How do Qilu and Yilian Biopharmaceuticals add next-generation ADC drugs?

However, the cleavable Linker is by no means perfect
.
Cleavable Linker has the risk of off-target cleavage, and off-target toxicity is usually higher than that of non-cleavable Linker
.
In addition, the Bystander effect may have the risk of "manslaughter", that is, when the neighboring cells are normal cells, the cytotoxic drug will penetrate the cell membrane to "manslaughter" the normal cells
.
In this regard, DolaLock Payload came into being.
DolaLock payload is a tubulin inhibitor.
After DolaLock payload is lysed in target cells, it can penetrate the membrane to exert a bystander effect
.
But soon DolaLock Payload will be metabolized into a form that is still efficient but unable to transmembrane, and “locks” in the target cell, thereby effectively controlling the bystander effect
.
Mersana did not disclose specific technical details, but it may be related to negatively charged products of metabolism
.

02 Random coupling (Lysine-Cysteine) is converted to site-specific coupling

Common random couplings include random coupling of lysine and random coupling of cysteine
.
Early ADC drugs often use lysine to couple randomly, but the new generation of ADC drugs more often use cysteine ​​to couple
.
The reason for this change is that the coupling method of cysteine ​​is less heterogeneous than that of lysine, and the attachment site is easier to predict
.
The presence of 80-100 lysine amino groups on a single antibody makes the coupling reaction highly random, resulting in high heterogeneity of ADC drugs
.

Site-specific coupling is a newly emerging connection method in recent years, which is expected to improve the uniformity of ADC products and reduce system toxicity
.
Common mode coupling point comprises Thiomab, ThioBridge, an unnatural amino acid technology, GlycoConnect the like
.
But it is too early to assert that site-directed coupling replaces random coupling
.
On the one hand, all listed ADC varieties use random coupling, while Seattle Genetics’ fixed-point coupling products have all failed; on the other hand, the fixed-point coupling products have a low DAR value (2-4), which means With ultra-high toxicity payload, but considering the success of Enhertu and Trodelvy, the future development trend may be a combination of high DAR + medium toxicity payload
.

3.
Optimization of Payload

01 Conversion of tubulin inhibitors to DNA inhibitors

Comparison of DM1 and Auristatin: Among the tubulin inhibitors, DM1 and Auristatin are both classic tubulin inhibitors, but because the cytotoxicity of MMAE/MMAF is stronger than that of DM1, it is more widely used
.
Among the ADC drugs on the market, only T-DM1 uses DM1, Adcetris, Polivy and Padcev use MMAE, and Blenrep uses MMAF
.

Auristatin comparison: It is not difficult to find from the marketed ADC drugs that use MMAE and MMAF that MMAE has a wider applicability
.
This is because MMAF can produce metabolites with negatively charged carboxy-terminal phenylalanine residues, which cannot play Bystander across the membrane
.

Comparison of tubulin inhibitors and DNA inhibitors: Although tubulin inhibitors have played a huge role in the design of ADC drugs, DNA inhibitors are gaining momentum
.
The great success of Enhertu and Trodelvy has led scientists to focus on this field
.

Compared with tubulin inhibitors, DNA inhibitors mainly include the following advantages:

First of all, the number of tubulin in cancer cells is large and the number of DNA isomerase is small, which causes the dose of tubulin inhibitors to far exceed the dose of DNA inhibitors;

Secondly, the inhibitor of tubulin in cancer cells has a shorter action time (2h), while the action time of DNA inhibitors can be as long as 24h, which has a longer anti-tumor effect;

Finally, tubulin inhibitors have a narrow anti-cancer spectrum and low activity on colorectal and gastrointestinal tumors.
For example, for breast and gastric cancers with low HER2 expression, tubulin inhibitors are not ideal
.

02 DAR value gradually increased

DAR refers to the Drug-Antibody Ratio, which is the drug-antibody ratio, which is used to reflect the number of payloads connected to the monoclonal antibody
.
The traditional view is that 2-4 is the best DAR value, but with the success of Enhertu (DAR≈8), scientists began to pay attention to the choice of high DAR
.
The combination of high DAR and medium toxins (DNA inhibitors) may be the next city of ADC drugs.
Not only can they exert better anti-tumor effects, but also the off-target toxicity is expected to be reduced
.

ADC drugs with higher DAR are gradually approaching
.
The Fleximer technology designed by Mersana can insert a biodegradable, water-soluble polymer into ADC drugs.
One end of the polymer is connected to the monoclonal antibody, and the other end can be connected to up to 10-12 cytotoxic drugs through the Cleavable linker
.
With this technology, ADC drugs with a DAR of 10-12 can be designed, laying the foundation for the use of lower-toxic payloads
.