A recombinational human derived bispecific c-Met/PD-1 antibody therapeutic potential in cancer

来源 :中国生物化学与分子生物学会2016年全国学术会议 | 被引量 : 0次 | 上传用户:zhangfegnlin
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  The bispecific antibody is a novel antibody,which can combine two different antigens or epitopes and mediate specific killin g effect by selectively raising the effector clls into the target cells closely.Hepatocyte growth factor receptor,HGFR,is a sing le pass tyrosine kinase receptor,RTK,encoded by the c‐MET proto‐oncogene.C‐MET was abnormally activated in man y tumors,responsible for tumor proliferation,invasion and metastasis.PD‐1,also known as Programmed cell death protein 1,is expressed on T cells and pro‐B cells.Upon binding to its ligands,PD‐1 can prevent T‐cells from activation.Here,we d esign and synthetize a bispecific antibody(BsAb)targeting c‐Met and programmed death‐1(PD‐1),which can bind to huma n c‐Met and PD‐1 with high affinity and specificity.We found that it can induce the degradation of c‐Met protein in cance r cells,including MKN45,a gastric cancer cell line,and A549,a lung cancer cell line.BsAb affects hepatocyte growth factor(HGF)mediating proliferation,migration,apoptosis and downregulates HGF‐stimulated the phosphorylation of c‐Met,AK T,and ERK1/2.BsAb can also rescue T cell activation,such as promoting T cell secretion IL‐2 and IFN‐γ.Furthermore,xenog raft analysis revealed that BsAb markedly inhibits the growth of subcutaneouly implanted tumors and chronic inflammation.On the basis of these results,we identified a potential drug efficacy of BsAb engaging c‐Met and PD‐1 in therapy of human cancers.
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