Global ADC drugs entering the golden development period: How to connect technical barriers behind the development and development?

The 21st Century Business Herald reporter Ji Yuanyuan Shanghai reported that ADC (antibody couplet drugs) has undoubtedly become one of the research hotspots in the tumor field in recent years. On the one hand, at the Annual Conference of the American Clinical Oncology Society (ASCO) in 2022, Chinese foreign pharmaceutical companies such as Rongchang Bio, Astraikon and other Chinese and foreign pharmaceutical companies successively demonstrated the research results of ADC drugs; Enterprise leader Seagen, accelerate the layout of the ADC market.

In fact, with the continuous disclosure of the clinical research results of ADC drugs in recent years, companies entering the market have continued to increase, and the "Internet celebrity" products of ADC have attracted widespread attention. According to Southwest Securities data, in recent years, a number of ADC drugs have been approved to be listed, and the market size has grown rapidly. Since 2019, a total of 9 ADC drugs have been listed in the world, exceeding the sum of the previous two years. In 2021, global ADC drug sales exceeded US $ 5 billion, and the compound growth rate was about 30%from 2014-2021.

This is mainly based on the toxicity of ADC than chemotherapy drugs. The new generation ADC has obtained clinical treatment data of chemotherapy therapy.相较传统靶向疗法，ADC进一步拓宽了治疗人群：应用于未被传统靶向疗法覆盖的新靶点；针对老靶点，应用于对传统靶向疗法不响应的患者；针对老靶点， Patients with lower target protein expression.

Earlier, Zhang Qingyuan, director of the Institute of Tumor Prevention and Harbin Medical University, said in an interview with the 21st Century Business Herald, said that the reason why ADC drugs were so concerned also originated from this type of drug. Efficacy.从药物的作用机制来看，更具有特异性，由于抗体携带的药物靶向性更强，携带着细胞毒的药物，往往这个毒素，细胞毒性更强，有高效的杀伤，例如DS-8201， Such a drug -targeted to tumor cells also has the effect of bystander, has good curative effect, and has good safety, so clinical is particularly expected.

"Now many pharmaceutical companies are developing ADC drugs, and they cannot be too blind. ADC's drug research and development has developed to the third generation, and dual -targeted ADCs have appeared. Differences. We clinically hope that drugs with better curative effects and more safety can be listed. "Zhang Qingyuan said.

ADC drug market competition is fierce

Since Pfizer's ADC drug MYLOTARG was launched for the first time in 2000, ADC drugs have also become a popular track for new drugs. The degree of fieryness is comparable to the situation when PD-1 monoclonal anti-anti-resistance in 2018 was just landing in China.

According to statistics from smart bud data, as of now, 13 ADC drugs have been listed in the world, of which a total of 3 ADC drugs have been promoted to the market from 2000-2016. In the past five years Bring to market. From the perspective of the R & D pipelines of domestic and foreign companies, ADC drugs have become the key direction of global innovative pharmaceutical companies, and it may usher in a new peak in 3-5 years. From the perspective of indications and target distribution, tumors are currently focusing on the core direction, but the center of gravity has shifted from hematoma to physical tumors. HER2 is still a popular target, but the exploration of new targets has become more diverse.

Not only that, the popularity of the ADC pipeline transaction has risen, and the introduction of the ADC project of overseas pharmaceutical companies is constantly focusing on new targets or new technology platforms. Since 2013, domestic and foreign companies have accelerated the layout of ADC drugs, and the number of pipeline transactions has continued to rise. Since 2019, several heavy varieties have refreshed the upper limit of the transaction amount. In April 2019, Astraika reached a total of $ 6.9 billion in transactions with the first and third, introducing the new generation of HER2 ADC drug ENHERTU; in September 2020, Gillette spent $ 21 billion to acquire IMMUNOnomedics, which is owned by the company. Have FIRST in Class ADC drug TRODELVY. Earlier in April 2019, Genting Xinyao reached an exclusive license agreement with Immunomedics for $ 8.35 million to obtain the development, registration and commercialization of TRODELVY in Greater China, South Korea and some Southeast Asian countries and regions. On June 10, 2022, the State Drug Administration approved Genting Xinyao Trop2 ADC therapy Trodelvy (IMMU-132) to be launched. TRODELVY is the world's first Trop2 ADC drug to be approved in China.

With the frequent variety of heavy varieties, the sales of many ADC drugs have made great achievements. Statistics of Southwest Securities pointed out that benefiting from the gradual expansion of ADC drugs and excellent curative effects, the sales of ADC drugs have repeatedly achieved great achievements. Global ADC sales in 2021 were nearly 5 billion US dollars, and the average growth rate of compound growth in 2014-2021 was about 30%. AdCetris was approved in 2011, with global sales of about 1.27 billion US dollars in 2021. KADCYLA was approved in 2013, with global sales of about 2.13 billion US dollars in 2021. The new generation of ADC drugs has great potential in the future. ENHERTU and Padcev are all approved by the FDA in 2019. In 2021, sales were 500 million and US $ 340 million. "Nature" is expected to reach 6.2 billion in sales in 2026, respectively. US dollars and US $ 3.5 billion. According to industry institutions, there are currently more than 400 ADCs worldwide researching drugs, including more than 200 in the clinical stage. There are more than 170 ADCs in China who are studying drugs, of which nearly 60 have entered the clinical stage.

