Anti-TNF

A critical step in radioprotection involves the IL-1 receptors. Monoclonal antibodies to the type 1 IL-1 receptor block IL-l-induced radioprotection (167). Although this receptor is not present on BM cells, it is present on fibroblasts, which suggests that the effects of IL-1 on stem cells maybe largely indirect and mediated by stromal cell activation (168). Anti-IL-1 receptor (type 1) also sensitizes normal mice to the effects of TBI, which suggests that endogenous IL-1 has an intrinsic radioprotective role. IL-6 induction by IL-1, but not CSF levels, is inhibited, which supports the concept that G-CSF and GM-CSF are insufficient by themselves at radioprotecting stem cells and indicates a contributory role for IL-6. Anti-IL-6 antibody blocks IL-1 and TNF-induced radioprotection and also decreases the intrinsic radioresistance of mice, as does anti-TNF- a (169). 

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. 

Palladino MA, Bahjat FR, Theodorakis EA et al (2003) Anti-TNF-alpha therapies the next generation. Nat Rev Drug Discov 2 736-746... 

Anti-TNF therapy, particularly when used in combination with methotrexate, gives rise to substantial... 

Adalimumab (Humira ) is a folly human anti-TNF monoclonal antibody that is mainly used in combination with methotrexate to treat rheumatoid arthritis in adults [3]. Meanwhile, it is also used against arthritis of psoriasis and ankylosing spondylitis. Its therapeutic value in Crohn s disease is under clinical trial. 

Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis what have we learned Annu Rev Immunol 2001 19 163-196. 

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. 

In chimpanzees, administration of Fab fragments of a monoclonal anti-F-VII antibody preceding an endotoxin bolus injection effectively blocked the activation of the coagulation pathway (B25). Administration of monoclonal anti-lL-6 under the same experimental conditions attenuated the activation of coagulation, while the fibrinolytic system remained unaltered. However, administration of monoclonal anti-TNF enhanced the tendency to microvascular thrombosis (P17,18). Monoclonal anti-TF antibodies administered to baboons as a pretreatment attenuated coagulopathy after induction of E. coli sepsis in these animals (T4). Primates pretreated with anti-C5a antibodies before infusion of E. coli developed less hypotension and had better survival rates than untreated animals, who developed ARDS and septic shock with a mortality rate of 75% (S35, Z6). No favorable treatment results have been published yet with one of these treatment modalities given to humans. 

Fig. 17.1. T reatment of normally resistant BALB/c IL-4 KO mice with anti-TNF-a monoclonal antibody prevents IL-13-mediated expulsion of T. muris. Mice were infected on day 0 with 200 T. muris eggs and worm burdens (+ sem) from four mice per group determined on days 18, 22 and 35 post-infection. (Data adapted from Artis etal., 1999a.)...

Fully human IgGl, Anti-TNF- 150 kDa Biotech / Schering-Plough Murine Sp2/0-cell line... 

TNF-a, therefore, promotes various aspects of immunity and inflammation. Blockage of its activity, e.g. by administration of anti-TNF-a antibodies, has been shown to compromise the body s ability to contain and destroy pathogens. 

One such product (tradename Beromun) has been approved for general medical use (Box 9.2). Most clinical interest in TNF, however, now centres around neutralizing its biological effects in situations where overexpression of TNF induces negative clinical effects. TNF has been firmly implicated in mediating many of the adverse effects associated with dozens of diseases (Table 9.7). Administration of anti-TNF monoclonal antibodies or soluble forms of the TNF receptor should help reduce the severity of many of the symptoms of these diseases. 

Brandt, J. and Braun, J. 2006. Anti-TNF-alpha agents in the treatment of psoriatic arthritis. Expert Opinion on Biological Therapy 6(2), 99-107. 

Humira (EU USA also sold as Trudexa in EU) (adalimumab r (anti-TNF) human monoclonal antibody created using phage display technology Cambridge Antibody Technologies Abbott (USA) Abbott (EU) Rheumatoid arthritis... 

The major types of drug therapy used in IBD include aminosalicylates, glucocorticoids, immunosuppressive agents (azathioprine, mercaptopu-rine, cyclosporine, and methotrexate), antimicrobials (metronidazole and ciprofloxacin), and agents to inhibit tumor necrosis factor-a (TNF-a) (anti-TNF-a antibodies). 

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... 

Knight, D.M. et al., Construction and initial characterization of mouse human chimeric anti TNF alpha antibody, Molecular Immunol., 30, 1443, 1993. 

Debandt, M. et al., Anti-TNF-alpha-induced systemic lupus syndrome, Clin. Rheumatol., 22, 56, 2003. 

Remicade Infliximab Gentocor Anti-TNF Rheumatoid arthritis 1999... 

Humira Adalimumab Abbott Laboratories, North Chicago, IL Anti-TNF Rheumatoid arthritis 2002... 

Tumor Necrosis Factor There are two types of tumor necrosis factor TNF-a and TNF- 8. Of the two, TNF-a has been studied in more detail. TNF-a is a 157 amino acid polypeptide. It is a mediator of immune regulation, including the activation of macrophages and induction of the proliferation of T cells. Another TNF-a function is its cytotoxic effects on a number of tumor cells. Recent research, however, concentrates on its property in the stimulation of inflammation, particularly in the case of rheumatoid arthritis. Clinical trials are being conducted with drugs to block TNF-a with anti-TNF-a monoclonal antibodies. These antibodies target the excessive levels of TNF-a in the synovial fluid of joints and provide relief to sufferers of rheumatoid arthritis (Exhibit 4.10). 

TNF-a is a cytokine produced by T cells and mast cells. TNF-a is involved in the gut inflammatory process in Crohn disease, where treatment with soluble TNF-a receptor and anti-TNF-a antibodies and soluble TNF-a receptor has the highest... 

Several studies have examined the relationship between these polymorphisms and the severity of RA and response to anti-TNF agents. They are discnssed next. 

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