LAG3 (CD223)

Target id: 2932

Nomenclature: LAG3 (CD223)

Systematic Nomenclature: CD223

Family: Other immune checkpoint proteins, CD molecules

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	1	525	12p13.31	LAG3	lymphocyte activating 3	9
Mouse	1	521	6 F2	Lag3	lymphocyte-activation gene 3
Rat	-	525	4q42	Lag3	lymphocyte activating 3
Gene and Protein Information Comments
The human LAG3 protein precursor is 525 amino acids including its 28 aa signal peptide. LAG3 cleavage to a soluble form is mediated by the metalloproteinases ADAM10 and ADAM17 [3,5], although the biological function of this soluble protein is not fully resolved.

Database Links
Alphafold	P18627 (Hs), Q61790 (Mm)
CATH/Gene3D	2.60.40.10
ChEMBL Target	CHEMBL4630881 (Hs)
Ensembl Gene	ENSG00000089692 (Hs), ENSMUSG00000030124 (Mm), ENSRNOG00000021334 (Rn)
Entrez Gene	3902 (Hs), 16768 (Mm), 297596 (Rn)
Human Protein Atlas	ENSG00000089692 (Hs)
KEGG Gene	hsa:3902 (Hs), mmu:16768 (Mm), rno:297596 (Rn)
OMIM	153337 (Hs)
Pharos	P18627 (Hs)
RefSeq Nucleotide	NM_002286 (Hs), NM_008479 (Mm), NM_212513 (Rn)
RefSeq Protein	NP_002277 (Hs), NP_032505 (Mm), NP_997678 (Rn)
UniProtKB	P18627 (Hs), Q61790 (Mm)
Wikipedia	LAG3 (Hs)

Download all structure-activity data for this target as a CSV file go icon to follow link

Antibodies

Key to terms and symbols

Click column headers to sort

Antibody											Sp.	Action	Value	Parameter	Reference
relatlimab											Hs	Antagonist	-	-	6
⤷	[6]

Immunopharmacology Comments
Membrane-bound LAG3 (CD223) is a T cell inhibitory co-receptor and immune checkpoint being investigated as a cancer immunotherapeutic target [1,4], akin to the checkpoints CTLA-4/CD80/86 and PD-1/PD-L1 which have already proven successful in the clinic [8,10]. LAG3's major ligand is MHC class II (MHCII), and this interaction is believed to play a role in modulating dendritic cell function [2]. Work published by Maruhashi et al. (2018) indicates that LAG3 preferentially binds stable peptide-bound MHCII complexes, rather than unbound MHCII molecules [7]. Understanding novel T cell inhibitory receptor pathways such as LAG3 could lead to the development of new combinatorial therapeutic approaches in immuno-oncology (see BMS-986016). Novartis is developing the high affinity anti-LAG3 mAb LAG525, which is being evaluated as a single agent and in combination with the anti-PD-1 mAb, spartalizumab (PDR001) in patients with advanced solid malignancies (see Phase 1/2 clinical trial NCT02460224). This is a highly competitive area of drug development that is evidenced by the number of pharmaceutical companies with active LAG3 programmes. For example, Symphogen have the anti-LAG3 mAb Sym022 in their immuno-oncology pipeline (see Phase 1 trial NCT03489369), Tesaro have TSR-033 in Phase 1 (NCT03250832), Merck have MK-4280 in Phase 2 (NCT03516981, and Regeneron have REGN3767 (fianlimab; Phase 1 NCT03005782). Macrogenics and F-star both have bispecific mAbs in Phase 1 trials; MGD013 which is anti-LAG3/PD-1 (NCT03219268) and FS118 which is anti-LAG3/PD-L1 (NCT03440437) respectively. Accumulating evidence links LAG3 activity with decreased proliferation and function of T_reg cells, and promotion of autoimmunity in chronic autoimmune-prone models, that may contribute to T_reg insufficiency in autoimmune diseases such as psoriasis (see NCT02195349- evaluating anti-LAG3 mAb GSK2831781) and type 1 diabetes [11]. A soluble form of LAG3 (sLAG3) appears to function as an immune adjuvant, and it is hoped that a sLAG3 mimetic would enhance the immune response to tumours. To this end, the development of a sLAG3 immunoglobulin fusion protein (IMP321, Prima BioMed) is in early development as an immune adjuvant. The most advanced IMP321 clinical trial is Phase 2 NCT02614833 that is evaluating the potential adjunctive effect of IMP321 alongside paclitaxel chemotherapy in patients with metastatic breast cancer. IMP321 trial (Phase 1) in combination with the immune checkpoint inhibitor pembrolizumab is also underway.

