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Common γ-chain cytokine (IL-2, IL-15, IL-7 and IL-21) signaling pathways, downstream effector molecules, and representative therapeutic candidates. (A) Common γ-chain cytokine (IL-2, IL-15, IL-7 and IL-21) signaling pathways and downstream effects. IL-2 and IL-15 are the only two of these cytokines to have three receptor chains. IL-2 exerts its biological function through high-affinity (IL-2Rαβγ) and intermediate-affinity (IL-2Rβγ) receptors. Engagement of IL-2 with IL-2Rαβγ strongly activates lymphocytes, driving beneficial effects on NK and T cells for development, increased effector function and enhanced B-cell function. The production of autocrine IL-2 can also lead to activation-induced cell death (AICD). Additionally, IL-2Rα is dramatically increased on Treg cells, so IL-2 is uniquely able to promote the expansion and development of immunosuppressive lymphocytes. IL-15 predominantly enhances the effector functions of NK and T lymphocytes without activating Treg cells. IL-7 primarily potentiates T-cell homeostasis, survival and thymic development, including both native and memory phenotypes. IL-21 dominantly promotes Th17 and Tfh differentiation and effector function and enhances the antitumor activity of CD8 + T and NK cells. (B, C) Representative therapeutic candidates of engineered IL-2 and IL-2 variants. (D-F) Representative therapeutic candidates of engineered IL-15, IL-7 and IL-21.

Journal: Frontiers in Immunology

Article Title: Engineering cytokines for cancer immunotherapy: a systematic review

doi: 10.3389/fimmu.2023.1218082

Figure Lengend Snippet: Common γ-chain cytokine (IL-2, IL-15, IL-7 and IL-21) signaling pathways, downstream effector molecules, and representative therapeutic candidates. (A) Common γ-chain cytokine (IL-2, IL-15, IL-7 and IL-21) signaling pathways and downstream effects. IL-2 and IL-15 are the only two of these cytokines to have three receptor chains. IL-2 exerts its biological function through high-affinity (IL-2Rαβγ) and intermediate-affinity (IL-2Rβγ) receptors. Engagement of IL-2 with IL-2Rαβγ strongly activates lymphocytes, driving beneficial effects on NK and T cells for development, increased effector function and enhanced B-cell function. The production of autocrine IL-2 can also lead to activation-induced cell death (AICD). Additionally, IL-2Rα is dramatically increased on Treg cells, so IL-2 is uniquely able to promote the expansion and development of immunosuppressive lymphocytes. IL-15 predominantly enhances the effector functions of NK and T lymphocytes without activating Treg cells. IL-7 primarily potentiates T-cell homeostasis, survival and thymic development, including both native and memory phenotypes. IL-21 dominantly promotes Th17 and Tfh differentiation and effector function and enhances the antitumor activity of CD8 + T and NK cells. (B, C) Representative therapeutic candidates of engineered IL-2 and IL-2 variants. (D-F) Representative therapeutic candidates of engineered IL-15, IL-7 and IL-21.

Article Snippet: N-803 (Inbakicept; ALT-803) , IL-15(N72D) bound to IL-15Rα sushi domain linked to IgG1-Fc domain; Locus mutation , Reconstituted and activated human NK cells , Solid tumours , BLA submitted , , ImmunityBio.

Techniques: Cell Function Assay, Activation Assay, Activity Assay

Characteristics of engineered IL-15 variants.

Journal: Frontiers in Immunology

Article Title: Engineering cytokines for cancer immunotherapy: a systematic review

doi: 10.3389/fimmu.2023.1218082

Figure Lengend Snippet: Characteristics of engineered IL-15 variants.

Article Snippet: N-803 (Inbakicept; ALT-803) , IL-15(N72D) bound to IL-15Rα sushi domain linked to IgG1-Fc domain; Locus mutation , Reconstituted and activated human NK cells , Solid tumours , BLA submitted , , ImmunityBio.

Techniques: Mutagenesis, Binding Assay, Recombinant