Antibody–drug conjugates for targeted anticancer drug delivery

Abstract

Antibody–drug conjugates (ADCs) are tumor-targeted therapeutic agents that combine the specificity of monoclonal antibodies (mAbs) with the potent anti-tumor effects of cytotoxic drugs. Over the past few years, ADCs have become a powerful tool in the field of cancer chemotherapy. Recently, two ADC products, brentuximab vedotin (Adcetris®) and trastuzumab emtansine (Kadcyla®), have received FDA approval and there are more than 40 ADC candidates in clinical trials for the treatment of various cancers. Despite the success of some products, considerable interests for the next generation of ADCs have focused on the development of homogeneous conjugates because most of the current ADCs are highly heterogeneous with different drug-to-antibody ratios and drug conjugation sites. Recent studies have demonstrated that the site-specific conjugation of drugs to mAbs could produce homogeneous ADC with better pharmacokinetic properties and improved therapeutic index. A number of approaches, including the use of engineered cysteines, the insertion of unnatural amino acids, and enzymatic ligation, have addressed the challenging issues for the synthesis of homogeneous ADC. This review discusses the limitations of current ADC technologies and describes recent site-specific conjugation methods that can be used to prepare homogeneous ADCs for targeted anticancer drug delivery.