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Bispecific antibody and bivalent hapten radioimmunotherapy in CEA-producing medullary thyroid cancer xenograft

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The purpose of this study was to compare the toxicity and efficacy of two-step radioimmunotherapy using a bispecific anticarcinoembryonic antigen (CEA)/anti-diethylenetriamine pentaacetic acid (DTPA) antibody (F6-734 bispecific monoclonal antibodies
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  BispecificAntibodyandBivalentHaptenRadioimmunotherapyinCEA-ProducingMedullaryThyroidCancerXenograft FrançoiseKraeber-Bodéré,lainFaivre-Chauvet,CatherineSaï-Maurel,EmmanuelGautherot,MaryseFiche,LoïcCampion,JeanLeBoterff,JacquesBarbet,Jean-FrançoisChatalandPhilippeThédrez INSERMResearchUnit463,AnatomopathologyDepartmentandRégionalCancerCenter,Nantes;andImmunotechSA,Marseille,France Thepurposeofthisstudywastocomparethetoxicityandefficacyoftwo-stepradioimmunotherapyusingabispecificanti-carcinoembryonicantigen(CEA)/anti-diethylenetriaminepenta-aceticacid(DTPA)antibody(F6-734bispecificmonoclonalantibodies(BsMAbs)andan131l-di-DTPA-TLbivalenthaptenwithF(ab )2fragmentsofthesamedirectlylabeledanti-CEA131I-F6. Methods:Eightgroupsofnudemicesubcutaneouslygrafted withthehumanTTmedullarythyroidcancercelllinewereinjectedoncetumorvolumereachedabout200mm3.Twogroupsreceived37or92.5MBq(1or2nmol)l31l-di-DTPA-TL48hafterinjectionof2or4nmolF6-734BsMAbandtwogroupsreceived37or92.5MBq(250ug)131I-F6.Fourcontrolgroupsweretreatedrespectivelywith(a)92.5MBqnonspecific131l-734fragments,(b)92.5MBql31l-di-DTPA-TL48hafterinjectionofamixtureofirrelevantF6-679(anti-CEA/anti-histamine)andG7A5-734(anti-melanoma/anti-DTPA)BsMAb,(c)250ugnonradiolabeledF6,and250M9F6-734BsMAbandthen48hlater1.25nmolofnonradiolabeledhapten.Acontrolgroupreceivednoinjections.Toxicitywasevaluatedbydetermininganimalweightandthenumberofleukocytesandplatelets,andefficacybyvariationintumorvolumeandthyrocalcitoninduringa90-dperiod.Histologi-calanalysisoftumorsandstatisticalstudieswereperformed. Results:Thetimerequiredforthetumortodoubleinsizewas respectively57and86dwith37and92.5MBqF6-734/131l-di-DTPA-TLand44and65dwith37and92.5MBq131I-F6.Changesinthyrocalcitoninlevelswereparalleltothoseintumorvolume.Weightlosswas5 ,leukocytenadirsrespectively1640±838and1560±1160/mm3andplateletnadirs1.46±0.52106/mm3and0.73±0.38106/mm3afterinjectionsof37and92.5MBqF6-734/131l-di-DTPA-TL.Weightlosswasrespectively8 and16 ,leukocytenadirs50±100/mm3and175±50/mm3andplateletnadirs0.71±0.18106/mm3and0.48±0.11106/mm3afterinjectionsof37and92.5MBq131I-F6.Conclu sion:Two stepradioimmunotherapywasasefficientasthe one-stepsystemandmarkedlylesstoxic. KeyWords:radioimmunotherapy;bispecificantibody;two step targeting;medullarythyroidcancer JNucÃ-Med1999;4 :198 2 4 