ArticlePloS one2015
Site-Dependent Degradation of a Non-Cleavable Auristatin-Based Linker-Payload in Rodent Plasma and Its Effect on ADC Efficacy.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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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
24 citing papers in PubMed, 63 citations in OpenAlex.
- Immunogenicity Management Strategies for PEGylated Drug Delivery Systems.International journal of nanomedicine · 2026Review
- Opportunities and Challenges in Antibody-Drug Conjugates for Cancer Therapy: A New Era for Cancer Treatment.Cancers · 2025Review
- Recent Advances in the Linkers of Drug Conjugates.Current medicinal chemistry · 2025Review
- Antibody-drug conjugates in cancer therapy: innovations, challenges, and future directions.Archives of pharmacal research · 2024Review
- Specific peptide conjugation to a therapeutic antibody leads to enhanced therapeutic potency and thermal stability by reduced Fc dynamics.Scientific reports · 2023Article
- Antibody drug conjugates as targeted cancer therapy: past development, present challenges and future opportunities.Archives of pharmacal research · 2023Review
- Stepping forward in antibody-drug conjugate development.Pharmacology & therapeutics · 2022Review
- Novel development strategies and challenges for anti-Her2 antibody-drug conjugates.Antibody therapeutics · 2022Review
- Targeted Fluorogenic Cyanine Carbamates EnableJournal of the American Chemical Society · 2021Article
- Introduction to Antibody-Drug Conjugates.Antibodies (Basel, Switzerland) · 2021Review
- Site-specific antibody-drug conjugates with variable drug-to-antibody-ratios for AML therapy.Journal of controlled release : official journal of the Controlled Release Society · 2021Article
- Antibody-Drug Conjugates: The New Frontier of Chemotherapy.International journal of molecular sciences · 2020Review
- Synthesis of site-specific antibody-drug conjugates by ADP-ribosyl cyclases.Science advances · 2020Article
- The "Utility" of Highly Toxic Marine-Sourced Compounds.Marine drugs · 2019Review
- Optimal design, anti-tumour efficacy and tolerability of anti-CXCR4 antibody drug conjugates.Scientific reports · 2019Article
- A novel anti-DR5 antibody-drug conjugate possesses a high-potential therapeutic efficacy for leukemia and solid tumors.Theranostics · 2019Article
- ADME Considerations and Bioanalytical Strategies for Pharmacokinetic Assessments of Antibody-Drug Conjugates.Antibodies (Basel, Switzerland) · 2018Review
- Drug conjugates-an emerging approach to treat breast cancer.Pharmacology research & perspectives · 2018Review
- Pharmacokinetic Considerations for Antibody-Drug Conjugates against Cancer.Pharmaceutical research · 2017Review
- Harnessing a catalytic lysine residue for the one-step preparation of homogeneous antibody-drug conjugates.Nature communications · 2017Article
Corrections and comments
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Authors and funding
21 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The efficacy of an antibody-drug conjugate (ADC) is dependent on the properties of its linker-payload which must remain stable while in systemic circulation but undergo efficient processing upon internalization into target cells. Here, we examine the stability of a non-cleavable Amino-PEG6-based linker bearing the monomethyl auristatin D (MMAD) payload site-specifically conjugated at multiple positions on an antibody. Enzymatic conjugation with transglutaminase allows us to create a stable amide linkage that remains intact across all tested conjugation sites on the antibody, and provides us with an opportunity to examine the stability of the auristatin payload itself. We report a position-dependent degradation of the C terminus of MMAD in rodent plasma that has a detrimental effect on its potency. The MMAD cleavage can be eliminated by either modifying the C terminus of the toxin, or by selection of conjugation site. Both approaches result in improved stability and potency in vitro and in vivo. Furthermore, we show that the MMAD metabolism in mouse plasma is likely mediated by a serine-based hydrolase, appears much less pronounced in rat, and was not detected in cynomolgus monkey or human plasma. Clarifying these species differences and controlling toxin degradation to optimize ADC stability in rodents is essential to make the best ADC selection from preclinical models. The data presented here demonstrate that site selection and toxin susceptibility to mouse plasma degradation are important considerations in the design of non-cleavable ADCs, and further highlight the benefits of site-specific conjugation methods.
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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.