8SOZ

Structure of the complex formed by human interleukin-2 and scFv 602

8SOZ の概要

• エントリーDOI: 10.2210/pdb8soz/pdb
• 関連するPDBエントリー: 8SOW
• 分子名称: 602 single chain fragment variable, Interleukin-2 (3 entities in total)
• 機能のキーワード: complex, antibody, interleukin, cytokine
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 41289.68

構造登録者

Gould, J.R.,Leonard, E.K.,Cao, S.D.,Spangler, J.B. (登録日: 2023-04-30, 公開日: 2024-09-04, 最終更新日: 2024-10-16)

主引用文献

Leonard, E.K.,Tomala, J.,Gould, J.R.,Leff, M.I.,Lin, J.X.,Li, P.,Porter, M.J.,Johansen, E.R.,Thompson, L.,Cao, S.D.,Hou, S.,Henclova, T.,Huliciak, M.,Sargunas, P.R.,Fabilane, C.S.,Vanek, O.,Kovar, M.,Schneider, B.,Raimondi, G.,Leonard, W.J.,Spangler, J.B.
Engineered cytokine/antibody fusion proteins improve IL-2 delivery to pro-inflammatory cells and promote antitumor activity.
JCI Insight, 9:-, 2024

PubMed Abstract: Progress 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.

PubMed: 39115939
DOI: 10.1172/jci.insight.173469

実験手法

X-RAY DIFFRACTION (1.64 Å)