BRGSF-HIS mice as a predictive tool for safety assessment of biologics

Background

Immunotherapies are efficacious but are often associated to immune-related adverse events, such as cytokine release syndrome (CRS). Safety assessment of therapeutics in preclinical models remains challenging, as they should be relevant and translational. Models exhibiting a human immune system are widely used, but the composition of the human immune system developed remains a concern. Here we report the use of BRGSF mice, an immunodeficient mouse model which can be reconstituted with human cord blood CD34⁺ cells (BRGSF-CD34⁺) or PBMC (BRGSF-PBMC). BRGSF-CD34⁺ develop functional human lymphoid and myeloid compartments, with systematic and persistent presence of plasmacytoid dendritic cells (pDCs), conventional dendritic cells (cDCs), and monocytes/macrophages. Their myeloid and dendritic compartments can be transiently boosted with exogenous human Flt3L injections. In contrary to other models which overexpress human cytokines to develop human myeloid cells, Flt3L-treated BRGSF-CD34⁺ mice do not show side effects.