Immunopharmacology Comments

Membrane-bound LAG3 (CD223) is a T cell inhibitory co-receptor and immune checkpoint being investigated as a cancer immunotherapeutic target [1,4], akin to the checkpoints CTLA-4/CD80/86 and PD-1/PD-L1 which have already proven successful in the clinic [8,10]. LAG3's major ligand is MHC class II (MHCII), and this interaction is believed to play a role in modulating dendritic cell function [2]. Work published by Maruhashi et al. (2018) indicates that LAG3 preferentially binds stable peptide-bound MHCII complexes, rather than unbound MHCII molecules [7]. Understanding novel T cell inhibitory receptor pathways such as LAG3 could lead to the development of new combinatorial therapeutic approaches in immuno-oncology (see BMS-986016). Novartis is developing the high affinity anti-LAG3 mAb LAG525, which is being evaluated as a single agent and in combination with the anti-PD-1 mAb, spartalizumab (PDR001) in patients with advanced solid malignancies (see Phase 1/2 clinical trial NCT02460224). This is a highly competitive area of drug development that is evidenced by the number of pharmaceutical companies with active LAG3 programmes. For example, Symphogen have the anti-LAG3 mAb Sym022 in their immuno-oncology pipeline (see Phase 1 trial NCT03489369), Tesaro have TSR-033 in Phase 1 (NCT03250832), Merck have MK-4280 in Phase 2 (NCT03516981, and Regeneron have REGN3767 (fianlimab; Phase 1 NCT03005782). Macrogenics and F-star both have bispecific mAbs in Phase 1 trials; MGD013 which is anti-LAG3/PD-1 (NCT03219268) and FS118 which is anti-LAG3/PD-L1 (NCT03440437) respectively.

Accumulating evidence links LAG3 activity with decreased proliferation and function of T_reg cells, and promotion of autoimmunity in chronic autoimmune-prone models, that may contribute to T_reg insufficiency in autoimmune diseases such as psoriasis (see NCT02195349- evaluating anti-LAG3 mAb GSK2831781) and type 1 diabetes [11].

A soluble form of LAG3 (sLAG3) appears to function as an immune adjuvant, and it is hoped that a sLAG3 mimetic would enhance the immune response to tumours. To this end, the development of a sLAG3 immunoglobulin fusion protein (IMP321, Prima BioMed) is in early development as an immune adjuvant. The most advanced IMP321 clinical trial is Phase 2 NCT02614833 that is evaluating the potential adjunctive effect of IMP321 alongside paclitaxel chemotherapy in patients with metastatic breast cancer. IMP321 trial (Phase 1) in combination with the immune checkpoint inhibitor pembrolizumab is also underway.

Cell Type Associations

Immuno Cell Type:	Natural killer cells
Cell Ontology Term:	natural killer cell (CL:0000623)
Comment:	LAG3 is expressed on activated human NK cells.
References:	9

Immuno Cell Type:	T cells
Cell Ontology Term:	CD4-positive, alpha-beta T cell (CL:0000624) CD8-positive, alpha-beta T cell (CL:0000625)
Comment:	LAG3 is an activation marker for CD4⁺ and CD8⁺ T cells.
References:	9

Immuno Process Associations

Immuno Process:

Antigen presentation

Immuno Process:

B cell (activation)

Immuno Process:

Immune system development

Immuno Process:

Inflammation

Immuno Process:

T cell (activation)

Immuno Process:

Immune regulation

Immuno Process:

Cytokine production & signalling

Immuno Process:

Chemotaxis & migration

Immuno Process:

Cellular signalling

General Comments
Residues in the proline-rich D1 loop of LAG3 facilitate binding to MHC class II molecules. LAG3 probably transmits inhibitory signals via its cytoplasmic domain but the precise signalling mechanism remains unknown. MHC class II expressed by melanoma cells may bind to LAG3 on melanoma-infiltrating T cells and this might facilitate their clonal exhaustion, and enhance tumour cell immune evasion. LAG3 may also interact with galectin-3, a T cell regulating lectin, and this could potentially contribute to LAG3's regulation of CD8⁺ cell function. A recombinant protein comprising the extracellular domain of LAG3 fused with human IgG1 Fc fragment (known as eftilagimod alfa or IMP 321) represents a soluble form of LAG3 that is being developed as an immuno-oncology therapeutic. The most advanced clinical trial (as of December 2017) evaluating IMP 321 is Phase 2 study NCT02614833 being carried out in patients with metastatic breast cancer (as an adjunct to standard chemotherapy).

