Future perspective: biologic agents in patients with severe COVID-19

Yalçın, Arzu Didem; Yalcin, Ata Nevzat

doi:10.1080/08923973.2020.1818770

Cited by 27 publications

(30 citation statements)

References 49 publications

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“…It has been described that omalizumab safely decreases the coagulant proteins (D-Dimer) and proinflammatory cytokines/mediators and increases the anti-coagulant proteins (protein C, S) in patients with sepsis (Yalcin et al, 2013;Criado et al, 2020). So, it could be anticipated that we may administer it for severe COVID-19 (Yalcin and Yalcin, 2021). We observed that those genes differentially expressed in COVID-19 and aripiprazole-treated patients were involved in Inflammatory bowel disease (IBD).…”

Section: Discussionmentioning

confidence: 96%

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Aripiprazole as a Candidate Treatment of COVID-19 Identified Through Genomic Analysis

et al. 2021

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Background: Antipsychotics modulate expression of inflammatory cytokines and inducible inflammatory enzymes. Elopiprazole (a phenylpiperazine antipsychotic drug in phase 1) has been characterized as a therapeutic drug to treat SARS-CoV-2 infection in a repurposing study. We aim to investigate the potential effects of aripiprazole (an FDA approved phenylpiperazine) on COVID-19-related immunological parameters.Methods: Differential gene expression profiles of non-COVID-19 vs. COVID-19 RNA-Seq samples (CRA002390 project in GSA database) and drug-naïve patients with non-affective psychosis at baseline and after three months of aripiprazole treatment were identified. An integrative transcriptomic analyses of aripiprazole effects on differentially expressed genes in COVID-19 patients was performed.Findings: 82 out the 377 genes (21.7%) with expression significantly altered by aripiprazole have also their expression altered in COVID-19 patients and in 93.9% of these genes their expression is reverted by aripiprazole. The number of common genes with expression altered in both analyses is significantly higher than expected (Fisher’s Exact Test, two tail; p value = 3.2e-11). 11 KEGG pathways were significantly enriched with genes with altered expression both in COVID-19 patients and aripiprazole medicated non-affective psychosis patients (p adj<0.05). The most significant pathways were associated to immune responses and mechanisms of hyperinflammation-driven pathology (i.e.,“inflammatory bowel disease (IBD)” (the most significant pathway with a p adj of 0.00021), “Th1 and Th2 cell differentiation” and “B cell receptor signaling pathway”) that have been also associated with COVID19 clinical outcome.Interpretation: This exploratory investigation may provide further support to the notion that a protective effect is exerted by aripiprazole (phenylpiperazine) by modulating the expression of genes that have shown to be altered in COVID-19 patients. Along with many ongoing studies and clinical trials, repurposing available medications could be of use in countering SARS-CoV-2 infection, but require further studies and trials.

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Section: Discussionmentioning

confidence: 96%

“…Among biologic agents in patients with severe COVID-19 inhibiting Fc epsilon RI signaling has been proposed (Yalcin and Yalcin, 2021). Omalizumab specifically binds to the CH3 domain, is near to the binding site for the high affinity IgE Fc receptors type-I (also called FceRI) of human IgE (Metz et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Aripiprazole as a Candidate Treatment of COVID-19 Identified Through Genomic Analysis

et al. 2021

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“…Previous studies have reported that omalizumab is effective in treating asthma patients with chronic obstructive pulmonary disease (COPD) overlap syndrome or with cardiovascular complications by decreasing coagulant proteins (D-Dimer) and proinflammatory cytokine levels (50,51). In consideration of these facts, Yalcin AD and Yalcin AN highlighted that omalizumab therapy for patients with severe COVID-19 might contribute to good clinical outcomes (52). AB1904Am15, a novel anti-IgE antibody, might have the potential in treating the asthma patients with COPD overlap syndrome and cardiovascular diseases, and protecting the patients with severe COVID-19 and leading to greater survival.…”

Section: Discussionmentioning

confidence: 99%

An Omalizumab Biobetter Antibody With Improved Stability and Efficacy for the Treatment of Allergic Diseases

Pan²,

Gu³

et al. 2020

Front. Immunol.

