Interleukin-21 (IL-21) is an immunostimulatory cytokine that belongs to the common gamma-chain cytokine family. It plays an important role in the development, differentiation, proliferation, and activation of immune cells, particularly T cells and natural killer (NK) cells. IL-21 has been shown to regulate adaptive and immune responses and play a key role in antiviral and antitumor responses.
Sources and cellular targets of IL-21
IL-21 is primarily produced by natural killer T (NKT) cells, follicular helper T cells (TFH) and TH17 cells, with other CD4 and CD8 cells also secreting lower levels of IL-21. IL-21 can regulate the proliferation, maturation and activation of many cells, including T cells, natural killer T cells, natural killer (NK) cells, B cells, monocytes, macrophages and dendritic cells (DCS), keratinocytes and intestinal fibroblasts.
(Data source: Spolski R, et al. Nat Rev Drug Discov. 2014)
Structure of IL-21
The IL-21 gene is located on chromosome 4q26-q27.12. IL-21 has 131 amino acids and is composed of four α-helical bundles. The IL-21 receptor (IL-21R) is a heterodimer composed of the IL21Rα protein and the γ chain. Binding of IL-21 to its receptor forms a ternary complex, with IL-21 binding to the IL-21R D1 domain via its A and C helices.
(Data source: Abhiraman GC, et al. Cell Rep. 2023)
IL-21 signaling pathway and regulation:
Binding of IL-21 to the IL21R receptor complex activates downstream signaling pathways, leading to the activation of Janus kinase 1 (JAK1) and JAK3, which in turn leads to the recruitment and phosphorylation of signal transducer and activator of transcription (STAT) proteins (primarily STAT3, but also STAT1 and STAT5). These STAT proteins dimerize, enter the nucleus, and activate transcriptional programs. IL-21 binding to the IL-21R also activates the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. IL-21 induces the transcription of suppressor of cytokine signaling 1 (SOCS1) and SOCS3 proteins, thereby downregulating the JAK-STAT pathway.
(Data source: Spolski R, et al. Nat Rev Drug Discov. 2014)
Clinical application of IL-21
IL-21 may play an important role in inhibiting tumor angiogenesis. IL-21's ability to regulate various immune cells and its angiostatic properties give this cytokine a potent ability to drive tumor cell clearance. Numerous studies have demonstrated that IL-21 can enhance anti-tumor responses mediated by CD8+ T cells, NK cells, and B cells. Currently, IL-21 is primarily used in cancer treatment through various approaches, including recombinant proteins, fusion proteins, combination therapies, and oncolytic viruses. While clinical research is ongoing, no approved drug has yet been developed.
(Data source: Isvoranu G, et al. Front Immunol. 2024)
The bifunctional protein αCD20-IL-21, obtained by fusing IL-21 to the anti-CD20 antibody rituximab, has shown superior anticancer potential compared to its individual components. In addition to stabilizing and extending the half-life of IL-21, αCD20-IL-21 also enhances IL-21R-mediated signaling, leading to direct lymphoma cell cytotoxicity and increased NK cell-mediated cytotoxicity.
By fusing the IL-21 protein and the C-terminus of the anti-PD-1 antibody, a bifunctional protein drug, Latikafusp, is obtained for the treatment of advanced malignant solid tumors and is currently in Phase 1 clinical trials.
(Data source: New Drug Intelligence Database)
