mAbs that are non-immunogenic in humans induce severe anaphylaxis in existing guinea-pig anaphylaxis models

mAbs that are non-immunogenic in humans induce severe anaphylaxis in existing guinea-pig anaphylaxis models.117 Animals models that are more relevant and in silico and in vitro assessments for predicting immunogenicity/hypersensitivity of mAbs were discussed previously. immune system (dendritic cell) activation and immunogenicity in humans are also described. The importance of selecting a relevant and sensitive toxicity species for human safety assessment in which the immunopharmacology of the mAb is similar to that expected in humans is usually CHIR-090 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 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. models and others have been used with some mAbs.89,100,114,115 Even if a mAb shows no effects in a range of host resistance assays, one cannot conclude that CHIR-090 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 Rabbit Polyclonal to ABCC2 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 combination of bacterial, viral and tumor models) and immune function tests are utilized to increase the weight-of-evidence.99 In these models, the primary endpoint is CHIR-090 usually often mortality, which is usually insensitive and of debatable utility as a predictor of immunosuppression. However, continuous endpoints, e.g., colony/plaque-forming units, are now being used to increase sensitivity.116 In addition, the susceptibility to infection in animals is dependent both on the degree of immunosuppression and number of challenge organisms. The predictivity of such models for humans, where the degree of immunosuppression may be variable in the out-bred population and the number/nature of challenge organisms cannot be controlled, is usually further questioned. Contamination in humans occurs on a background of concomitant medication and underlying disease, e.g., RA, psoriasis, variables not tested in host resistance models. The available host resistance database is limited to a small number of usually high immunosuppressive drugs and hence the question remains as to whether these models can detect the effect of a moderate/moderate immunosuppressant on host defence. One should first consider whether the target is usually involved in mediating defense against particular organisms that might be a risk in humans and if existing class effect data is known in animals or humans or whether infectious agent/tumor challenge data exists from animals treated with a mAb against the same target or from target knockout mice. In these cases host resistance studies may be of little value since a negative result CHIR-090 in a challenge model would not negate the existing data. In many cases it.