Anti-claudin18.2 antibody and method of making and using thereof

Abstract

An isolated monoclonal antibody (mAb) or antigen-binding fragment thereof having a binding specificity to CLDN18, wherein the isolated mAb or antigen-binding fragment thereof selectively binds to CLDN18.2 with measurable affinity and avidity, but not CLDN18.1.

Description

[0001]^^oc-e^o.:^.^o. s, aceaona ca-m,se,e unneer oe..n.aee o,e. e.nrreovssconoasures oc waocn aer.ncororae reerenceeren. re eraeuces, arnese mnoresacroscuureare rneeraaeso re anae-saoune.ec anncaoese. o ano cancer asrc caanscrecr asn aancreac cancers are amone mos common manances worwe. asernuroe.n maor, ca wuases r oaneeaen mtha mnosa cromsm oons caan,ceorue an we mnorraeamerca, an new cases reore1.ne, was esmaea, cases woue n mon anaea wou occurn, oose cases.eween an ,e caonosen -ear survva rae was2.ancreac cancerse mne overa w morean, cases reoren3. mos common cancer worwe, anasrc cancer, ne,ancreac ca4ncers more common sa accounnor o cancers an o cancereas.ueoe avance one o2s.easeoeoawrneeaenroasse,uces arroenmosrsovsnoo,r wese m a caomnannece-ear survva rae o cear unm s reresen an area o ee ov mereexcraes nee. manances,ncuson oaun.aa, .aseenneo severauman mucosa eea cens aansr,c aunrnan ncorremaac e cxanrceesrss.on,sur.es w a senecvee mareurnorasrc ea ssues5.owever,urn carcnoeness,esruo cons o aowsore exosure o . eoesa cane an oe eea cearr5-e7r ssncon maes . a unue,asrc canccesse areeeraeucs. n aonoasrc cancer,e o cer-seccareormmuneeraes. cancers,ncunreas, coonv,er eesxoreasseoan, oarrac.,a asneenancereeacec cnan secveer6armar .s noeecen normaancreacssues,n cases orma rs. e aenocarcnoma,. o casesa ces w .osverancre5acuca anoesaren .or cancermmunoera a exresson.evera aveeen aroveor cnca use5reneveomenowever, none secc an- . anoes.ereore, a nee remansoreeveomen o cancers. orrean manances suc asasrc anancreac ^ ^^^omorearceceuasrc^oors.:eu^areeseone arna^o reease asaonse seeccncc eaoees o o anauoeraeuc aens, an anor n,ncun . nnnr oanem aes. ne. sc,ereeoscoasvunrer aovnesnsoa seec mocnocoona ano.es,ms or. an, oren- comnaonereo.n one emomen,e ms or anen-nnramenereo a nn ano ..n one emomen, ave a av e ms or anen-nnramenereo ereeo anaven a ano ..n one emomen,e ms or anen-nnramen amno acn o snee eumn encon em aenn,eosoae m. asn or anen-.n.nramenereo comrse an e :,,avn aeas ,,,,,,, or en w ramenereo com,,, or.n one emomen,esoae ms or anen-nn ,, or ernse a wn amneo ac seuen:ce oarvn.n a oneas ,,,,, or anen-nnramenereo comrse an amno e emomen,esoae ms ,,,, ac seuenceavn aeas ,, oneu eemnco , or en we :,,,,, or.n se men,esoae ms or anen-nnramenereo comrse an amno ac :ea,vn, a,e oars.n, one, emo,men,,e,s,, or en we ereo comrse an amno ac seuenceav oae ms or anen-nnramen or mens or w anene-nnra:men,,n a ereo,eas ,,,,,,,soae c,om,rse, an, a omrno. acn on see eumenocemaevnn, aeeas ,e ex,resso,n o,,.,s asso,c orae we snever we : or. asrc anancreac cancers.escosu auman manances,ncun . anoesorr reurerscoseseeveomen o an- n a ean cancer. er noer asec,escosureroves ansoae m or anen-nnrameneaseoa,vn a,n,n secco , comrsn an amno ac seuenceavn a ,,,,,,,,,,,, or en we :,,,, n one e ,,,,,,,,,,,,,,, or.o .mu noomen,e.so.ae m or anen-nnramenereo seecvens ereoas ann anon one. emaovmen,soae m or anen-nnramen .,, or. n.n one emomen,soaen a vaue o no morean,,,.,., nn av o .avn a vaue m o no or m aonreena-nnnramenereoas a .,.,., or. n.n one emomen,e rao on.n,. o,.e,s.o,.,., anen-nnramenereoo ae m or .n one e .o .s aeas,,,,,,, or ereoomom.eno,e rao. osrnon oesoae m or anen-nnramen aouo aou, orrom aouo amo auou.o aou,rom aouo aou,rom ^ ^^^umanrnoam ocneee^wo ermo.:^romen,e^soae m or anen-nnramenurerncues a or a reconm onnea enm anoemo oenn. .,ne onseo eae m mae aumanze ano, a cmerc ano, esoae m mae aseccm anomoen,esoae ms an.n one emomen, n one emomen,e anen-nn,r-secc ano, or mu-secc ano. scv or a ramen mancue av, aa, aa', a n s ocnev emraomen. anen-nnrmen,escosureroves an eav canoresoae m or ,,,am,ene,reo, comrsn an amno ac seuenceavn aeas ,, ,,,,, o or en we :,,,,,,,, anen-nn onen emraor mm. enen as,escossceosuerreenr,oves aaa canoresoae m or ,,,,,,, or comernsn ane amno ac s:e,ue,nceavn aeas ,,,,,, ,,,,, or anenn o-nen emnoram or menen,. aesssccoossuereerroevn,e csomer vasrnae canoresoae meas an amno ac seuenceavn a ,,,,,,,,,,, or en we :,,,, or anenn o-nen em, no, ramme,nen,, ae, o ssscr coossu. erereorevn,es come vrasrnae ane aav canoresoae meas ,, mno ac seuenceavn a ,,,,,,,,,,, or en we :,,,, ereonav onne e amnonme, sne,, ce, o cscr oos.urerov.ens o anne esomaoem men, ore ansoaene- mnn orramen