The FDA officially approved the listing of Opdualag, a "first-in-class" product for lymphocyte activation gene-3 (LAG-3).

On March 18, 2022, the FDA officially approved The Opdualag, a "first-in-class" product of the lymphocyte activation gene 3 (LAG-3) for the treatment of patients

LAG-3 is a transmembrane protein with a molecular weight of about 70ku

Professor Frédéric Triebel discovered LAG-3

LAG-3 was in an awkward and uninvited position in the early days of development, and neither academia nor investors were optimistic about this target

Some of the listed and researchED LAG-3 projects (Source: Nature Reviews Drug Discovery)

*Relatlimab was approved for marketing on March 18, 2022

After the Relatlimab and Nivolumab Clinical Phase II/III data were released, Jason Luke, an oncologist at the University of Pittsburgh Medical Center who had consulted for BMS, said: "This is a transformative data

At present, LAG-3 has only approved one indication for melanoma, and the performance of LAG-3 in other disease areas remains to be seen

Previously, preclinical data from BMS and other companies showed little activity

The turnaround occurred when BMS published one of its phase II/III clinical results

Hussein Tawbi, a researcher in the clinical trial and an oncologist at the University of Texas MD Anderson Cancer Center, said: "I'm excited to see these data, we've never seen a combination therapy have such significant benefits

Previously, BMS has conducted clinical trials
against PD-1 monoclonal antibody Nivolumab and anti-CTLA-4 monoclonal antibody Ipilimumab.
Nivolumab in combination with Ipilimumab extends PFS with a higher objective response rate
than Ipilimumab alone.
CTLA-4 combination therapy is destined to compete
with LAG-3 therapy.
In the REARIVITY-047 study, the PFS ratio for 12 months was 47% for LAG-3 combination therapy, which was not much
different from the 49% of CTLA-4 combination therapy in the CheckMate 067 study.
However, 59% of patients who received combined Ipilimumab and Nivolumab experienced serious or life-threatening adverse reactions, compared with 19%
in the combination of Linearimab and Nivolumab.
Professor Luke introduced: "The toxicity profile of the LAG-3 combination is much
better than the CTLA-4 combination we have seen.
”

Nivolumab in combination with Ipilimumab is currently the standard of care for
patients with advanced melanoma.
According to BMS estimates, about 30% of patients still receive only PD-1 monotherapy to avoid toxic reactions
.
Professor Luke said the new data suggested that the new LAG-3 combination therapy was expected to replace monotherapy
.

However, it will take some time to see
whether the new combination therapies of BMS can get a piece of the pie from nivolumab in combination with Ipilimumab.
The 5-year overall survival rate of Nivolumab in combination with Ipilimumab is 52%.

Luke said: "We wanted to have a biomarker that could layer
patients.
"If patients with elevated PD-1 or LAG-3 expression are better at responding to the combination therapy, this can help guide the development of clinical treatment options
.
" However, Luke said: "In fact, we didn't see that
.
”

Greater potential

Another therapeutic potential of LAG-3 is whether other tumors can respond
positively to the combination of LAG-3 and PD-1.
BMS is actively laying out more than 40 clinical trials
including non-small cell lung cancer, hepatocellular carcinoma and colorectal cancer.

Cheng said preclinical data suggest that the combination of Competentimab and Nivolumab provides better value
than the use of the two alone.
People have been looking for ways to make "cold" tumors "hot" and enhance immune system function, expand the scope of treatment, and improve the level of
benefit.
BMS is expected to block both immune checkpoints of T cells at the same time, significantly enhancing efficacy
.
Cheng believes: "The potential for synergy is already evident
.
”

Tumors are classified
based on immune scores.
There are many immune cells around tumor cells, and the tumor is defined as a "hot tumor" and vice versa as a "cold tumor"
.
Immune checkpoint inhibitors are effective against a large number of "hot tumors" and are basically ineffective against "cold tumors
".
(Source: Nature Reviews Drug Discovery)

However, Adam Palmer, a pharmacologist from the University of North Carolina School of Medicine, is skeptical
.
He believes that the synergy of "1+1>2" is basically based on the results of preclinical research
.
But these results can be interfered with
by models used in the lab.
While many immuno-oncologists oppose the idea that combinations don't work synergistically, Palmer argues that the outcome of at least trying to change two less effective drugs through a combination of drugs is often hundreds of millions of dollars lost
.

