Neutralizing antibodies are unable to inhibit direct viral cell-to-cell spread of human cytomegalovirus

Jacob, Christian L.; Lamorte, Louie; Sepulveda, Eliud; Lorenz, Ivo C.; Gauthier, Annick; Franti, Michael

doi:10.1016/j.virol.2013.06.002

Cited by 37 publications

(32 citation statements)

References 39 publications

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“…This finding further stresses the complexity of the fusion process based on stoichiometry, as well as geometry, of complex formation. In addition, a recent paper using a plaque reduction assay format concluded that LJP539 (previously designated 4I22) was unable to inhibit cell-to-cell spread at an antibody concentration of 10ϫ EC 50 (26). In our studies, we observed a 76-fold shift in the EC 50 of LJP539 between the neutralization and syncytium formation assays, demonstrating that significantly larger amounts of antibody are needed to inhibit cellcell spread.…”

Section: Discussionsupporting

confidence: 45%

In Vitro Characterization of Human Cytomegalovirus-Targeting Therapeutic Monoclonal Antibodies LJP538 and LJP539

Patel

Nikitin

Gesner

et al. 2016

Antimicrob Agents Chemother

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Human cytomegalovirus (HCMV) infection is usually benign in healthy individuals but can cause life-threatening disease in those with compromised immune systems. Approved drugs available to treat HCMV disease, including ganciclovir, cidofovir, and foscarnet, have significant toxicities that limit their use in certain patient populations. LJP538 and LJP539 are human monoclonal antibodies that are being evaluated as immunoglobulin therapeutics. The antibodies target glycoproteins gB and the gH/ gL/UL128/UL130/UL131a pentameric complex, respectively. Here we present an in vitro characterization of these antibodies. We show that LJP538 and LJP539 are more potent than a marketed immunoglobulin at inhibiting HCMV infection of various cell lines relevant to pathogenesis. We find that LJP538 and LJP539 are active against a panel of clinical isolates in vitro and demonstrate minor-to-moderate synergy in combination. Passage of HCMV in the presence of LJP538 or LJP539 alone resulted in resistance-associated mutations that mapped to the target genes. However, no loss of susceptibility to the combination of antibodies was observed for >400 days in culture. Finally, the binding regions of LJP538 and LJP539 are conserved among clinical isolates. Taken together, these data support the use of LJP538 and LJP539 in combination for clinical trials in HCMV patients.

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Section: Discussionsupporting

confidence: 45%

In Vitro Characterization of Human Cytomegalovirus-Targeting Therapeutic Monoclonal Antibodies LJP538 and LJP539

Patel

Nikitin

Gesner

et al. 2016

Antimicrob Agents Chemother

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“…In addition, although RG7667 inhibits CMV entry into epithelial cells, endothelial cells, macrophages, and fibroblasts (21) and would also likely inhibit entry into dendritic cells (37), the formal possibility exists that RG7667 does not neutralize entry into an unidentified cell type. RG7667 may also not inhibit CMV cell-to-cell spread, which may contribute to CMV viremia (38). Even though we observed robust neutralization in vitro using two antibodies, we might have demonstrated greater activity if RG7667 had included a greater number of monoclonal antibodies directed at different targets.…”

Section: Discussionmentioning

confidence: 74%

Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of RG7667, a Combination Monoclonal Antibody, for Prevention of Cytomegalovirus Infection in High-Risk Kidney Transplant Recipients

