The Yin and Yang of Immunomodulatory Biologics: Assessing the Delicate Balance between Benefit and Risk

A number of therapeutic immunomodulatory biologics, including antibodies, fusion proteins, and recombinant proteins, have been causally linked with serious adverse effects in humans. In nearly all cases, these serious adverse effects have been directly associated with the immunomodulatory biologic’s intended pharmacologic activity or exaggerated pharmacology. Examples of immunomodulatory biologics known to cause serious adverse effects in the clinic ranging from immunostimulation and cytokine release syndrome (e.g., TGN1412) to immunosuppression with increased risk of opportunistic infections (e.g., TNF-α antagonists, anti-integrins) are presented. Specific examples of the nonclinical testing strategy used for the clinical risk assessment of these immunomodulatory biologics are discussed, with an emphasis on the clinical relevance and predictivity of the models. Infectious challenge animal models, in particular, were critically evaluated for their utility in evaluating clinical risk assessment versus unde...