Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates.
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.
Green
Damian J
DJ
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. dgreen@fhcrc.org
Pagel
John M
JM
Nemecek
Eneida R
ER
Lin
Yukang
Y
Kenoyer
Aimee
A
Pantelias
Anastasia
A
Hamlin
Donald K
DK
Wilbur
D Scott
DS
Fisher
Darrell R
DR
Rajendran
Joseph G
JG
Gopal
Ajay K
AK
Park
Steven I
SI
Press
Oliver W
OW
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*
D000911:Antibodies, Monoclonal; C405616:DOTA-biotin; D009942:Organometallic Compounds; D011993:Recombinant Fusion Proteins; D001710:Biotin; D019809:Streptavidin; D017493:Leukocyte Common Antigens