"Magic Bullet" in Precision Treatment of Tumors: Antibody Drug Conjugates (ADC Drugs)

The History of ADC Drugs

ADC drug history begins with "magic bullet". Physicians have long had high cytotoxic chemotherapy drugs for tumour treatment. As they target cancer cells, chemotherapeutics will also random attack healthy cells and become systemically toxic. Paul Ehrlich came up with the term "magic bullet" in 1913. He pictured fitting chemotherapy drugs on carriers that would shoot to tumour cells – as they do with missiles – to send them to tumor tissue so that they could precise "bomb" and precise strikes on cancer cells, leaving normal cells unaffected. Technological development of ADC drugs is now being accelerated by monoclonal antibody technology and recombinant protein technology, which are already the rage in the 1980s. The FDA first approved the ADC treatment gemtuzumab in 2000 for acute myeloid leukemia, and ADC has come down to earth from an ideal.

The Structure of ADC Drugs

The chemistry of ADC drugs is not ingenious. It's comprised mostly of three elements: monoclonal antibodies, chemotherapy agents (payloads) and linkers between them. (1) MAbs function like missile guidance system. They can bind to particular antigens in certain tumour cells and direct chemotherapy drugs right to the tumour. They're the fingerprints for tumour cells. (2) Chemotherapy agents are cytotoxic agents, which are equivalent to high-explosive warheads of great killing power. The chemotherapy agents chosen in ADCs are highly anti-tumor. For example, DXD contained in trastuzumab is a derivative of the topoisomerase I inhibitor exotecan, and its anti-tumor activity is 100 to 1000 times that of common chemotherapy drugs such as doxorubicin. (3) Linkers are the key structure that connects MAbs and chemotherapy drugs together, similar to the connection device of missiles. Whether ADC drugs are stable before reaching the target tumor cells, whether chemotherapy drugs can successfully reach the tumor site, and whether they will be accidentally released prematurely, all play a decisive role in this. If the linker breaks before the ADC drug reaches the tumor cells, the killing effect cannot be achieved and adverse reactions will increase; if the connection is too strong, the ADC drug cannot successfully unload the "ammunition" when it reaches the tumor cells, and the efficacy is reduced.

Mechanism of Action of ADC Drugs

The monoclonal antibodies of ADC drugs are adapted for particular molecules (antigens) found on the surface of tumor cells, and they are extremely responsive to them. Through monoclonal antibodies targeting action, ADC drugs will adhere to their target antigens on the surface of the tumour cells and be "swallowed" by the tumor cells; then the linkers in ADC drugs will be digested by systems including lysosomes on the tumor cells releasing cytotoxic drugs and participating in the destruction of tumor cells. Moreover, monoclonal antibodies in ADC drugs can be somewhat directly anti-tumor.

"Bystander Effect": the Special Weapon of ADC Drugs

Early ADC drugs were very "simple" and would only kill target tumor cells that highly expressed a certain specific antigen, but would not kill other tumor cells that did not express or expressed this antigen at a low level. Later, this “simple” changed: after some ADC drugs entered the target tumor cells, the cytotoxic drugs would not only be released in situ, but would also spread further, producing killing activity on other tumor cells. This is the "bystander effect". In fact, in addition to early ADC drugs, most of the ADC drugs currently on the market have this effect. However, it should be noted that the "bystander effect" is a double-edged sword: while enhancing the tumor killing effect of ADC drugs, it may also increase certain adverse reactions.

The Efficacy of ADC Drugs

Currently, a variety of ADC drugs have been approved for marketing, such as emtansine trastuzumab, vedicizumab, ogamicin, gosartan, vepotuzumab, and detrastuzumab. These ADC drugs are loaded with different types and proportions of cytotoxic drugs, and the way of releasing cytotoxic drugs is also different. According to previous clinical data, ADC drugs have advantages in efficacy over traditional therapeutic drugs. For example, compared with trastuzumab monotherapy, the HER-2-targeted ADC drug emtansine trastuzumab can reduce the risk of recurrence or death by 50% in the treatment of HER2+ breast cancer patients. In another large-scale global clinical study, compared with traditional chemotherapy, emtansine trastuzumab is more effective in treating HER-2 low-expressing, second-line and above metastatic breast cancer, and can significantly improve patients' survival.

Safety of ADC Drugs

While ADC drugs have achieved breakthrough efficacy, their safety issues have also attracted public attention. Target selection, drug mechanism of action, and linkers are all important factors affecting ADC-related adverse reactions. On the one hand, ADC drugs can cause target-related adverse reactions. For example, cardiotoxicity is a common adverse reaction of anti-HER-2 ADC drugs (such as trastuzumab emtansine and trastuzumab desmoduzumab), which is usually manifested as a decrease in left ventricular ejection fraction. On the other hand, adverse reactions characterized by payload categories can be observed during ADC treatment. For example, ADC drugs with MMAE as a payload (such as vedicizumab, vebutuximab, and vepotuzumab) are prone to induce peripheral neuropathy, which manifests as numbness or pain in the hands and feet. In addition, off-target-related toxic side effects caused by unstable linkers are also an important cause of adverse reactions in ADCs. ADC drugs are generally safe. For predictable adverse reactions, individualized monitoring and adverse reaction management are required according to the characteristics of different drugs.