Antibody-Vincristine Conjugates as Potent Anticancer Therapeutic Agents - Archive ouverte HAL
Article Dans Une Revue Journal of Medicinal Chemistry Année : 2024

Antibody-Vincristine Conjugates as Potent Anticancer Therapeutic Agents

Julien Most
Igor Dovgan
  • Fonction : Auteur
Sergii Kolodych
  • Fonction : Auteur
Alain Wagner
Maria Zeniou
  • Fonction : Auteur
  • PersonId : 972550

Résumé

Antibody drug-conjugates (ADC) are a well-established class of therapeutics primarily used in oncology to selectively deliver highly cytotoxic agents into cancer cells. While ADC 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 towards safer payloads, we used the conventional chemotherapeutic drug vincristine to develop antibody-vincristine conjugates. Vincristine was N-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, two orders of magnitude lower than free vincristine and comparable with marketed ADC. In vivo, trastuzumabvincristine conjugates led to remarkable efficacy when compared to two standards of care, with complete tumor regression just nine days after single administration. This highlights the untapped potential of the chemotherapeutic arsenal towards the development of novel ADC.

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Chimie
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vendredi 16 mai 2025
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Dates et versions

hal-04856907 , version 1 (27-12-2024)

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Agathe Boos, Julien Most, Héloïse Cahuzac, Louis Moreira da Silva, François Daubeuf, et al.. Antibody-Vincristine Conjugates as Potent Anticancer Therapeutic Agents. Journal of Medicinal Chemistry, 2024, ⟨10.1021/acs.jmedchem.4c02425⟩. ⟨hal-04856907⟩
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