ReceivedNov.3,1997;revisionacceptedMay8.1998.Forcorrespondenceorreprintscontact:FrançoiseKraeber-Bodéré,MD,ResearchUnit,463INSERM,Institutdebiologie,9,quaiMoncousu,Nantes44093,Cedex01,France. Lonoclonalantibodies(MAbs)directlylabeledwith13llhaveprovedonlymodestlyefficientforradioimmunotherapy(RIT)ofsolidtumorsotherthanlow-gradelympho-mas.Uptakeisgenerallybelow0.01%forlargetumors,andtumor-to-normaltissueratiosaremoderate(usually<10)  1,2 .Thefrequencyofcompleteandevenpartialresponses hasbeenlow,notattaining5%inphaseI/IIstudiesincludingpatientsmostoftenwithlargetumormasses(J).However,theaffinity-enhancementsystem(AES),atwo-steptargetingtechniqueusingbispecificmonoclonalantibody(BsMAb)andbivalenthapten,developedbyImmunotech(Marseille,France),allowstumor-to-normaltissueratiostobeincreasedthree-tofive-foldinnormaltissuesbyloweringradioactivitylevels(4,5).Medullarythyroidcarcinoma(MTC),aneoplasmoftheparafollicularcells,representsaround10%ofthyroidcancers.Theresidualormetastaticformsofthisneuroendo-crinetumor,whichisonlyslightlychemosensitive,constituteapotentialapplicationforRIT(6).Ithasbeenclearlyestablishedthatitsneoplasticcellsexpressandsecretecarcinoembryonicantigen(CEA)(7).Aclinicalimmunoscin-tigraphicstudyperformedwith 'I-labeledbivalenthaptenhasgivenencouragingresults,visualizingoccultmetastaticsitesbiologicallysuspectedafterariseinserumthyrocalcitonin(TCT)concentration(8).AclinicaldosimetriestudyperformedwithI3'l-labeledbivalenthaptenindicatedthattumordosesofmorethan100cGy/mCiwereprobablytumoricidalinneoplasmsweighinglessthanafewgramswheninjectedactivitieswereabove100mCi(9).ThepurposeofthisstudyinthenudemousegraftedsubcutaneouslywithahumanMTClinewastocomparethetoxicityandefficacyoftherapeuticinjectionsofanti-CEA/anti-diethylenetriaminepentaaceticacid(DTPA)BsMAbandl31I-di-DTPA-TLhaptenwiththoseoftheF(ab')2fragmentofthesameantibodydirectlylabeledwithI3II.Theactivitiesoftheinjectedreagents(37and92.5MBq)andtheprelocalizationperiod(48h)ofthetwo-stepsystemwerechosenaccordingtothepharmacokineticanddosimetrieresultsobtainedduringpreliminarystudiesintheanimal  10,11 . 198THEJOURNALOFNUCLEARMEDICINE€¢Vol 4 •o 1•anuary1999 by on March 11, 2016. For personal use only.  jnm.snmjournals.org Downloaded from   MATERIALSANDMETHODSCellLine TheTTcelllineofhumanMTCobtainedfromtheAmericanTypeCultureCollection(Rockville,MD)foruseinthisstudyexpressesCEAonitscellmembraneandsecretesTCT.Itwasculturedinadherent-cellmonolayersinRPMI1640medium(GibcoBRL,Cergy-Pontoise,France)towhichwasadded10 fetalcalfserum(PCS;GibcoBRL),1 glutamine(L-glutamine200mm;GibcoBRL)and1 antibiotic(penicillin100U/mL,streptomycin100U/mL;GibcoBRL;LifeTechnologies,Cergy-Pontoise,France). AnimalModel Nudemiceover10wkofageweregraftedsubcutaneouslyintherightflankwithIO6TTcellsin0.3mLofsterilephysiologicalserum.Theanimalswerehousedinasepticconditionsandusedoncethetumorsreachedasizeofapproximately200mm3,about6wkafterinjection.Lugol'ssolution0.1 