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PD-1/PD-L1 monoclonal antibody drugs form a tens of billions of commercial market
PD-1/PD-L1 monoclonal antibody drugs form a tens of billions of commercial market The PD-1/L1 pathway is known as the most successful target in the field of tumor immunotherapy so far, and its application and commercialization have been expanded rapidly, covering almost all major tumor indications.
The immunotherapy represented by PD-1/L1 antibody was rated as the top ten scientific breakthrough of the year by "Science", and it is even considered as the most likely drug to effectively control tumors.
At present, 7 PD-1/L1 monoclonal antibody products have been approved for marketing in China, 4 of which are domestically produced.
Although China's PD-1/L1 monoclonal antibody market is in the early stages of development, it has strong growth potential.
According to the analysis of the Frost & Sullivan Report, with the ever-expanding indications and increased accessibility brought about by patient education, China’s PD-1/L1 monoclonal antibody market ushered in rapid growth and is expected to reach The scale of RMB 66.
4 billion.
In view of the huge clinical demand for anti-tumor drugs, the research and development of innovative drugs for the PD-1/L1 pathway by local pharmaceutical companies has become extremely hot in recent years.
According to the Insight database, there are more than 35 pharmaceutical companies, involving 38 varieties, and 298 PD-1/L1 monoclonal antibody clinical studies are in progress, including 137 phase III clinical trials.
Compared with the scale of the developing tumor immunotherapy market,5s ease 0s;color:#337FE5;">5s ease 0s;color:#337FE5;">The competition for the development of PD-1/L1 innovative drugs has become increasingly fierce.
The PD-1/L1 monoclonal antibody market with strong development momentum and huge potential already has a red sea.
The core reason for the formation of this phenomenon is that the development is clustered and the product lacks differentiation.
It is expected that even if the product is finally approved for listing, it will lead to the lack of pricing power due to homogenized competition.
Because of this, some companies have set their sights on the research and development of PD-L1 small molecule inhibitors.
Geli Pharmaceutical (1672.
HK), a member unit of our association, recently announced that it will accelerate investment in its oncology product pipeline, except for FASN, which has proven the efficacy of bevacizumab in glioblastoma in phase II clinical trials in the United States.
In addition to the inhibitor series, it also includes an oral PD-L1 inhibitor series in its oncology product pipeline.
So what kind of unique clinical value can PD-L1 small molecule inhibitors create?
The necessity of PD-L1 small molecule inhibitor development
To demonstrate the necessity of the development of PD-L1 small molecule inhibitors, it is necessary to understand what are the clinical problems of PD-1/L1 monoclonal antibodies that have not been resolved? Why can't it be solved? Can small molecules be solved?
First of all, although PD-1/L1 monoclonal antibody has made considerable progress in the clinical treatment of various tumors.
The survival period of some tumor patients is significantly prolonged, and some patients even have complete remission.
However, the PD-1/L1 monoclonal antibody is still insufficient in terms of tumor response rate.
Most patients have low response values to PD-1/L1 monoclonal antibody, and different tumors have very different responses to PD-1/L1 monoclonal antibody.
The reason may be the overly complex tumor microenvironment.
Studies have shown that in tumor tissues, strong blood vessel leakage, collagen solidification, and increased hyaluronic acid will affect PD-1/L1 monoclonal antibodies as the representative Penetration and distribution of macromolecular drugs in tissues.
Especially for solid tumors, the PD-1/L1 monoclonal antibody has poor penetrating ability, and the effective part may only be limited to some cancer cells next to the blood vessels, resulting in a low objective remission rate (ORR) of tumor treatment.
Compared with the PD-1/L1 antibody with a molecular weight of more than 140,000 Da, small molecule inhibitors have inherent advantages in this regard.
Secondly, the immunogenicity of the PD-1/L1 monoclonal antibody is also very prominent.
After biological macromolecules enter the human body, it is easy to cause a cytokine storm, a strong immune response, and a variety of serious adverse reactions.
