Abstract 3906: PK-PD modelling of an anti-CTLA-4 antibody on immune checkpoint humanized mice

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; also known as CD152) is expressed on the surface of T cells, where it primarily suppresses the early stages of T cell activation. In preclinical studies, blockade of CTLA-4 led to an increase in T-cell proliferation. Anti-CTLA-4 monoclonal antibodies (mAbs) have been shown to be an effective approach for tumor immunotherapy. Preclinical pharmacokinetic (PK) and pharmacodynamic (PD) characterization of these antibodies is essential for designing first-in human trials. PK prediction is especially challenging for monoclonal antibodies attributed to target-mediated drug disposition (TMDD). We generated a humanized B-hCTLA-4 mouse model, in which exon 2 of the murine CTLA-4 gene was replaced with its human counterpart. In homozygous mice, only human protein expression can be detected, while mouse CTLA-4 was knocked out. Using B-hCTLA-4 mice, we developed a mAb PK/PD model to characterize the anti-tumor effects of hCTLA-4 antibodies. MC38 cancer cells were inoculated into both C57BL/6 wild type and humanized CTLA-4 animals. After administering different antibody concentrations (ranging from 3.0, 1.0, 0.3, 0.1mg/kg), serum samples from each animal were taken at specific time points for PK/PD analysis. An NCA approach was used to determine serum concentrations of mAb in mice. The levels of 13 cytokines (IL-23, IL-1α, IFN-r, TNF-a, IL-6 etc.) were quantified using LEGENDplex bead-based immunoassays. The PK half-life was 50~100h and the cytokine concentration ranged from 0-2000pg/ml depending on the dose used. The Tumor Growth Inhibition (TGI) value was also evaluated as a PD effect in the MC38/B-hCTLA-4 model. The TGI value reached nearly 100% when the dose was above 0.3mg/kg. The PK/PD assays showed that the anti hCTLA-4 mAb tested has a dose-dependent tumor inhibition effect in hCTLA-4 mice. Results from TMDD model data showed that the humanized mice reached QuasiSteady State faster than wild type mice, indicating that the humanized mice are an appropriate TMDD model. In conclusion, humanized B-hCTLA-4 mice are a promising PK/PD model for CTLA-4 mAb preclinical trials. Citation Format: Madeline Lee, Jie Xiang, Tian Gan, Yuelei Shen, Chaoshe Guo. PK-PD modelling of an anti-CTLA-4 antibody on immune checkpoint humanized mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3906.