Mechanistic Modeling of Tumor Immune Microenvironment Reveals Strategies to Enhance Antibody-Drug Conjugates’ Efficacy

BACKGROUND:Antibody-drug conjugates (ADCs) and bispecific antibodies represent a rapidly advancing frontier in oncology, yet the abnormal tumor microenvironment (TME) hinders their delivery and reduces efficacy. Emerging immunomodulatory ADCs (IM-ADCs) demand mechanistic mathematical models that couple drug transport with immune dynamics. METHODS:Here, we present a mechanistic framework for the delivery of HE-S2 ADC, an anti-programmed cell death ligand 1 (PD-L1) antibody bearing the bifunctional immunomodulator D18. Our model integrates cancer-immune cells interactions, TME properties, such as dysfunctional vessels, elevated interstitial fluid pressure, tissue hydraulic conductivity, and vascular permeability, spatiotemporal distributions across growing tumor and adjacent host tissue, convective-diffusive transport, ADCs binding and internalization kinetics and tumor-draining lymph node biology governing antigen presentation and the generation of effector CD8+ T cells. Parameters were calibrated simultaneously with the murine MC38 and B16 tumor growth data and effector CD8+T cell data following treatment with D18, anti-PD-L1, and ADC. RESULTS:Our mechanistic spatiotemporal model captures the superior antitumor efficacy of the HE-S2 ADC relative to its individual components and provides mechanistic predictions for unmeasured variables, such as spatiotemporal dynamics of drug/immune-cell distributions. It explains reduced intratumoral D18 exposure via rapid clearance, while antibody/ADC achieves higher tumor retention through leaky tumor vasculature. The model suggests a reinforcing loop in which improved ADC exposure enhances CD8+T cell infiltration, driving tumor shrinkage that lowers fluid pressure and improves drug delivery. Parametric analyses findings support TME normalization strategies that increase functional vessel density prior to ADC administration; however, such approaches should preserve sufficient vascular permeability by maintaining vessel pore radius >~40 nm, ensuring pores remain large enough for ADC extravasation and effective intratumoral delivery. CONCLUSION:The proposed mechanistic model successfully captures how TME properties regulate the delivery and efficacy of IM-ADCs while suggesting TME normalization as a potential strategy to improve treatment outcomes.