[Turn] The next battle of the ADC of Tomorrow's ADC, the argument of the joint therapy

[Turn] The next battle of the ADC of Tomorrow's ADC, the argument of the joint therapy

Source: amino observation/Fang Taozhi

Since the DS-8201 detonated ADC track, many players have swarmed in.

Although ADC drugs have higher barriers to research and development, they are inevitably rolled up. In this case, how to break the situation through differentiated play and consolidate its own advantages is undoubtedly worth considering.

So how to differentiate? Joint medication provides us with a problem -solving idea.

Theoretically, ADC can combine medication with various therapies such as immune examination point inhibitors, chemotherapy, and antiovascular planting agents, and the possibility of 1+1> 2.

Compared to the people with single medicines, ADC combined medicine is still a fertile land to be reclaimed. How to find the best partner among many options?

It was time to test the strength of major pharmaceutical companies.

/ 01 /

ADC+immunosuppressor, the hottest combination therapy battlefield

DS-8201 has proved the explosion effect of ADC single medicine, but the imagination space of ADC is not limited to this. In addition to single medicine, the combination therapy also has great imagination.

At present, not only overseas giants, but also many pharmaceutical companies such as Rongchang Biological, Hengrui Pharmaceutical, Coron Pharmaceutical, and Lu Lu Pharmaceutical, have carried out the exploration of ADC drug combination therapy.

The hottest route is the ADC combined immunohistochemical point inhibitor, which is also the main battlefield of ADC combination therapy. The reason is not difficult to understand that ADC drugs and immune checkpoints can complement each other.

We know that the development of a variety of immunosuppressive agents such as PD-1/PD-L1, CTLA-4 has opened a new era of immunotherapy, but the overall effect of various immunosuppressive agents is not satisfactory. For example, the effect of PD-1 single drug is relatively limited, and most of the cancer species of only 20%-30%of patients have immune response.

The problem lies in the micro -environment of the tumor. Depending on the different environment of tumor, we can divide the tumor into cold tumors and thermal tumors.

Among them, thermal tumor contains a large amount of infiltrating T cells, which has a higher response rate for immune examination point inhibitors, while cold tumors are opposite, and the response rate of immune examination points is low.

Therefore, in order to increase the PD-1 response, it is necessary to increase the infiltration of these immune cold tumors, or transform "cold" tumors into "heat" tumors.

At present, ADC has the ability to heat up tumors. There are clinical trials that the combined therapy of the second-generation ADC drug T-DM1 and CTLA-4/PD-1 monoclonal anti-resistance can simultaneously trigger congenital and adaptive immunity, leading to a large number of T cells infiltration.

In addition, ADC can induce immunogenic cell death. Immune cell death is a special form of cell death that can stimulate the immune response and produce a corresponding immune response for the antigen expressed by the dead cells.

The form of cell death is used on cancer cells, while killing cancer cells while inducing anti -cancer immunity and forming immune memory. In this way, without any additional treatment, the human body can also resist the challenge of tumor recurrence.

ADC -mediated immunogonal cell death and recruitment of tumor infiltrating lymphocytes can promote the recognition and activity of immune effects to immune cold tumors.

In addition, while ADC drugs promote immunotherapy activity, immune examination point inhibitors can also enhance the activity of ADC drugs. A clinical trial of a mouse shows that the CTLA-4 monoclonal anti-resistance can enhance the lethality of ADC on breast cancer.

This is the basis for ADC to achieve each other with immunosuppressive agents, and the key to attracting pharmaceutical companies to enter the bureau.

/ 02 /

The combination therapy of "Zhengzheng and Evil" needs more exploration

Of course, the above is only based on the theoretical foundation to illustrate the potential of ADC+immunosuppressant combination therapy. In the field of pharmaceutical research and development, there is often a barrier between theory and reality.

The exploration of the combination of ADC drugs and immunosuppressive agents will inevitably be extremely complicated in the actual situation in clinical practice.

In some clinical trials, the combination of ADC and immune checkpoint inhibitors has indeed achieved the effect of 1+1> 2. For example, in the first phase clinical trial of K-drug and the second-generation ADC drug T-DM1, the combination therapy showed the gratifying effect.

The test was entered into 20 patients with advanced metastatic breast cancer after the treatment of infection with the treatment of infected with the treatment of rutoperum.

