title: Pretargeted radioimmunotherapy using anti-CD45 monoclonal antibodies to deliver radiation to murine hematolymphoid tissues and human myeloid leukemia.
abstract: Radioimmunotherapy (RIT) for treatment of hematologic malignancies frequently fails because of disease recurrence. We therefore conducted pretargeted (P)RIT studies to augment the efficacy in mice of therapy using a pretargeted anti-human (h)CD45 antibody (Ab)-streptavidin (SA) conjugate followed by a biotinylated clearing agent and radiolabeled 1,4,7,10-tetraazacylodode cane N,N',N",N'''-tetraacetic (DOTA)-biotin. Tumor-to-blood ratios at 24 hours were 20:1 using pretargeted anti-hCD45 RIT and <1:1 with conventional RIT. In vivo imaging studies confirmed that the PRIT approach provided high-contrast tumor images with minimal blood-pool activity, whereas directly labeled anti-hCD45 Ab produced distinct tumor images but the blood pool retained a large amount of labeled Ab for a prolonged time. Therapy experiments showed that (90)Y-DOTA-biotin significantly prolonged survival of mice treated with pretargeted anti-hCD45 Ab-SA compared with mice treated with conventional RIT using (90)Y-labeled anti-hCD45 Ab at 200 muCi. Because human CD45 antigens are confined to xenograft tumor cells in this model, and all murine tissues are devoid of hCD45 and will not bind anti-hCD45 Ab, we also compared one-step and PRIT using an anti-murine (m)CD45 Ab where the target antigen is present on normal hematopoietic tissues. After 24 h, 27.3% +/- 2.8% of the injected dose of activity was delivered per gram (% ID/g) of lymph node using (131)I-A20-Ab compared with 40.0 +/- 5.4% ID/g for pretargeted (111)In-DOTA-biotin. These data suggest that pretargeted methods for delivering RIT may be superior to conventional RIT when targeting CD45 for the treatment of leukemia and may allow for the intensification of therapy, while minimizing toxicities.
authors.affiliation: Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, WA 98109, USA. jpagel@fhcrc.org
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
authors.forename: Dana C
authors.initials: DC
authors.lastname: Matthews
authors.forename: Aimee
authors.initials: A
authors.lastname: Kenoyer
authors.forename: Donald K
authors.initials: DK
authors.lastname: Hamlin
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Wilbur
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Fisher
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Gopal
authors.forename: Yukang
authors.initials: Y
authors.lastname: Lin
authors.forename: Laura
authors.initials: L
authors.lastname: Saganic
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Appelbaum
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D001710:Biotin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D007205:Indium Radioisotopes / Q000008:administration & dosage / Q000493:pharmacokinetics; D007951:Leukemia, Myeloid / Q000276:immunology / Q000378:metabolism / Q000532:radiotherapy*; D017493:Leukocyte Common Antigens / Q000276:immunology*; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics; D016499:Radioimmunotherapy / Q000379:methods*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays; D015021:Yttrium Radioisotopes / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000911:Antibodies, Monoclonal; C405616:DOTA-biotin; D000922:Immunotoxins; D007205:Indium Radioisotopes; D009942:Organometallic Compounds; D015021:Yttrium Radioisotopes; D001710:Biotin; D017493:Leukocyte Common Antigens