Conventional and pretargeted radioimmunotherapy using bismuth-213 to target and treat non-Hodgkin lymphomas expressing CD20: a preclinical model toward optimal consolidation therapy to eradicate minimal residual disease.

Publication Type:

Journal Article

Source:

Blood, Volume 116, Issue 20, p.4231-9 (2010)

Keywords:

2010, Animals, Antibodies, Neoplasm, Antibody Development Core Facility, Antigens, CD20, Biologics Production Core Facility, Biotin, Bismuth, Blood Cell Count, Cell Line, Tumor, Cell Processing Core Facility, Center-Authored Paper, Clinical Research Division, Comparative Medicine Core Facility, Flow Cytometry Core Facility, Genomics Core Facility, Humans, Immunoglobulin Variable Region, Kidney, Liver Function Tests, Lymphoma, Non-Hodgkin, MICE, Neoplasm, Residual, Organometallic Compounds, Proteomics Core Facility, Radioimmunotherapy, Radiometry, Recombinant Fusion Proteins, Shared Resources, Survival Analysis, TISSUE DISTRIBUTION, Xenograft Model Antitumor Assays

Abstract:

Radioimmunotherapy (RIT) with α-emitting radionuclides is an attractive approach for the treatment of minimal residual disease because the short path lengths and high energies of α-particles produce optimal cytotoxicity at small target sites while minimizing damage to surrounding normal tissues. Pretargeted RIT (PRIT) using antibody-streptavidin (Ab-SA) constructs and radiolabeled biotin allows rapid, specific localization of radioactivity at tumor sites, making it an optimal method to target α-emitters with short half-lives, such as bismuth-213 (²¹³Bi). Athymic mice bearing Ramos lymphoma xenografts received anti-CD20 1F5(scFv)(4)SA fusion protein (FP), followed by a dendrimeric clearing agent and [²¹³Bi]DOTA-biotin. After 90 minutes, tumor uptake for 1F5(scFv)₄SA was 16.5% ± 7.0% injected dose per gram compared with 2.3% ± .9% injected dose per gram for the control FP. Mice treated with anti-CD20 PRIT and 600 μ Ci [²¹³Bi]DOTA-biotin exhibited marked tumor growth delays compared with controls (mean tumor volume .01 ± .02 vs. 203.38 ± 83.03 mm³ after 19 days, respectively). The median survival for the 1F5(scFv)₄SA group was 90 days compared with 23 days for the control FP (P < .0001). Treatment was well tolerated, with no treatment-related mortalities. This study demonstrates the favorable biodistribution profile and excellent therapeutic efficacy attainable with ²¹³Bi-labeled anti-CD20 PRIT.