nnramenereo comrses a varaeeav can an a varae c anen- comemenareermnn r anavn o :,,,,eo,n an ,,,,, , , , an ,,,,, an or,, ,, an ,,,,, an n aurer asec,escos,,, an. m or anen-nnra ureroves ansoae nucec ac enconesoae can, ore varaeeavm ceann,, ae eavan,eaa can,e varae acas aeas ,,,sscoseeren.n one emomen,esoae nucec ,,,,,,,,, ,,,, or en we .:, n a ,,,,,,,,,,,,,,,,, or. nucec ac ausrescr aosseec,ereen, wsceorseunreero vveceosr asn e exxrreessssoen vnecor comrsnesoae scosen aereurn, were arseenc,eeos csceossur aerorovareosc a ceos or c ae eu coam a c rores.ne nucec ac as cuurnn aeuroser ce as aesc,sceosescoesrueren, sroovaes ae m aenoo osroroucunc ce a c .ne an.o comrsn ^ ^^^m ornoan acuer^en-eor.:n a^snec,rae^mesncosuerreeoro cvones anmmuno-conuae, comrsn esoae emomen, uaeo aru un rou aner.n one amneon, anener comrses a covaenon seecerom an eseron, an eeron, an osorus ese armone, aone, aesuoneon, anmeon, a suoneon, a osaeon, a n one emomen,eru, u an coramzonreseson a c oro ao cxomc anaonereo. reaen, or a comnaonereo.n one emomen, cooxc aenen, anmmune reuaorn or aen or a cemoeraeuc aenrom a cass ouunnse sres,eceronmer acrow a aors, enzmen ors,mmune m aaors,so ouaors, anmeaoe aens, raoacve caoceeasomrc a comnaonereo.n one emomen,e cooxc aens seece rom a ereo.n onn,e ozoamcn, monome aursan, emansneaervave or a comnaon ce, ce, em ceo,men,emmune reuaor reaens acvae or suressmmune ces,soaen aurer ase mca,croeasce,o osurreenrorvce cse a.armaceuca comos c m or anen-nn rame on, comrsn e arma n ereo or emmuno-conuae, an a raonucneu oenc ,ea a em ac oxoce n, amaene er, ca aeerrer uca. armenac,e au cceam coomeraoseuonc aurene,r o cro am cormses a raosooe, a n one emomen,eeraeuc aen comrses an an-esroenn aaeonn, ae rreeco. rosnenasen or, anasen or, a c eorn or, a n o e ccen or, a , orroen sness one emno amuern,er aes mecr, e, or oe a co cosm mcorsn sua erseon aromver nee sso e a. rn meooe o sureaecn an a e suececve w amo cuannce or.ne asomanese mrn oor ane sen-nnramen ereo.n one emomen,e meo comrses one emomen,eu meeco an eecve amoun o emmuno-conuae asscose eren.n armaceuca comoson as comscrosses amnsernoe suec an eecve amoun o e e nmasooamn ren on,e eem caoncemren co,mrese csane ccoere or cr eoe cmn. ar csaensce cre,san ecxreraescsn cancera,u esnoa.e.a cnan ocenre, nn oneea em canocerm, aenna, caenc meer, reoca o carneacern,a csanrc cancer, oraer cancer. ee cerurer comrses co-amnsern an ancove, am ao cun o aeraeuc aen.n one emomen,eeraeuc aen comrses ann or, anaesmeoera aen, an enzme, an-esroen aen, a receor rosne nase n or or a cnomnor, a ce ccen or, a , orroen snessn or, a n one em aonereo. o esona aeur mero asm ore acen n,, anee s esu nc-ose nucres a nrorvum ameasn en a. soeureoon, c womerresnne an so eueconves coonocenraonn a suec.n one emomen,escosureroves a souon comrsn an eeacsmvae ^ ^^coonocenr^aaosmocaneo^o.:nee^summecun.e-con^uae asscoseeren.n one emomen,e souons eoowenoreeoscnr anon o aner aeaeunrees o camss,scaoesnuren m caonuenccomoen m woreue a accoamrenanronm acracwornansc.e wnersaensncosuare anese are,rawerneosre,e noco one co senvera emomens arranen scosure maeescre w aona secc aneaseremn os scoe,e rawns rou use oe accomannenure, am sn no w owsc: ace a seunemnecens o en ecxoraceuar caunomans an neu- au numan an cnomous moneaun. an sanuren s.owseeecon o an-aun. anoesn ce cuure screen rec couw mrec er s usownseeecon o an-aun. anoesn ce cuure screen ow vec ransece w eer aaun. or aaun. exresson usnuorrex sowse caracerzaon o cmerc an-aun. anoes ow comer ure sows cesransece w eer aaun. or aaun. exresson vecor ane caracerza,on onn an o cmerc an-aun. anoes, usnv manuacurer o-aernereromeroowe s an cacuaons ro -rove sowareoowe s an cacuaons usn manuacurer- ou-ree ae s so rnoww ersare ereom cearracoerozwaeon osn ann c aavcuao ons c usmner mca an-aun. anoes ure sowse caracerzaon o . se nuacurer-rove soware ano ow comer anx cesransenc ecxre oumanze an-aun. roen ssn -aunuson anuroes sowresce cara ucserzaon o . secc oumanze an-aun. ure sowse n recomnanroens aernerero caracerzaon o eoennn o an-aun. anoes o-ounrce sowmseress o .-exressn ces -aun.n resonse oreasnoses oumanze an-aun. anoesnomemen-eenen reuroexc sows aessass oaun.