Four monoclonal antibodies to human TNF are approved for the treatment of IBD: infliximab, adalimumab, golimumab, and certolizumab (Table 62–3). Infliximab, adalimumab, and golimumab are antibodies of the IgG1 subclass. Certolizumab is a recombinant antibody that contains an Fab fragment that is conjugated to polyethylene glycol (PEG) but lacks an Fc portion. The Fab portion of infliximab is a chimeric mouse-human antibody, but adalimumab, certolizumab, and golimumab are fully humanized. Infliximab is administered as an intravenous infusion. At therapeutic doses of 5–10 mg/kg, the half-life of infliximab is approximately 8–10 days, resulting in plasma disappearance of antibodies over 8–12 weeks. Adalimumab, golimumab, and certolizumab are administered by subcutaneous injection. Their half-lives are approximately 2 weeks.
All four agents bind to soluble and membrane-bound TNF with high affinity, preventing the cytokine from binding to its receptors. Binding of all three antibodies to membrane-bound TNF also causes reverse signaling that suppresses cytokine release. When infliximab, adalimumab, or golimumab bind to membrane-bound TNF, the Fc portion of the human IgG1 region promotes antibody-mediated apoptosis, complement activation, and cellular cytotoxicity of activated T lymphocytes and macrophages. Certolizumab, without an Fc portion, lacks these properties.
TABLE 62–3 Anti-TNF antibodies used in inflammatory bowel disease.
TNF, tumor necrosis factor.
Infliximab, adalimumab, and certolizumab are approved for the acute and chronic treatment of patients with moderate to severe Crohn’s disease who have had an inadequate response to conventional therapies. Infliximab, adalimumab, and golimumab are approved for the acute and chronic treatment of moderate to severe ulcerative colitis. With induction therapy, these approved agents lead to symptomatic improvement in 60% and disease remission in 30% of patients with moderate to severe Crohn’s disease, including patients who have been dependent on glucocorticoids or who have not responded to 6-MP or methotrexate. The median time to clinical response is 2 weeks. Induction therapy is generally given as follows: infliximab 5 mg/kg intravenous infusion at 0, 2, and 6 weeks; adalimumab 160 mg (in divided doses) initially and 80 mg subcutaneous injection at 2 weeks; and certolizumab 400 mg subcutaneous injection at 0, 2, and 4 weeks. Patients who respond may be treated with chronic maintenance therapy, as follows: infliximab 5 mg/kg intravenous infusion every 8 weeks; adalimumab 40 mg subcutaneous injection every 2 weeks; certolizumab 400 mg subcutaneous injection every 4 weeks. With chronic, regularly scheduled therapy, clinical response is maintained in more than 60% of patients and disease remission in 40%. However, one-third of patients eventually lose response despite higher doses or more frequent injections. Loss of response in many patients may be due to the development of antibodies to the TNF antibody or to other mechanisms.