title: Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates.
abstract: Pretargeted radioimmunotherapy (PRIT) is designed to enhance the directed delivery of radionuclides to malignant cells. Through a series of studies in 19 nonhuman primates (Macaca fascicularis), the potential therapeutic advantage of anti-CD45 PRIT was evaluated. Anti-CD45 PRIT demonstrated a significant improvement in target-to-normal organ ratios of absorbed radiation compared with directly radiolabeled bivalent antibody (conventional radioimmunotherapy [RIT]). Radio-DOTA-biotin administered 48 hours after anti-CD45 streptavidin fusion protein (FP) [BC8 (scFv)(4)SA] produced markedly lower concentrations of radiation in nontarget tissues compared with conventional RIT. PRIT generated superior target:normal organ ratios in the blood, lung, and liver (10.3:1, 18.9:1, and 9.9:1, respectively) compared with the conventional RIT controls (2.6:1, 6.4:1, and 2.9:1, respectively). The FP demonstrated superior retention in target tissues relative to comparable directly radiolabeled bivalent anti-CD45 RIT. The time point of administration of the second step radiolabeled ligand (radio-DOTA-biotin) significantly impacted the biodistribution of radioactivity in target tissues. Rapid clearance of the FP from the circulation rendered unnecessary the addition of a synthetic clearing agent in this model. These results support proceeding to anti-CD45 PRIT clinical trials for patients with both leukemia and lymphoma.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. dgreen@fhcrc.org
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Green
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
authors.forename: Eneida R
authors.initials: ER
authors.lastname: Nemecek
authors.forename: Yukang
authors.initials: Y
authors.lastname: Lin
authors.forename: Aimee
authors.initials: A
authors.lastname: Kenoyer
authors.forename: Anastasia
authors.initials: A
authors.lastname: Pantelias
authors.forename: Donald K
authors.initials: DK
authors.lastname: Hamlin
authors.forename: D Scott
authors.initials: DS
authors.lastname: Wilbur
authors.forename: Darrell R
authors.initials: DR
authors.lastname: Fisher
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Rajendran
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Gopal
authors.forename: Steven I
authors.initials: SI
authors.lastname: Park
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001710:Biotin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D007938:Leukemia / Q000628:therapy; D017493:Leukocyte Common Antigens / Q000037:antagonists & inhibitors* / Q000276:immunology; D008223:Lymphoma / Q000628:therapy; D008252:Macaca fascicularis; D051379:Mice; D009942:Organometallic Compounds / Q000494:pharmacology*; D016499:Radioimmunotherapy / Q000379:methods*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D019809:Streptavidin / Q000494:pharmacology*
chemical_list: D000911:Antibodies, Monoclonal; C405616:DOTA-biotin; D009942:Organometallic Compounds; D011993:Recombinant Fusion Proteins; D001710:Biotin; D019809:Streptavidin; D017493:Leukocyte Common Antigens