Case Study: Immunogenicity of Anti-TNF Antibodies
Anti-tumor necrosis factor (TNF) therapy has become an important alternative in the management of several chronic immunoinflammatory diseases. Three recombinant anti-TNF drugs are currently approved for clinical use in patients with various chronic inflammatory diseases such as rheumatoid arthritis, Crohn’s diseases, and severe psoriasis: (1) Remicade™ (infliximab), a mouse-human IgG1-kappa anti-TNF-alpha monoclonal antibody, (2) Enbrel™ (etanercept), a fusion protein of human TNF receptor 2 and human IgG1, and (3) Humira™ (adalimumab), a fully human IgG1-kappa anti-TNF-alpha monoclonal antibody. Two other anti-TNF-alpha antibody constructs have shown promise in pivotal phase III trials in patients with some of the same diseases: (4) Cimzia™ CDP870 (certolizumab pegol), a PEGylated Fab fragment of a humanized anti-TNF-alpha monoclonal antibody, and (5) CNTO 148 (golimumab), a fully human IgG1-kappa anti-TNF-alpha monoclonal antibody. All these proteins dramatically lower disease activity and, in some patients, may induce remission. Unfortunately, however, not all patients respond favorably to anti-TNF antibodies. Some patients either do not respond at all (primary response failure) or they respond initially but have later relapses (secondary response failure) despite increased dosage and/or more frequent administration of the drugs. The reason(s) for these response failures is(are) not entirely clear, but interindividual and even intraindividual differences in bioavailability and pharmacokinetics may contribute to the problem. Furthermore, immunogenicity of the drugs causing patients to develop anti-antibodies is a problem now recognized by many investigators, drug-controlling agencies, health insurance companies, and drug manufacturers. Monitoring of patients for circulating levels of functional anti-TNF drugs and anti-antibody development is therefore warranted so that administration can be tailored to the individual patient and so that prolonged therapies can be provided effectively and economically with little or no risk to the patients.
KeywordsTumor Necrosis Factor Inhibitor Certolizumab Pegol Infliximab Therapy Response Failure Tumor Necrosis Factor Activity
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