Cancer has become the second largest health threat in the world, with about 10 million people dying of cancer in 2020. For decades, cytotoxic-based chemotherapy has been the main treatment for all kinds of cancers. These cytotoxic drugs include DNA base analogs, antimetabolic drugs, tubulin inhibitors, etc. However, most of these chemotherapeutic drugs show a low therapeutic index, and serious side effects are usually attributed to the exposure of non-specific drugs to off-target tissues. In order to solve this problem, scientists have been devoting themselves to developing new cancer therapeutic drugs with higher targeting ability.
Antibody-drug conjugates (ADCs) are complex targeted agents composed of a cytotoxic drug hanging on an antibody scaffold. It combines the advantages of high specific targeting ability and strong killing effect to achieve accurate and efficient clearance of cancer cells, and has become one of the hotspots in the research and development of anticancer drugs.
Key components of Antibody-drug conjugates
Antibody-drug conjugates consist of antibodies, cytotoxic drugs, and chemical linkers. Ideal ADC drugs can remain stable in the blood circulation, then accurately reach the therapeutic target, and finally release cytotoxic drugs near the target. Each factor will affect the ultimate efficacy and safety of ADC. Usually, all these key components should be considered in the development of ADC, including target antigens, antibodies, cytotoxic drugs, linkers, and conjugation methods.
The mechanism of ADC killing cancer cells through different pathways
The main mechanism of action is shown in the following figure. The upper right part is the main core mechanism of ADC; the lower left one shows how the antibody components of ADC contact with immune effector cells to induce anti-tumor immunity, including CDC, ADCC and ADCP effects; the lower right part indicates that the antibody components of ADC can maintain their active characteristics, so they can interfere with the target function and inhibit downstream signals to inhibit tumor growth.
The overview of the mechanisms of ADC for killing cancer cells via different approaches. (Fu, 2022)
Clinical research progress of ADC
After decades of efforts, more than 100 ADCs are currently under clinical development. As of December 2021, 14 Antibody-drug conjugate drugs have been approved for sale in different countries around the world. Coincidentally, half of the approved ADCs are mainly used for the treatment of hematological malignancies, and the rest is mainly used for solid tumors. The approval of 14 ADC drugs and the exciting clinical manifestations of other ADC drug candidates have also attracted more attention in this field, which is important for this relatively young but highly complex field.
Fortunately, a large number of studies have provided insight into the key factors that determine the final behavior of ADC. Therefore, it is very important to establish a suitable method to evaluate the components of ADC in vitro and in vivo. Identifying and validating new antigens/antibodies, developing new cytotoxic drugs with optimal toxicity, and designing new linkers to balance stability and payload release seem to be the key to the next generation of ADC. With the continuous efforts of researchers in these fields, it is not difficult to imagine that the future ADC will show more surprises in the targeted treatment of cancer.