-exressn ces -aun.ne ans-encaeu onon.or an coeess asn eencoor ce-see :neonaree- cmeesa anencreoaosxncoses oum asanze ure sowse caracerzaon o cross-seccneracons am sa anoes ouman, ra, an murne ornsow comer on an-aun. ^ ^^nur ae^ocn senow^cso.:^onceen craaraocnesrz^a uosnn omseo-sseormeasrvae-ccenuo ore ascnen-cea mucrnosc.o an aoes a ure sowse seuence anmeneween n eenes o a s anr an comaraor anoes eenes oe enre varaamee rewoorn on., uer anoweranes, resecve, an .e anscoosurescoseseeneraon, caracerzaon, an acaon o an- eaeescron,esorrean manances suc asasronesnaumors.neoown nerawns, sm reaerences maeoe accomannrawns, wcorm aarereo. oerwse.eusrar svem emosocaen smar comonens, uness conexcaes cams are no meanoemn.menesr emescoreneeaeescron,rawns, an e mae, wouearnrome sr or scoem oense m suaee uze, an oer canes ma e rea unersooae asecs oeresenscosure,c as maerreseneeren. w usraeneures, cane arrane, susue, comne,e sneraescreeren, an we vare oeren conuraons, a o wc are exc coeneamraea,e anesnen a aunsaa, s are aam oroensa eren. uncons. averec roesneormaon o eween ces. su anconsorm aaraceuararrera conroseow o moecues oar oe eeare c cercaaerosr8.eormaso an oesearrers aneo mananeransmemraneomans:- an-ermna enreerasannroens comose oour omanoos8. s are exressen normasssu wne coasm, anwo exraceuar aveeenneoeormaon o ca5-6,8esowever, aereuncon an exresson wcaseenneo severaumannc meran.ancearcuarneressaun. .5-6, euman ene conans exons anns,ronncunasrc anancreac cancers. ormswosoorms, . an .9.s.esee srnacvee v saracnns a o exonsa an erenssues, w5-.reomnan exressen normaunssue aren resrce.o e oxnress aemnnoa ascrcsseureenc6.e seuence o .s amosencao . w seuence smara maeess wensc eoxverarce ouaroo.-secsnure.ss caen c anoes sncan morencunenv me. orano asnecoce msonaroceonna anoe.smor casn,cersmecmucno aneraoe asresnesv,eomen, anen receor ces -, an ano- cmerc armas a m ru conuaes .oeuxmaseas ecacoraouenses c wmerc m-osav see acvacans5. anas sown sae an cencess aumanze m aas sown cnocmearaasrec a cancer. a5saceo- maor o anoes unereveomen are ms,ssc avnoosaevuex amsao.roee va meos oreamenoroasrc anancreac cancers,ncun -venmoene, ^ ^^sraesm aen^ocns csean s^oen c.:a^ea coee oce cr ao^nss- conncen anen.e aroraeracon conanna e nrae memraneraon anee.orurer exsacmreon oeneraecnuesoresoaon o acveramens o anoes, seeor nzmo,o,aw,:.-. e, a..uc.e.:- ousseaux e a.eos eer caemcress, . monocona anmo “aneso an”s useneroaes sense an secca covers sne anoes, ano comosoron rsec womnoane anoeoesncun aons an anaons e..,a,a′, anv, soon ase ex seececsre, as woeoc aas a ancoramens emomens,e2ano mae monocona,ocona, cmerc, sne canv, mu.-n some or mu-eecve,uman anumanze anoes, anor acveramensereo.xsecc o acveramens o moecuesano ames ra nown anensncuea,a′2, scv anv rammeennss, onc auneroucs o aammunooun exressonrar an eoe-nn eernm “ ov”e re anersooees m annmraumm aenns moenroaneme anove. reconon annn se.s reon consss o amer w o ocne coenans a comee anen varaeomann, non-covaen assocaon.sns conuraavon ana onee can o eac varaeomanneracoene ree s mer.o an anennn se one surace oe- even a sneec varvea,eoem saxns coner anennn seccoe ano.owever, ase a o reconze anorna o an anenv, c aomorsn onree s seccor an anen se. u a aower anane enrennmmunono scoame ac emveoomrenonss, o anmmouno moaunnc muoeecumesm,u.ne.o, moouecnues moaecues an nn se ana canmmunoseccan conan a eeroeram o an anen. ca ano reerso aceav ceracnros ceonm cormsers on aeaca owoeav cans anwo cans. eav can consanomansarevaev a csan v,ara,eomanarevae as anree o a can varaeomanarevae as an an a.ac can c caonnsasn comomrsaen caanreev asasen as.e cans o anoesmmunoounsrom an vererae seces ac seuencees oo oneer o cwo cearsnces, caeaa anama,ase one amno omans o ervaraoens coanmoemmeanns.e an reons caneurer suveno reons caeramewor reonsa.racee vrmnn reons s, an more conserve comose oree s anours, arranenaraeeooowmann oreere:r, or,s,ca , , rom amno-ermnuso carox-er , aneav can mnus. ne varae reons oe eenn onseere am arenon acn se reueonncse oaneer caocnss we anen.mmunoouns cane assneoeren casses.anereom araen oereav cans,mmunoouns:,,, an , an severa oese maveeu mraeorr cvasesesn oo ^ ^^sucass^esocseo^oe.s:^, e..^omansa , , , , an an .eeav can consan amma, an c mourresonoeeren casses ommunoouns are cae aa,ea, eson, eren casses, resecve.e suun srucures anree-mensona conuraons o ouaone oe srum o s “mm anomnaoucnoonoao mo aunns eneo are ous” w a ae ns uosneown es,e.r.ee.n, reeenrsvo auna a annooe os coamnersrom a ouaon areenca exceorosse naur ne mnor a occurrn muaonsa maeresenn anen acm souen.s.ureornmoocrona anoes are secc,enrece aans a sne cancueerene, ann coonreassore cconevenonaocona anorearaons wc monocona anosrece aans a sne aeaenrsmnanereneermnanseoes, eac secc,e monocona anoes are avanaeousn onae aen aerne. snn aesonoer roma cuure, unconamnae oerm ze encae munoouns.e moer “monocona” ouason oe a cnaraoceers o anes n ano asen oanerom a susanaomoeneous arcuar meo.or exameo,oe meo connoscroue as reurnroucon oe ano