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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.

Összefoglaló. Egészen az ezredfordulóig a gyógyszeripari kutatás-fejlesztés világszerte hagyományosan nagyvállalati keretek között folyt. Az elmúlt évtizedekben azonban ebben a szegmensben jelentős átrendeződések tapasztalhatók, ugyanis a korai kutatási és fejlesztési projektek sok esetben már az egyetemi-akadémiai, illetve kkv-szektorból indulnak. A szervezeti keretek mellett a fejlesztések szakmai tartalma is változott, a hagyományos kismolekulás gyógyszerek mellett egyre meghatározóbb szerep jut a biológiai terápiáknak, valamint a hatóanyagok fejlesztése mára összekapcsolódott a releváns diagnosztikumok fejlesztésével. A projektek finanszírozásában is fontos változások történtek, egyre jelentősebb szerep jut az állami KFI finanszírozásnak és a (kockázati) tőkebefektetéseknek. A gyógyszeripari K+F szakmai, szervezeti és finanszírozási kereteinek változása jelentősen felértékelte és szélesítette a korábban is meglévő akadémiai-ipari kapcsolatokat. Az együttműködések fontos szerepet játszanak a COVID–19 járványra adott válaszokban is, amit a magyar egyetemek, kutatóintézetek, kis- és középvállalatok, valamint gyógyszeripari nagyvállalatok részvételével indult kutatások igazolnak.

Summary. Until the turn of the millennium, pharmaceutical research and development worldwide had traditionally taken place in pharmaceutical companies. In recent decades, however, significant rearrangements have been witnessed, as early-stage research and development projects often start at the universities or the academic and SME sectors. In addition to the organizational framework, the professional content has also changed: in addition to traditional small molecule drugs, biological therapies are playing an increasingly important role, and the development of active ingredients is now linked to the development of relevant diagnostics. Important changes have also taken place in the financing of projects, with public RDI financing and (venture) capital investments playing an increasing role. Changes in the professional, organizational and funding frameworks for pharmaceutical R&D have significantly enhanced and broadened existing academic-industrial relations. Collaborations also play an important role in the responses to the COVID-19 epidemic, as evidenced by research involving Hungarian universities, research institutes, small and medium-sized enterprises, and large pharmaceutical companies. The first example is a collaboration of an academic research group and a spin-off company formed from this environment. Researchers of the Eötvös University (ELTE) and others working at the Research Centre for Natural Sciences (RCNS) applied phage display technology to discover new protease inhibitors. They established EvolVeritas Ltd, a spin-off company developing high affinity and high specificity inhibitors of the TMPRSS2 protease that is involved in the SARS-CoV-2 viral entry to host cells. In a parallel research program, the same consortium is working on new inhibitors of the MASP2 protease contributing to the coronavirus mediated activation of innate immunity, particularly the complement system. This latter approach would result in the effective control of microthrombosis events associated with serious COVID-19 infections. Both of the approaches are in the early preclinical phase and further investment would be needed to push these projects into clinical testing. The second example is a collaboration between an academic research group and an SME to reposition of azelastine, an approved antihistamine drug that was found to be effective in blocking SARS-CoV-2 mediated pathogenesis. After successful preclinical studies, the partners have now initiated clinical trials to demonstrate the efficacy of azelastine nasal drops in the prevention and treatment of COVID-19 infections. The third example is a collaboration of academic research groups, a SME and a pharmaceutical company. This consortium develops an antibody-like fusion protein therapeutics that can neutralize the SARS-CoV-2 virus. One component of the ACE2-Fc fusion protein is the relevant portion of angiotensin-converting enzyme 2 (ACE2) produced by recombinant technologies, which binds to the spike protein of the pathogen. The virus thus binds to the fusion protein instead of the ACE2 receptors in human cells. Another component is responsible for the long half-life of IgG, the so-called Fc region. The consortium confirmed that the ACE2-Fc fusion protein inhibits SARS-CoV-2 infection in cell culture, and prevents disease in experimental animals. Preclinical development and the preparation of the core documentation is ongoing, which will soon be submitted to the European Medicines Agency (EMA) to initiate clinical trials. The final example is a joint development project that involved a research group, an SME and two pharmaceutical companies. The objective of this program is process development and pharmaceutical formulation of favipiravir, a broad-spectrum antiviral with a treatment potential against COVID-19. The consortium completed the process development of the active pharmaceutical ingredient (API) and developed finished dosage formulations available for clinical testing. Clinical trials are ongoing that aim investigating safety and efficacy of favipiravir in COVID-19 infected patients. All of the examples described here demonstrate the power of collaborations that helped the participants to give diverse and effective responses to the unprecedented pandemic challenge of COVID-19. We believe that these experiences would encourage the members of the academic and industry community to formulate further collaborations to tackle the unmet medical need in our societies.