A native-like bispecific antibody suppresses the inflammatory cytokine response by simultaneously neutralizing tumor necrosis factor-alpha and interleukin-17A

被引：24

作者：

Xu, Tianshu ^{[1
]}

Ying, Tianlei ^{[2
]}

Wang, Lili ^{[2
]}

Zhang, Xiaohua Douglas ^{[3
]}

Wang, Ying ^{[4
]}

Kang, Lishan ^{[5
]}

Huang, Tao ^{[5
]}

Cheng, Liang ^{[5
]}

Wang, Liping ^{[1
]}

Zhao, Qi ^{[3
]}

机构：

[1] Jilin Univ, Sch Life Sci, Changchun, Jilin, Peoples R China

[2] Fudan Univ, Sch Basic Med Sci, Shanghai, Peoples R China

[3] Univ Macau, Fac Hlth Sci, Taipa, Macau, Peoples R China

[4] Univ Macau, Inst Chinese Med Sci, Taipa, Macau, Peoples R China

[5] Novo Nordisk Res Ctr China, Beijing, Peoples R China

来源：

ONCOTARGET | 2017年 / 8卷 / 47期

基金：

中国国家自然科学基金;

关键词：

bispecific antibody; Fc heterodimerization; TNF-alpha; IL-17; rheumatoid arthritis; Immunology and Microbiology Section; Immune response; Immunity; TARGETING NONOVERLAPPING EPITOPES; ARTHRITIS SYNOVIAL FIBROBLASTS; NF-KAPPA-B; RHEUMATOID-ARTHRITIS; IL-17; DISEASES; TNF; SYNOVIOCYTES; MOLECULES; THERAPY;

D O I：

10.18632/oncotarget.19899

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Anti-tumor necrosis factor (TNF) therapies are successful in the treatment of inflammatory disorders. However, some patients with rheumatoid arthritis (RA) fail to response anti-TNF drugs due to the compensation of other inflammatory signals. In this study, to reduce compensatory responses of interleukin-17A (IL-17A) during TNF-alpha inhibition, we generated an IgG-like bispecific antibodiy (bsAb) against TNF-alpha and IL-17A through a combination method of electrostatic Fc pairing and light chain crossover. This bsAb exhibited relatively high stability comparable to natural IgG antibodies, and retained the unaltered affinities to both of two targets. BsAb significantly decreased not only the expression level of neutrophil or Th17 chemokines, but also the secretion of IL-6/IL-8 on fibroblast-like synoviocytes (FLS) from a patient with RA. Meanwhile, TNF-alpha-mediated cellular cytotoxicity of fibroblasts was neutralized by bsAb. Importantly, we demonstrate that the combined blockade of TNF-alpha and IL-17A is more efficient than inhibition of either factor alone. Our results suggest the IgG-like anti-TNF-alpha/IL-17A bispecific molecule overcome the limited therapeutic responses using anti-TNF drugs. It may be a promising therapeutic agent for the treatment of autoimmune diseases.

引用

页码：81860 / 81872

页数：13

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