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Anti-CD40 Antibodies Fused to CD40 Ligand Have Superagonist Properties
The Journal of Immunology ( IF 4.4 ) Pub Date : 2021-10-15 , DOI: 10.4049/jimmunol.2000704
Valentina Ceglia 1, 2, 3 , Sandra Zurawski 1, 3 , Monica Montes 1, 3 , Aurélie Bouteau 4, 5 , Zhiqing Wang 1, 3 , Jerome Ellis 1, 3 , Botond Z Igyártó 5 , Yves Lévy 2, 3 , Gerard Zurawski 3, 6
Affiliation  

CD40 is a potent activating receptor within the TNFR family expressed on APCs of the immune system, and it regulates many aspects of B and T cell immunity via interaction with CD40 ligand (CD40L; CD154) expressed on the surface of activated T cells. Soluble CD40L and agonistic mAbs directed to CD40 are being explored as adjuvants in therapeutic or vaccination settings. Some anti-CD40 Abs can synergize with soluble monomeric CD40L. We show that direct fusion of CD40L to certain agonistic anti-CD40 Abs confers superagonist properties, reducing the dose required for efficacy, notably greatly increasing total cytokine secretion by human dendritic cells. The tetravalent configuration of anti-CD40–CD40L Abs promotes CD40 cell surface clustering and internalization and is the likely mechanism of increased receptor activation. CD40L fused to either the L or H chain C termini, with or without flexible linkers, were all superagonists with greater potency than CD40L trimer. The increased anti-CD40–CD40L Ab potency was independent of higher order aggregation. Moreover, the anti-CD40–CD40L Ab showed higher potency in vivo in human CD40 transgenic mice compared with the parental anti-CD40 Ab. To broaden the concept of fusing agonistic Ab to natural ligand, we fused OX40L to an agonistic OX40 Ab, and this resulted in dramatically increased efficacy for proliferation and cytokine production of activated human CD4+ T cells as well as releasing the Ab from dependency on cross-linking. This work shows that directly fusing antireceptor Abs to ligand is a useful strategy to dramatically increase agonist potency.



中文翻译:

与 CD40 配体融合的抗 CD40 抗体具有超激动剂特性

CD40 是免疫系统 APC 上表达的 TNFR 家族中的一种有效激活受体,它通过与活化 T 细胞表面表达的 CD40 配体(CD40L;CD154)相互作用来调节 B 和 T 细胞免疫的许多方面。可溶性 CD40L 和针对 CD40 的激动性 mAb 正在探索作为治疗或疫苗接种环境中的佐剂。一些抗 CD40 抗体可以与可溶性单体 CD40L 协同作用。我们表明 CD40L 与某些激动性抗 CD40 Abs 的直接融合赋予了超激动剂特性,减少了疗效所需的剂量,特别是大大增加了人树突状细胞的总细胞因子分泌。抗 CD40–CD40L Abs 的四价构型促进 CD40 细胞表面聚集和内化,并且是增加受体激活的可能机制。与 L 或 H 链 C 末端融合的 CD40L,有或没有柔性接头,都是比 CD40L 三聚体具有更大效力的超激动剂。增加的抗 CD40-CD40L Ab 效力与高阶聚集无关。此外,与亲本抗 CD40 Ab 相比,抗 CD40-CD40L Ab 在人 CD40 转基因小鼠体内显示出更高的效力。为了拓宽将激动性抗体与天然配体融合的概念,我们将 OX40L 与激动性 OX40 Ab 融合,这导致活化的人类 CD4 的增殖和细胞因子产生的功效显着提高 与亲本抗 CD40 Ab 相比,抗 CD40–CD40L Ab 在人 CD40 转基因小鼠体内显示出更高的效力。为了拓宽将激动性抗体与天然配体融合的概念,我们将 OX40L 与激动性 OX40 Ab 融合,这导致活化的人类 CD4 的增殖和细胞因子产生的功效显着提高 与亲本抗 CD40 Ab 相比,抗 CD40–CD40L Ab 在人 CD40 转基因小鼠体内显示出更高的效力。为了拓宽将激动性抗体与天然配体融合的概念,我们将 OX40L 与激动性 OX40 Ab 融合,这导致活化的人类 CD4 的增殖和细胞因子产生的功效显着提高+ T 细胞以及从依赖交联中释放抗体。这项工作表明,将抗受体抗体与配体直接融合是一种显着提高激动剂效力的有用策略。

更新日期:2021-10-06
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