ArticleThe AAPS journal2020
An Agent-Based Systems Pharmacology Model of the Antibody-Drug Conjugate Kadcyla to Predict Efficacy of Different Dosing Regimens.
Article in The AAPS journal, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
22 citing papers in PubMed, 29 citations in OpenAlex.
- Exploring the immunological effects of antibody-drug conjugates.Nature reviews. Clinical oncology · 2026Review
- Antibody-drug conjugate engineering: from design to efficacy and safety.Signal transduction and targeted therapy · 2026Review
- Agent-based modeling demonstrates how target-independent processes supplement killing by antibody-drug conjugates in cancer therapy.PLoS computational biology · 2026Article
- In Vivo Auto-tuning of Antibody-Drug Conjugate Delivery to Maximize Efficacy Using High-Avidity, Low-Affinity Antibodies.Molecular cancer therapeutics · 2026Article
- Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers.Cancer research communications · 2024Article
- Towards a platform quantitative systems pharmacology (QSP) model for preclinical to clinical translation of antibody drug conjugates (ADCs).Journal of pharmacokinetics and pharmacodynamics · 2024Article
- Optimizing Solid Tumor Treatment with Antibody-drug Conjugates Using Agent-Based Modeling: Considering the Role of a Carrier Dose and Payload Class.Pharmaceutical research · 2024Article
- Clinical translation of antibody drug conjugate dosing in solid tumors from preclinical mouse data.Science advances · 2024Review
- Integrated PK/PD Modeling Relates Smoothened Inhibitor Biomarkers to The Heterogeneous Intratumor Disposition of Cetuximab in Pancreatic Cancer Tumor Models.Journal of pharmaceutical sciences · 2024Article
- An agent-based model of monocyte differentiation into tumour-associated macrophages in chronic lymphocytic leukemia.iScience · 2023Article
- A framework for multi-scale intervention modeling: virtual cohorts, virtual clinical trials, and model-to-model comparisons.Frontiers in systems biology · 2023Article
- Pharmacokinetics and Pharmacodynamics of TAK-164 Antibody Drug Conjugate Coadministered with Unconjugated Antibody.The AAPS journal · 2022Article
- Development of and insights from systems pharmacology models of antibody-drug conjugates.CPT: pharmacometrics & systems pharmacology · 2022Review
- Design of high avidity and low affinity antibodies for in situ control of antibody drug conjugate targeting.Scientific reports · 2022Article
- In Vitro and In Vivo Fluorescence Imaging of Antibody-Drug Conjugate-Induced Tumor Apoptosis Using Annexin V-EGFP Conjugated Quantum Dots.ACS omega · 2022Article
- Development and Evaluation of Competitive Inhibitors of Trastuzumab-HER2 Binding to Bypass the Binding-Site Barrier.Frontiers in pharmacology · 2022Article
- Predictive Simulations in Preclinical Oncology to Guide the Translation of Biologics.Frontiers in pharmacology · 2022Article
- Simulating the Selection of Resistant Cells with Bystander Killing and Antibody Coadministration in Heterogeneous Human Epidermal Growth Factor Receptor 2-Positive Tumors.Drug metabolism and disposition: the biological fate of chemicals · 2022Article
- Key metrics to expanding the pipeline of successful antibody-drug conjugates.Trends in pharmacological sciences · 2021Review
- Transient Competitive Inhibition Bypasses the Binding Site Barrier to Improve Tumor Penetration of Trastuzumab and Enhance T-DM1 Efficacy.Cancer research · 2021Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
The pharmaceutical industry has invested significantly in antibody-drug conjugates (ADCs) with five FDA-approved therapies and several more showing promise in late-stage clinical trials. The FDA-approved therapeutic Kadcyla (ado-trastuzumab emtansine or T-DM1) can extend the survival of patients with tumors overexpressing HER2. However, tumor histology shows that most T-DM1 localizes perivascularly, but coadministration with its unconjugated form (trastuzumab) improves penetration of the ADC into the tumor and subsequent treatment efficacy. ADC dosing schedule, e.g., dose fractionation, has also been shown to improve tolerability. However, it is still not clear how coadministration with carrier doses impacts efficacy in terms of receptor expression, dosing regimens, and payload potency. Here, we develop a hybrid agent-based model (ABM) to capture ADC and/or antibody delivery and to predict tumor killing and growth kinetics. The results indicate that a carrier dose improves efficacy when the increased number of cells targeted by the ADC outweighs the reduced fractional killing of the targeted cells. The threshold number of payloads per cell required for killing plays a pivotal role in defining this cutoff. Likewise, fractionated dosing lowers ADC efficacy due to lower tissue penetration from a reduced maximum plasma concentration. It is only beneficial when an increase in tolerability from fractionation allows a higher ADC/payload dose that more than compensates for the loss in efficacy from fractionation. Overall, the multiscale model enables detailed depictions of heterogeneous ADC delivery, cancer cell death, and tumor growth to show how carrier dosing impacts efficacy to design the most efficacious regimen.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.