an resenscosure mae mae eronmaa a mneooesrsoeesc ursen accorance we aure,: , or mae mae recom e oer sen, ,,. "eco nan meossee, e..,..a.o.ecnuesn exoemnenan" meanse anoes areenerae usn recomnan nucec ac maononocona aonusooses ce casn.erouce usn varous meos,ncun wou recr,o mmoursemarro cmeas,,aesa, recomnan , moecuar conn o anoes er.ewoecno. an aneeoer es ac.over meneo.ssee.eoe.ransus.n.o.ncue “cmerc” anoe nocona anoes ma c smmunoounsn wc aoron oeeav anor aarncusarenca w oromooouso corresonn seuencesn anoeserverom a e cans sesceesn orcaeonno aarcuar ano cass or sucass, wee remaner o anoer seces oreo wn oromooouso corresonn seuencesn anoeserverom anoes, soon asen exo anoeer aeno cass or sucass, as we asramens o suc orrson e sreooca acv ..a.o.,, an e aer.m, “rocu.maanz.ca.c.,:- . erverom a non-umaneo annormomu”n roeeorsuo ae o enneere anoavns s oe moecueenerverom oneor mno,ree ruemmaannnmmmunooun-ervears ramewor suor resues mae aereoreservennmu anono.unes.osn ao oon, “aumancaze anoes” are wenownoose sene ar.see, e..,ueen e a.,raocn. ecerms “a,n:en- or- eoe-nn,oorsoonn o er ara.,meon”ecnoo,: . reon”, “varae reon seuence”, or “nnoman” re , “varaeoman”, “varae are caae onno an anensuc as an ernoras amencsa oon an. aneo anena- ^ ^^nn^roacmee^no.:^as a re^ona reon on an anoanso anens.ese arnamoen.s maxae caae oe anen-nnuncon an aonauncons oenac ramenscvm conesss onnnramensncue,u are nomeo, a sne-canv o a sne arm o an ano o ceo vnanreaceen can an varaeeav can omans aramen wcs a monovaenrame an s cnonsesoee can a snecner, or a consaneav oma n oe, consan , an reon seeueenrcme”s, “ oarn “enn- onrn e. omoaen-”nnoron orramen”, “varae reon”, “varae severa ar-nownecnues.or exam maeerverom an ano oescosure an enzme, suc asesn, an suee,ure monocona anoes cane ceave w rouceswoenca anenncneraomens, ceaeraon.aaneson o anoes anennn se, an a resua “c”ramen, wose n “aa”ramens, eac w a sne rea.esnreamenes ana′ramenaasmweo re anecesn cs a o crsaze s caae o cross-nn anen.e aroraeracon conannaomrann ses ans e coece an concenrae memraneraon anee.orurermeenss canen eneraecnuesoresoaon o acveramens o anoesseeor examcron o . e a..uc.e.:- ousseau e,aw,. caemcress x e a.eosnzmoo,:-, - eerm, “ce.” reerso-aernereromer , aae-ree meoor measurn memanosecuarneracons.e aneaecnoo emnaee nee o mcroucs annormaoeres no neeour anoesoe vauae anennn an secc eaeeen. scrreseonn os sceosure mae unersoo more rea reerenceoeoown scosureaseenescrcc emomens an examesncueeren.oueresens nonenea suceeas w sou reereen rceeaor see acscmeaaosn os u ceornane e smcooe omenessceroesou,re. xamemm.uneznaeraon o ra anoesoaun: ras.as. w-o esns ree: sccn anowoo ceos woresre. ooaonre recemvemu anzramoenm omunezwaoena wan wxe aauuvann..-ransec cees wereumanmroncne cesnomeereun’s7u-en . urera,nsece w. a eu.aroooc exresson vecor enconuman ae, rasen receveooss a-anervas conawnnnemmunzaonrooconn aernanncomeereun’s auvan anum .-oerecreasthn ce numers ras receveooss a-anervas. ooss conane-oecreeammunzaon,n aernanncomeereun’s auvan anum , exceorassn a cne nu,mers ras receve o recomnanumanaun. assemeno vrus-ea wrceeres ^ ^^orauos^ooracce,u es^o.xceo:^s rasemss reace.^veo.-o- er. ce neu smameersm anmunzao rnec sormaenan wasu umsea s,n an..oro coors, woeererao n oo o was coeceree wees aer eac so waeoresoae an sorenu nroenor sorn. aune cenorou wn: eas aaere r omnoorm monuees.eoearaoneaearane,a.o. was careu asrae an wase. remann wnowene ceen wruaon,e aer ueraen,a.o. .erss, ces were wase an reesruesesnee usn ssn a a ce concenraon ox7ceser n soaon oa -es m. wereawenmmu : mx conann recomnanumanne ce me.a a,enncuae w an ano sann ce marers.oownncuaon, were wasne reaens secco ra -ce an- mcroeas. were enrceor-ces mane acnncuae wuoroore-secc uaro earaor mane enoec,a.o.-ac-vae- ce. sorens wer usn a w euor va eeoscence,a.o.--, wase, resuseneeenn suanee an sore a un sorn uorescenc r, o sor-ces,e aror ecvaeeorn . an manua ausmen ae comensaon waserorme usno sorer soware were soreromes.aes were auseo oanve,-osve ra -ces.-ces -ce cuure me naae as sne cesno-weaes conannrevousreare eac sor, uoa caonann , ra senoce conone mea, aneeer ces.or roro s es were sore.aes werencuae a° w2oras xamecre.enn. noencrcaon o an-aun. anoes: sanwc-ce cu.ureesen a weesre we srceree: cnoeaeo wr secrmeo ann an-raaun.crann rec mmunoesearc,a.o. menacson . -- oraun. acusossemsa.o.- -ce suernaaeasn w weares waarsveeserreemes w ,enoce w n . e cuureas were om cuureaes an useor screenn.-ces remannn amcaon o ano sor vearnae reoanes.rnveroen,a.o. a -°or- ce suernaan was aeo eacae a rocn,aes were wase aseore, an- were wase aseore,enncuae w a an: uon.oownourncuaon,aes acsonmmunoesearc,a.o.