Toxicity of ADC drugs

On February 3rd, Johnson & Johnson announced that it had reached a cooperation agreement with Mersana Therapeutics to jointly develop three new generation ADC drugs. Therefore, the author re-examined the whole technology platform of Mersana and noticed Dolasynthen.

This technology is to use polymer linker to realize richer changes in the number of toxin molecular coupling, so as to meet the technical requirements of different targets and indications. DAR can be up to 24.

However, considering one of the biggest limitations of ADC-the toxicity of toxin molecules in vivo, the author thinks that the improvement of DAR combined with the appropriate reduction of toxicity of toxin molecules is an improvement direction that can be explored.

Toxic and side effects of ADC drugs

The toxicity of ADC drugs mainly comes from two aspects, That is, the toxicity produced by antibody molecules and toxin molecules, in which the toxicity produced by antibody molecules varies greatly with different targets, indications and other factors, while the toxicity produced by toxin molecules is mainly reflected in the damage to rapidly proliferating healthy cells, such as lymphocyte reduction, hair loss, gastrointestinal reactions and so on. The author counted the main side effects of ADC drugs approved by FDA (subject to the instructions), which are summarized as follows:

Except for Belantamab mafodotin, which surprisingly has ocular toxicity as the main side effect, the side effects of other drugs are common side effects during chemotherapy, including neutropenia, anemia, hair loss and so on.

In addition, in the clinical stage, many ADC drugs were terminated due to chemotherapy-like toxicity such as blood toxicity, such as SGN-CD33A.

The actual effect of "low blood-to-tumor ratio" by Bicycle Therapeutics

Bicycle Therapeutics in Britain takes the screening and development of cyclic peptide molecules as its core technology platform. On this basis, they have explored a variety of application scenarios, including polypeptide-drug conjugates (PDC). At present, some projects have entered the clinical trial stage.

Regarding the application of PDC direction, Bicycle emphasizes that its advantage lies in low "blood-to-tumor ratio": because PDC drugs have small molecular weight and good tissue penetration, it can help toxin molecules quickly enrich to tumor sites and quickly exercise the function of killing cancer cells; At the same time, the drug molecules in the blood are quickly removed, and the half-life is very short, which is beneficial to systematic toxic and side effects. This theory has been verified by BT8009 PK test in vivo. Based on this characteristic, the dose adjustment of PDC administration can have a large space.

In addition, because the molar dose of PDC can have a large adjustment range, the theoretical defect of low DAR (equal to 1) can also be remedied. Take the comparison between BT8009 and the same target ADC drug Enfortumab vedotin as an example: the dose of BT8009 is assumed to be 13 mg/m2 of one of the climbing doses (the surface area of adult skin is set to 2 m2), and the current standard dose of Enfortumab vedotin is 1.25 mg/kg (assuming the adult body weight is 80 kg); The molecular weight of BT8009 is about 4 kDa, and that of Enfortumab vedotin is about 160 kDa. Then:

It can be seen that the molar dose of BT8009 is 10 times that of Enfortumab vedotin, and the toxin load is relatively sufficient.

However, the preliminary clinical trial data published before are not ideal.

The security results of BT5528 show that, The common serious bleeding events of the standard ADC drug MEDI-547 (therefore, the development was terminated) did not appear, and the serious side effects of skin and nerve were not found, but the blood toxic events above grade 3 did not decrease significantly (the incidence of neutropenia above grade 3 was > 30%), and the unique side effects of ADC drugs such as infection and fatigue were also reflected.

Similarly, the early data of BT8009 showed that although grade 1-2 ocular toxicity and DLT were not found (slightly better than the target ADC drug Enfortumab), the proportion of patients with grade 3 or above blood toxicity was not low (> 10%).

Therefore, the PDC concept emphasized by the company has not been well reflected. Since the toxin molecules used in PDC of the company are all toxins commonly used in ADC (MMAE or DM1), the optimization of toxin molecules themselves seems to be more important.

On the balance of toxins

The toxin molecules used in early ADC are traditional chemotherapy drugs, such as adriamycin and mitomycin, because the original intention of ADC concept is "targeted chemotherapy". However, due to the large molecular weight of antibody, the effective concentration of chemotherapy drugs cannot be reached within the appropriate ADC dose window. Therefore, people try to develop small molecules with stronger toxicity as payload of ADC in the later stage. However, in this way, new toxicity problems will follow, because toxin molecules will inevitably be released nonspecifically, which is due to many reasons, including the premature breakage of linker, the nonspecific endocytosis of ADC molecules by cells (through pinocytosis, etc.) and so on.

Therefore, the toxicity of toxins is one of the core issues in ADC drug development. The author thinks that it is one of the optimization trends to reduce the toxicity of toxin properly and increase DAR value at the same time. The toxin molecule used in Sacituzumab govitecan of Immunomedics is SN-38, which is the active metabolite of irinotecan, and DAR is 7 ~ 8. In fact, there is this improvement trend, but the effect is still not ideal. Researchers in this field still need to work hard, and technologies like Dolasynthen may be able to achieve this goal.