Antibody-Vincristine Conjugates as Potent Anticancer Therapeutic Agents
Antibody-drug conjugates (ADCs) are a well-established class of therapeutics primarily used in oncology to selectively deliver highly cytotoxic agents into cancer cells. While ADCs should theoretically spare healthy tissues and diminish side effects in patients, off-target toxicity is still observed, all the more serious, as the drugs are extremely potent. In the quest toward safer payloads, we used the conventional chemotherapeutic drug vincristine to develop antibody-vincristine conjugates. Vincristine was <i>N</i>-alkylated with a cleavable linker and the resulting linker-payload conjugated to free cysteines of antibodies. We show that trastuzumab-vincristine conjugates display subnanomolar potency in vitro on HER2-positive cells, 2 orders of magnitude lower than free vincristine and comparable with marketed ADC. In vivo, trastuzumab-vincristine conjugates led to remarkable efficacy when compared to two standards of care, with complete tumor regression just 9 days after single administration. This highlights the untapped potential of the chemotherapeutic arsenal toward the development of novel ADC.
Authors
- Oscar Hernandez‐Alba (ORCID: https://orcid.org/0000-0001-5524-4983)
- Stéphane Erb (ORCID: https://orcid.org/0000-0001-7707-644X)
- François Daubeuf (ORCID: https://orcid.org/0000-0001-8061-5897)
- Igor Dovgan (ORCID: https://orcid.org/0000-0002-1178-8118)
- Maria Zeniou (ORCID: https://orcid.org/0000-0002-3237-0263)
- Julien Most
- Héloïse Cahuzac
- Françoise Dantzer (ORCID: https://orcid.org/0000-0003-0945-8483)
- Guilhem Chaubet (ORCID: https://orcid.org/0000-0001-6462-5112)
- Sergii Kolodych (ORCID: https://orcid.org/0000-0001-5963-361X)
- Sarah Cianférani (ORCID: https://orcid.org/0000-0003-4013-4129)
- L. Silva (ORCID: https://orcid.org/0009-0005-6082-5201)
- Agathe Boos
- Alain Wagner (ORCID: https://orcid.org/0000-0003-3125-601X)
- Alexandre Detappe (ORCID: https://orcid.org/0000-0001-9364-1621)
- Constantin Semenchenko
Institutions
- Centre National de la Recherche Scientifique (FR)
- Institut Pluridisciplinaire Hubert Curien (FR)
- Institut de Cancérologie Strasbourg (FR)
- École Supérieure de Biotechnologie de Strasbourg (FR)
- International Drug Development (FR)
- Institut Polytechnique de Bordeaux (FR)
- Université de Strasbourg (FR)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2024-12-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.4c02425
- Citations
- 5
- Primary Topic
- HER2/EGFR in Cancer Research
- Type
- article
- Field-Weighted Citation Impact
- 1.41
Funders
- Agence Nationale de la Recherche
- Université de Strasbourg
- Ligue Contre le Cancer
- Centre National de la Recherche Scientifique