---or sec monnuares ano conuaeoncuae w susraeermosercenc,a.o...aeesac were wase,en an commerca so souonermosercenc,a.o. anonsa weesre soe u wsenre c ao snercmreooasoeme oer a vau nems. exceeeecnon oe s reaconar o ann noeaesv see cconcroo.a wueren rea. ^ ^^^oces ecrae^o.:^anoes^wereroue anoenure.oror,. o- or sor,e. were o--ceoss sve.oa o conesoun seccaoaun..or aun..ororore, were o--ceoss svoer.oa o conesoun seccao oun se e were-osve.oa o cones ncocacoaun.. o reen owomer: exresse o cnonrem secc, cones wereeseornnoaun. anaun. exresseaun sur.ace wa os aransece .eecon o anonno suraceransece w euaroc excreevsseon vow comer. ces wereransen aun. ure, . aneco,r rses eneccoven.umanu-raenns aun. an were use as a neave conro.woasoownransecoece wrreevan sane w ceracereermosercenc,a.o. n a,n cesa were coece5, ceser we.-ce suernaan was aeoe ces a a:uon anncueae a ~o.x a°.es were wase,enncua rour seco e w exauor conuae an-ra c enr oanre a wnasoacsonmmunoesearc,a.o.-- or mnues a°. comer usn, c aes weroer reesssusenen uer.nn waseermne ow aun.,u noaun.a oro nwea cvomeer.ones exressn anoesaoun ano varae reons e conro, were seeceor moecuar “rescue” oe auno. aen an-.aun. anoes,-ce conesaoun surace exresse eres naun.,u noe neave conro, were seeceorurer screenn. suernaenanasv oe caonnesounaun.,u noaun..enn acv o-ce aun. aneauromno.r,s was an e are sownure.ne cone, wcouno .escose anoes sexecresse seccaor use as a screenn reaen or: . e areene wac arrowsor: , xamem.rocaucono on on raoumaarna cmerc monocona anoes: eav an-ce con cesane vnaraee seuences aene wereoown am cs:omer wereawerom sorae a -°. seccoeeaer seuence an consan reon oe ra mu aex- usnrmers mcons wereurer amen a seconar usn nesne rarmaa seuences. resrcon ses.eav can an can amcons were conenoersa conane conannuman oruman, resecve.er seuenc an exresson vecor asms wereransen co-ranseceno cesore vercaon, exresson anoes. ouce ra uman cmerc aracerzaon omercn-aun.noes –o aunec.omnaonw a cnomoer s.uexrnaans w ceeres w scerreeenreansoernnranw nsecoo e smure warce: e euxarresosec ^ ^^ex,r reesss^eocnocvveeec^o.ros.e:^xncon ceum^sanranus-ecene waurreneva.n an waueren use. as a neav. an woasoownransecon, ces were saneorow comer as e conro. cuure,owever ces werencuae w cmerc anoes se escreor-ce . m ra uerom mo w s so.wnnure, reresenave anoes wnaun. a u au nonn.naunn w. ore neave conro. cmerc anoesounoaun.. aunner, serveass as n ao conereoceor a anoes exce . , aan- anaun. onransenransecoreaun. exresson.eecon ooaun. aun. x suorse reore secc oe an- ara ccoenrezsaoonaun.. ecomnan an oom suerecrnanan-s waueren va.aenoores – n:nereromerasonown as usn aoreoceaeun.nsrunmenn o-aer m were caure ono an-umancosensors,en assocae w re.noes au.nenso.rs- wesreu m-oevneo wroee comnanuman n sn concaronnossneemcss,ua.er,o a.n-essocaoune o:e arnom romaun. was measure.urves an an cacuaons were anaze uso manuacurer-rove soware.merc anoesoun recomnanuman n o-aernereromer a an w v aun. a auesno n rane as sownnure. o-raaceerrznaeroner oomerme.rec.,n-au wan.noes – v: o recomnanumanaun..onae rs aso useo evauae cmerc ano av caure ono sreavnosensors,en assecomnanumanaun. m was n.ensors were moveo wes conanocae w cmerc anoesue:rom anoaun. comex.urves ann anvecs cuaero anazessocaon oe manuacurer-rove soware.e av ore c cuaons were anaze usn aun. was wno n rane as sownnureme.rcu anoo recomnanuman was no eoen on a conro reaen, xame.rou ecvaonua oeor av. uma umanze monocona anoes: enezaon oeav an anaraeeons: ‘recumaanvz an can varae reonsor anoes wereumanze usne umanzaonncuneeusa sonns’ aormnscoveruo. eos cosenor ermnera . seuencees m euncaoon ,reuen resue susuon , or coneno mammaan exresson veconeumanze ano an reons were eneramensenewz.ueosrs conannuman aa consan reons usn was nouman use as a researcoo,ean-aunner roenzea. -: ^ ^^^usmonmcee^aaeeo.:^rs aceurrs-se^ro-eanss wurcaon, anoes werre anaze anaca .mm xmm,.m coumn. m sou oen , . was use as moeaseor-mnue runsm a.os mame, m soum core, roens wereuer-excaneno m soum aceae, mn,an,ecn roen. no sames werenecenoe same coumn aer aroxma sucrose,.. wees aerenaurcaonoes sa overme. -eracerese wees an sxnoree caeores: r werenerae o oen oneres, moecuar we, an ew moereecnuar we.e canen eac seces, , was cacuaease onnae,cenenerae areaeweeners anas sa meons.s summarze aeas eaaemonsraea mosumanze an-aun. anoes were saeornereouro sx wees unerese conons, sown ne e caneneroen o xams seec.esa orvaecreme. owomerzaon oumanze anoes: or comuamrsaonnz,e an anr -o anes w.er aen sc:roeeneesncowomer an asescre earer. an-aun ne ue:eumanze ano, e osve conro