Evaluation of an IgG therapeutic efficacy in a humanized immune system mouse model lacking murine Fc gamma receptors

Fc gamma receptors (FcγRs) on residual murine immune cells in humanized immune system (HIS) mice can interact with human IgG-based therapeutics and confound preclinical results. We assessed impact of murine FcγRs on anti-PD1 efficacy in HIS mice engrafted with lung adenocarcinoma cells treated with pembrolizumab or vehicle. We also present humanization results for the newly generated FcγR knockout NOG-EXL. Methods: HIS NOG (huNOG) or HIS FcγR knockout NOG mice (FcResolv™ huNOG) were made using identical protocols with CD34+ cells (3 shared donors). Reconstitution was evaluated in naïve animals and HCC827 cells were inoculated in remaining animals. From D7, mice were dosed twice weekly for 4 wks then euthanized for blood, spleen, and tumor analysis. Results: Humanization was equivalent between strains. Pembro treatment showed significant tumor growth inhibition in 1 donor in FcResolv huNOG, but not in donor-matched huNOG. Human TILs in pembro-treated mice were significantly different between the strains for all donors, with more CD8+ T cells and fewer TAMs in FcResolv huNOG compared to vehicle-treated mice, and no significant differences in huNOG. Murine TIL analysis showed differences in murine macrophage populations between strains. Conclusions: Anti-PD1-treated FcResolv huNOG mice show expected pharmacodynamic changes and donor-dependent efficacy, whereas pembro-treated huNOG mice showed neither, demonstrating the impact of murine FcγRs on antibody IgG-based therapeutics.