专利作业课件

专利汇报,2,介绍一个美国药品专利humira（修美乐-阿达木单抗）,3,发明名称:,MethodforthetreatmentofrheumatoidarthritisusingaTLR2antagonisticantibody使用一个TLR2逆反应抗体治疗风湿性心脏病的方法,4,5,摘要Abstract,Thepresentinventionprovidescompositionsandmethodsforthetreatmentofautoimmunediseases,inparticularrheumatoidarthritis.CompoundswhichfunctionasantagonistsofToll-likeReceptor2areshowntosuppresstheimmuneresponsewhichresultintheonsetandprogressionofautoimmunedisease.InparticularmonoclonalantibodieswhichhaveabindingspecificitytoToll-likereceptor2aredisclosedforuseinmethodsforthetreatmentand/orprophylaxisofautoimmunedisease.本发明提供了一种组成成分和用于治疗自身免疫病的方法，特别是治疗风湿性关节炎。作为TLR2拮抗剂的这种物质能够抑制导致自身免疫性疾病发生和发展的免疫应答。特别公开了一种对TLR2有专一性的单克隆抗体在治疗和/或预防自身免疫疾病时的方法。,6,权利要求书Claims,1.Theinventionclaimedis:1.Amethodforthetreatmentofrheumatoidarthritis,themethodcomprisingthestepof:administeringatherapeuticallyeffectiveamountofapharmaceuticalcompositionconsistingofanantibodyorbindingfragmentthereofwhichantagonizesthefunctionofToll-likeReceptor2toasubjectinneedofsuchtreatment.一种治疗类风湿关节炎的方法，这种方法包括以下步骤：给一定量的有治疗作用的包含一种抗体的药物成分，或者在治疗需要时，给药物连接一个片段使它对抗TLR2的作用。,7,2.Themethodasclaimedinclaim1,whereinthetherapeuticallyeffectiveamountisadministeredtothesubjectinordertoreduceorinhibitoneormoreTLR2biologicalactivitiesinaTLR2expressingcellortissueofthesynovium.权利要求1所述的方法，所给的治疗量是为了减轻或者抑制TLR2在TLR2表达细胞或滑膜组织中的生物活性。,8,3.Themethodofclaim2,whereintheantibodyisahuman,camelid,orinvitrogeneratedantibodytohumanTLR2.权利要求2所述的方法，其中的抗体是人的、羊的或者是对人TLR2在体外生成的抗体。4.Themethodasclaimedinclaim2,whereintheantibodyisselectedfromthegroupconsistingof:(a)achimericantibodyorfragmentthereof,(b)asyntheticantibodyorfragmentthereof,(c)ahumanisedantibodyorafragmentthereof,and(d)aFabfragment.权利要求2中所述的方法，其中的抗体选择的组成包含：(a)嵌合抗体或其片段；(b)合成抗体或其片段；(c)人源抗体或其片段；(d)Fab片段。,9,5.Themethodasclaimedinclaim2,whereintheantibodyisofanisotypeselectedfromthegroupconsistingoflgG,IgA,IgM,andIgE.权利要求2所述的方法，其中的抗体是一种选自lgG,IgA,IgM和IgE组成的相似物。6.Themethodasclaimedinclaim1,whereintheTLR2antagonisticantibodybindstotheextracellulardomainofhumanTLR2.权利要求1所述的方法，其中的TLR2逆反应抗体连接在人的TLR2的胞外域。,10,7.Themethodasclaimedinclaim1,whereintheantibodyisselectedfromthegroupconsistingofamonoclonalantibody,apolyclonalantibodyandahumanantibody.权利要求1所述的方法，其中的选择的抗体包含一个单克隆抗体、一个多克隆抗体和一个人源抗体。8.Themethodasclaimedinclaim1,whereintheantibodybindstoaninhibitoryepitopepresentonToll-likeReceptor2withadissociationconstant(Kd)selectedfromthegroupoffrom10-7Mto10-11M.权利要求1所述的方法，其中连接在一个抑制性抗原表位的抗体呈现在TLR2受体的离解常数(Kd)的范围为：10-7Mto10-11M。,11,9.Themethodasclaimedinclaim1,whereintheToll-likeReceptor2ishumanToll-likeReceptor2ormurineToll-likeReceptor2.权利要求1所述的方法，其中的TLR2是人源TLR2或者是鼠源的TLR2。10.Themethodofclaim1,whereintheTLR2antagonisticantibodyistheanti-TLR2monoclonalantibodyfromthecloneT2.5orahumanisedversionoftheantibodyorafragmentthereofwhichactsasanantagonistofTLR2activityorexpression.权利要求1所述的方法，其中的TLR2逆反应抗体是来自于克隆的抗-TLR2的单克隆抗体，或是人源的抗体，或是做为TLR2活动或表达的拮抗剂的片段。,12,11.Amethodforthetreatmentofrheumatoidarthritis,themethodcomprisingthestepof:administeringatherapeuticallyeffectiveamountofapharmaceuticalcompositionconsistingofanantibodyorbindingfragmentthereofwhichantagonizesthefunctionofToll-likeReceptor2andoneormorecompoundsselectedfromthegroupconsistingofapharmaceuticallyacceptablecarrier,adiluent,asolubilizer,anemulsifier,apreservativeandanadjuvanttoasubjectinneedofsuchtreatment.