Inhibitors of tumor necrosis factor-α and mechanisms of their action

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.