Competition is fierce

According to the NextPharma database of Medulfax, there are currently more than 20 LAG-3 products in the clinical trial stage
around the world.
Luke asked, "Are these products all the same?" "For example, depending on the binding site with LAG-3, the ability of these antibodies to block LAG-3 and its various ligands may also be different
.
" Much more needs to be done
for the LAG-3.
He added
.

The competition around up-and-coming bispecific LAG-3 antibodies is more complicated
.

At the LAG3 Targeted Drug Development Summit in January, Paul Moore from MacroGenics said that the PD-1×LAG-3 bispecific antibody Tebotelimab can simultaneously block two immune checkpoints on a single T cell, increasing the likelihood of synergy.
This advantage is not available when targeting PD-1 and LAG-3, respectively
.
Phase I data showed that Tebotelimab's ORR in the treatment of diffuse large B-cell lymphoma (DLBCL) reached 53.
8%.

"We didn't see higher toxicity
than PD-1.
" Moore added
.
MacroGenics is already advancing Phase II/III clinical trials
of Tebotelimab.
It is worth mentioning that MacroGenics hopes to achieve better clinical results by combining antibodies that target B7-H3 with Tebotelimab (B7-H3 is an immunomodulatory factor expressed in many tumors
).

Also at this summit, Roche reported the cell-specific advantages
of PD-1× LAG-3 dual-antibody RG6139.
Roche chief scientist Laura Codarri Deak believes that regulatory T cells also express LAG-3, and blocking LAG-3 may make it more immunosuppressive
.
The affinity of RG6139 for PD-1 is higher than LAG-3, making it preferentially bind
to tumor-infiltrating activated T cells.
Codarri Deak said: "I think our dual antibody is more selective
than the combination.
We can avoid targeting regulatory T cells
.
”

Luke said that convenience is one
of the advantages of dual resistance.
In practical applications, factors such as antibody infusion timing hinder the combined use of PD-1, LAG-3, TIGIT, and CD73, which is where multi-antibody can really play an
advantage.

Immutep is developing a new strategy
based on LAG-3.
Triebel does not inhibit the LAG-3 signaling pathway within T cells, but rather wants to regulate antigen-presenting cell function
.
Triebel believes that T cells are warriors of the immune system, but dendritic cells with antigen presentation are the generals
.
These cells provide energy to the T cell troops, direct directions, and provide proof of
destruction.
Immutep's drug candidate, Eftilagimod alpha, consists of a LAG-3 fusion protein that binds
to MHC class II proteins.
The drug candidate, which is in clinical trials for metastatic breast cancer, head and neck squamous cell carcinoma and non-small cell lung cancer, also hopes to improve efficacy
by combining with chemotherapy drugs or Pembroizumab.

Future breakthroughs

Up to now, more than 10 PD-1/PD-L1 monoclonal antibodies have been approved for marketing worldwide, providing new treatment options
for dozens of tumors.
Because of the more complex mechanism of action of CTLA-4, the path to developing CTLA-4 inhibitors is more difficult
.
At present, only 1 CTLA-4 monoclonal antibody in the world has been approved for marketing
.
Judging from the number of products under development, ctLA-4 is only about 70, far less popular than the PD-1 and PD-L1
tracks.

As the fourth immune checkpoint to be approved, there is still a lot of uncertainty
about the future of LAG-3.
The first ligand that appears in LAG-3 is the MHC class II protein
on antigen-presenting cells.
Conventional wisdom holds that, similar to PD-1, T cell activity
can be restored by blocking the interaction between LAG-3 and MHC II.
However, the subsequent appearance of other ligands has made the physiological significance of LAG-3 more complicated, and the effect of LAG-3 on the body needs to be further studied
.
It is worth mentioning that the latest study published in Nature Immunology on April 18 shows that LAG-3 can block TCR signaling and inhibit T cell function without acting with MHC class II molecules
.
LAG-3 molecules migrate to immune synapses with the help of TCR-CD3 complexes, and EP repeat units in lag-3 structures reduce the pH of immune synapses, dissociate tyrosine kinase Llk from CD4 or CD8 co-receptors, block co-receptor-TCR signaling pathways and inhibit T cell activity
.

MHC II protein, Galectin-3, LSECtin and FGL1 can all bind to LAG-3 (Source: Seminars in Immunology)

These findings have brought new opportunities and challenges to drug research and development around LAG-3, and whether the LAG-3 pathway can produce more anti-cancer breakthroughs in the next 5-10 years is worth further expectations
.

"We hope to be able to better understand the unique biology associated with LAG-3 so that we can explore the types of tumors and other indications
that have the greatest potential benefit.
" Cheng said
.