治疗风湿性关节炎的方法，这种的方法包含下述步骤：给一定量的有治疗作用的包含一种抗体的药物成分，或者在治疗风湿性关节炎需要时，给药物连接一个片段使它对抗TLR2的作用或者所选择的一个或多个成分包含制药上一个合适的载体，一种稀释剂，一种增溶剂，一种粘合剂，一种防腐剂。（独权2）（和独权1对比）,13,12.Amethodforthetreatmentofrheumatoidarthritis,themethodconsistingofthestepsof:administeringatherapeuticallyeffectiveamountofanantibodyorbindingfragmentthereofwhichantagonizesthefunctionofToll-likeReceptor2toasubjectinneedofsuchtreatment;andadministeringtothesubjectanimmunosuppressantcompoundselectedfromthegroupconsistingofananti-CD20antibody,ananti-TNFantibody,aninterleukin-1blocker,ablockerofTcellactivation,anon-steroidalanti-inflammatoryagent,anorganicgoldderivative,D-penicillamine,4-aminoquinoline,azathioprine,methotrexate,cyclosporine,anangiogenesisinhibitor,amonoclonalantibodywithbindingspecificitytoTcells,amonoclonalantibodywithbindingspecificitytoanadhesionmoleculeandamonoclonalantibodywithbindingspecificitytoacytokineoragrowthfactor.,14,治疗风湿性关节炎的方法，这种的方法包含下述步骤：给一定量的有治疗作用的包含一种抗体的药物成分，或者在治疗风湿性关节炎需要时，给药物连接一个片段使它对抗TLR2抗体的作用；针对治疗目的可给于一种选择的包含抗-CD20的抗体、抗-TNF的抗体、自免疫抑制剂、白细胞介素-1阻滞剂、T细胞激活的阻滞剂、非甾体抗炎药、有机金属衍生物、青霉胺、4-氨基喹啉、咪唑巯嘌呤、甲氨蝶呤、环孢霉素、血管生成抑制剂、连接在特定T细胞上的单克隆抗体、连接在特定粘附分子上的单克隆抗体、连接在特定细胞因子或生长因子上的单克隆抗体。（独权3）,15,13.Amethodforthetreatmentofrheumatoidarthritis,themethodconsistingofthestepsof:administeringatherapeuticallyeffectiveamountofanantibodyorbindingfragmentthereofwhichantagonizesthefunctionofToll-likeReceptor2andoneormorecompoundsselectedfromthegroupconsistingofapharmaceuticallyacceptablecarrier,adiluent,asolubilizer,anemulsifier,apreservativeandanadjuvanttoasubjectinneedofsuchtreatment;andadministeringtothesubjectanimmunosuppressantcompoundselectedfromthegroupconsistingofananti-CD20antibody,ananti-TNFantibody,aninterleukin-1blocker,ablockerofTcellactivation,anon-steroidalanti-inflammatoryagent,anorganicgoldderivative,D-penicillamine,4-aminoquinoline,azathioprine,methotrexate,cyclosporine,anangiogenesisinhibitor,amonoclonalantibodywithbindingspecificitytoTcells,amonoclonalantibodywithbindingspecificitytoanadhesionmoleculeandamonoclonalantibodywithbindingspecificitytoacytokineoragrowthfactor.,16,治疗风湿性关节炎的方法，这种的方法包含下述步骤：给一定量的有治疗作用的包含一种抗体的药物成分，或者在治疗风湿性关节炎需要时，给药物连接一个片段使它对抗TLR2抗体的作用；所选择的一个或多个成分包含制药上一个合适的载体，一种稀释剂，一种增溶剂，一种粘合剂，一种防腐剂。针对治疗目的可给于一种选择的包含抗-CD20的抗体、抗-TNF的抗体、自免疫抑制剂、白细胞介素-1阻滞剂、T细胞激活的阻滞剂、非甾体抗炎药、有机金属衍生物、青霉胺、4-氨基喹啉、咪唑巯嘌呤、甲氨蝶呤、环孢霉素、血管生成抑制剂、连接在特定T细胞上的单克隆抗体、连接在特定粘附分子上的单克隆抗体、连接在特定细胞因子或生长因子上的单克隆抗体。（独权4）（和独权3对比）,17,参看有关的应用CROSSREFERENCETORELATEDAPPLICATIONS,Thisapplicationisanationalstagefilingunder35U.S.C.sctn.371ofinternationalapplicationPCT/EP2008/058339,filedJun.27,2008,whichwaspublishedunderPCTArticle21(2)inEnglish,andwhichclaimsthebenefitunder35USC.sctn.119(e)ofU.S.ProvisionalApplicationNo.61/038,372,filedMar.20,2008,andalsoIrelandApplicationsNo.2007/0468,filedJun.28,2007,andNo.2008/0209filedMar.20,2008,thedisclosuresofallofwhichareincorporatedbyreferencehereinintheirentirety.,18,说明书Description,技术领域FIELDOFTHEINVENTIONThepresentinventionrelatestocompoundsandmethodsforthetreatmentofarthritis.Inparticularthereisprovidedmethodsforthetreatmentandprophylaxisofrheumatoidarthritiswhichfunctionbyinhibitingthefunctionand/orexpressionofToll-likeReceptor2.