wasaddedtodrinkingwater(1mL/100mL)1wkbeforeand2wkafterinjectionoftheradioiodinatedreagent. AntibodyandHapten Thereferenceantibodywasananti-CEAF(ab')2fragmentdesignatedF6.ThismouseIgG|antibody,usedinF(ab'>2-fragmentform(12),wasprovidedbyCISBioInternational(Gif-sur-Yvette,France).TheF6-734BsMAb,obtainedbychemicalcouplingoftheFab'fragmentofF6antibodywiththeFab'fragmentof734antibody(anti-DTPA-InIgG,),wasdevelopedandprovidedbyImmunotech.TheF(ab')2fragmentofnonspecific734antibodyandtheirrelevantBsMAbusedascontrolswereobtainedrespectivelybycouplingtheFab'fragmentofF6antibodytothetheFab'fragmentof679antibody(antihistaminemurineIgG|)andtheFab'fragmentofG7A5antibody(antimelanomamurineIgGi)totheFab'fragmentof734antibody.TheseantibodiesweredevelopedandprovidedbyImmunotech,togetherwithbivalenthapten.Not-(diethylenetriamine-N,N,N',N -tetraaceticacid-N -acetyl)-tyrosyl-Ne-(diethylenetriamine-N,N,N',N -tetraaceticacid-N -acetyl)-lysine(di-DTPA-TL)(5). LabelingandControlsoftheF6Fragment DirectLabelingofF6Fragmentwith • /.heantibodieswere labeledwithiodogenmethodtechnicasdescribedbyParkerandSpeck(13). MeasurementoftheSpecificActivityofIJII-F6.Theactivityof labeledantibodywasmeasuredinanionizationchamber(Medi-202;Medisysteme,Guyancourt,France),whichgavevaluesrangingfrom185to555MBq/mgforthedifferentgroups. MeasurementoftheRadiochemicalPurityofI3I1-F6.After purification,2mlofthe131I-F6solutionweredepositedona10X2cmstripofITLC-SGChromatographiepaper(Gelman,AnnArbor,MI).Afterdrying,thestripwasplacedinaChromatographietankcontainingtrichloraceticacid10 .Afterdevelopmentofthin-layer(around8cm)chromatography,thestrip,protectedbyaplasticfilm,wasexposedonaphosphorusscreenfor5min.Thescreenwasthenscanned,andthechromatogramobtainedwasanalyzedwithIPLAB-Gelsoftware(SignalAnalytics,Vienna,VA).Radio-chemicalpurity(theratioofthenumberofpixelsoftheChromatographiedeposittothetotalnumberofpixelsofthechromatogram)wasalwaysabove98 . MeasurementoftheImmunoreactivityof - /-F6.TenuLofan 13II-F6solutiondiluted1:1000weredepositedintubescoatedwithanti-idiotypeantibody(IgG44.12.13),providedbyImmunotech,whichcontained250mlphosphatebuffer0.lmol/L,pH7,plus0.5 bovineserumalbumin(BSA).Thetotalactivitywasmeasuredafterlhofincubationatroomtemperaturewithslowstirring.Thetubeswerethenwashedthreetimeswithphosphatebuffer0.1mol/L,pH7,plus0.01 Tween20,andtheboundactivitywasmeasured.Theimmunoreactivity(theratioofboundactivityinthetubesafterwashingtototalactivity)was85 -96 . LabelingandControlsofdi DTPA TLHapten Labelingofdi-DTPA-TL-InHaptenwith • /.Di-DTPA-TL