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 their early stages of T cell activation. Anti-CTLA-4 monoclonal antibodies (mAbs) demonstrated an effective approach for tumor immunotherapy. Preclinical pharmacokinetics (PK) and pharmacodynamics (PD) characterizations are essential for designing of the first-in human trial.
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 mouse CTLA-4 gene exon 2 were replaced with human counterparts. Using B-hCTLA-4 mice, we developed a mAb PK/PD model to characterize anti-tumor effect of hCTLA-4 antibodies.
MC 38 cancer cells were inoculated into C57BL/6 wild type and humanized CTLA-4 animals. After antibody treatment, serum samples were taken at specific times from each animal for PK/PD analysis. Data were analyzed using the WinNolin8.1 software. One compartmental model was used to describe serum concentrations of mAb in mice. The Tumor Growth Inhibition (TGI) value was evaluated as PD effect with MC38 and B-hCTLA-4 mice model. The PK/PD assays showed that tested anti hCTLA-4 mAb has dose-dependent tumor inhibition effect in hCTLA-4 mice. Humanized B-hCTLA-4 mouse represents a promising PK/PD model for CTLA-4 mAb preclinical trials.