This will allow a better understanding of the expected immunological effects in humans and the likely immunotoxicological consequences of any exaggerated pharmacology in FIH studies and beyond. for human safety assessment in which the immunopharmacology of the mAb is similar to that expected in humans is usually highlighted, as is the importance of understanding the limitations of the species selected for human safety assessment and supplementation of in vivo safety assessment with appropriate in vitro human assays. A tiered approach to assess effects on immune Melanotan II status, immune function and risk of contamination and cancer, governed by the mechanism of action and structural features of the mAb, is usually described. Finally, the use of immunopharmacology and immunotoxicity data in determining a minimum anticipated biologic effect Level (MABEL) and in the selection of safe human starting dose is usually discussed. Key words: monoclonal antibodies, non-clinical testing, immunopharmacology, immunotoxicity, cytokine release, immunosuppression, autoimmunity, hypersensitivity, immunogenicity, anti-drug antibody, MABEL Introduction Since the major indications for therapeutic monoclonal antibodies (mAbs), defined here as mAbs, fragments thereof and Fc-fusion proteins, are cancer and inflammatory/autoimmune disease,1C8 a large proportion of the products approved for human use (Table 1) or in clinical development are designed to directly or indirectly modulate one or more aspects of the immune system (humoral, cell-mediated and innate immunity), and therefore have the potential to induce either immune suppression or immune activation. Therapeutic mAbs, including immunomodulatory mAbs, have generally Melanotan II Melanotan II proven to be safe, and in many cases, effective pharmaceuticals. Their toxicity is usually related to exaggerated pharmacology and can, in many cases, be predicted based on an understanding of the intended function of the mAb and the results of appropriate non-clinical studies in pharmacologically-responsive test systems; however the recent well-publicized adverse events observed with an immunomodulatory anti-CD28 superagonist mAb (TGN-1412) in a clinical trial in the United Kingdom9 have highlighted the potential toxicity of some therapeutic mAb approaches, as well as the potential pitfalls in interpreting and extrapolating non-clinical findings to the clinical setting. The profound toxic BA554C12.1 effects observed in healthy volunteers in this trial has emphasized the importance in considering all available Melanotan II biological data, including knowledge of the comparative pharmacological effects in animals and humans, when evaluating the safety of mAbs and in the selection of the starting dose in humans. Such data will be scrutinized more than ever by the regulatory authorities in the years to come. Table 1 FDA and/or EMA-Approved mABs and Fc-fusion proteins models and others have been used with some mAbs.89,100,114,115 Even if a mAb shows Melanotan II no effects in a range of host resistance assays, one cannot conclude that no such effects will occur in humans. In addition, a mAb with an immunosuppressive MoA or that neutralizes cytokines/cell types involved in host defense is likely to get a general label of potential increased risk of contamination and cancer, even if host defense studies prove unfavorable. Many investigators instead choose to address the potential impaired resistance to microbial pathogens in clinical trials and in the subsequent clinical risk management and pharmacovigilence plans. Host resistance assays are rarely performed in the NHP due to lack of qualified models, low animal numbers, high inter-animal variation and lack of Specific Pathogen-Free (SPF) animals, hence NHPs carry different pathogens. Rodent models are available, usually requiring the use of a surrogate mAb. These rodent models are time-consuming and expensive, require specialist external CRO expertise and, due to overlapping and compensatory immune pathways, effects on immune function may not result in decreased host resistance unless multiple host resistance models (a.
