D. Wilbur | University of Washington (original) (raw)
Papers by D. Wilbur
Scientific Reports, Oct 26, 2022
Cancer Research, Dec 31, 2008
Radioimmunotherapy (RIT) for treatment of hematologic malignancies frequently fails because of di... more Radioimmunotherapy (RIT) for treatment of hematologic malignancies frequently fails because of disease recurrence. We therefore conducted pretargeted (P)RIT studies to augment the efficacy in mice of therapy using a pretargeted antihuman (h)CD45 antibody (Ab)-streptavidin (SA) conjugate followed by a biotinylated clearing agent and radiolabeled 1,4,7,10-tetraazacylodode cane N,N ¶,N 00 ,N Ø-tetraacetic (DOTA)biotin. Tumor-to-blood ratios at 24 hours were 20:1 using pretargeted anti-hCD45 RIT and <1:1 with conventional RIT. In vivo imaging studies confirmed that the PRIT approach provided high-contrast tumor images with minimal bloodpool activity, whereas directly labeled anti-hCD45 Ab produced distinct tumor images but the blood pool retained a large amount of labeled Ab for a prolonged time. Therapy experiments showed that 90 Y-DOTA-biotin significantly prolonged survival of mice treated with pretargeted anti-hCD45 Ab-SA compared with mice treated with conventional RIT using 90 Y-labeled anti-hCD45 Ab at 200 MCi. Because human CD45 antigens are confined to xenograft tumor cells in this model, and all murine tissues are devoid of hCD45 and will not bind anti-hCD45 Ab, we also compared one-step and PRIT using an anti-murine (m)CD45 Ab where the target antigen is present on normal hematopoietic tissues. After 24 h, 27.3% F 2.8% of the injected dose of activity was delivered per gram (% ID/g) of lymph node using 131 I-A20-Ab compared with 40.0 F 5.4% ID/g for pretargeted 111 In-DOTA-biotin. These data suggest that pretargeted methods for delivering RIT may be superior to conventional RIT when targeting CD45 for the treatment of leukemia and may allow for the intensification of therapy, while minimizing toxicities.
BACKGROUND Early intrahepatic recurrence is common after surgical resection of hepatocellular car... more BACKGROUND Early intrahepatic recurrence is common after surgical resection of hepatocellular carcinoma (HCC) and leads to increased morbidity and mortality. Insensitive and nonspecific diagnostic imaging contributes to EIR and results in missed treatment opportunities. In addition, novel modalities are needed to identify targets amenable for targeted molecular therapy. In this study, we evaluated a zirconium-89 radiolabeled glypican-3 (GPC3) targeting antibody conjugate (89Zr-αGPC3) for use in positron emission tomography (PET) for detection of small, GPC3+ HCC in an orthotopic murine model. Athymic nu/J mice received hepG2, a GPC3+ human HCC cell line, into the hepatic subcapsular space. Tumor-bearing mice were imaged by PET/computerized tomography (CT) 4 days after tail vein injection of 89Zr-αGPC3. Livers were then excised for the tumors to be identified, measured, bisected, and then serially sectioned at 500mm increments. Sensitivity and specificity of PET/CT for 89Zr-αGPC3-avi...
