Prediction of pharmacokinetics and pharmacodynamics profile for a fixed dosing and body weight-based dosing of GI-102 based on cell-level pharmacodynamics-mediated drug disposition model in patients with advanced or metastatic solid tumors

GI-102 (CD80/IL2v3) is designed to direct IL-2 variant to immune cells and tumor cells, and to block CTLA-4 via CD80. Proliferation of cytotoxic T (T c ) cells and natural killer (NK) cells is enhanced through selective binding to IL-2Rbetagamma. CD80-CTLA4 binding further inhibits immunosuppressive function of regulatory T (T reg ) cells. Based on GI-102 monotherapy dose-escalation data of the phase 1/2 first-in-human study (KEYNOTE-G08), a cell-level pharmacodynamics-mediated drug disposition (PDMDD) model was constructed to assess the relationship between drug exposure, target receptor occupancy, and pharmacodynamic (PD) effect. Historically, IL-2 therapies relied on body-weight-based dosing due to narrow therapeutic windows and high interpatient variability. Leveraging GI-102 safety and tolerability in humans, model-informed simulations compared overall pharmacokinetic (PK) and PD profiles of fixed-dose versus weight-based dosing.The model was constructed by simultaneously fitting drug concentrations (n=1185) and total lymphocyte (n=826), T c cell, NK cell, and T reg cell counts (n=529 each) from 54 patients with advanced or metastatic solid tumors who received GI-102 intravenously every three weeks at doses of 0.06-0.45 mg/kg. The target-mediated drug disposition (TMDD) model incorporated time-varying PD-mediated disposition at the cellular level. Lymphocyte diapedesis after treatment was described empirically, and time delay between drug concentrations and lymphocyte increase driven by GI-102-IL-2Rbetagamma stimulation was captured by an indirect response model with the operational model of agonism. Following model diagnostics, Monte-Carlo simulations with 1000 replicates were performed for each scenario using the final model. Modeling was conducted using NONMEM® v7.5.0, and data processing and plotting using R v4.3.3. The two-compartment, cell-level PDMDD model adequately described central tendency of observed PK/PD data. Simulations showed a clear exposure-response relationship across doses. At 0.24-0.45 mg/kg, total lymphocytes and T c cells, accounting for diapedesis, reached levels around 3640-4136 cells/μL and 515-572 cells/μL, respectively. At the same range, NK cells were predicted to exceed 1000 cell/μL, indicating robust expansion at receptor occupancy < 50%. In addition, simulations for fixed-dose regimen of 10, 20, and 30 mg showed increased immune cell proliferation, largely comparable to corresponding weight-based doses of 0.12, 0.24, and 0.35 mg/kg, respectively. Our modeling and simulation provides preliminary prediction of PD effect at tested doses and fixed-dose regimens, serving as reference for determining optimal dose and dosing regimen.