EGFR二聚体界面靶向单克隆抗体.doc

广东药学院硕士研究生学位论文 Monoclonal Antibodies Targeting The Dimer Interface of Epidermal Growth Factor Receptor Zhange Chen(pharmaceutics) Supervisor: professor HuangJing Li Abstract Epidermal growth factor receptor (EGFR) is one of the key members of the EGFR family, It is a transmembrane glycoprotein, including the extracellular domain that containing the ligand binding region, the transmembrane region and the intracellular domain that containing the tyrosine kinase active region. The statistical data represents that EGFR overexpressed in 30% of epithelial cancers, including non-small cell lung cancer, head and neck cancer, colorectal cancer, glioma, breast cancer, renal cancer, prostate cancer, ovarian cancer and gastric cancer,and sadly the kinds of cancer patients always associated with poor prognose, short survival and risestent to chemical therapy. So , EGFR is the attractive therapical target, also the first international cancermolecular target. There are the two very popular strategies for EGFR tumor : the EGFR monoclonal antibody targeting the extracellular domain and tyrosine kinase inhibitors against the intracellular domain .However, statistics demonstrates that both drugs have very low respose rate (about 10-30%),which is closely related to deletion or hypemutation of extracellular domain of EGFR and intracellular domain.The “dimerization” played a crucial role in the activation of the EGFR family in most case, furthermore, The interface region exposure which participates in dimerization mainly is a necessary for forming dimers ,and it is highly conservative, so targeting the dimer interface may promote the clinic response rates in the anti-EGFR therapeutic. Monoclonal antibody is the antibody targeting the single epitope, it is capable of specifically binding and killing of selective target cells. The experiments intended to preparate a class of murine monoclonal antibodies targeting the EGFR dimer interface , use the B cell epitope peptide-EGFR267-297that ou