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As the ADC track becomes more crowded, some players are hoping for miracles from innovation
.
It seems to be a feasible way
to combine the popular technology ADC and bispecific antibody in the two tumor fields to develop a bispecific antibody ADC.
Some pharmaceutical companies began to expect that after the collision of two super technologies, they could create a bigger spark and beat the tumor to the ground
.
However, innovative drug research and development is not a game, and you can successfully clear the level
by stacking buffs.
Just like at opposite ends of the scale, after the ADC and the two supergiants of the double antibody join hands, the problem arises:
If the hand is too heavy, it is easy to beat the normal cells of the human body to the ground, and it is easy to let go of the "bad guys"
if the hand is too light.
"The way of balance" has always been a science
.
Unfortunately, in the field of bispecific ADCs, this science seems to be 100% mastered
.
/ 01 /
/ 01 /A combination full of potential
A combination full of potentialADC drugs are the hottest track this year, none of them
.
From the beginning to the end of the year, the heat of the ADC track has never stopped
.
Even in the last days of December, the global pharmaceutical companies Amgen and Merck were still busy "rushing performance" and introduced ADC drugs
one after another.
In the face of the explosion of the track, some innovative drug players began to consider another way, and the dual antibody ADC came into being
.
Dual antibody ADCs are divided into two categories, one is ADC drugs that target two targets to improve the range
of the drug.
For example, the combination of EGFR and HER3 targets can enable ADC drugs to target and bind to both EGFR and HER3 targets of tumor cells
.
At present, Bally's EGFR/HER3 bispecific ADC drug BL-B01D1 has entered the clinical stage
.
The other category is two-epitope ADC drugs, that is, different epitopes
for the same target.
Why target two epitopes at the same time?
We know that the mechanism of action of ADC is that the antibody specifically binds to antigens on tumor cells and is then endocytosed by tumor cells; The drug degrades after being phagocytosed, eventually releasing toxins inside the cells to kill cancer cells
.
In this process, a key factor in determining the efficacy of ADC is the efficiency with
which the drug is endocytosed.
It is not difficult to understand that if it cannot enter the enemy's interior, the killing effect of the ADC cannot be discussed
.
However, many potential ADC targets are either too inefficient to endocytosis, or they are endocytosed by tumors and go through a cycle, and eventually return to the cell surface intact, unable to release toxins in cancer cells, making it difficult for drugs to work
.
Faced with this problem, the advantages of dual-epitope ADCs are highlighted
.
Biepitope ADC drugs can bind to poorly internalized and better internalized antigens through both hands
.
To put it simply, through the strategy of "good students with poor students", improve the overall internalization efficiency
of drugs.
The benefits of strong alliances don't stop there
.
Theoretically, two-epitope ADCs can also overcome drug resistance
.
Taking HER2-resistant patients as an example, many patients with advanced breast cancer will gradually become resistant to first-line treatment HER2 monoclonal antibody and lead to disease progression
.
One of the reasons for the emergence of drug resistance of HER2 monoclonal antibody is the absence or decrease of HER2 receptor expression on the surface of tumor cells
.
The two-epitope ADC can be combined
with two different epitopes of HER2 at the same time.
This also means that even if one epitope is missing, the two-epitope ADC can enter cancer cells by binding to another epitope to overcome drug resistance caused by decreased expression of a single target
.
Given the multiple advantages of bispecific ADCs, more and more pharmaceutical companies are beginning to rush into this field
.
Globally, pharmaceutical companies such as Zymeworks, Sutro Biopharma, and ImmunoGen have laid out the research and development
of bispecific antibody ADCs.
In China, the number of players deploying dual antibody ADCs is also increasing
.
In October this year, Corning Jerry's HER2 bispecific antibody ADCJSKN-003 conducted a Phase Ia/Ib clinical study
.
Since December, Chia Tai Tianqing and Xuanzhu Biology have also opened HER2
Layout
of the ADC.
The dual antibody ADC track is visible to the naked eye
.
/ 02 /
/ 02 /A balance between effectiveness and safety
A balance between effectiveness and safetyHowever, behind the excitement, there are also hidden worries
that cannot be concealed in the dual antibody ADC.
The research and development of innovative drugs is not a simple arithmetic problem, it involves a complex and exquisite mechanism of action, and the drama of vigorously producing miracles is not always true
in the track of innovative drug research and development.
