Recent progress in development of monoclonal antibodies against human cytomegalovirus

2022 ◽  
Vol 52 ◽  
pp. 166-173
Author(s):  
Xiaohua Ye ◽  
Zhiqiang Ku ◽  
Ningyan Zhang ◽  
Tong-Ming Fu ◽  
Zhiqiang An
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus ◽  
Recent Progress

scholarly journals Neutralizing Mechanisms of Two Human Monoclonal Antibodies Against Human Cytomegalovirus Glycoprotein 130/55

1992 ◽  
Vol 73 (10) ◽  
pp. 2705-2707 ◽  
Author(s):  
Y. Ohizumi ◽  
H. Suzuki ◽  
Y.-I. Matsumoto ◽  
Y. Masuho ◽  
Y. Numazaki
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus ◽  
Human Monoclonal Antibodies

scholarly journals Specificity and effector functions of non-neutralizing gB-specific monoclonal antibodies isolated from healthy individuals with human cytomegalovirus infection

2020 ◽  
Author(s):  
Matthew L. Goodwin ◽  
Helen S. Webster ◽  
Hsuan-Yuan Wang ◽  
Jennifer A. Jenks ◽  
Cody S. Nelson ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus ◽  
Effector Cell ◽  
Natural Infection ◽  
Congenital Infection ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Domain Specificity ◽  
Cell Functions ◽  
The Impact

AbstractHuman cytomegalovirus (HCMV) is the most common congenital infection, and the leading nongenetic cause of sensorineural hearing loss (SNHL) in newborns globally. A gB subunit vaccine administered with adjuvent MF59 (gB/MF59) is the most efficacious tested to-date, achieving 50% efficacy in preventing infection of HCMV-seronegative mothers. We recently discovered that gB/MF59 vaccination elicited primarily non-neutralizing antibody responses, that HCMV strains acquired by vaccinees more often included strains with gB genotypes that are distinct from the vaccine antigen, and that protection against HCMV acquisition correlated with ability of vaccine-elicited antibodies to bind to membrane associated gB. Thus, we hypothesized that gB-specific non-neutralizing antibody binding breadth and function are dependent on their epitope and genotype specificity as well as their ability to interact with membrane-associated gB. Twenty-four gB-specific monoclonal antibodies (mAbs) isolated from naturally HCMV-infected individuals were mapped for gB domain specificity by binding antibody multiplex assay (BAMA) and for genotype preference binding to membrane-associated gB presented on transfected cells. We defined their non-neutralizing functions including antibody dependent cellular phagocytosis (ADCP) and antibody dependent cellular cytotoxicity (ADCC). The isolated gB-specific non-neutralizing mAbs were primarily specific for Domain II and linear antigenic domain 2 site 2 (AD2). We observed variability in mAb gB genotype binding preference, with increased binding to gB genotypes 2 and 4. Functional studies identified two gB-specific mAbs that facilitate ADCP and have binding specificities of AD2 and Domain II. This investigation provides novel understanding on the impact of gB domain specificity and antigenic variability on gB-specific non-neutralizing antibody responses.ImportanceHCMV is the most common congenital infection worldwide, but development of a successful vaccine remains elusive. gB-specific non-neutralizing mAbs, represent a distinct anti-HCMV Ab subset implicated in the protection against primary infection during numerous phase-II gB/MF59 vaccine trials. By studying non-neutralizing gB-specific mAbs from naturally infected individuals, this study provides novel characterization of binding site specificity, genotypic preference, and effector cell functions mediated by mAbs elicited in natural infection. We found that a panel of twenty-four gB-specific non-neutralizing mAbs bind across multiple regions of the gB protein, traditionally through to be targeted by neutralizing mAbs only, and bind differently to gB depending if the protein is soluble versus embedded in a membrane. This investigation provides novel insight into the gB-specific binding characteristics and effector cell functions mediated by non-neutralizing gB-specific mAbs elicited through natural infection, providing new endpoints for future vaccine development.