本发明涉及一种组成成分和关节炎的治疗方法。特别是提供了一种能够通过抑制TLR2的活动和表达的类风湿性关节炎的治疗和预防方法。,19,技术背景BACKGROUNDTOTHEINVENTION,Arthritisisaprogressive,autoimmunedisease.Themostprevalentformofarthritisisrheumatoidarthritis,achronicinflammatorydisorderwhichischaracterisedbyinflammationofthejoints.Althoughrheumatoidarthritisrarelyleadstomortality,theassociatedsymptomsofrheumatoidarthritis,whichmosttypicallyincludethelossofjointmobility,cancauseasignificantimpairmenttoanindividualsqualityoflife.,20,Rheumatoidarthritis(RA)istypicallymultiarticular,thatisthatitaffectsmanyjoints.Oncetriggered,itresultsininflammationofthesynovium,leadingtoedema（浮肿）,vasodilation（血管舒张）andactivationofCD4+Tcells.Earlyandintermediatemarkersofdiseaseprogressionincludetheexpressionofthecytokines;tumournecrosisfactoralpha,IL-1,IL-6,IL-8andIL-15aswellastransforminggrowthfactor(TGF).Onceinflammationofthejointoccurs,thesynoviumthickens.Thisseriesofeventsresultsinjointdestructionandlossofjointmobility.,21,TherapeuticapproachesusedtotreatRAgenerallytargetthemediatorsofinflammation.Inparticular,tumournecrosisfactorinhibitorshavebeenwidelyprescribedtosubjectpresentingwiththiscondition.Othertherapiesrelatetoanti-CD20antibodies,interleukin-1(IL-1)blockers,aswellasblockersofTcellactivation.Toll-likereceptors(TLRs)formafamilyofpatternrecognitionreceptors（模式识别载体）whichhaveakeyroleinactivatingtheinnateimmuneresponse.11Toll-likereceptorshavebeenidentifiedinhumanstodate.ThemembersoftheTLRfamilyarehighlyconserved,withmostmammalianspecieshavingbetween10to15TLRs.EachTLRrecognisesspecificpathogen-associatedmolecularsignatures.,22,ItisrecognisedthattheidentificationthatTLR2mediatedimmunesignalinghasimportanceininflammationanddiseasehasresultedinanumberoftherapeuticapproachesbeingdesignedwhichservetoblockorsuppressthefunctionactivityofTLR2.TheinventorshavesurprisinglyidentifiedthatTLR2-mediatedIL-8(interleukin8)cytokineproductionisinvolved,asanimportantpro-inflammatorymediator（炎症介质）,inthedevelopmentandprogressionofrheumatoidarthritis.,23,TheinventorshavethereforeidentifiedthatblockingtheactivationorsuppressingthefunctionorintracellularcapabilityofToll-likeReceptor2will,inturn,resultinareductionintheproductionofIL-8,thisinturncausingadown-regulationoftheaberrantimmuneresponsewhichcharacterisesthedevelopmentofrheumatoidarthritisinasubject.发明总览SUMMARYOFTHEINVENTION,24,各图示的简要说明BRIEFDESCRIPTIONOFTHEFIGURES发明的详细说明DETAILEDDESCRIPTIONOFTHEINVENTION,Thepresentinventionisbased,atleastinpart,amethodofreducingoneormorebiologicalactivitiesofTolllikereceptor2(TLR2)inaTLR2expressingcellortissueimplicatedintheonsetorprogressionofautoimmunearthritis,comprisingcontactingthecellortissuewithanantagonistofTLR2activityorexpression,inanamountsufficienttoreduceoneormorebiologicalactivitiesofTLR2inthecellortissue.,25,Accordingly,incertainaspects,thepresentinventionprovidestobindingcompoundsorfragmentsthereofwhichspecificallybindtoToll-likeReceptor2(TLR2)inordertoinhibitToll-likeReceptor2function.Theinventionfurtherprovidescompositions,usesandmethodsforthetreatmentofimmune-mediateddiseases,moreparticularlyautoimmunecondition