Optimizing human FcRn mouse models to improve pharmacokinetic evaluation of antibody drug candidates

The use of animal models that can reliably predict drug performance in human patients is critical to antibody therapeutic development. Along with assessing toxicity and efficacy, determining the pharmacokinetic (PK) properties of therapeutics in Tg32 and Tg276 mice is essential to preclinical characterization. While Tg32 mice have been well established as indispensable in their ability to model the PK properties of antibody therapeutics, their intact immunity leaves them capable of mounting anti-drug antibody responses that interfere with PK interpretation. Here, we demonstrate the negative impact anti-drug responses can have on PK parameters derived from Tg32 mice, and provide strong evidence to support the use of immunodeficient Tg32 SCID mice as an equivalent means to model human PK. In addition, we investigate one possible cause for reduced FcRn function observed in Tg276 mice when compared to Tg32 mice in spite of evidence that their FcRn protein levels are actually higher. We also introduce NSG Tg32 mice and our attempts to block off-target binding of human IgGs to their high-affinity Fc gamma receptors, which failed to recover FcRn function similar to that observed from Tg32 mouse controls, dramatically limiting their utility for PK analysis. Taken together, our results provide a comparison of these preclinical animal models, so they can be used to improve human PK predictions of antibody therapeutic candidates in development.