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 Blood, 6 August 2009, Vol. 114, No. 6, pp. 1226-1235.
Prepublished online as a Blood First Edition Paper on June 10, 2009; DOI 10.1182/blood-2009-03-210344.

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LYMPHOID NEOPLASIA

Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates

Damian J. Green1,2, John M. Pagel1,2, Eneida R. Nemecek3, Yukang Lin1, Aimee Kenoyer1, Anastasia Pantelias1, Donald K. Hamlin4, D. Scott Wilbur4, Darrell R. Fisher5, Joseph G. Rajendran6, Ajay K. Gopal1,2, Steven I. Park1,2, and Oliver W. Press1,2

1 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 2 Department of Medicine, University of Washington, Seattle; 3 Department of Pediatrics, Oregon Health & Science University, Portland; 4 Department of Radiation Oncology, University of Washington, Seattle; 5 Pacific Northwest National Laboratory, Richland, WA; and 6 Department of Radiology, University of Washington, Seattle

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)4SA] 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.


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