Fu W.,Chinese PLA General Hospital |
Fu W.,International Medical University |
Fu W.,Tianjin Joint Academy of Biomedicine and Technology |
Wang X.,Nagoya University |
And 14 more authors.
Amino Acids | Year: 2015
Abstract Previously, we reported on the crystal structures of the Fab fragments of two food and drug administration approved therapeutic antibodies, Infliximab and Adalimumab, in complex with TNFα. The structurally identified epitopes on TNFα reveal the mechanism of TNFα inhibition by partially overlapping with the TNFα-receptor interface. In this study, we launched a screen of a phage display library to isolate novel anti-TNFα antibodies based on the adalimumab epitope. Structural analysis, the phage display antibody isolation technology, step-by-step antibody optimization, complementarity-determining region residues random mutagenesis, phage ELISA, binding affinity characterization, and cell signaling assays were used for the development and optimization of the novel anti-TNFα antibodies. Moreover, one of the novel antibodies, hAta09, has a superior inhibitory effect on TNFα function and signaling. Taken together, our report established that the novel anti-TNFα antibody hAta09 may achieve clinical efficacy in a TNFα-associated disease. © 2015 Springer-Verlag Wien.
Hu S.,International Medical University |
Hu S.,Cancer Center |
Hu S.,Tianjin Joint Academy of Biomedicine and Technology |
Dai H.,Nanjing University |
And 11 more authors.
Cancer Letters | Year: 2015
Dysfunction of the epidermal growth factor receptor (EGFR) family, is the key process in tumorigenesis, and anti-EGFR therapeutic strategies such as cetuximab therapy now are used in the treatment of cancer. However, resistance to cetuximab is commonly reported. Comprehensive blockade of EGFR signaling using different antibodies might be critical to treat cancer effectively and limit drug resistance with potent novel mechanisms. Here, we launch a screen of a phage display library to isolate a novel anti-EGFR antibody, YAH627. YAH627 exhibits superior efficacy in inhibiting EGFR activation, particularly by blocking EGF/HRG-induced EGFR/HER3 heterodimerization and signaling, verifying it as an impressive candidate for clinical translation as a therapeutic antibody. Moreover, we use epitope analysis validates that the epitope of this antibody is within domains II and IV of EGFR and traps EGFR in a silent conformation. Moreover, combining YAH627 with cetuximab produces synergistic antitumor activity in vitro and in vivo. Taken together, our report establishes that YAH627 possesses a novel mechanism of action that, in combination with cetuximab, may achieve clinical efficacy in EGFR-driven cancers. © 2014 Elsevier Ireland Ltd.