Neutralizing antibodies for the treatment of COVID-19

Jiang, Shibo; Zhang, Xiujuan; Yang, Yang; Hotez, Peter J.; Du, Lanying

doi:10.1038/s41551-020-00660-2

Cited by 100 publications

(114 citation statements)

References 45 publications

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“…The novel SARS-CoV-2 pandemic has led to a worldwide health and socioeconomic crisis. At present, despite numerous investments and scientific reports, hyperimmune plasma (a hundred-year-old practice) is the only SARS-CoV-2-specific therapy that is routinely used in clinical practice, although a few neutralising mAbs specific to SARS-CoV-2 antigens are now in clinical trials [1,2]. For severely affected patients not responding to chloroquine, antiviral, anti-inflammatory and anticoagulation combination therapies, hyperimmune plasma represents the last option despite some drawbacks [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

Zamai

2021

Cells

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The article describes the rationale for the administration of zinc-chelating agents in COVID-19 patients. In a previous work I have highlighted that the binding of the SARS-CoV spike proteins to the zinc-metalloprotease ACE2 has been shown to induce ACE2 shedding by activating the zinc-metalloprotease ADAM17, which ultimately leads to systemic upregulation of ACE2 activity. Moreover, based on experimental models, it was also shown the detrimental effect of the excessive systemic activity of ACE2 through its downstream pathways, which leads to “clinical” manifestations resembling COVID-19. In this regard, strong upregulation of circulating ACE2 activity was recently reported in COVID-19 patients, thus supporting the previous hypothesis that COVID-19 may derive from upregulation of ACE2 activity. Based on this, a reasonable hypothesis of using inhibitors that curb the upregulation of both ACE2 and ADAM17 zinc-metalloprotease activities and consequent positive feedback-loops (initially triggered by SARS-CoV-2 and subsequently sustained independently on viral trigger) is proposed as therapy for COVID-19. In particular, zinc-chelating agents such as citrate and ethylenediaminetetraacetic acid (EDTA) alone or in combination are expected to act in protecting from COVID-19 at different levels thanks to their both anticoagulant properties and inhibitory activity on zinc-metalloproteases. Several arguments are presented in support of this hypothesis and based on the current knowledge of both beneficial/harmful effects and cost/effectiveness, the use of chelating agents in the prevention and therapy of COVID-19 is proposed. In this regard, clinical trials (currently absent) employing citrate/EDTA in COVID-19 are urgently needed in order to shed more light on the efficacy of zinc chelators against SARS-CoV-2 infection in vivo.

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Section: Introductionmentioning

confidence: 99%

Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

Zamai

2021

Cells

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“…S proteins for both viruses have served as vaccine antigens that could elicit antibodies to prevent virus entry by blocking the binding of RBD to ACE2 (Hoffmann et al 2020), and all the leading COVID-19 vaccines currently in clinical trials, including the mRNA vaccines, use the S protein to elicit immunity (Haynes et al 2020). Overwhelmingly, such vaccines protect through their induction of virus-neutralizing antibodies, together with T cell responses (Jiang et al 2020).…”

Section: Introductionmentioning

confidence: 99%

Process development and scale-up optimization of the SARS-CoV-2 receptor binding domain–based vaccine candidate, RBD219-N1C1

Lee

Liu

Chen

et al. 2021

Appl Microbiol Biotechnol

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A SARS-CoV-2 RBD219-N1C1 (RBD219-N1C1) recombinant protein antigen formulated on Alhydrogel® has recently been shown to elicit a robust neutralizing antibody response against SARS-CoV-2 pseudovirus in mice. The antigen has been produced under current good manufacturing practices (cGMPs) and is now in clinical testing. Here, we report on process development and scale-up optimization for upstream fermentation and downstream purification of the antigen. This includes production at the 1-L and 5-L scales in the yeast, Pichia pastoris, and the comparison of three different chromatographic purification methods. This culminated in the selection of a process to produce RBD219-N1C1 with a yield of >400 mg per liter of fermentation with >92% purity and >39% target product recovery after purification. In addition, we show the results from analytical studies, including SEC-HPLC, DLS, and an ACE2 receptor binding assay that were performed to characterize the purified proteins to select the best purification process. Finally, we propose an optimized upstream fermentation and downstream purification process that generates quality RBD219-N1C1 protein antigen and is fully scalable at a low cost. Key points • Yeast fermentation conditions for a recombinant COVID-19 vaccine were determined. • Three purification protocols for a COVID-19 vaccine antigen were compared. • Reproducibility of a scalable, low-cost process for a COVID-19 vaccine was shown. Graphical abstract

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“…Moreover, while the pathogenic mechanisms of the viral infection are not totally clear [ 10 ], effective therapeutic agents have been developed. For example, neutralizing antibodies (nAbs) targeting the viral spike protein or human convalescent plasma have been employed in clinical practice by passively transferring them to patients [ 11 , 12 , 13 , 14 ]. Although with varying degrees of effectiveness, these therapies generally tend to improve the disease conditions and to reduce viral load especially if administered in early phases of the disease.…”

Section: Introductionmentioning

confidence: 99%

Prediction and Evolution of the Molecular Fitness of SARS-CoV-2 Variants: Introducing SpikePro

Pucci

Rooman

2021

Viruses

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The understanding of the molecular mechanisms driving the fitness of the SARS-CoV-2 virus and its mutational evolution is still a critical issue. We built a simplified computational model, called SpikePro, to predict the SARS-CoV-2 fitness from the amino acid sequence and structure of the spike protein. It contains three contributions: the inter-human transmissibility of the virus predicted from the stability of the spike protein, the infectivity computed in terms of the affinity of the spike protein for the ACE2 receptor, and the ability of the virus to escape from the human immune response based on the binding affinity of the spike protein for a set of neutralizing antibodies. Our model reproduces well the available experimental, epidemiological and clinical data on the impact of variants on the biophysical characteristics of the virus. For example, it is able to identify circulating viral strains that, by increasing their fitness, recently became dominant at the population level. SpikePro is a useful, freely available instrument which predicts rapidly and with good accuracy the dangerousness of new viral strains. It can be integrated and play a fundamental role in the genomic surveillance programs of the SARS-CoV-2 virus that, despite all the efforts, remain time-consuming and expensive.

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Neutralizing antibodies for the treatment of COVID-19

Cited by 100 publications

References 45 publications

Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

Upregulation of the Renin–Angiotensin System Pathways and SARS-CoV-2 Infection: The Rationale for the Administration of Zinc-Chelating Agents in COVID-19 Patients

Process development and scale-up optimization of the SARS-CoV-2 receptor binding domain–based vaccine candidate, RBD219-N1C1

Prediction and Evolution of the Molecular Fitness of SARS-CoV-2 Variants: Introducing SpikePro

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