anor aens,o-,,- ,- an-o.euxecmaca,- an oer anoes were exresse ransenransecex aneeves oe e axnr-e . scoreerneareerom.ero w evaasu uasee sson were a oe mneasnure an va aunes a avs sow on ann-ae. aneoes, vaueeso- an- . anoes were cusereewe o oor a en. n an. n or wn a rane o- an mnro,v werease vauesor av wereeween. n an. n or a more aaonem oenanuunnc.ona an o overoeuxma. ou ecc owomer: aun.,rer con-rmaue secc o reresenave anoesoaun. an no x .ow comer mneusonroens were exressenransenransece waseece usn an an-os wereoowe asescrerevous. exresson -aun. an -a aunno.. ase seocwonn onur conrme exresson o conrme usnean-aunner, .o conros coen.xresson was aso umanze anoes was noueoac o exresson.onermeaoacun onn aun.,u no -aun.,urer suor - aaon oaun.ecc n seccoaun.. rec sanewccc o re asresenave anonn:oaun. wasurer vaae w m recomnanrervousescre, weoown canes.aes were coae ,aun. oceronosss:emasu,na..o.-croo,s osems,a.o.- conrocroossems,a.o.- .noes wereese ar emm, ansnone ^ ^^wmamsune^oecocesee^earc uso.,n:^a. ano. an-^-u-. seconar ano conuaeo acson ,u no .- or e resu sowsa oun .- ,ouno . an-on. co,nuro noure-on. coneroa.n-aun ner, ow comer an aaemo aenoeer,e nonnn onsraee secc o oaun.. anemess ea uosens o a aonreooe-sa weerrenenr eneeromer nsor-umaener.n: oerneroameer reco.em.,nanuman- staun.-su-enroencroosse n ca ausrse ono sreavn-conuaeosensors,emns a,ssoaca.eo w.-m, o anom w.ean.sd, assocaocoan.on.snensores wnserreumeenn m soovweareo, a wneso coensa wnerne anneereanse an ooera.rec., cusern oe canen resonseromestassocaonoendassoc ca ocn or nonocn anoars, areso was se ae aroraaon.oeermne noesaocenn were cuserenoe samen an consee se-nn sna. eoes.noesa noocnn were cusereno searaerensoave smaroaveeren eoes. an consere conro coemaerraarocr acna cousesern- oscoose- ano aeres, s caonae anoes, anosve ure.ue canae anoesocennw onne ceomnanranor m aarxaencanaese conesave smar eoesoosea are areanevenooes, oweveer,s,necuscose cone, men. ano , sowe unreconann acvo a nno moosc comnanrao or anoes.enounoaun. asno , enoun asno , e can wasaeo ocr ceomar aaor anoes, exce-. was oranzeno ana wassnusaerom a an coanes.aer cusern, anoescrce.s suessa as a unue eoe-ocen anr coomearaor comamareeo om. o wen x ene-raoucnn a.n anooes.-eenen coox eermneemm reeen ara- eeee c: ec- nen eaures a oc avoo n an oxc aonoa- ena: asee aerraeeucs cane comaren vroo acon.o comaree uncon o anaerooeeunxamaeraeucs moe o ovaran ces wereransuceo exressaun.aeo au,neseamser are ces -aun. werereae w anoeuxmaoresncene rerorer. an asence oormaumanerum o evauae nours.es were esence a envauoaen ue aassea o ra mnemnrarnoemm.ermeanouor nesce ancrosse a me-asoure uusnon curve..reae w was ^ ^^^osowe eece^ouvaen a.:c^v oo^euxma waseecaens assa ssem. uraon oe assa an a acccevsso. ass conssen w euvaennn acv overe n ssemee mumerc commen cascae. eoc-m-eeaeenene-meaeooxc : oeermneere areeaures acv o ano-aseeraeucs cane comaren vro o acon.nsesn ssem o, a anow ano ra enae areaeroenaeraeucs moe exressoneve overeuraon oe assa.esonses maeueoe avaae anen anonernazaon maave anmac ones a re ascu,10erennnroeres, or oess,umanrmar auraer ces wve. neave seecon re enrcerom woeoo cesa wer,eoraonwseu ensraen cenruaonoecome “eecor” ces.e ces.e -aunce.oar exeressaun.aeo auorescen reorer wereare ruxma, rannrom no. ces w nerenr aeae-o w serauon., coeuxma or a a::eecor :are raoo e es were ae was vauae wne-our assamerame. mcro esvcaouae oss o -aun. ce reorer sna usnme-seresuorescen secce. uxma acv no oemoonesruaxma waseecaens assa ssem ane erenarmaconecs caracerzee exen acnve. acv. soew eena sncan acv o comareooeuxmas conss nce overe cours en wreaer anen avaa xame.ne oernaezaesonn aownorreaer ce enaemen an cocuncon. or man ano- oru an co-nuae. anoruess, a anes soesom oarea mcn:nvovesnernazaon11.oown anonn,nernazaon canecansm o acon cooxcaoa anracno cancer cesosomes weresosomacesa acee uae o ceners wn ces.eenn on as reccn m ees o cooxcaoa, cessoowseren eeceanasm ces o acon.aun.s a unconroen norma exresse onasrc cance12s anas aonaeeneecenasrc,ancreac,arrac an cooreca aursn.. maus,eee m saemcansm onernazaon anracnososomes an- auor-e a rne-, anau acn-se.e, ns anu veoe e uoerse,cac maeen scen reaena an on aowoe a sen uaunxomcaa,n o wnen ore. eareaec w onernazeroenso accsosomes n eene .euorescen sna oauor- res anoens oneow envronmen ososomes.ns wa,e accumuaon onernaze mc nososoma comarmens maeuane overme usnme-seresuorescen enrosrceo a.n - c.eense w weares seawe an cuuren mea suemene w rounoom aesornn.eeec aeu,er, ceswen, an oo cueuurexmna-weaee wauor- accornoe manuacurer’snsrucons. mcroer wse ore ^ ^^anuo^cro-ocencena^raeo.e:^ons