Anti-TNF antibodies

Inhibition of inflammatory cytokines (Fig. 2) Humanized monoclonal anti-TNF antibodies (Infliximab (Remicade ), Adalimumab (Humira )) bind with high selectivity to human TNF-a and neutralize its activity. Thereby, infliximab decreases the effects of enhanced TNF levels during inflammatory disease such as production of proteases, chemokines, adhesion molecules, cyclooxygenase products (prostaglandins), and proinflammatory molecules such as interleukin-1 and -6. The antibodies may also recognize membrane-bound TNF-a on lymphocytes and other immune cells. These cells may subsequently become apoptotic or are eliminated via Fc-receptor-mediated phagocytosis. 

Pretreatment with monoclonal anti-TNF antibodies prevents mortality (B23, M32) and organ damage (M16) in experimental sepsis. In clinical studies using anti-TNF antibodies, however, the overall benefit of this treatment showed encouraging but no evident results (L22). Recently, the INTERSEPT study suggests a possible role for anti-TNF antibody as an adjunctive therapy, but with no reduction of mortality (C21). There is no plain cause-effect relation between TNF re-... 

The effects of corticosteroids, cyclooxygenase blockers, leukotriene blockers, PAF antagonists, anti-TNF antibodies, oxygen radical scavengers, opiate antagonists, antihistamines, and calcium channel blockers in endotoxic shock were reviewed in 1990 (H17). In this section studies on this subject that have been published during the last few years are summarized. 

Infliximab is an anti-TNF antibody that is useful in moderate to severe active disease and steroid-dependent or fistulizing disease but the cost far exceeds that of other regimens. Adalimumab is another anti-TNF antibody... 

IX.b.3.4. Genetically engineered antibodies. Anti-TNF antibody treatment with infliximab or adalimumab is now accepted as of value in treating severe and fistulating exacerbations of Crohn s disease when standard treatments are not tolerated or have failed. Adverse effects which limit usefulness include the occurrence of tuberculosis and septicaemia, leucopenia and pancytopenia, and risk of exacerbation of demyelinating disease. Considerations of benefits versus risks of such treatment are complex, but probably positive. 

Therapeutic pyramid approach to inflammatory bowel diseases. Treatment choice is predicated on both the severity of the illness and the responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. Drugs may be used alone or in various combinations. Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn s colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn s colitis or Crohn s perianal disease), or budesonide (Crohn s ileitis). Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with oral corticosteroids to promote disease remission immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with severe Crohn s disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used primarily for patients with severe ulcerative colitis who have failed a course of intravenous corticosteroids. TNF, tumor necrosis factor. 

Table 62-3 Anti-TNF Antibodies Used in Inflammatory Bowel Disease. ...

Anti-TNF antibodies, eg, infliximab, others Bind tumor necrosis factor and prevent it from binding to its receptors Suppression of several aspects of immune function, especially ThI lymphocytes Infliximab Moderately severe to severe Crohn s disease and ulcerative colitis others approved in Crohn s disease Infusion reactions reactivation of latent tuberculosis increased risk of dangerous systemic fungal and bacterial infections... 

Knight DM, Trinh H, Le J, Siegel S, et al. 1993. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol. 30 1443-1453. 

TNF-rt effects cellular function via activation of specific membrane-bound TNF receptors (TNFRi, TNFR2). Administered soluble TNF receptors, by combining with soluble TNF-, can inhibit the effects of the endogenous cytokine. Monoclonal anti-TNF antibodies can, in theory, cross-link TNF receptors on the cell surface and inhibit T cell and macrophage function. Three drugs interfering with TNF- have been approved for the treatment of rheumatoid arthritis. 

Vincent, J. L., Bakker, J., Marcecaux, G. et al. (1992). Administration of anti-TNF-antibody improves left ventricular function in septic shock patients. Results of a pilot study. Chest 101, 810-815. 

