ArticleMolecular cancer therapeutics2022
An Enzymatically Cleavable Tripeptide Linker for Maximizing the Therapeutic Index of Antibody-Drug Conjugates.
Article in Molecular cancer therapeutics, 2022. 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, 46 citations in OpenAlex.
- Discovery of a Novel Tripeptide Linker that Broadens the Therapeutic Window of Auristatin-Based Antibody-Drug Conjugates by Reducing Bone Marrow Toxicity.Bioconjugate chemistry · 2026Article
- Linker Design in Antibody-Drug Conjugates: Balancing Stability and Drug Release.Pharmaceutics · 2026Review
- Affinity-optimized TROP2 antibodies support potent antitumor activity in antibody-drug conjugates.Antibody therapeutics · 2026Article
- Bench-to-Bedside Perspectives on Ocular Toxicity of Antibody-Drug Conjugates: Toxicology, Clinical Management and Molecule Optimization.Pharmaceutical research · 2026Review
- Expanding the payload scope in antibody-drug conjugates by delivery of hydroxy-containing drugs through self-immolative phosphoramidates.Nature communications · 2026Article
- Bispecific antibody-drug conjugates: a modular blueprint for next-generation cancer therapeutics.Archives of pharmacal research · 2026Review
- Article
- Beyond amyloid: nanobody-mediated neuroinflammatory therapy for Alzheimer's disease.Translational neurodegeneration · 2025Review
- Tumor Microenvironment-Responsive Nanomedicines for Potentiating Cancer Immunotherapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Navigating the future of gastric cancer treatment: a review on the impact of antibody-drug conjugates.Cell death discovery · 2025Review
- Towards precision medicine using biochemically triggered cleavable conjugation.Communications chemistry · 2025Review
- Antibody-Drug Conjugates Targeting the EGFR Ligand Epiregulin Elicit Robust Antitumor Activity in Colorectal Cancer.Cancer research · 2025Article
- HER2-positive gastric cancer: from targeted therapy to CAR-T cell therapy.Frontiers in immunology · 2025Review
- Branched Linkers for Homogeneous Antibody-Drug Conjugates: How Long Is Long Enough?International journal of molecular sciences · 2024Article
- Article
- Antibody-Drug Conjugates Targeting the EGFR Ligand Epiregulin Elicit Robust Anti-Tumor Activity in Colorectal Cancer.bioRxiv : the preprint server for biology · 2024Article
- Exo-Cleavable Linkers: Enhanced Stability and Therapeutic Efficacy in Antibody-Drug Conjugates.Journal of medicinal chemistry · 2024Article
- Caged aminoluciferin probe for bioluminescent immunoproteasome activity analysis.RSC chemical biology · 2024Article
- Exploring the next generation of antibody-drug conjugates.Nature reviews. Clinical oncology · 2024Review
- Impact of dipeptide on ADC physicochemical properties and efficacy identifies Ala-Ala as the optimal dipeptide.RSC medicinal chemistry · 2024Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Valine-citrulline is a protease-cleavable linker commonly used in many drug delivery systems, including antibody-drug conjugates (ADC) for cancer therapy. However, its suboptimal in vivo stability can cause various adverse effects such as neutropenia and hepatotoxicity, leading to dose delays or treatment discontinuation. Here, we report that glutamic acid-glycine-citrulline (EGCit) linkers have the potential to solve this clinical issue without compromising the ability of traceless drug release and ADC therapeutic efficacy. We demonstrate that our EGCit ADC resists neutrophil protease-mediated degradation and spares differentiating human neutrophils. Notably, our anti-HER2 ADC shows almost no sign of blood and liver toxicity in healthy mice at 80 mg kg-1. In contrast, at the same dose level, the FDA-approved anti-HER2 ADCs Kadcyla and Enhertu show increased levels of serum alanine aminotransferase and aspartate aminotransferase and morphologic changes in liver tissues. Our EGCit conjugates also exert greater antitumor efficacy in multiple xenograft tumor models compared with Kadcyla and Enhertu. This linker technology could substantially broaden the therapeutic windows of ADCs and other drug delivery agents, providing clinical options with improved efficacy and safety.
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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.