Approaches to improve the translation of safety, pharmacokinetics and therapeutic index of ADCs.

1. Antibody-drug conjugates (ADCs) are an important class of cancer therapies. They are complex molecules, comprising an antibody, a cytotoxic payload, and a linker. ADCs intend to confer high specificity by targeting a unique antigen expressed predominately on the surface of the tumour cells than on the normal cells and by releasing the potent cytotoxic drug inside the tumour causing cytotoxic cell death. Despite high specificity to tumour antigens, many ADCs are associated with off-target and on-target off-tumour toxicities, often leading to safety concerns before achieving the desirable clinical efficacy. Therefore, it is crucial to improve the therapeutic index (TI) of ADCs to enable the full potential of this important therapeutic modality. 2. The review summarises current approaches to improve the translation of safety, pharmacokinetics, and TI of ADCs. Common safety findings of ADCs resulting from off-target and on-target toxicities and nonclinical approaches to de-risk ADC safety will be discussed; multiple approaches of using preclinical and clinical dose and exposure data to calculate TI to guide clinical dosing will be elaborated; different approaches to improve TI of ADCs, including selecting the right target, right payload-linker and patients, optimising physicochemical properties, and using fractionation dosing, will also be discussed.