A New Venue of TNF Targeting

Abstract

The first Food and Drug Administration-(FDA)-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects, followed by protein-based medicines such as antibodies. Conventional antibodies bind a specific protein and are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals are the anti-tumor necrosis factor (TNF) drugs that are applied in several inflammatory diseases that are characterized by dysregulated TNF levels. Marketing of TNF inhibitors revolutionized the treatment of diseases such as Crohn's disease. However, these inhibitors also have undesired effects, some of them directly associated with the inherent nature of this drug class, whereas others are linked with their mechanism of action, being pan-TNF inhibition. The effects of TNF can diverge at the level of TNF format or receptor, and we discuss the consequences of this in sepsis, autoimmunity and neurodegeneration. Recently, researchers tried to design drugs with reduced side effects. These include molecules with more specificity targeting one specific TNF format or receptor, or that neutralize TNF in specific cells. Alternatively, TNF-directed biologicals without the typical antibody structure are manufactured. Here, we review the complications related to the use of conventional TNF inhibitors, together with the anti-TNF alternatives and the benefits of selective approaches in different diseases.

Keywords: TNF receptor (TNFR); biologicals; tumor necrosis factor (TNF).

Figure 1

Cytokine kinetics in sepsis. Tumor necrosis factor (TNF) and interleukin (IL-)1 are the first cytokines to be released in sepsis and promote the secretion of IL-6. Together, these cytokines are the orchestrators during the pro-inflammatory phase in sepsis. After some time, compensation mechanisms arise to dampen the pro-inflammatory response such as IL-10, IL-1 receptor antagonist (IL-1Ra) and soluble TNF receptor (sTNFR). Figure adapted from [63].

Figure 2

Multiple roles for tumor necrosis factor (TNF) receptor (TNFR) signaling in multiple sclerosis (MS) pathology. In the central nervous system (CNS), TNF is primarily expressed by astrocytes, microglia and neurons and can stimulate its own release via TNFR1. A detrimental role for TNFR1 has been described in the pathology of MS. TNFR1 signaling triggers oligodendrocyte (OLG) death and contributes to primary demyelination via macrophages. Conversely, TNFR2 has protective effects in the CNS, as the interaction with tmTNF on astrocytes stimulates remyelination and neuronal TNFR2 protects against excitotoxicity. In the periphery, TNFR2 induces the development of effector T cells, but in the CNS, microglial-expressed TNFR2 is protective. TNF, possibly via TNFR2, mediates regression of activated myelin-specific T cells. Furthermore, TNFR2 signaling also facilitates the expansion of regulatory T cells (T_regs) and improves their suppressive capacities against effector T cells. Normal arrows indicate the action of a mediator or the processes that are induced; bold arrows represent mediators produced by a specific cellular subset. T bars represent the inhibition of the indicated pathway.

Figure 3

Structure (A); and mechanisms of action (B) of anti-TNF biologics. All anti-TNF biologics neutralize membrane-bound (tmTNF) and soluble TNF (sTNF) but, in addition to that, some inhibitors also induce outside-to-inside signaling via tmTNF and their Fc-regions mediate antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). ADCC: antibody-dependent cellular cytotoxicity; CDC: complement-dependent cytotoxicity, Fab: fragment antigen binding; IgG: immunoglobulin G; IL: interleukin; NK: natural killer; ROS: reactive oxygen species tmTNF: transmembrane TNF.

Figure 4

Beneficial and side effects of anti-TNF medication. In addition to the well-known beneficial effects in several autoimmune diseases, anti-TNF medication is associated with many side effects.