“Complement-ing” positive outcomes during the COVID-19 pandemic

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Dr Dimitrios Mastellos (@dmastellos)

The COVID-19 pandemic has had a huge impact on research worldwide. Multiple projects have been halted and researchers have lost their jobs. But it hasn’t all been bad – the emergence of COVID-19 vaccines is a testament to the tremendous work undertaken to combat this deadly virus.

Dr Dimitrios Mastellos (@dmastellos) is a Senior Investigator at the National Center for Scientific Research “Demokritos” in Athens, Greece. He studied Biology at the University of Patras and received his PhD in Molecular Immunology from the same Institution. His main research interests lie in the field of innate immunity and complement biology. His group at “Demokritos” contributes to developing new diagnostic and therapeutic agents for tracking and modulating complement activity in human disease.

YoungEHA’s Dr Eleni Gavriilaki had the opportunity to interview Dr Mastellos regarding his work during the COVID-19 pandemic.

1. Let’s start with what we deal with every day: the COVID-19 pandemic. Tell us how this has affected your everyday life at work (productivity, funding, personnel) and home (childcare, etc.).

Obviously, the pandemic has shifted many priorities in my everyday life, both as a researcher and a parent. Very soon after the first wave started spreading through Europe, all scientists realized that we had to do our fair share in understanding this new infectious agent, its biology within its new host and the way the immune system reacts to this invader.  The realization that we all had to pull together, sharing diverse resources and ‘know-hows’ to fight this pandemic was swift and this had a considerable impact on my everyday life. Despite the unavoidable slowdown of research activities within the lab, productivity has been kept ‘alive’ through vital collaborations with other scientists and collaborators across Europe and the US.  Restrictions imposed by nation-wide quarantine measures have had a negative impact on our research not only by slowing down daily lab operations, but also increasing the burden for the preparation of competitive grant applications and restricting personnel mobility and recruitment. Most of our everyday research planning has to be carried out from a distance (home) and combining this with family needs such as home-schooling has been a tough challenge throughout this pandemic.

2. What are you trying to do better in a second wave of the pandemic compared to the first one?

As we have already entered the second wave of the pandemic across Europe, it seems that all countries, including Greece, have tried to adapt to the new status quo, implementing measures that aim to counterbalance the drawbacks of social distancing with the maintenance of daily operations. We have all tried to adapt our research activities to this new mode. As many scientists have done, I now rely much more on teleconference-mediated communication and mentoring, with the balance of some safe and socially distanced on-site interaction. Trying to make the most out of these difficult circumstances is a way of facing the new daily routine in a mentally balanced way. This is very important for students too. My hopes are still high that through collective, ‘bottom-up’ social engagement and adaptation we will persevere. The approval of effective vaccines will help us transition to a more stable and sustainable future.

Through collective, ‘bottom-up’ social engagement and adaptation we will persevere.

3. Tell us how you decided to contribute to the fight against COVID-19. How is your field of expertise involved in COVID-19?

My research focus is on complement pathobiology and therapeutics. Very early during the pandemic it became evident that complement dysregulation or overactivation is intricately involved with COVID19 pathogenesis, affecting the patients’ risk for adverse clinical outcomes (Ramlall V et al, Nat Medicine, 2020) and driving molecular and cellular processes that fuel microvascular endothelial damage and immunothrombosis (Gavriilaki et al, B J Haematol, 2020; Skendros P et al, J Clin Invest, 2020). In fact, both complement and coagulation pathways have emerged as key drivers of pathology in this complex multi-system disease.

Prof John Lambris, a leading immunologist at the University of Pennsylvania, has been instrumental in mobilizing an international network of scientists that actively participate in the effort to develop complement C3 therapeutics as novel anti-inflammatories for severe COVID-19. His lab has spearheaded the development of C3-targeted therapeutics through the discovery of compstatins, a series of small-sized peptide inhibitors that bind C3 and potently block C3 activation. In close collaboration with academic and clinical centers that share a common interest in developing immunotherapies for COVID19 we postulated that complement C3 is a key driver of SARS-CoV-2 triggered hyperinflammation and an ‘orchestrator’ of the ensuing thrombotic complications that increase patient morbidity and mortality (Risitano A et al, Nat Rev Immunol, 2020). I have been very fortunate to collaborate with him over the years and especially through this pandemic. We share a strong sense of dedication and commitment in trying to develop a science-driven therapeutic intervention that may hopefully help patients cope with the life-threatening complications of this insidious disease.

4. How do you feel you can translate the knowledge that you accumulated all these years into life-saving actions that could change the course of this pandemic?

The feeling of being able to share some of your research experience with other scientists and contribute to the design of clinical protocols and therapeutic interventions that may relieve the suffering of patients is both rewarding and motivating. After all, this is the ultimate hope of every scientist: to be able to translate his/her primary research into tangible and beneficial clinical interventions. C3 inhibition has been long discussed as a treatment option for many complement mediated diseases. The realization that C3 dysregulation contributes to many facets of the pathophysiology of COVID-19, including acute lung injury, endotheliopathy, thrombotic microangiopathy and immunothrombosis, has geared up our efforts  to translate this knowledge into a beneficial therapy for these patients.

This is the ultimate hope of every scientist: to be able to translate his/her primary research into tangible and beneficial clinical interventions.

5. What actions against COVID-19 do you participate in?

I have been collaborating with Prof. Lambris and an international team of  clinical collaborators in developing AMY-101 as a treatment option for severe COVID-19. AMY-101 is a third generation C3 inhibitor with subnanomolar binding affinity for C3, consistent inhibitory activity in many disease models and a favorable PK and PD profile. AMY-101 treatment has shown promising results in a compassionate use program in severe COVID-19 patients (Mastaglio et al, Clin Immunol  2020) . In a comparative study with eculizumab, an anti-C5 monoclonal antibody that is already in the clinic, AMY-101 attenuated – to a greater extent – markers of COVID-19 thromboinflammation (i.e., NET release in plasma), indicating a broader therapeutic profile that may translate in more significant clinical gains in patients (Mastellos et al, Clin Immunol 2020).  AMY-101 is currently being evaluated in a randomized, placebo-controlled Phase II study in severe COVID-19 patients in Greece, while similar trials approved by the FDA and other regulatory agencies are also planned in other countries.

6. What do you think that social media could offer through this pandemic? Which platform do you prefer?

In the age of big data generation and rapid knowledge communication, I feel that social media platforms offer a great opportunity to disseminate key information about the pandemic to the broader public and alert us about all the latest clinical developments about vaccines and therapeutics. Our responsibility is to make this communication to the public as transparent, responsible and evidence based as possible. I have been using Twitter as a platform for sharing scientific papers on complement biology and immunology in general, as well as new information about the pandemic. I have to admit though that I am still a novice in social media platforms.

Dr Mastellos has no financial disclosures.

Last Updated on Wednesday 23 December 2020.