Optimized nonclinical safety assessment strategies supporting clinical development of therapeutic monoclonal antibodies targeting inflammatory diseases.

An increasing number of immunomodulatory monoclonal antibodies (mAbs) and IgG Fc fusion proteins are either approved or in early-to-late stage clinical trials for the treatment of chronic inflammatory conditions, autoimmune diseases and organ transplant rejection. The exquisite specificity of mAbs, in combination with their multi-functional properties, high potency, long half-life (permitting intermittent dosing and prolonged pharamcological effects), and general lack of off-target toxicity makes them ideal therapeutics. Dosing with mAbs for these severe and debilitating but often non life-threatening diseases is usually prolonged, for several months or years, and not only affects adults, including sensitive populations such as woman of child-bearing potential (WoCBP) and the elderly, but also children. Immunosuppression is usually a therapeutic goal of these mAbs and when administered to patients whose treatment program often involves other immunosuppressive therapies, there is an inherent risk for frank immunosuppression and reduced host defence which when prolonged increases the risk of infection and cancer. In addition when mAbs interact with the immune system they can induce other adverse immune-mediated drug reactions such as infusion reactions, cytokine release syndrome, anaphylaxis, immune-complex-mediated pathology and autoimmunity. An overview of the nonclinical safety assessment and risk mitigation strategies utilized to characterize these immunomodulatory mAbs and Fc fusion proteins to support first-in human (FIH) studies and futher clinical development in inflammatory disease indications is provided. Specific emphasis is placed on the design of studies to qualify animal species for toxicology studies, early studies to investigate safety and define PK/PD relationships, FIH-enabling and chronic toxicology studies, immunotoxicity, developmental, reproductive and juvenile toxicity studies and studies to determine the potential for immunosuppression and reduced host defence against infection and cancer. Nonclinical strategies to facilitate clinical and market entry in the most efficient timeframe are presented.