On June 23, China Biopharma spent US$161 million to acquire F-star. Innovent Biological's IBI323 is a 2+2 symmetrical double antibody that simultaneously targets PD-L1 and LAG-3. According to a paper published in "OncoImmunology" in 2021, IBI323 was used to double block PD in pre

htmlOn June 23, China Biopharmaceutical spent US$161 million to acquire F-star. The product with the most advanced clinical progress in F-star's pipeline is a LAG-3/PD-L1 dual antibody.

I believe most people are already familiar with the combination of PD-1 and LAG-3.

In March this year, Bristol-Myers Squibb 's PD-1+LAG-3 combination therapy was approved for marketing, making LAG-3 a "rookie" in the field of immunosuppressants .

The research and development surrounding LAG-3 has also become popular, and many pharmaceutical companies at home and abroad have put LAG-3 and PD-1 combined therapy on their agenda.

In addition, there are also players who have taken a different approach. Innovent Biologics , Zai Lab Biotech, Amni Biologics, and Kangfang Biologics have chosen to develop LAG-3 in the form of dual antibodies.

Although the technical barriers to LAG-3/PD-1 research and development are higher in terms of process, theoretically speaking, LAG-3/PD-1 dual antibodies can stimulate stronger T cell activation than combination therapy, and Has the potential to overcome PD-1 resistance.

With the acquisition of F-star by China Biopharmaceuticals, there is another LAG-3 dual antibody player. It seems that this track is still attracting more players.

So, between dual antibodies and combination therapy, which one is the best solution for LAG-3/PD-1?

/ 01 /

LAG-3+PD-1 combination therapy opens the way for dual-antibody therapy

It is no exaggeration to say that the "life" of LAG-3 was saved by PD-1.

Although LAG-3 was discovered as early as 1990, the development of LAG-3 single drug has not been smooth.

Previously Merck released phase 1 clinical data of LAG-3 monoclonal antibody MK-4280. Among 18 patients with solid tumors who failed other treatments, the objective response rate was only 6% and the disease control rate was only 17%; Glaxo History Gram2 directly terminated the Phase II clinical research project of LAG-3 monoclonal antibody IMP731.

Fortunately, with the rise of PD-1 combination therapy, the LAG-3 target has also ushered in a turning point.

We all know that PD-1 is a checkpoint inhibitor that can combine with PD-L1 to calm down the "upper" T cells to avoid accidentally damaging normal cells in the human body.

However, this inhibitory mechanism can also prevent the immune system from killing cancer cells. Therefore, we use PD-1/PD-L1 monoclonal antibodies to block this inhibitory mechanism and restore the lethality of T cells, which is to "release the brakes" on the immune system.

Similar to PD-1, LAG-3 is also a checkpoint inhibitor that binds to MHC class II molecules (major histocompatibility complex). MHC proteins are responsible for presenting foreign antigens to the immune system, activating T cells to attack. However, when MHC binds to LAG-3, T cell activation is also inhibited, which gives cancer cells an opportunity.

Therefore, inhibiting LAG-3 can also "release the brakes" on the immune system. So, if the two brakes are loosened together, will it be more lethal to cancer cells? The answer is, yes.

Although LAG-3 and PD-1 are both immune checkpoint inhibitors, they mediate different signaling pathways and can produce synergistic effects, leading to the exhaustion of effector T cells.

Moreover, preclinical studies have found that LAG3 and PD-1 are co-expressed on infiltrating lymphocytes of human tumor tissues. In theory, inhibiting the two signaling pathways of PD-1/PD-L1 and LAG-3/MHC-II can improve the Effectively relieve the immune suppression of and to achieve anti-tumor effect.

In other words, releasing these two brakes at the same time will have the effect of 1+12.

html In March, Bristol-Myers Squibb’s LAG-3 antibody Relatlimab combined with PD-1 antibody Nivolumab was approved for marketing for the treatment of metastatic melanoma, further proving the effectiveness of the synergistic mechanism of LAG-3 and PD-1.

Research and development around the combination therapy of LAG-3+PD-1 has become in full swing, but many players are also aiming at another problem-solving method of LAG-/PD-1 combination, dual antibodies.

has the success of combination therapy, and the feasibility of LAG-3/PD-1 dual antibodies has been further proven. So, will the performance of double resistance be better?

/ 02 /

potential efficacy, drug resistance and advantages, can

dual resistance overtake in corners?

You may have doubts. Combination therapy has been proven to be feasible, why do we need to develop more complex dual antibodies? The answer may be that dual-antibody therapy is more effective than combination therapy.

Specifically, the room for improvement of dual-antibody therapy mainly lies in two aspects.

On the one hand, multiple pathways to relieve immune checkpoint inhibition can stimulate stronger anti-tumor synergistic effects.

