ArticleCancer research2006
Antibody-maytansinoid conjugates are activated in targeted cancer cells by lysosomal degradation and linker-dependent intracellular processing.
Article in Cancer research, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 192 papers, 1 of them a synthesis that pooled it.
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The trial behind it
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
192 citing papers in PubMed, 1 synthesis or guideline pooled it, 569 citations in OpenAlex.
- Structure-Activity Relationships of Antibody-Drug Conjugates: A Systematic Review of Chemistry on the Trastuzumab Scaffold.Bioconjugate chemistry · 2022Pooled it
- Randomized Phase II Study of Bevacizumab with Weekly Anetumab Ravtansine or Weekly Paclitaxel in Platinum-Resistant/Refractory High-Grade Ovarian Cancer (NCI Trial).Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Trial
- Covariate analysis of tusamitamab ravtansine, a DM4 anti-CEACAM5 antibody-drug conjugate, based on first-in-human study.CPT: pharmacometrics & systems pharmacology · 2022Trial
- Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2015Trial
- The anti-CD19 antibody-drug conjugate SAR3419 prevents hematolymphoid relapse postinduction therapy in preclinical models of pediatric acute lymphoblastic leukemia.Clinical cancer research : an official journal of the American Association for Cancer Research · 2013Trial
- Semi-mechanistic population pharmacokinetic model of multivalent trastuzumab emtansine in patients with metastatic breast cancer.Clinical pharmacology and therapeutics · 2012Trial
- Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody-drug conjugate in development for the treatment of HER2-positive cancer.Cancer chemotherapy and pharmacology · 2012Trial
- Trial watch: antibody-drug conjugates in cancer therapy.Oncoimmunology · 2026Review
- Extracellular payload release from non-internalizing antibody-drug conjugates: mechanisms and linker technologies.Drug delivery · 2026Review
- A modular framework for antibody-drug conjugate biomarkers.Nature reviews. Clinical oncology · 2026Review
- Clinical toxicity of ADCs and ICI-ADC combinations: mechanisms, patterns and management.Nature reviews. Clinical oncology · 2026Review
- The next generation of antibody-drug conjugates.Nature medicine · 2026Review
- Site-specific trastuzumab Fab-DM1 via butelase-1 with ABD fusion for potent HER2-positive tumor control.Medical oncology (Northwood, London, England) · 2026Article
- Antibody-Drug Conjugates in Solid Tumor Oncology and the Frontier of Precision Immunosuppression: A Mechanistic, Translational, and Clinical Review.International journal of molecular sciences · 2026Review
- Corneal Toxicity of Mirvetuximab Soravtansine: Multimodal Imaging Features and Implications for Ophthalmologic Management.Diagnostics (Basel, Switzerland) · 2026Article
- Recent advances in bispecific antibody-drug conjugates for breast cancer therapy.Cancer chemotherapy and pharmacology · 2026Review
- Developing an antibody drug encapsulation nanoagent targeting HER2 for cancer treatment.Journal of translational medicine · 2026Article
- Mirvetuximab Soravtansine: Mechanism of Action, Clinical and Translational Science.Clinical and translational science · 2026Review
- From intracellular processing to renal phenotypes: a mechanism-informed framework for interpreting kidney injury and electrolyte patterns with antibody-drug conjugates in solid tumors.Frontiers in pharmacology · 2026Review
- Nanobody-Based Drug Delivery: Emerging Strategies for Targeted Cancer Therapy.International journal of nanomedicine · 2026Review
132 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Antibody-drug conjugates are targeted anticancer agents consisting of a cytotoxic drug covalently linked to a monoclonal antibody for tumor antigen-specific activity. Once bound to the target cell-surface antigen, the conjugate must be processed to release an active form of the drug, which can reach its intracellular target. Here, we used both biological and biochemical methods to better define this process for antibody-maytansinoid conjugates. In particular, we examined the metabolic fate in cells of huC242-maytansinoid conjugates containing either a disulfide linker (huC242-SPDB-DM4) or a thioether linker (huC242-SMCC-DM1). Using cell cycle analysis combined with lysosomal inhibitors, we showed that lysosomal processing is required for the activity of antibody-maytansinoid conjugates, irrespective of the linker. We also identified and characterized the released maytansinoid molecules from these conjugates, and measured their rate of release compared with the kinetics of cell cycle arrest. Both conjugates are efficiently degraded in lysosomes to yield metabolites consisting of the intact maytansinoid drug and linker attached to lysine. The lysine adduct is the sole metabolite from the thioether-linked conjugate. However, the lysine metabolite generated from the disulfide-linked conjugate is reduced and S-methylated to yield the lipophilic and potently cytotoxic metabolite, S-methyl-DM4. These findings provide insight into the mechanism of action of antibody-maytansinoid conjugates in general, and more specifically, identify a biochemical mechanism that may account for the significantly enhanced antitumor efficacy observed with disulfide-linked conjugates.
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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.