Ishida

Patel²,

Mehta

et al. 2017

Antimicrob Agents Chemother

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Cytomegalovirus (CMV) infection is a significant complication after kidney transplantation. We examined the ability of RG7667, a combination of two monoclonal antibodies, to prevent CMV infection in high-risk kidney transplant recipients in a randomized, double-blind, placebo-controlled trial. CMV-seronegative recipients of a kidney transplant from a CMV-seropositive donor (DϩRϪ) were randomized to receive RG7667 (n ϭ 60) or placebo (n ϭ 60) at the time of transplant and 1, 4, and 8 weeks posttransplant. Patients were monitored for CMV viremia every 1 to 2 weeks posttransplant for 24 weeks. Patients who had seroconverted (DϩRϩ) or withdrawn before dosing were excluded from the analysis (n ϭ 4). CMV viremia occurred in 27 of 59 (45.8%) patients receiving RG7667 and 35 of 57 (61.4%) patients receiving placebo (stratum-adjusted difference, 15.3%; P ϭ 0.100) within 12 weeks posttransplant and in 30 of 59 (50.8%) patients receiving RG7667 and 40 of 57 (70.2%) patients receiving placebo (stratum-adjusted difference, 19.3%; P ϭ 0.040) within 24 weeks posttransplant. Median time to CMV viremia was 139 days in patients receiving RG7667 compared to 46 days in patients receiving placebo (hazard ratio, 0.53; P ϭ 0.009). CMV disease was less common in the RG7667 than placebo group (3.4% versus 15.8%; P ϭ 0.030). Adverse events were generally balanced between treatment groups. In high-risk kidney transplant recipients, RG7667 was well tolerated, numerically reduced the incidence of CMV infection within 12 and 24 weeks posttransplant, delayed time to CMV viremia, and was associated with less CMV disease than the placebo. (This study has been registered at ClinicalTrials.gov under registration no. NCT01753167.)

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“…There are reports suggesting that cell-associated HCMV spread may be totally independent of virion glycoproteins or dependent on glycoproteins different from those promoting cell-free HCMV spread [40,41]. This was supported by findings that cell-associated spread in cell culture cannot be inhibited by neutralizing antibodies directed against virion proteins know to be involved in cell-free virus spread [47]. Similarly, by using recombinant PDGFR-α-Fc, we could not reduce spread of wt TB40 or TB40-UL131Astop viruses to a level below the level achieved by methylcellulose overlays known to block spread of supernatant virus.…”

Section: Discussionmentioning

confidence: 94%

Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry

et al. 2017

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Herpesvirus gH/gL envelope glycoprotein complexes are key players in virus entry as ligands for host cell receptors and by promoting fusion of viral envelopes with cellular membranes. Human cytomegalovirus (HCMV) has two alternative gH/gL complexes, gH/gL/gO and gH/gL/UL128,130,131A which both shape the HCMV tropism. By studying binding of HCMV particles to fibroblasts, we could for the first time show that virion gH/gL/gO binds to platelet-derived growth factor-α (PDGFR-α) on the surface of fibroblasts and that gH/gL/gO either directly or indirectly recruits gB to this complex. PDGFR-α functions as an entry receptor for HCMV expressing gH/gL/gO, but not for HCMV mutants lacking the gH/gL/gO complex. PDGFR-α-dependent entry is not dependent on activation of PDGFR-α. We could also show that the gH/gL/gO—PDGFR-α interaction starts the predominant entry pathway for infection of fibroblasts with free virus. Cell-associated virus spread is either driven by gH/gL/gO interacting with PDGFR-α or by the gH/gL/UL128,130,131A complex. PDGFR-α-positive cells may thus be preferred first target cells for infections with free virus which might have implications for the design of future HCMV vaccines or anti-HCMV drugs.

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Neutralizing antibodies are unable to inhibit direct viral cell-to-cell spread of human cytomegalovirus

Cited by 37 publications

References 39 publications

In Vitro Characterization of Human Cytomegalovirus-Targeting Therapeutic Monoclonal Antibodies LJP538 and LJP539

In Vitro Characterization of Human Cytomegalovirus-Targeting Therapeutic Monoclonal Antibodies LJP538 and LJP539

Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial of RG7667, a Combination Monoclonal Antibody, for Prevention of Cytomegalovirus Infection in High-Risk Kidney Transplant Recipients

Human cytomegalovirus glycoprotein complex gH/gL/gO uses PDGFR-α as a key for entry

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