A New Venue of TNF Targeting

Abstract

The first FDA-approved drugs were small, chemically-manufactured and highly active molecules with possible off-target effects. After this first successful wave of small drugs, biotechnology allowed the development of 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-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 such as immunogenicity, whereas others are linked with their mechanism of action. Recently, researchers tried to design innovative drugs with reduced side effects aiming to make them more effective and safer. Molecules with more specificity e.g. that target one specific TNF format or receptor, or that neutralize the TNF signaling pathway in specific cells, are generated. 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 different (neurodegenerative) diseases that might benefit from selective approaches.

TNF receptor signalling in autoinflammatory diseases

“…Anti-TNF therapeutics have revolutionised treatment for a number of inflammatory diseases with dysregulated TNF levels. At present, 25 drugs which inhibit or modulate the effects of TNF, are approved clinically by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of RA, AS, psoriasis, PsA, JIA, CD and UC (101). Although many patients benefit from treatment with anti-TNF drugs, a number of patients do not respond well to the therapy (102) and it is of some concern that prolonged use of anti-TNF biologics has also been shown to increase the prevalence of neurological diseases, such as MS, with several reports showing increased CNS demyelination as a possible contribution to disease onset (103).…”

Lysophosphatidic acid induces tumor necrosis factor‐alpha to regulate a pro‐inflammatory cytokine network in ovarian cancer

“…Both approaches have been approved by the FDA for the treatment of arthritis and other TNF-αdriven medical conditions. 57 Incubation of Caov-3, SKOV-3, and OVCAR-3 cells with one of the TNF-α-blocking agents decreased cellular production of IL-8 ( Figure 6A), IL-6 ( Figure 6B), and CXCL1 ( Figure 6D). In general, the inhibitory effect of TNF-α Ab and TNF-α SR on IL-6 production was less dramatic than that on IL-8, particularly in Caov-3 cells.…”

The Role of TNF in the Pathogenesis of Inflammatory Bowel Disease

“…Subsequent studies have demonstrated that infliximab treatment results in a positive clinical response as well as in a significant endoscopic improvement, confirmed also by histological examination as a complete reduction in the inflammation infiltrate. The breakthrough in the treatment of patients with IBD with anti-TNF therapy has firmly established the dogma that TNF is a major cytokine in this disease [32,33]. Anti-TNF drugs such as infliximab, adalimumab, and etanercept are nowadays commonly used in the treatment of a variety of inflammatory and autoimmune diseases (IBD, rheumatoid arthritis, psoriasis, psoriasiform arthritis, and ankylosing spondylitis).…”