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In recent years, a new type of anti-cancer drug called Antibody-Drug Conjugate (ADC) has continuously made breakthroughs in clinical practice, enabling it to quickly rise in the global innovative drug field. What kind of drug is ADC? Why can it become a new hope for anti-cancer treatment?

Compared with chemotherapy, what are the advantages of ADC drugs?

ADC drugs can be vividly understood as precision missiles for killing tumors. They directly deliver cytotoxic drugs into tumor cells, reducing damage to healthy cells and side effects. It can be said to be "only hitting the bad guys without harming the innocent bystanders".

The structure of ADC consists of three parts: an antibody, a linker, and a cytotoxic drug (payload). Among them, the antibody is the "navigation system" of the missile, responsible for finding tumor cells and transporting the cytotoxic drug into them; the linker is the "safety device" of the missile, which is triggered in a suitable environment (such as under the action of acidity or specific enzymes) to release the cytotoxic drug connected to the antibody; the cytotoxic drug is the "warhead" of the missile. After being released inside the tumor cell, it directly destroys the tumor cell by damaging DNA or preventing cell division.

This set of designs is precise and efficient. Compared with traditional chemotherapy, its advantages are very obvious.

However, the development of ADC has been a long and tortuous process.

As early as the beginning of the 20th century, German physicist and scientist Paul Ehrlich proposed the concept of the "magic bullet", hoping to develop a drug that could precisely destroy specific cells without harming normal cells. However, this vision faced many challenges. It was not until the 1950s that breakthroughs in chemical technology made it possible to combine cytotoxic drugs with antibodies. For example, the experiment of combining methotrexate with polyclonal antibodies marked an initial attempt.

In the 1970s, the innovation of hybridoma technology promoted the development of monoclonal antibodies (mAb). In the 1980s, Greg Winter pioneered the humanized monoclonal antibody technology, laying the foundation for ADC. ADCs during this period showed good results in models. However, ADC clinical trials were frustrated due to drug toxicity and insufficient efficacy.

It was not until 2000 that the first ADC drug, gemtuzumab ozogamicin, was approved by the US FDA. It was initially used to treat relapsed and/or refractory acute myeloid leukemia but was withdrawn from the market in 2010 due to adverse events.

ADC has been challenged due to its complex structure, but research in this field has never stopped. More than a century after Paul Ehrlich proposed the "Magic Bullet" concept, ADC technology has ushered in a new dawn.

In 2011, the ADC drug brentuximab vedotin was approved. This drug can target the protein molecule CD30 on the surface of lymphoma cells to aim at and kill tumor cells, and is used to treat Hodgkin lymphoma and anaplastic large cell lymphoma. In 2013, trastuzumab emtansine (T-DM1), which targets HER2 (a protein molecule overexpressed on the surface of some breast cancer cells), was approved for the treatment of breast cancer. These milestone achievements have proven the potential of ADC and promoted the rapid development of this field.

Currently, as many as 12 ADC drugs have been approved by the US FDA for marketing. The ADC field has attracted much attention in recent years, and it is expected that more ADC drugs will be approved for marketing in the next five years.

How do ADC drugs kill tumor cells?

As a "missile for precise tumor strike", how does ADC work? Let's understand it from its "operational process":

First, after being injected into the body, ADC exists in three forms. Among them, the main active form is the intact conjugate - the antibody and the cytotoxic drug are combined together through a stable linker to ensure efficacy and stability. In addition, there will also be some antibodies that failed to successfully bind to the drug during the production process. Due to the unstable linker, some cytotoxic drugs may fall off from the antibody and float freely in the body.

Next, when the antibody part of ADC binds to the target on the surface of the tumor cell, the entire molecule will be "phagocytosed" by the cell and internalized into the cell. Whether the target is easily internalized and the efficiency of this process will directly affect the activity of ADC.

Finally, after entering the cell, ADC will enter the lysosome or endosome of the cell. In these environments, due to acidic conditions, proteolysis, or chemical reactions, the cytotoxic drug will be released from the antibody. Subsequently, the drug diffuses into the cytoplasm, acts on specific targets, and finally kills the tumor cell. Since the drug payload of some ADCs is hydrophobic, it can penetrate the cell membrane. This means that even adjacent tumor cells that do not express the ADC target may be killed due to drug diffusion. This "bystander effect" is particularly important when the expression of tumor cell targets is uneven.

It is worth noting that the antibody in ADC is not only a "carrier" for the drug, but also has its own functions: it can bind to the target of the tumor cell and interfere with the tumor's signal transduction; it can bind to immune cells (such as natural killer cells, NK) and activate the anti-tumor immune response - such multiple mechanisms can enhance the efficacy of ADC. However, for some ADCs, their specific contributions still need further research.

The main process of ADC exerting its efficacy.

How to design ADC drugs with better efficacy?

From the above "operational process", we can see that every step of ADC in the body precisely affects the balance of efficacy. For developers, what challenges will they face in creating a sophisticated ADC "missile"?

First, they need to choose the right "enemy", that is, select a suitable target. The primary task of ADC is to find and lock tumor cells. A good target is like a unique mark on tumor cells, which only appears on tumor cells or in tumor areas and is hardly found on healthy cells. This can ensure that ADC disturbs normal body tissues as little as possible when performing its task.

