title: A preclinical model of CD38-pretargeted radioimmunotherapy for plasma cell malignancies.
abstract: The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on malignant plasma cells. In this report, both conventional RIT (directly radiolabeled antibody) and streptavidin-biotin pretargeted RIT (PRIT) directed against the CD38 antigen were assessed as approaches to deliver radiation doses sufficient for multiple myeloma cell eradication. PRIT demonstrated biodistributions that were markedly superior to conventional RIT. Tumor-to-blood ratios as high as 638:1 were seen 24 hours after PRIT, whereas ratios never exceeded 1:1 with conventional RIT. (90)Yttrium absorbed dose estimates demonstrated excellent target-to-normal organ ratios (6:1 for the kidney, lung, liver; 10:1 for the whole body). Objective remissions were observed within 7 days in 100% of the mice treated with doses ranging from 800 to 1,200 μCi of anti-CD38 pretargeted (90)Y-DOTA-biotin, including 100% complete remissions (no detectable tumor in treated mice compared with tumors that were 2,982% ± 2,834% of initial tumor volume in control animals) by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor xenografts treated with 800 μCi of anti-CD38 pretargeted (90)Y-DOTA-biotin achieved long-term myeloma-free survival (>70 days) compared with none (0%) of the control animals.
authors.affiliation: Authors' Affiliations: Clinical Research Division, Fred Hutchinson Cancer Research Center; Departments of Medicine, Radiation Oncology, and Laboratory Medicine, University of Washington, Seattle; and Dade Moeller Health Group, Richland, Washington.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Green
authors.forename: Nural N
authors.initials: NN
authors.lastname: Orgun
authors.forename: Jon C
authors.initials: JC
authors.lastname: Jones
authors.forename: Mark D
authors.initials: MD
authors.lastname: Hylarides
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
authors.forename: Donald K
authors.initials: DK
authors.lastname: Hamlin
authors.forename: D S
authors.initials: DS
authors.lastname: Wilbur
authors.forename: Yukang
authors.initials: Y
authors.lastname: Lin
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Fisher
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Kenoyer
authors.forename: Shani L
authors.initials: SL
authors.lastname: Frayo
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Gopal
authors.forename: Johnnie J
authors.initials: JJ
authors.lastname: Orozco
authors.forename: Theodore A
authors.initials: TA
authors.lastname: Gooley
authors.forename: Brent L
authors.initials: BL
authors.lastname: Wood
authors.forename: William I
authors.initials: WI
authors.lastname: Bensinger
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002478:Cells, Cultured; D005260:Female; D006571:Heterocyclic Compounds / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods*; D054219:Neoplasms, Plasma Cell / Q000532:radiotherapy*; D009942:Organometallic Compounds / Q000627:therapeutic use*; D016499:Radioimmunotherapy / Q000379:methods*; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes / Q000627:therapeutic use
chemical_list: D000911:Antibodies, Monoclonal; D006571:Heterocyclic Compounds; D009942:Organometallic Compounds; D015021:Yttrium Radioisotopes; C113625:yttrium(III)-1,4,7,10-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid; D051997:ADP-ribosyl Cyclase 1