Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial

Bian, Huijie; Zheng, Zhaohui; Ding, Wei; Zhang, Zheng; Wu, Kang Hsi; Hao, Chi; Dong, Ke; Wen, Kai; Xia, Jielai; Miao, Jinlin; Rong, Xie; Wang, Bin; Sun, Xiuxuan; Yang, Xingbin; Peng, Lin; Geng, Jie-Jie; Wang, Ke; Cui, Hong‐Yong; Zhang, Kui; Chen, Xiaochun; Tang, Hao; Du, Hongwu; Yao, Na; Liu, Shuangshuang; Liu, Linna; Zhang, Zhe; Gao, Zhaowei; Nan, Gang; Wang, Qingyi; Lian, Jiangshan; Chen, Zhinan; Zhu, Ping

doi:10.1101/2020.03.21.20040691

Cited by 140 publications

(152 citation statements)

References 20 publications

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“…We also used primary human airway epithelial cells and the bronchial epithelial cell line (HBEC-6KT). We performed immunoblots for ACE2 and TMPRSS2 as these have been highlighted as interacting with SARS-CoV-2, while we probed CD147 as recent pre-clinical and clinical studies have provided proof of concept as a candidate SARS-CoV-2 receptor[26, 27]. Lastly, GRP78 was dominantly expressed throughout transcriptomic studies and was selected as a positive control as previous expression has been confirmed in human airway epithelial cells[58].…”

Section: Discussionmentioning

confidence: 99%

“…Indirect evidence for a role of CD147 in SARS-CoV-2 binding has been demonstrated in vitro with the use of an anti-CD147 intervention that prevented virus replication[26]. Furthermore, a clinical study with an anti-CD147 intervention reduced symptoms and duration of hospital admission for COVID-19 patients[27]. In summary, although there is evidence that SARS-CoV-2 and SARS-CoV both utilize ACE2 as a receptor to facilitate virus entry, it is possible that differences in host-entry mechanisms play a role in the large epidemiological differences between the two viruses, which may include additional unidentified receptors.…”

Section: Introductionmentioning

confidence: 99%

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Gene expression andin situprotein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue

Aguiar

Tremblay

Mansfield

et al. 2020

Preprint

117

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words):In December 2019, SARS-CoV-2 emerged causing the COVID-19 pandemic. SARS-CoV, the agent responsible for the 2003 SARS outbreak, utilizes ACE2 and TMPRSS2 host molecules for viral entry. ACE2 and TMPRSS2 have recently been implicated in SARS-CoV-2 viral infection.Additional host molecules including ADAM17, cathepsin L, CD147, and GRP78 may also function as receptors for SARS-CoV-2.To determine the expression and in situ localization of candidate SARS-CoV-2 receptors in the respiratory mucosa, we analyzed gene expression datasets from airway epithelial cells of 515 healthy subjects, gene promoter activity analysis using the FANTOM5 dataset containing 120 distinct sample types, single cell RNA sequencing (scRNAseq) of 10 healthy subjects, immunoblots on multiple airway epithelial cell types, and immunohistochemistry on 98 human lung samples.We demonstrate absent to low ACE2 promoter activity in a variety of lung epithelial cell samples and low ACE2 gene expression in both microarray and scRNAseq datasets of epithelial cell populations. Consistent with gene expression, rare ACE2 protein expression was observed in the airway epithelium and alveoli of human lung. We present confirmatory evidence for the presence of TMPRSS2, CD147, and GRP78 protein in vitro in airway epithelial cells and confirm broad in situ protein expression of CD147 in the respiratory mucosa.Collectively, our data suggest the presence of a mechanism dynamically regulating ACE2 expression in human lung, perhaps in periods of SARS-CoV-2 infection, and also suggest that alternate receptors for SARS-CoV-2 exist to facilitate initial host cell infection.In 2003, the severe acute respiratory syndrome (SARS) outbreak caused by the SARS coronavirus (CoV) resulted in 8096 probable cases with 774 confirmed deaths [1, 2] In patients with SARS, deaths were attributed to acute respiratory distress associated with diffuse bilateral pneumonia and alveolar damage [3]. In December 2019, SARS-CoV-2 emerged causing the COVID-19 pandemic. SARS-CoV-2 is spreading at a much more rapid rate than SARS-CoV [4][5][6]. Similar clinical reports of diffuse bilateral pneumonia and alveolar damage have been reported [7][8][9]. Severe cases of SARS-CoV-2 have been associated with infections of the lower respiratory tract with detection of the virus throughout this tissue as well as the upper respiratory tract [7][8][9]. The biological mechanisms that may govern differences in the number of SARS and COVID-19 cases remain undefined. It is possible that SARS-CoV-2 possesses distinct molecular mechanisms that impact the virulence through viral proteins, greater susceptibility of host cells to infection, permissivity of host cells to virus replication, or some combination of these and other potentially unknown factors [10][11][12][13]. Understanding SARS and SARS-CoV-2 virus similarities and differences at the molecular level in the host may provide insights into transmission, pathogenesis, and interventions.The seminal report identifying the receptor for SARS-CoV used a HEK29...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gene expression andin situprotein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue

