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From the 1910s to the present: What are the secrets behind the development of antibody-drug conjugates?
Antibody drug conjugates (ADCs) are a class of biopharmaceuticals designed for cancer treatment. Compared with traditional chemotherapy, ADCs are designed to effectively target and destroy tumor cells while sparing healthy cells as much as possible. According to 2019 data, about 56 pharmaceutical companies are developing various models of ADCs, a trend that shows the importance the medical community attaches to such therapies.
Mechanism of antibody drug conjugates
The basic structure of ADCs is composed of antibodies and biologically active cytotoxic agents or drugs. Antibodies specifically recognize and attach to tumor antigens on the surface of cancer cells. When the antibody attaches, it triggers a chemical reaction in the cells, prompting the tumor cells to absorb the antibody and its linked cytotoxic agent. As ADCs are internalized, the cytotoxic agent destroys the cancer cells. Such targeting capabilities are thought to reduce side effects for cancer patients and provide a broader window for treatment, although in the clinic, this promise has yet to be fully realized.
The concept of the "magic bullet" can be traced back to 1900, when German Nobel Prize winner Paul Ehrlich first proposed a drug that could specifically attack tumor cells. This drug concept has now evolved into antibody drug conjugates, showing its importance.
History of Antibody Drug Conjugates
The development history of ADCs is full of trials and challenges. In 2001, Pfizer and Wyeth's drug Gemtuzumab ozogamicin (trade name: Mylotarg) was approved. However, after several years of evaluation, it was finally withdrawn by the FDA in 2010 due to lack of benefits and significant toxicity. It was not re-marketed until 2017. Subsequently, a series of other ADCs were approved by the FDA, including Brentuximab vedotin and Trastuzumab emtansine.
Composition of ADCs
The core components of every antibody drug conjugate include three parts: antibody, cytotoxic agent and linker. Antibodies are mainly used to locate cancer cells, and cytotoxic agents give the desired therapeutic response. The role of linkers is to attach the toxic agents to the antibodies and keep them stable in the circulation. The cytotoxic agents are only released in the target cells. This exquisite design improves the safety and efficacy of ADCs.
The key roles of cytotoxic agents and linking agents
The selection of cytotoxic agents is crucial to the efficacy of ADCs, and many cytotoxic agents are derived from natural products. The stability and design of the linker affect whether the release of cytotoxic agents can be precise and appropriate. Recent studies have shown that some linkers can be cleaved within tumor cells, releasing toxic agents while effectively attacking neighboring cells. This phenomenon is called "bystander killing."
"The stable linker ensures that the cytotoxic agent is not released prematurely before reaching the tumor cells, thereby improving the safety of the treatment."
Current and future research directions
With the development of the field of antibody drug conjugates, designers are constantly seeking new combination models of improved linkage technology and cytotoxic agents. Researchers are even exploring the use of unnatural amino acids to provide more precise binding of drugs to antibodies. This specific combination of technologies allows researchers to produce uniform ADCs with improved efficacy and safety.
Conclusion
The development process of antibody drug conjugates is the epitome of the continuous progress of medical science. With the innovation of new technologies, the application of ADCs is no longer limited to the field of oncology. Looking forward to the future, if we can unravel the secrets behind these complex mechanisms, we may be able to gain a deeper understanding of cancer treatment and develop more precise treatment options. So, where will drug treatments develop in the future?
