We have continued to identify and characterize neutralizing mAbs to the following biodefense-related microbes which are on the NIAID list of category A or C pathogens: Nipah and Hendra viruses (Henipaviruses) (causing acute infections with high, up to 70%, mortality, category C), Ebola and Marburg viruses (causing hemorrhagic fever with high, up to 90%, mortality, category A), Crimean-Congo virus (CCHFV) (causing hemorrhagic fever with relatively high, up to 50%, mortality, category C), and dengue virus (which causes dengue hemorrhagic fever with relatively low mortality, category A). 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. HeV is categorized as a biosafety level 4 agent, which has made development of animal models and testing of potential therapeutics and vaccines challenging. The results from two animal studies and three humans administered with this mAb confirm our proposition that m102.4 has potential as a therapeutic for treatment of diseases caused by henipaviruses, and could save human lives now. It could be also used for prophylaxis, diagnosis and as a research reagent. Animal studies with this antibody continue and more are planned with GMP produced m102.4. 2) We have previously identified several novel potent hmAbs against Yersinia pestis which are the first human antibodies against this category A agent. Yersinia pestis is the etiologic agent of plague that has killed more than 200 million people throughout the recorded history of mankind. Antibiotics may provide little immediate relief to patients who have a high bacteremia or to patients infected with an antibiotic resistant strain of plague. Two virulent factors of Y. pestis are the capsid F1 protein and the low-calcium response (Lcr) V-protein or V-antigen that have been proven to be the targets for both active and passive immunization. There are mouse monoclonal antibodies (mAbs) against the F1- and V-antigens that can passively protect mice in a murine model of plague;however, there are no anti-Yersinia pestis monoclonal antibodies available for prophylactic or therapeutic treatment in humans. We identified one anti-F1-specific human mAb (m252) and two anti-V-specific human mAb (m253, m254) by panning a nave phage-displayed Fab library against the F1- and V-antigens. The Fabs were converted to IgG1s and their binding and protective activities were evaluated. M252 bound weakly to peptides located at the F1 N-terminus where a protective mouse anti-F1 mAb also binds. M253 bound strongly to a V-antigen peptide indicating a linear epitope;m254 did not bind to any peptide from a panel of 53 peptides suggesting that its epitope may be conformational. M252 showed better protection than m253 and m254 against a Y, pestis challenge in a plague mouse model. A synergistic effect was observed when the three antibodies were combined. Incomplete to complete protection was achieved when m252 was given at different times post-challenge. These antibodies can be further studied to determine their potential as therapeutics or prophylactics in Y. pestis infection in humans. 3) We have also performed experiments to identify neutralizing hmAbs against dengue virus and Ebola virus. Several mAbs against dengue virus were identified and are being characterized. The mAbs against dengue could be used as candidate therapeutics and diagnostics and as tools for development of vaccine immunogens.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011156-03
Application #
8349357
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2011
Total Cost
$241,297
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
van Doremalen, Neeltje; Falzarano, Darryl; Ying, Tianlei et al. (2017) Efficacy of antibody-based therapies against Middle East respiratory syndrome coronavirus (MERS-CoV) in common marmosets. Antiviral Res 143:30-37
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
Agrawal, Anurodh Shankar; Ying, Tianlei; Tao, Xinrong et al. (2016) Passive Transfer of A Germline-like Neutralizing Human Monoclonal Antibody Protects Transgenic Mice Against Lethal Middle East Respiratory Syndrome Coronavirus Infection. Sci Rep 6:31629
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; 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
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

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