抗体靶向治疗药物.ppt

抗体靶向治疗药物,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，北京，2019,甄永苏，邵荣光主编：抗体工程药物化学工业出版社，北京，2019,B淋巴细胞杂交瘤技术,MechanismofAction:MonoclonalAb,Malignantcell,MonoclonalAb,TumorspecificAg,Complement,Killerleukocyte,ADCC(Abdependentcell-mediatedcytotoxicity),CDC(Complementdependentcytotoxicity),MonoclonalAb,Liganddependentapoptosis,GraphicrepresentationofprogressionofmonoclonalantibodiesfrommurinetochimerictohumanizedtoPRIMATIZEDandhuman.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,碘砹铋镧铜,MonoclonalantibodiesintheorderofFDA-approval,FDA:35SFDA:1115BUS1/3BIO,USandEUtherapeuticmAbapprovalstodate,1,chimericmAbs,allproducts(n=39);2,oncologicalchimericmAbs(n=21);3,immunologicalchimericmAbs(n=9);4,chimericmAbs,19872019(n=20);5,humanizedmAbs,allproducts(n=102);6,oncologicalhumanizedmAbs(n=46);7,immunologicalhumanizedmAbs(n=34);8,humanizedmAbs,19882019(n=46).,Dataarepresentedastwo-yearmovingaverages,NumberoftherapeuticmAbsenteringclinicalstudyperyear,ClinicalphasetransitionpercentagesfortherapeuticmAbs(FDAdata),ApprovalsuccessratesformAbs,Misc.,miscellaneouscategoryincludingophthalmic,neuropharmacologicandcardiovascularindications.,TherapeuticcategoriesformAbsinclinicalstudy,影响抗体治疗的主要障碍1.异源抗体的免疫原性(Immunogenicityofxenogeneicantibodies)2.抗原脱落进入血循环(Sheddingofantigenintocirculation)3.肿瘤内血管的失调(Disorderedvasculatureintumors)4.肿瘤内静水压的增加(Increasedhydrostaticpressureintumors)5.肿瘤表面抗原的异质性(Heterogeneityofantigenontumorsurface)6.肿瘤效应细胞数量的限制(Limitednumbersofeffectorcellsattumor)7.免疫抑制性肿瘤微环境(Immunosuppressivetumormicroenvironment),SerialmicroPETimagingof124I-labeledanti-CEAscFv-FcfragmentsParentalhuman1andH310A/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,tetrabodiesandchemicallyconjugatedFabmultimers(sizesgiveninkilodaltonsareapproximate).,Schematicrepresentationofdifferentantibodyformats,showingintactclassicIgGmoleculesalongsidecamelidVhH-IgandsharkIg-NARimmunoglobulins,Structuralcomparisonofantibodyfragmentsandsingledomains,FDA批准用于治疗肿瘤的抗体药物,Rituxan(2019):非霍奇金B细胞淋巴瘤Herceptin(2019):乳腺癌Mylotarg(2000):复发的急性髓细胞性白血病Campath-1H(2019):难治的慢性淋巴细胞白血病Zevalin(2019):难治的非霍奇金B细胞淋巴瘤Bexxar(2019):难治的非霍奇金B细胞淋巴瘤Erbitux(2019):结肠直肠癌Avastin(2019):结肠直肠癌Vectibix(2019):结肠直肠癌,单克隆抗体肿瘤靶向治疗bindtoantigenspresentpreferentiallyorexclusivelyontumorcells.,ZevalinBexxar,Mylotarg,单克隆抗体作为肿瘤治疗的体内应用策略,AntibodyAloneComplementmediatedcytotoxicity(CMC)Antibodydependentcell-mediatedcytotoxicity(ADCC)Regulatory(ligand/receptor)interactionsAnti-idiotypevaccineImmunoconjugatesRadiolabeledAntibodiesImmunotoxinsChemotherapy-AntibodyConjugatesCytokineImmunoconjugatesCellularImmunoconjugates,Antibodyfragmentsinclinicalandpreclinicaldevelopment,Antibodyfragmentsinclinicalandpreclinicaldevelopment,TherapeuticmAbscurrentlyinphase3studies,CTLA,cytotoxicT-lymphocyteassociatedprotein;EGF,epidermalgrowthfactor;MRSA,methicillin-resistantStaphylococcusaureus;RANKL,receptorforactivationofnuclearfactor-Bligand;RSV,respiratorysyncytialvirus;TNF,tumornecrosisfactor;VEGF,vascularendothelialgrowthfactor.,近几年处在临床实验中的免疫毒素,AAPSJ2019,近几年处在临床实验中的免疫毒素,AAPSJ2019,ThanksYou!,Schematicrepresentationofimmunoglobulinfragments,Fab,scFv,diabody,dAb(VHorVL),Possibledifferentconfigurationsoffusionproteinsofcytokineswitheitherfull-lengthantibodymoleculesortheantigen-bindingsites(scFv)ar