Journal of Nuclear Medicine, 2021
Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide with l... more Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide with limited therapeutic options for advanced disease. Targeted alpha therapy (TAT) is an emerging class of targeted cancer therapy in which alpha-particle-emitting radionuclides, such as thorium-227, are specifically delivered to cancer tissue. Glypican-3 (GPC3) is a cell surface glycoprotein highly expressed on HCC. In this study, we describe the development and in vivo efficacy of a 227 Th-labeled GPC3 targeting antibody conjugate (227 Th-octapa-αGPC3) for treatment of HCC in an orthotopic murine model. METHODS The chelator p-SCN-Bn-H4octapa-NCS (octapa) was conjugated to a GPC3 targeting antibody (αGPC3) for subsequent 227 Th radiolabeling (octapa-αGPC3). Conditions were varied to optimize radiolabeling of 227 Th. In vitro stability was evaluated by measuring percentage of protein-bound 227 Th by gamma-ray spectroscopy. An orthotopic athymic Nu/J murine model using HepG2 cells was developed. Biodistribution and blood clearance of 227 Th-octapa-αGPC3 was evaluated in tumor bearing mice. Efficacy of 227 Th-octapa-αGPC3 was assessed in tumor bearing animals with serial measurement of serum alpha-fetoprotein at 23 days after radionuclide injection. RESULTS Octapa-conjugated αGPC3 provided up to 70% 227 Th labeling yield in 2 h at room temperature. In the presence of ascorbate, 97.8% of 227 Th was bound to αGPC3-octapa after 14 d in phosphate buffered saline. In HepG2 tumor-bearing mice, highly specific GPC3 targeting was observed, with significant 227 Th-octapa-αGPC3 accumulation in the tumor over time and minimal accumulation in normal tissue. 23 days after treatment, significant reduction in tumor burden was observed in 4 mice receiving 500 kBq/kg 227 Th-octapa-αGPC3 by tail vein injection. No acute off-target toxicity was observed and no animals died prior to termination of the study. CONCLUSION 227 Th-octapa-αGPC3 was observed to be stable in vitro, maintain high specificity for GPC3 with favorable biodistribution in vivo, and result in significant antitumor activity without significant acute off-target toxicity in an orthotopic murine model of HCC.
Scientific Reports, 2021
Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells... more Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody αGPC3 conjugated to zirconium-89 (89Zr) and yttrium-90 (90Y) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated. Animals were injected with 89Zr-labeled αGPC3 and imaged with a small-animal positron emission/computerized tomography (PET/CT) imaging system (immuno-PET) before and 30 days after radioimmunotherapy (RIT) with 90Y-labeled αGPC3. Serum alpha fetoprotein (AFP), a marker of tumor burden, was measured. Gross tumor volume (GTV) and SUVmax by immuno-PET was measured using fixed intensity threshold and manual segmentation methods. Immuno-PET GTV measurements reliably quantified tumor burden prior to RIT, strongly correlating with serum AFP (R2 = 0.90). Serum AFP was significantly lower 30 days afte...
Journal of Medical Imaging and Radiation Sciences, 2019
Journal of Medical Imaging and Radiation Sciences, 2019
Cancer Research, 2017
Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein... more Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein and is implicated in the pathogenesis of many types of B-cell non-Hodgkin lymphoma (B-NHL). The BCL-2 small-molecule inhibitor venetoclax shows promising clinical response rates in several lymphomas, but is not curative as monotherapy. Radiotherapy is a rational candidate for combining with BCL-2 inhibition, as DNA damage caused by radiotherapy increases the activity of pro-apoptotic BCL-2 pathway proteins, and lymphomas are exquisitely sensitive to radiation. We tested B-NHL responses to venetoclax combined with either external beam radiotherapy or radioimmunotherapy (RIT), which joins the selectivity of antibody targeting with the effectiveness of irradiation. We first tested cytotoxicity of cesium-137 irradiation plus venetoclax in 14 B-NHL cell lines representing five lymphoma subtypes. Combination treatment synergistically increased cell death in 10 of 14 lines. Lack of synergy was...
Radiochimica Acta, 2017
Production of high specific activity 186gRe is of interest for development of theranostic radioph... more Production of high specific activity 186gRe is of interest for development of theranostic radiopharmaceuticals. Previous studies have shown that high specific activity 186gRe can be obtained by cyclotron irradiation of enriched 186W via the 186W(d,2n)186gRe reaction, but most irradiations were conducted at low beam currents and for short durations. In this investigation, enriched 186W metal targets were irradiated at high incident deuteron beam currents to demonstrate production rates and contaminants produced when using thick targets. Full-stopping thick targets, as determined using SRIM, were prepared by uniaxial pressing of powdered natural abundance W metal or 96.86% enriched 186W metal encased between two layers of graphite flakes for target material stabilization. An assessment of structural integrity was made on each target preparation. To assess the performance of graphite-encased thick 186W metal targets, along with the impact of encasing on the separation chemistry, target...
