Inhibitors of tumor necrosis factor-α and mechanisms of their action
Inhibitori faktora nekroze tumora–α i mehanizmi njihovog dejstva
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Tumor necrosis factor (TNF)-α is a proinflammatory cytokine with a role in immunity to pathogens, as well as in the pathogenesis of several autoimmune/inflammatory diseases. Biological drugs targeting this cytokine and inhibiting its effects are designed. Until today, five TNF-α inhibitors are approved: infliximab, adalimumab, golimumab (monoclonal antibodies), certolizumab pegol (pegylated antigen-binding fragment of immunoglobulin), and etanercept [TNF receptor type 2-fragment crystallizable (Fc) of immunoglobulin fusion protein]. Their approved biosimilars are on the market, too. They are mainly used for the treatment of rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Although TNF-α inhibitors are present in clinical practice for more than two decades and are established as an efficacious therapeutics, researchers are still occupied by revealing the complex mechanisms of their action. Namely, in addition to binding and neutralisation of soluble TNF-α, these drugs al...so bind/block transmembrane form of TNF-α (tmTNF-α), trigger diverse intracellular signals in tmTNF-α positive cells (a process named “reverse signalling”) or, if they have an Fc fragment, mediate killing of tmTNF-α-expressing cells by other immune cells or the complement system. Also, TNF-α inhibitors that contain Fc portion of the IgG antibody may affect Fc receptor-expressing cells and have an effector function quite independent of their TNF-α neutralisation capacity.
Faktor nekroze tumora (TNF)-a je citokin koji ima značajnu ulogu u patogenezi nekih autoimunskih/inflamatornih bolesti. Shodno tome, dizajnirani su biološki lekovi koji ciljano inhibiraju efekte koje on ostvaruje posredstvom svojih receptora. Do danas je odobreno pet lekova koji inhibiraju TNF-a: infliksimab, adalimumab, golimumab (monoklonska antitela), certolizumab pegol (pegilovani antigen-vezujući fragment imunoglobulina) i etanercept [TNF receptor 2-kristalizujući fragment (Fc) imunoglobulina fuzioni protein]. Takođe, brojni biosimilari ovih lekova su odobreni za primenu. Glavne indikacije za primenu anti-TNF-a lekova su: reumatoidni artritis, inflamatorne bolesti creva, psorijaza. Iako se TNF-a inhibitori više od dve decenije uspešno koriste u kliničkoj praksi, složeni mehanizmi njihovog delovanja još uvek nisu potpuno poznati. Naime, pokazano je da se ovi lekovi, osim vezivanja i neutralizacije solubilnog TNF-a, mogu vezati i za transmembransku formu ovog citokina i blokirati je... i/ili pokrenuti prenos signala u ćeliju koja ispoljava ovaj molekul ("reverzni prenos signala"). Takođe, ovi lekovi, ukoliko poseduju Fc fragment, mogu posredovati i u ubijanju ćelija koje ispoljavaju membransku formu TNF-a aktivacijom drugih ćelija imunskog sistema ili sistema komplementa ili modulisati funkciju ćelija koje ispoljavaju receptore za Fc fragmanet i ostvarivati efektorske funkcije nezavisno od njihove sposobnosti da blokiraju/neutrališu TNF-a.
