An Agent-Based Systems Pharmacology Model of the Antibody-Drug Conjugate Kadcyla to Predict Efficacy of Different Dosing Regimens

Abstract

DM1 localizes perivascularly, as seen in multiple mouse models (4), due to its large size and high affinity to HER2 receptors.We and others have demonstrated that some ADC regimens can improve ADC distribution, efficacy, and tolerability. As previously established in our lab, the co-administration of T-DM1 with its unconjugated antibody, trastuzumab, improves drug penetration and efficacy (5). Other work from Hinrichs et al. and Jumbe et al. show that fractionating a single dose into 3 weekly doses can lead to similar efficacy, but better tolerability (6, 7). Despite these findings, the design principles underlying the best choice of regimen and drug combinations are not well-understood. For example, it is not clear if/when a 'carrier dose' will increase drug penetration and improve efficacy. The impact of HER2 expression level and payload potency on the increase or reduction in efficacy from a carrier dose are also not well defined. Finally, the interplay of dose fractionation with carrier doses on overall efficacy is currently unknown.Testing all combinations of receptor expression, payload potencies, carrier doses, dose fractionation regimes, etc. in vivo would be a daunting and expensive process. For this

Simulating the Selection of Resistant Cells with Bystander Killing and Antibody Coadministration in Heterogeneous Human Epidermal Growth Factor Receptor 2–Positive Tumors

“…We extended our hybrid agent-based model (ABM) framework introduced previously (Menezes et al, 2020) to incorporate additional physical and biological phenomena. Briefly, the model is comprised of cells and blood vessels that behave based on probabilistic rules and their microenvironment.…”

“…ADC monotherapy with T-DM1 at a clinical dose (3.6 mg/kg) shows that the drug is localized around blood vessels in solid tumors, and most of the tumor does not receive the treatment (Rhoden & Wittrup, 2012). As shown both in mice and in simulations, coadministration of trastuzumab and T-DM1 can improve penetration and efficacy of these therapeutics in solid tumors (Cornelius Cilliers, Menezes, Nessler, Linderman, & Thurber, 2018 Menezes, Cilliers, Wessler, Thurber, & Linderman, 2020). At the same time, this coadministration reduces the number of payloads in targeted cells (which is important for cell killing (F. Li et al, 2016)), thereby making these cells theoretically more susceptible to continued growth and division.…”

“…Here, we use a validated agent-based model described previously (Menezes et al, 2020) to quantify how ADCs with bystander payloads modulate efficacy in heterogeneous solid tumors, both with and without coadministered antibody, specifically focusing on overall efficacy and selection of resistant cells. In particular, we ask three questions: 1) How do carrier doses and bystander effects (MMAE vs. SMCC-DM1) impact the distribution, uptake, and efficacy of ADC treatment in tumors with heterogeneous HER2 expression?…”

Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions

“…In an agent-based model, individual discrete agents can represent antibodies or the diverse cell populations that interact with each other under defined rules. A tridimensional heterogeneous TME can be constructed by moving along a 3D lattice, providing real-time simulations of antibody diffusion in TME and the resultant cellular responses [ 145 , 146 , 147 , 148 , 149 ]. For example, Kather et al designed a 3D agent-based model of human colorectal cancer, which includes TME components such as lymphocytes and fibrotic stroma, to evaluate treatment effects of immunotherapy [ 148 ].…”

“…For example, Kather et al designed a 3D agent-based model of human colorectal cancer, which includes TME components such as lymphocytes and fibrotic stroma, to evaluate treatment effects of immunotherapy [ 148 ]. Menezes et al developed a hybrid agent-based model to capture antibody delivery in solid tumors for predicting tumor killing and growth kinetics [ 149 ].…”