haptenwasprovidedintheformofa1.11mmol/Lsolutionincitrate-acetatebuffer(10-100mmol/L),pH5.Inasterile2-mlplastictubeweredepositedsuccessively25mLofdi-DTPA-TL-In(25nmol),25mLofphosphatebuffer0.3mol/L(pH6).50mLofachloramine-Tsolutionat1mg/mLinphosphatebuffer0.3mol/L(pH6)and100mLofaI3IIsolutionat16.650GBq/mLinsodiumbicarbonate0.1mol/L(pH8)(13II-S3B,CISBioInternational).After10minincubationatroomtemperature,thereactionwasstoppedbyadditionofsodiummetabisulfiteat1mg/mLinphosphatebuffer0.3mol/L,pH6.ThepHofthesolutionwasbroughttobetween5and6byadditionof750mlN(2-hydroxyethyl)piperazine-N'2-ethanesulfonicacid1mol/L.TheresultingsolutionwaspurifiedonaCIS-graftedsilicacolumn(Sepack-C18;Millipore,St.QuentinYuelines,France).Freeiodinewaselutedwith5mLphosphatebuffer0.1mol/L,pH7,andtheradiolabeledhaptenby5mLphosphatebuffer0.1mol/L(pH7)-ethanolmixture(3:2). MeasurementoftheSpecificActivityofI3>¡-di-DTPA-TL.The ethanolicsolutionactivitycorrespondingtoI3IIboundtothehaptenwasmeasuredinanionizationchamber.Thespecificactivitywas59.2-70.3MBq/nmol. MeasurementoftheRadiochemicalPurityofl3lI-di-DTPA-TL. Tenmicrolitersofa131I-di-DTPA-TLsolutiondiluted1:1000weredepositedintubescoatedwitha734antibodyprovidedbyImmunotech,whichcontained250mlphosphatebuffer0.1mol/L,pH7,0.5 BSA.Afterlhincubationatroomtemperaturewithslowstirring,totalactivitywasmeasured.Thetubeswerethenwashedthreetimeswithphosphatebuffer0.1mol/L,pH7,0.01 Tween20,andtheboundactivitywasmeasured.Radiochemicalpurity(theratioofboundactivityinthetubesafterwashingtototalactivity)wasabove90 . Radioimmunotherapy Eightgroupsof6-8miceeachwereinjectedinthelateraltailveinwitha0.2mLsolutionofdilutedimmunoconjugateorhapteninsterilephysiologicalserum.Twogroupswithinitialtumorvolumesof180±88and245±123mm3wereinjectedrespectivelywith37and92.5MBq(250jag)I3II-F6fragment.Twoothergroupswithinitialtumorvolumesof302±50and170±55mm3wereinjectedrespectivelywith2and4nmol(200and400|ag)BsMAbF6-734,andthen48hlaterwith37and92.5MBq(1and2nmol)l31I-di-DTPA-TLhapten.Preliminarystudiesdeterminedthat400ugBsMAbrepresentedanamountlessthanthatrequiredtosaturatethetumor(unpublishedresults)andthataratioof0.5atinjectionbetweenthehaptenandBsMAbwasmostfavorablefortargeting(//).Fourcontrolgroupsweretreatedrespectivelywith(a)92.5MBqnonspecific131I-734fragment,(b)92.5MBq13lI-di-DTPA-TLhaptenadministered48haftertheadministrationofamixtureof4nmolirrelevantF6-679BsMAband4nmolirrelevantG7A5-734BsMAb,(c)250\ignonradiolabeledF6fragmentand(d)2.5nmolF6-734BsMAbfollowed48hlaterby1.25nmolofnonradiolabeledhapten.Theinitialtumorvolumesof RADIOIMMUNOTHERAPYNMEDULLARYHYROIDCANCER•Kraeber-Bodérétal.199 by on March 11, 2016. For personal use only.  jnm.snmjournals.org Downloaded from   