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 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, 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.