Comparison of the inhibition mechanisms of adalimumab and infliximab in treating tumor necrosis factor α-associated diseases from a molecular view.
TNFα-targeting therapy with the use of the drugs Etanercept, Infliximab, and Adalimumab is used in the clinical treatment of various inflammatory and immune diseases. Although all of these reagents function to disrupt the interaction between TNFα and its receptors, clinical investigations showed the advantages of Adalimumab treatment compared with Etanercept and Infliximab. However, the underlying molecular mechanism of action of Adalimumab remains unclear. In our previous work, we presented structural data on how Infliximab binds with the E-F loop of TNFα and functions as a TNFα receptor-binding blocker. To further elucidate the variations between TNFα inhibitors, we solved the crystal structure of TNFα in complex with Adalimumab Fab. The structural observation and the mutagenesis analysis provided direct evidence for identifying the Adalimumab epitope on TNFα and revealed the mechanism of Adalimumab inhibition of TNFα by occupying the TNFα receptor-binding site. The larger antigen-antibody interface in TNFα Adalimumab also provided information at a molecular level for further understanding the clinical advantages of Adalimumab therapy compared with Infliximab.
Laboratory of Structural Biology and Ministry of Education Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing 100084, China; International Joint Cancer Institute, Second Military Medical University, Shanghai 200433, China.
Shi
S
Hu
Laboratory of Structural Biology and Ministry of Education Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing 100084, China.
Shuaiyi
S
Liang
International Joint Cancer Institute, Second Military Medical University, Shanghai 200433, China; National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai 201203, China; People's Liberation Army (PLA) General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing 100853, China.
Huaizu
H
Guo
International Joint Cancer Institute, Second Military Medical University, Shanghai 200433, China; National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai 201203, China; People's Liberation Army (PLA) General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing 100853, China.
Dapeng
D
Zhang
People's Liberation Army (PLA) General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing 100853, China.
Hui
H
Li
School of Medicine, Nankai University, Tianjin 300071, China.
Xiaoze
X
Wang
School of Medicine, Nankai University, Tianjin 300071, China.
Weili
W
Yang
International Joint Cancer Institute, Second Military Medical University, Shanghai 200433, China; National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai 201203, China; People's Liberation Army (PLA) General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing 100853, China.
Weizhu
W
Qian
International Joint Cancer Institute, Second Military Medical University, Shanghai 200433, China; National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai 201203, China; People's Liberation Army (PLA) General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing 100853, China.
Sheng
S
Hou
International Joint Cancer Institute, Second Military Medical University, Shanghai 200433, China; National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai 201203, China; People's Liberation Army (PLA) General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing 100853, China.
Hao
H
Wang
International Joint Cancer Institute, Second Military Medical University, Shanghai 200433, China; National Engineering Research Center for Antibody Medicine and Shanghai Key Laboratory of Cell Engineering & Antibody, Shanghai 201203, China; People's Liberation Army (PLA) General Hospital Cancer Center, PLA Postgraduate School of Medicine, Beijing 100853, China; School of Medicine, Nankai University, Tianjin 300071, China. Electronic address: yjguo@smmu.edu.cn.
Yajun
Y
Guo
Laboratory of Structural Biology and Ministry of Education Laboratory of Protein Science, School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: louzy@xtal.tsinghua.edu.cn.
Zhiyong
Z
Lou
D000068879:Adalimumab; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000627:therapeutic use; D001666:Binding Sites, Antibody; D018360:Crystallography, X-Ray; D006801:Humans; D000069285:Infliximab; D008958:Models, Molecular; D016296:Mutagenesis; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab
Adalimumab; Antibodies; Autoimmune Diseases; Crystal Structure; Epitope; Mechanism; Protein Targeting; Tumor Necrosis Factor (TNF)