ArticleThe AAPS journal2016
Determination of Cellular Processing Rates for a Trastuzumab-Maytansinoid Antibody-Drug Conjugate (ADC) Highlights Key Parameters for ADC Design.
Article in The AAPS journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 77 citations in OpenAlex.
- NPTXR as a novel therapeutic target: efficacy of antibody-drug conjugates in preclinical tumor models.Cancer cell international · 2026Article
- Review
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- Antibody-Drug Conjugates in Breast Cancer: Navigating Innovations, Overcoming Resistance, and Shaping Future Therapies.Biomedicines · 2025Review
- N‑Terminal Conjugation of a Near-Infrared Photosensitizer to an Antibody for Cancer Diagnosis and Treatment.ACS omega · 2025Article
- Targeting uPAR with an antibody-drug conjugate suppresses tumor growth and reshapes the immune landscape in pancreatic cancer models.Science advances · 2025Article
- Hedgehog Pathway Is a Regulator of Stemness in HER2-Positive Trastuzumab-Resistant Breast Cancer.International journal of molecular sciences · 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
- Increased imaging ligand hydrophilicity and improved pharmacokinetic properties provides enhanced in vivo targeting of fibroblast activation protein.Npj imaging · 2024Article
- Quantitative evaluation of trastuzumab deruxtecan pharmacokinetics and pharmacodynamics in mouse models of varying degrees of HER2 expression.CPT: pharmacometrics & systems pharmacology · 2024Article
- HER2 quantitative continuous scoring for accurate patient selection in HER2 negative trastuzumab deruxtecan treated breast cancer.Scientific reports · 2024Article
- Modeling the subcutaneous pharmacokinetics of antibodies co-administered with rHuPH20.Clinical and translational science · 2024Article
- Antibody-mediated delivery of viral epitopes to redirect EBV-specific CD8Cancer gene therapy · 2024Article
- Clinical validation of translational antibody PBPK model using tissue distribution data generated withJournal of pharmacokinetics and pharmacodynamics · 2023Article
- Probing the Internalization and Efficacy of Antibody-Drug Conjugate via Site-Specific Fc-Glycan Labelling of a Homogeneous Antibody Targeting SSEA-4 Bearing Tumors.Israel journal of chemistry · 2023Article
- Pharmacokinetics and Pharmacodynamics of Antibody-Drug Conjugates Administered via Subcutaneous and Intratumoral Routes.Pharmaceutics · 2023Article
- Tumor-specific intracellular delivery: peptide-guided transport of a catalytic toxin.Communications biology · 2023Article
- Development of and insights from systems pharmacology models of antibody-drug conjugates.CPT: pharmacometrics & systems pharmacology · 2022Review
- Mathematical Models to Characterize the Absorption, Distribution, Metabolism, and Excretion of Protein Therapeutics.Drug metabolism and disposition: the biological fate of chemicals · 2022Review
- Predictive Simulations in Preclinical Oncology to Guide the Translation of Biologics.Frontiers in pharmacology · 2022Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
Antibody-drug conjugates (ADCs) are a promising class of cancer therapeutics that combine the specificity of antibodies with the cytotoxic effects of payload drugs. A quantitative understanding of how ADCs are processed intracellularly can illustrate which processing steps most influence payload delivery, thus aiding the design of more effective ADCs. In this work, we develop a kinetic model for ADC cellular processing as well as generalizable methods based on flow cytometry and fluorescence imaging to parameterize this model. A number of key processing steps are included in the model: ADC binding to its target antigen, internalization via receptor-mediated endocytosis, proteolytic degradation of the ADC, efflux of the payload out of the cell, and payload binding to its intracellular target. The model was developed with a trastuzumab-maytansinoid ADC (TM-ADC) similar to trastuzumab-emtansine (T-DM1), which is used in the clinical treatment of HER2+ breast cancer. In three high-HER2-expressing cell lines (BT-474, NCI-N87, and SK-BR-3), we report for TM-ADC half-lives for internalization of 6-14 h, degradation of 18-25 h, and efflux rate of 44-73 h. Sensitivity analysis indicates that the internalization rate and efflux rate are key parameters for determining how much payload is delivered to a cell with TM-ADC. In addition, this model describing the cellular processing of ADCs can be incorporated into larger pharmacokinetics/pharmacodynamics models, as demonstrated in the associated companion paper.
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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.