Nuclear medicine and biology, Jan 3, 2017
Rhenium-186g (t1/2 = 3.72 d) is a β(-) emitting isotope suitable for theranostic applications. Cu... more Rhenium-186g (t1/2 = 3.72 d) is a β(-) emitting isotope suitable for theranostic applications. Current production methods rely on reactor production by way of the reaction (185)Re(n,γ)(186g)Re, which results in low specific activities limiting its use for cancer therapy. Production via charged particle activation of enriched (186)W results in a (186g)Re product with a higher specific activity, allowing it to be used more broadly for targeted radiotherapy applications. This targets the unmet clinical need for more efficient radiotherapeutics. A target consisting of highly enriched, pressed (186)WO3 was irradiated with protons at the Los Alamos National Laboratory Isotope Production Facility (LANL-IPF) to evaluate (186g)Re product yield and quality. LANL-IPF was operated in a dedicated nominal 40 MeV mode. Alkaline dissolution followed by anion exchange chromatography was used to isolate (186g)Re from the target material. Phantom and radiolabeling studies were conducted with the produ...
Applied Radiation and Isotopes, 2016
This investigation evaluated target fabrication and beam parameters for scale-up production of hi... more This investigation evaluated target fabrication and beam parameters for scale-up production of high specific activity 186 Re using deuteron irradiation of enriched 186 W via the 186 W(d,2n) 186 Re reaction. Thick W and WO 3 targets were prepared, characterized and evaluated in deuteron irradiations. Full-thickness targets, as determined using SRIM, were prepared by uniaxially pressing powdered natural abundance W and WO 3 , or 96.86% enriched 186 W, into Al target supports. Alternatively, thick targets were prepared by pressing 186 W between two layers of graphite powder or by placing pre-sintered (1105°C, 12 hours) natural abundance WO 3 pellets into an Al target support. Assessments of structural integrity were made on each target prepared. Prior to irradiation, material composition analyses were conducted using SEM, XRD, and Raman spectroscopy. Within a minimum of 24 hours post irradiation, gamma-ray spectroscopy was performed on all targets to assess production yields and radionuclidic byproducts. Problems were encountered with the structural integrity of some pressed W and WO 3 pellets before and during irradiation, and target material characterization results could be correlated with the structural integrity of the pressed target pellets. Under the conditions studied, the findings suggest that all WO 3 targets prepared and studied were unacceptable. By contrast, 186 W metal was found to be a viable target material for 186 Re production. Thick targets prepared with powdered 186 W pressed between layers of graphite provided a particularly robust target configuration.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 3, 2015
Alpha-radioimmunotherapy targeting CD45 may substitute for total body irradiation in hematopoieti... more Alpha-radioimmunotherapy targeting CD45 may substitute for total body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for lymphoma. Our goal was to optimize the anti-CD45 monoclonal antibody (MAb; CA12.10C12) protein dose for astatine-211 ((211)At)-radioimmunotherapy, extending the analysis to include intra-organ (211)At activity distribution and α-imaging-based small-scale dosimetry, along with immunohistochemical staining. Eight normal dogs were injected with either 0.75 (n = 5) or 1.00 mg/kg (n = 3) of (211)At-B10-CA12.10C12 (11.5-27.6 MBq/kg). Two were euthanized and necropsied 19-22 hours post injection (p.i.), and six received autologous HCT three days after (211)At-radioimmunotherapy, following lymph node and bone marrow biopsies at 2-4 and/or 19 hours p.i. Blood was sampled to study toxicity and clearance; CD45 targeting was evaluated by flow cytometry. (211)At localization and small-scale dosimetry were assessed using two α-imaging systems: α-ca...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2003
Koral et al. have highlighted an important aspect related to tumor-absorbed dose versus response.... more Koral et al. have highlighted an important aspect related to tumor-absorbed dose versus response. We completely agree with them and thank them for emphasizing this point. It is encouraging that radioimmunotherapy has evolved to a stage at which it is being used as a first-line therapy. As Koral et al. suggest, the availability of such studies will remove an important confounding factor in establishing tumor (and normal organ) absorbed dose-response relationships.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2003
