Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 (cluster of differentiation 223) after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.
LAG-3 is closely related to CD4, with which it shares the ability to bind MHC class II molecules. Although there has been conflicting information on which motifs in the LAG-3 cytoplasmic tail are important for function, evolutionary conservation patterns combined with functional studies imply that the evolutionarily conserved core function of LAG-3 is an inhibitory competition through an immunoreceptor tyrosine-based inhibitory motif (ITIM)–like motif with the activating receptors CD4 or CD8 for binding the kinase LCK.
Gene The LAG3 gene contains 8 exons. The sequence data, exon/intron organization, and chromosomal localization all indicate a close relationship of LAG3 to CD4. The gene for LAG-3 lies adjacent to the gene for CD4 on human chromosome 12 (12p13) and is approximately 20% identical to the CD4 gene, and this gene organization can already be found in sharks.
Protein The LAG3 protein, which belongs to immunoglobulin (Ig) superfamily, comprises a 503-amino acid type I transmembrane protein with four extracellular Ig-like domains, designated D1 to D4. When human LAG-3 was cloned in 1990 it was found to have approx. 70% homology with murine LAG3. The homology of pig LAG3 is 78%.
Tissue distribution LAG-3 is expressed on activated T cells, natural killer cells, B cells and plasmacytoid dendritic cells.
Function LAG3's main ligand is MHC class II, to which it binds with higher affinity than CD4. The protein negatively regulates cellular proliferation, activation, and homeostasis of T cells, in a similar fashion to CTLA-4 and PD-1 and has been reported to play a role in Treg suppressive function. Fibrinogen-like protein1 FGL1, a liver-secreted protein, is another (major) LAG3 functional ligand independent of MHC-II. LAG3 also helps maintain CD8+ T cells in a tolerogenic state and, working with PD-1, helps maintain CD8 exhaustion during chronic viral infection. LAG3 is known to be involved in the maturation and activation of dendritic cells. LAG3 has also been implicated in the transmission pathologic α-synuclein in Parkinson's disease
Use as a pharmaceutical and as a drug target There are three approaches involving LAG3 that are in clinical development.
The first is IMP321, a soluble LAG3 which activates dendritic cells. The second are antibodies to LAG3 which take the brakes off the anti-cancer immune response. An example is relatlimab, an anti-LAG3 monoclonal antibody that is currently in phase 2 clinical testing. A number of additional LAG3 antibodies are in preclinical development. LAG-3 may be a better checkpoint inhibitor target than CTLA-4 or PD-1 since antibodies to these two checkpoints only activate effector T cells, and do not inhibit Treg activity, whereas an antagonist LAG-3 antibody can both activate T effector cells (by downregulating the LAG-3 inhibiting signal into pre-activated LAG-3+ cells) and inhibit induced (i.e. antigen-specific) Treg suppressive activity. Combination therapies are also ongoing involving LAG-3 antibodies and CTLA-4 or PD-1 antibodies. The third are agonist antibodies to LAG3 in order to blunt an autoimmune response. An example of this approach is GSK2831781 which has entered clinical testing (for plaque psoriasis).
History
1990 to 1999 LAG3 was discovered in 1990 by Frédéric Triebel (currently Chief Scientific Officer at Immutep) when he headed the cellular immunology group in the Department of Clinical Biology at the Institut Gustave Roussy. An initial characterization of the LAG-3 protein was reported in 1992 showing that it was a ligand for MHC class II antigens while a 1995 paper showed that it bound MHC Class II better than CD4. In 1996 INSERM scientists from Strasbourg showed, in knockout mice that were deficient in both CD4 and LAG-3, that the two proteins were not functionally equivalent. The first characterization of the MHC Class II binding sites on LAG-3 were reported by Triebel's group in 1997. The phenotype of LAG-3 knockout mice, as established by the INSERM Strasbourg group in 1996, demonstrated that LAG-3 was vital for the proper functioning of natural killer cells but in 1998 Triebel, working with LAG-3 antibodies and soluble protein, found that LAG-3 did not define a specific mode of natural killing. In May 1996, CD4+ T cells that were LAG-3+ were shown to preferentially express IFN-γ, which was up-regulated by IL-12. In 1997, it was demonstrated that IFN-γ production drives LAG-3 expression during the lineage commitment of human naive T cells. In 1998, further research showed that IFN-γ is not required for the expression but rather for the up-regulation of LAG-3. LAG-3 expression on activated human T cells is upregulated by IL-2, IL-7, and IL-12, and its expression may be controlled by CD4 regulatory elements. It was also found that LAG-3 down-modulates T cell proliferation and activation when LAG-3/MHC Class II co-caps with the CD3/TCR complex. This was confirmed in 1999 with co-capping experiments and fluorescence microscopy. In 1999, it was demonstrated that LAG-3 could be used as a cancer vaccine through cancer cell lines transfected with LAG-3.
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