ArticlePharmaceutical research2022
Fcγ Receptor-Dependent Internalization and Off-Target Cytotoxicity of Antibody-Drug Conjugate Aggregates.
Article in Pharmaceutical research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 67 citations in OpenAlex.
- Exploring the immunological effects of antibody-drug conjugates.Nature reviews. Clinical oncology · 2026Review
- Clinical toxicity of ADCs and ICI-ADC combinations: mechanisms, patterns and management.Nature reviews. Clinical oncology · 2026Review
- Real-world pharmacovigilance signals of antibody-drug conjugates: reporting patterns by payload, linker, target, and sex in FAERS.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Site-specific trastuzumab Fab-DM1 via butelase-1 with ABD fusion for potent HER2-positive tumor control.Medical oncology (Northwood, London, England) · 2026Article
- Development of Glypican 3-Targeting Antibody-Drug Conjugates for Hepatocellular Carcinoma Therapy.Cancer research communications · 2026Article
- Antibody-drug conjugates in breast cancer: from mechanism to revolutionizing clinical practice.Molecular cancer · 2026Review
- Antibody-Drug Conjugates Drug Product Formulation and Process Development, Scalability and Stability Considerations.AAPS PharmSciTech · 2026Review
- Antibody-drug conjugates in cancer therapy: do we need biomarkers? A comprehensive review.Cancer metastasis reviews · 2026Review
- An update on patent issues regarding antibody-drug conjugates.Nature biotechnology · 2026Article
- Antibody-Drug Conjugates (ADCs): A Review of Structural Design, Technological Evolution, and Future Perspectives.Molecules (Basel, Switzerland) · 2026Review
- Article
- Optical imaging and spectroscopic characterization of subvisible particles in protein therapeutics.Advanced drug delivery reviews · 2026Review
- Formulation Matters: The Overlooked Engine of Stability and Success in Antibody-Drug Conjugates.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Frontiers in Antibody-Drug Conjugates: Mechanisms, Design Innovations, and Clinical Applications in Targeted Cancer Therapy.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Bench-to-Bedside Perspectives on Ocular Toxicity of Antibody-Drug Conjugates: Toxicology, Clinical Management and Molecule Optimization.Pharmaceutical research · 2026Review
- Stereoselective design of amino acid bioconjugates: targeting strategies and physicochemical optimization.RSC medicinal chemistry · 2026Review
- Bispecific antibody-drug conjugates: a modular blueprint for next-generation cancer therapeutics.Archives of pharmacal research · 2026Review
- Multi-parameter optimization of a novel anti-TROP2 MMAE antibody-drug-conjugate for solid tumor therapy.Frontiers in oncology · 2026Article
- Bispecific antibody-drug conjugates in cancer: therapeutic-window determinants, tumour-immune interactions, and clinical translation.Frontiers in immunology · 2026Review
- The mechanisms and therapeutic advances of interactions between breast cancer and cardiovascular diseases.Frontiers in pharmacology · 2026Review
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposeAntibody-drug conjugates (ADCs), which are monoclonal antibodies (mAbs) conjugated with highly toxic payloads, achieve high tumor killing efficacy due to the specific delivery of payloads in accordance with mAbs' function. On the other hand, the conjugation of payloads often increases the hydrophobicity of mAbs, resulting in reduced stability and increased aggregation. It is considered that mAb aggregates have potential risk for activating Fcγ receptors (FcγRs) on immune cells, and are internalized into cells via FcγRs. Based on the mechanism of action of ADCs, the internalization of ADCs into target-negative cells may cause the off-target toxicity. However, the impacts of aggregation on the safety of ADCs including off-target cytotoxicity have been unclear. In this study, we investigated the cytotoxicity of ADC aggregates in target-negative cells.
methodsThe ADC aggregates were generated by stirring stress or thermal stress. The off-target cytotoxicity of ADC aggregates was evaluated in several target-negative cell lines, and FcγR-activation properties of ADC aggregates were characterized using a reporter cell assay.
resultsAggregation of ADCs enhanced the off-target cytotoxicity in several target-negative cell lines compared with non-stressed ADCs. Notably, ADC aggregates with FcγR-activation properties showed dramatically enhanced cytotoxicity in FcγR-expressing cells. The FcγR-mediated off-target cytotoxicity of ADC aggregates was reduced by using a FcγR-blocking antibody or Fc-engineering for silencing Fc-mediated effector functions.
conclusionsThese results indicated that FcγRs play an important role for internalization of ADC aggregates into non-target cells, and the aggregation of ADCs increases the potential risk for off-target toxicity.
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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.