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The critical role of IgE in allergic diseases is well-documented and clinically proven. Omalizumab, a humanized anti-IgE antibody, was the first approved antibody for the treatment of allergic diseases. Nevertheless, omalizumab still has some limitations, such as product instability and dosage restriction in clinical application. In this study, we attempted to develop an omalizumab biobetter antibody with the potential to overcome its limitations. We removed two aspartic acid isomerization hotspots in CDRs of omalizumab to improve antibody candidate’s stability. Meanwhile, several murine amino acids in the framework region of omalizumab were replaced with human source to reduce the potential immunogenicity. Yeast display technology was then applied to screen antibody candidates with high binding affinity to IgE. Moreover, YTE mutation in Fc fragment was introduced into the candidates for extending their serum half-life. A lead candidate, AB1904Am15, was screened out, which showed desired biophysical properties and improved stability, high binding affinity and elevated potency in vitro, prolonged half-life in human FcRn transgenic mouse, and enhanced in vivo efficacy in cynomolgus monkey asthma model. Overall, our study developed a biobetter antibody of omalizumab, AB1904Am15, which has the potential to show improved clinical benefit in the treatment of allergic diseases.

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“…The model of innate immunity regulation proposed here may also be useful for evaluating the likelihood that other therapies will be useful in treating severe COVID-19 and, particularly, the cytokine storm accompanying it. Consider, as examples, Anakinra, a human IL-1 receptor antagonist, and Tocilizumab and Sarilumab, monoclonal antibodies that block the IL-6 receptor and, thus, its signal transduction pathway [256,257]. Each one neutralizes only one type of cytokine among the dozen that are released during a cytokine storm (Figure 12).…”

Section: Implications Of Innate Receptor Activation Profiles For Tretmentioning

confidence: 99%

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

Root‐Bernstein

2021

IJMS

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Severe COVID-19 is characterized by a “cytokine storm”, the mechanism of which is not yet understood. I propose that cytokine storms result from synergistic interactions among Toll-like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLR) due to combined infections of SARS-CoV-2 with other microbes, mainly bacterial and fungal. This proposition is based on eight linked types of evidence and their logical connections. (1) Severe cases of COVID-19 differ from healthy controls and mild COVID-19 patients in exhibiting increased TLR4, TLR7, TLR9 and NLRP3 activity. (2) SARS-CoV-2 and related coronaviruses activate TLR3, TLR7, RIG1 and NLRP3. (3) SARS-CoV-2 cannot, therefore, account for the innate receptor activation pattern (IRAP) found in severe COVID-19 patients. (4) Severe COVID-19 also differs from its mild form in being characterized by bacterial and fungal infections. (5) Respiratory bacterial and fungal infections activate TLR2, TLR4, TLR9 and NLRP3. (6) A combination of SARS-CoV-2 with bacterial/fungal coinfections accounts for the IRAP found in severe COVID-19 and why it differs from mild cases. (7) Notably, TLR7 (viral) and TLR4 (bacterial/fungal) synergize, TLR9 and TLR4 (both bacterial/fungal) synergize and TLR2 and TLR4 (both bacterial/fungal) synergize with NLRP3 (viral and bacterial). (8) Thus, a SARS-CoV-2-bacterium/fungus coinfection produces synergistic innate activation, resulting in the hyperinflammation characteristic of a cytokine storm. Unique clinical, experimental and therapeutic predictions (such as why melatonin is effective in treating COVID-19) are discussed, and broader implications are outlined for understanding why other syndromes such as acute lung injury, acute respiratory distress syndrome and sepsis display varied cytokine storm symptoms.

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Future perspective: biologic agents in patients with severe COVID-19

Abstract: The SARS-CoV-2 is a b-CoV, which is enveloped by non-segmented positive-stranded RNA vir€ us. When b-CoV infects the respiratory tract, it can cause mild and/or severe acute respiratory syndrome (SARS) with consequent release of cytokines/mediators, including interleukin (IL)

Cited by 27 publications

References 49 publications

Aripiprazole as a Candidate Treatment of COVID-19 Identified Through Genomic Analysis

Aripiprazole as a Candidate Treatment of COVID-19 Identified Through Genomic Analysis

An Omalizumab Biobetter Antibody With Improved Stability and Efficacy for the Treatment of Allergic Diseases

Innate Receptor Activation Patterns Involving TLR and NLR Synergisms in COVID-19, ALI/ARDS and Sepsis Cytokine Storms: A Review and Model Making Novel Predictions and Therapeutic Suggestions

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