抗体靶向治疗药物课件

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1、抗体靶向治疗药物邵荣光医药生物技术研究所邵荣光，甄永苏：抗体靶向治疗药物见：王晓良主编.应用分子药理学.中国协和医科大学出版社，北京，2005甄永苏，邵荣光主编：抗体工程药物化学工业出版社，北京，2002LYMPHOCYTEHYBRIDOMAMYELOMAB淋巴细胞杂交瘤技术MechanismofAction:MonoclonalAbMalignantcellMonoclonalAbTumorspecificAgComplementKillerleukocyteADCC(Ab-dependentcell-mediatedcytotoxicity)CDC(Co

2、mplementdependentcytotoxicity)MonoclonalAbLiganddependentapoptosisGraphicrepresentationofprogressionofmonoclonalantibodiesfrommurinetochimerictohumanizedtoPRIMATIZED®andhuman.Themorehumantheantibodyis,thelesslikelyitwillgenerateanimmuneresponseandthemoreutilityithasforchronic(repea

3、t)therapy.Generationsofantibodytechnology与单抗偶联的常用“弹头”药物毒素植物蓖麻毒素，相思豆毒素，saporin，gelonin，modecin等微生物绿脓杆菌外毒素，白喉毒素药物抗代谢类氨基蝶呤，MTX，Ara-C，5-FU，5-氟脱氧尿苷等蒽环类阿霉素，柔红霉素，去甲氧柔红霉素，吗啉阿霉素等烷基化类苯丙氨酸氮芥，苯丁酸氮芥，丝裂霉素C，顺铂等抗有丝分裂长春花碱，秋水仙碱，鬼臼毒素等抗生素Calicheamicin，博莱霉素，平阳霉素，力达霉素核素131I、125I、90Y、67Cu、111In、99mTc等Phy

4、sicalcharacteristicsofsometherapeuticradionuclidesMonoclonalantibodiesintheorderofFDA-approval2006Panitumumab(Vectibix)GEFRHumanizedIgG2kColorectalcancer2006Ranibizumab(Lucentis)VEGF-AHumanizedIgG1kAMD(黄斑变性）USandEUtherapeuticmAbapprovalstodate1,chimericmAbs,allproducts(n=39);2,onco

5、logicalchimericmAbs(n=21);3,immunologicalchimericmAbs(n=9);4,chimericmAbs,1987–1997(n=20);5,humanizedmAbs,allproducts(n=102);6,oncologicalhumanizedmAbs(n=46);7,immunologicalhumanizedmAbs(n=34);8,humanizedmAbs,1988–1997(n=46).Dataarepresentedastwo-yearmovingaveragesNumberoftherapeut

6、icmAbsenteringclinicalstudyperyearClinicalphasetransitionpercentagesfortherapeuticmAbs(FDAdata)ApprovalsuccessratesformAbsMisc.,miscellaneouscategoryincludingophthalmic,neuropharmacologicandcardiovascularindications.TherapeuticcategoriesformAbsinclinicalstudy影响抗体治疗的主要障碍1.Immunogeni

7、cityofxenogeneicantibodies2.Sheddingofantigenintocirculation3.Disorderedvasculatureintumors4.Increasedhydrostaticpressureintumors5.Heterogeneityofantigenontumorsurface6.Limitednumbersofeffectorcellsattumor7.ImmunosuppressivetumormicroenvironmentSerialmicroPETimagingof124I-labeledan

8、ti-CEAscFv-FcfragmentsPare