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Structure of the complex formed by human interleukin-2 and scFv 602
Structural highlights
DiseaseIL2_HUMAN Note=A chromosomal aberration involving IL2 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(4;16)(q26;p13) with involves TNFRSF17. FunctionIL2_HUMAN Produced by T-cells in response to antigenic or mitogenic stimulation, this protein is required for T-cell proliferation and other activities crucial to regulation of the immune response. Can stimulate B-cells, monocytes, lymphokine-activated killer cells, natural killer cells, and glioma cells. Publication Abstract from PubMedProgress in cytokine engineering is driving therapeutic translation by overcoming these proteins' limitations as drugs. The interleukin-2 (IL-2) cytokine is a promising immune stimulant for cancer treatment but is limited by its concurrent activation of both pro-inflammatory immune effector cells and anti-inflammatory regulatory T cells, toxicity at high doses, and short serum half-life. One approach to improve the selectivity, safety, and longevity of IL-2 is complexation with anti-IL-2 antibodies that bias the cytokine towards immune effector cell activation. Although this strategy shows potential in preclinical models, clinical translation of a cytokine/antibody complex is complicated by challenges in formulating a multi-protein drug and concerns regarding complex stability. Here, we introduced a versatile approach to designing intramolecularly assembled single-agent fusion proteins (immunocytokines, ICs) comprising IL-2 and a biasing anti-IL-2 antibody that directs the cytokine towards immune effector cells. We optimized IC construction and engineered the cytokine/antibody affinity to improve immune bias. We demonstrated that our IC preferentially activates and expands immune effector cells, leading to superior antitumor activity compared to natural IL-2, both alone and combined with immune checkpoint inhibitors. Moreover, therapeutic efficacy was observed without inducing toxicity. This work presents a roadmap for the design and translation of cytokine/antibody fusion proteins. Engineered cytokine/antibody fusion proteins improve IL-2 delivery to pro-inflammatory cells and promote antitumor activity.,Leonard EK, Tomala J, Gould JR, Leff MI, Lin JX, Li P, Porter MJ, Johansen ER, Thompson L, Cao SD, Hou S, Henclova T, Huliciak M, Sargunas PR, Fabilane CS, Vanek O, Kovar M, Schneider B, Raimondi G, Leonard WJ, Spangler JB JCI Insight. 2024 Aug 8:e173469. doi: 10.1172/jci.insight.173469. PMID:39115939[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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