Biologic Therapies Targeting TNFa

At the present time, biologics represent the only available class of specific TNF inhibitors available for clinical practice. Three drugs are currently approved. These are infliximab (Remicade), a chimeric monoclonal anti-TNF-a antibody comprising a human IgG-1K antibody with a mouse SV fragment of high affinity and neutralizing capacity; adalimumab (Humira), a mono clonal human antibody produced by phage display; and etanercept (Enbrel), an engineered p75 TNF receptor dimer with a fully human amino acid sequence linked to the Fc portion of human IgG-1. The monoclonal antibodies have specificity for TNF-a. Binding assays using radioactively labelled TNF- demonstrate that antibodies such as infliximab bind both monomeric (inactive) and trimeric (biologically active) forms of soluble TNF-a (Scallon et al. 2002). In contrast, the fusion protein etanercept acts as a competitive inhibitor of TNF- and can also bind lymphotoxin (TNF- ). Etanercept forms relatively unstable complexes with TNF- , allowing dissociation and the potential to form a reservoir for binding TNF-a (Scallon et al. 2002). Aside from the three currently approved biologic TNF inhibitors for rheumatoid arthritis, others are in development, including certolizumab pegol (formerly known as CDP-870, now Cimzia), a pegylated Fab fragment which can be produced in Escherichia coli (Hazle-man et al. 2000).

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