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.

Related pathways

• MAPK/Erk and PI3K/Akt survival pathways
• LAG-3-MHC II pathway

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

Creative Biolabs offers a wide range of services designed to study immune checkpoints, including LAG-3. Our experienced service team provides the following services for worldwide customers.

• Custom Immune Checkpoint Protein Development
• Antibody Development for Immune Checkpoints
• Immune Checkpoint Targeted Peptide Development
• Immune Checkpoint Targeted Small Molecule Drug Development
• Biomarker Development for Immune Checkpoint Inhibitor (ICI)
• Immune Checkpoint Assays
• Preclinical Research for Immune Checkpoint Targeting Drugs

For any questions, please feel free to contact us for more information.

References

1. Goldberg, M.V.; et al. LAG-3 in cancer immunotherapy. Cancer Immunology and Immunotherapy. 2010, pp.269-278.
2. Solinas, C.; et al. LAG-3: the biological processes that motivate targeting this immune checkpoint molecule in human cancer. Cancers. 2019, 11(8), p.1213.

All listed customized services & products are for research use only, not intended for pharmaceutical, diagnostic, therapeutic, or any in vivo human use.