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Monoklonális antitestek és egyéb biológiai terápiák a COVID–19 kezelésére

Monoclonal antibodies and other biologics for treatment of COVID-19

Scientia et Securitas
Author: Imre Kacskovics

Összefoglaló. A SARS-CoV-2 koronavírus által kiváltott pandémia az elmúlt mintegy 100 év legsúlyosabb közegészségügyi, gazdasági és társadalmi válságát okozza. Az emberiség soha nem látott tudással, példa nélküli sebességgel állította elő azokat a hatékony védőoltásokat, amelyek a megfelelő átoltottság mellett kontrollálhatják a COVID–19-járványt.

A SARS-CoV-2 fertőzéssel az emberiségnek meg kell tanulnia együtt élni, és mivel a vakcinák nem mindenkinek adhatók, vagy nem mindenkiben váltanak ki immunvédelmet, szükséges a jelenleginél hatékonyabb COVID–19-specifikus terápiák kifejlesztése. Több COVID–19 kezelésére kifejlesztett gyógyszerhatóanyagot is sikerrel tesztelnek, közülük is kiemelkednek a monoklonális antitestek, illetve más biológiai terápiák. Ezek egyfelől olyan gyógyszerek, amelyek a betegség korai fázisában semlegesítik a vírust, azaz megakadályozzák, hogy a sejteket megfertőzze, míg mások a már kialakult súlyos megbetegedésben csökkenthetik a gyulladás mértékét. Biologikumok közé tartozik a SARS-CoV-2-t semlegesítő hACE2-Fc fúziós fehérje is, amely a neutralizáló monoklonális antitestek hatásához hasonlítható; előnye, hogy minden mutáns ellen hatékony lehet.

Virológusok, járványügyi szakemberek szerint fel kell készülnünk arra, hogy a jelenlegihez hasonló járványok rendszeressé válnak. Ökológiai okok miatt egyre nő az állati eredetű kórokozók adaptálódása az emberhez, de nem zárhatók ki az ún. laborszökevény vírusok, sőt a bioterrorizmus veszélye sem. Mindezek hatékony kezelésére erősítenünk kell a hazai biotechnológiai kapacitásokat. A hatóanyagfejlesztésben a már kialakult hazai egyetemi-kutatóintézeti-ipari együttműködésekre számíthatunk, a gyártás során pedig a hazai korszerű biotechnológiai, gyógyszeripari kapacitásra, amelyek növelhetik az önellátásból származó biztonságot.

Summary. The SARS-CoV-2 coronavirus pandemic is causing the worst public health, economic and social crisis in the last 100 years. New and effective vaccines were developed and produced with the application of unprecedented know how and speed, which can control the COVID-19 epidemic with the right vaccination coverage.

Humanity needs to learn to live with the SARS-CoV-2 infection, and because vaccines cannot be given to everyone or cannot induce immune protection in all vaccinated individuals, it is necessary to develop more effective COVID-19-specific therapies than those presently available. Several drugs developed for the treatment of COVID-19 have been successfully tested, including monoclonal antibodies and other biological therapies. These are, on the one hand, drugs that neutralize the virus in the early stages of the disease, that is, it prevents it from infecting the cells, while others can reduce the rate of inflammation in a severe disease status. This review article provides an update about the current status of monoclonal antibodies that have been developed to treat COVID-19.

In early 2020 Eotvos Lorand University, Pecs University, Gedeon Richter Plc and ImmunoGenes Ltd formed a consortium to develop a molecular trap, the human ACE2-Fc fusion protein that binds to the spike protein of SARS-CoV-2 and inhibits its binding to the ACE2 receptors on the cell surfaces. We successfully produced this recombinant protein and proved that it neutralizes this virus using VERO E6 cells and protects animals (Syrian hamster) from serious disease when administered before infection. We have also shown that it has a long half-life due to its (IgG) Fc-region component. Based on these proof of concept data, we created mutant versions of this drug candidate that do not have catabolic activity for angiotensin II and thus would not influence blood pressure. This is important since this drug should be administered in log-fold higher concentrations than ACE2 receptors in the body in order to efficiently neutralize the virus. The virus neutralization capacity of these new versions remained intact based on in vitro virus neutralization tests. We believe that after successful animal experiments, these drug candidates can be efficiently used in COVID-19 therapy in mild or moderate disease status. As compared to the COVID-19 specific monoclonal antibodies, we believe that these recombinant, mutant hACE2-Fc drugs can be more effective than the mAbs as they effectively bind and neutralize the new variants of SARS-CoV-2 (if they are able to bind the endogenous ACE2 receptor).

According to virologists and epidemiologists, we need to be prepared for epidemics like the current one becoming more regular. Due to ecological reasons, the adaptation of animal pathogens to humans is increasing, but there are threats due to lab leak viruses and even bioterrorism. To deal with all this effectively, we need to strengthen domestic biotechnology capacities. In the development of drug substances, we can count on the already established Hungarian university-research institute-industry collaborations, which can increase the safety resulting from self-sufficiency.

Open access

Folyadékbiopszia-vizsgálatok alkalmazási lehetőségei az onkohematológiában

Potential applications of liquid biopsy analyses in oncohematology

Hematológia–Transzfuziológia
Authors: Ákos Nagy, Bence Bátai, Laura Kiss, Anita Marx, László Imre Pinczés, Gergő Papp, Imre Kacskovics, Donát Alpár, and Csaba Bödör

Abstract:

Advances in molecular biology techniques during the past decades allowed for the scrutiny of tumor derived biomolecules, including circulating tumor DNA fragments at an unprecedented level. In case of metastatic tumors, the minimally invasive liquid biopsy sampling provides great opportunity to simultaneously detect and monitor genetic aberrations emerging at distinct anatomical sites, and to identify alterations associated with clonal evolution. Consequently, several studies have recently interrogated the utility of liquid biopsy in the analysis of solid tumors, with this approach already being incorporated into the diagnostic workflow of some diseases. In oncohematology, diffuse large B-cell lymphoma, Hodgkin lymphoma and multiple myeloma are the most intensively studied entities in this regard. Based on data previously published by our group and others, the investigation of circulating tumor DNA in hematology has a potential to convey invaluable prognostic information prior to treatment, to detect actionable genetic alterations, to monitor treatment efficacy and minimal residual disease as well as to identify therapy resistant clones. In this review, we provide an overview of the potential applications of liquid biopsy analysis in oncohematology.

Open access