Production of Monoclonal Antibodies Against Phosphoprotein 65 from Human Cytomegalovirus

Hybridoma ◽  
2007 ◽  
Vol 26 (3) ◽  
pp. 173-177 ◽  
Author(s):  
Li-Jun Xu ◽  
Hang-Ping Yao ◽  
Jun Fan ◽  
Dan Li ◽  
Nan-Ping Wu
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus

Development of Human Monoclonal Antibodies Against Human Cytomegalovirus

Hybridoma ◽  
1992 ◽  
Vol 11 (5) ◽  
pp. 569-579 ◽  
Author(s):  
YOSHIAKI KANOH ◽  
MIKIHIRO YUNOKI ◽  
TOMOKUNI TANIGUCHI ◽  
YUKIO SUZUKI ◽  
SHOJI IDENO ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus ◽  
Human Monoclonal Antibodies

scholarly journals Neutralizing Monoclonal Antibodies Reduce Human Cytomegalovirus Infection and Spread in Developing Placentas

Vaccines ◽  
2019 ◽  
Vol 7 (4) ◽  
pp. 135 ◽  
Author(s):  
Takako Tabata ◽  
Matthew Petitt ◽  
June Fang-Hoover ◽  
Daniel C. Freed ◽  
Fengsheng Li ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Human Cytomegalovirus ◽  
Virus Transmission ◽  
Passive Immunization ◽  
First Trimester ◽  
Clinical Strain ◽  
Stromal Fibroblasts ◽  
Virion Assembly ◽  
Effective Strategies ◽  
Hyperimmune Globulin

Congenital human cytomegalovirus (HCMV) infection is a leading cause of birth defects worldwide, yet the most effective strategies for preventing virus transmission during pregnancy are unknown. We measured the efficacy of human monoclonal antibodies (mAbs) to HCMV attachment/entry factors glycoprotein B (gB) and the pentameric complex, gH/gL-pUL128–131, in preventing infection and spread of a clinical strain in primary placental cells and explants of developing anchoring villi. A total of 109 explants from five first-trimester placentas were cultured, and infection was analyzed in over 400 cell columns containing ~120,000 cytotrophoblasts (CTBs). mAbs to gB and gH/gL, 3-25 and 3-16, respectively, neutralized infection in stromal fibroblasts and trophoblast progenitor cells. mAbs to pUL128-131 of the pentameric complex, 1-103 and 2-18, neutralized infection of amniotic epithelial cells better than mAbs 3-25 and 3-16 and hyperimmune globulin. Select mAbs neutralized infection of cell column CTBs, with mAb 2-18 most effective, followed by mAb 3-25. Treatment of anchoring villi with mAbs postinfection reduced spread in CTBs and impaired formation of virion assembly compartments, with mAb 2-18 achieving better suppression at lower concentrations. These results predict that antibodies generated by HCMV vaccines or used for passive immunization have the potential to reduce transplacental transmission and congenital disease.

Comparative study with monospecific and monoclonal antibodies gainst a 65 K human cytomegalovirus protein

1988 ◽  
Vol 101 (1-2) ◽  
pp. 79-86 ◽  
Author(s):  
K. Shimokawa ◽  
Xu Bin ◽  
T. Furukawa
Keyword(s):  
Monoclonal Antibodies ◽  
Comparative Study ◽  
Human Cytomegalovirus

scholarly journals Monoclonal Antibodies to Different Components of the Human Cytomegalovirus (HCMV) Pentamer gH/gL/pUL128L and Trimer gH/gL/gO as well as Antibodies Elicited during Primary HCMV Infection Prevent Epithelial Cell Syncytium Formation

2016 ◽  
Vol 90 (14) ◽  
pp. 6216-6223 ◽  
Author(s):  
Giuseppe Gerna ◽  
Elena Percivalle ◽  
Laurent Perez ◽  
Antonio Lanzavecchia ◽  
Daniele Lilleri
Keyword(s):  
Endothelial Cells ◽  
Monoclonal Antibodies ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Human Cytomegalovirus ◽  
Protein Complex ◽  
Syncytium Formation ◽  
Large Set ◽  
Viral Fusion Protein ◽  
Virus Dissemination

