title: Potent neutralization of Hendra and Nipah viruses by human monoclonal antibodies.
abstract: Hendra virus (HeV) and Nipah virus (NiV) are closely related emerging viruses comprising the Henipavirus genus of the Paramyxovirinae. Each has a broad species tropism and can cause disease with high mortality in both animal and human hosts. These viruses infect cells by a pH-independent membrane fusion event mediated by their attachment (G) and fusion (F) envelope glycoproteins (Envs). Seven Fabs, m101 to -7, were selected for their significant binding to a soluble form of Hendra G (sG) which was used as the antigen for panning of a large naïve human antibody library. The selected Fabs inhibited, to various degrees, cell fusion mediated by the HeV or NiV Envs and virus infection. The conversion of the most potent neutralizer of infectious HeV, Fab m101, to immunoglobulin G1 (IgG1) significantly increased its cell fusion inhibitory activity: the 50% inhibitory concentration was decreased more than 10-fold to approximately 1 microg/ml. The IgG1 m101 was also exceptionally potent in neutralizing infectious HeV; complete (100%) neutralization was achieved with 12.5 microg/ml, and 98% neutralization required only 1.6 microg/ml. The inhibition of fusion and infection correlated with binding of the Fabs to full-length G as measured by immunoprecipitation and less with binding to sG as measured by enzyme-linked immunosorbent assay and Biacore. m101 and m102 competed with the ephrin-B2, which we recently identified as a functional receptor for both HeV and NiV, indicating a possible mechanism of neutralization by these antibodies. The m101, m102, and m103 antibodies competed with each other, suggesting that they bind to overlapping epitopes which are distinct from the epitopes of m106 and m107. In an initial attempt to localize the epitopes of m101 and m102, we measured their binding to a panel of 11 G alanine-scanning mutants and identified two mutants, P185A and Q191 K192A, which significantly decreased binding to m101 and one, G183, which decreased binding of m102 to G. These results suggest that m101 to -7 are specific for HeV or NiV or both and exhibit various neutralizing activities; they are the first human monoclonal antibodies identified against these viruses and could be used for treatment, prophylaxis, and diagnosis and as research reagents and could aid in the development of vaccines.
authors.affiliation: CCRNP, CCR, NCI-Frederick, NIH, Frederick, MD 21702, USA.
authors.forename: Zhongyu
authors.initials: Z
authors.lastname: Zhu
authors.forename: Antony S
authors.initials: AS
authors.lastname: Dimitrov
authors.forename: Katharine N
authors.initials: KN
authors.lastname: Bossart
authors.forename: Gary
authors.initials: G
authors.lastname: Crameri
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bishop
authors.forename: Vidita
authors.initials: V
authors.lastname: Choudhry
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Mungall
authors.forename: Yan-Ru
authors.initials: YR
authors.lastname: Feng
authors.forename: Anil
authors.initials: A
authors.lastname: Choudhary
authors.forename: Mei-Yun
authors.initials: MY
authors.lastname: Zhang
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.forename: Lin-Fa
authors.initials: LF
authors.lastname: Wang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Xiao
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Eaton
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Broder
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
mesh_terms: D000911:Antibodies, Monoclonal / Q000096:biosynthesis / Q000276:immunology*; D000914:Antibodies, Viral / Q000096:biosynthesis / Q000276:immunology*; D000918:Antibody Specificity; D003429:Cross Reactions; D004306:Dose-Response Relationship, Immunologic; D000939:Epitopes / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology; D045404:Hendra Virus / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D009500:Neutralization Tests; D045405:Nipah Virus / Q000276:immunology*; D019151:Peptide Library; D012995:Solubility; D014759:Viral Envelope Proteins / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000914:Antibodies, Viral; D000939:Epitopes; D006023:Glycoproteins; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D019151:Peptide Library; D014759:Viral Envelope Proteins