Ključne reči:
TNF receptors / TNF-α inhibitors / TNF-α neutralisation / Transmembrane TNF-α / TNF-α inhibitori / neutralizacija TNF-α / TNF receptori / transmembranski TNF-αIzvor:
Arhiv za farmaciju, 2020, 70, 3, 109-129Izdavač:
- Beograd : Savez farmaceutskih udruženja Srbije
Institucija/grupa
PharmacyTY - JOUR AU - Bufan, Biljana AU - Jančić, Ivan AU - Stojić-Vukanić, Zorica PY - 2020 UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3642 AB - Tumor necrosis factor (TNF)-α is a proinflammatory cytokine with a role in immunity to pathogens, as well as in the pathogenesis of several autoimmune/inflammatory diseases. Biological drugs targeting this cytokine and inhibiting its effects are designed. Until today, five TNF-α inhibitors are approved: infliximab, adalimumab, golimumab (monoclonal antibodies), certolizumab pegol (pegylated antigen-binding fragment of immunoglobulin), and etanercept [TNF receptor type 2-fragment crystallizable (Fc) of immunoglobulin fusion protein]. Their approved biosimilars are on the market, too. They are mainly used for the treatment of rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Although TNF-α inhibitors are present in clinical practice for more than two decades and are established as an efficacious therapeutics, researchers are still occupied by revealing the complex mechanisms of their action. Namely, in addition to binding and neutralisation of soluble TNF-α, these drugs also bind/block transmembrane form of TNF-α (tmTNF-α), trigger diverse intracellular signals in tmTNF-α positive cells (a process named “reverse signalling”) or, if they have an Fc fragment, mediate killing of tmTNF-α-expressing cells by other immune cells or the complement system. Also, TNF-α inhibitors that contain Fc portion of the IgG antibody may affect Fc receptor-expressing cells and have an effector function quite independent of their TNF-α neutralisation capacity. AB - Faktor nekroze tumora (TNF)-a je citokin koji ima značajnu ulogu u patogenezi nekih autoimunskih/inflamatornih bolesti. Shodno tome, dizajnirani su biološki lekovi koji ciljano inhibiraju efekte koje on ostvaruje posredstvom svojih receptora. Do danas je odobreno pet lekova koji inhibiraju TNF-a: infliksimab, adalimumab, golimumab (monoklonska antitela), certolizumab pegol (pegilovani antigen-vezujući fragment imunoglobulina) i etanercept [TNF receptor 2-kristalizujući fragment (Fc) imunoglobulina fuzioni protein]. Takođe, brojni biosimilari ovih lekova su odobreni za primenu. Glavne indikacije za primenu anti-TNF-a lekova su: reumatoidni artritis, inflamatorne bolesti creva, psorijaza. Iako se TNF-a inhibitori više od dve decenije uspešno koriste u kliničkoj praksi, složeni mehanizmi njihovog delovanja još uvek nisu potpuno poznati. Naime, pokazano je da se ovi lekovi, osim vezivanja i neutralizacije solubilnog TNF-a, mogu vezati i za transmembransku formu ovog citokina i blokirati je i/ili pokrenuti prenos signala u ćeliju koja ispoljava ovaj molekul ("reverzni prenos signala"). Takođe, ovi lekovi, ukoliko poseduju Fc fragment, mogu posredovati i u ubijanju ćelija koje ispoljavaju membransku formu TNF-a aktivacijom drugih ćelija imunskog sistema ili sistema komplementa ili modulisati funkciju ćelija koje ispoljavaju receptore za Fc fragmanet i ostvarivati efektorske funkcije nezavisno od njihove sposobnosti da blokiraju/neutrališu TNF-a. PB - Beograd : Savez farmaceutskih udruženja Srbije T2 - Arhiv za farmaciju T1 - Inhibitors of tumor necrosis factor-α and mechanisms of their action T1 - Inhibitori faktora nekroze tumora–α i mehanizmi njihovog dejstva VL - 70 IS - 3 SP - 109 EP - 129 DO - 10.5937/arhfarm2003109B ER -
