Double-resistant or union, who is PD-1 partner LAG-3 optimal solution

[Transfer] Double-resistant or combined therapy, who is the optimal solution of PD-1 gold partner LAG-3?

Source: amino observation/Fang Taozhi

On June 23, Chinese biopharmaceuticals spent $ 161 million to acquire F-Star. The most clinical product in F-Star's pipeline is a LAG-3/PD-L1 dual resistance.

I believe most people are no stranger to the combination of PD-1 and LAG-3.

In March of this year, Beltay Squibb's PD-1+LAG-3 combination therapy was approved for listing, making LAG-3 a "rookie" in the field of immunosuppressive agents.

The R & D of LAG-3 has also been on fire. Many domestic and foreign pharmaceutical companies have put LAG-3 and PD-1 combination on the agenda.

In addition, some players have a different approach. Four players of Cinda Biology, Ding Ding Pharmaceutical, Kishimai Bio, and Kangfang Biological choose to develop LAG-3 in the form of dual-resistant forms.

Although in terms of technology, LAG-3/PD-1 has higher technical barriers to develop and develop, but theoretically, LAG-3/PD-1 dual-resistance can stimulate stronger T cell activation than combined therapy, and have ownership Over the potential of PD-1 drug resistance.

With Chinese biopharmaceutical mergers and acquisitions F-Star, LAG-3 double anti-players have one more. It seems that this track is still attracting more players to enter the game.

So, who is the optimal solution of LAG-3/PD-1?

/ 01 /

LAG-3+PD-1 combination therapy is double resistance

It is no exaggeration to say that LAG-3's "life" was rescued by PD-1.

Although LAG-3 was discovered as early as 1990, LAG-3 single medicines have not been developed smoothly.

Previously, the LAG-3 monoclonal anti-anti-anti-anti-anti-MK-4280 clinical data released by Merhado before, the objective relief rate of the objective relief rate of 18 other patients in the treatment of physical tumor was only 6 %, and the disease control rate was only 17 %; -3 The II phase II clinical research project of monoclonal antibody IMP731.

Fortunately, with the rise of the PD-1 combination therapy, the LAG-3 target also ushered in the moment of peak circuit turning.

We all know that PD-1 is a test point inhibitor that can be combined with PD-L1 to calm down the T cells on the "upper" to avoid accidental injury to the normal cell of the human body.

However, this suppression mechanism can also prevent the immune system from killing cancer cells. Therefore, we use PD-1/PD-L1 monoclonal resistance to block this inhibitory mechanism to restore the lethality of T cells, that is, "loose brakes" to the immune system.

Similar to PD-1, LAG-3 is also a checkpoint inhibitor, which can be combined with MHC-II molecules (mainly tissue compatibility complex). MHC protein is responsible for handing the external antigen to the immune system to activate T cell attacks. However, when MHC and LAG-3 are combined, T cells activation is also suppressed, which gives cancer cells.

Therefore, inhibitory LAG-3 can also give the immune system "loose brakes". So, will the two brakes loose together, will it be more lethal to cancer cells? The answer is, yes.

Although LAG-3 and PD-1 are also immune checkpoints inhibitors, they can media different signal pathways, which can produce synergistic effects and cause the depletion of effect T cells.

In addition, pre-clinical studies have found that LAG3 and PD-1 are expressed on the infiltrated lymphocytes of human tumor tissues, which theoretically inhibits PD-1/PD-L1, LAG-3/MHC-II. The ground is relieved to achieve the effect of anti -tumor.

In other words, the two brakes at the same time will play a role in 1+1> 2.

In March, the LAG-3 antibody Relatlimab combined with PD-1 antibody Nivolumab, which was approved by Belky Bibao, was approved for the treatment of metastatic melanoma, which further proved the effectiveness of the Lag-3 and PD-1 synergy mechanism.

The research and development of combination therapy around LAG-3+PD-1 became in full swing, but many players also targeted another problem-solving method of LAG-/PD-1 combination, dual-resistant.

The success of the combination therapy is before, the feasibility of LAG-3/PD-1 dual-resistant is further proven. So, will the performance of double resistance be better?

/ 02 /

Can potential curative effect and drug resistance, can double resistance overtaking?

You may have doubts, and the combination therapy has been proven to be feasible. Why should we develop more complicated double resistance? The answer may be that the role of dual antidthies will be stronger than the combined therapy.

Specifically, the room for improvement of dual antidote is mainly in two aspects.

On the one hand, the inhibitory of the Duoyuraxia's immune checkpoint can stimulate a stronger anti -tumor coordination effect.

LAG3/PD-1 dual resistance can bridge PD-L1 positive cells and LAG3-positive cells. This bridge can pull up tumor cells that express PD-L1 and T cells that express LAG-3, thereby forming a stable T cell antigen receptor, further activating T cells, and allowing T cells to gain stronger immune activation capabilities.

