Cutting Edge: Mechanism of Enhancement of In Vivo Cytokine Effects by Anti-Cytokine Monoclonal Antibodies1
Cutting Edge: Mechanism of Enhancement of In Vivo Cytokine Effects by Anti-Cytokine Monoclonal Antibodies1
复制标题
最前沿：抗细胞因子单克隆抗体增强体内细胞因子效应的机制1
作者：
J. Phelan;Tatyana Orekov;F. Finkelman
抑制性抗细胞因子mAb用于治疗马槟榔碱介导的病症。然而，最近，S4 B6（一种阻断IL-2与IL-2 R α结合的抗IL-2 mAb，IL-2 R α是一种增强亲和力但不是信号传导所需的受体组分）被证明可增强体内IL-2激动剂效应。我们评估了S4 B6如何增强IL-2的作用，以及是否有类似的机制允许IL-4的mAb增强IL-4的作用。IL-2/S4 B6复合物诱导T细胞增殖不需要复合物解离，并且不依赖于IL-2 R α。S4 B6通过增加体内半衰期而不是通过Fc受体将IL-2聚集到细胞上来增加IL-2激动剂效应。与IL-2/S4 B6复合物相反，抗IL-4 mAb增强体内IL-4效应需要IL-4/抗IL-4 mAb复合物解离。因此，在高剂量抗IL-2 mAb中观察到的激动剂效应很可能仅适用于维持细胞因子半衰期而不阻断与受体信号传导组分结合的mAb。
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-2Rα, 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-2Rα 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.