ABSTRACT
Paul Ehrlich’s magic bullet concept of drugs that go straight to their intended cell-structural targets without harming healthy tissues is more than 100 years old. This chapter describes the important steps for developing an antibody-drug conjugate (ADC) through early- and late-stage development and challenges faced especially during pharmaceutical development in order to maintain a balance between physical and chemical stability of the ADC and its ultimate use in a patient. Cytotoxic drugs are generally conjugated to antibodies either through lysine e-amino groups or through cysteine sulfhydryl groups that are activated by reducing the existing interchain disulfide bonds and/or other engineered amino acids. With the recent success of two ADCs in the clinic, the field is ripe with innovation and several clinical trials to optimize the linker, payload, antibody, and the target indication. The tumor antigen should be readily accessible to a circulating ADC, and therefore, it must be localized on the cell surface.
