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.
Highlights
Cancer, responsible for about 8.2 million deaths per year globally, is the second most common deadly disease which severely affects the human health worldwide [1]
Chemotherapeutic agents are not specific to tumor cells and they can affect normal cells with high mitotic rates. This can lead to life-threatening side effects in cancer patients. The severity of such uninvited side effects can be reduced by conjugating different types of highly potent un-targeted drugs such as tubulin polymerization inhibitors, DNA damaging agents conjugated to a monoclonal antibody
Used cytotoxic payloads in Antibody-drug conjugate (ADC), such as calicheamicin, auristatins, maytansines, taxnes, and doxorubicin are well-known substrates of efflux transporter of P-gp, which pumps out the drug from intracellular space
Summary
Responsible for about 8.2 million deaths per year globally, is the second most common deadly disease which severely affects the human health worldwide [1]. The severity of such uninvited side effects can be reduced by conjugating different types of highly potent un-targeted drugs such as tubulin polymerization inhibitors, DNA damaging agents conjugated to a monoclonal antibody (mAb) Another proven approach to minimize chemotherapy side effects is nanotechnology. A site-specific targeted delivery of cytotoxic drugs is proving to be a better option for efficient drug delivery This can be achieved by conjugating cytotoxic drugs to a suitable and validated mAb. ADC strategy enhances the therapeutic window of potent cytotoxic drugs, and minimizes chemo-associated side effects. ADCs are typically comprised of a fully humanized mAb targeting an antigen /preferentially expressed on tumor cells, a cytotoxic payload, and a suitable linker (Figure 1c). In this review, we attempt to discuss various advancements and challenges in ADC technologies with a special focus on linkers and conjugation methods
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