08-抗体靶向治疗药物.ppt
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08-抗体靶向治疗药物.ppt
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抗体靶向治疗药物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:
甄永苏,邵荣光主编:
抗体工程药物化学工业出版社,北京,2002LYMPHOCYTEHYBRIDOMAMYELOMABB淋巴细胞杂交瘤技术淋巴细胞杂交瘤技术MechanismofAction:
MonoclonalAbMalignantcellMonoclonalAbTumorspecificAgComplementKillerleukocyteADCC(Abdependentcell-mediatedcytotoxicity)CDC(Complementdependentcytotoxicity)MonoclonalAbLiganddependentapoptosisGraphicrepresentationofprogressionofmonoclonalantibodiesfrommurinetochimerictohumanizedtoPRIMATIZEDandhuman.Themorehumantheantibodyis,thelesslikelyitwillgenerateanimmuneresponseandthemoreutilityithasforchronic(repeat)therapy.Generationsofantibodytechnology与单抗偶联的常用与单抗偶联的常用“弹头弹头”药物药物毒素毒素植物植物蓖麻毒素,相思豆毒素,蓖麻毒素,相思豆毒素,saporinsaporin,geloningelonin,modecinmodecin等等微生物微生物绿脓杆菌外毒素,白喉毒素绿脓杆菌外毒素,白喉毒素药物药物抗代谢类抗代谢类氨基蝶呤,氨基蝶呤,MTXMTX,AraAra-C-C,5-FU5-FU,5-5-氟脱氧尿苷等氟脱氧尿苷等蒽环类蒽环类阿霉素,柔红霉素,去甲氧柔红霉素,吗啉阿霉素等阿霉素,柔红霉素,去甲氧柔红霉素,吗啉阿霉素等烷基化类烷基化类苯丙氨酸氮芥,苯丁酸氮芥,丝裂霉素苯丙氨酸氮芥,苯丁酸氮芥,丝裂霉素CC,顺铂等,顺铂等抗有丝分裂抗有丝分裂长春花碱,秋水仙碱,鬼臼毒素等长春花碱,秋水仙碱,鬼臼毒素等抗生素抗生素CalicheamicinCalicheamicin,博莱霉素,平阳霉素,力达霉素,博莱霉素,平阳霉素,力达霉素核素核素131131II、125I、9090YY、6767CuCu、111111InIn、99mTc等等Physicalcharacteristicsofsometherapeuticradionuclides碘碘砹砹铋铋镧镧铜铜MonoclonalantibodiesintheorderofFDA-approval2006Panitumumab(Vectibix)EGFRHumanizedIgG2kkColorectalcancer2006Ranibizumab(Lucentis)VEGF-AHumanizedIgG1kkAMD(黄斑变性)FDA:
35SFDA:
1115BUSFDA:
35SFDA:
1115BUS1/3BIO1/3BIOUSandEUtherapeuticmAbapprovalstodate1,chimericmAbs,allproducts(n=39);2,oncologicalchimericmAbs(n=21);3,immunologicalchimericmAbs(n=9);4,chimericmAbs,19871997(n=20);5,humanizedmAbs,allproducts(n=102);6,oncologicalhumanizedmAbs(n=46);7,immunologicalhumanizedmAbs(n=34);8,humanizedmAbs,19881997(n=46).Dataarepresentedastwo-yearmovingaveragesNumberoftherapeuticmAbsenteringclinicalstudyperyearClinicalphasetransitionpercentagesfortherapeuticmAbs(FDAdata)ApprovalsuccessratesformAbsMisc.,miscellaneouscategoryincludingophthalmic,neuropharmacologicandcardiovascularindications.TherapeuticcategoriesformAbsinclinicalstudy影响抗体治疗的主要障碍影响抗体治疗的主要障碍1.1.异源抗体的免疫原性异源抗体的免疫原性(ImmunogenicityImmunogenicityofofxenogeneicxenogeneicantibodies)antibodies)2.2.抗原脱落进入血循环抗原脱落进入血循环(Sheddingofantigenintocirculation)(Sheddingofantigenintocirculation)3.3.肿瘤内血管的失调肿瘤内血管的失调(Disorderedvasculatureintumors)(Disorderedvasculatureintumors)4.4.肿瘤内静水压的增加肿瘤内静水压的增加(Increasedhydrostaticpressureintumors)(Increasedhydrostaticpressureintumors)5.5.肿瘤表面抗原的异质性肿瘤表面抗原的异质性(Heterogeneityofantigenontumorsurface)(Heterogeneityofantigenontumorsurface)6.6.肿瘤效应细胞数量的限制肿瘤效应细胞数量的限制(Limitednumbersof(Limitednumbersofeffectoreffectorcellsattumor)cellsattumor)7.7.免疫抑制性肿瘤微环境免疫抑制性肿瘤微环境(Immunosuppressivetumormicroenvironment)(Immunosuppressivetumormicroenvironment)SerialmicroPETimagingof124I-labeledanti-CEAscFv-FcfragmentsParentalhuman1andH310A/H435QdoublemutantinLS174Txenograft-bearingmice.TheimagemarkedscFv-FcSMisaH310AsinglemutantofthemAb;scFv-FcDMisaH310A/H435Qdoublemutant.Relationshipbetweenengineeredantibodyformat,targetingandimaging,andbloodclearanceSchematicshowingdomaincompositionofengineeredfragments(25kDa)(55kDa)(80kDa)(105kDa)(150kDa)TumoruptakeandbloodclearancecurvesForradioiodine-labeledanti-CEAscFvmAbfragmentsinathymicmicebearingsubcutaneousLS174Thumancoloncarcinomaxenografts.ID/g:
injecteddosepergram.BiodistributionofdifferentmAbformatsintwoxenograftmodelsAcartoonrepresentationofdifferentantibodyformatsusedforinvivoimagingMicroPETscanofathymicmicewithLS174Tcoloncarcinoma(leftarrow)andC6glioma(rightarrow)tumors18hpostinfusionof124I-labeledanti-CEAT84.66diabody,minibodyorscFv-FcAntibodyformatsusedinimagingCamelidVhH-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,tetrabodiesandchemicallyconjugatedFabmultimers(sizesgiveninkilodaltonsareapproximate).Schematicrepresentationofdifferentantibodyformats,showingintactclassicIgGmoleculesalongsidecamelidVhH-IgandsharkIg-NARimmunoglobulinsStructuralcomparisonofantibodyfragmentsandsingledomainsFDAFDA批准用于治疗肿瘤的抗体药物批准用于治疗肿瘤的抗体药物RituxanRituxanRituxanRituxan(1997):
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非霍奇金非霍奇金非霍奇金非霍奇金BBBB细胞淋巴瘤细胞淋巴瘤细胞淋巴瘤细胞淋巴瘤HerceptinHerceptinHerceptinHerceptin(1998):
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乳腺癌乳腺癌乳腺癌乳腺癌MylotargMylotargMylotargMylotarg(2000):
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复发的急性髓细胞性白血病复发的急性髓细胞性白
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- 08 抗体 靶向 治疗 药物