抗体靶向治疗药物课件

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 2002 B淋巴细胞杂交瘤技术 MechanismofAction MonoclonalAb Malignantcell MonoclonalAb TumorspecificAg Complement Killerleukocyte ADCC Ab dependentcell mediatedcytotoxicity CDC Complementdependentcytotoxicity MonoclonalAb Liganddependentapoptosis GraphicrepresentationofprogressionofmonoclonalantibodiesfrommurinetochimerictohumanizedtoPRIMATIZED andhuman Themorehumantheantibodyis thelesslikelyitwillgenerateanimmuneresponseandthemoreutilityithasforchronic repeat 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 Physicalcharacteristicsofsometherapeuticradionuclides MonoclonalantibodiesintheorderofFDA approval 2006Panitumumab Vectibix GEFRHumanizedIgG2kColorectalcancer2006Ranibizumab Lucentis VEGF AHumanizedIgG1kAMD 黄斑变性 USandEUtherapeuticmAbapprovalstodate 1 chimericmAbs allproducts n 39 2 oncologicalchimericmAbs 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 yearmovingaverages NumberoftherapeuticmAbsenteringclinicalstudyperyear ClinicalphasetransitionpercentagesfortherapeuticmAbs FDAdata ApprovalsuccessratesformAbs Misc miscellaneouscategoryincludingophthalmic neuropharmacologicandcardiovascularindications TherapeuticcategoriesformAbsinclinicalstudy 影响抗体治疗的主要障碍1 Immunogenicityofxenogeneicantibodies2 Sheddingofantigenintocirculation3 Disorderedvasculatureintumors4 Increasedhydrostaticpressureintumors5 Heterogeneityofantigenontumorsurface6 Limitednumbersofeffectorcellsattumor7 Immunosuppressivetumormicroenvironment SerialmicroPETimagingof124I labeledanti CEAscFv FcfragmentsParentalhuman 1andH310A H435QdoublemutantinLS174Txenograft bearingmice TheimagemarkedscFv FcSMisaH310AsinglemutantofthemAb scFv FcDMisaH310A H435Qdoublemutant Relationshipbetweenengineeredantibodyformat targetingandimaging andbloodclearance Schematicshowingdomaincompositionofengineeredfragments 25kDa 55kDa 80kDa 105kDa 150kDa TumoruptakeandbloodclearancecurvesForradioiodine labeledanti CEAscFvmAbfragmentsinathymicmicebearingsubcutaneousLS174Thumancoloncarcinomaxenografts ID g injecteddosepergram BiodistributionofdifferentmAbformatsintwoxenograftmodels Acartoonrepresentationofdifferentantibodyformatsusedforinvivoimaging MicroPETscanofathymicmicewithLS174Tcoloncarcinoma leftarrow andC6glioma rightarrow tumors18hpostinfusionof124I labeledanti CEAT84 66diabody minibodyorscFv Fc Antibodyformatsusedinimaging CamelidVhH IgandsharkIg NARsareunusualimmunoglobulin likestructurescomprisingahomodimericpairoftwochainsofV likeandC likedomains neitherhasalightchain inwhichthedisplayedVdomainsbindtargetindependently SharkIg NARscompriseahomodimerofonevariabledomain V NAR andfiveC likeconstantdomains C NAR Avarietyofantibodyfragmentsaredepicted includingFab scFv single domainVH VhHandV NARandmultimericformats suchasminibodies bis scFv diabodies triabodies tetrabodiesandchemicallyconjugatedFab multimers sizesgiveninkilodaltonsareapproximate Schematicrepresentationofdifferentantibodyformats showingintact classic IgGmoleculesalongsidecamelidVhH IgandsharkIg NARimmunoglobulins Structuralcomparisonofantibodyfragmentsandsingledomains Schematicrepresentationofimmunoglobulinfragments Fab scFv diabody dAb VHorVL Possibledifferentconfigurationsoffusionproteinsofcytokineswitheitherfull lengthantibodymoleculesortheantigen bindingsites scFv aredepicted ThecytokineorchemokinemoietyhasbeenfusedattheN orC terminaloftheheavychain a and b orattheN terminalend c orC terminalendofthescFv d orboth e Inaddition fusionproteinsoftwocytokineshavealsobeendescribed Immunocytokinesandtheirconfigurations Antibodyfragmentsinclinicalandpreclinicaldevelopment Antibodyfragmentsinclinicalandpreclinicaldevelopment TherapeuticmAbscurrentlyinphase3studies CTLA cytotoxicT lymphocyteassociatedprotein EGF ep