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

In recent years, the ADC track has continued to be hot, showing a situation of competition for capital.

On March 19, the EpCAM ADC drug Vicineum introduced by Qilu for US$35 million has been approved for clinical use by default and is intended for non-muscular invasive bladder cancer.

At present, ten ADC drugs have been approved for marketing worldwide, of which T-DM1 and Adcetris have been launched in my country.

In the future, with the continuous maturity of technology and the improvement of design, the quality and quantity of ADC drugs are expected to increase significantly, and the development prospects are very broad.

1.

Some early ADC drugs used mouse monoclonal antibodies and human-mouse chimeric monoclonal antibodies, such as Lumoxiti and Adcetris.

02 Gradually improved affinity and reduced adverse reactions

The affinity of an antibody refers to the strength of the binding capacity of the antibody to the antibody, usually expressed by EC50 and IC50.

Trastuzumab is an Antibody commonly used in HER2 ADC drugs.

03 Conversion of IgG4 to IgG1

The first-generation ADC drug Mylotarg uses IgG4 as an antibody, but IgG4 molecules cannot cause Fc-mediated ADCC, CDC and ADCP effects.

However, an unresolved question is whether ADC drugs depend on the effects of ADCC and CDC, which needs to be further studied.

2.

Compared with the non-cleavable linker, the cleavable linker has the advantage of being able to exert the Bystander Effect (Bystander Effect).

However, the cleavable Linker is by no means perfect.

DolaLock Linker

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

Common random couplings include random coupling of lysine and random coupling of cysteine.

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 site-directed coupling methods include Thiomab, ThioBridge, unnatural amino acid technology, GlycoConnect, etc.
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 carboxyl-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.

SN-38 and DXd chemical structure

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.