Antibody-Vincristine Conjugates as Potent Anticancer Therapeutic Agents
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.