In response to the popularity of ADC drug research and development, the number of pipelines is booming, Yang Haiying, vice president of Astraikon China and head of the medical affairs department, pointed out in an interview with the 21st Century Business Herald reporter that with the continuous iteration of antibody couplet technology, ADC drugs More and more potential is being excavated. There are quite a few exploration opportunities in the ADC field:

First, ADC is a very good mechanism. The antibody connecting chemotherapy drugs can integrate the two classic, after many years of verified tumor solutions. But in different tumor diseases, its target biological characteristics may not be the same. Some are protein expression levels, some are genetic mutation levels, and others are gene value -added levels. Therefore, we need to explore and study the biological characteristics of different diseases and the target.

Second, when the disease progresses, how do you need to solve the problem of drug resistance? ADC combined treatment is a very important treatment strategy. For example, ADC connects small molecules and connects immunotherapy. These aspects need to be explored in the future.

Third, the BISPECICICFIC ANTIBODY (double -specific antibody) of the dual -target is considered a major trend. There may be different targets on a tumor cell. How to connect chemotherapy drugs with different target drive gene dual -resistance in the future to produce a larger effect. That is to promote the development of dual -target ADC research, and the future may also be a trend.

"The pharmaceutical industry is a accumulated industry with science and research, and is based on the cognition of the disease field. This also requires enlisted to deepen the disease Biomarker (biomarkers) and target genomeology through continuous scientific research exploration. Cognition, in the future, developing more accurate tumor treatment plans and truly helping patients is a question that requires everyone to pay attention. "Yang Haiying emphasized.

Breaking through technical barriers to become industry trends

Although the ADC drug market has attracted much attention, concerns about the toxicity of ADC drugs have also caused this drug field to be questioned. How to balance the effectiveness and safety of drugs has also become a major direction for clinical experts.

Zhang Qingyuan pointed out that the correct target, antibodies, connectors, and effective loads are the four key factors affecting ADC drugs. On the one hand, there must be a stable and reliable connector, connecting antibodies, and effective loads, which can keep it stable in the blood circulation. It can quickly crack in the tumor cells. Reduce adverse reactions. On the other hand, cytotoxic drugs with sufficient efficacy are connected to antibodies, so as to be low toxic and good curative effect. The first generation of drugs, due to the low efficiency of the valid load, the effectiveness of the maximum tolerance dose is limited.

The second -generation ADC drug uses higher toxins and more stable connectors, but the connector cannot be "reversible", so it also affects the curative effect. The third -generation ADC applies better technology. There are more cytotoxic molecules that can carry, more effective cytotoxic molecules, higher accuracy, and cracked connectors. So such drugs will also show better efficacy and safety clinically. In addition, different drugs may still be very different because of different production technology.

"The safety of drugs is particularly important. If it is not safe, no matter how good the efficacy is in clinical practice, it is not welcome, especially those serious adverse reactions." Zhang Qingyuan believes that we feel that only those who really bring to patients while safe and controllable are safe and controllable. Drugs can finally get better applications, go public, and go to the clinic. Now ADC drugs have a unique mechanism, and the ADCs for different targets have developed rapidly. We see that the ADC for HER2 is not only in patients with breast cancer, gastric cancer, but also physical tumor patients with amplification of HER2 genes may benefit from this drug in the future.

In this regard, Yang Haiying also pointed out in an interview with the 21st Century Business Herald reporter that from a structural point of view, ADC is an antibody, and the chemotherapy drugs occasionally connected through a connector. Although there are many antibodies in the industry, different antibody coupling craftsmanship determines that they are very different.

Specifically: First of all, antibodies are all human nature, or there are still some animal origin. The antigen itself is different, and the immune antigen reaction is different; secondly, whether the antibody can accurately identify these tumor cells through targets and send the coupling chemotherapy drugs into the tumor cells; more, whether the connection is enough, whether How long does it take to decompose after entering the body can carry several chemotherapy drug molecules, and so on. It can be seen that the pharmaceutical molecular structure determines that the difference in each point may bring great differences. We also see that ADC drugs are also effective on the breast cancer expressed in HER2 low. In the future, more effective ADC drugs are the direction of future treatment. Not only for HER2, but also in the field of lymphoma therapy will also have good research and development prospects. However, before seizing the market scene, as Professor Zhang Qingyuan said, due to the complexity of the ADC structure, there were many factors that affect the clinical effects of the drug, and the difficulty of development brought multiple barriers. As a result, how enterprises have opened technical barriers have become a major direction.

This also explains the criticality of global ADC R & D giants, including the first and third Communist ADC R & D giants. According to the 21st Century Business Herald reporter, the first and third DXDADC technology platforms have well balanced the contradiction between the curative effect and toxicity of ADC drugs and toxicity. The above products are under research, where Enhertu has successfully realized commercialization.

SEAGEN is alone in the global ADC field for more than 20 years. Its VC-MMAE platform is currently using the most widely used ADC technology. Holding this technology has also made SEAGEN stock prices from listed in 2001 to 2021 to a maximum increase of 20 times. Among the 13 ADC drugs that have been listed around the world, there are 3 ADC drugs participated in developed by Seagen. Among them, AdCetris has ended the history of more than 40 years of treatment in the field of difficult Hodgkin lymphoma. New benchmark for first -line treatment.

"Some antibodies can only connect four chemotherapy drug molecules, some can not only connect eight, but also control the toxicity of chemotherapy drugs. After entering the tumor cells, it can produce a very good killing effect. The effect of diaphragm can return to the surface of the cell membrane of tumor cells to form bystander effects. "Yang Haiying said that the ADC drug molecular structure determines that the differences in each link point may cause the effectiveness and safety of the drug Therefore, in different diseases, the real clinical effects should be based on different diseases. It is still one of the basic points based on clinical research evidence.

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