Clinical translation of antibody drug conjugate dosing in solid tumors from preclinical mouse data
Baron Rubahamya1, Shujun Dong1, Greg M Thurber1,2,3
1Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA.
Abstract:
Antibody drug conjugates (ADCs) have made impressive strides in the clinic in recent years with 11 Food and Drug Administration approvals, including 6 for the treatment of patients with solid tumors. Despite this success, the development of new agents remains challenging with a high failure rate in the clinic. Here, we show that current approved ADCs for the treatment of patients with solid tumors can all show substantial efficacy in some mouse models when administered at a similar weight-based [milligrams per kilogram (mg/kg)] dosing in mice that is tolerated in the clinic. Mechanistically, equivalent mg/kg dosing results in a similar drug concentration in the tumor and a similar tissue penetration into the tumor due to the unique delivery features of ADCs. Combined with computational approaches, which can account for the complex distribution within the tumor microenvironment, these scaling concepts may aid in the evaluation of new agents and help design therapeutics with maximum clinical efficacy.
Insights
Approved antibody drug conjugates (ADCs) show efficacy in mouse models at clinically relevant doses. Equivalent weight-based dosing ensures similar tumor drug levels and penetration, aiding new ADC development for solid tumors.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- Antibody drug conjugates (ADCs) have achieved significant clinical success, with 11 FDA approvals, including 6 for solid tumors.
- Despite progress, ADC development faces high failure rates in clinical trials.
Purpose of the Study:
- To investigate if current approved ADCs for solid tumors demonstrate efficacy in mouse models at clinically relevant, weight-based doses.
- To understand the mechanistic basis for ADC efficacy and tumor targeting.
- To explore how scaling concepts can improve the evaluation and design of new ADC therapeutics.
Main Methods:
- Administration of approved ADCs to mouse models at weight-based (mg/kg) doses comparable to clinical tolerability.
- Assessment of ADC efficacy in mouse models.
- Analysis of drug concentration and tissue penetration within tumors.
- Integration of computational approaches to model drug distribution in the tumor microenvironment.
Main Results:
- Approved ADCs exhibited substantial efficacy in specific mouse models when dosed at equivalent weight-based levels.
- Equivalent mg/kg dosing led to comparable drug concentrations and tumor penetration, characteristic of ADC delivery.
- Computational modeling provided insights into complex tumor microenvironment distribution.
Conclusions:
- Weight-based dosing is a critical factor for translating ADC efficacy from preclinical models to clinical settings.
- Understanding ADC pharmacokinetics, including tumor drug concentration and penetration, is key to successful development.
- Scaling concepts and computational tools can enhance the evaluation of new ADCs and optimize therapeutic design for solid tumors.
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