Semi-Mechanistic Modeling of S-531011, a Humanized Anti-CCR8 Monoclonal Antibody, for Prediction of CCR8 Receptor Occupancy in Human Tumor Tissues.

Semi-mechanistic modeling approaches could be useful for optimal dose selection, and one of the approaches is pharmacokinetic (PK)/receptor occupancy (RO) model for monoclonal antibodies. This study aimed to develop a semi-mechanistic PK/RO model of S-531011, a humanized monoclonal antibody against human CCR8 and under development for the treatment of solid tumors, in order to predict human RO values in tumor tissues which are not available in the ongoing clinical study. The model consists of three compartments (central, peripheral, and tumor) and includes four compartments (S-531011, CCR8, and complexes 1/2 within each compartment). The model parameters were set using available clinical data, non-clinical data, and physiological information. The human PK/RO model was developed by refinement of a mouse PK/RO model. The time courses of RO values in the tumor compartment were simulated using the model, together with a conservative condition of slow transfer of S-531011 from blood to the tumor. It was predicted that the RO value in the tumor compartment at 21 days (trough after the third dose after administration of S-531011 80 mg) would be maintained at > 90% under typical model assumptions. Under the conservative condition, the RO value in the tumor after administration of S-531011 800 mg would remain at > 90%. The developed semi-mechanistic PK/RO model could predict human RO values of S-531011 in tumor tissues. Under typical model assumptions, simulations suggested the dose range of 80-800 mg of S-531011 every 3 weeks would achieve > 90% RO in tumor tissues.