Aguiar

Tremblay

Mansfield

et al. 2020

Preprint

117

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“…Since the beginning of January 2020, an extraordinary number of investigational programs and clinical trials has been initiated in a concerted effort to identify therapeutics against the rapidly growing COVID-19 pandemic. Clinical trials using repurposed clinical-stage or approved drugs such as remdesivir, favipiravir, lopinavir/ritonavir, hydroxychloroquine and others have been under investigation for treating COVID-19 patients 15,16,20,[54][55][56][57][58][59] . Some other therapies, such as treatment with antibodies from seroconverted idividuals, are also being investigated.…”

Section: Discussionmentioning

confidence: 99%

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

Riva

Yuan

Yin

et al. 2020

Preprint

108

111

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The emergence of novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 . To date, more than 2.1 million confirmed cases and 139,500 deaths have been reported worldwide, and there are currently no medical countermeasures available to prevent or treat the disease. As the development of a vaccine could require at least 12-18 months, and the typical timeline from hit finding to drug registration of an antiviral is >10 years, repositioning of known drugs can significantly accelerate the development and deployment of therapies for COVID-19. To identify therapeutics that can be repurposed as SARS-CoV-2 antivirals, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDAapproved small molecules. Here, we report the identification of 30 known drugs that inhibit viral replication. Of these, six were characterized for cellular dose-activity relationships, and showed effective concentrations likely to be commensurate with therapeutic doses in patients. These include the PIKfyve kinase inhibitor Apilimod, cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334, and the CCR1 antagonist MLN-3897. Since many of these molecules have advanced into the clinic, the known pharmacological and human safety profiles of these compounds will accelerate their preclinical and clinical evaluation for COVID-19 treatment.

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“…3 Infection of the human cells with viral particles occurs through the binding of S viral 4 proteins to the receptors of the host cell and their subsequent priming with proteases. 5 ACE2 is considered the classic receptor for SARS-CoV-2, but there is evidence that it 6 can also use the BSG receptor (CD147) [33]. The priming of viral proteins is carried out 7 by the TMPRSS2 protease.…”

Section: Introductionmentioning

confidence: 99%

“…The exact role of BSG in COVID-19 is still 102 unknown, but recently it was found that CD147 may bind spike protein of 103 SARS-CoV-2 [33]. The preliminary data on a small sample of COVID-19 patients 104 demonstrated that Meplazumab, a humanized anti-CD147 antibody, efficiently improved 105 the recovery of patients with SARS-CoV-2 pneumonia with a favorable safety profile [6]. 106 Expression of ACE2, BSG and TMPRSS2 in single cells 107 Data on expression profiles of SARS-CoV-2-interacting genes in various tissues 108 demonstrates that ACE2 has a high level of expression only in testicles ( Fig.…”

mentioning

confidence: 99%

Structural variability, expression profile and pharmacogenetics properties of TMPRSS2 gene as a potential target for COVID-19 therapy

Zarubin

Степанов

Марков

et al. 2020

Preprint

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The human serine protease TMPRSS2 gene is involved in the priming of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins being one of the possible targets for COVID-19 therapy. TMPRSS2 gene is possibly co-expressed with SARS-CoV-2 cell receptor genes ACE2 and BSG, but only TMPRSS2 demonstrates tissue-specific expression in alveolar cells according to single cell RNA sequencing data. Our analysis of the structural variability of the TMPRSS2 gene based on genome-wide data of 76 human populations demonstrates that functionally significant missense mutation in exon 6/7 in TMPRSS2 gene, was found in many human populations in relatively high frequency, featuring region-specific distribution patterns. The frequency of the missense mutation encoded by the rs12329760, which previously was found to be associated with prostate cancer, is ranged between 10% and 63% being significantly higher in populations of Asian origin compared to European populations. In addition to SNPs, two copy numbers variants (CNV) were detected in the TMPRSS2 gene. Number of microRNAs have been predicted to regulate TMPRSS2 and BSG expression levels, but none of them is enriched in lung or respiratory tract cells. Several well studied drugs can downregulate the expression of TMPRSS2 in human cells, including Acetaminophen (Paracetamol) and Curcumin. Thus TMPRSS2 interaction with the SARS-CoV-2, its structural variability, gene-gene interactions, and expression regulation profiles, and pharmacogenomics properties characterize this gene as a potential target for COVID-19 therapy.

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Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial

Cited by 140 publications

References 20 publications

Gene expression andin situprotein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue

Gene expression andin situprotein profiling of candidate SARS-CoV-2 receptors in human airway epithelial cells and lung tissue

A Large-scale Drug Repositioning Survey for SARS-CoV-2 Antivirals

Structural variability, expression profile and pharmacogenetics properties of TMPRSS2 gene as a potential target for COVID-19 therapy

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