Formulation Development for Antibody-Drug Conjugates

AbstractAntibody–drug conjugates (ADCs) are complex molecules designed to provide targeted therapy to cancer patients. An ADC is formed commonly by conjugating an antibody with small cytotoxic drugs generally either through lysine ε-amino groups to form a lysine-linked ADC or through sulfhydryl groups of reducing interchain cystine. THIOMAB®–drug conjugates (TDCs) are a new subclass of ADCs in which the engineered free cysteine residues at specific sites of the antibody are conjugated with cytotoxins. The majority of ADCs currently in the market and under development contains a common moiety: a thio-succinimide linker that is susceptible to hydrolysis of succinimide and cleavage of the thioether bond. ADC contains a heterogeneous mixture of different drug-loaded antibody species, whereas TDC exhibits a more homogeneous distribution of linker drugs. Linker stability, drug load distribution, and drug-to-antibody ratio (DAR) are believed to play critical roles in the efficacy and safety of ADC products. This chapter describes analytical methods and formulation strategies to understand and characterize these critical quality attributes in order to develop a stable formulation for ADC product. The effect of DAR on ADC aggregation is presented. In addition, formulation parameters such as pH and buffers, antioxidants, and surfactants are described. Finally, the advantages and drawbacks of a lyophilized formulation are discussed.KeywordsFormulationsDrug–antibody ratioStabilityADC aggregationLyophilization