ArticleAntibodies (Basel, Switzerland)2020
Molecular Mechanism of HER2 Rapid Internalization and Redirected Trafficking Induced by Anti-HER2 Biparatopic Antibody.
Article in Antibodies (Basel, Switzerland), 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 56 citations in OpenAlex.
- Antibody-drug conjugates in breast cancer: from mechanism to revolutionizing clinical practice.Molecular cancer · 2026Review
- Pertuzumab Enhances the Antitumor Activity of T-DXd in HER2-Positive Gastric Cancer Cells.Molecular cancer therapeutics · 2026Article
- Evolving antibody-drug conjugates in breast cancer from precision delivery to tumor microenvironment reprogramming.Journal of hematology & oncology · 2026Review
- CD25-Targeted Aptamer-Drug Conjugate for the Treatment of CD25-Expressing Hematological Malignancies.Pharmaceutics · 2026Article
- Reply to "Critical Evaluation of HER2 PET Imaging in Metastatic Breast Cancer: Addressing Key Challenges and Future Directions" and "The Role of HER2 PET in Treatment of Breast Cancer".Journal of nuclear medicine : official publication, Society of Nuclear Medicine · 2026Article
- Mechanisms of resistance to antibody-drug conjugates in cancer: molecular barriers and pharmacological solutions.Cancer chemotherapy and pharmacology · 2025Review
- Article
- Synthesis and Biological Evaluation of Herceptin-Conjugated Liposomes Loaded with Lipocalin-2 siRNA for the Treatment of Inflammatory Breast Cancer.Pharmaceuticals (Basel, Switzerland) · 2025Article
- The Autophagy Inhibitor Bafilomycin Inhibits Antibody-Dependent Natural Killer Cell-Mediated Killing of Breast Carcinoma Cells.International journal of molecular sciences · 2025Article
- Tumor-specific cytosol-penetrating antibodies for antigen- and TME-dependent intracellular cargo delivery.Molecular therapy. Oncology · 2025Article
- Bispecific antibodies and CLEM: an analytical approach to advanced cell imaging for therapeutic strategies.Applied microscopy · 2025Review
- CD37 in acute myeloid leukemia: a novel surface target for drug delivery.Blood advances · 2025Article
- Engineering HER2-targeted biparatopic antibodies to promote receptor internalization and restore antitumor efficacy.Frontiers in immunology · 2025Article
- Biparatopic HER2-targeted nanobody binder synergizes with trastuzumab in resistant tumor cells.Frontiers in immunology · 2025Article
- Fluorescence Lifetime Imaging for Quantification of Targeted Drug Delivery in Varying Tumor Microenvironments.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- The Evolving Applications of Bispecific Antibodies: Reaping the Harvest of Early Sowing and Planting New Seeds.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2025Review
- Proteolysis targeting chimera (PROTAC)-driven antibody internalization of oncogenic cell surface receptors.Communications biology · 2024Article
- A trafficking regulatory subnetwork governs αScience advances · 2024Article
- Poly(Epsilon-Lysine) Dendrons Inhibit Proliferation in HER2-Overexpressing SKBR3 Breast Cancer Cells at Levels Higher than the Low-Expressing MDA-MB-231 Phenotype and Independently from the Presentation of HER2 Bioligands in Their Structure.International journal of molecular sciences · 2024Article
- Antibody-displaying extracellular vesicles for targeted cancer therapy.Nature biomedical engineering · 2024Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Amplification and overexpression of HER2 (human epidermal growth factor receptor 2), an ErbB2 receptor tyrosine kinase, have been implicated in human cancer and metastasis. A bispecific tetravalent anti-HER2 antibody (anti-HER2-Bs), targeting two non-overlapping epitopes on HER2 in domain IV (trastuzumab) and domain II (39S), has been reported to induce rapid internalization and efficient degradation of HER2 receptors. In this study, we investigated the molecular mechanism of this antibody-induced rapid HER2 internalization and intracellular trafficking. Using quantitative fluorescent imaging, we compared the internalization kinetics of anti-HER2-Bs and its parental arm antibodies, alone or in combinations and under various internalization-promoting conditions. The results demonstrated that concurrent engagement of both epitopes was necessary for rapid anti-HER2-Bs internalization. Cellular uptake of anti-HER2-Bs and parental arm antibodies occurred via clathrin-dependent endocytosis; however, inside the cells antibodies directed different trafficking pathways. Trastuzumab dissociated from HER2 in 2 h, enabling the receptor to recycle, whereas anti-HER2-Bs stayed associated with the receptor throughout the entire endocytic pathway, promoting receptor ubiquitination, trafficking to the lysosomes, and efficient degradation. Consistent with routing HER2 to degradation, anti-HER2-Bs significantly reduced HER2 shedding and altered its exosomal export. Collectively, these results enable a better understanding of the mechanism of action of anti-Her2-Bs and can guide the rational design of anti-HER2 therapeutics as well as other bispecific molecules.
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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.