thesefourgroupswererespectively113±55,167±50,228±94and192±125mm3.Finally,acontrolgroupof12micewithaninitialtumorvolumeof228±94mm3receivednoinjections.Thelength(L),width(w)andthickness(t)oftumorsweremeasuredwithaslidingcalipertwiceaweekfor90d.Tumorvolume(V)wascalculatedaccordingtotheformula:V=ir/6XLXwXt(14).Allanimalswereweighedonthedayofinjectionandthentwiceaweekfor90d.Biologicalmonitoringwasperformedonabloodsampledrawnfromtheinnerborderoftheeye.Theparametersusedtoevaluatethetoxicityofeachtypeoftreatmentweremaximalweightlossandthevariationinthenumberofleukocytesandplateletsmeasuredondays0,7,15,21,30and60.Theseassayswereperformedon4micefromeachgroup.Theparametersusedtoevaluatetheefficacyofeachtypeoftreatmentweretheminimalrelativevolume(ratioofthesmallesttumorvolumeobservedtotheinitialsizebeforetreatment),thegrowthdelay(timerequiredforthetumortodoubleinsizeaftermeasurementonthedayoftreatment)andthevariationinserumTCTconcentrationmeasuredbyradioimmunoassayondays0,15,30,45and60(calcitoninimmunoradiometricassay,CISBioInternationalCo.).Thedetectionlimitwas50pg/mL.Thesecountswereperformedon2micefromeachgroup. StatisticalAnalysis Owingtothelimitednumberofanimals,themeansforthequantitativevariablesofthedifferentgroupswerecomparedusingnonparametrictests(theMann-WhitneyUtestforcomparisonoftwogroupsandtheKruskal-Wallistestforcomparisonofmorethantwogroups).Pvalues<0.05wereconsideredsignificant.BMDPStatisticalSoftware,Version7.0(Cork,Ireland),wasusedfortheanalysis. Histológica Study Ahistológica analysisoftumorstreatedwithspecificradioiodin-atedreagentswasperformedatthetimeofminimumtumorvolumeandafterresumptionofgrowth.Untreatedtumorswerealsosubjectedtohistologicalanalysis.Thefragmentswerefixedina10%formolsolution,embeddedinparaffin,cutinto4-umsectionsandstainedwithhemalum-eosin-safran.Thedegreeofcellularpleomorphismwasstudiedquantitativelybycellsizeanddensity,thenucleocytoplasmicratio,theappearanceofchromatinandthesizeofnucleoli.Theproliferationindexwasestimatedfromthenumberofmitosesperfieldathighmagnification(X400)andbyanimmunoperoxidasetechniqueusingMißantibodydirectedagainstKÃŒ67ntigen,thenuclearproteinexpressedinallactivephasesofthecellcycle(G,,S,G2andM)butabsentinG0andearlyG,(75).Cellularreactivitywithanti-CEAandanti-TCTMAbswasstudiedbyanindirectimmunoperoxidasetechnique. RESULTSRadioimmunotherapyToxicity Themeanmaximalweightlossesobservedduringthe2wkaftertreatmentwererespectively8%and5%afterinjectionsof37MBq131I-F6andF6-734/'3'I-di-DTPA-TL(P=0.12),and16%and5%after92.5MBqI3II-F6andF6-734/131I-di-DTPA-TL(P=0.004)(Table1).BloodcellcountsareindicatedinTable2.Inuntreatedcontrols,themeanleukocyteconcentrationwas2700/mm3(range800-7000)andthatofplatelets1.4106/mm3(range0.57-2.7IO6).Therewasasignificantdifferencerelativetotoxicityonleukocytes(expressedasapercentageofvariationbetweenthenadiratday15andthebasalvalueatday0)betweenthegrouptreatedwith37MBqI31I-F6(-98%±3%)andthattreatedwith37MBqF6-734/l3lI-di-DTPA-TL(+11%±80%)(P=0.01),andbetweenthegrouptreatedwith92.5MBqI3II-F6(-89%±8%)andthat TABLE TumorEffectandToxicityofRadioimmunotherapy Groups131l-F637MBqF6-734/131l-di-DTPA-TL37Bq131I-F692.5BqF6-734/131l-di-DTPA-TL92.5BqNoinjectionNonradiolabeledF6NonradiolabeledF6-734/di-DTPA-TL 