title: A high-affinity native human antibody neutralizes human cytomegalovirus infection of diverse cell types.
abstract: Human cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission are major causes of permanent birth defects. Although no active vaccines to prevent HCMV infection have been approved, passive immunization with HCMV-specific immunoglobulin has shown promise in the treatment of both transplant and congenital indications. Antibodies targeting the viral glycoprotein B (gB) surface protein are known to neutralize HCMV infectivity, with high-affinity binding being a desirable trait, both to compete with low-affinity antibodies that promote the transmission of virus across the placenta and to displace nonneutralizing antibodies binding nearby epitopes. Using a miniaturized screening technology to characterize secreted IgG from single human B lymphocytes, 30 antibodies directed against gB were previously cloned. The most potent clone, TRL345, is described here. Its measured affinity was 1 pM for the highly conserved site I of the AD-2 epitope of gB. Strain-independent neutralization was confirmed for 15 primary HCMV clinical isolates. TRL345 prevented HCMV infection of placental fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells, and it inhibited postinfection HCMV spread in epithelial cells. The potential utility for preventing congenital transmission is supported by the blockage of HCMV infection of placental cell types central to virus transmission to the fetus, including differentiating cytotrophoblasts, trophoblast progenitor cells, and placental fibroblasts. Further, TRL345 was effective at controlling an ex vivo infection of human placental anchoring villi. TRL345 has been utilized on a commercial scale and is a candidate for clinical evaluation.
authors.affiliation: Trellis Bioscience, Menlo Park, California, USA lkauvar@trellisbio.com.
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Kauvar
authors.affiliation: Trellis Bioscience, Menlo Park, California, USA.
authors.forename: Keyi
authors.initials: K
authors.lastname: Liu
authors.affiliation: Trellis Bioscience, Menlo Park, California, USA.
authors.forename: Minha
authors.initials: M
authors.lastname: Park
authors.affiliation: Trellis Bioscience, Menlo Park, California, USA.
authors.forename: Neal
authors.initials: N
authors.lastname: DeChene
authors.affiliation: Trellis Bioscience, Menlo Park, California, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Stephenson
authors.affiliation: Trellis Bioscience, Menlo Park, California, USA.
authors.forename: Edgar
authors.initials: E
authors.lastname: Tenorio
authors.affiliation: Trellis Bioscience, Menlo Park, California, USA.
authors.forename: Stote L
authors.initials: SL
authors.lastname: Ellsworth
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Takako
authors.initials: T
authors.lastname: Tabata
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Petitt
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Tsuge
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: June
authors.initials: J
authors.lastname: Fang-Hoover
authors.affiliation: Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Stuart P
authors.initials: SP
authors.lastname: Adler
authors.affiliation: Department of Pediatrics, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Cui
authors.affiliation: Department of Pediatrics, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: McVoy
authors.affiliation: Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Lenore
authors.initials: L
authors.lastname: Pereira
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology; D000915:Antibody Affinity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology / Q000821:virology; D002460:Cell Line; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000821:virology; D042783:Endothelial Cells / Q000276:immunology / Q000821:virology; D004847:Epithelial Cells / Q000276:immunology / Q000821:virology; D000939:Epitopes / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000821:virology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000821:virology; D010920:Placenta / Q000276:immunology / Q000821:virology; D011247:Pregnancy; D014759:Viral Envelope Proteins / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000939:Epitopes; D007074:Immunoglobulin G; D014759:Viral Envelope Proteins