Pretargeted radioimmunotherapy (RIT) using streptavidin (sAv)-conjugated antibodies before radiol... more Pretargeted radioimmunotherapy (RIT) using streptavidin (sAv)-conjugated antibodies before radiolabeled-biotin is a promising approach to improve absorbed dose ratios and achieve high durable remission rates with diminished systemic toxicity. This study compared the immunoscintigraphy, toxicity, and therapeutic efficacy of pretargeted RIT with conventional RIT using an anti-CD20 antibody. Athymic mice bearing Ramos human Burkitt's lymphoma xenografts were injected intraperitoneally with a 1F5-sAv conjugate followed 24 h later by a galactosylated, biotinylated clearing agent (CA) and, finally, 3 h later by (111)In- or (90)Y-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin. The comparison groups consisted of mice injected with conventional, directly labeled (111)In- or (90)Y-1F5. Rapid tumor uptake of radioactivity within 2 h was observed with the pretargeting approach, resulting in high-contrast tumor images at 24 h with minimal blood-pool radioactiv...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1989
A method of radioiodinating monoclonal antibodies such that the labeled antibodies do not undergo... more A method of radioiodinating monoclonal antibodies such that the labeled antibodies do not undergo in vivo deiodination has been studied. The method utilizes conjugation of succinimidyl para-iodobenzoate to the antibody. The iodobenzoate was radiolabeled by using an organometallic intermediate to facilitate the reaction. Thus, succinimidyl para-tri-n-butylstannylbenzoate was radiolabeled in 60-90% radiochemical yield and subsequently conjugated to the antibody in 80-90% yield. Animal biodistribution studies were carried out with two separate anti-melanoma antibodies (9.2.27 and NR-M1-05) labeled by this method, and examined in nude mice bearing human melanoma tumor xenografts. Very large differences in the localization of radioactivity were observed in the thyroids and stomachs of mice when the iodobenzoyl-labeled antibodies were compared with the same antibodies labeled using the chloramine-T method of radioiodination. Few other significant differences in the tissue distribution of ...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1989
F(ab')2 and Fab fragments of murine monoclonal antibody 9.2.27, that recognizes the 250 kD me... more F(ab')2 and Fab fragments of murine monoclonal antibody 9.2.27, that recognizes the 250 kD melanoma-associated antigen, were labeled with 99mTc using the bifunctional chelate method of Fritzberg et al. Twenty-seven (27) patients received, intravenously, 10 mg of either F(ab')2 (8), or the Fab (27), labeled with up to 30 mCi of 99mTc. These doses were preceded by an infusion of cold irrelevant antibody. The average serum T1/2 of the F(ab')2 and the Fab were 11 hr and 2 hr, respectively. Twenty-two percent (22%) of the total injected F(ab')2 dose was excreted in the urine in 20 hr, compared to 55% for the Fab group. Imaging was optimal 6-9 hr postinjection for the Fab patients. No nonspecific uptake in liver, spleen, bone marrow, or lung was observed for either antibody form. Overall, (43/53) 81% of known metastases were seen with visualization of tumors as small as 250 mg and tumor localization as high as 0.03% injected dose/g. Immunoperoxidase staining of freshly-fro...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1991
Tumor uptake was examined with respect to antigen expression, time-dependent biodistribution, dos... more Tumor uptake was examined with respect to antigen expression, time-dependent biodistribution, dose of Mab injected, tumor size, and tumor site (i.e., subcutaneous versus lung or liver metastases). NR-ML-05, 96.5, and P94 showed significantly greater uptake in subcutaneous tumors than CL207 and 5.1 (p less than 0.05). NR-ML-05 had a significantly higher tumor uptake at 24 hr (11.9 +/- 0.51) than at 72 hr (4.0 +/- 0.37) or 144 hr (2.7 +/- 0.84) after injection (p less than 0.001). The other four Mabs had similar tumor distribution at all three time points. The tumor uptake of four Mabs (96.5, P94, CL207. 5.1) differed with respect to in vitro versus in vivo binding to tumor, tumor type, dose of Mab, and tumor site (subcutaneous versus metastases). In contrast, NR-ML-05 demonstrated consistent uptake in tumors independent of the above parameters. These data suggest that certain host parameters can influence in vivo tumor targeting depending on characteristics of each Mab studied.
