ArticleCell reports. Medicine2021
NOTCH3-targeted antibody drug conjugates regress tumors by inducing apoptosis in receptor cells and through transendocytosis into ligand cells.
Article in Cell reports. Medicine, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 29 citations in OpenAlex.
- Recent advances in function-enhanced antibody-drug conjugates: Antibody optimization and payload combination.Acta pharmacologica Sinica · 2026Article
- Notch3/4 Knockdown Inhibits Colon Adenocarcinoma Progression by Suppressing Tumor Cell Activity and Orchestrating VEGFA-Dependent Tumor Immune Microenvironment.Cancer medicine · 2026Article
- ProNotch converts extracellular protease activity into programmable transcriptional outputs.bioRxiv : the preprint server for biology · 2026Article
- Network-based single-cell analysis identifies a proliferative GZMBJournal of translational medicine · 2026Article
- Frontiers in Antibody-Drug Conjugates: Mechanisms, Design Innovations, and Clinical Applications in Targeted Cancer Therapy.Pharmaceuticals (Basel, Switzerland) · 2026Review
- The NOTCH3 extracellular domain is a serum biomarker for pulmonary arterial hypertension.Nature medicine · 2026Article
- Notch Signaling and PD-1/PD-L1 Interaction in Hepatocellular Carcinoma: Potentialities of Combined Therapies.Biomolecules · 2024Review
- Article
- Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets.Signal transduction and targeted therapy · 2024Review
- Novel insights into Notch signaling in tumor immunity: potential targets for cancer immunotherapy.Frontiers in immunology · 2024Review
- Recent Advances in Mesoporous Silica Nanoparticles Delivering siRNA for Cancer Treatment.Pharmaceutics · 2023Review
- Krüppel-like factor 10 modulates stem cell phenotypes of pancreatic adenocarcinoma by transcriptionally regulating notch receptors.Journal of biomedical science · 2023Article
- Caveolar and non-Caveolar Caveolin-1 in ocular homeostasis and disease.Progress in retinal and eye research · 2022Review
- Emerging drug targets for triple-negative breast cancer: a guided tour of the preclinical landscape.Expert opinion on therapeutic targets · 2022Review
- A comprehensive multi-omics analysis reveals molecular features associated with cancer via RNA cross-talks in the Notch signaling pathway.Computational and structural biotechnology journal · 2022Article
Corrections and comments
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Authors and funding
23 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberrant NOTCH3 signaling and overexpression is oncogenic, associated with cancer stem cells and drug resistance, yet therapeutic targeting remains elusive. Here, we develop NOTCH3-targeted antibody drug conjugates (NOTCH3-ADCs) by bioconjugation of an auristatin microtubule inhibitor through a protease cleavable linker to two antibodies with differential abilities to inhibit signaling. The signaling inhibitory antibody rapidly induces ligand-independent receptor clustering and internalization through both caveolin and clathrin-mediated pathways. The non-inhibitory antibody also efficiently endocytoses via clathrin without inducing receptor clustering but with slower lysosomal co-localization kinetics. In addition, DLL4 ligand binding to the NOTCH3 receptor mediates transendocytosis of NOTCH3-ADCs into ligand-expressing cells. NOTCH3-ADCs internalize into receptor and ligand cells independent of signaling and induce cell death in both cell types representing an atypical mechanism of ADC cytotoxicity. Treatment of xenografts with NOTCH3-ADCs leads to sustained tumor regressions, outperforms standard-of-care chemotherapy, and allows targeting of tumors that overexpress NOTCH3 independent of signaling inhibition.
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