@article{ author = "Bufan, Biljana and Jančić, Ivan and Stojić-Vukanić, Zorica", year = "2020", abstract = "Tumor necrosis factor (TNF)-α is a proinflammatory cytokine with a role in immunity to pathogens, as well as in the pathogenesis of several autoimmune/inflammatory diseases. Biological drugs targeting this cytokine and inhibiting its effects are designed. Until today, five TNF-α inhibitors are approved: infliximab, adalimumab, golimumab (monoclonal antibodies), certolizumab pegol (pegylated antigen-binding fragment of immunoglobulin), and etanercept [TNF receptor type 2-fragment crystallizable (Fc) of immunoglobulin fusion protein]. Their approved biosimilars are on the market, too. They are mainly used for the treatment of rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Although TNF-α inhibitors are present in clinical practice for more than two decades and are established as an efficacious therapeutics, researchers are still occupied by revealing the complex mechanisms of their action. Namely, in addition to binding and neutralisation of soluble TNF-α, these drugs also bind/block transmembrane form of TNF-α (tmTNF-α), trigger diverse intracellular signals in tmTNF-α positive cells (a process named “reverse signalling”) or, if they have an Fc fragment, mediate killing of tmTNF-α-expressing cells by other immune cells or the complement system. Also, TNF-α inhibitors that contain Fc portion of the IgG antibody may affect Fc receptor-expressing cells and have an effector function quite independent of their TNF-α neutralisation capacity., Faktor nekroze tumora (TNF)-a je citokin koji ima značajnu ulogu u patogenezi nekih autoimunskih/inflamatornih bolesti. Shodno tome, dizajnirani su biološki lekovi koji ciljano inhibiraju efekte koje on ostvaruje posredstvom svojih receptora. Do danas je odobreno pet lekova koji inhibiraju TNF-a: infliksimab, adalimumab, golimumab (monoklonska antitela), certolizumab pegol (pegilovani antigen-vezujući fragment imunoglobulina) i etanercept [TNF receptor 2-kristalizujući fragment (Fc) imunoglobulina fuzioni protein]. Takođe, brojni biosimilari ovih lekova su odobreni za primenu. Glavne indikacije za primenu anti-TNF-a lekova su: reumatoidni artritis, inflamatorne bolesti creva, psorijaza. Iako se TNF-a inhibitori više od dve decenije uspešno koriste u kliničkoj praksi, složeni mehanizmi njihovog delovanja još uvek nisu potpuno poznati. Naime, pokazano je da se ovi lekovi, osim vezivanja i neutralizacije solubilnog TNF-a, mogu vezati i za transmembransku formu ovog citokina i blokirati je i/ili pokrenuti prenos signala u ćeliju koja ispoljava ovaj molekul ("reverzni prenos signala"). Takođe, ovi lekovi, ukoliko poseduju Fc fragment, mogu posredovati i u ubijanju ćelija koje ispoljavaju membransku formu TNF-a aktivacijom drugih ćelija imunskog sistema ili sistema komplementa ili modulisati funkciju ćelija koje ispoljavaju receptore za Fc fragmanet i ostvarivati efektorske funkcije nezavisno od njihove sposobnosti da blokiraju/neutrališu TNF-a.", publisher = "Beograd : Savez farmaceutskih udruženja Srbije", journal = "Arhiv za farmaciju", title = "Inhibitors of tumor necrosis factor-α and mechanisms of their action, Inhibitori faktora nekroze tumora–α i mehanizmi njihovog dejstva", volume = "70", number = "3", pages = "109-129", doi = "10.5937/arhfarm2003109B" }
Bufan, B., Jančić, I.,& Stojić-Vukanić, Z.. (2020). Inhibitors of tumor necrosis factor-α and mechanisms of their action. in Arhiv za farmaciju Beograd : Savez farmaceutskih udruženja Srbije., 70(3), 109-129. https://doi.org/10.5937/arhfarm2003109B
Bufan B, Jančić I, Stojić-Vukanić Z. Inhibitors of tumor necrosis factor-α and mechanisms of their action. in Arhiv za farmaciju. 2020;70(3):109-129. doi:10.5937/arhfarm2003109B .
Bufan, Biljana, Jančić, Ivan, Stojić-Vukanić, Zorica, "Inhibitors of tumor necrosis factor-α and mechanisms of their action" in Arhiv za farmaciju, 70, no. 3 (2020):109-129, https://doi.org/10.5937/arhfarm2003109B . .