100 billion!

Author: Fennel

In 2019, AstraZeneca invested nearly 7 billion U.

In 2020, Gilead announced the acquisition of the antibody drug company Immunomedics for US$21 billion, thus obtaining the first antibody-drug conjugate (ADC) Trodelvy;

In 2021, Treasure Island announced that it will set up a wholly-owned subsidiary to engage in the research and development of anti-tumor ADC drugs.

According to incomplete statistics, since 2019, global ADC drug transactions have reached more than 100 billion U.

Behind the sky-high transaction, what is the magic of ADC drugs?

Three generations of ADC "transformation"

ADC drugs are composed of three parts: monoclonal antibody (mAb), linker (Linker) and cytotoxin/payload.

"In simple terms, it is the combination of the antibody on the ADC with the target antigen, through the endocytosis of the cell, the endocytosis into the cell to release the payload, and then the chimerization with the DNA, the inhibition of tubulin, etc.

In fact, as early as the early 20th century, the Nobel Prize winner and German scientist Paul Ehrlich already proposed the concept of ADC and called it the "magic bullet"

"ADC drugs are divided into three generations according to their development history

The first generation ADC

Such as mitomycin C, idarubicin, anthracyclines, mainly through non-cleavable linkers (using amide or succinimide spacers) and mouse mAb coupling

In 2000, the first antibody-conjugated drug was approved by the FDA for the treatment of acute myeloid leukemia, but it was later withdrawn from the market due to stability issues

Second-generation ADC

With the development of mAb technology, stronger anti-cancer small molecules have been discovered.

However, most of the second-generation ADCs currently have a narrow therapeutic window due to off-target toxicity, competition with unbound antibodies, and aggregation or rapid clearance of ADCs with a drug-to-antibody ratio (DAR) of 8

Third-generation ADC

On the basis of the first and second generations, it has a very good foundation for the development of third-generation ADC drugs

The third-generation ADC uses small molecule drugs to specifically bind to the site of engineered mAbs to make DARs 2 or 4, no increase in system toxicity, no unbound mAb, improved stability and pharmacokinetics, slow depolymerization speed, and The price is high, and it has higher activity on cells with lower antigen levels

ADC Drugs-Difficulties in R&D

In the past three years, with the "invasion" of the capital frenzy, ADC drugs seem to show signs of the next "PD-1", and a fierce "target war" is already on the way

According to the Guosheng Securities Research Report, there are currently 152 target projects for ADCs worldwide.

The global distribution of ADC drug targets under research

Source: Guosheng Securities Research Institute

How to take the lead in this "target war" feast is a question that many R&D companies urgently need to think about

"ADC drug is a combination of monoclonal antibodies and small molecule cytotoxic drugs through the coupling chain Linker, and combined into a targeted biological drug, which has both the precise targeting advantages of monoclonal antibodies and the efficient killing of small molecule cytotoxic drugs.
Advantages, can reduce the systemic side effects of drugs, increase the drug treatment window and expand the potential of antibody therapy
.
" Liu Yongsheng introduced
.

"Therefore, the correct target, antibody, Linker and payload (cytotoxic/payloads) are the four key factors affecting ADC drugs
.
" Liu Yongsheng said, specifically:

The structure and chemical properties of Linker connecting small molecule cytotoxic drugs and monoclonal antibodies have an important impact on the efficacy of ADCs, and are very important for specificity and safety
.
The premise of Linker's design is that it is stable in the blood circulation, but can be decomposed when it reaches a certain state, so that toxic substances can be smoothly released at the tumor site
.

At the same time, it is also very important for Linker to maintain proper stability in the buffer solution, so that intravenous administration can be developed
.

"At present, ADC drugs are conducting research on a variety of new payloads, new connection technologies, and various engineered antibodies.
These ADCs are expected to achieve safer and more effective anti-tumor treatments
.
In addition, double antibodies and polyclonal antibodies are also future ADCs.
One of the ideas that drug research and development can learn from
.
" He thinks
.

How to find the ideal target?

At present, ADC drugs are mainly used in the field of tumors.
Because there are only a limited number of antigens on the surface of tumor cells, the amount of drugs delivered by ADC to tumor cells is also very low, so the choice of ideal antigen targets is very important
.

Professor Gao Jing, Shenzhen Hospital of Cancer Hospital of Chinese Academy of Medical Sciences believes that an ideal ADC target needs to meet three points:

One is to be highly expressed on the surface of tumor cells, that is, the target has better antigenicity;

The second is to have low or no expression in normal tissues, or at least the expression is restricted to specific tissues, so as to avoid some adverse toxic and side effects;

The third is that its expression is best negatively correlated with the patient's prognosis, that is, the higher the degree of target expression, the worse the patient's prognosis
.

Satisfying the above three points, it is possible to find an ideal target
.

However, there are real differences between ideals and reality.
How to successfully transform theoretical content into practice combined with clinical practice is the key to finding the ideal target of ADC drugs
.

Professor Gao Jing said that ADC drugs have become one of the next wave of new drug research and development in China.
“It can start with some special targets and become a special case of'first-in-class' ADC drug research
.
” [3]

Experience art including tumors, endocrine, respiratory, digestive, rheumatism and the like
.
Assist a number of Biotech companies and Biopharm companies to sort out medical strategies and design plans
.

Reference source:

1.
BioValley: ADC drugs? What is sacred

2.
The same freehand brushwork: Dilemma and strategy: Talking about ADC drug history, technology and clinical development

[3]: Department of Hematology: CSCO Speed ​​| Professor Gao Jing: Opportunities and Challenges of ADC Drug Targets