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Title: 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.

Abstract

Radioimmunotherapy (RIT) with α-emitting radionuclides is an attractive approach for the treatment of minimal residual disease (MRD) 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)4SA fusion protein (FP), followed by a dendrimeric clearing agent and [213Bi]DOTA-biotin. After 90 min, tumor uptake for 1F5(scFv)4SA was 16.5 ± 7.0 % injected dose per gram (ID/g) compared with 2.3 ± 0.9 % ID/g for the control FP. Mice treated with anti-CD20 PRIT and 600 µCi [213Bi]DOTA-biotin exhibited marked tumor growth delays compared to controls (mean tumor volume 0.01 ± 0.02 vs. 203.38 ± 83.03 mm3 after 19 days, respectively). The median survival for the 1F5(scFv)4SA group was 90 days compared to 23 days for the control FP (p<0.0001). 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.

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Lab. (PNNL), Richland, WA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1001119
Report Number(s):
PNNL-SA-72413
Journal ID: ISSN 0006-4971; BLOOAW; 600306000; TRN: US1100272
DOE Contract Number:
AC05-76RL01830
Resource Type:
Journal Article
Resource Relation:
Journal Name: Blood, 116(20):4231-4239; Journal Volume: 116; Journal Issue: 20
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 62 RADIOLOGY AND NUCLEAR MEDICINE; 99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; BEARINGS; BIOTIN; BISMUTH 213; DISEASES; LYMPHOMAS; MICE; NEOPLASMS; PROTEINS; RADIOACTIVITY; RADIOIMMUNOTHERAPY; RADIOISOTOPES; TARGETS; THERAPY; Radioimmunotherapy, bismuth-213, minimal residual disease, lymphoma

