Model-Informed Optimal Dosing of Anti-CD47 Antibody Using Target-Mediated Drug Disposition Model.

IMC-002, an anti-cluster of differentiation 47 (CD47) antibody, was developed as a fully human immunoglobulin (Ig) G4 monoclonal antibody targeting CD47. IMC-002 blocks CD47-signal regulatory protein alpha (SIRPα) interactions, increasing the phagocytosis of cancer cells by macrophages. This study established a target-mediated drug disposition (TMDD) pharmacokinetics (PK) model for IMC-002 to explain the characteristics of the neonatal Fc receptor (FcRn) of IgG based on phase I trial data to perform model-informed optimal dosing for a phase I study. The PK data were obtained from a phase I dose escalation study on 12 patients with advanced solid tumors. Each patient received multiple doses (5, 10, 20, or 30 mg/kg) via intravenous infusion over 3 h every 2 weeks. The IMC-002 PK data were analyzed using NONMEM software (version 7.5) using the first-order conditional estimation method with interaction (FOCEI). The semi-mechanistic TMDD model explained the nonlinear PK properties of IMC-002, including FcRn recirculation. Weight, sex, and age were investigated as covariates using stepwise covariate testing. No statistical covariates were identified. Simulations were performed to determine the optimal dosing regimen for patients with solid tumors that extend the administration period and maintain the mean concentrations above the minimum effective concentration (MEC). The ideal regimen of 20 mg/kg every 3 weeks ensured that the mean plasma concentration remained above the MEC throughout the dosing interval. Our study developed a robust TMDD PK model for IMC-002, which provides the rationale for a dose regimen in a phase 1 study.