工程化的人源细胞因子/抗体融合蛋白扩增调节性 T 细胞并赋予自身免疫性疾病保护。

Engineered human cytokine/antibody fusion proteins expand regulatory T cells and confer autoimmune disease protection.

机构信息

Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD 21218, USA; Translational Tissue Engineering Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.

Vascularized Composite Allotransplantation Laboratory, Department of Plastic and Reconstructive Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

出版信息

Cell Rep. 2022 Oct 18;41(3):111478. doi: 10.1016/j.celrep.2022.111478.

Low-dose human interleukin-2 (hIL-2) treatment is used clinically to treat autoimmune disorders due to the cytokine's preferential expansion of immunosuppressive regulatory T cells (Tregs). However, off-target immune cell activation and short serum half-life limit the clinical potential of IL-2 treatment. Recent work showed that complexes comprising hIL-2 and the anti-hIL-2 antibody F5111 overcome these limitations by preferentially stimulating Tregs over immune effector cells. Although promising, therapeutic translation of this approach is complicated by the need to optimize dosing ratios and by the instability of the cytokine/antibody complex. We leverage structural insights to engineer a single-chain hIL-2/F5111 antibody fusion protein, termed F5111 immunocytokine (IC), which potently and selectively activates and expands Tregs. F5111 IC confers protection in mouse models of colitis and checkpoint inhibitor-induced diabetes mellitus. These results provide a roadmap for IC design and establish a Treg-biased immunotherapy that could be clinically translated for autoimmune disease treatment.

低剂量人白细胞介素-2（hIL-2）治疗由于细胞因子优先扩增免疫抑制性调节性 T 细胞（Tregs），因此被临床用于治疗自身免疫性疾病。然而，由于细胞因子对免疫细胞的非靶向激活和血清半衰期短，限制了 IL-2 治疗的临床潜力。最近的研究表明，由 hIL-2 和抗 hIL-2 抗体 F5111 组成的复合物通过优先刺激 Tregs 而不是免疫效应细胞克服了这些限制。尽管这一方法很有前景，但由于需要优化剂量比以及细胞因子/抗体复合物的不稳定性，其治疗转化仍然很复杂。我们利用结构见解来设计一种称为 F5111 免疫细胞因子（IC）的单链 hIL-2/F5111 抗体融合蛋白，它能够有效地选择性激活和扩增 Tregs。F5111 IC 在结肠炎和检查点抑制剂诱导的糖尿病的小鼠模型中提供了保护。这些结果为 IC 设计提供了路线图，并建立了一种偏向 Treg 的免疫疗法，可用于治疗自身免疫性疾病。