Structural analysis of the epitopes on erbB2 interacted with inhibitory or non-inhibitory monoclonal antibodies.
erbB2 oncogene encodes a growth factor receptor. The overexpression of erbB2 was correlated with more aggressive tumors and a poorer prognosis. Some antibodies directed to this molecule have an antitumor effect in vivo, but some antibodies do not. In an attempt to understand the molecular basis of the anti-erbB2 antibody interaction with erbB2 ectodomain (ECD), we analyzed binding epitopes on erbB2 for inhibitory and non-inhibitory antibodies, Herceptin and HF by computer-guided protein engineering and site-directed mutagenesis. Two different interaction domains were identified by molecular docking, computer graphics and distance geometry method and confirmed through studies on a series of mutants of erbB2 ECD. Non-inhibitory antibody HF only recognized N-terminal portion of erbB2 ECD, but inhibitory antibody Herceptin bound to C-terminal portion of it exclusively. The region interacted with inhibitory antibody Herceptin can be an important target for anticancer therapies.
Wang
J N
JN
Department of Molecular Immunology, Institute of Basic Medical Sciences, Taiping Road 27, Beijing 100850, PR China.
Feng
J N
JN
Yu
M
M
Xu
M
M
Shi
M
M
Zhou
T
T
Yu
X D
XD
Shen
B F
BF
Guo
N
N
D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology*; D061067:Antibodies, Monoclonal, Humanized; D001943:Breast Neoplasms / Q000276:immunology; D000939:Epitopes / Q000276:immunology*; D005260:Female; D017930:Genes, Reporter / Q000235:genetics / Q000276:immunology; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D020539:Sequence Analysis, Protein; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000939:Epitopes; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D000068878:Trastuzumab