Human cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission is a major cause of permanent birth defects. Although no active vaccines to prevent HCMV infection are approved, passive immunization with HCMV-specific immunoglobulin has shown promise in 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 a desirable trait, both to compete with low affinity antibodies that promote transmission of virus across the placenta and to displace non-neutralizing antibodies binding nearby e... More
Human cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission is a major cause of permanent birth defects. Although no active vaccines to prevent HCMV infection are approved, passive immunization with HCMV-specific immunoglobulin has shown promise in 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 a desirable trait, both to compete with low affinity antibodies that promote transmission of virus across the placenta and to displace non-neutralizing 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 and epithelial cells, and inhibited post-infection HCMV spread in epithelial cells. The potential utility for preventing congenital transmission is supported by 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 ex vivo infection of human placental anchoring villi. TRL345 has been expressed at commercial scale and is a candidate for clinical evaluation.Copyright 2014, American Society for Microbiology. All Rights Reserved.
