Etanercept – TNF receptor and IgG1 Fc fusion protein: is it different from other TNF blockers?

Abstract

TNF blockers have been available to treat various inflammatory disorders since more than a decade. T cells and macrophages mainly express TNF and activate many cells through two types of receptors. Pharmaceutical companies developed two types of TNF blockers: soluble receptors and monoclonal antibodies. Understanding of differences of structure and function can explain divergence of efficacy or side effects. Etanercept has the best retention rate in rheumatic diseases, but is less or not effective in granulomatous diseases, such as inflammatory bowel diseases or uveitis. However, etanercept induces less tuberculosis infections than anti-TNF blocker monoclonal antibodies.

Keywords::

• efficacy
• etanercept
• side effect
• TNF blockers

Introduction of biologic agents for the treatment of inflammatory joint disorders has opened a new therapeutic area. TNF blockers were the first members of these biologic agents. These TNF blockers were developed from a better knowledge on rheumatoid arthritis (RA) pathogenesis research. Previously, all RA therapies had evolved primarily from unanticipated observations.

1. TNF cytokine

TNF (previously named TNF-α) is generated as a precursor form called transmembrane TNF, which is mainly expressed as a 26-kD cell-surface type II polypeptide on activated macrophages and lymphocytes [1]. After being processed by TACE, a soluble form of TNF (17 kD) is released and mediates its biologic activities through type I and type II TNF receptors. Transmembrane TNF also exerts cytotoxic activity and induces polyclonal B-cell activation, in a cell-to-cell contact manner. Nearly every mammalian cell expresses TNF receptors. This explains the variety of TNF effects, from apoptosis to various proteins expression. The two types of receptors, type I (p55) and type II (p75), are capable to bind TNF, but also lymphotoxin (previously named TNF-β). TNF receptors can be cleaved from the cell surface to a soluble form to inhibit the effects of TNF, which mediates the immune response by increasing the transport of white blood cells to sites of inflammation, and through additional molecular mechanisms, which initiate and amplify inflammation. In the rheumatoid joint, TNF induces the synthesis and secretion from synovial fibroblasts of matrix-degrading proteases and other proinflammatory cytokines. Inhibition of its action by etanercept reduces the inflammatory response, which is especially useful to treat arthritis.

2. TNF blockers

Pharmaceutical companies developed two types of anti-TNF agents according to their structures; one type is engineered from human TNF receptors and the other type is generated as an antibody against human TNF. Here, we focus only on drugs commercially available in 2014.

Etanercept is the only TNF blocker commercially available consisting in a fusion protein combining two extracellular ligand-binding portions of the human soluble TNF receptor p75 with the end Fc fragment of human immunoglobulin G1. The Fc fragment prolongs the half-life of the compound in the bloodstream, therefore, with a more profound and long-lasting biologic effect than a naturally occurring soluble TNF receptor. This drug inhibits the binding of soluble TNF to cell-surface TNF receptors, functioning as a decoy receptor. Like the soluble forms of TNF receptors, it also blocks lymphotoxin, but the pharmacological meaning of this binding is not known. Etanercept binds to transmembrane TNF, but it has only antibody-dependent cell-mediated cytotoxicity (ADCC) without activities of complement-dependent cytotoxicity (CDC) [2]. Despite efficacy of p75 inhibition by etanercept, inhibition of TNF by two drugs containing soluble receptor type I p55 was not successful [3,4]. This discrepancy can be explained by intrinsic differences between the p55 type I TNF receptor and p75 type II TNF receptor [5].

Monoclonal antibodies targeting TNF (anti-TNF mAbs) bind to both soluble and membrane-bound forms of TNF. So they prevent soluble TNF from binding to its receptor. They have the abilities of CDC, ADCC and outside-to-inside signals (apoptosis/cell cycle arrest) through transmembrane TNF [2]. Three anti-TNF mAbs are available in 2014, i.e., infliximab, adalimumab and golimumab. Pharmaceutical companies also built a partial antibody combining humanised Fab fragment targeting TNF with a PEG fragment. The only member of this class of drug is certolizumab pegol. In contrast to other anti-TNF mAbs, certolizumab pegol induces direct cytotoxic effect, but not apoptosis. Due to the lack of Fc component, a transplacental passage is unlikely [6]. However, the clinical significance of this remains uncertain.

The most important mechanism of TNF blockers action seems to be the binding of free soluble TNF, thereby preventing its binding to the TNF receptor, and this effect is shared by all TNF blocker agents. Due to their differences of structure, actions of TNF blocker have some differences as previously reported [7].

