Evaluation of a reference antibody panel for prediction of cytokine release in humanised mouse models in vivo

Introduction A diverse range of innovative biological therapies is being developed to treat various human diseases. The safety assessment of these biologics is a critical factor determining clinical success. Enhanced humanised mouse models have the potential to revolutionise immunotoxicological profiling by refining procedures for effective in vivo safety assessments. Methods We evaluated a novel reference panel of recombinant monoclonal antibodies (mAbs), 19/156, with varying cytokine release (CR) potential to assess the sensitivity of specific humanised mouse models. The in vitro CR capacity of the reference panel has previously been evaluated in an international collaborative study. We present here the in vivo assessment of the reference Ab panel using NOD-scid-gamma (NSG) mice reconstituted with either umbilical cord-derived hematopoietic human (CD34 + ) stem cells (HSC) or human peripheral blood mononuclear cells (PBMC) from healthy donors. Results Our manuscript discusses a comparative evaluation of both forms of engraftment and the CR patterns in response to the reference panel. The in vivo CR pattern is discussed in relation to in vitro assays using the same PBMC donor cohort. The manuscript discusses the utility of these humanised mice as a model for translational use in hazard identification and preclinical safety assessment. Discussion The results highlight the importance of incorporating standardised reference materials to evaluate, qualify, and harmonise preclinical models for translational use. This approach aims to enhance the predictability and reliability of both in vitro and in vivo safety assessments, thereby supporting the development of safe and effective biological therapies.