Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor.
Molecular Basis of Selective Cytokine Signaling Inhibition by Antibodies Targeting a Shared Receptor.
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DOI：
10.3389/fimmu.2021.779100
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发表时间：
2021
影响因子：
7.3
通讯作者：
Sundberg EJ
中科院分区：
文献类型：
--
作者：
Fields JK;Kihn K;Birkedal GS;Klontz EH;Sjöström K;Günther S;Beadenkopf R;Forsberg G;Liberg D;Snyder GA;Deredge D;Sundberg EJ
白细胞介素-1（IL-1）家族细胞因子是炎症的有效介质，起着协调对广泛刺激的局部和全身免疫应答的作用。然而，IL-1家族细胞因子成员的异常信号传导与无数炎症综合征、自身免疫性疾病和癌症有关。因此，阻断IL-1家族信号传导所固有的炎症信号是一种既定的和扩展的治疗策略。虽然存在几种FDA批准的IL-1抑制剂，包括Fc融合蛋白、中和抗体和拮抗剂细胞因子，但没有一种特异性靶向共受体IL-1受体辅助蛋白（IL-1 RAcP）。大多数IL-1家族细胞因子通过首先结合其同源受体- IL-1α和IL-1β的IL-1 RI; IL-33的ST 2;以及IL-36α、IL-36β和IL-36γ的IL-36 R-形成生产性信号传导复合物，之后它们募集共享的第二受体IL-1 RAcP以形成三元细胞因子/受体/共受体复合物。最近，IL-1 RAcP被确定为AML和CML的生物标志物。IL-1 RAcP也与实体瘤中的肿瘤进展有关，并且抗IL 1 RAP抗体（nadunolimab，CAN 04）处于胰腺癌和非小细胞肺癌的II期临床研究中（NCT 03267316）。由于IL-1 RAcP是所有上述IL-1家族细胞因子共有的，因此靶向该共受体提高了选择性抑制不同IL-1家族细胞因子的信号传导的可能性。事实上，先前对IL-1β和IL-33信号传导复合物的研究已经揭示，这些细胞因子采用不同的IL-1 RAcP募集机制，即使它们的总体细胞因子/受体/共受体复合物在结构上相似。在这里，使用功能，生物物理学和结构分析，我们表明，IL-1 RAcP特异性抗体可以通过IL-1家族细胞因子依赖于不同的IL-1 RAcP表位，他们从事差异阻断信号。我们的研究结果表明，针对共享的细胞因子受体是一个可行的治疗策略选择性细胞因子信号转导抑制。
Interleukin-1 (IL-1) family cytokines are potent mediators of inflammation, acting to coordinate local and systemic immune responses to a wide range of stimuli. Aberrant signaling by IL-1 family cytokine members, however, is linked to myriad inflammatory syndromes, autoimmune conditions and cancers. As such, blocking the inflammatory signals inherent to IL-1 family signaling is an established and expanding therapeutic strategy. While several FDA-approved IL-1 inhibitors exist, including an Fc fusion protein, a neutralizing antibody, and an antagonist cytokine, none specifically targets the co-receptor IL-1 receptor accessory protein (IL-1RAcP). Most IL-1 family cytokines form productive signaling complexes by binding first to their cognate receptors – IL-1RI for IL-1α and IL-1β; ST2 for IL-33; and IL-36R for IL-36α, IL-36β and IL-36γ – after which they recruit the shared secondary receptor IL-1RAcP to form a ternary cytokine/receptor/co-receptor complex. Recently, IL-1RAcP was identified as a biomarker for both AML and CML. IL-1RAcP has also been implicated in tumor progression in solid tumors and an anti-IL1RAP antibody (nadunolimab, CAN04) is in phase II clinical studies in pancreatic cancer and non-small cell lung cancer (NCT03267316). As IL-1RAcP is common to all of the abovementioned IL-1 family cytokines, targeting this co-receptor raises the possibility of selective signaling inhibition for different IL-1 family cytokines. Indeed, previous studies of IL-1β and IL-33 signaling complexes have revealed that these cytokines employ distinct mechanisms of IL-1RAcP recruitment even though their overall cytokine/receptor/co-receptor complexes are structurally similar. Here, using functional, biophysical, and structural analyses, we show that antibodies specific for IL-1RAcP can differentially block signaling by IL-1 family cytokines depending on the distinct IL-1RAcP epitopes that they engage. Our results indicate that targeting a shared cytokine receptor is a viable therapeutic strategy for selective cytokine signaling inhibition.