4.7 Article

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

Journal

BLOOD
Volume 114, Issue 6, Pages 1226-1235

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2009-03-210344

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Funding

  1. Lymphoma Research Foundation
  2. National Institutes of Health [PO1 CA44991, RO1 CA109663, K23 CA100394]
  3. American Society of Clinical Oncology Young Investigator Award Program
  4. Damon Runyan Cancer Research Foundation
  5. David and Patricia Giuliani, Mary and Geary Britton-Simmons, James and Sherry Raisbeck, the Wyner-Stokes Foundation
  6. Hext Family Foundation

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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. (Blood. 2009; 114: 1226-1235)

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