LAG-3 Immune Checkpoint Molecule for Drug Development
LAG-3 Basic Structure
Lymphocyte activation gene 3 (LAG-3, CD223) is a transmembrane protein with four extracellular IgG domains. The membrane-distal IgG domain contains a short amino acid sequence (extra loop) that is not found in other IgG superfamily proteins. The intracellular domain has a unique amino acid sequence (KIEELE) required for LAG-3 to exert a negative effect on T cell function. LAG-3 can be cleaved at the connecting peptide (CP) by metalloproteases to generate a soluble form, detectable in serum.
Fig.1 LAG-3 structure. (Goldberg, 2010)
LAG-3 Expression and Its Ligands
As an emerging targetable inhibitory immune checkpoint molecule, the LAG-3 receptor is expressed on activated human CD4+ and CD8+ T cells, a subset of natural killer (NK) cells, T cells, and murine plasmacytoid dendritic cells (DCs). LAG-3 principally interacts with major histocompatibility complex class II (MHC-II) molecules as its ligand, expressed on the surface of antigen-presenting cells (APCs) and tumor cells. Other potential LAG-3 ligands include:
Liver sinusoidal endothelial cell lectin (LSECtin), a member of the DC-SIGN family.
Galectin-3, expressed by stromal cells and CD8+ T cells.
α-synuclein in neurons.
Fibrinogen-like protein 1, released in the liver (at low levels) and by tumor cells.
Fig.2 Molecular mechanisms of LAG-3 function. (Solinas, 2019)
Function of LAG-3
LAG-3 plays an important role in T cell proliferation and activation as a negative regulator of these processes. Along with other inhibitory receptors, LAG-3 helps to keep cytotoxic CD8+ T cells in an exhausted state during highly inflammatory environments such as a chronic viral infection. LAG-3 has also been implicated in memory T cell expansion, Treg function, and the activation and maturation of dendritic cells. For immune-oncologic applications, two main strategies are being employed in targeting LAG-3:
Use of a soluble dimeric Fc-fusion protein consisting of four LAG-3 extracellular domains. This strategy is intended to activate antigen-presenting cells.
Use of antagonistic antibodies against LAG-3. This strategy is akin to the typical checkpoint inhibitor strategies employed with PD-1/PD-L1 blockade.
Clinical Development of LAG-3 Targeted Immunotherapy
There are currently four LAG-3 modulating agents that have entered the clinic as anti-cancer therapeutics, with several more in preclinical development. Three different LAG-3-specific mAbs have been developed for the treatment of cancer. A fourth anti-LAG-3 antagonistic mAb is designed to deplete LAG-3+ expressing cells in patients with autoimmune diseases.
Services at Creative Biolabs
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