Scientific Reports, Oct 26, 2022
Cancer Research, Dec 31, 2008
Radioimmunotherapy (RIT) for treatment of hematologic malignancies frequently fails because of di... more Radioimmunotherapy (RIT) for treatment of hematologic malignancies frequently fails because of disease recurrence. We therefore conducted pretargeted (P)RIT studies to augment the efficacy in mice of therapy using a pretargeted antihuman (h)CD45 antibody (Ab)-streptavidin (SA) conjugate followed by a biotinylated clearing agent and radiolabeled 1,4,7,10-tetraazacylodode cane N,N ¶,N 00 ,N Ø-tetraacetic (DOTA)biotin. Tumor-to-blood ratios at 24 hours were 20:1 using pretargeted anti-hCD45 RIT and <1:1 with conventional RIT. In vivo imaging studies confirmed that the PRIT approach provided high-contrast tumor images with minimal bloodpool activity, whereas directly labeled anti-hCD45 Ab produced distinct tumor images but the blood pool retained a large amount of labeled Ab for a prolonged time. Therapy experiments showed that 90 Y-DOTA-biotin significantly prolonged survival of mice treated with pretargeted anti-hCD45 Ab-SA compared with mice treated with conventional RIT using 90 Y-labeled anti-hCD45 Ab at 200 MCi. Because human CD45 antigens are confined to xenograft tumor cells in this model, and all murine tissues are devoid of hCD45 and will not bind anti-hCD45 Ab, we also compared one-step and PRIT using an anti-murine (m)CD45 Ab where the target antigen is present on normal hematopoietic tissues. After 24 h, 27.3% F 2.8% of the injected dose of activity was delivered per gram (% ID/g) of lymph node using 131 I-A20-Ab compared with 40.0 F 5.4% ID/g for pretargeted 111 In-DOTA-biotin. These data suggest that pretargeted methods for delivering RIT may be superior to conventional RIT when targeting CD45 for the treatment of leukemia and may allow for the intensification of therapy, while minimizing toxicities.
BACKGROUND Early intrahepatic recurrence is common after surgical resection of hepatocellular car... more BACKGROUND Early intrahepatic recurrence is common after surgical resection of hepatocellular carcinoma (HCC) and leads to increased morbidity and mortality. Insensitive and nonspecific diagnostic imaging contributes to EIR and results in missed treatment opportunities. In addition, novel modalities are needed to identify targets amenable for targeted molecular therapy. In this study, we evaluated a zirconium-89 radiolabeled glypican-3 (GPC3) targeting antibody conjugate (89Zr-αGPC3) for use in positron emission tomography (PET) for detection of small, GPC3+ HCC in an orthotopic murine model. Athymic nu/J mice received hepG2, a GPC3+ human HCC cell line, into the hepatic subcapsular space. Tumor-bearing mice were imaged by PET/computerized tomography (CT) 4 days after tail vein injection of 89Zr-αGPC3. Livers were then excised for the tumors to be identified, measured, bisected, and then serially sectioned at 500mm increments. Sensitivity and specificity of PET/CT for 89Zr-αGPC3-avi...
Journal of Nuclear Medicine, 2021
Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide with l... more Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality worldwide with limited therapeutic options for advanced disease. Targeted alpha therapy (TAT) is an emerging class of targeted cancer therapy in which alpha-particle-emitting radionuclides, such as thorium-227, are specifically delivered to cancer tissue. Glypican-3 (GPC3) is a cell surface glycoprotein highly expressed on HCC. In this study, we describe the development and in vivo efficacy of a 227 Th-labeled GPC3 targeting antibody conjugate (227 Th-octapa-αGPC3) for treatment of HCC in an orthotopic murine model. METHODS The chelator p-SCN-Bn-H4octapa-NCS (octapa) was conjugated to a GPC3 targeting antibody (αGPC3) for subsequent 227 Th radiolabeling (octapa-αGPC3). Conditions were varied to optimize radiolabeling of 227 Th. In vitro stability was evaluated by measuring percentage of protein-bound 227 Th by gamma-ray spectroscopy. An orthotopic athymic Nu/J murine model using HepG2 cells was developed. Biodistribution and blood clearance of 227 Th-octapa-αGPC3 was evaluated in tumor bearing mice. Efficacy of 227 Th-octapa-αGPC3 was assessed in tumor bearing animals with serial measurement of serum alpha-fetoprotein at 23 days after radionuclide injection. RESULTS Octapa-conjugated αGPC3 provided up to 70% 227 Th labeling yield in 2 h at room temperature. In the presence of ascorbate, 97.8% of 227 Th was bound to αGPC3-octapa after 14 d in phosphate buffered saline. In HepG2 tumor-bearing mice, highly specific GPC3 targeting was observed, with significant 227 Th-octapa-αGPC3 accumulation in the tumor over time and minimal accumulation in normal tissue. 23 days after treatment, significant reduction in tumor burden was observed in 4 mice receiving 500 kBq/kg 227 Th-octapa-αGPC3 by tail vein injection. No acute off-target toxicity was observed and no animals died prior to termination of the study. CONCLUSION 227 Th-octapa-αGPC3 was observed to be stable in vitro, maintain high specificity for GPC3 with favorable biodistribution in vivo, and result in significant antitumor activity without significant acute off-target toxicity in an orthotopic murine model of HCC.
