Antibody-drug conjugates in cancer

Abstract

Antibody drug conjugates (ADCs) are emerging as powerful anti-cancer treatments. They are designed to combine the tumor specificity, pharmacokinetics and biodistribution properties of antibodies with the potent cell-killing activity of small molecules. The approval of brentuximab vedotin (Adcetris) for the treatment of Hodgkin lymphoma and trastuzumab emtansine (Kadcyla) for the treatment of metastatic breast cancer has spurred clinical development of ADCs. As the field of ADCs is rapidly emerging, a better understanding of the requirements needed for optimal intracellular delivery of ADCs seems mandatory. The aim of this thesis was to better understand the antibody and antigen requirements that are needed for effective ADC treatment. Different tumor antigens and targeting antibodies were compared for their capacity to deliver a cytotoxic payload to tumor cells, uncovering general mechanisms. In the course of this work, TF was identified as an excellent ADC target because of its rapid internalization and lysosomal targeting characteristics. Furthermore we have explored a novel Ab platform that improves the intracellular delivery of cytotoxic payloads. These findings provide a better insight in the Ab and antigen requirements needed for optimal payload delivery and support the development of novel and further improved ADCs for the treatment of cancer.