Mechanistic Modeling of Intra‐Tumor Spatial Distribution of Antibody‐Drug Conjugates: Insights into Dosing Strategies in Oncology

Abstract

Antibody drug conjugates (ADCs) provide targeted delivery of cytotoxic agents directly inside tumor cells. However, many ADCs targeting solid tumors have exhibited limited clinical efficacy, in part, due to insufficient penetration within tumors. To better understand the relationship between ADC tumor penetration and efficacy, previously applied Krogh cylinder models that explore tumor growth dynamics following ADC administration in preclinical species were expanded to a clinical framework by integrating clinical pharmacokinetics, tumor penetration, and tumor growth inhibition. The objective of this framework is to link ADC tumor penetration and distribution to clinical efficacy. The model was validated by comparing virtual patient population simulations to observed overall response rates from trastuzumab‐DM1 treated patients with metastatic breast cancer. To capture clinical outcomes, we expanded upon previous Krogh cylinder models to include the additional mechanism of heterogeneous tumor growth inhibition spatially across the tumor. This expansion mechanistically captures clinical response rates by describing heterogeneous ADC binding and tumor cell killing; high binding and tumor cell death close to capillaries vs. low binding, and high tumor cell proliferation far from capillaries. Sensitivity analyses suggest that clinical efficacy could be optimized through dose fractionation, and that clinical efficacy is primarily dependent on the ADC‐target affinity, payload potency, and tumor growth rate. This work offers a mechanistic basis to predict and optimize ADC clinical efficacy for solid tumors, allowing dosing strategy optimization to improve patient outcomes.

The Rise of the TROP2-Targeting Agents in NSCLC: New Options on the Horizon

“…The safety profile of sacituzumab govitecan in this phase 2 trial was consistent with that previously reported in the phase 1 trial (NCT01631552) and phase 1/2 trial (NCT01631552) of this agent in other metastatic solid tumours [16,22]. The most common adverse events (AEs) of any grade were nausea (80%), diarrhoea (61%), fatigue (46%), alopecia (39%), and neutropenia (37%) [16].…”

Clinical Pharmacology of Antibody-Drug Conjugates

“…PBPK is widely used for the characterization of PK and drug-drug interaction studies for small and large molecules. PBPK models have been developed for several ADCs [85][86][87][88]. Considering the complexities of an ADC molecule, the predictive power of PBPK models requires extensive validation from external data (observed data) before its use can be justified for ADCs.…”

“…Considering the complexities of an ADC molecule, the predictive power of PBPK models requires extensive validation from external data (observed data) before its use can be justified for ADCs. It is also important to establish if a whole body or minimal PBPK [88] model is needed for ADCs. In short, modeling and simulation is a helpful tool to obtain relevant information regarding ADCs before clinical trials are initiated.…”

Engineered Ultrasmall Nanoparticle Drug‐Immune Conjugates with “Hit and Run” Tumor Delivery to Eradicate Gastric Cancer

“…[23] ADCs (Tables S1 and S2, Supporting Information), have demonstrated rapid growth in recent decades for treating a variety of cancers, with 5 ADCs alone approved over the past 2 years. Despite these successes, several limitations have persisted, [24] including off-target toxicity, drug resistance, relatively low drugantibody ratios, and poor solid tumor penetration, [25,26] that, in turn, may reduce efficacy. [25] As a result, several ADCs used in the clinic have been discontinued.…”

“…Despite these successes, several limitations have persisted, [24] including off-target toxicity, drug resistance, relatively low drugantibody ratios, and poor solid tumor penetration, [25,26] that, in turn, may reduce efficacy. [25] As a result, several ADCs used in the clinic have been discontinued. Such developments have spurred explosive growth over the past decade in a diverse array of alternative targeted nanodelivery vehicles used as monotherapies or as part of combinatorial regimens [27] for treating AGC; these have been summarized in a number of excellent comprehensive reviews.…”