Scientific Reports, 2021
Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells... more Glypican-3 (GPC3) is a tumor associated antigen expressed by hepatocellular carcinoma (HCC) cells. This preclinical study evaluated the efficacy of a theranostic platform using a GPC3-targeting antibody αGPC3 conjugated to zirconium-89 (89Zr) and yttrium-90 (90Y) to identify, treat, and assess treatment response in a murine model of HCC. A murine orthotopic xenograft model of HCC was generated. Animals were injected with 89Zr-labeled αGPC3 and imaged with a small-animal positron emission/computerized tomography (PET/CT) imaging system (immuno-PET) before and 30 days after radioimmunotherapy (RIT) with 90Y-labeled αGPC3. Serum alpha fetoprotein (AFP), a marker of tumor burden, was measured. Gross tumor volume (GTV) and SUVmax by immuno-PET was measured using fixed intensity threshold and manual segmentation methods. Immuno-PET GTV measurements reliably quantified tumor burden prior to RIT, strongly correlating with serum AFP (R2 = 0.90). Serum AFP was significantly lower 30 days afte...
Journal of Medical Imaging and Radiation Sciences, 2019
Journal of Medical Imaging and Radiation Sciences, 2019
Cancer Research, 2017
Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein... more Constitutive B-cell receptor signaling leads to overexpression of the antiapoptotic BCL-2 protein and is implicated in the pathogenesis of many types of B-cell non-Hodgkin lymphoma (B-NHL). The BCL-2 small-molecule inhibitor venetoclax shows promising clinical response rates in several lymphomas, but is not curative as monotherapy. Radiotherapy is a rational candidate for combining with BCL-2 inhibition, as DNA damage caused by radiotherapy increases the activity of pro-apoptotic BCL-2 pathway proteins, and lymphomas are exquisitely sensitive to radiation. We tested B-NHL responses to venetoclax combined with either external beam radiotherapy or radioimmunotherapy (RIT), which joins the selectivity of antibody targeting with the effectiveness of irradiation. We first tested cytotoxicity of cesium-137 irradiation plus venetoclax in 14 B-NHL cell lines representing five lymphoma subtypes. Combination treatment synergistically increased cell death in 10 of 14 lines. Lack of synergy was...
Radiochimica Acta, 2017
Production of high specific activity 186gRe is of interest for development of theranostic radioph... more Production of high specific activity 186gRe is of interest for development of theranostic radiopharmaceuticals. Previous studies have shown that high specific activity 186gRe can be obtained by cyclotron irradiation of enriched 186W via the 186W(d,2n)186gRe reaction, but most irradiations were conducted at low beam currents and for short durations. In this investigation, enriched 186W metal targets were irradiated at high incident deuteron beam currents to demonstrate production rates and contaminants produced when using thick targets. Full-stopping thick targets, as determined using SRIM, were prepared by uniaxial pressing of powdered natural abundance W metal or 96.86% enriched 186W metal encased between two layers of graphite flakes for target material stabilization. An assessment of structural integrity was made on each target preparation. To assess the performance of graphite-encased thick 186W metal targets, along with the impact of encasing on the separation chemistry, target...
