Apoptosis and the FLIP and NF-kappa B proteins as pharmacodynamic criteria for biosimilar TNF-alpha antagonists

Abstract

Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale. The imminent expiration of the patents on reference biological products which block the cytokine TNF-α (tumor necrosis factor-α) raises the possibility of bringing so-called biosimilars to the market (similar to the biologicals of reference products). This occurrence is inevitable, but criteria to adequately evaluate these medications are now needed. Even among controversy, there is a demand from publications correlating the pro-apoptotic mechanism of the original TNF-α antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol) in the treatment of rheumatoid arthritis and other diseases. In this article, the authors discuss the possibility of utilizing the pro-apoptotic effect correlated with the regulation of the anti-apoptotic proteins FLIP and NF-κB as new criteria for analyzing the pharmacodynamics of possible biosimilar TNF-α antagonists which should be submitted to regulatory agencies for evaluation.

Tnf-α inhibition by infliximab as a new target for the prevention of glycerol-contrast-induced nephropathy

“…Similar to our own results, several studies have concluded that NF-kB levels, which are determined by IHC, have a significant role in nephrotoxicity damage (Yang et al, 2012). Further, infliximab and other TNF-α inhibitors have been shown to reduce NF-kB levels (Urbano et al, 2014). Regarding tissue damage, the existence of a mechanism between TNF-α, TGF-1β, and NF-kB for inducing each other has been identified (Sanchez-Capelo, 2005).…”

Etanercept administration prevents the inflammatory response induced by carrageenan in the murine air pouch model

“…It is important to note that several biologics agents including etanercept will lose patent protection in Europe by 2015, which increased the interest in the development of new biologic agents (Willrich et al 2014); therefore, data regarding the characteristics of action of these drugs are important for the formulation of comparison criteria of the efficacy and safety (Urbano et al 2014). The effects of etanercept on inflammation reported in this paper contribute for a better knowledge of the in vivo action of this drug on inflammation.…”

“…Bars indicate the mean±SEM of five animals. *p < 0.05, **p < 0.01 pathway, promoting the reduction of antiapoptotic genes expression in these inflammatory cells (Sabroe et al 2005;Urbano et al 2014).…”

Accelerated Infliximab Infusion: Safety, Factors Predicting Adverse Events, Patients’ Satisfaction and Cost Analysis. A Cohort Study in IBD Patients

“…The CRS is associated with the binding of IFX to the transmembrane TNF alpha in immune cells that activates a cascade of apoptotic signalling which is observed within few hours from the administration with cell degradation and massive release of cytokines in Rheumatoid Arthritis (RA) and CD patients [8, 21]. A shorter infusion duration may interfere with cytokine release for instance reducing the IFX exposure time needed to activate the apoptosis.…”