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LAG-3 is the third immune brake to reach approval, combined with PD-1 blockade in melanoma.
LAG-3 is an inhibitory receptor that binds MHC class II and FGL1 and is co-expressed with PD-1 on exhausted T cells, so blocking both releases two brakes on the same cell. Relatlimab plus nivolumab (Opdualag) improved progression-free survival over nivolumab alone in untreated advanced melanoma in RELATIVITY-047, with less toxicity than the ipilimumab combination, making LAG-3 the third immune checkpoint to reach approval. LAG-3 expression of at least 1 percent on immune cells was seen in roughly 75 to 80 percent of the RELATIVITY-047 population. Fianlimab and favezelimab are in phase 3 across tumour types, and whether the benefit extends beyond melanoma is the central open question. For a newcomer: LAG-3 is the immune brake that joined PD-1 blockade to make melanoma immunotherapy work better without much extra toxicity.
In plain words · LAG-3 is the third immune brake to reach approval, combined with PD-1 blockade in melanoma.
Backbone ribbon from PDB 7UM3. RCSB PDB 7UM3. The ribbon widens where the chain is folded into a regular pattern and narrows where it is a loose loop.
LAG-3 is the third immune brake to reach approval, combined with PD-1 blockade in melanoma.
Binds MHC class II and FGL1; co-expressed with PD-1 on exhausted T cells.
4 products aim at LAG-3: antibodies and bispecific antibodies. Checkpoint drugs are antibodies that cover one side of an immune ‘stand down’ handshake so T cells stay active.
Immune or microenvironment target: the record's class is immune checkpoint. HPA LAG3: RNA tissue enhanced (choroid plexus 13 nTPM, lymphoid tissue 22 nTPM, ovary 18 nTPM); blood lineage lineage enriched (T-cells 13 nTPM); no normal tissue stained high. Distribution: 1 cancer family in the corpus carries a prevalence row, label threshold or catalogue link for it (Skin cancer (all types)); Open Targets associates it with 1 specific cancer type at or above 0.5 (melanoma). (Rule 1 of scripts/fetch-target-specificity.ts.)
Sources: Human Protein Atlas LAG3 tissue; UniProt P18627; Open Targets ENSG00000089692 associations
First described 1990. Earliest sequence paper UniProt cites for the protein: Triebel et al, J. Exp. Med, 1990, "LAG-3, a novel lymphocyte activation gene closely related to CD4". Source.
Binds MHC class II and FGL1; co-expressed with PD-1 on exhausted T cells.
RNA: tissue enhanced (choroid plexus 13 nTPM, lymphoid tissue 22 nTPM, ovary 18 nTPM), detected in many normal tissues. Blood: lineage enriched (T-cells 13 nTPM).
No normal tissue stained high.
No cancer sample stained medium or high.
HPA LAG3 tissue · HPA LAG3 pathology · HPA protein class: CD markers, FDA approved drug targets
Human Protein Atlas version 25.1, antibody staining at reliability approved, enhanced or supported; used under CC BY-SA 3.0. Staining counts are patients per level in the atlas cohort, not population prevalence.
Favezelimab is Merck's LAG-3 antibody, tested with pembrolizumab in phase 3 trials in colorectal cancer and classical Hodgkin lymphoma; the colorectal trial did not succeed.
Fianlimab is Regeneron's LAG-3 blocking antibody, paired with the PD-1 blocker cemiplimab. A 60% phase 1 response rate in untreated melanoma prompted phase 3 trials, but the metastatic trial against pembrolizumab missed its progression endpoint in 2026.
HLX26 is an experimental monoclonal antibody from Shanghai Henlius Biotech in phase 2 trials for non-small-cell lung cancer, aimed at LAG-3.
Opdualag combines relatlimab, the first drug targeting the LAG-3 immune brake, with nivolumab for melanoma.
For patients with advanced melanoma, immunotherapy offers a realistic chance of long-term survival and probably cure, and the ten-year data show that patients who are alive and progression-free at three years rarely die of melanoma afterwards. Nivolumab plus ipilimumab gives the best long-term results but at a high price in serious side effects; nivolumab alone or nivolumab plus relatlimab are alternatives for patients at lower risk or with autoimmune concerns. The trial is also a caution about surrogate endpoints: the survival plateau took years to become visible.
Patients with newly diagnosed advanced melanoma have a dual-checkpoint option that improves on nivolumab alone with only a modest increase in serious side effects, making it attractive for those unable to tolerate or unwilling to risk the toxicity of ipilimumab. It did not prove superior survival, and it has not been compared with nivolumab plus ipilimumab, which remains preferred for patients with brain metastases or other high-risk features. LAG-3 is now an established target under study in many other cancers.
This is the most cited map of the immunotherapy revolution and a good first read before the trials. Its predictions largely held: PD-1 pathway antibodies became the most widely used cancer drugs, PD-L1 testing entered practice, and LAG-3 blockade was approved in melanoma a decade later.
Query for this target: (TITLE:"LAG-3" OR ABSTRACT:"LAG-3" OR TITLE:"LAG3" OR ABSTRACT:"LAG3") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about LAG-3, not a curated reading list.
Shares VISTA, Pardoll 2012: the blockade of immune checkpoints in cancer immunotherapy, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, Hallmark: avoiding immune destruction and the tag checkpoint.
Shares VISTA, RELATIVITY-047, Hussein A. Tawbi, Fianlimab + cemiplimab phase 3 (first-line melanoma) and the tag checkpoint.
Shares TIM-3, T-cell exhaustion, Immune checkpoint, Checkpoint (two meanings) and the tag checkpoint.
Shares Pardoll 2012: the blockade of immune checkpoints in cancer immunotherapy, Hallmark: avoiding immune destruction, T cell, T-cell exhaustion and the tag checkpoint.
Shares Checkpoint (two meanings), Cold tumours and the immunosuppressive microenvironment and the tag checkpoint.
Shares RELATIVITY-047, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, RELATIVITY-047: relatlimab plus nivolumab, the first LAG-3 checkpoint combination, in untreated advanced melanoma, CheckMate 067 at ten years: nivolumab plus ipilimumab produces long-term survival in half of patients with advanced melanoma.
Shares Fianlimab, Relatlimab + nivolumab, Advanced melanoma (unresectable stage III and stage IV), Melanoma.
Shares LAG-3 blockade, Favezelimab, Immune checkpoint inhibitors.