[Transfer] From the dominant breast cancer to entering the lung cancer, the ADC leader does not talk about Wude

Source: amino observation/Fang Taozhi

Whether it is the "Old Medicine King" to repair Meile or the "New Medicine King" K medicine that is about to reach the summit, there is a common point: the scope of adaptation is extremely wide.

At present, there are nearly 20 indications approved by Xiu Meile around the world, and there are more than 30 types of K -drug indications. The huge scale of the application of the group is the secret of the new and old medicine king that can sell tens of billions of dollars in annual sales.

In other words, if you want to be a blockbuster product, the number of indications is very critical. This is the challenge of popular fried chicken ADC drugs, but also hope.

Due to technical reasons, adaptives are mostly concentrated on blood tumors; now after three generations of change, ADC drugs seem to have the potential to become "broad -spectrum" anticancer drugs.

The third-generation ADC king DS-8201, three years of adaptation, not only covered breast cancer and gastric cancer, but also entered non-small cell lung cancer.

And this is just the beginning. At present, the DS-8201 is constantly expanding the territory, layout of clinical trials for more than ten kinds of different physical tumors, and it seems to threaten the living space of the entire HER 2 targeted drugs.

With the continuous breakthrough of technical nature, adaptive ceiling has increased, which may be the charm of ADC drugs.

/ 01 /

The preparation of the first ADC indication

The use scenario of the initial ADC is limited to hematoma indications, which is not related to the limited partial selection of key parts of the ADC at that time.

In the first generation of ADC, the cutable bonds were mostly available as connectors. This kind of connection is easy to hydrolyze in a low -pH environment, so when the drug enters the blood, it will occur slowly and hydrolysis, resulting in a breakthrough. Studies have found that the stable time of the bond in the blood is about 30 minutes.

This also means that this ADC has not achieved the role of the tumor, and it is first separated from the blood. Therefore, the ADC using the bond is only suitable for treating hematological tumors and cannot be used for physical tumors.

Therefore, before 2019, among the 6 ADC approved around the world, except for the adaptive disease of the second-generation ADC drug T-DM1 for the treatment of breast cancer, other ADC indications are hematoma.

Compared with solid tumors, patients with hematoma are much smaller. Specifically, in 2019, there were 18.5 million global cancer patients, of which 17.3 million were physical tumors, and 93%of patients with physical tumors accounted for 93%.

There are not much markets, and there are several ADC melon markets. In this case, the imagination space for blood tumor ADC is relatively limited.

As an example, after ten years, the sales of the Mipide, which came out in 2011, have just reached US $ 1.306 billion in 2021, becoming a blockbuster bomb. However, in the era when the billions of dollars or even tens of billions of dollars have been frequent, it is still not enough to watch.

The same is true, at that time, the ADC market was naturally not so attractive.

/ 02 /

The second -generation ADC failed to solve the problem

However, you may have such a question. In 2012, T-DM1 was approved to be listed to treat HER2-positive breast cancer. The ADC has shown the role of physical tumors. Why are there very few ADC players who bet on physical tumors? Intersection

Because the treatment of solid tumors is more complicated than hematological tumors. For example, there is a binding site barrier in the physical tumor. The high affinity between the antibodies and the antigen will cause the ADC to be trapped near the blood vessels after their combination, but it penetrates less tumor cells far away from the blood vessels.

Although the T-DM1 is optimized in structure compared to the initial ADC and uses non-cracking connecting sublofer connections, but because of the hydrophilicity of its primary metabolites and carrying charge, it is difficult to penetrate the cell membrane to take advantage of watching observations. The effect of killing peripheral cells.

This makes the effect of T-DM1 effective, especially for those with low HER2 low-expression cancer. Therefore, in addition to breast cancer, T-DM1's clinical trials of other cancer species ended in failure, and it was not surprising.

Specifically, in a 2/3 clinical study called Gatsby, in the total survival period and no progressive survival period, the effect of T-DM1 after the progress of the first-line treatment is not better than chemotherapy.

After this experiment, T-DM1 also carried out a basket experiment to try to find other physical tumors that can produce effects. But unfortunately, for the test of 10 different types of tumors, none of them have reached the end point of the predetermined objective relief rate. T-DM1's wish to expand indications also ended in failure.

