ArticlemAbs
Site-specific antibody-drug conjugate heterogeneity characterization and heterogeneity root cause analysis.
Article in mAbs. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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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
23 citing papers in PubMed, 44 citations in OpenAlex.
- Optimized iCIEF Fractionation Enables Deep Profiling of Antibody Drug Conjugate Charge Heterogeneity.Electrophoresis · 2026Article
- Antibody-Drug Conjugates Reshape the Landscape of Cancer Therapy: Evolution, Challenges and Future Perspectives from the Concept of "Magic Bullet" to Clinical Application.Current oncology reports · 2026Review
- Nanobody-Based Drug Delivery: Emerging Strategies for Targeted Cancer Therapy.International journal of nanomedicine · 2026Review
- New Frontiers in ADC Analysis: Advances in Chromatography, Electrophoresis, and Mass Spectrometry.The AAPS journal · 2025Review
- Preclinical Characterization of XB010: A Novel Antibody-Drug Conjugate for the Treatment of Solid Tumors that Targets Tumor-Associated Antigen 5T4.Molecular cancer therapeutics · 2025Article
- Kinetic Modeling of the Antibody Disulfide Bond Reduction Reaction With Integrated Prediction of the Drug Load Profile for Cysteine-Conjugated ADCs.Biotechnology and bioengineering · 2025Article
- Monoclonal antibodies: From magic bullet to precision weapon.Molecular biomedicine · 2024Review
- In-Depth Structure and Function Characterization of Heterogeneous Interchain Cysteine-Conjugated Antibody-Drug Conjugates.ACS pharmacology & translational science · 2024Article
- Kinetic models towards an enhanced understanding of diverse ADC conjugation reactions.Frontiers in bioengineering and biotechnology · 2024Article
- Atypical Asparagine Deamidation of NW Motif Significantly Attenuates the Biological Activities of an Antibody Drug Conjugate.Antibodies (Basel, Switzerland) · 2023Article
- Review
- Production in Bacteria and Characterization of Engineered Humanized Fab Fragment against the Nodal Protein.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Multi-Attribute Monitoring Method for Process Development of Engineered Antibody for Site-Specific Conjugation.Journal of the American Society for Mass Spectrometry · 2023Article
- Antibody-drug conjugates: the paradigm shifts in the targeted cancer therapy.Frontiers in immunology · 2023Review
- Kinetic studies and CFD-based reaction modeling for insights into the scalability of ADC conjugation reactions.Frontiers in bioengineering and biotechnology · 2023Article
- A comprehensive overview on antibody-drug conjugates: from the conceptualization to cancer therapy.Frontiers in pharmacology · 2023Review
- Challenges and progress toward tumor-targeted therapy by systemic delivery of polymer-complexed oncolytic adenoviruses.Cancer gene therapy · 2022Review
- Antibody-drug conjugate as targeted therapeutics against hepatocellular carcinoma: preclinical studies and clinical relevance.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2022Review
- Mechanistic insights into inter-chain disulfide bond reduction of IgG1 and IgG4 antibodies.Applied microbiology and biotechnology · 2022Article
- The Use of Antibody-Antibiotic Conjugates to Fight Bacterial Infections.Frontiers in microbiology · 2022Review
Corrections and comments
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Authors and funding
9 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Site-specific antibody-drug conjugates (ADCs) are designed to overcome the heterogeneity observed with first-generation ADCs that use random conjugation to surface-exposed lysine residues or conjugation to interchain disulfide bonds. Despite significantly enhanced homogeneity, however, the production of site-specific ADCs yields some process-related species heterogeneity, including stereoisomers, unconjugated antibody, underconjugated species, and overconjugated species. An elevated level of size variants, such as heavy chain-light chain species (half ADC), heavy chain-heavy chain-light chain species, and light chain species, is also observed with the final site-specific ADC product. To understand the root cause of heterogeneity generated during the ADC conjugation process, we designed time-course studies for each conjugation step, including reduction, oxidation, conjugation, and quenching. We developed both non-reduced peptide map and LabChip-based capillary electrophoresis sodium dodecyl sulfate methods for time-course sample analysis. On the basis of our time-course data, the half ADC and unconjugated antibody were generated during oxidation as a result of alternative disulfide bond arrangements. During oxidation, two hinge cysteines formed an intra-chain disulfide bond in the half ADC, and three inter-chain hinge disulfide bonds were formed in the unconjugated antibody. Time-course data also showed that the elevated level of size variants, especially heavy chain-heavy chain-light chain species and light chain species, resulted from the quenching step, where the quenching reagent engaged in a disulfide bond exchange reaction with the ADC and broke the disulfide bonds connecting the heavy chain and light chain. Underconjugated and overconjugated species arose from the equilibrium established during the conjugation reaction.
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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.