Increased longevity of circulating human IgG in an NSG Fc gamma receptor-1 deficient humanized mouse model

Monoclonal antibodies (mAbs) are powerful therapeutic tools that are used to treat multiple types of human cancer as well as a diverse set of non-malignant diseases. Humanized NOD.Cg-Prkdc^scid Il2rgt^m1Wjl/SzJ (NSG) mice implanted with human tumors and with immune cells and tissues are widely used in studies of mAb-based therapeutics. However, due to a gain of function mutation in the Fcgr1 gene in the NOD strain background, NSG mice rapidly clear human IgG1, IgG3, and IgG4. As most mAbs are either IgG1 or IgG4 isotypes, the use of NOD-based mouse models for preclinical testing of therapeutic mAbs is limited by the reduced half-life in vivo. In order to extend the half-life of mAbs in NSG mice and create a more physiologically relevant model, we created NSG Fcγ Receptor I knock out (NSG-Fcgr1^null) mice. IgG clearance was measured for three different cancer therapeutic mAbs: rituximab (IgG1), trastuzumab (IgG1), and pembrolizumab (IgG4), by comparing the levels of circulating human IgG over the course of 5 weeks post IV injection in NSG and NSG-Fcgr1^null mice. Preliminary pharmacokinetic analyses found significant increases in the half-lives and exposure of each of these mAbs in the NSG-Fcgr1^null mice when compared to NSG controls. Additionally, when engrafted with human hematopoietic stem cells (HSCs), NSG-Fcgr1^null mice supported higher levels of serum IgG when compared to NSG controls. Overall, the NSG-Fcgr1^null mouse presents a more physiologically relevant and translatable model for the in vivo testing of human therapeutic mAbs.