Inhibition of TNFa by Biologics

A new class of TNF-a inhibitors are the so-called "biologics," which are either recombinant monoclonal antibodies or soluble TNF receptor fusion proteins. These proteins can be either isolated from animal tissues or commonly synthesized by biotechnological methods. The more defined understanding of the pathophysiolo-gy of autoimmune diseases has led to the therapeutic use of biologics in chronic inflammatory disorders (Scheinfeld 2004). At present, a few uncontrolled case reports suggest that the therapeutic blockade of TNF-a maybe a novel option for the short-term control of otherwise recalcitrant autoimmune bullous skin disorders (Table 8.1).

Infliximab is a chimeric monoclonal antibody consisting of a murine anti-TNF-a Fab fragment and the constant region (Fc) of human IgGj. Infliximab binds with high specificity and affinity to free and membrane-bound TNF- , which is expressed at the surface by activated T cells and macrophages. Besides the blocking of TNF- , the lysis of the target cell may also occur through activation of complement. This probably accounts for the antibody conveying a cytotoxic effect of infliximab. Inhibition of the pro-inflammatory effects of TNF-a results through the formation of stable complexes. In addition, the migration of leukocytes and the release of TNF-a-dependent proinflammatory cytokines like IL-1 and IL-6 is inhibited.

Adalimumab is a human monoclonal IgGj antibody containing only human peptide sequences. It binds with high specificity and affinity to soluble and membrane-bound TNF-a and blocks its interaction with the p55 and p75 cell surface TNF receptors, thereby neutralizing the biological activities of this cytokine. Ada-limumab also modulates TNF-induced or regulated biological responses, such as changes in the levels of adhesion molecules responsible for leukocyte migration.

Etanercept is a recombinant human fusion protein which consists of two soluble p75 TNF receptors and the Fc portion of human IgG1. Etanercept possesses a dimeric structure with high affinity to TNF-a, and the linkage to the Fc portion of human IgG produces a longer half-life. Etanercept neutralizes TNF- better than the monomeric soluble p75 receptor. By blocking the

Table 8.1. TNF-a inhibitors and application in autoimmune bullous dermatoses

Infliximab (Remicade^) Adalimumab (Humiraß) Etanercept (Enbrel^)

Molecule

Target structure Dosage

Efficacy in autoimmune bullous skin disorders

Chimeric (murine-human) monoclonal antibody (IgGj)

Free and membrane-bound TNF-

3-5 mg/kg/day intravenous infusion at weeks 0, 2 and 6; then every 8 weeks

Pemphigus vulgaris

Jacobi et al. 2005 Pardo et al. 2005

Fully human monoclonal IgG1antibody

Free and membrane-bound TNF-a

40 mg every other week subcutaneously

IgA pemphigus

Howell et al. 2005

Human receptor fusion protein (p75-TNF-receptor dimer and IgGi)

Free TNF-a and lymphotoxin-a (TNF- )

25 mg (children 0.4 mg/kg/day) twice weekly subcutaneously; alternative 50 mg twice weekly at first i2 weeks

Pemphigus vulgaris

Berookhim et al. 2004 Lin et al. 2005

Mucous membrane pemphigoid

Sacher et al. 2002 Bullous Pemphigoid

Yamauchi et al. 2006

circulating TNF- trimers the interaction of TNF-with the cell bound receptors is prevented and the pro-inflammatory cytokine cascade interrupted. Etaner-cept, in addition, binds lymphotoxin (TNF-|3). Cells with membrane-bound TNF-a bind etanercept; lysis due to ADCC of these cells does not occur in contrast to the binding of infliximab (Table 8.1).

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