ArticleThe AAPS journal2017
Site Selection: a Case Study in the Identification of Optimal Cysteine Engineered Antibody Drug Conjugates.
Article in The AAPS journal, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 63 citations in OpenAlex.
- Advances and Future Directions in Antibody-Drug Conjugates: From Paradigm Shifts to Data-Driven Design.Cancers · 2026Review
- Multi-parameter optimization of a novel anti-TROP2 MMAE antibody-drug-conjugate for solid tumor therapy.Frontiers in oncology · 2026Article
- Structural Characterization of Linker Shielding in ADC Site-Specific Conjugates.Pharmaceutics · 2025Article
- A review of targeted drug delivery with antibody-drug complexes.The Journal of pharmacology and experimental therapeutics · 2025Review
- Identification of a Novel Linker Enabling the Bioconjugation of a Cyclic Dinucleotide for the STING Antibody-Drug Conjugate TAK-500.Bioconjugate chemistry · 2025Article
- Chemotherapeutic Drug-Antibody Conjugates (ChemoBodies): Recent Advances and Future Directions.Current oncology reports · 2025Review
- Resin-Supported Site-Specific Antibody Conjugation Method Leads to Antibody-Drug Conjugates with Retained Efficacy and Improved Stability.Bioconjugate chemistry · 2025Article
- A comparison of the activity, lysosomal stability, and efficacy of legumain-cleavable and cathepsin-cleavable ADC linkers.Xenobiotica; the fate of foreign compounds in biological systems · 2024Article
- Homogeneous multi-payload antibody-drug conjugates.Nature chemistry · 2024Review
- A Genetically Encoded Photocaged Cysteine for Facile Site-Specific Introduction of Conjugation-Ready Thiol Residues in Antibodies.Bioconjugate chemistry · 2024Article
- Introduction of Carbonyl Groups into Antibodies.Molecules (Basel, Switzerland) · 2023Review
- Site-Specific Antibody Conjugation with Payloads beyond Cytotoxins.Molecules (Basel, Switzerland) · 2023Review
- Instability Challenges and Stabilization Strategies of Pharmaceutical Proteins.Pharmaceutics · 2022Review
- Evaluation of an ester-linked immunosuppressive payload: A case study in understanding the stability and cleavability of ester-containing ADC linkers.Bioorganic & medicinal chemistry letters · 2022Article
- Cysteine metabolic engineering and selective disulfide reduction produce superior antibody-drug-conjugates.Scientific reports · 2022Article
- Impact of Drug Conjugation on Thermal and Metabolic Stabilities of Aglycosylated andBioconjugate chemistry · 2022Article
- Site-Specific Antibody Conjugation to Engineered Double Cysteine Residues.Pharmaceuticals (Basel, Switzerland) · 2021Article
- The Chemistry Behind ADCs.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Bispecific Antibodies and Antibody-Drug Conjugates for Cancer Therapy: Technological Considerations.Biomolecules · 2020Review
- Click Chemistry Conjugations.Methods in molecular biology (Clifton, N.J.) · 2020Article
Corrections and comments
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Authors and funding
19 authors at 6 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
As the antibody drug conjugate (ADC) community continues to shift towards site-specific conjugation technology, there is a growing need to understand how the site of conjugation impacts the biophysical and biological properties of an ADC. In order to address this need, we prepared a carefully selected series of engineered cysteine ADCs and proceeded to systematically evaluate their potency, stability, and PK exposure. The site of conjugation did not have a significant influence on the thermal stability and in vitro cytotoxicity of the ADCs. However, we demonstrate that the rate of cathepsin-mediated linker cleavage is heavily dependent upon site and is closely correlated with ADC hydrophobicity, thus confirming other recent reports of this phenomenon. Interestingly, conjugates with high rates of cathepsin-mediated linker cleavage did not exhibit decreased plasma stability. In fact, the major source of plasma instability was shown to be retro-Michael mediated deconjugation. This process is known to be impeded by succinimide hydrolysis, and thus, we undertook a series of mutational experiments demonstrating that basic residues located nearby the site of conjugation can be a significant driver of succinimide ring opening. Finally, we show that total antibody PK exposure in rat was loosely correlated with ADC hydrophobicity. It is our hope that these observations will help the ADC community to build "design rules" that will enable more efficient prosecution of next-generation ADC discovery programs.
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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.