Biologic therapies in rheumatology: lessons learned, future directions

Key Points During the past decade biologic therapies such as monoclonal antibodies and fusion proteins have revolutionized the management of rheumatic disease. By targeting key cytokines and immune cells they have provided more specific therapeutic interventions with less immunosuppression. Clinical use of biologic therapies has revealed that their theoretical simplicity hides a more complex reality. Efficacy, toxicity and even pharmacodynamic effects can deviate from those predicted, as poignantly illustrated by the catastrophic effects witnessed during the first-into-human administration of TGN1412. This review summarizes lessons gleaned from practical experience with biologic therapies and discusses how these can inform future discovery and development of new biologic therapies for rheumatology. The exquisite specificity of monoclonal antiboides (mAbs) and soluble receptors can limit the information provided by preclinical models, making prediction of beneficial and adverse effects in humans challenging. The Fc regions of mAbs and fusion proteins can modulate their clinical effects, influencing their potency (for example, for target cell lysis), immunogenicity and adverse effects (for example, the cytokine storm associated with first administration of some mAbs). Immunogenicity is common with all biologic therapies, including 'fully human' products. The consequences vary but antiglobulins shorten circulating half-life, can reduce efficacy and result in adverse effects ranging from infusion reactions to anaphylaxis. Subtle changes in manufacturing processes can significantly alter efficacy and tolerability profiles, and can result in previously unrecognized immunogenicity. With most biologic agents clinical trials have been designed to maximize efficacy so that it is not known whether pharmacokinetic or pharmacodynamic effects might best predict efficacy or safety (for example, C max , C min or AUC or whole-blood assay results). This information can significantly inform treatment regimens and advisability of induction regimens. Efficacy is not always explicable by expected mechanisms of action. For example, etanercept, adalimumab, infliximab and certolizumab pegol each neutralize TNFα.Certolizumab pegol, an Fab' construct lacking an Fc, cannot mediate ADCC, CDC or apoptosis in ex vivo assays, in contrast to the other three. Adalimumab, infliximab and certolizumab are effective in Crohn's disease whereas etanercept is not. Clinical use of biologic therapi