Antibody-drug conjugates as novel anti-cancer chemotherapeutics

Abstract

Over the past couple of decades, antibody-drug conjugates (ADCs) have revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumour-associated target antigens and deliver a highly potent cytotoxic agent. The synergistic combination of mAbs conjugated to small-molecule chemotherapeutics, via a stable linker, has given rise to an extremely efficacious class of anti-cancer drugs with an already large and rapidly growing clinical pipeline. The primary objective of this paper is to review current knowledge and latest developments in the field of ADCs. Upon intravenous administration, ADCs bind to their target antigens and are internalized through receptor-mediated endocytosis. This facilitates the subsequent release of the cytotoxin, which eventually leads to apoptotic cell death of the cancer cell. The three components of ADCs (mAb, linker and cytotoxin) affect the efficacy and toxicity of the conjugate. Optimizing each one, while enhancing the functionality of the ADC as a whole, has been one of the major considerations of ADC design and development. In addition to these, the choice of clinically relevant targets and the position and number of linkages have also been the key determinants of ADC efficacy. The only marketed ADCs, brentuximab vedotin and trastuzumab emtansine (T-DM1), have demonstrated their use against both haematological and solid malignancies respectively. The success of future ADCs relies on improving target selection, increasing cytotoxin potency, developing innovative linkers and overcoming drug resistance. As more research is conducted to tackle these issues, ADCs are likely to become part of the future of targeted cancer therapeutics.

Keywords: antibody–drug conjugates; brentuximab vedotin; cancer; chemotherapy; monoclonal antibodies; trastuzumab emtansine.

Figure 1. Evolution of chemotherapeutic drugs [6]

Figure 2. Structure of an ADC [28]

Figure 3. Mechanism of action of ADCs

Figure 4. Mechanism of ADCC, CDCC and CDC [103]

Figure 5. Mechanisms of traditional conjugation with DARs [138]

Figure 6. Effect of auristatins and maytansines on microtubule formation [138,173]

Figure 7. Structures of IgG antibody, minibody and diabody [196]