Van de Putte, L. B. A., van Riel, P., den Broeder, A., Sander, O., Rau, R., Binder, C. et al. (1996). A single dose placebo controlled phase I study of the fully human anti TNF antibody D2E7 in patients with RA. Arthritis Rheum. 41, S57 (abstract). 

Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006 295 2275-85. 

Despite a good overall safety profile, anti-TNF antibodies can induce a number of adverse effects, including autoimmunity and infections. A trial in the treatment of Crohn s disease noted infusion reactions, transient increased of anti-dsDNA antibodies, and serum sickness-like delayed hypersensitivity with retreatment. Induction of human-antichimeric-antibodies was suggested as the cause of some of the infusion reactions [90]. A prospective study in 35 patients with Crohn s disease showed induction of ANA and anti-dsDNA autoantibodies in 53% and 35% of infliximab-treated patients [91]. A single patient showed clinical features consistent with drug-induced lupus, including the presence of ANA and anti-dsDNA autoantibodies, which quickly resolved after discontinuation of infliximab. Reports on renal adverse effects of anti-TNF antibodies are very rare. Saint Marcoux described the occurrence of crescentic GN in as few as 2 patients out of a cohort of 39 patients, treated with an anti-TNF antibody for rheumatoid arthritis [92]. A case report by Chin et al. [93] described the case of a 29-year-old Australia-born Vietnamese who presented with nephrotic syndrome. A renal biopsy showed membranous nephropathy. Symptoms attenuated after discontinuation of infliximab therapy. 

The clinical effects of Etanercept are comparable to those of Infliximab. One advantage of Etanercept is that it is given subcutaneously twice a week, whereas Infliximab is given by slow intravenous infusion every 4-8 weeks. Another advantage is that Etanercept also recognizes lymphotoxin, and this may account for its efficacy in juvenile chronic arthritis. Currently, D2E7, a fully human anti-TNF antibody, is being developed (Knoll). It appears to be effective in RA without the need for methotrexate cotreatment (575). 

Infliximab is a chimeric antibody combining portions of mouse and human IgGi. An anti-TNF antibody was created by exposing mice to human TNF. The binding portion of that antibody was fused to a... 

Fig. 6. The role of endogenous tumor necrosis factor TNF) in D-galactosamine (GalN)-induced liver damage. All mice were injected with 2.1 g/kg GalN. Serum transaminases ALT) and hepatic DNA fragmentation were determined after 24 h. Animals pretreated with neutralizing anti-TNF antibodies or mice lacking TNF receptor-1 tnf-rl°) were protected...

Anti-TNF antibodies human-mouse chimeric antibody (infliximab or Remicade). A trial in the treatment of Crohn s disease noted infusion reactions, transient increased of anti-dsDNA antibodies, and serum sickness-like delayed hypersensitivity with retreatment. Induction of human-antichimeric-antibodies was suggested as the cause of some of the infusion reactions [31]. 

The role of cytokines in anti-CD3-mAb-mediated nephropathy was analyzed by pretreating mice with either neutralizing anti-TNF antibodies or mPDS [156]. The histologic lesions and the renal excretion of endopeptidase 24.11 were moderately prevented by anti-TNF antibodies, suggesting the involvement of other mediators, which could act in synergy with TNF-a. In support of this view, steroid pretreatment before anti-CD3 challenge almost completely abohshed IL-2, TNF-a and IL6 release and resulted in preservation of renal histology. 

Other data have not supported a role for TNF-a in the development of acetaminophen toxicity. WUd-type and TNFa knockout mice had equal sensitivity to acetaminophen (Boess et al. 1998), and treatment with anti-TNF antibody or soluble TNF receptor did not alter acetaminophen toxicity in mice (Simpson et al. 2000). Subsequent work by James reported no difference in toxicity between TNHil knockout mice and wild-type mice (James et al. 2005). Conflicting data from these studies, compared to the findings of Blaska (Blazka et al. 1995b, 1996), may be related to strain or dose differences, or variations in repair processes among mice strains. 

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