anoroes^orn caon arsosare vaomumenesw weer.e aees woerea cueu creesn a a n or ve cemaerarorusn a ℃, nncuce snme-ser umencuaororours. snas wer esve-ceuorescence mcrosco,enernazaon anracn concenraoen rse.ae senecaas weeroro anoeuxma a eern orn a wasnernaeze au momoraeca coune anoe overme.e resu sows cooxcaoan case o ososo emecsenan anrace more snasncave o xame.aracerzao oeuxma ure. ross-ecesnnn ooouse an:aau an raumauannze an-owau cnom.e arn.oxes were w anean rez.e: ror cross-secesnno mouse exressn ansenransece w asms waseerm mnouse or raaun. anaun..nn o surace-exresseaun oun mousee an us ranaruevnous.,escre meos.ae sowsae ano .oro exraceuaromauns n,o cnaun..ueo seuence smarouman assa.enn o o mooumseouasu mnon.e waasu conn was noncuene nn an o. rme , w a asrc caonceeruxnm caoms n n aauomna wnurmeou cse. em comeerrac a.nno conrearsa,eucsorreansaens w ano. reuc aereree oumann aumanze eec ess, ma exermroveeraeuc rnmmunoenc or oer unwane se eecs aer amnsraon.n aon, oeuxmaeco-nze a an osnec eoenromsoorm oaun- wen comareo - , an -r an-u. anoes,ncun - ,-eao unuen re.snn caracer o ma nee, n an soececux, cusern,nernazaon, an oerooca acves. ure an , as we asmaereanve exarmaceo snmeacrs ueren acvesracn ur nnernazaon ansosoma eounevnecsee aen.meen s oruceuara anassom oaraornoes: seuen ’s unue caracers,e con numercens sceme usn,ene , an comaraor anoes were aneneaa comemenar-eermnnousrmeonormacs soware an sownnure.e anoesoxen uer an reowoenrs s oeav an cans were ane across a on,eramewor reons on, ananees e onrure .eercenaeenor a snure an . ane seueen vcaersae reon were cacuaeor comarson eac comaraor wereas eac comaraor sare,- en w sare ano- en w awo-raameew,o orne- resamonse,-es,eerc senaraee ueno oen w eoac a covmer c enao croam mora a.rao raosr. rn wa as ^ ^^ener com^oacree^oo.:^e averae o^ercenaeenes amone remann comaraors.e rameewnocres r weeroen ssnca.n a.e.noe sncsa anneereun varae reonsu non a enconermar sr cesne amno ac seuences c ucure o s uneree caracersceaures o as aocmvare.o comaraor anoesn eoenn ure an conseuen,eooca av,n an sum smecarc,oauns. a, wumeraenze an- . ano w an, nnoaun. anaun..as s aan-aunner caae o ano era as we asanosnauena exr ores asnonones areere unseuormosr oeve caon ona,ueoe sncanecnca avanaes o ncer. e smar caeorncuns seec over oer anoesn sncaneraeuca avanaeorrean canvcers o w oavuerenxr.es,son oaun.ro.ves ^ ^^eer^oce^o.:^ ^.ence reonmsac cancer sascs nernaona s:www.wcr.orcanc csaonmaacnc-ec er- .mer rancoecr-esa:sancsceracs anures .mer renr. seaa cananceroce, .ancancn c cc rae enr acea crc -c ss aancscsu -res nernaona s:www.wcr.orcancer- . caeascsorancerre-asacsacnscers:www.cancer.orcancerancreac- .an oocer mar,ao ernue oru,-sa mor-,sc aras en.m e,mmonuno,eraan.,omuar.aeus.n.sa a nove mo:ec.uaor . sosow-s-,a-en. : .an, e,:sene : . .aun- sce va r,ranenur,ez,uer,rec eveomen.nancrans aan-cancerare suaeoreraeuc ano . eres. ec :-.o:. - . caumn-,- ,a aa- nsovmea. ow,nsa: rreama,rn.oo,monc,oescu,mura. ranscronacor, encoesun- ane seonmeacor-seeccsoorms.rooumeooman scn.oeo aernave .. . ov :-.o:. ...- ..aren ca:unsn cancer:a:noss,ro. aucu n-,oesnoew: noss anera.manceres. .re ss- rucu,re,e. reeunaeon: n, a,na esxer,oe:,aene,e.z,an. mammas. essons evouonar conserven a ene. u :-.o:..ene....u .aervn.,ec:a,e.n,an,raer,arne,an,on,en. oeurmmnnensceneorcer-vas oenoasosas-.asuereraeucoecues usnwo .u e a.ronersoecuaro rrooc. ov :e. .onon e a.ransancersecsences.. ^ ^^^oce^o.:^ ^ae.mmunzaonroocooreneorsaenor an- . ano –oor an mmaunzoas-onmmunoenoor coer no ooose r coeror no uvan eoee ^ ^^anae^m.oceae^o.an o:^aneumaonwzee^ra ann-aun. anoes ame anmeuerane, no ae mee. ae me ae ees ^ ^^ane^.ocone-^o.:^.n ano^es aneeves o exressonn ces. oe amoe acnrooun xum on sn sss onvs sss no.oe. ouse a ^ ^^eawee^en.ocome^aro.s:o^n o con^seuencesor s anramewor oe varae reon oeuxma an o-er an- .ar anoes. - - veraeen ae.eon .n ramewo.rn ^ ^^^oce^o.:^ ^noaaraeeon ucecc. mnoc. ^ ^^^oce^o.:^ ^>euence : a ucecc euence >euence : a mnoc euence >euence : a ucecc euence >euence : a mnoc euence >euence : ucecc euence >euence : mnoc euence >euence : ucecc euence ^ ^^^oce^o.:^ ^>euence : mnoc euence >euence : ucecc euence >euence : mnoc euence >euence : ucecc euence >euence : mnoc euence >euence : a ucecc euence >euence : a mnoc euence ^ ^^^oce^o.:^ ^>euence : a ucecc euence >euence : a mnoc euence >euence : a ucecc euence >euence : a mnoc euence >euence : a ucecc euence ^ ^^^oce^o.:^ ^>euence : a mnoc euence >euence : ucecc euence >euence : mnoc euence >euence : ucecc euence >euence : mnoc euence >euence : ucecc euence >euence : mnoc euence ^ ^^^oce^o.:^ ^>euence : ucecc euence >euence : mnoc euence >euence : a ucecc euence >euence : a mnoc euence >euence : a ucecc euence >euence : a mnoc euence ^ ^^^oce^o.:^ ^>euence : ucecc euence >euence : mnoc euence >euence : ucecc euence >euence : mnoc euence >euence : a ucecc euence >euence : a mnoc euence >euence : a ucecc euence ^ ^^^oce^o.:^ ^>euence : a mnoc euence >euence : ucecc euence >euence : mnoc euence >euence : ucecc euence >euence : mnoc euence >euence : ucecc euence ^ ^^^oce^o.:^ ^>euence : mnoc euence >euence : ucecc euence >euence : mnoc euence >euence : ucecc euence >euence : mnoc euence >euence : ucecc euence >euence : mnoc euence ^ ^^^oce^o.:^ ^>euence : a ucecc euence >euence : a mnoc euence >euence : a ucecc euence >euence : a mnoc euence >euence : - >euence : - >euence : - >euence : - >euence : - ^ ^^^oce^o.:^ ^>euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - ^ ^^>eu^eonccee^o.:^:^- >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence : - >euence :uman aun. ucecc euence ^ ^^^oce^o.:^ ^>euence :uman aun. ucecc euence^^ ^

Claims

^^oc-e^o.:^.^as c nn s.amnesosa:e monocona anom or anen-nnramenereoavn a weecco:,,,,, co,m,rsn, an, am,no, ac seuenceavn aeas en ,,,,, ,,,,,,,,,,, or ane.n-ensnoae, o ra mr. men ore arneoe sne-ecnvenramen oam, werenesoae m .esoae m or anen-nnranmseoner.u no .. umanramewor reon. eo oam,urer comrsn a ms a.umeasnozaee an mo or, a an cmene-rcn annora,m orenereo oam, werenesoae .esoae m or anen-nnram a recomnan ano. ms an enereo oam, werenesoae anen-.ne. nsoraaeme mns a or avn, aean-, anna'ra, am scenv, oerre ao sc ovaramm, werene .esoae m or anen-nnramenereo oame,n. soae ms asecc ano,r-secc ano, or werene .esoae m or anen-nnramen mu-secc ano. eav canavn an amno a ereo oam, comrsn an ,,,,,,,,c, s,eu,enceavn aeas en we :, ca.naevsnoa ane am mno o acr an seeune-ncen, o anr vr.amenereo oam, comrsn aaa ,,,, n aeas en e :,,, .eso,ae, m,,,, or. varaeeav canavn a onr a amnnoen ac-n senuenrcaemaevnne areoeas oam, comrsn a :,,,,,,,,,,,,, or, or a varaeen ca wne amno ac seuenceavn aeas en we :,, avn an ,,, ,,,,, ,. wn, erseo, nae, o e mr. soae or m ane onr- annramenereoavn ann secco eav c nen-nnramenereo comrses a varae :,an,avn comemenareermnn reon , , an o varae an cana,, an ,, an ,, an or,, an an a ,, an ,vn, an, or,, a,n an. o :,, an ,, an ^ ^^^oam,.cene^soo.a:^eeav nuceacn a oc^eancmo,neeasoaae m ca onr o anaen-nnramen o can oam, ore varaee m,e varae vecors e.n exresson vecor comavrs cnan oesoaame nu.cec ac oam, werene roaro.xres c ceoss or ce aen eu c aom cer.sne nucec ac oam, wereneos ces a am,. so meo oarrooucc cne a.n ano comrsn cuurneos ce o one o .nammuen aon-coonusrouce. ereo oam conuaeaoe a, corum urnsnesoae m or anen-nnramen covaenon seecerom an esero rou aner, werenener comrses a sueon, anmeon, a suonen, an eeron, an amneon, an ameon, a eeon, arazoneon or a comonna, aosaeon, aosorus eseron, a cooxc a.ene,m anmmunmo-ucnoen rueuaea aoccornoon camereo,. wereneru un comrses a .e r reaen, or a comnaonereo. rom a mmuno-conuae accorno cam, werene cooxc aens seecenercaarownor aen or a cemoeraeuc aenrom a cass ouunners, raoacvoers, aaors, enzmenors,mmune mouaors, anmeaoe aens, rom a ca.so ceeo amme cms, nu o ,nr oo a z-oc coo anm mucana ne, ao mcn ocnoorereno.o cam, werene cooxc aens seece comnaonere me aursan, emansneaervave or a reaens a.cvaeemo om. r suuno-conuae accorno cam, werenemmune reuaor .armaceurecssmmune ces, ce, ce, ce, macroae, orenrc ce. ramenereo oama o cromeomsmon, comrsnesoae m or anen-nn acceae carr uno-conuae oam, an aarmaceuca raonuc.e, aeer. oxarnm, aaceueca comoson oam,urer comrsn a raosooe, a .earmaceuraceuc aen, a cemoeraeuc aen or a comnaonereo. comrses an an-esroen aae comoson oam, wereneeraeuc aen ccenor, a , onr,r ao reeceorrosnenasenor, anasenor, a ce ereo. n snessnor, a nor, or a comnaon an eecv.e am moeuno o oereasonae a s muec or w an ae cancer, comrsn amnsernoe suec .e meo oam, werene cna-ncner cnomrarsmesen ceereo oam. .e meo oam, werene cancer comrses coosre ecxaressnaun.. cancer, esoaea cancer, nasoarnea cance cancer,ancreac aer cancer. r, ana cancer, reca cancer,asrc cancer, or ^ ^^^oaeraeu.cece^moe.:^o oam^,urer comrsn co-amnsern an eecve amoun o cemoer. a ae a men ee. n,o an o enzamme,, wereneeraeuc aen comrses an ano, a nasen an an-esroen aen, a receorrosnenasenor, anor or ao cro,m a ce ccenor, a , orroen snessnor, a .. seo muen onoao onearemo., werene suecs auman. nnramenere coom orsanm an, e weecrevne coen scoenuraonons oooesoasamea mn a su ore acn. anen- ^ ^

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