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PreprintCC BY-NC-NDChemRxiv

Expanding Antibody-Drug Conjugates Mechanistic Diversity with Verubulin: A Dual Tubulin-Binding and Vascular-Disrupting Payload.

  • Héloïse Cahuzac1
  • Louis Moreira da Silva1
  • Yoann Colas1
  • Fanny Bousson1
  • Caroline Mursch1
  • Ketty Pernod1
  • Julien Most1
  • François Daubeuf2
  • Stéphane Erb3
  • Alexandre Detappe4,5
  • Sarah Cianférani3
  • Alain Wagner1
1 more authors
  • Guilhem Chaubet1
5 affiliations
  1. 1Faculté de Pharmacie de Strasbourg, Centre National de la Recherche Scientifique/Université de Strasbourg, 74 Route du Rhin, Illkirch-Graffenstaden, France, 67400
  2. 2ESBS – Pôle API, 300, boulevard Sébastien Brant, CS 10413, Illkirch-Graffenstaden Cedex, France, 67412
  3. 3UMR7178, Institut pluridisciplinaire Hubert Curien, 23 rue du Lœss, BP 28, Strasbourg Cedex, France, 67037
  4. 4Nanomedecine laboratory
  5. 5Institut Strauss
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Abstract

Antibody-Drug Conjugates (ADCs) have revolutionized targeted cancer therapy, yet their clinical success remains restricted by the limited diversity of cytotoxic payloads. Here we describe the development of verubulin as a novel ADC payload with a dual mechanism of action, combining tubulin inhibition with vascular disruption. Two successive ADC generations were designed and evaluated. First-generation conjugates used amide/carbamate linkage but were hampered by instability and modest efficacy. These limitations were addressed by a quaternarization approach, which delivered stable conjugates with subnanomolar, target-dependent cytotoxicity, and limited bystander activity. In vivo, these ADCs induced tumour regression with excellent tolerability and more durable tumour control than bevacizumab, the clinical reference for vascular disruption, although efficacy remained below benchmark ADCs T-DM1 and T-Dxd. These results support verubulin as a promising payload scaffold for next-generation ADCs.

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Cite

BibTeXRIS
BibTeX
@misc{cahuzac2026expanding,
  title = {{Expanding Antibody-Drug Conjugates Mechanistic Diversity with Verubulin: A Dual Tubulin-Binding and Vascular-Disrupting Payload.}},
  author = {Héloïse Cahuzac and Louis Moreira da Silva and Yoann Colas and Fanny Bousson and Caroline Mursch and Ketty Pernod and Julien Most and François Daubeuf and Stéphane Erb and Alexandre Detappe and Sarah Cianférani and Alain Wagner and Guilhem Chaubet},
  howpublished = {ChemRxiv},
  year = {2026},
  month = oct,
  doi = {10.26434/chemrxiv.15010926/v1},
  url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010926/v1},
  note = {CC BY-NC-ND},
}
RIS
TY  - UNPB
TI  - Expanding Antibody-Drug Conjugates Mechanistic Diversity with Verubulin: A Dual Tubulin-Binding and Vascular-Disrupting Payload.
AU  - Héloïse Cahuzac
AU  - Louis Moreira da Silva
AU  - Yoann Colas
AU  - Fanny Bousson
AU  - Caroline Mursch
AU  - Ketty Pernod
AU  - Julien Most
AU  - François Daubeuf
AU  - Stéphane Erb
AU  - Alexandre Detappe
AU  - Sarah Cianférani
AU  - Alain Wagner
AU  - Guilhem Chaubet
PY  - 2026
DA  - 2026/10/23
PB  - ChemRxiv
DO  - 10.26434/chemrxiv.15010926/v1
UR  - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010926/v1
AB  - Antibody-Drug Conjugates (ADCs) have revolutionized targeted cancer therapy, yet their clinical success remains restricted by the limited diversity of cytotoxic payloads. Here we describe the development of verubulin as a novel ADC payload with a dual mechanism of action, combining tubulin inhibition with vascular disruption. Two successive ADC generations were designed and evaluated. First-generation conjugates used amide/carbamate linkage but were hampered by instability and modest efficacy. These limitations were addressed by a quaternarization approach, which delivered stable conjugates with subnanomolar, target-dependent cytotoxicity, and limited bystander activity. In vivo, these ADCs induced tumour regression with excellent tolerability and more durable tumour control than bevacizumab, the clinical reference for vascular disruption, although efficacy remained below benchmark ADCs T-DM1 and T-Dxd. These results support verubulin as a promising payload scaffold for next-generation ADCs.
ER  -