Abstract 7174: Pharmacokinetics and immunogenicity of anti-PD-1 antibody in humanized FcRn mouse models compared to immunocompetent mouse models

Abstract

Abstract Introduction: The development and use of therapeutic antibodies in cancer therapy has increased significantly in recent years, led by the success of approved immune checkpoint blockade antibodies targeting PD-1 and PD-L1 axis. However, obtaining more clinically relevant pharmacokinetics (PK), safety and efficacy data for antibodies is still challenging in preclinical phase. Humanized FcRn (hFcRn) transgenic mouse model has a more faithful catabolism compared to WT mice, providing more accurate and predictable PK data of innovative antibody-based therapeutics at discovery stage[1]. In this study, we sought to investigate pharmacokinetics and immunogenicity characteristics of anti-PD-1 antibody in hFcRn transgenic mice and provide guidance for its differentiation of prediction value for drug PK and safety by comparing to WT mice. Methods: Non-tumor bearing hFcRn mice and wild type C57BL/6 mice were divided into 2 groups, 5 mice were enrolled into each group. Mice were administered anti-PD-1(Nivolumab) at 10 mg/kg single dose after grouping by intravenous (IV) injection. Blood samples at 12 timepoints (15min, 6h, 1, 2, 4, 7, 10, 14, 21, 28, 35, 42 days) post-dosing were collected for PK and Anti-Drug Antibody (ADA) analysis by MSD and ELISA. Results: Nivolumab clearance in hFcRn mice followed a typical linear profile with rapid distribution phase and slow elimination phase (t1/2 = 350 to 400 h). While the PK profile in C57BL/6 mice displayed non-linear clearance and very short elimination phase (t1/2 = 45 to 50 h). This data demonstrated that hFcRn mice have better correlated half-life with human (Nivolumab single dose by IV with 10mg/kg, t1/2 = 595 h) [2]. ADA analysis revealed that it was produced starting from Day 10 in wild type C57BL/6 mice and the frequency of ADA induced by Nivolumab in wild type mice (2/5) was higher than hFcRn mice (0/5). The variation of Nivolumab level was correlated with ADA production in wild type mice. This suggested hFcRn shows lower immunogenicity than wild type mice for human IgG drug and can potentially improve negative effect of ADA interference on PK evaluation. Conclusion: The result of this study demonstrated that the PK data in hFcRn mouse model was more predictive of human PK profile compared to wild type C57BL/6 mice. This advances innovation in antibody-based therapeutics and translational applications, with improved PK, safety and efficacy evaluation for preclinical human IgG drug development in cancer therapy.