HER1-Targeted 86Y-Panitumumab Possesses Superior Targeting Characteristics than 86Y-Cetuximab for PET Imaging of Human Malignant Mesothelioma Tumors Xenografts 英文参考文献.docVIP

HER1-Targeted 86Y-PanitumumabPossessesSuperior TargetingCharacteristicsthan 86Y-CetuximabforPET ImagingofHumanMalignantMesotheliomaTumors Xenografts TapanK.Nayak*,KayhanGarmestani,DianeE.Milenic,KwamenaE.Baidoo,MartinW.Brechbiel* Radioimmune Inorganic ChemistrySection,RadiationOncology Branch,NationalCancerInstitute,NationalInstitute ofHealth, Bethesda,Maryland, UnitedStates of America Abstract Malignantmesothelioma(MM),arareformofcancerisoftenassociatedwithpreviousexposuretofibrousminerals,suchas asbestos. Asbestos exposure increases HER1-activity and expression in pre-clinical models. Additionally, HER1 over- expressionisobservedinthemajorityofMMcases.Inthisstudy,theutilityofHER1-targetedchimericIgG1,cetuximab,and 86 ahumanIgG2,panitumumab,radiolabeledwith Y,wereevaluatedforPETimagingtodetectMMnon-invasivelyinvivo, andtoselectanantibodycandidateforradioimmunotherapy(RIT). Methods: Radioimmunoconjugates (RICs) of cetuximab and panitumumab were prepared by conjugation with CHX-A’’- DTPAfollowedbyradiolabelingwith 86Y.TheHER1expressionofNCI-H226,NCI-H2052,NCI-H2452andMSTO-211Hhuman mesotheliomacellswascharacterizedbyflowcytometry.Invivobiodistribution,pharmacokineticanalysis,andPETimaging wereperformedintumorbearingathymicmice. Results: In vivo studies demonstrated high HER1 tumor uptake of both RICs. Significant reduction in tumor uptake was observed in mice co-injected with excess mAb (0.1mg), demonstrating that uptake in the tumor was receptor specific. SignificantdifferenceswereobservedintheinvivocharacteristicsoftheRICs.ThebloodclearanceTKaof 86Y-cetuximab 86 (0.9–1.1h)wasfasterthan Y-panitumumab(2.6–3.1h).Also,thetumorareaunderthecurve(AUC)toliverAUCratiosof 86Y-panitumumab were 1.5 to 2.5 times greater than 86Y-cetuximab as observed by the differences in PET tumor to background ratios, which could be critical when imaging orthotopic tumors and concerns regarding radiation doses to normalorganssuchastheliver. Conclusion: This study de