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

Publication Type:

Journal Article

Source:

Blood, Volume 114, Issue 6, p.1226-35 (2009)

Keywords:

2009, Animals, Antibodies, Monoclonal, Antibody Development Core Facility, Antigens, CD45, Biologics Production Core Facility, Biotin, Cell Processing Core Facility, Center-Authored Paper, Clinical Research Division, Comparative Medicine Core Facility, Drug Screening Assays, Antitumor, Flow Cytometry Core Facility, Genomics Core Facility, LEUKEMIA, Lymphoma, Macaca fascicularis, MICE, Organometallic Compounds, Proteomics Core Facility, Radioimmunotherapy, Recombinant Fusion Proteins, Shared Resources, Streptavidin

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.