Citation Formats

Park, Steven I., Shenoi, Jaideep, Pagel, John M., Hamlin, Donald K., Wilbur, D. Scott, Orgun, Nural, Kenoyer, Aimee L., Frayo, Shani, Axtman, Amanda, Back, Tom, Lin, Yukang, Fisher, Darrell R., Gopal, Ajay K., Green, Damian J., and Press, Oliver W. 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.. United States: N. p., 2010. Web. doi:10.1182/blood-2010-05-282327.
Park, Steven I., Shenoi, Jaideep, Pagel, John M., Hamlin, Donald K., Wilbur, D. Scott, Orgun, Nural, Kenoyer, Aimee L., Frayo, Shani, Axtman, Amanda, Back, Tom, Lin, Yukang, Fisher, Darrell R., Gopal, Ajay K., Green, Damian J., & Press, Oliver W. 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.. United States. doi:10.1182/blood-2010-05-282327.
Park, Steven I., Shenoi, Jaideep, Pagel, John M., Hamlin, Donald K., Wilbur, D. Scott, Orgun, Nural, Kenoyer, Aimee L., Frayo, Shani, Axtman, Amanda, Back, Tom, Lin, Yukang, Fisher, Darrell R., Gopal, Ajay K., Green, Damian J., and Press, Oliver W. Thu . "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.". United States. doi:10.1182/blood-2010-05-282327.
@article{osti_1001119,
title = {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.},
author = {Park, Steven I. and Shenoi, Jaideep and Pagel, John M. and Hamlin, Donald K. and Wilbur, D. Scott and Orgun, Nural and Kenoyer, Aimee L. and Frayo, Shani and Axtman, Amanda and Back, Tom and Lin, Yukang and Fisher, Darrell R. and Gopal, Ajay K. and Green, Damian J. and Press, Oliver W.},
abstractNote = {Radioimmunotherapy (RIT) with α-emitting radionuclides is an attractive approach for the treatment of minimal residual disease (MRD) 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)4SA fusion protein (FP), followed by a dendrimeric clearing agent and [213Bi]DOTA-biotin. After 90 min, tumor uptake for 1F5(scFv)4SA was 16.5 ± 7.0 % injected dose per gram (ID/g) compared with 2.3 ± 0.9 % ID/g for the control FP. Mice treated with anti-CD20 PRIT and 600 µCi [213Bi]DOTA-biotin exhibited marked tumor growth delays compared to controls (mean tumor volume 0.01 ± 0.02 vs. 203.38 ± 83.03 mm3 after 19 days, respectively). The median survival for the 1F5(scFv)4SA group was 90 days compared to 23 days for the control FP (p<0.0001). 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.},
doi = {10.1182/blood-2010-05-282327},
journal = {Blood, 116(20):4231-4239},
number = 20,
volume = 116,
place = {United States},
year = {Thu Nov 18 00:00:00 EST 2010},
month = {Thu Nov 18 00:00:00 EST 2010}
}
  • Pretargeted radioimmunotherapy (PRIT) using an anti-CD45 antibody (Ab)-streptavidin (SA) conjugate and DOTA-biotin labeled with β-emitting radionuclides has been explored as a strategy to decrease relapse and toxicity. α-emitting radionuclides exhibit high cytotoxicity coupled with a short path-length, potentially increasing the therapeutic index and making them an attractive alternative to β-emitting radionuclides for patients with Acute Myeloid Leukemia (AML). Accordingly, we have used 213Bi in mice with human leukemia xenografts. Results demonstrated excellent localization of 213Bi-DOTA-biotin to tumors with minimal uptake into normal organs. After 10 minutes, 4.5 ± 1.1% of the injected dose of 213Bi was delivered per gram ofmore » tumor. α imaging demonstrated uniform radionuclide distribution within tumor tissue 45 minutes after 213Bi-DOTA-biotin injection. Radiation absorbed doses were similar to those observed using a β-emitting radionuclide (90Y) in the same model. We conducted therapy experiments in a xenograft model using a single-dose of 213Bi-DOTA-biotin given 24 hours after anti-CD45 Ab-SA conjugate. Among mice treated with anti-CD45 Ab-SA conjugate followed by 800 μCi of 213Bi- or 90Y-DOTA-biotin, 80% and 20%, respectively, survived leukemia-free for >100 days with minimal toxicity. These data suggest that anti-CD45 PRIT using an α-emitting radionuclide may be highly effective and minimally toxic for treatment of AML.« less
  • Chromosomal analyses of myeloid cells were performed on ten patients who had acute nonlymphocytic leukemia (ANLL) following treatment for malignant lymphoma. Seven patients had Hodgkin disease and three had non-Hodgkin lymphoma, poorly differentiated lymphocytic type. Six patients were treated with radiotherapy and chemotherapy; two had radiotherapy only, and two chemotherapy only. The median time between diagnosis of lymphoma and subsequent leukemia was 58 mo. Four patients had the blast phase of a myeloproliferative syndrome, four had acute myelogenous leukemia, one had acute promyelocytic leukemia, and the tenth, erythroleukemia. None of four patients whose leukemia was treated with intensive chemotherapy responded.more » Every patient had an abnormal karyotype. Seven of the patients showed hypodiploid cell lines, two a pseudodiploid, and one a hyperdiploid cell line. Cells from every patient except one were lacking a B chromosome; in eight, this could be identified as a No. 5. Five of nine patients were lacking a No. 7. Loss or rearrangement of No. 17 was found in four and of Nos. 6 or 8 in three patients. Many of the karyotypes were bizarre, with marker chromosomes and minute chromosomes. The karyotypic pattern seen in these patients showed no correlation with the nature of the original lymphoma, the type of leukemia, or the therapy used. The chromosomal pattern of hypodiploid cell lines found in ANLL that arose de novo was similar to that occurring in treated lymphoma. However, in ANLL de novo, less than half of the patients had fewer than 46 chromosomes, and less than 10% had fewer than 45 chromosomes. In this study, 70% of the patients had fewer than 46 and 40% had fewer than 45 chromosomes. The critical question thus concerns the factors, as yet unknown, that predispose to the development of hypodiploid modal numbers in ANLL in lymphoma.« less
  • If costs of medical care are to be reduced, the choice of which imaging modality to use must be made as carefully as possible. This study was done to show how radiological modalities were used to evaluate patients with Hodgkin disease and non-Hodgkin lymphoma. We kept a record of every radiological study performed on 66 children with both diseases seen in the past 6 1/3 years. The results of these studies were analyzed to see which areas of the body were studied, which imaging modality was used, how frequently the studies were repeated, and how frequently the studies gave abnormalmore » results. Our findings disclosed that radiological studies have been appropriately performed in anatomic regions of the body in which disease is present. New imaging modalities have been introduced, and the use of some of the older modalities has been decreased. With some modalities, such as skeletal survey, liver/spleen scan, whole-lung tomography, contrast studies of the bowel, and excretory urography, utilization is higher than it ought to be in view of the fact that the yield of positive results is low and the information is obtainable in many cases from other more sensitive procedures. These studies should not be performed as a routine on initial evaluation or follow-up of all patients with Hodgkin or non-Hodgkin lymphomas. On initial presentation all patients should undergo chest radiography and CT scanning of both chest and abdomen. A problem area is that the timing of follow-up studies has been somewhat erratic, with some inappropriate studies particularly 3 or 4 years after diagnosis. Too many imaging procedures have probably been done in follow-up of our patients.« less
  • Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 (90Y) and lutetium-177 (177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potential of targeting eithermore » 90Y or 177Lu to human B-cell lymphoma xenografts in mice.« less
  • Purpose Pretargeted radioimmunotherapy (PRIT) is a multi-step method of selectively delivering high doses of radiotherapy to tumor cells while minimizing exposure to surrounding tissues. Yttrium-90 ( 90Y) and lutetium-177 ( 177Lu) are two of the most promising beta-particle emitting radionuclides used for radioimmunotherapy, which despite having similar chemistries differ distinctly in terms of radiophysical features. These differences may have important consequences for the absorbed dose to tumors and normal organs. Whereas 90Y has been successfully applied in a number of preclinical and clinical radioimmunotherapy settings, there have been few published pretargeting studies with 177Lu. We therefore compared the therapeutic potentialmore » of targeting either 90Y or 177Lu to human B-cell lymphoma xenografts in mice. Methods Parallel experiments evaluating the biodistribution, imaging, dosimetry, therapeutic efficacy, and toxicity were performed in female athymic nude mice bearing either Ramos (Burkitt lymphoma) or Granta (mantle cell lymphoma) xenografts, utilizing an anti-CD20 antibodystreptavidin conjugate (1F5-SA) and an 90Y- or 177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin second step reagent. Results The two radionuclides displayed comparable biodistributions in tumors and normal organs; however, the absorbed radiation dose delivered to tumor was more than twice as high for 90Y (1.3 Gy/MBq) as for 177Lu (0.6 Gy/MBq). More importantly, therapy with 90Y-DOTAbiotin was dramatically more effective than with 177Lu-DOTA-biotin, with 100% of Ramos xenograft-bearing mice cured with 37 MBq 90Y, whereas 0% were cured using identical amounts of 177Lu-DOTA-biotin. Similar results were observed in mice bearing Granta xenografts, with 80% of the mice cured with 90Y-PRIT and 0% cured with 177Lu-PRIT. Toxicities were comparable with both isotopes. Conclusion 90Y was therapeutically superior to 177Lu for streptavidin-biotin PRIT approaches in these human lymphoma xenograft models.« less