There are more than 650 active traditional ADC drugs currently, with only 14 having been approved to enter the market, and nearly 200 products still in different clinical research stages. Among them, HER2 ADC has the highest proportion. Therefore, as an outstanding representative of HER2 ADC, the success of DS-8201 may change the development pattern and product strategy in the ADC area. The most direct change has been reflected in the load selection of ADC drugs.
It is well known that ADC products are different from chemotherapy, targeted small molecules, and monoclonal antibodies. ADC drugs compose of antibodies and cytotoxic drugs (payloads) bridging through linkers. In terms of mechanism, it is generally believed that the antibodies in ADC drugs play a role of “navigation”, accurately guiding the drugs to the focus area by targeting antigens specifically expressed on the surface of tumor cells, releasing cytotoxic drugs with high therapeutic effect inside the tumor, and finally specifically killing tumor cells.
Taking DS-8201 as an example, the antibody (trastuzumab analogue) in the drug binds to the antigen HER2, fuses with the lysosome after endocytosis, which cleaves the linker by lysosomal enzyme degradation and thereby releases cytotoxic drugs (DXd). DXd, having outstanding cell permeability, can also kill nearby HER2-negative tumor cells, a manifestation of the bystander effect.
Of course, not all ADCs adopt cleavable linkers—nmetrozumab and Blenrep (dropped out of the market) use non- cleavable linkers. Similarly, not all loads have cellular permeability. For example, the toxin (lysine-MCC-DM1) degraded by nmetrozumab cannot efficiently permeate the cell membrane. Therefore, there are some differences in the mechanisms. Generally speaking, the industry has formed a relatively unanimous consensus on the mechanism of action of ADC drugs, but the understanding of ADC drugs may be open to question.
First of all, based on the understanding of the mechanism of action of ADC, the clinical value of ADC is generally attributed to cytotoxic drugs (payloads) that are even called “delivery tools”. Review experts have openly stated that ADC is a chemotherapeutic drug, which is reasonable, but it is difficult to say that it applys to different ADC drugs under different clinical application scenarios.
Take DS-8201 as an example, which uses trastuzumab analogs to target HER2, but in the DESTINY-Breast04 study, DS-8201 has been used in patients with breast cancer with low expression of HER2. Obviously, this study would not have been carried out as a delivery tool, and there would not be a new treatment for breast cancer with low expression of HER2. In addition, the DESTINY-Breast09 study is a clear example, in which the standard therapy of DS-8201 and trastuzumab opens a first-line head-to-head comparative trial for the treatment of HER2-positive breast cancer. There is no doubt about the clinical value of trastuzumab combined with chemotherapy in HER2 positive breast cancer patients. In the past 20 years, few drugs have been able to win in the head-to-head research DS-8201DS-8201.
In fact, there is also a hypothesis that ADC is different from chemotherapy. For newly diagnosed HER2-positive breast cancer patients who have not been treated with trastuzumab and/or patuzumab, DS-8201 containing trastuzumab analogues will not only act as a “delivery tool”, but may have a superimposed effect on clinical outcomes. In addition, the targeting effect of ADC drugs can avoid or reduce the safety problems caused by systemic exposure to chemotherapeutic drugs, and increase the tolerance of chemotherapeutic drugs. Therefore, in terms of efficacy and safety, ADC drugs are also different from the clinical treatment of monoclonal antibody plus chemotherapy.
Secondly, ADC drugs are still under improvement and development. In recent years, the load has also undergone dramatic changes. In addition to cytotoxic drugs, immunostimulatory molecules, targeted small molecules, and protein degradation molecules are also the orientation of ADC drug development, and thus it is not appropriate to define ADC as chemotherapeutic drugs.
In short, ADC is different from chemotherapy since its birth time, targeting small molecules and antibodies, which also determines the different clinical mechanisms of various ADCs. Meanwhile, with the development of ADC technology, more differentiated products will emerge and bring about a change in the paradigm of clinical treatments like detrazumab.