TNF-α: Autoimmune Disease Drug Target in Cytokines & Growth factors

Introduction of TNF-α as a Cytokine

Human TNF-α is a non-glycosylated protein of 17 kDa and a length of 157 amino acids. The human gene maps to chromosome 6p23-6q12. It is located between the class I HLA region for HLA-B, and the gene encoding complement factor C.
TNF-α exists in both soluble and membrane bound forms. It is secreted by macrophages, monocytes, neutrophils, T-cells, and NK-cells following stimulation by bacterial lipopolysaccharides. Cells expressing CD4 secrete TNF-α, while CD8 cells secrete little or no TNF-α. Both stimulated and unstimulated peripheral neutrophilic granulocytes, several transformed cell lines, astrocytes, microglia, smooth muscle cells, and fibroblasts also secrete TNF.

Targeting TNF-α Signaling for Autoimmune Disease Therapy

TNF-α has been described as a proinflammatory cytokine associated with certain autoimmune diseases. Under the presumption that excess TNF-α causes deleterious effects, several anti-TNF therapies have been designed to treat autoimmune diseases. All of these agents were designed to negate TNF-α activity by inhibiting TNF transcription, TNF protein, TNF receptors, and TNF-mediated downstream signaling. There have been four different TNF-α inhibitors used in humans.


Infliximab is a recombinant, chimeric (75% human 25% mouse) monoclonal antibody against TNF-α. It consists of the variable mouse region coupled to the constant human IgG1 region, and has a half life of 8-10 days. Although Infliximab failed as a treatment for septic shock, it has been approved for use as a treatment for rheumatoid arthritis. It has also been approved for use in patients with Crohn's disease.


Etanercept is a fully human recombinant dimeric fusion protein. It consists of two soluble p75 TNF Type II receptors linked to the Fc portion of human IgG, which increases its half life to 3-5.5 days. It binds and inactivates soluble and cell-bound TNF-α and lymphotoxin, preventing their interaction with their receptors.


Adalimumab is the first fully human monoclonal antibody used to treat TNF-induced disorders. It is indistinguishable from naturally occurring human IgG1 and possesses high specificity and affinity for TNF-α. Its halflife is 10-20 days, and shows lower immunogenicity compared to Infliximab. Adalimumab binding to TNF-α results in the lysis of cells expressing TNF-α, and blocks the binding of the cytokine to its receptors.


Lenercept consists of two p55 soluble TNF receptors fused to a human IgG Fc constant region, and targets TNF and lymphotoxin a. Lenercept development for human use was interrupted due to its induction of anti-lenercept antibodies, and therefore will not be discussed further in this review.

TNF-α as Drug Target in Autoimmune Disease: Conclusion

More than half a million autoimmune patients have received therapy with anti-TNF-α antibodies, usually because they were refractory to conventional treatments.

TNF-α: Autoimmune Disease Drug Target in Cytokines & Growth factors: Reference

Chatzantoni K, et al. Anti-TNF-α antibody therapies in autoimmune diseases[J]. Current topics in medicinal chemistry, 2006, 6(16): 1707-1714.