However, due to the small molecular weight of PD-L1 small molecule inhibitors, the immunogenicity can be ignored.
Again, there are issues of cost, compliance, and accessibility.
Monoclonal antibodies are difficult to prepare, storage and transportation are inconvenient, and this causes high costs.
In addition, the current way of administration of PD-1/L1 monoclonal antibody is still mainly intravenous, once every 2-3 weeks, patients' compliance with treatment is far less than oral small molecule targeted drugs.
The oral PD-L1 small molecule inhibitor has the characteristics of convenient transportation and storage, and good stability.
At present, research on the combination of small molecule targeted drugs and PD-1/L1 monoclonal antibody is in full swing.
In the future, if targeted drugs and PD-L1 small molecule inhibitors are taken orally at the same time, it will greatly improve patient compliance and life quality.
PD-L1 small molecule inhibitors-under the opportunity, the challenge is greater
Compared with the current upsurge of PD-1/L1 monoclonal antibody innovative drug research, the research on PD-L1 small molecule inhibitors is relatively deserted.
The evolutionary route of molecular form blocking the action of PD1-PDL1, the order from simple to difficult should be antibody→polypeptide→small molecule.
For the development of PD-L1 small molecule inhibitors, how to design a high-efficiency blocking of the protein-protein interactions (PPI) between PD-1 and PD-L1, small molecular weight, oral bioavailability, and PK performance Excellent and safe small molecule compounds are the biggest challenge.
At present, there are two ways in which PD-L1 small molecule inhibitors prevent the binding of PD-1 and PD-L1 protein (Figure 1):
In the first way, the PD-L1 small molecule inhibitor binds to two PD-L1 proteins on the surface of tumor cells to form a dimer, and the binding site of the small molecule and PD-L1 is highly overlapped with the binding site of PD-1.
The conformation of the PD-L1 dimer changes compared to the monomer conformation, which greatly reduces its binding force to the PD-1 protein.
In the second way, the PD-L1 dimer combined with small molecules is endocytosed by tumor cells, thereby losing the possibility of binding to the PD-1 protein on the surface of immune cells.
5s ease 0s;color:#337FE5;text-indent:2em;">5s ease 0s;color:#337FE5;text-indent:2em;">.
5s ease 0s;color:#337FE5;text-indent:2em;">5s ease 0s;color:#337FE5;text-indent:2em;">.
Figure 1 The principle of PD-L1 small molecule inhibitors preventing the binding of PD-1 to PD-L1 protein
Although many pharmaceutical companies around the world have begun to deploy the research and development of PD-L1 small molecule inhibitors, the challenges of the research and development stage and the high barriers to the preparation of drugs have also built a wider moat for the commercial value of this field.
Currently, clinical progress has been made.
There are not many companies, but two companies, Incyte (INCB086550) and Gilead (GS-4224), which have already entered the clinical stage, are both in clinical phase I.
The pre-clinical data of the newly developed PD-L1 small molecule inhibitor ASC63 by Gerry Pharmaceuticals shows that ASC63 not only induces a stronger PD-L1 endocytosis effect, but also has a stronger endocytosis effect (Figure 2) .
According to the official website of Gale Pharmaceuticals, Gale’s product pipeline includes two PD-L1 small molecule inhibitors, which are currently about to complete the preclinical development phase.
Figure 2 ASC63 efficiently induces PD-L1 dimerization and endocytosis on the surface of tumor cells
Although the development of oral PD-L1 small molecule inhibitors is more difficult, compared to PD-1/L1 monoclonal antibodies, it has higher penetration in the tumor microenvironment and can also avoid clinical side effects due to immunogenicity , And reduce the cost of preparation, transportation and storage, while improving the compliance and accessibility of tumor immunotherapy.
Oral PD-L1 small molecule inhibitors have the potential to come from behind in tumor immunotherapy in the future.
We expect PD-L1 small molecule inhibitors to "make progress in the anti-tumor R&D market in the future.