Antibody-Drug Conjugates for Cancer Therapy: Chemistry to Clinical Implications

Abstract

Chemotherapy is one of the major therapeutic options for cancer treatment. Chemotherapy is often associated with a low therapeutic window due to its poor specificity towards tumor cells/tissues. Antibody-drug conjugate (ADC) technology may provide a potentially new therapeutic solution for cancer treatment. ADC technology uses an antibody-mediated delivery of cytotoxic drugs to the tumors in a targeted manner, while sparing normal cells. Such a targeted approach can improve the tumor-to-normal tissue selectivity and specificity in chemotherapy. Considering its importance in cancer treatment, we aim to review recent efforts for the design and development of ADCs. ADCs are mainly composed of an antibody, a cytotoxic payload, and a linker, which can offer selectivity against tumors, anti-cancer activity, and stability in systemic circulation. Therefore, we have reviewed recent updates and principal considerations behind ADC designs, which are not only based on the identification of target antigen, cytotoxic drug, and linker, but also on the drug-linker chemistry and conjugation site at the antibody. Our review focuses on site-specific conjugation methods for producing homogenous ADCs with constant drug-antibody ratio (DAR) in order to tackle several drawbacks that exists in conventional conjugation methods.

Antibodies can be Spontaneously Loaded onto Monosialoganglioside Micelles Containing Oncological Drugs

“…The use of antibodies against selectively expressed antigens on the surface of cancer cells is a therapeutic strategy widely studied not only as directed immunotherapy but also for its potential to selectively target drugs or drug delivery systems [24,25].…”

Antibody Conjugates-Recent Advances and Future Innovations

“…This class of payloads still predominates in clinical stage research, including novel derivates of these small molecules, despite efforts to use payloads with alternative MOAs [13,39,95]. DNA damaging agents are another class of well-studied payloads [96][97][98]. Enediynes, such as calicheamicin c, are the warhead in Mylotarg ® and Besponsa ® (Table 1, Figure 3).…”

“…With superior pharmacodynamic and safety properties, in large part from the payload, DS-8201a has shown promising response in trastuzumab emtansine-insensitive cancers [31]. DNA damaging agents are another class of well-studied payloads [96][97][98]. Enediynes, such as calicheamicin c, are the warhead in Mylotarg ® and Besponsa ® (Table 1, Figure 3).…”

Homogeneous antibody-drug conjugates: DAR 2 anti-HER2 obtained by conjugation on isolated light chain followed by mAb assembly

“…4 Different approaches have been developed to obtain homogeneous ADCs by site-specific conjugation, including cysteine residue(s) addition, non-natural amino acids, enzymemediated conjugation (including transglutaminase, sortase A, glycosyltransferase or endoglycosidase) and linker-based conjugation. [5][6][7][8][9][10][11][12] Cysteine-engineered residues have been introduced into different antibodies by site-directed mutation to provide free thiol groups for conjugation using conventional thiolspecific maleimide linkers, 13 a technology developed by Seattle Genetics and used to produce the heterogeneous ADC brentuximab vedotin (Adcetris), which was approved by FDA in 2011. The process generates almost homogeneous ADCs containing approximately two drug molecules per antibody, but additional antibody reduction/oxidation steps are required for selective conjugation of the added cysteines.…”