<i>In Vitro</i>
            Characterization of Human Cytomegalovirus-Targeting Therapeutic Monoclonal Antibodies LJP538 and LJP539

Patel, Hetalkumar D.; Nikitin, Pavel A.; Gesner, Thomas G.; Lin, Yi-Chan; Barkan, David T.; Ciferri, Claudio; Carfı́, Andrea; Yazdi, Tahmineh Akbarnejad; Skewes-Cox, Peter; Wiedmann, Brigitte; Jarousse, Nadine; Zhong, Weidong; Feire, Adam L.; Hebner, Christy M.

doi:10.1128/aac.00382-16

Cited by 27 publications

(25 citation statements)

References 31 publications

(38 reference statements)

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“…Consequently, the mode of action of PDGFR␣-Fc differed between these cell types, with adsorption being inhibited in both cell types while penetration was affected specifically in fibroblasts (31). Notably, PDGFR␣-Fc inhibits HCMV infection in different cell types with similar efficiencies, while monoclonal antibodies usually inhibit infection of fibroblasts 5-to 10-fold less efficiently than infection of endothelial or epithelial cells (34)(35)(36). In line with that, the vast majority of human sera have a much higher neutralizing capacity for endothelial and epithelial cells than for fibroblasts (35,(37)(38)(39).…”

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confidence: 99%

The N Terminus of Human Cytomegalovirus Glycoprotein O Is Important for Binding to the Cellular Receptor PDGFRα

Stegmann¹,

Rothemund²,

Sampaio³

et al. 2019

J Virol

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The human cytomegalovirus (HCMV) glycoprotein complex gH/gL/gO is required for the infection of cells by cell-free virions. It was recently shown that entry into fibroblasts depends on the interaction of gO with the platelet-derived growth factor receptor alpha (PDGFR␣). This interaction can be blocked with soluble PDGFR␣-Fc, which binds to HCMV virions and inhibits entry. The aim of this study was to identify parts of gO that contribute to PDGFR␣ binding. In a systematic mutational approach, we targeted potential interaction sites by exchanging conserved clusters of charged amino acids of gO with alanines. To screen for impaired interaction with PDGFR␣, virus mutants were tested for sensitivity to inhibition by soluble PDGFR␣-Fc. Two mutants with mutations within the N terminus of gO (amino acids 56 to 61 and 117 to 121) were partially resistant to neutralization. To validate whether these mutations impair interaction with PDGFR␣-Fc, we compared binding of PDGFR␣-Fc to mutant and wild-type virions via quantitative immunofluorescence analysis. PDGFR␣-Fc staining intensities were reduced by 30% to 60% with mutant virus particles compared to wild-type particles. In concordance with the reduced binding to the soluble receptor, virus penetration into fibroblasts, which relies on binding to the cellular PDGFR␣, was also reduced. In contrast, PDGFR␣-independent penetration into endothelial cells was unaltered, demonstrating that the phenotypes of the gO mutant viruses were specific for the interaction with PDGFR␣. In conclusion, the mutational screening of gO revealed that the N terminus of gO contributes to efficient spread in fibroblasts by promoting the interaction of virions with its cellular receptor. IMPORTANCE The human cytomegalovirus is a highly prevalent pathogen that can cause severe disease in immunocompromised hosts. Currently used drugs successfully target the viral replication within the host cell, but their use is restricted due to side effects and the development of resistance. An alternative approach is the inhibition of virus entry, for which understanding the details of the initial virus-cell interaction is desirable. As binding of the viral gH/gL/gO complex to the cellular PDGFR␣ drives infection of fibroblasts, this is a potential target for inhibition of infection. Our mutational mapping approach suggests the N terminus as the receptor binding portion of the protein. The respective mutants were partially resistant to inhibition by PDGFR␣-Fc but also attenuated for infection of fibroblasts, indicating that such mutations have little if any benefit for the virus. These findings highlight the potential of targeting the interaction of gH/gL/gO with PDGFR␣ for therapeutic inhibition of HCMV.

