Radiation Dosimetry for 90Y-21T-BAD-Lym-1 Extrapolated from ...

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onoclonal antibodies (MAbs) labeled with I3l1have proven effective for radioimmunotherapy (RIT) of hemato logic malignancies but less so for solid tumors (1).
Radiation Dosimetry for 90Y-21T-BAD-Lym-1 Extrapolated from Pharmacokinetics Using 111In- 21T-B

AD-Lym-

1 in Patients

with

Non-Hodgkin ‘ s Lymphoma Gerald L. DeNardo, Robert T. O'Donnell, Sui Shen, Linda A. Kroger, Ama Yuan, Claude F. Meares, David L. Kukis, and Sally J. DeNardo Department ofinternal Medicine, University ofCalifornia Davis Medical Center, Sacramento; and Department ofChemistry, University ofCaltfornia Davis, Davis, California

onoclonal antibodies (MAbs) labeled with I3l1 have proven effective for radioimmunotherapy (RIT) of hemato en@ targets malignant lymphocytes, has induced therapeutic logic malignancies but less so for solid tumors (1). @°Y is an responsesand prolongedsurvival in patientswith non-Hodgkin's attractive radionuclide for RIT because of the range and IymphOma(NHL)when labeled with1311Because radiometal-labeled energy of its @3 emissions; absence of ‘y emissions, allowing monodonalanbbodiesprov@ehighertumor rad@on doses than outpatient RIT; and ready availability at moderate cost. Its corresponding‘31l-Iabe@d monodonalanthodies,theradiationdosim half-time is suitable to the uptake and residence time of etry of @Y-2-iminothioIane-24p-(bromoacetamido)benzyl]-1 .4,7,10te@cydododecane-N,N',N―,N―-tetraace@c acki-Lym-1(@°Y-21r-many MAbs in tumors. Clinical trials of RIT using @°Y BAD-Lym-1) is of importance because of its potential for labeled MAbs in hematologic malignancies (2—8)and solid radioimmunotherapy.Although @‘VhaSattractiVe propertiesfortherapy, tumors (9—13)have been encouraging. Although @°Y has itssecondarybremsstrahlung islesssuftabieforimagingandpharma favorable characteristics for therapy, its lack of a ‘y photo cokineticstudiesinpatients.Thus,thepharmacokinetic dataObtained peak has led many to use IIlln as a surrogate tracer. To for 111ln-21T-BAD-Lym-1 in patientswith NHLwereusedto calculate dosimetryfor @Y-2fl@BAD-Lym-1 . Methods: Thirteenpatientswfth conjugate 90Y for RIT, the macrocyclic chelating agent advanced-stageNHLweregivena preloaddoseofunmodifiedLym-1 l,4,7,10-tetraazacyclododecane-N,N',N―,N―-tetraacetic acid followed by an imagingdose of 111In-2IT-BAD-Lym-1. Sequential (DOTA) (14) was developed and has been shown to provide of @°Y and IIlln (15). Because imaging and blood and urine samples obtained for up to 10 d after stable radiopharmaceuticals infusionwereusedto assesspharmacokinetics. UsingtttIn pharma ‘311-Lym-lhas been shown effective in non-Hodgkin's cokineticdata and @Y physicalconstants,radiationdosimetryfor lymphoma (NHL), and radiometals are retained longer in @°V-2IT-BAD-Lym-1 wasdetermined.Results:Theuptakeof 111In-2lT tumors than corresponding radioiodinated MAbs, the radia BAD-Lym-1in tumors was greaterthan uptakesin the lung and kidneybut similarto uptakesin the liver and spleen.The biOkglc tion dosimetry for @°Y-2-iminothiolane-2-[p-(bromoacetami (@°Y-2IT-BAD-Lym-l)was calcu haN-timein tumors was greater than in lungs. The mean rad@tion do)benzyl]-DOTA-Lym-l dose to tumors was 6.57 ±3.18 GyIGBq.The mean tumor-to lated using the pharmacokinetics of IIIIn..2ff..BAD..Lym..l marrow(fromblood)radiationratiowas66:1,tumor-to-totalbodywas obtained in patients with NHL. 13:1,and tumor-to-liverwas 1:1. Imagesof 111lnwere of excellent qu&fty@ tumorsand normalorganswere readilyidentified.Mildand MATERIALS AND METHODS transientLym-1toxlcityoccurredin3 patients.Conclusion: Because ofthe longresidencetimeof 111In-2IT-BAD-Lym-1 intumors,high @Y PatientPopulation therapeuticratios(tumor-to-tissueradiationdose)wereachievedfor Thirteen patients (10 men, 3 women; age range, 33—71 y; mean sometissues,butthe liveralsoshowedhighuptakeand retentionof age, 51 y) with advanced B-cell NHL were enrolled in the study the radiometal. (Table 1). According to the Working Formulation of NHL for KeyWords:antibody;radioimmunotherapy; radiationdosimetry; Clinical Usage (16), 2 patients had low-grade, 7 had intermediate pharmacokinetics; @Y grade, and 4 had high-grade lymphoma. Lym-1 reactivity was documented on 10 of the patients by immunohistochemical stain J NucIMed2000;41:952—958 ing and on 3 by imaging. All patients, except I, had quantifiable Severalmonoclonalantibodies,includingLym-1, haveproveneffec

tive for treatment of hematologic malignancies. Lym-1, which prefer

tumors,

including

at least I tumor of

2-cm diameter.

One patient

had undergone splenectomy, 5 others had enlarged spleens, and I Received May 3. 1999; revision accepted Sep. 14, 1999. patient had evidence of circulating malignant cells reactive with Forcorrespondence or reprintscontact:GeraldL DeNardo,MD,Molecular Lym-1. Three patients had marrow NHL documented by biopsy to Cancerlnstitute, Section ofRadiodiagnosis andTherapy, l5O8Alhambra Blvd., Ste.3100,Sacramento, CA95816. be