A Physiologically Based Pharmacokinetic Framework for Quantifying Antibody Distribution Gradients from Tumors to...

Immune checkpoint blockades prescribed in the neoadjuvant setting are now under active investigation for many types of tumors, and many have shown early success. The primary tumor (PT) and tumor-draining lymph node (TDLN) immune factors, along with adequate therapeutic antibody distributions to the PT and TDLN, are critical for optimal immune activation and anti-tumor efficacy in neoadjuvant immunotherapy. However, it remains largely unknown how much of the antibody can be distributed into the PT-TDLN axis at different clinical scenarios. The goal of the current work is to build a physiologically based pharmacokinetic (PBPK) model framework capable of characterizing antibody distribution gradients in the PT-TDLN axis across various clinical and pathophysiological scenarios. The model was calibrated using clinical data from immuno-PET antibody-imaging studies quantifying antibody pharmacokinetics (PK) in the blood, PTs, and TDLNs. The effects of metastatic lesion location, tumor-induced compression, and inflammation, as well as surgery, on antibody concentration gradients in the PT-TDLN axis were characterized. The PBPK model serves as a valuable tool to predict antibody exposures in various types of tumors, metastases, and the associated lymph node, supporting effective immunotherapy.