A non-internalizing antibody-drug conjugate based on an anthracycline payload displays potent therapeutic activity in vivo
Open accessAbstract
Antibody-drug conjugates are generally believed to crucially rely on internalization into cancer cells for therapeutic activity. Here, we show that a non-internalizing antibody-drug conjugate, based on the F16 antibody specific to the alternatively spliced A1 domain of tenascin-C, mediates a potent therapeutic activity when equipped with the anthracycline PNU159682. The peptide linker, connecting the F16 antibody in IgG format at a specific cysteine residue to the drug, was stable in serum but could be efficiently cleaved in the subendothelial extracellular matrix by proteases released by the dying tumor cells. The results indicate that there may be a broader potential applicability of non-internalizing antibody-drug conjugates for cancer therapy than what had previously been assumed.
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Upon intravenous injection, the antibody-drug conjugate bound tenascin-C and the drug was discharged when the protease-sensitive linker between antibody and drug was cleaved.
“In the case of intravenous injection, the antibody-drug conjugate was found to bind to tenascin-C and the drug was discharged when the protease-sensitive linker between the antibody and the drug was cleaved.”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [135]
The Abstract identifies F16 as binding the A1 domain of tenascin-C, and the Therapy experiments section reports intravenous administration of F16-PNU159682 to mice (page numbers unavailable). The Abstract describes a protease-cleavable linker, but the Discussion calls extracellular protease cleavage in the tumor a conceivable mechanism rather than an established observation after injection. The claim overstates that part as a finding. (LLM, conf=0.84)
Experimental — accuracy not yet measuredA non-internalizing antibody against tenascin-C transported anthracycline PNU159682 into the ECM of cancer cells.
“Dal Corso et al. introduced a study in which a non-internalizing antibody against tenascin-C was exploited to transport anthracycline (PNU159682), a chemotherapeutic agent, into the ECM of cancer cells (Fig. 2d).”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [135]
This antibody-drug conjugate resulted in significant tumor growth inhibition of epidermoid carcinoma mouse xenografts.
“This in turn resulted in significant tumor growth inhibition of epidermoid carcinoma mouse xenografts [135].”
From Tumor microenvironment complexity and therapeutic implications at a glance (2020) · cites this paper as [135]
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References 48 · Cited by 75
- Authors
- Dal Corso, A., Gébleux, R., Murer, P., Soltermann, A., & Neri, D.
- Affiliations
- ETH Zurich (CH)
- University Hospital Zurich (CH)
- Corresponding author
- Neri, Dario
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 264
- Pages
- 211-218
- ISSN
- 0168-3659 (ISSN-L)
- PMC
- PMC5844458
- OpenAlex
- W2750969044
- Cited by
- 75
- References
- 48
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 5 · 2023: 9 · 2022: 13 · 2021: 8 · 2020: 7 · 2019: 13 · 2018: 7
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 341 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Journal of Controlled Release (acceptedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- ETH Zürich
- Swiss National Science Foundation (310030B_163479/1)
- SINERGIA (CRSII2_160699/1)
- ERC Advanced Grant (670603)
- Kommission für Technologie und Innovation (17072.1)
- Bovena Foundation and Maiores Foundation
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Monoclonal and Polyclonal Antibodies Research
- Life Sciences › Immunology and Microbiology › Immunology › Toxin Mechanisms and Immunotoxins
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- antibody-drug conjugates, tenascin-C, A1 domain, peptide linkers, extracellular matrix proteolysis, cancer cell death, cancer therapy, antibody internalization
- MeSH terms
- Animals, Antineoplastic Agents, Doxorubicin, Female, Humans, Immunoglobulin G, Mice, Inbred BALB C, Mice, Nude, Neoplasms, Immunoconjugates, Tenascin, Cell Line, Tumor, Tumor Burden
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