As an emerging technology, the development of bispecific ADCs is not clear, and the two predecessors in this field have overturned one after another
.
AstraZeneca is one of the pioneers of bispecific ADCs, and has developed a biepitope bispecific ADC drug, MEDI4276, which can act on both the 39S epitope and ECD4 epitope
of HER2.
Preclinical data showed that MEDI4276 had antitumor activity in HER2-positive tumor models and cell lines with low HER2 expression resistant to T-DM1 acquisition, and also showed good results
in trastuzumab and pertuzumab resistant patients.
However, while the effect is enhanced, the toxicity of MEDI4276 is difficult to avoid.
In the phase I clinic, 21.
3% of the 47 treated patients with advanced HER2 overexpression breast cancer and gastric cancer had elevated aminotransferases, that is, more than one-fifth of patients had liver damage, and 5
patients discontinued treatment
due to drug-related adverse events.
When the maximum tolerated dose exceeded 0.
9 mg/kg, two patients had dose-limiting toxicity
.
This also means that the dose of the drug can no longer be increased, and the safety window is extremely low
.
The reason for this problem may be the wrong choice of toxins in MEDI4276
.
Tubulin inhibitors were selected as toxins, tubulin has liver enrichment and hepatotoxicity, coupled with the targeted toxicity brought by double epitopes, which eventually overturns the drug due to safety issues
.
However, MEDI4276 is old, and the third generation ADC was not yet available at that time, and in this context, the failure of an advanced dual antibody ADC can be understood
.
However, in the context of the increasing maturity of ADC and bispecific antibody technology, the folding of ZW49, another pioneer of bispecific ADC, undoubtedly makes people lack some confidence
in bispecific ADC technology.
The ZW49 in the Zymeworks pipeline is also a HER2 dual antibody ADC
that can combine different epitopes of HER2 at the same time.
In terms of safety, ZW49 did not have too serious adverse reactions
.
Most treatment-related adverse events (TRAEs) were grade
1 or 2.
Unfortunately, the ZW49 grasped the sail of safety, but failed to grasp the effectiveness of the sail
.
On September 4 this year, the company disclosed phase I clinical data
for the treatment of HER2+ patients with ZW49 in the 2022 ESMO summary.
The results showed that the efficacy of ZW49 was not satisfactory, and the ORR (objective response rate) of only 28%
in 29 patients treated with 2 doses.
You know, in HER2
In the ADC field, the DS8201 is the most capable of fighting, and the ORR of each indication is basically more than 50%.
The clinical data of ZW49 even "can't beat" domestic ADCs
.
While the ZW49 is still in the Zymeworks pipeline, expectations for it have been dampened
.
It can be said that the choice of efficacy and safety of bispecific ADC is like a precise balance, which may bring serious side effects while bringing better efficacy, making the drug treatment window too narrow
.
However, if it is too biased towards safety, it may lose its efficacy
.
How to maintain a delicate balance between the two is a difficult challenge
.
/ 03 /
/ 03 /Clear directions and winding paths
Clear directions and winding pathsThe balance between efficacy and safety is by no means the only problem
facing bispecific ADCs.
There are many obstacles
in the development of dual antibody ADCs.
For example, the lack of an adequate "skeleton"
"For the rapid construction of stably expressed bispecific ADC molecules
.
" After all, there are few antibody backbone molecules that can be used for bispecific antibody construction, and the targets are very concentrated, with only a few targets such as HER2, HER3, EGFR, and MUC1
.
For example, from the perspective of the production process, the production of dual antibodies is inefficient due to mismatch, and the difficulty of production is not small, and now coupled with complex ADCs, it further increases the difficulty and challenges
of the production process.
It can be expected that the development path of bispecific antibody ADC will not be too easy
.
But one thing is for sure, dual antibody ADCs are still a promising area
.
However, then again, the only thing that needs to be solved on the road to the research and development of bispecific antibody ADCs is nothing more than specific problems
in the process of innovative drug research and development.
Looking back at the development of biantibodies and ADCs, it took decades of stumbling to find the right direction
.
Today, dual antibody ADCs are just getting started, and it's normal to
experience some setbacks.
In general, the direction of the dual antibody ADC is clear, the road is tortuous, and the future will definitely be bright
.