After receiving the treatment of T-DM1 combined with K drugs, the objective relief rate of patients in the Asian group of <1 in PD-L1 expression reached 29%, the median no progressive survival period was 2.9 months, and PD-L1 expression ≥1 expression ≥1 Patients have an objective relief rate of 33%, and the mid -level no progressive survival period is 8.7 months.

However, not all ADC and immune checkpoints can achieve better results.

In a clinical trial called Kate2, the combined use of PD-L1 and T-DM1 failed to bring better effect to patients with advanced breast cancer.

In this experiment, compared with the T-DM1 alone, the combined scheme of PD-L1 and T-DM1 brings limited improvement to the total survival period of HER2-positive breast cancer patients, and it is not available in no progressive survival period. Show benefits. In addition, the incidence of serious adverse events of PD-L1 and T-DM1 combination therapy is higher, and the case of patients stopped by patients due to adverse events.

This case of 1+1 <2 is not an example.

It was found in the clinical experiments of another ADC drug Teliso-V combined with O to treat C-MET-positive NSCLC patients that although the clinical trials have achieved the main goal of safety and anti-tumor activity, the combined therapy in total objective relief rate The performance is not ideal.

In this clinical trial, the objective relief rate of Teliso-V+O drug combination therapy is only 7.4%, and it is not as good as the objective relief rate of K-drug single medicine or Teliso-V single medicine.

As for why the result of 1+1 <2 appears, there is no clear answer yet.

In fact, the mechanism of the combination of the two has not been fully studied, and it takes more exploration to make a better effect on the combined medication.

/ 03 /

Who is the good match of ADC? To give the answer to time

According to the effect of existing ADC drugs, theoretically, there are multiple improvement directions in combination therapy, such as increasing ADC's transportation capacity to tissue, regulating antibody target protein expression, and promoting anti -tumor immunity.

It is for this reason that in addition to immunosuppressant combination therapy, many pharmaceutical companies have tried in other directions. For example, the ADC combined antibrokest agent is currently a feasible idea of ​​combined medication.

We know that vascular production is a necessary process for solid tumor proliferation, and the endothelial growth factor (VEGF) is an important accomplice in tumor blood vessels.

This also hinders the delivery of ADC drugs to the tumor tissue, which affects the treatment effect. Therefore, the combined medication of antibodies and ADC drugs will have the effect of 1+1 greater than 2:

Antiovascular production drugs can make tumor blood vessels normally, thereby improving the delivery of ADC to tumor tissue, and enhancing ADC cytotoxic effects.

At present, ADC drugs have been conducting clinical trials for treating cancer with antemomhological agents.

For example, Mirvetuximab Soravtansine (Mirv), which is the first ADC drug developed by IMMUNOGEN to target folic acid receptors α (FRα).

In the 1B clinical trial named Forward II, the effect of Mirv and VEGF inhibitors Bayzab from patients with a positive patients with FRα combined with the effect of ovarian cancer.

Preliminary clinical data showed that the six patients responded objectively, with an objective relief rate of 43%; in the analysis of the sub -group analysis of 33 FRα high -expression tumor patients, the objective relief rate was higher to 61%.

This clinical data also preliminarily explained that the combination of MIRV and Bevarzumab has the treatment potential for patients with recurrent ovarian cancer, especially among patients with high levels of FRα in tumor expression.

Of course, as mentioned above, there are many partnerships of ADC combination therapy, nor are they limited to immune examination point inhibitors and antibodies. There are still a variety of ADC partners still exploring, and ADC combined chemotherapy is also a popular match.

For example, Polivy, a ADC product that targets the CD79B of Robe, passed the combined chemotherapy. Polivy reached the main end in the third phase of the first -line treatment of diffuse large B -cell lymphoma patients.

Compared with standard therapy, the combination therapy has brought significantly improvement to patients' no progressive survival. This is also the first treatment plan that has improved relative to standard therapy in recent years.

In addition, ADC also has some novel combinations.

For example, using irreversible excitement inhibitors for ADC targets to pant -HER inhibitors to use it with targeted HER2 ADC, which can stimulate antigenic internalization and strengthen the internal swallowing and activity of ADC;

For another example, by regulating the upsurge of receptor tyrosine kinase AXL, the AXL targeted ADC's activity of melanoma cell line is enhanced.

However, there are fewer clinical explorations around these combined therapies, and more clinical verification is needed to discover the best choice of ADC.

In other words, compared to ADC single drugs, the ADC combination therapy still has many unknown and more possibilities. For domestic pharmaceutical companies, in the crowded ADC market to highlight the siege, considering trying to develop ADC combination therapy may also bring unexpected results.

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