Structural basis for tumor necrosis factor blockade with the therapeutic antibody golimumab
Structural basis for tumor necrosis factor blockade with the therapeutic antibody golimumab
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DOI：
10.1002/pro.3407
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发表时间：
2018-06-01
期刊：
影响因子：
8
通讯作者：
Nomura, Norimichi
中科院分区：
文献类型：
--
作者：
Ono, Masatsugu;Horita, Shoichiro;Nomura, Norimichi
肿瘤坏死因子是一种促炎细胞因子，血清中肿瘤坏死因子水平的升高与多种自身免疫性疾病有关，包括类风湿性关节炎(RA)、强直性脊柱炎(AS)、克罗恩病(CD)、银屑病和系统性红斑狼疮。肿瘤坏死因子通过与两种结构不同的跨膜受体--肿瘤坏死因子受体(TNFR)1和TNFR2结合来发挥其多效性。基于抗体的治疗策略，阻断过多的肿瘤坏死因子信号，已被证明在抑制这种有害的炎症条件方面是有效的。Golimumab(Simponi(R))是FDA批准的针对肿瘤坏死因子的全人单抗，已被广泛用于治疗RA、AS和CD。然而，Golimumab抑制作用的结构基础仍不清楚。在这里，我们报道了Golimumab的Fv片段与肿瘤坏死因子的络合物的晶体结构，分辨率为2.73埃。分辨结构表明，Golimumab与肿瘤坏死因子上的一个不同的表位结合，该表位不与TNFR2的结合残基重叠。Golimumab通过空间位阻阻止TNFR1和TNFR2与肿瘤坏死因子的结合而发挥其抑制作用。Golimumab不会引起可能影响受体结合的肿瘤坏死因子的构象变化。在目前批准用于临床的四种抗肿瘤坏死因子治疗性抗体中，这种作用模式是针对Golimumab的。
Tumor necrosis factor (TNF) is a proinflammatory cytokine, and elevated levels of TNF in serum are associated with various autoimmune diseases, including rheumatoid arthritis (RA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis, and systemic lupus erythaematosus. TNF performs its pleiotropic functions by binding to two structurally distinct transmembrane receptors, TNF receptor (TNFR) 1 and TNFR2. Antibody-based therapeutic strategies that block excessive TNF signaling have been shown to be effective in suppressing such harmful inflammatory conditions. Golimumab (Simponi (R)) is an FDA-approved fully human monoclonal antibody targeting TNF that has been widely used for the treatment of RA, AS, and CD. However, the structural basis underlying the inhibitory action of golimumab remains unclear. Here, we report the crystal structure of the Fv fragment of golimumab in complex with TNF at a resolution of 2.73 angstrom. The resolved structure reveals that golimumab binds to a distinct epitope on TNF that does not overlap with the binding residues of TNFR2. Golimumab exerts its inhibitory effect by preventing binding of TNFR1 and TNFR2 to TNF by steric hindrance. Golimumab does not induce conformational changes in TNF that could affect receptor binding. This mode of action is specific to golimumab among the four anti-TNF therapeutic antibodies currently approved for clinical use.