 17:142-8
Geisbert, Thomas W; Mire, Chad E; Geisbert, Joan B et al. (2014) Therapeutic treatment of Nipah virus infection in nonhuman primates with a neutralizing human monoclonal antibody. Sci Transl Med 6:242ra82
Ying, Tianlei; Du, Lanying; Ju, Tina W et al. (2014) Exceptionally potent neutralization of Middle East respiratory syndrome coronavirus by human monoclonal antibodies. J Virol 88:7796-805
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; Streaker, Emily D; Russ, Daniel E et al. (2012) Characterization of germline antibody libraries from human umbilical cord blood and selection of monoclonal antibodies to viral envelope glycoproteins: Implications for mechanisms of immune evasion and design of vaccine immunogens. Biochem Biophys Res Commun 417:1164-9
Zhao, Qi; Zhu, Zhongyu; Dimitrov, Dimiter S (2012) Yeast display of engineered antibody domains. Methods Mol Biol 899:73-84

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