LAG3/PD-1 double antibody can bridge PD-L1 positive cells and LAG3 positive cells. This bridging effect can bring PD-L1-expressing tumor cells and LAG-3-expressing T cells closer, thereby forming a stable T cell antigen receptor , further activating T cells, allowing T cells to gain stronger immune activation ability. .

Taking the dual antibody FS118 as an example, preclinical experiments have initially demonstrated the stronger efficacy of the LAG-3/PD-L1 dual antibody. Research shows that in T cells that highly express LAG-3 and PD-L1, FS118 shows stronger activity than a single antibody or the LAG-3/PD-L1 combination.

On the other hand, the advantage of dual antibodies is the potential to combat drug resistance.

Although PD-1/PD-L1 has a powerful effect in fighting tumors, due to primary and acquired drug resistance during treatment, a considerable number of patients will gradually become unavailable.

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

A study in mice found that LAG-3 shedding contributes to resistance to PD-1 blockade. This study shows that LAG-3 that cannot be shed from the surface of of T cells makes mice resistant to PD-1 treatment. And clinically, high expression of LAG-3 is often associated with adverse outcomes of PD-1 treatment.

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

Compared with LAG-3+PD-1 combination therapy, dual antibodies can drive the shedding of LAG-3 on the surface of T cells to reduce the expression of LAG-3 on the surface of T cells.

still takes FS118 as an example. Its dual-antibody design increases the PD-L1-mediated LAG-3 shedding function to prevent drug resistance caused by up-regulation of LAG3 after the PD-1 pathway is inhibited.

In the clinical II trial of FS118 monotherapy for late-line advanced PD-1-resistant head and neck squamous cell carcinoma, the potential of dual-antibody design to solve PD-1 resistance has been demonstrated. In the trial, the time for complete remission and disease stabilization in patients with acquired drug resistance was longer than three months, while the time for disease progression and stability in patients with initial drug resistance was less than or equal to three months.

However, more clinical data are needed to verify whether the LAG-3/PD-1 dual antibody can achieve a better synergistic effect than the combination of two monoclonal antibodies. In addition to the potential advantages of

in the above two aspects, the advantage of dual antibodies that has been studied clearly is that it is more convenient to use than the combination of multiple monoclonal antibodies.

In the future, if the potential advantages of dual antibodies can be proven by clinical trials, then LAG-3/PD-1 dual antibodies may be able to complete the overtaking of LAG-3+PD-1 combination therapy.

/ 03 /

Domestic players’ LAG-3 dual-antibody competition

Many domestic players have deployed LAG-3, but in comparison, more players have deployed LAG-3 single-antibody and LAG-3 dual-antibody. There are very few players on the track.

According to the statistics of CICC research report, as of March 21, only four domestic pharmaceutical companies have deployed LAG-3 dual antibodies: Zai Lab, Innovent Biologics, Kangfang Biologics, and Amni Biologics.

Among them, Zai Lab is making the fastest progress. As early as 2018, Zai Lab introduced the LAG-3/PD-1 dual anti-tebotelimab from MacroGenics. Phase I data released by

at the 2020 SITC conference showed that the initial overall response rate (ORR) of MGD013 in combination with a HER2 monoclonal antibody in advanced first-line patients was 40%.

In terms of safety, MGD01 has good safety, the incidence rate of grade 3 adverse events is 19.4%, and there are no grade 4-5 serious adverse reactions. Currently, the fastest clinical study of MGD013 has entered Phase III and is expected to be completed in 2023. Perhaps in the near future, we will be able to see the true strength of LAG-3 dual resistance.

At this year’s ASCO conference, Kangfang Biotech also presented preclinical results of LAG-3/PD-1 dual anti-AK129.

In preclinical studies, AK129 can effectively block immunosuppression mediated by PD-1 and LAG-3, and compared with the combination therapy of PD-1+LAG-3, AK129 dual antibody can mediate stronger immunity. activation.

In addition, the in vivo activity study results of Amai Biotechnology’s dual antibody EMB-02 also show that the LAG-3/PD-1 dual antibody is not only better than the LAG-3 monoclonal antibody, but also better than the combination of LAG-3+PD-1 .

Innovent Biological's IBI323 is a 2+2 symmetrical double antibody that targets PD-L1 and LAG-3 at the same time. According to a paper published in "OncoImmunology" in 2021, IBI323 was used for double blocking in preclinical studies. The PD-L1/LAG-3 pathway can overcome primary and acquired anti-PD-(L)1 resistance.

It is worth mentioning that Innovent Biologics is the only player that has deployed both LAG-3 monoclonal antibodies and LAG-3 dual antibodies. From this, it is not difficult to guess that Innovent Biologics has great expectations for LAG-3.

However, most of the above studies are in their early stages. To truly prove that our own LAG-3 dual antibodies are better than combination therapy, more clinical studies are needed.

Who can take the lead in overtaking in corners in the future? Let's keep looking.