June 27, 2022

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LAG-3 antibody project ushered in major benefits

LAG-3 antibody project ushered in major benefits

 


LAG-3 antibody project ushered in major benefits.  On March 25, 2021, Bristol-Myers Squibb (BMS) announced the preliminary results of Phase 2/3 RELATIVITY-047 (CA224-047) trial, which evaluated the immobilization of anti-LAG-3 antibodies relatlimab and Opdivo (nivolumab) Preliminary results of the dose combination and Opdivo alone in the treatment of previously untreated patients with metastatic or unresectable melanoma.

The trial reached the primary endpoint of progression-free survival (PFS). Follow-up of overall survival rate (secondary endpoint) is ongoing. The fixed-dose combination was well tolerated, and no new safety signals were found in the relatlimab and Opdivo combination group or the Opdivo group. Relatlimab is the third different checkpoint inhibitor of BMS (anti-PD-1, anti-CTLA-4 and anti-LAG-3). The results of this study indicate that targeting the LAG-3 pathway combined with PD-1 inhibition may be a key strategy to enhance the immune response and help improve the prognosis of patients with melanoma.

Among the checkpoint inhibitory receptors, lymphocyte activation gene-3 (LAG-3, CD223) is the primary target after PD-1. LAG-3 is a type I transmembrane protein with four Ig-like domains. LAG-3 is highly glycosylated and has multiple N-glycosylation sites in D2-D4. Galectin-3 and hepatic sinusoidal endothelial cell lectin (LSECtin) are believed to interact with LAG-3 glycans.

LAG-3 antibody project ushered in major benefits


Like PD-1 and CTLA-4, LAG-3 is not expressed on primitive T cells, but can be induced to express on CD4+ and CD8+ T cells under antigen stimulation. Since the inhibitory function of LAG-3 is closely related to its expression level on the cell surface, the regulation of LAG-3 expression is very critical. LAG-3 is also expressed in CD4+ T cell subsets with inhibitory function. Treg cells structurally express LAG-3. LAG-3 is also expressed on CD4+1 type regulatory T cells (Tr1) and naturally regulated plasma cells that produce IL-10. LAG-3 is outside of these non-classical regulatory cells. The role of inhibitory function is still unclear, and further research is needed. In addition, LAG-3 is expressed on NK cells, B cells and plasmacytoid dendritic cells.

LAG-3 antibody project ushered in major benefits


LAG-3 is expressed on failed CD4+ and CD8+ tumor-infiltrating T cells. These T cells are also expressed in the peripheral blood and tumor tissues of patients with melanoma and colorectal cancer. This LAG-3 expressing Treg cells produce high levels The immunomodulatory cytokines IL-10 and TGF-β, and inhibit tumor-specific T cells. For a long time, the expression level of LAG-3 and LAG-3+ cell infiltration in tumors have been associated with tumor progression, poor prognosis and various types of human tumors. These results strongly indicate that LAG-3 is involved in a tumor immune escape mechanism similar to PD-1. Therefore, targeting LAG-3 is considered a very promising direction for tumor immunotherapy.

At present, there are many companies deploying this target, and the clinical advancement speed is also very fast. In addition to BMS, Sanofi, Novartis, Roche and domestic Cinda, Hengrui have projects in the clinical stage. With the success of BMS, it is estimated that other companies will accelerate the development of this target.

 

 

 

(source:internet, reference only)


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