《抗體靶向治療藥物》

抗體靶向治療藥物編輯ppt

邵榮光，甄永蘇：

抗體靶向治療藥物

見：王曉良主編.

應(yīng)用分子藥理學(xué).中國協(xié)和醫(yī)科大學(xué)出版社，北京，2005甄永蘇，邵榮光主編：

抗體工程藥物化學(xué)工業(yè)出版社，北京，2002編輯ppt編輯pptLYMPHOCYTE

HYBRIDOMAMYELOMAB淋巴細(xì)胞雜交瘤技術(shù)編輯pptMechanismofAction:MonoclonalAbMalignantcellMonoclonalAbTumorspecificAgComplementKillerleukocyteADCC(Abdependentcell-mediatedcytotoxicity)CDC(Complementdependentcytotoxicity)MonoclonalAbLiganddependentapoptosis編輯ppt編輯pptGraphicrepresentationofprogressionofmonoclonalantibodiesfrommurinetochimerictohumanizedtoPRIMATIZED?andhuman.Themorehumantheantibodyis,thelesslikelyitwillgenerateanimmuneresponseandthemoreutilityithasforchronic(repeat)therapy.Generationsofantibodytechnology編輯ppt編輯ppt與單抗偶聯(lián)的常用“彈頭”藥物

毒素 植物 蓖麻毒素，相思豆毒素，saporin，gelonin，modecin等

微生物 綠膿桿菌外毒素，白喉毒素藥物 抗代謝類氨基蝶呤，MTX，Ara-C，5-FU，5-氟脫氧尿苷等

蒽環(huán)類 阿霉素，柔紅霉素，去甲氧柔紅霉素，嗎啉阿霉素等

烷基化類苯丙氨酸氮芥，苯丁酸氮芥，絲裂霉素C，順鉑等

抗有絲分裂長春花堿，秋水仙堿，鬼臼毒素等

抗生素

Calicheamicin，博萊霉素，平陽霉素，力達(dá)霉素核素 131I、125I、90Y

、67Cu

、111In、99mTc等編輯pptPhysicalcharacteristicsofsometherapeuticradionuclides碘砹鉍鑭銅編輯ppt編輯ppt編輯pptMonoclonalantibodiesintheorderofFDA-approval2006Panitumumab(Vectibix?)EGFRHumanizedIgG2kColorectalcancer2006Ranibizumab(Lucentis?)VEGF-AHumanizedIgG1kAMD(黃斑變性）FDA:35SFDA:11>15BUS＄>1/3BIO編輯pptUSandEUtherapeuticmAbapprovalstodate編輯ppt1,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-yearmovingaveragesNumberoftherapeuticmAbsenteringclinicalstudyperyearClinicalphasetransitionpercentagesfortherapeuticmAbs(FDAdata)編輯pptApprovalsuccessratesformAbsMisc.,miscellaneouscategoryincludingophthalmic,neuropharmacologicandcardiovascularindications.TherapeuticcategoriesformAbsinclinicalstudy編輯ppt編輯ppt影響抗體治療的主要障礙1.異源抗體的免疫原性

(Immunogenicityofxenogeneicantibodies)2.抗原脫落進入血循環(huán)

(Sheddingofantigenintocirculation)3.腫瘤內(nèi)血管的失調(diào)

(Disorderedvasculatureintumors)4.腫瘤內(nèi)靜水壓的增加

(Increasedhydrostaticpressureintumors)5.腫瘤表面抗原的異質(zhì)性

(Heterogeneityofantigenontumorsurface)6.腫瘤效應(yīng)細(xì)胞數(shù)量的限制

(Limitednumbersofeffectorcellsattumor)7.免疫抑制性腫瘤微環(huán)境

(Immunosuppressivetumormicroenvironment)編輯ppt編輯ppt編輯ppt編輯ppt編輯pptSerialmicroPETimagingof124I-labeledanti-CEAscFv-Fcfragments

Parentalhumanγ1andH310A/H435QdoublemutantinLS174Txenograft-bearingmice.TheimagemarkedscFv-FcSMisaH310AsinglemutantofthemAb;scFv-FcDMisaH310A/H435Qdoublemutant.Relationshipbetweenengineeredantibodyformat,targetingandimaging,andbloodclearanceSchematicshowingdomaincompositionofengineeredfragments(25kDa)(55kDa)(80kDa)(105kDa)(150kDa)TumoruptakeandbloodclearancecurvesForradioiodine-labeledanti-CEAscFvmAbfragmentsinathymicmicebearingsubcutaneousLS174Thumancoloncarcinomaxenografts.ID/g:injecteddosepergram.編輯pptBiodistributionofdifferentmAbformatsintwoxenograftmodelsAcartoonrepresentationofdifferentantibodyformatsusedforinvivoimagingMicroPETscanofathymicmicewithLS174Tcoloncarcinoma(leftarrow)andC6glioma(rightarrow)tumors18hpostinfusionof124I-labeledanti-CEAT84.66diabody,minibodyorscFv-FcAntibodyformatsusedinimaging編輯pptCamelidVhH-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編輯pptStructuralcomparisonofantibodyfragmentsandsingledomains編輯ppt編輯ppt編輯ppt編輯ppt編輯ppt編輯ppt編輯ppt編輯pptFDA批準(zhǔn)用于治療腫瘤的抗體藥物Rituxan(1997):

非霍奇金B(yǎng)細(xì)胞淋巴瘤Herceptin(1998):

乳腺癌Mylotarg(2000):

復(fù)發(fā)的急性髓細(xì)胞性白血病Campath-1H(2001): 難治的慢性淋巴細(xì)胞白血病Zevalin(2002): 難治的非霍奇金B(yǎng)細(xì)胞淋巴瘤Bexxar(2003): 難治的非霍奇金B(yǎng)細(xì)胞淋巴瘤Erbitux(2004):

結(jié)腸直腸癌Avastin(2004):

結(jié)腸直腸癌Vectibix(2006):

結(jié)腸直腸癌編輯ppt編輯ppt編輯ppt編輯ppt編輯ppt編輯ppt編輯ppt單克隆抗體腫瘤靶向治療

bindtoantigenspresentpreferentiallyorexclusivelyontumorcells.ZevalinBexxarMylotarg編輯ppt單克隆抗體作為腫瘤治療的體內(nèi)應(yīng)用策略AntibodyAlone

Complementmediatedcytotoxicity(CMC)Antibodydependentcell-mediatedcytotoxicity(ADCC)Regulatory(ligand/receptor)interactions

Anti-idiotypevaccineImmunoconjugates

RadiolabeledAntibodiesImmunotoxinsChemotherapy-AntibodyConjugates

CytokineImmunoconjugatesCellularImmunoconjugates編輯pptAntibodyfragmentsinclinicalandpreclinicaldevelopment編輯pptAntibodyfragmentsinclinicalandpreclinicaldevelopment編輯pptTherapeuticmAbscurrentlyinphase3studiesCTLA,cytotoxicT-lymphocyteassociatedprotein;EGF,epidermalgrowthfactor;MRSA,methicillin-resistantStaphylococcusaureus;RANKL,receptorforactivationofnuclearfactor-κBligand;RSV,respiratorysyncytialvirus;TNF,tumorn