The payloads used in ADCs are often cytotoxic compounds that are too toxic to be used alone as anticancer drugs. After intravenous administration, only about 2% of ADCs can reach the target tumor site. Therefore, the ADC payload must be a highly active molecule. The optimization of the payload played an important role in increasing the ADC therapeutic window from less than 2 times that of the first generation to 12 times that of the third generation.
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ADC cytotoxins are cytotoxic agents that induce target cell death in Antibody-Drug Conjugates (ADCs), which are targeted drugs consisting of monoclonal antibodies, linkers and cytotoxins. Cytotoxin is the most important component because it determines the ability of ADCs to kill cancer cells. Cytotoxins can be divided into two categories according to their mechanism of action: DNA damaging agents and microtubulin inhibitors. Among them, galicin, doxorubicin and PBD are DNA grove-binding agents; hippocrine and erythromycin/doxorubicin are topoisomerase inhibitors, which are DNA damaging agents. Auristatins and maytansinoids are microtubulin inhibitors. In addition to the aforementioned cytotoxins, many traditional cytotoxic agents with similar mechanisms of killing cancer cells can also be used in ADC development.
Microtubulin inhibitor payloads act during cell growth through mitotic arrest leading to cell death. Due to their favorable biochemical properties, microtubulin inhibitorsrepresent a major payload class. The best known compounds of this class are monomethyl auristatin E (MMAE) and F (MMAF). Currently, a number of approved ADCs carry MMAE, including brentuximab vedotin, polatuzumab vedotin, and enfortumab vedotin.
The action of DNA-damaging agents is independent of the cell growth process. They are often described as molecular scissors because of their ability to cleave genomic DNA, leading to cell death. Other types of drug payloads currently in active clinical development are RNA-modifying drugs (amatoxins), protein toxins, antibiotics and enzymes.
| Target | Mechanism of action | Classification | Products |
| Microtubulin | Microtubulin Inhibitors |
| |
| DNA | DNA-Damaging Agents |
|
|
Table 1. Commonly used cytotoxic payloads.
One of the biggest challenges in ADC development is balancing cytotoxins efficacy with ADC safety. These two properties depend not only on the inherent toxicity of the payload, but also on the stability of the drug-to-antibody ratio (DAR) and linking chemistry. Currently, several approaches are being developed in an attempt to increase the synergy between antibodies and small drug payloads. Most of these strategies have focused on improving linking chemistry and the combination of ADCs with other therapies, such as immune checkpoint inhibitors. In addition, experts believe that payload improvements should focus on developing cost-effective rapid synthesis precursors and enhanced drug dissolution mechanisms.
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