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1.
biorxiv; 2022.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2022.12.20.521247

ABSTRACT

Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This hyperinflammation is dependent on high levels of anti-spike IgG with aberrant Fc tail glycosylation, leading to Fc{gamma} receptor hyperactivation. For development of immune-regulatory therapeutics, drug specificity is crucial to counteract excessive inflammation while simultaneously minimizing inhibition of antiviral immunity. We here developed an in vitro activation assay to screen for small molecule drugs that specifically counteract antibody-induced pathology. We identified that anti-spike induced inflammation is specifically blocked by small molecule inhibitors against SYK and PI3K. We identified SYK inhibitor entospletinib as the most promising candidate drug, which also counteracted anti-spike-induced endothelial dysfunction and thrombus formation. Moreover, entospletinib blocked inflammation by different SARS-CoV-2 variants of concern. Combined, these data identify entospletinib as a promising treatment for severe COVID-19.


Subject(s)
COVID-19 , Thrombosis , Inflammation
2.
ClinicalTrials.gov; 26/02/2021; TrialID: NCT04794088
Clinical Trial Register | ICTRP | ID: ictrp-NCT04794088

ABSTRACT

Condition:

ARDS;Acute Respiratory Distress Syndrome;Covid19;Endothelial Dysfunction;Pulmonary Edema

Intervention:

Drug: Imatinib Mesylate intravenous solution;Drug: Placebo

Primary outcome:

Change in extravascular lung water index

Criteria:


Inclusion Criteria:

- Age = 18 years;

- Moderate-severe ARDS, as defined by Berlin definition for ARDS (onset within 1 week of
a known clinical insult or new or worsening respiratory symptoms, bilateral opacities
not fully explained by effusions, lobar/lung collapse, or nodules, respiratory failure
not fully explained by cardiac failure or fluid overload and P/F ratio =200 mmHg with
PEEP =5 cmH2O), and intubated for mechanical ventilation.

- PCR positive for SARS-CoV2 within the current disease episode.

- Provision of signed written informed consent from the patient or patient's legally
authorised representative;

Exclusion Criteria:

- Persistent septic shock (>24h) with a Mean Arterial Pressure (MAP) = 65 mm Hg and
serum lactate level > 4 mmol/L (36 mg/dL) despite adequate volume resuscitation and
vasopressor use (norepinephrine > 0.2 µg/kg/min) for > 6 hours;

- Pre-existing chronic pulmonary disease, including:

- Known diagnosis of Interstitial Lung disease

- Known diagnosis of COPD GOLD Stage IV or FEV1<30% predicted

- DLCO <45% (if test results are available)

- Total lung capacity (TLC) < 60% of predicted (if test results are available);

- Chronic home oxygen treatment;

- Pre-existing heart failure with a known left ventricular ejection fraction <40%;

- Active treatment of haematological or non-haematological cancer with targeted immuno-
or chemotherapy, or thoracic radiotherapy in the last year;

- Currently receiving extracorporeal life support (ECLS);

- Severe chronic liver disease with Child-Pugh score > 12;

- Subjects in whom a decision to withdraw medical care is made (e.g. palliative
setting);

- Inability of the ICU staff to initiate IMP administration within 48 hours of
intubation;

- Known to be pregnant or breast-feeding;

- Enrolled in a concomitant clinical trial of an investigational medicinal product;

- White blood count < 2.5x109/l;

- Haemoglobin < 4.0 mmol/l;

- Thrombocytes < 50x109/l;

- The use of strong CYP3A4 inducers, including the following drugs:

- Carbamazepine, efavirenz, enzalutamide, fenobarbital, fenytoine, hypericum,
mitotaan, nevirapine, primidon, rifabutine, rifampicine;


3.
biorxiv; 2020.
Preprint in English | bioRxiv | ID: ppzbmed-10.1101.2020.07.13.190140

ABSTRACT

For yet unknown reasons, severely ill COVID-19 patients often become critically ill around the time of activation of adaptive immunity. Here, we show that anti-Spike IgG from serum of severely ill COVID-19 patients induces a hyper-inflammatory response by human macrophages, which subsequently breaks pulmonary endothelial barrier integrity and induces microvascular thrombosis. The excessive inflammatory capacity of this anti-Spike IgG is related to glycosylation changes in the IgG Fc tail. Moreover, the hyper-inflammatory response induced by anti-Spike IgG can be specifically counteracted in vitro by use of the active component of fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of Syk. One sentence summaryAnti-Spike IgG promotes hyper-inflammation.


Subject(s)
COVID-19
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