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Update on antibody-drug conjugates in breast cancer.

HR These anticancer drugs have a fascinating construct that combines an antibody, a toxin, and a linker. The idea is to use a “smart bomb” approach in which a unique antigen that is expressed on cancer cells, but less or not at all on normal cells, is targeted by using the corresponding antibody. The antibody binds to the cancer cell, and the ADC becomes internalized. After the ADC enters the vesicle of the cell, it is digested, and the linker releases the toxin into the cancer cell. We want to have the biggest “bang for the buck” with these toxins, so researchers choose agents that are highly toxic in very small amounts and that would not be safe given as naked drugs. By using a linker to attach the toxin to the antibody, we are able to deliver small amounts of the toxin directly to the cancer cells. This approach can be highly effective. A critical aspect of ADCs is using the right linker. The linker needs to be digested after it enters the cancer cell so that it can release the drug directly to the cell. If the linker is digested too early, we end up with systemic drug administration. It took some time to develop the current generation of linkers, and improvements are ongoing. A final important feature of ADCs is their ability to kill cells that are adjacent to cancerous cells, which is known as the bystander effect. Even if these neighboring cells do not express the target antigen in large amounts, they can pose a threat by being part of the tumor environment. Bad-actor cells like to keep company with one another. A toxin that has the ability to pass through the cell membrane holds the potential to kill bystander cells at the same time that the ADC kills the antigenexpressing cells. The first ADC to receive US Food and Drug Administration (FDA) marketing authorization was gemtuzumab ozogamicin (Mylotarg, Pfizer), which was approved in 2000 for treating acute myeloid leukemia. The first ADCs to receive FDA approval in breast cancer were the second-generation agents trastuzumab emtansine, also known as T-DM1 (Kadcyla, Genentech), in February 2013, and trastuzumab deruxtecan (Enhertu, DaiichiSankyo/AstraZeneca), in December 2019. The thirdgeneration agent sacituzumab govitecan-hziy (Trodelvy, Immunomedics) received FDA approval in April 2020. One advantage of the newer agents over first-generation ADCs is that technologic improvements have made it possible to increase the drug-to-antibody ratio (DAR).