Phelan James D, Orekov Tatyana, Finkelman Fred D
Immunobiology Graduate Program, University of Cincinnati College of Medicine, and Division of Immunobiology, Children's Hospital Medical Research Foundation, Cincinnati, OH 45267, USA.
J Immunol. 2008 Jan 1;180(1):44-8. doi: 10.4049/jimmunol.180.1.44.
Inhibitory anti-cytokine mAbs are used to treat cytokine-mediated disorders. Recently, however, S4B6, an anti-IL-2 mAb that blocks IL-2 binding to IL-2Ralpha, a receptor component that enhances affinity but is not required for signaling, was shown to enhance IL-2 agonist effects in vivo. We evaluated how S4B6 enhances IL-2 effects and whether a similar mechanism allows mAbs to IL-4 to enhance IL-4 effects. Induction of T cell proliferation by IL-2/S4B6 complexes did not require complex dissociation and was IL-2Ralpha independent. S4B6 increased IL-2 agonist effects by increasing in vivo half-life, not by focusing IL-2 onto cells through Fc receptors. In contrast to IL-2/S4B6 complexes, anti-IL-4 mAb enhancement of in vivo IL-4 effects required IL-4/anti-IL-4 mAb complex dissociation. Thus, agonist effects observed with high doses of anti-IL-2 mAb are most likely only applicable for mAbs that maintain cytokine half-life without blocking binding to receptor signaling components.
抑制性抗细胞因子单克隆抗体用于治疗细胞因子介导的疾病。然而，最近有研究表明，S4B6作为一种抗IL-2单克隆抗体，可阻断IL-2与IL-2Rα的结合，IL-2Rα是一种增强亲和力但对信号传导并非必需的受体成分，在体内却能增强IL-2激动剂的作用。我们评估了S4B6如何增强IL-2的作用，以及类似的机制是否能使抗IL-4单克隆抗体增强IL-4的作用。IL-2/S4B6复合物诱导T细胞增殖并不需要复合物解离，且不依赖于IL-2Rα。S4B6通过延长体内半衰期来增强IL-2激动剂的作用，而非通过Fc受体将IL-2聚焦于细胞上。与IL-2/S4B6复合物不同，抗IL-4单克隆抗体增强体内IL-4作用需要IL-4/抗IL-4单克隆抗体复合物解离。因此，高剂量抗IL-2单克隆抗体所观察到的激动剂作用很可能仅适用于那些在不阻断与受体信号成分结合的情况下维持细胞因子半衰期的单克隆抗体。
