Mechanistic Modeling of Intra-Tumor Spatial Distribution of Antibody-Drug Conjugates: Insights into Dosing Strategies...

Area of Science:

• Pharmacology
• Oncology
• Mathematical Modeling

Background:

• Antibody drug conjugates (ADCs) offer targeted cancer therapy but face challenges with solid tumor penetration and clinical efficacy.
• Insufficient tumor penetration limits the effectiveness of many ADCs in solid tumors.

Purpose of the Study:

• To develop a predictive framework linking ADC tumor penetration and distribution to clinical efficacy.
• To understand the relationship between ADC pharmacokinetics, tumor penetration, and tumor growth inhibition for solid tumors.

Main Methods:

• Expanded Krogh cylinder models to a clinical framework, integrating pharmacokinetics, tumor penetration, and growth inhibition.
• Incorporated heterogeneous tumor growth inhibition to mechanistically capture ADC binding, tumor cell killing, and proliferation rates.
• Validated the model using virtual patient populations against observed overall response rates in metastatic breast cancer patients treated with trastuzumab-DM1.

Main Results:

• The model successfully linked ADC tumor penetration and distribution to clinical efficacy.
• Simulations revealed heterogeneous tumor cell killing, with higher efficacy near capillaries and increased proliferation further away.
• Sensitivity analyses indicated that dose fractionation, ADC-target affinity, payload potency, and tumor growth rate are key determinants of clinical efficacy.

Conclusions:

• This mechanistic framework provides a basis for predicting and optimizing ADC clinical efficacy in solid tumors.
• The findings support optimizing dosing strategies, such as dose fractionation, to improve patient outcomes.
• Understanding ADC penetration and distribution is crucial for enhancing therapeutic effectiveness in solid tumor treatment.