Abstract
Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family of receptor tyrosine kinases that play important roles in all processes of cell development. Their overexpression is related to many cancers, including examples in the breast, ovaries and stomach. Anticancer therapies targeting the HER2 receptor have shown promise, and monoclonal antibodies against subdomains II and IV of the HER2 extra-cellular domain (ECD), Pertuzumab and Herceptin, are currently used in treatments for some types of breast cancers. Since anti HER2 antibodies targeting distinct epitopes have different biological effects on cancer cells; in this research linear and conformational B cell epitopes of HER2 ECD, subdomain III, were identified by bioinformatics analyses using a combination of linear B cell epitope prediction web servers such as ABCpred, BCPREDs, Bepired, Bcepred and Elliprro. Then, Discotope, CBtope and SUPERFICIAL software tools were employed for conformational B cell epitope prediction. In contrast to previously reported epitopes of HER2 ECD we predicted conformational B cell epitopes P1C: 378-393 (PESFDGDPASNTAPLQ) and P2C: 500-510 (PEDECVGEGLA) by the integrated strategy and and P4: PESFDGD-X-TAPLQ; P5: PESFDGDP X TAPLQ; P6: ESFDGDP X NTAPLQP; P7: PESFDGDP-X-NTAPLQ; P8: ESFDG-XX-TAPLQPEQL and P9: ESFDGDP- X-NTAPLQP by SUPERFICIAL software. These epitopes could be further used as peptide antigens to actively immune mice for development of new monoclonal antibodies and peptide cancer vaccines that target different epitopes or structural domains of HER2 ECD.
Highlights
Human epidermal growth factor receptor 2 (HER2), known as ErbB2, c-erbB2 or HER2/neu, is a 185 kDa protein (p185) involved in signal transduction as well as regulating cell growth
Since anti HER2 antibodies targeting distinct epitopes have different biological effects on cancer cells; in this research linear and conformational B cell epitopes of HER2 extra-cellular domain (ECD), subdomain III, were identified by bioinformatics analyses using a combination of linear B cell epitope prediction web servers such as ABCpred, BCPREDs, Bepired, Bcepred and Elliprro
Diagnosed without treatment Newly diagnosed with treatment Persistence or recurrence Remission None Chemotherapy related to subdomain III of HER2 ECD
Summary
Human epidermal growth factor receptor 2 (HER2), known as ErbB2, c-erbB2 or HER2/neu, is a 185 kDa protein (p185) involved in signal transduction as well as regulating cell growth. More studies in clinical application showed that Patients who have had a significant therapeutic effect by Herceptin treatment started to appear the drug resistant (Calabrich et al, 2008) These results urge researchers to conduct more investigations and develop novel humanized recombinant MAbs for HER2. MAb muA21 was found inhibited the growth of the human breast cancer SK-BR-3 cells and MAb CH401 had cytotoxity against HER2 expressing tumor cells These MAbs were targeted the subdomain I of HER2 ECD. The identification of B-cell epitopes for subdomain III of HER2 ECD can provide important information for the development of new MAb and cancer vaccines that target different epitopes or structural domains of HER2 ECD. We used SUPERFICIAL software that based on protein structures and generates library proposals including linear and nonlinear peptides
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