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As early as 1913, Nobel Prize winner and German immunologist Paul Ehrlich first put forward the idea of "Magic Bullets": If toxic drugs (that is, bullets) are installed specifically to target tumor cells Based on the carrier, it is possible to accurately kill cancer cells without harming normal cells
.
However, this vision far exceeded the technical capabilities of the time
.
It was not until 1975 that two biologists from the United Kingdom and Germany, Cesar Milstein and Georges Kohler, prepared monoclonal antibodies for the first time, which made this vision a big step forward
.
Since then, with the advancement of monoclonal antibody technology and the unremitting efforts of scientists, the world's first antibody-drug conjugate (ADC) finally came into being in 2000
.
ADC is composed of three parts: antibody, cytotoxic drug, and linker
.
Ideally, when ADC enters the circulatory system in the body, the antibody recognizes and binds to the epitope on the surface of tumor cells.
The tumor cells swallow the ADC, which is then degraded by lysosomes in the cell, and cytotoxic drugs are released to kill the tumor.
Cell
.
If antibody-conjugated drugs are compared to nuclear missiles, then antibodies are equivalent to missiles, and cytotoxic drugs are nuclear warheads
.
ADC drugs use specific linkers to connect antibodies and small-molecule cytotoxic drugs "bombs".
Antibody molecules are targeted to bind to antigen targets through receptor-regulated endocytosis.
ADC drugs are internalized by tumor cells under the action of lysosomes.
ADC is decomposed and "releases the bomb" to exert cytotoxicity, causing tumor cell death.
ADC drugs seem to be very simple.
Monoclonal antibodies are combined with strong cytotoxic chemotherapeutic drugs through linkers
.
Ideally, after the ADC drug enters the body, the antibody part specifically binds to the target cell expressing the tumor antigen.
After the ADC drug is internalized by the tumor cell, it enters the lysosome for degradation, and the small molecule cytotoxic drug is highly active in the cell The form is released in sufficient quantity to complete the killing of tumor cells
.
The ideal is full, but the reality is skinny
.
A successful ADC drug needs to complete many steps of screening
.
Ideal ADC drug design needs to consider ① Selection of antibodies: clear target, high expression in tumor cells, low expression in normal tissues; support drug loading, stability, and internalization into cells; good PK characteristics; less non-specific binding; ② connection Site: Generally, there are lysine or cysteine residues, which can be restructured for directional coupling; ③ Linker: stable in the circulation, and can be released in the cell (such as cleavage and release in the lysosome, or antibody Released after degradation); ④ Cytotoxic drugs: high pharmacodynamic effects, no immunogenicity, can be combined with the linker through modification, the mechanism is clear
.
Compared with tumor immunotherapy, ADC drugs are not a new thing, but after the first ADC drug gemtuzumab ozogamicin was launched, it was withdrawn from the market in 2007 due to toxicity problems and insufficient benefits, which caused the ADC track to fall into the next 10 years.
During the quiet period, trastuzumab emtansine and brentuximab vedotin became one of the few highlights in the past 10 years
.
Until 2017, gemtuzumab ozogamicin was re-listed, and the FDA approved the first new drug for CD22 ADC, which allowed the ADC track to pick up again
.
In 2019, the FDA followed up and approved three new ADC drugs.
Except DS8201, the other two are new ADCs targeting CD79b and Nectin-4, which thoroughly stimulated the industry’s enthusiasm for investment in ADC drugs.
A series of multi-billion-dollar and tens of billion-dollar transactions occur frequently, and there are countless small-scale ADC project transactions
.
In March 2021, Nature Reviews Drug Discovery made sales forecasts for 10 ADC drugs that have been approved for marketing, and the market size is expected to exceed 16.
4 billion U.
S.
dollars in 2026
.
Whether it is from the global ADC drug pipeline reserve, or market space forecast and imagination, ADC drugs can be said to be one of the hottest tracks nowadays
.
Up to now, there are 339 ADC projects disclosed globally, and 104 projects of Chinese companies, accounting for 30%; a total of 13 ADC drugs have been marketed worldwide, including vedicitumumab, which was approved by the NMPA in June 2021 , Is the first domestically produced ADC drug to be marketed
.
As more new target ADC drugs are approved for the market, the development competition of ADC track has opened a new chapter
.
Especially as more and more similar target ADCs enter the clinic or advance to the later clinical stage, the development strategy and clinical design of differentiated indications determine the success or failure of the ADC project, and large-scale commercial production has also become a need for enterprises to consider in advance And layout issues
.
In view of the particularity of ADC drugs, whether it is self-built or outsourced, the formation of a complete commercial production capacity does not happen overnight, nor is it all
.
In order to effectively and rationally promote product development and listing plans, commercial production capacity must be deployed as soon as possible, and the selection of CDMO partners is also an important strategy in the current market environment
.
But it is not easy to find a CDMO partner that matches your own project
.
The upsurge of ADC is not accidental, it is built on the basis of continuous technological iterative update
.
New ADC construction methodologies, such as new linkers and more payload technologies, are emerging in endlessly
.
New linkers, new toxins, new targets, and new coupling technologies.
In the past two years, we have seen various unconstrained drug concepts, and technological innovations have also brought huge challenges to the production of ADCs.
.
The complexity of ADC drugs itself puts forward extremely high requirements on R&D, preparation and production processes.
GMP management, supply chain management and safety protection management also bring great challenges, and there are risks in the process of drug R&D and scale-up production.
And the challenge is undoubtedly revealed
.
ADC drug developers turned their attention to CDMO
.
At present, 70%-80% of ADC drug development and production will be carried out in the form of a contract development and production organization (CDMO)
.
