Therapeutic index improvement of antibody-drug conjugates

The commentary by Colombo and Rich recently published in Cancer Cell provides a timely and comprehensive review of the clinical maximum tolerated doses (MTDs) of antibody-drug conjugates (ADCs) and their corresponding small molecules/chemotherapies. The authors identified similarities between their MTDs and therefore question the historic assumptions made for ADCs, namely, that they increase the MTDs of their corresponding cytotoxic molecules. However, the authors did not address the superior anti-tumor responses of ADCs compared to their corresponding chemotherapies, as reported in clinical trials. In this point of view, we propose a revised model wherein the anti-tumor activities of ADCs and consequently their therapeutic indexes (TIs) are not solely associated with changes not only in their MTDs but also in their minimal effective doses (MEDs). In addition, when using an exposure-based TI calculation method, the superior anti-tumor activities of ADCs relative to their corresponding chemotherapy can readily be explained. We discussed the clinical and preclinical data in support of lower MEDs of ADCs and generated a revised graph illustrating the TI improvements of ADCs vs chemotherapy more accurately. We believe that our revised model can provide a blueprint for future improvements in protein engineering and chemical engineering of toxins to further advance ADC research and development.