Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates.
Submitted by Eneida R Nemecek on
Title | Pretargeting CD45 enhances the selective delivery of radiation to hematolymphoid tissues in nonhuman primates. |
Publication Type | Journal Article |
Year of Publication | 2009 |
Authors | Green, DJ, Pagel, JM, Nemecek, ER, Lin, Y, Kenoyer, A, Pantelias, A, Hamlin, DK, D Wilbur, S, Fisher, DR, Rajendran, JG, Gopal, AK, Park, SI, Press, OW |
Journal | Blood |
Volume | 114 |
Issue | 6 |
Pagination | 1226-35 |
Date Published | 2009 Aug 06 |
ISSN | 1528-0020 |
Keywords | Animals, Antibodies, Monoclonal, Biotin, Drug Screening Assays, Antitumor, Leukemia, Leukocyte Common Antigens, Lymphoma, Macaca fascicularis, Mice, Organometallic Compounds, Radioimmunotherapy, Recombinant Fusion Proteins, 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. |
DOI | 10.1182/blood-2009-03-210344 |
Alternate Journal | Blood |
PubMed ID | 19515724 |
PubMed Central ID | PMC2723017 |
Grant List | K23 CA100394 / CA / NCI NIH HHS / United States P01 CA044991 / CA / NCI NIH HHS / United States R01 CA109663 / CA / NCI NIH HHS / United States P01 CA44991 / CA / NCI NIH HHS / United States |