In this case, ADC's treatment effect on cancer is mediocre, and it is limited to several cancer species in indications. The imagination space is extremely limited, so it is not surprising that the ADC at that time did not become a hot spot.

/ 03 /

The third -generation ADC began to "not talk about martial arts"

But now, the third -generation ADC enrolled in 2019, because of the change of technology, seems to have said goodbye to the dilemma of being trapped in the past.

Compared with the previous two generations of ADC, the third -generation ADC began to choose a higher drug antibody ratio, as well as connectors that can be cut and can trigger the onlooker effect.

Theoretically, the new generation of ADC can be satisfied, regardless of the antibody -targeted antigen expression level, it can exert anti -cancer activity.

So, what is the actual situation? It seems that theory and reality have reached an agreement. The new generation of ADC shows the effect in multiple cancers, and the shackles of ADC on indications are being broken by the new generation ADC layer. For example, in April 2020, Trop2 ADC drug TRODELVY was approved to be listed in the United States for treatment of Sanyin breast cancer. Two years later, they were approved for new indications. Indications.

For another example, the representative of the third-generation ADC drug DS-8201's breakthrough in indications is more brave.

From 2019, the DS-8201 has been approved by five adaptive diseases, which are involved in HER2 positive breast cancer advanced backline. HER2 positive gastric cancer advanced second line and later, HER2 positive breast cancer secondary second line, HER2 low expression breast cancer expressions Essence

Just a few days ago, DS-8201 created another history.

On August 11, the FDA accelerated the adaptation of DS-8201 for advanced non-small cell lung cancer used for HER2 mutations. This is also the first ADC drug that treats non -small cell lung cancer targeting HER 2 for approval.

And this may be just a beginning. The third -generation ADC is still constantly pioneering the imagination of indications.

/ 04 /

How much does the ADC indication still have imagination?

It can be said that under the leadership of the third -generation ADC, ADC has begun to move closer to the broad -spectrum anti -cancer drugs.

I still take DS-8201 as an example. In addition to the indications of breast cancer, gastric cancer, and non-small cell lung cancer, it has been approved for listing, and the pipeline of the first three communities has also been deployed. Cancer, bladder cancer, endometrial cancer, etc.

And most of the cancer species have entered the clinical stage in clinical research, and many of them have excellent performance.

For example, the performance of DS-8201 in HER2's transmitted colorectal cancer is very powerful.

In a clinical study called Destiny-CRC 01, in patients with 2+ or 3+ in HER2, the objective relief rate of patients with DS-8201 patients is 45.3%, and the duration of the median reaction is 7 months. The median total survival period is 15.5 months.

In view of the currently approved ADCs for solid tumors, there are many researchers that have shown cross-tissue anti-tumor activity, and many researchers have put forward assumptions: ADC can become a broad-spectrum anticancer drug like PD-1.

In addition, as the technology of the third -generation ADC matures, more new targets can be applied to ADC to open more new indications.

The expansion of indications will also create greater imagination for the third -generation ADC. According to the GlobalData database prediction, the sales of DS-8201, the king of the third-generation ADC drug in 2028, will reach $ 6.5 billion.

Looking back at the sales of the second-generation ADC, even the leader T-DM1, the peak sales of sales in 20121 were not more than 2.178 billion US dollars.

With the advent of the third-generation ADC and the squeeze of ME TOO products, the market share of the second-generation ADC will continue to be squeezed. In the next few years, the sales of T-DM1's sales can only go downhill.

In the field of monoclonal anti -resistance, there is a saying "those who are adaptable to the world", and in the field of ADC, this sentence still seems to be used.

As the third-generation ADC technology represented by DS-8201 has continued to improve, the ceiling, which has been adapted, has been breaking through.

This is also the imagination space of ADC pharmaceutical companies. At present, domestic pharmaceutical companies include Rongchang Biology, Hengrui Pharmaceutical, and Coronbo Tai, which are also making articles around indications.

In the future, how many indications can ADC break through and how much imagination will bring? We wait and see.

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