General Comments

Residues in the proline-rich D1 loop of LAG3 facilitate binding to MHC class II molecules. LAG3 probably transmits inhibitory signals via its cytoplasmic domain but the precise signalling mechanism remains unknown. MHC class II expressed by melanoma cells may bind to LAG3 on melanoma-infiltrating T cells and this might facilitate their clonal exhaustion, and enhance tumour cell immune evasion. LAG3 may also interact with galectin-3, a T cell regulating lectin, and this could potentially contribute to LAG3's regulation of CD8⁺ cell function. A recombinant protein comprising the extracellular domain of LAG3 fused with human IgG1 Fc fragment (known as eftilagimod alfa or IMP 321) represents a soluble form of LAG3 that is being developed as an immuno-oncology therapeutic. The most advanced clinical trial (as of December 2017) evaluating IMP 321 is Phase 2 study NCT02614833 being carried out in patients with metastatic breast cancer (as an adjunct to standard chemotherapy).

References

Show »« Hide

1. Andrews LP, Marciscano AE, Drake CG, Vignali DA. (2017) LAG3 (CD223) as a cancer immunotherapy target. Immunol Rev, 276 (1): 80-96. [PMID:28258692]

2. Camisaschi C, De Filippo A, Beretta V, Vergani B, Villa A, Vergani E, Santinami M, Cabras AD, Arienti F, Triebel F et al.. (2014) Alternative activation of human plasmacytoid DCs in vitro and in melanoma lesions: involvement of LAG-3. J Invest Dermatol, 134 (7): 1893-1902. [PMID:24441096]

3. Clayton KL, Douglas-Vail MB, Nur-ur Rahman AK, Medcalf KE, Xie IY, Chew GM, Tandon R, Lanteri MC, Norris PJ, Deeks SG et al.. (2015) Soluble T cell immunoglobulin mucin domain 3 is shed from CD8+ T cells by the sheddase ADAM10, is increased in plasma during untreated HIV infection, and correlates with HIV disease progression. J Virol, 89 (7): 3723-36. [PMID:25609823]

4. Goldberg MV, Drake CG. (2011) LAG-3 in Cancer Immunotherapy. Curr Top Microbiol Immunol, 344: 269-78. [PMID:21086108]

5. Li N, Workman CJ, Martin SM, Vignali DA. (2004) Biochemical analysis of the regulatory T cell protein lymphocyte activation gene-3 (LAG-3; CD223). J Immunol, 173 (11): 6806-12. [PMID:15557174]

6. Lonberg N, Srinivasan M. (2014) Optimization of antibodies that bind lymphocyte activation gene-3 (lag-3), and uses thereof. Patent number: WO2014008218. Assignee: Bristol-Myers Squibb Company. Priority date: 02/07/2012. Publication date: 09/01/2014.

7. Maruhashi T, Okazaki IM, Sugiura D, Takahashi S, Maeda TK, Shimizu K, Okazaki T. (2018) LAG-3 inhibits the activation of CD4⁺ T cells that recognize stable pMHCII through its conformation-dependent recognition of pMHCII. Nat Immunol, 19 (12): 1415-1426. [PMID:30349037]

8. Sharpe AH. (2017) Introduction to checkpoint inhibitors and cancer immunotherapy. Immunol Rev, 276 (1): 5-8. [PMID:28258698]

9. Triebel F, Jitsukawa S, Baixeras E, Roman-Roman S, Genevee C, Viegas-Pequignot E, Hercend T. (1990) LAG-3, a novel lymphocyte activation gene closely related to CD4. J Exp Med, 171 (5): 1393-405. [PMID:1692078]

10. Turnis ME, Andrews LP, Vignali DA. (2015) Inhibitory receptors as targets for cancer immunotherapy. Eur J Immunol, 45 (7): 1892-905. [PMID:26018646]

11. Zhang Q, Chikina M, Szymczak-Workman AL, Horne W, Kolls JK, Vignali KM, Normolle D, Bettini M, Workman CJ, Vignali DAA. (2017) LAG3 limits regulatory T cell proliferation and function in autoimmune diabetes. Sci Immunol, 2 (9). [PMID:28783703]

How to cite this page

CD molecules: LAG3 (CD223). Last modified on 26/02/2024. Accessed on 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2932.

LAG3 (CD223)

Contents:

References

How to cite this page