ADC drug developers hope to use CDMO's platform advantages and production experience to accelerate the process from the laboratory to the patient and solve various challenges in the production of ADC drugs
.
Poke "read the original text", we make progress together
.
However, this vision far exceeded the technical capabilities of the time
.
It was not until 1975 that two biologists from the United Kingdom and Germany, Cesar Milstein and Georges Kohler, prepared monoclonal antibodies for the first time, which made this vision a big step forward
.
Since then, with the advancement of monoclonal antibody technology and the unremitting efforts of scientists, the world's first antibody-drug conjugate (ADC) finally came into being in 2000
.
ADC is composed of three parts: antibody, cytotoxic drug, and linker
.
Ideally, when ADC enters the circulatory system in the body, the antibody recognizes and binds to the epitope on the surface of tumor cells.
The tumor cells swallow the ADC, which is then degraded by lysosomes in the cell, and cytotoxic drugs are released to kill the tumor.
Cell
.
If antibody-conjugated drugs are compared to nuclear missiles, then antibodies are equivalent to missiles, and cytotoxic drugs are nuclear warheads
.
ADC drugs use specific linkers to connect antibodies and small-molecule cytotoxic drugs "bombs".
Antibody molecules are targeted to bind to antigen targets through receptor-regulated endocytosis.
ADC drugs are internalized by tumor cells under the action of lysosomes.
ADC is decomposed and "releases the bomb" to exert cytotoxicity, causing tumor cell death.
ADC drugs seem to be very simple.
Monoclonal antibodies are combined with strong cytotoxic chemotherapeutic drugs through linkers
.
Ideally, after the ADC drug enters the body, the antibody part specifically binds to the target cell expressing the tumor antigen.
After the ADC drug is internalized by the tumor cell, it enters the lysosome for degradation, and the small molecule cytotoxic drug is highly active in the cell The form is released in sufficient quantity to complete the killing of tumor cells
.
The ideal is full, but the reality is skinny
.
A successful ADC drug needs to complete many steps of screening
.
Ideal ADC drug design needs to consider ① Selection of antibodies: clear target, high expression in tumor cells, low expression in normal tissues; support drug loading, stability, and internalization into cells; good PK characteristics; less non-specific binding; ② connection Site: Generally, there are lysine or cysteine residues, which can be restructured for directional coupling; ③ Linker: stable in the circulation, and can be released in the cell (such as cleavage and release in the lysosome, or antibody Released after degradation); ④ Cytotoxic drugs: high pharmacodynamic effects, no immunogenicity, can be combined with the linker through modification, the mechanism is clear
.
Compared with tumor immunotherapy, ADC drugs are not a new thing, but after the first ADC drug gemtuzumab ozogamicin was launched, it was withdrawn from the market in 2007 due to toxicity problems and insufficient benefits, which caused the ADC track to fall into the next 10 years.
During the quiet period, trastuzumab emtansine and brentuximab vedotin became one of the few highlights in the past 10 years
.
Until 2017, gemtuzumab ozogamicin was re-listed, and the FDA approved the first new drug for CD22 ADC, which allowed the ADC track to pick up again
.
In 2019, the FDA followed up and approved three new ADC drugs.
Except DS8201, the other two are new ADCs targeting CD79b and Nectin-4, which thoroughly stimulated the industry’s enthusiasm for investment in ADC drugs.
A series of multi-billion-dollar and tens of billion-dollar transactions occur frequently, and there are countless small-scale ADC project transactions
.
In March 2021, Nature Reviews Drug Discovery made sales forecasts for 10 ADC drugs that have been approved for marketing, and the market size is expected to exceed 16.
4 billion U.
S.
dollars in 2026
.
Whether it is from the global ADC drug pipeline reserve, or market space forecast and imagination, ADC drugs can be said to be one of the hottest tracks nowadays
.
Up to now, there are 339 ADC projects disclosed globally, and 104 projects of Chinese companies, accounting for 30%; a total of 13 ADC drugs have been marketed worldwide, including vedicitumumab, which was approved by the NMPA in June 2021 , Is the first domestically produced ADC drug to be marketed
.
As more new target ADC drugs are approved for the market, the development competition of ADC track has opened a new chapter
.
Especially as more and more similar target ADCs enter the clinic or advance to the later clinical stage, the development strategy and clinical design of differentiated indications determine the success or failure of the ADC project, and large-scale commercial production has also become a need for enterprises to consider in advance And layout issues
.
In view of the particularity of ADC drugs, whether it is self-built or outsourced, the formation of a complete commercial production capacity does not happen overnight, nor is it all
.
In order to effectively and rationally promote product development and listing plans, commercial production capacity must be deployed as soon as possible, and the selection of CDMO partners is also an important strategy in the current market environment
.
But it is not easy to find a CDMO partner that matches your own project
.
The upsurge of ADC is not accidental, it is built on the basis of continuous technological iterative update
.
New ADC construction methodologies, such as new linkers and more payload technologies, are emerging in endlessly
.
New linkers, new toxins, new targets, and new coupling technologies.
In the past two years, we have seen various unconstrained drug concepts, and technological innovations have also brought huge challenges to the production of ADCs.
.
The complexity of ADC drugs itself puts forward extremely high requirements on R&D, preparation and production processes.
GMP management, supply chain management and safety protection management also bring great challenges, and there are risks in the process of drug R&D and scale-up production.
And the challenge is undoubtedly revealed
.
ADC drug developers turned their attention to CDMO
.
At present, 70%-80% of ADC drug development and production will be carried out in the form of a contract development and production organization (CDMO)
.
ADC drug developers hope to use CDMO's platform advantages and production experience to accelerate the process from the laboratory to the patient and solve various challenges in the production of ADC drugs
.
Poke "read the original text", we make progress together
