The cytokine interleukin-6 (IL-6) signals through three mechanisms called classic signaling, trans-signaling, and trans-presentation. IL-6 trans-signaling is distinctly mediated through a soluble form of its transmembrane receptor IL-6R (sIL-6R) and the coreceptor gp130 and is implicated in multiple autoimmune diseases. Although a soluble form of gp130 (sgp130) inhibits only IL-6 trans-signaling, it also blocks an analogous trans-signaling mechanism of IL-11 and its soluble receptor sIL-11R. Here, we report miniaturized chimeric soluble gp130 variants that efficiently trap IL-6:sIL-6R but not IL-11:sIL-11R complexes. We designed a novel IL-6 trans-signaling trap by fusing a miniaturized sgp130 variant to an IL-6:sIL-6R complex–binding nanobody and the Fc portion of immunoglobulin G (IgG). This trap, called cs-130Fc, exhibited improved inhibition of as well as increased selectivity for IL-6 trans-signaling compared to the conventional fusion protein sgp130Fc. We introduced affinity-enhancing mutations in cs-130Fc and sgp130Fc that further improved selectivity toward IL-6 trans-signaling. Moreover, cs-130Fc efficiently inhibited the expansion of T helper 17 (T_H17) cells in cultures of mouse CD4⁺ T cells treated with IL-6:sIL-6R. Thus, these variants may provide or lead to the development of more precisely targeted therapeutics for inflammatory disorders associated with IL-6 trans-signaling.

细胞因子白细胞介素 6 (IL-6) 通过三种机制发出信号，称为经典信号传导、反式信号传导和反式呈递。IL-6 反式信号传导明显通过其跨膜受体 IL-6R (sIL-6R) 和辅助受体 gp130 的可溶形式介导，并且与多种自身免疫性疾病有关。虽然可溶形式的 gp130 (sgp130) 仅抑制 IL-6 反式信号传导，但它也阻断 IL-11 及其可溶性受体 sIL-11R 的类似反式信号传导机制。在这里，我们报道了小型嵌合可溶性 gp130 变体，它能有效捕获 IL-6:sIL-6R 但不能捕获 IL-11:sIL-11R 复合物。我们通过将小型化的 sgp130 变体与 IL-6:sIL-6R 复合物结合纳米抗体和免疫球蛋白 G (IgG) 的 Fc 部分融合，设计了一种新型 IL-6 反式信号传导陷阱。与传统的融合蛋白 sgp130Fc 相比，这种名为 cs-130Fc 的陷阱对 IL-6 反式信号传导的抑制作用有所改善，选择性也有所提高。我们在 cs-130Fc 和 sgp130Fc 中引入了亲和力增强突变，进一步提高了对 IL-6 反式信号传导的选择性。此外，cs-130Fc 有效抑制用 IL-6:sIL-6R 处理的小鼠 CD4 ^{+ T 细胞培养物中 T 辅助细胞 17 (} _TH 17) 细胞的扩增。因此，这些变体可能为与IL-6反式信号转导相关的炎症性疾病提供或导致开发更精确的靶向疗法。