3. Differences of efficacy and safety due to distinction of structure and function

3. 1 Etanercept is effective for the treatment of arthritis

Direct comparison of results from different randomised clinical trials is not feasible, but no superiority of one TNF blocker was demonstrated in RA, psoriatic arthritis, ankylosing spondylitis (AS) or juvenile idiopathic arthritis (JIA). After clinical assessment, physicians also explored effects on structural damage. In RA, TNF blockers are effective for both bone and joint destruction prevention [8]. In AS no clear effect was demonstrated on the spine; however, data from registries suggest a reduction of hip replacement surgery due to prevention of radiographic progression in AS patients treated with TNF blockers [9].

3.2 Psoriasis: efficacy and paradoxal effect

All TNF blockers are efficient for skin psoriasis. However, paradoxal psoriasis lesion mainly like pustular lesions on the palms and/or soles was observed during all TNF blockers [10]. An imbalance between cytokines secondary to TNF blockade is suspected [10], suggesting interest to propose anti-IL-12/IL-23 monoclonal antibody [11].

3.3 Malignancies induction

In a recent systematic literature review including observational studies, patients on TNF blockers did not have an increased risk for malignancies in general, lymphoma or non-melanoma skin cancer, but the risk of melanoma may be slightly increased [12].

3.4 Granulomatous diseases: etanercept is less effective than anti-TNF mAbs

3.4.1 Anterior uveitis

Uveitis can occur in the context of many inflammatory joint disorders, including spondyloarthropathies, RA and especially JIA. TNF blockers demonstrate a reduction of incidence of uveitis (new onset and flares). Compared to other TNF blockers, etanercept is less effective than anti-TNF mAbs to prevent new onset of uveitis [13]. Contrary to anti-TNF mAbs, etanercept did not show efficacy in the treatment of JIA-associated uveitis in randomised, controlled and open trials [14]. A better performance with adalimumab was recently suggested [15].

3.4.2 Inflammatory bowel disease

Etanercept failed to demonstrate efficacy in inflammatory bowel diseases [16], whereas anti-TNF mAbs are efficient [17]. The lower avidity of etanercept to transmembrane TNF than other TNF inhibitors could be one explanation. Recently, the modulation of non-apoptotic pathways through down-regulation of proinflammatory growth differentiation factor 1 was identified with anti-TNF mAbs [18].

3.4.3 Sarcoidosis

Some cases of sarcoidosis associated with TNF were reported with an estimated incidence around 1/2800 [19]. In majority of these cases, etanercept was involved with a recent report of sarcoidosis induced by etanercept and treated by adalimumab [19].

Overall, anti-TNF mAbs appeared to be more effective to treat granulomatous diseases (anterior uveitis, IBD, sarcoidosis) than etanercept. However, this good effect of anti-TNF mAbs on granulomatous diseases can explain some complications as tuberculosis.

3.5 Tuberculosis

The major side effect of TNF blockers is infection. However, chronic inflammation as in RA patients naïve to TNF blockers is associated with a baseline increased risk of tuberculosis infection compared to the general population. Understanding defects in cell-mediated immunity in chronic inflammation is of major interest since cases of severe tuberculosis have been reported in RA patients receiving TNF blockers [20]. First, cases of active tuberculosis were described soon after the initiation of treatment with infliximab [20]. Later, etanercept was described to be also associated with tuberculosis, but this was lower and associated with longer time to tuberculosis onset when compared to infliximab and adalimumab [21,22]. These differences could be explained by differences in structure and function of these drugs on membrane-bound TNF, leading to a differential effect on the binding to membrane TNF on effector T cells and Treg cells.

3.6 No neutralising anti-drug antibodies induced by etanercept

Owing to structures of TNF blockers, these drugs can induce development of anti-drug antibodies (ADAb). A recent exhaustive review discussed heterogeneity of detection method and heterogeneity according to each drug [23]. For anti-TNF mAbs, ADAb presence was associated with low trough drug levels, low clinical response, or adverse event. Due to its structure, etanercept appeared to be less immunogenic than anti-TNF mAbs without functional effect of its ADAb.

3.7 Better maintenance rate with etanercept

Persistence and adherence to TNF blockers have recently been measured in a number of observational studies within specific indications. Data from various registries suggest higher maintenance rates for etanercept than for infliximab in RA [24]. The highest maintenance rate of etanercept could be due to many factors including less painful injection, lack of development of ADAb, etc.

4. Conclusion

Etanercept appeared to be as effective in arthritis than other TNF blockers, with a higher retention rate. Differences in efficacy in granulomatous disease or for paradoxal and side effects may be explained by its specific structure.

Declaration of interest

The authors have no competing interests to declare and have received no funding in preparation of the manuscript.