Nuclear medicine and biology, Jan 3, 2017
Rhenium-186g (t1/2 = 3.72 d) is a β(-) emitting isotope suitable for theranostic applications. Cu... more Rhenium-186g (t1/2 = 3.72 d) is a β(-) emitting isotope suitable for theranostic applications. Current production methods rely on reactor production by way of the reaction (185)Re(n,γ)(186g)Re, which results in low specific activities limiting its use for cancer therapy. Production via charged particle activation of enriched (186)W results in a (186g)Re product with a higher specific activity, allowing it to be used more broadly for targeted radiotherapy applications. This targets the unmet clinical need for more efficient radiotherapeutics. A target consisting of highly enriched, pressed (186)WO3 was irradiated with protons at the Los Alamos National Laboratory Isotope Production Facility (LANL-IPF) to evaluate (186g)Re product yield and quality. LANL-IPF was operated in a dedicated nominal 40 MeV mode. Alkaline dissolution followed by anion exchange chromatography was used to isolate (186g)Re from the target material. Phantom and radiolabeling studies were conducted with the produ...
Applied Radiation and Isotopes, 2016
This investigation evaluated target fabrication and beam parameters for scale-up production of hi... more This investigation evaluated target fabrication and beam parameters for scale-up production of high specific activity 186 Re using deuteron irradiation of enriched 186 W via the 186 W(d,2n) 186 Re reaction. Thick W and WO 3 targets were prepared, characterized and evaluated in deuteron irradiations. Full-thickness targets, as determined using SRIM, were prepared by uniaxially pressing powdered natural abundance W and WO 3 , or 96.86% enriched 186 W, into Al target supports. Alternatively, thick targets were prepared by pressing 186 W between two layers of graphite powder or by placing pre-sintered (1105°C, 12 hours) natural abundance WO 3 pellets into an Al target support. Assessments of structural integrity were made on each target prepared. Prior to irradiation, material composition analyses were conducted using SEM, XRD, and Raman spectroscopy. Within a minimum of 24 hours post irradiation, gamma-ray spectroscopy was performed on all targets to assess production yields and radionuclidic byproducts. Problems were encountered with the structural integrity of some pressed W and WO 3 pellets before and during irradiation, and target material characterization results could be correlated with the structural integrity of the pressed target pellets. Under the conditions studied, the findings suggest that all WO 3 targets prepared and studied were unacceptable. By contrast, 186 W metal was found to be a viable target material for 186 Re production. Thick targets prepared with powdered 186 W pressed between layers of graphite provided a particularly robust target configuration.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Jan 3, 2015
Alpha-radioimmunotherapy targeting CD45 may substitute for total body irradiation in hematopoieti... more Alpha-radioimmunotherapy targeting CD45 may substitute for total body irradiation in hematopoietic cell transplantation (HCT) preparative regimens for lymphoma. Our goal was to optimize the anti-CD45 monoclonal antibody (MAb; CA12.10C12) protein dose for astatine-211 ((211)At)-radioimmunotherapy, extending the analysis to include intra-organ (211)At activity distribution and α-imaging-based small-scale dosimetry, along with immunohistochemical staining. Eight normal dogs were injected with either 0.75 (n = 5) or 1.00 mg/kg (n = 3) of (211)At-B10-CA12.10C12 (11.5-27.6 MBq/kg). Two were euthanized and necropsied 19-22 hours post injection (p.i.), and six received autologous HCT three days after (211)At-radioimmunotherapy, following lymph node and bone marrow biopsies at 2-4 and/or 19 hours p.i. Blood was sampled to study toxicity and clearance; CD45 targeting was evaluated by flow cytometry. (211)At localization and small-scale dosimetry were assessed using two α-imaging systems: α-ca...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2003
Koral et al. have highlighted an important aspect related to tumor-absorbed dose versus response.... more Koral et al. have highlighted an important aspect related to tumor-absorbed dose versus response. We completely agree with them and thank them for emphasizing this point. It is encouraging that radioimmunotherapy has evolved to a stage at which it is being used as a first-line therapy. As Koral et al. suggest, the availability of such studies will remove an important confounding factor in establishing tumor (and normal organ) absorbed dose-response relationships.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2003