Second, they need to build a "navigation truck", that is, prepare high-quality antibodies. This "truck" not only needs to be able to accurately find the target tumor cells, but also needs to be strong and durable and have good biological properties to ensure that the drug can be safely and efficiently delivered to the destination.

Third, they need to achieve precise docking to ensure a strong binding ability of the antibody. Whether the "truck" can dock tightly with the target is directly related to whether ADC can smoothly enter the inside of the tumor cell and implement a "precise strike". If the docking is not firm, ADC may malfunction on the way and fail to effectively enter or eliminate tumor cells.

Fourth, they need to choose a powerful "warhead" to ensure the effectiveness of the payload. The cytotoxic "warhead" carried by ADC must be powerful enough to ensure a one - shot kill of tumor cells. However, excessive power may also bring risks, so a perfect balance needs to be found between efficacy and safety.

Fifth, they need to design a reliable "bridge", that is, select a suitable linker. The linker is like a "bridge" built between the antibody and the drug. It needs to be stable enough to ensure that the drug will not be released prematurely in the blood circulation, and it also needs to be able to release the "warhead" in a timely manner after entering the tumor cell to allow the drug to take effect. This requires the linker design to be both "stable" and "releasable".

Sixth, they need to achieve precise loading and optimize the binding sites and quantity of the drug and the antibody. The binding site of the drug and the antibody is crucial as it affects the stability and release timing of the drug. If the binding position is incorrect, the drug may "derail" prematurely, increasing the damage to healthy tissues. The number of drugs loaded on each antibody (DAR) also needs to be carefully regulated. Too few drugs will not achieve the desired efficacy, while too many may lead to ADC instability, affecting efficacy and increasing toxicity.

What are the representative ADC drugs?

With the continuous deepening of research, the design of ADC drugs has been optimized generation by generation (Table 2), and new research results and candidate drugs have emerged continuously. Since the development of the new - generation ADC to date, multiple technological breakthroughs have been achieved. For the three components that make up ADC, researchers and developers have optimized and improved their performance one by one, making this "missile" targeting tumor cells more powerful:

In terms of antibodies, the use of humanized antibodies and site - specific conjugation technology has significantly reduced immunogenicity and improved tumor targeting;

In terms of linkers, by introducing cleavable linkers, drugs can be controllably released under specific conditions, enhancing the precision of treatment. The latest technology is further optimizing linker stability to reduce the risk of non - specific release;

In terms of cytotoxic drugs, the latest technology uses more potent cytotoxic drugs and diversified indication strategies, such as topoisomerase I inhibitors and high drug - to - antibody payloads, to improve efficacy.

For example, the ADC drugs Enhertu and Kadcyla for the treatment of breast cancer represent the achievements of different development stages of HER2 - targeted ADC technology (Table 3). As a new - generation ADC, Enhertu has significantly broadened the treatment scope with its high drug - to - antibody ratio and bystander effect, benefiting patients with HER2 - low - expressing cancers. Kadcyla is one of the first successful HER2 - targeted ADCs, focusing on the treatment of HER2 - positive breast cancer, with mature technology and mild side effects.

On June 2, 2024, the results of a key clinical trial (DESTINY - Breast 03) of the above two ADC drugs for the treatment of HER2 - positive breast cancer and HER2 - low - expressing breast cancer were published in "Nature Medicine", from which the advantages of the latest - generation ADC drugs can be seen.

HER2 - positive breast cancer is a type of breast cancer with a relatively high degree of malignancy. Patients express a large amount of HER2 protein in their bodies. Although traditional therapies (such as the monoclonal antibody drug trastuzumab) can target HER2, their effectiveness is limited for advanced patients or drug - resistant cases.

In the DESTINY - Breast03 trial, Enhertu showed excellent efficacy in patients with HER2 - positive advanced breast cancer who had previously received multiple lines of treatment. The objective response rate (ORR) of patients in the Enhertu group reached 78.5%, significantly higher than that of the Kadcyla control group (ORR was only 34.2%); the progression - free survival (PFS) of the Enhertu group was 29 months, while that of the control group was 7.2 months; the median overall survival of the Enhertu group was 52.6 months, while that of the control group was 42.7 months. It can be seen that the new - generation ADC drug Enhertu has significantly prolonged the disease - free progression time of patients and improved the prognosis of drug - resistant patients.

In addition, Enhertu has been proven to have significant efficacy in HER2 - low - expressing breast cancer in other series of DESTINY trials. This patient population was traditionally not considered suitable for HER2 - targeted treatment, but Enhertu has broken this limitation and further extended the concept of precision medicine to more patient populations.

Conclusion

As can be seen from the above examples, ADC drugs have redefined the possibilities of cancer treatment. With their excellent precision, powerful lethality, and innovative design concepts, they can be regarded as a perfect combination of modern medicine and science and technology.

As the competition in the ADC drug market becomes increasingly fierce, how to stand out among many candidate drugs has become a key issue that developers must face. How to further optimize off - target toxicity and reduce potential side effects is still the focus of current research. To build core competitiveness, developers need to conduct comprehensive innovation and optimization in target selection, platform technology, indication selection, clinical design, and project planning. Only in this way can ADCs with higher efficacy be introduced into clinical practice and bring more good news to cancer patients.