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confidence: 99%

The N Terminus of Human Cytomegalovirus Glycoprotein O Is Important for Binding to the Cellular Receptor PDGFRα

Stegmann¹,

Rothemund²,

Sampaio³

et al. 2019

J Virol

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“…48 LJP538, also known as 7H3, and LJP539, as 4I22, were isolated from EBV immortalized B cells from HCMV-immune human donors as described. 52 , 53 Results from clinical trials show CSJ148 and its component mAbs were safe and well tolerated, with pharmacokinetics as expected for human immunoglobulin. 48 Phase 2 clinical trials of CSJ148 in stem cell transplant patients are ongoing.…”

Section: Introductionmentioning

confidence: 98%

Antibody therapies for the prevention and treatment of viral infections

et al. 2017

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Antibodies are an important component in host immune responses to viral pathogens. Because of their unique maturation process, antibodies can evolve to be highly specific to viral antigens. Physicians and researchers have been relying on such high specificity in their quest to understand host–viral interaction and viral pathogenesis mechanisms and to find potential cures for viral infection and disease. With more than 60 recombinant monoclonal antibodies developed for human use in the last 20 years, monoclonal antibodies are now considered a viable therapeutic modality for infectious disease targets, including newly emerging viral pathogens such as Ebola representing heightened public health concerns, as well as pathogens that have long been known, such as human cytomegalovirus. Here, we summarize some recent advances in identification and characterization of monoclonal antibodies suitable as drug candidates for clinical evaluation, and review some promising candidates in the development pipeline.

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“…CSJ148 consists of two anti-HCMV human monoclonal antibodies (LJP538 and LJP539) (9) and offers the potential to be a safe and well-tolerated alternative to currently available therapies for the prevention and treatment of HCMV. Each antibody binds to and inhibits the function of essential viral glycoproteins; LJP538 binds to glycoprotein B (gB), and LJP539 binds to the pentameric complex (consisting of glycoproteins gH, gL, UL128, UL130, and UL131).…”

mentioning

confidence: 99%

“…Each antibody binds to and inhibits the function of essential viral glycoproteins; LJP538 binds to glycoprotein B (gB), and LJP539 binds to the pentameric complex (consisting of glycoproteins gH, gL, UL128, UL130, and UL131). CSJ148 neutralizes HCMV infection of all the cell types tested by blocking both initial infection and the subsequent cell-to-cell spread of virus (9).…”

mentioning

confidence: 99%

Phase 2 Study of Anti-Human Cytomegalovirus Monoclonal Antibodies for Prophylaxis in Hematopoietic Cell Transplantation

Maertens

Logan

Jang

et al. 2020

Antimicrob Agents Chemother

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Human 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 functions of viral HCMV glycoprotein B (gB) and the pentameric complex, consisting of glycoproteins gH, gL, UL128, UL130, and UL131. In this phase 2, randomized, placebo-controlled trial, we evaluated the safety and efficacy of CSJ148 for prophylaxis of HCMV in patients undergoing allogeneic hematopoietic stem cell transplantation. As would be expected in the study population, all the patients (100%) reported at least one treatment-emergent adverse event. There were 22 deaths during this study, and over 80% of the patients receiving placebo or CSJ148 developed at least one adverse event of grade 3 or higher severity. No subject who received antibody developed a hypersensitivity- or infusion-related reaction. CSJ148-treated patients showed trends toward decreased viral load, shorter median duration of preemptive therapy, and fewer courses of preemptive therapy. However, the estimated probability that CSJ148 decreases the need for preemptive therapy compared to placebo was 69%, with a risk ratio of 0.89 and a 90% credible interval of 0.61 to 1.31. The primary efficacy endpoint was therefore not met, indicating that CSJ148 did not prevent clinically significant HCMV reactivation in recipients of allogeneic hematopoietic cell transplants. (This study has been registered at ClinicalTrials.gov under identifier NCT02268526 and at EudraCT under number 2017-002047-15.)

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

Cited by 27 publications

References 31 publications

The N Terminus of Human Cytomegalovirus Glycoprotein O Is Important for Binding to the Cellular Receptor PDGFRα

The N Terminus of Human Cytomegalovirus Glycoprotein O Is Important for Binding to the Cellular Receptor PDGFRα

Antibody therapies for the prevention and treatment of viral infections

Phase 2 Study of Anti-Human Cytomegalovirus Monoclonal Antibodies for Prophylaxis in Hematopoietic Cell Transplantation

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