Taking Double Anti-FS118 as an example, in clinical experiments, the LAG-3/PD-L1 dual resistance has been preliminarily displayed. Studies have shown that in high-expression LAG-3 and PD-L1 T cells, FS118 shows stronger activity than single antibodies or LAG-3/PD-L1 combination components. On the other hand, the advantage of dual resistance is the potential of resistance to resistance.

Although PD-1/PD-L1 plays a strong role in fighting tumors, a considerable part of the patients will gradually have no medicine to use due to the primary and obtaining resistance during the treatment process.

Today, LAG-3/PD-1 dual resistance may have the potential to solve this problem.

A study of mice found that LAG-3 falls off the effect of PD-1 blocking drug resistance. The study shows that LAG-3, which cannot fall off from the surface of the T cell, will cause the mice to resist PD-1 treatment. And clinically, high-expression LAG-3 is often related to the adverse results of PD-1 treatment.

This also means that the increase in LAG-3 expression may be one of the mechanisms that cause patients to produce PD-1 /PD-L1 treatment resistance.

Compared with LAG-3+PD-1 combination therapy, dual-resistant can drive the falling of LAG-3 on the surface of the T cell to reduce the LAG-3 expression on the surface of the T cell.

It still takes FS118 as an example. Its dual-resistant design adds PD-L1-mediated LAG-3 drop-off function to prevent the resistance of the PD-1 channel suppression after compensation to increase LAG3.

In the clinical II test of FS118 single drug treatment at the end of the advanced PD-1 drug head and neck squamous species carcinoma, the potential of dual-resistant design solve the potential of PD-1 drug resistance has been reflected. In the experiment, the complete relief of patients with sexual resistance and the stability of the disease longer than three months, while the disease progress and stability time of patients with early drug resistance should be less than three months.

However, whether the LAG-3/PD-1 dual resistance can achieve a better synergistic effect than two monoclonal anti-anti-combination, it also needs more clinical data to verify.

In addition to the potential advantages of the above two aspects, the advantages of dual anti -resistance have been studied clearly, which is more convenient than the use of multiple monoclonal combination.

In the future, if the potential advantages of dual resistance can obtain clinical experiments, then LAG-3/PD-1 dual-resistance may be able to complete the curve overtaking for LAG-3+PD-1 combination therapy.

/ 03 /

Domestic player's LAG-3 dual anti-competition competition

Many domestic players have layout LAG-3, but in comparison, more players are layout of LAG-3 monoclonal anti-resistance.

According to the statistics of the China Golden Research News, as of March 21, only the domestic pharmaceutical companies' LAG-3 dual-resistant four-anti-Ding Medicine, Cinda Bio, Kangfang Biological, and Kishimai Biological.

Among them, Ding Ding Medicine is the fastest. As early as 2018, Ding Ding Pharmaceutical introduced LAG-3/PD-1 dual-resistant Tebotelimab from Macrogenics.

Phase I data published at the SITC conference in 2020 shows that MGD013 and HER2 monoclonal combination is used in advanced first -tier patients with a preliminary overall relief rate (ORR) to 40%.

In terms of security, MGD01 has good security, and the incidence of level 3 adverse events is 19.4%, and there is no serious adverse reaction at 4-5 levels. At present, the fastest clinical study of MGD013 has entered three phases, and it is expected to be completed in 2023. Perhaps after a long time, we can see that the real strength of LAG-3 double resistance.

At this year's ASCO conference, Kangfang Bio also brought LAG-3/PD-1 dual anti-AK129 clinical results.

In preclinical research, AK129 can prevent the immunosuppressive suppression of PD-1 and LAG-3, and compared with the combination of PD-1+LAG-3 Essence

In addition, the results of the dual-resistant EMB-02 activity research results of Kishimai creatures also show that LAG-3/PD-1 dual resistance is not only better than LAG-3 monoclonal resistance, but also better than LAG-3+PD-1.

The IBI323 of Cinda Bio is a dual-resistant dual-resistant 2+2 symmetrical type of PD-L1 and LAG-3 at the same time. According to a paper published in 2021 in "Oncoimmunology", IBI323 dual blocking PD is used in pre-clinical research. -L1/LAG-3 channels can overcome the original and acquired anti-PD-(L) 1 resistance.

It is worth mentioning that Cinda Bio is the only one, which not only laid out the LAG-3 monoclonal anti-resistance and the LAG-3 dual-resistant player. It is not difficult to guess that Cinda Bio has great expectations for LAG-3.

However, most of these studies are in the early days. To truly prove that their LAG-3 dual anti-preferential therapy is required, more clinical research is needed.

Who can take the lead in overtaking in the future? Let's continue watching.

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