Pretargeted radioimmunotherapy (RIT) using streptavidin (sAv)-conjugated antibodies before radiol... more Pretargeted radioimmunotherapy (RIT) using streptavidin (sAv)-conjugated antibodies before radiolabeled-biotin is a promising approach to improve absorbed dose ratios and achieve high durable remission rates with diminished systemic toxicity. This study compared the immunoscintigraphy, toxicity, and therapeutic efficacy of pretargeted RIT with conventional RIT using an anti-CD20 antibody. Athymic mice bearing Ramos human Burkitt's lymphoma xenografts were injected intraperitoneally with a 1F5-sAv conjugate followed 24 h later by a galactosylated, biotinylated clearing agent (CA) and, finally, 3 h later by (111)In- or (90)Y-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-biotin. The comparison groups consisted of mice injected with conventional, directly labeled (111)In- or (90)Y-1F5. Rapid tumor uptake of radioactivity within 2 h was observed with the pretargeting approach, resulting in high-contrast tumor images at 24 h with minimal blood-pool radioactiv...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1989
A method of radioiodinating monoclonal antibodies such that the labeled antibodies do not undergo... more A method of radioiodinating monoclonal antibodies such that the labeled antibodies do not undergo in vivo deiodination has been studied. The method utilizes conjugation of succinimidyl para-iodobenzoate to the antibody. The iodobenzoate was radiolabeled by using an organometallic intermediate to facilitate the reaction. Thus, succinimidyl para-tri-n-butylstannylbenzoate was radiolabeled in 60-90% radiochemical yield and subsequently conjugated to the antibody in 80-90% yield. Animal biodistribution studies were carried out with two separate anti-melanoma antibodies (9.2.27 and NR-M1-05) labeled by this method, and examined in nude mice bearing human melanoma tumor xenografts. Very large differences in the localization of radioactivity were observed in the thyroids and stomachs of mice when the iodobenzoyl-labeled antibodies were compared with the same antibodies labeled using the chloramine-T method of radioiodination. Few other significant differences in the tissue distribution of ...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1989
F(ab')2 and Fab fragments of murine monoclonal antibody 9.2.27, that recognizes the 250 kD me... more F(ab')2 and Fab fragments of murine monoclonal antibody 9.2.27, that recognizes the 250 kD melanoma-associated antigen, were labeled with 99mTc using the bifunctional chelate method of Fritzberg et al. Twenty-seven (27) patients received, intravenously, 10 mg of either F(ab')2 (8), or the Fab (27), labeled with up to 30 mCi of 99mTc. These doses were preceded by an infusion of cold irrelevant antibody. The average serum T1/2 of the F(ab')2 and the Fab were 11 hr and 2 hr, respectively. Twenty-two percent (22%) of the total injected F(ab')2 dose was excreted in the urine in 20 hr, compared to 55% for the Fab group. Imaging was optimal 6-9 hr postinjection for the Fab patients. No nonspecific uptake in liver, spleen, bone marrow, or lung was observed for either antibody form. Overall, (43/53) 81% of known metastases were seen with visualization of tumors as small as 250 mg and tumor localization as high as 0.03% injected dose/g. Immunoperoxidase staining of freshly-fro...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1991
Tumor uptake was examined with respect to antigen expression, time-dependent biodistribution, dos... more Tumor uptake was examined with respect to antigen expression, time-dependent biodistribution, dose of Mab injected, tumor size, and tumor site (i.e., subcutaneous versus lung or liver metastases). NR-ML-05, 96.5, and P94 showed significantly greater uptake in subcutaneous tumors than CL207 and 5.1 (p less than 0.05). NR-ML-05 had a significantly higher tumor uptake at 24 hr (11.9 +/- 0.51) than at 72 hr (4.0 +/- 0.37) or 144 hr (2.7 +/- 0.84) after injection (p less than 0.001). The other four Mabs had similar tumor distribution at all three time points. The tumor uptake of four Mabs (96.5, P94, CL207. 5.1) differed with respect to in vitro versus in vivo binding to tumor, tumor type, dose of Mab, and tumor site (subcutaneous versus metastases). In contrast, NR-ML-05 demonstrated consistent uptake in tumors independent of the above parameters. These data suggest that certain host parameters can influence in vivo tumor targeting depending on characteristics of each Mab studied.