31l-734IrrelevantBsMAb/131l-di-DTPA-TLMinimalrelativetumorvolume )63±465±2842±2742±8100±t100±f100±t100±0t100±0tGrowthdelay(d)44 ±1*57±9*65±1*86±2*12±0409±223±019±0412±04Maximalweightoss8 *(14-5)5 (10-1)16 *(25-5)5 (11-0)3 (7-2)2 (5-0 ofmicethatied02(D36,D67)2(D28,D75)2(D52,D75)0002(D20,D52)1(D60)P -0.600.180.03-----*P<0.05comparedtothenoninjectedcontrolgroup.tNotumorshrinkageoccurredinthesemice.d=dayofdeath;pr=comparisonofgrowthdelaytoreferencetreatment(131I-F637MBq);DTPA=diethylenetriaminepentaaceticacid. 200THEJOURNALFNUCLEARMEDICINE€¢ol.40•o.1•anuary1999 by on March 11, 2016. For personal use only.  jnm.snmjournals.org Downloaded from   TABLE2 BloodCellsatDifferentDaysAfterTherapeuticnjectionGroupsDayODay 7Day15Day21Day30Day0Leukocytes(/mm3)37MBq131I-F6F6-734/131ldi-DTPA-TL92.5MBq131I-F6F6-734/131ldi-DTPA-TLControls13ll-734IrrelevantBsMAb/131l-di-DTPA-TL248019002525220024003360±454±806±2483±535±570±795ND2040±375±2020±1000±2300±69917199852468150164017515606251380±100±838±50±1160±206±6373375±3200±800±3000±2675±3020±1830200029419205675842075±10214252840±12902201550±7597001580±1100450ND0332420±8903050±531±988±816±900±1167±981Platelets(106/mm3)37MBq131I-F6F6-734/131l-di-DTPA-TL92.5MBq131I-F6F6-734/131l-di-DTPA-TLControls13ll-734IrrelevantBsMAb/131l-di-DTPA-TLND=Notdone.1.701.181.471.121.351.17±0.55±0.53±0.25±0.58±0.21±0.20ND1.70±0.95±0.88±0.80±1.59±0.440.460.440.190.620.711.460.480.731.041.35±0.18±0.52±0.11±0.38±0.45±0.251.52±2.00±0.88±1.92±0.88±1.35±0.680.800.160.440.310.74ND1.012.42±0.891501.23±0.65128ND1.80ND0.971.23±0.511.37±0.26±0.20±0.65±0.50±0.32±0.28 treatedwith92.5MBqF6-734/131I-di-DTPA-TL(-34 ±41 )(P=0.04).Forplatelettoxicity,nosignificantdifferencewasfoundbetweenthegrouptreatedwith37MBqI3 I-F6(-50 ±26 )andthattreatedwith37MBqF6-734/13lI-di-DTPA-TL(+45 ±64 )(P=0.08).Conversely,thedifferencebetweenthegrouptreatedwith92.5MBqI3II-F6 (-66 ±10 )andthattreatedwith92.5MBqF6-734/l3lI-di-DTPA-TL(-39 ±24 )wassignificant(P=0.04).Afterreachingthenadirpointatday14,hematopoiesiswasrestoredspontaneously.Nineanimalsdiedduringthismonitoringperiod(Table1).Thedeathsoccurring28dafterinjectionof92.5MBqI3II-F6and20dafterinjectionsof92.5MBql3 I-734wererelatedtoleukopeniacomplicatingthetreatments.Theotherdeathsthatoccurredlater,aftertherapy,wererelatedtoinfection(asverifiedbyhistologicalstudyatautopsy). Efficacyof131I F6andF AfterinjectionsofL3II-F6andF6-734BsMAb/l3lI-di-DTPA-TLhapten,alltumorsdecreasedinsize(Fig.lA-D).TheminimalmeanrelativetumorvolumesofeachgroupareindicatedinTable1.Aresumptionoftumorgrowthwasnotedinallanimals.Thegrowthdelayswererespectively44±21and65±lidwith37and92.5MBqI3II-F6,and57±9and86±22dwith37and92.5MBqF6-734/ 31I-di-DTPA-TL(Table1).Whentreatmentwith37MBqI3II-F6wasusedasreference,onlythegrowthdelayafterinjectionof92.5MBqF6-734/ 