ArticleMolecular cancer therapeutics2012
The effect of different linkers on target cell catabolism and pharmacokinetics/pharmacodynamics of trastuzumab maytansinoid conjugates.
Article in Molecular cancer therapeutics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers, 1 of them a synthesis that pooled it.
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Who cites it
57 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Structure-Activity Relationships of Antibody-Drug Conjugates: A Systematic Review of Chemistry on the Trastuzumab Scaffold.Bioconjugate chemistry · 2022Pooled it
- Relationship between Tumor Biomarkers and Efficacy in EMILIA, a Phase III Study of Trastuzumab Emtansine in HER2-Positive Metastatic Breast Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2016Trial
- Precision theranostics in oncology: integrating antibody-drug conjugates, radioimmunotherapy, and immuno‑PET for adaptive cancer care.Discover oncology · 2026Review
- The potential of antibody-drug conjugates in immunotherapy for non-small cell lung cancer: current progress and future.Frontiers in oncology · 2025Review
- Towards a platform quantitative systems pharmacology (QSP) model for preclinical to clinical translation of antibody drug conjugates (ADCs).Journal of pharmacokinetics and pharmacodynamics · 2024Article
- Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities.Acta pharmacologica Sinica · 2024Article
- Review
- Cellular-Resolution Imaging of Bystander Payload Tissue Penetration from Antibody-Drug Conjugates.Molecular cancer therapeutics · 2022Article
- An Innovative Site-Specific Anti-HER2 Antibody-Drug Conjugate with High Homogeneity and Improved Therapeutic Index.OncoTargets and therapy · 2022Article
- Development and Evaluation of Competitive Inhibitors of Trastuzumab-HER2 Binding to Bypass the Binding-Site Barrier.Frontiers in pharmacology · 2022Article
- Unlocking the potential of antibody-drug conjugates for cancer therapy.Nature reviews. Clinical oncology · 2021Review
- Tumor Extrinsic Factors Mediate Primary T-DM1 Resistance in HER2-Positive Breast Cancer Cells.Cancers · 2021Article
- Targeting the autophagy promoted antitumor effect of T-DM1 on HER2-positive gastric cancer.Cell death & disease · 2021Article
- A bifunctional molecule-based strategy for the development of theranostic antibody-drug conjugate.Theranostics · 2021Article
- A Novel Proteomic Method Reveals NLS Tagging of T-DM1 Contravenes Classical Nuclear Transport in a Model of HER2-Positive Breast Cancer.Molecular therapy. Methods & clinical development · 2020Article
- Improving the Stability of Maleimide-Thiol Conjugation for Drug Targeting.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- Antibody-Drug Conjugates: The Last Decade.Pharmaceuticals (Basel, Switzerland) · 2020Review
- Capturing the Magic Bullet: Pharmacokinetic Principles and Modeling of Antibody-Drug Conjugates.The AAPS journal · 2020Review
- Improving Receptor-Mediated Intracellular Access and Accumulation of Antibody Therapeutics-The Tale of HER2.Antibodies (Basel, Switzerland) · 2020Review
- An Agent-Based Systems Pharmacology Model of the Antibody-Drug Conjugate Kadcyla to Predict Efficacy of Different Dosing Regimens.The AAPS journal · 2020Article
Corrections and comments
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Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate consisting of the anti-HER2 antibody trastuzumab linked via a nonreducible thioether linker to the maytansinoid antitubulin agent DM1. T-DM1 has shown favorable safety and efficacy in patients with HER2-positive metastatic breast cancer. In previous animal studies, T-DM1 exhibited better pharmacokinetics (PK) and slightly more efficacy than several disulfide-linked versions. The efficacy findings are unique, as other disulfide-linked antibody-drug conjugates (ADC) have shown greater efficacy than thioether-linked designs. To explore this further, the in vitro and in vivo activity, PK, and target cell activation of T-DM1 and the disulfide-linked T-SPP-DM1 were examined. Both ADCs showed high in vitro potency, with T-DM1 displaying greater potency in two of four breast cancer cell lines. In vitro target cell processing of T-DM1 and T-SPP-DM1 produced lysine-N(ε)-MCC-DM1, and lysine-N(ε)-SPP-DM1 and DM1, respectively; in vivo studies confirmed these results. The in vitro processing rates for the two conjugate to their respective catabolites were similar. In vivo, the potencies of the conjugates were similar, and T-SPP-DM1 had a faster plasma clearance than T-DM1. Slower T-DM1 clearance translated to higher overall tumor concentrations (conjugate plus catabolites), but unexpectedly, similar levels of tumor catabolite. These results indicate that, although the ADC linker can have clear impact on the PK and the chemical nature of the catabolites formed, both linkers seem to offer the same payload delivery to the tumor.
Indexed as
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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.