LONDON – With COVID-19 infection varying in severity from asymptomatic to lethal the search is now underway for biomarkers to predict which patients are most at risk of suffering severe disease.
As one possibility, Menarini Silicon Biosystems (MSB) is using its Cellsearch liquid biopsy technology to capture and count circulating endothelial cells, as a marker of lung damage and a potential indicator of patients at risk of suffering a hyperimmune response.
Meanwhile, Oxford Biodynamics plc is applying its Episwitch platform to find prognostic and predictive epigenetic markers of disease severity and response to antiviral therapy.
These projects are getting off the ground as an expert group in the U.K. pointed to characterization of biomarkers that can pick out patients who will develop dysregulated immune responses following infection by SARS-CoV-2, as a critical research priority.
The group of 15 leading immunologists reached this conclusion after conducting a review of the current state of knowledge and gaps in understanding of the immune response to the novel coronavirus.
“Biomarkers to identify which people may develop more severe disease will be extremely valuable to predict and prevent intensive care admission,” says the review, published by the U.K. Academy of Medical Sciences on May 1.
A number of immune modulator drugs, including treatments for cancer and rheumatoid arthritis, are being tested in COVID-19 trials. The review says biomarkers will contribute to better understanding of the disease progression. “[That] is key to choosing the correct immunological pathway to modulate, and when to do so,” the expert group says.
In its work applying Cellsearch, MSB is building on earlier studies showing circulating endothelial cells are a marker of damage in a number of diseases. SAR-CoV-2 infects the lungs through the angiotensin-converting enzyme 2 (ACE-2) receptor in the epithelial-endothelial barrier, damaging the endothelium. It is thought this may play a central role in amplifying and perpetuating the proinflammatory cascade that leads to acute respiratory distress syndrome, the most serious complication of COVID-19 infection.
“We know ACE-2 mediated damage of the endothelium plays a role in leading to more severe complications of COVID-19,” said Fabio Piazzalunga, president of Bologna, Italy-based MSB. An increase in the number endothelial cells in the bloodstream may predict the onset and worsening of respiratory distress, and the subsequent cardiovascular complications caused by the inflammatory cascade.
“Counting circulating endothelial cells can be considered a biomarker,” Piazzalunga said. “We think it could be used in evaluating the risk of cardiovascular events and severe respiratory events. It could also eventually be a marker of response to drugs,” he told BioWorld.
Cellsearch picks out the cells from whole blood by immuno magnetic capture of cells displaying the CD146 endothelial cell surface marker. “It’s noninvasive; you can do repeat tests,” said Piazzalunga. The technology is extensively validated in oncology and has FDA clearance for detecting circulating tumor cells. MSB says this experience can easily be transferred to COVID-19 research.
MSB is finalizing agreements with research centers in Europe and the U.S. to apply the technology. “We are ramping up the manufacturing side to have the kits available,” Piazzalunga said. Cellsearch is for research use only.
Oxford Biodynamics is making its move into COVID-19 research in the first clinical trial to look for epigenetic biomarkers in COVID-19 patients. The company is providing its Episwitch technology to identify biomarkers in 167 hospitalized patients who are due be recruited to the trial, which is assessing use of the influenza drug Avigan (favipiravir).
The Scottish government is funding the study, ‘Viral and immunological correlates of clinical severity and response to antiviral therapy,’ taking place at the Institute of Infection, Immunity and Inflammation at Glasgow University.
Oxford-based Oxford Biodynamics has data showing Episwitch can be used for patient stratification and to assess response to therapy in diseases including rheumatoid arthritis, diabetes and breast, prostate and pancreatic cancer.
Based on this, Alexandre Akoulitchev, chief scientific officer, is confident of finding relevant COVID-19 biomarkers. “It is pretty clear from previous experience we can apply the same approach,” he said. “We see this as a prognosis as to what complications a patient is likely to develop,” he told BioWorld.
The biomarkers will be predictive not only of severe complications in the lungs, but also of other problems, including renal failure, neurological complications and abnormal blood clotting.
Episwitch works by assessing and tracking changes in the 3D organization of chromosomes that occur in disease states. These epigenetic changes in conformation lead to disease-associated changes in gene expression.
The 3D chromosome conformation signatures (CCS) are detected using proprietary pattern recognition algorithms to look for DNA sequences that are packed physically close to each other, but are linearly far apart on the DNA strand.
Initial hits are subject to screening and statistical analysis, before validation, DNA sequencing to identify which genes are involved, and cross-validation on sample cohorts.
Oxford Biodynamics previously worked with the clinical lead on the study, Iain McInnes, in applying Episwitch to identify newly diagnosed rheumatoid arthritis patients who will not respond to standard steroid therapies. The company also has contracts with pharma companies and research institutes, in which it is applying Episwitch for patient stratification, to identify drug responders and to monitor response to treatment.
While the Glasgow study is solely looking at responses to Avigan, a number of other antiviral, anti-inflammatory and immuno-oncology drugs are now being tested as treatments for COVID-19.
Ewan Hunter, chief development officer of Oxford Biodynamics said Episwitch also could be applied to these trials. The epigenetic markers will be different in COVID-19 compared to biomarkers picked out in response to these drugs in treating other conditions, but would be in the same biological networks. “The problem is with dysregulation in the immune system; you would expect similar networks to pop up,” he said.