The Secret to Improving the Therapeutic Index of Antibody Drug Conjugates

Antibody-drug conjugates (ADCs) were initially developed to provide a selective targeting mechanism for cytotoxic small molecule drugs with the goal of improving the therapeutic index in clinical practice. But despite a careful target selection and a high degree of specificity afforded through the antibody part of the ADC, a sufficiently improved therapeutic index has been challenging to achieve. It often remains a challenge to reach desirable efficacious doses with repeated cycles of treatment due to the toxicity profile induced by the cytotoxic warhead. The clinical landscape of ADC therapeutics in both hematological and solid cancers has grown in recent years considerably to nearly 600 clinical trials incorporating numerous ADC modalities. These new molecular entities utilize many different tumor-associated antigen targets, new conjugation technologies, and payload warheads of various mechanisms such as tubulin inhibitors, DNA damaging, topoisomerase inhibition, or DNA polymerase II inhibitors.