MOE_HumanizedAntibodyDesign_2012

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1、人源化抗体设计HumanizedAntibodyDesignTaoHuang黄韬MolecularOperatingEnvironment康昱盛信息科技有限公司

2、CloudScientificTechnologyCo.LtdMOECopyright©2012CloudScientificAllRightsReserved.治疗性抗体TherapeuticAntibody▪杂交瘤抗体Hybridomasantibody人源免▪嵌合抗体Chimericantibody抗体疫序列原▪人源化抗体Humanizedantibody相似性度▪全人源抗体Fullyhumanantibody左上

3、：杂交瘤抗体MolecularOperatingEnvironment右上：嵌合抗体左下：人源化抗体下中：嵌合/人源化抗体右下：全人源化抗体MOECopyright©2012CloudScientificAllRightsReserved.上市抗体药RegulatoryApprovedAntibody▪FDA批准了近30种治疗性抗体药物▪治疗性抗体药物目前的年销售额大约在500亿美金，到2014年，该市场有望达到1000亿美金，增长势头十分迅猛名称Name类型Type上市时间备注RemarkTimeonMarketmuromomabhybridomas1986Thefirstap

4、provedtherapeuticantibodyabciximabchimeric1994Thefirstchimericfabrituximabchimeric1997ThefirstfulllengthchimericantibodyMolecularOperatingEnvironmentdaclizumabhumanized1997Thefirsthumanizedantibodyinfliximabchimeric1998trastuzumabhumanized1998adalimumabfullyhuman2002Thefirstfullyhumanantibody

5、MOEbevacizumabhumanized2004BeckA,etal.NatureReviews.2010Copyright©2012CloudScientificAllRightsReserved.已批准的人源化抗体药HumanizedAntibodyApprovedFDAApprovedFrom1986From2000Total:30Total:22Humanized:13Humanized:10MolecularOperatingEnvironmentMOECopyright©2012CloudScientificAllRightsReserved.人源化抗体Hum

6、anizedAntibody人源化抗体之目标在于通过基因工程方法增加与人类自然产生抗体的序列相似度，从而降低潜在的免疫原性。常见的人源化方法为CDRGraftingNon-humanAntibodyFR1CDR1FR2CDR2FR3CDR3FR4HumanGermlineVGeneFR1CDR1FR2CDR2FR3CDR3FR4HumanizedAntibodyMolecularOperatingEnvironmentFR1CDR1FR2CDR2FR3CDR3FR4MOECopyright©2012CloudScientificAllRightsReserved.目前人源化抗

7、体设计中存在的问题IssueswithCurrentHumanizedAntibodyDesign采用通用的序列比对方法，没有考虑抗体Fab序列的特殊性；通常只考虑FR区相似性来选择模板；靠经验而非结构信息确认CanonicalResidue*；很少考虑CanonicalResidue相似性；基本没有考虑CDR区的序列相似性;功能恢复反突变(BackMutation)实验随意，缺乏理性指导；…MolecularOperatingEnvironment需要一套完整的建模、序列比对以及评分方法来完善人源化抗体设计！*Canonicalresiduesarekeyresi

8、duesintheCDRand/orframeworkthatdeterminetheconformationoftheCDRloop.MOECopyright©2012CloudScientificAllRightsReserved.人源化抗体设计策略OurApproachtoHumanizedAntibodyDesigninMOEGivenNon-humanAntibodySequenceBuild3DmodelinAntibodyModelingIdentifyCanoni