3 I-di-DTPA-TLwassignificantlylonger(Table1).ThechangesintheTCTconcentrationsofthe2micetestedfromeachgroup(Fig.2AandB)wereparalleltothoseintumorvolume.Minimalserumconcentrationswererespectively168pg/mLatday15and<50pg/mLatday30afterinjectionsof37and92.5MBqI3II-F6,and142.5and<50pg/mLatday30after37and92.5MBqF6-734/13lI-di-DTPA-TL.Biologicalresponseslasted15din2miceand30dintheother2with13II-F6,and30din2miceand45dintheother2withF6-734/l3lI-di-DTPA-TL. EfficacyofTreatmentsinControlGroups Inthefivecontrolgroups,rapidtumorgrowthwasassociatedwithariseinserumTCTconcentration(Figs.1E-Gand2CandD).Growthdelayswerenotsignificantlydifferentbetweenthesegroups(Table1). HistologicalStudy Tumorproliferationwasmicroscopicallycomparableinthedifferentsamplesobtainedfromgrowingtumors,consistingofadensegrowthoflargecellswithahighnucleocyto-plasmicratio.Thelargenucleidisplayedregularborders,finechromatinandsmallnucleoli.Proliferationtooktheformofrowsandlobulesseparatedbyathinfibrovascularstroma.Controltumorobtainedfromuntreatedmicewascharacterizedbyanabsenceofnecrosisandamitoticindexof50mitosesper10high-powerfields(oneHPF=0.312mm2).MiBllabeled300nucleiper10HPF,and100 ofthecellsexpressedCEAandTCT. RADIOIMMUNOTHERAPYNMEDULLARYHYROIDCANCER•raeber-Bodérétal.201 by on March 11, 2016. For personal use only.  jnm.snmjournals.org Downloaded from   FIGURE1.Variationoftumorsizeintreated miceandcontrols.(A)131I-F637MBq,(B)131I-F692.5MBq,(C)F6-734/l31l-di-DTPA-TL37MBq,(D)F6-734/131l-di-DTPA-TL92.5MBq,(E)noinjection,(F)nonradiolabeledF6(—)andnonradiolabeledF6-734/di-DTPA-TL(—)and(G)131l-734(—)andirrelevantBsMAb/131 -di-DTPA-TL(--). o   2 l« oc 30 6 9 30 6 90 153 45O153 45 Daysaftertreatment 30 6 90153045 Thetumorfragmentsremovedatthetimeofthesmallestrelativevolumeshowed50 -60 fibrosis.Mitoseswererare <10per10HPF).Antibodylabeled100nucleiper10HPF,and100 ofthecellsexpressedCEAandTCT.However,recurringtumorsshowedavaryingnumberofnecroticareas:fewerthan10 afterinjectionof92.5MBq13II-F6and30 -50 afterinjectionof92.5MBqF6-734Yl31I-di-DTPA-TL.Themitoticindexwas100-120mitosesper10HPF.MiBlantibodylabeled1500-2000nucleiper10HPF,and100 ofthecellsexpressedCEAandTCT. DISCUSSION SeveralstudiesinanimalshaveclearlyshownthattherapeuticinjectionofdirectlylabeledMAbsgenerally FIGURE2.Variationofthyrocalcitonin concentration(pg/mL)intreatedmiceandcontrols(2mice/group).(A)131I-F637MBq(O)and92.5MBq(•),B)F6-734/131l-di-DTPA-TL37MBq(A)and92.5MBq(A),(C)noinjection(D),nonradiolabeledF6(O)andnonradiolabeledF6-734/di-DTPA-TL(A)and(D)131l-734(•}andirrelevantBsMAb/13 l-di-DTPA-TL(A). 2000150011000500 0 20002000204060204060 020 Daysaftertreatment 2 2THEJOURNALOFNUCLEARMEDICINE€¢ol 4 •o 1•anuary1999 by on March 11, 2016. For personal use only.  jnm.snmjournals.org Downloaded from 
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