ABSTRACTHuman cytomegalovirus (HCMV) may cause disseminated/end-organ disease in congenitally infected newborns and immunosuppressed transplant recipients. Two glycoprotein complexes, gH/gL/gO and gH/gL/pUL128/pUL130/pUL131 (gH/gL/pUL128L; referred to as the pentamer), are required for HCMV entry into fibroblasts and endothelial/epithelial cells, respectively, in the presence of the viral fusion protein gB. In addition, gH/gL/gO was recently reported to also be required for infection of endothelial/epithelial cells. Virus entry into human fibroblasts involves fusion of the virus envelope with the plasma membrane, whereas entry into endothelial/epithelial cells involves macropinocytosis or endocytosis and low-pH-dependent fusion with endosomes. A large set of neutralizing monoclonal antibodies (MAbs), directed to gH, gB, and multiple components of the pentamer, was developed. In addition, novel anti-gO human monoclonal antibodies were recently isolated. It is known that epithelial cell infection with a wild HCMV strain at a high multiplicity of infection produces a large number of syncytia. Incubation of heavily HCMV VR1814-infected ARPE-19 epithelial cells with neutralizing MAbs to one, two, or three components of the pUL128L portion of the pentamer blocked syncytium formation at an antibody concentration of 10 μg/ml, whereas only a partial inhibitory effect was displayed for MAbs to gO, gH, or gB at the same concentration. A blocking effect was also exhibited by convalescent-phase sera from primary HCMV infections. These findings indicate that the pentamer is required for syncytium formation in epithelial cells.IMPORTANCEHuman cytomegalovirus (HCMV) mostly infects epithelial and endothelial cellsin vivo. Recently, the pentamer protein complex (gH/gL/pUL128L) was identified as being required for infection of these cells, in association with the other protein complex, gH/gL/gO. In primary infections, HCMV migrates to endothelial cells and then to leukocytes, which disseminate the infection throughout the body. The virus then spreads to organs and tissues, mostly infecting either single cells or multinucleated epithelial giant cells (syncytia), depending on the viral load. Potent neutralizing human MAbs directed to distinct binding sites of the pUL128L portion of the pentamer were shown in the past to block virus dissemination. In the present study, MAbs to pUL128L were shown to block syncytium formation with a higher potency than that of MAbs to gO, gH, or gB, thus suggesting their role in limiting virus dissemination. This finding provides additional information useful for the development of anti-HCMV therapeutic antibodies and subunit vaccines.

scholarly journals A First-in-Human Study To Assess the Safety and Pharmacokinetics of Monoclonal Antibodies against Human Cytomegalovirus in Healthy Volunteers

2016 ◽  
Vol 60 (5) ◽  
pp. 2881-2887 ◽  
Author(s):  
Kiran Dole ◽  
Florencia Pereyra Segal ◽  
Adam Feire ◽  
Baldur Magnusson ◽  
Juan C. Rondon ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Healthy Volunteers ◽  
Human Cytomegalovirus ◽  
Treatment Options ◽  
Human Study ◽  
Pharmacokinetic Parameters ◽  
Apparent Relationship ◽  
Pharmacokinetic Properties ◽  
Human Igg1 ◽  
The Individual

ABSTRACTHuman cytomegalovirus (HCMV) can cause significant disease in immunocompromised patients and treatment options are limited by toxicities. CSJ148 is a combination of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) that bind to and inhibit the function of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. Here, we evaluated the safety, tolerability, and pharmacokinetics of a single intravenous dose of LJP538 or LJP539 or their combination in healthy volunteers. Adverse events and laboratory abnormalities occurred sporadically with similar incidence between antibody and placebo groups and without any apparent relationship to dose. No subject who received antibody developed a hypersensitivity, infusion-related reaction or anti-drug antibodies. After intravenous administration, both LJP538 and LJP539 demonstrated typical human IgG1 pharmacokinetic properties, with slow clearances, limited volumes of distribution, and long terminal half-lives. The pharmacokinetic parameters were linear and dose proportional for both antibodies across the 50-fold range of doses evaluated in the study. There was no apparent impact on pharmacokinetics when the antibodies were administered alone or in combination. CSJ148 and the individual monoclonal antibodies were safe and well tolerated, with pharmacokinetics as expected for human immunoglobulin.

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