84 results on '"Ovarian Neoplasms radiotherapy"'
Search Results
2. TAG-72-Targeted α-Radionuclide Therapy of Ovarian Cancer Using 225 Ac-Labeled DOTAylated-huCC49 Antibody.
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Minnix M, Li L, Yazaki PJ, Miller AD, Chea J, Poku E, Liu A, Wong JYC, Rockne RC, Colcher D, and Shively JE
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- Animals, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal pharmacokinetics, Cell Line, Tumor, Cell Transformation, Neoplastic, Female, Humans, Isotope Labeling, Mice, Molecular Targeted Therapy, Ovarian Neoplasms immunology, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Tissue Distribution, Actinium therapeutic use, Alpha Particles therapeutic use, Antibodies, Monoclonal immunology, Antigens, Neoplasm metabolism, Heterocyclic Compounds, 1-Ring chemistry, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
Radioimmunotherapy, an approach using radiolabeled antibodies, has had minimal success in the clinic with several β-emitting radionuclides for the treatment of ovarian cancer. Alternatively, radioimmunotherapy with α-emitters offers the advantage of depositing much higher energy over shorter distances but was thought to be inappropriate for the treatment of solid tumors, for which antibody penetration is limited to a few cell diameters around the vascular system. However, the deposition of high-energy α-emitters to tumor markers adjacent to a typical leaky tumor vascular system may have large antitumor effects at the tumor vascular level, and their reduced penetration in normal tissue would be expected to lower off-target toxicity. Methods: To evaluate this concept, DOTAylated-huCC49 was labeled with the α-emitter
225 Ac to target tumor-associated glycoprotein 72-positive xenografts in a murine model of ovarian cancer. Results: Ac-labeled DOTAylated-huCC49 radioimmunotherapy significantly reduced tumor growth in a dose-dependent manner (1.85, 3.7, and 7.4 kBq), with the 7.4-kBq dose extending survival by more than 3-fold compared with the untreated control. Additionally, a multitreatment regime (1.85 kBq followed by 5 weekly doses of 0.70 kBq for a total of 5.4 kBq) extended survival almost 3-fold compared with the untreated control group, without significant off-target toxicity.225 These results establish the potential for antibody-targeted α-radionuclide therapy for ovarian cancer, which may be generalized to α-radioimmunotherapy in other solid tumors.Conclusion: These results establish the potential for antibody-targeted α-radionuclide therapy for ovarian cancer, which may be generalized to α-radioimmunotherapy in other solid tumors., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2021
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3. Intraperitoneal α-Emitting Radioimmunotherapy with 211 At in Relapsed Ovarian Cancer: Long-Term Follow-up with Individual Absorbed Dose Estimations.
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Hallqvist A, Bergmark K, Bäck T, Andersson H, Dahm-Kähler P, Johansson M, Lindegren S, Jensen H, Jacobsson L, Hultborn R, Palm S, and Albertsson P
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- Adult, Aged, Alpha Particles, Animals, Antibodies, Monoclonal chemistry, Carcinoma, Ovarian Epithelial mortality, Catheters, Disease Progression, Female, Follow-Up Studies, Humans, Immunoglobulin Fab Fragments, Infusions, Parenteral, Maximum Tolerated Dose, Mice, Middle Aged, Neoplasm, Residual, Ovarian Neoplasms mortality, Radiation Dosage, Radiometry, Recurrence, Reproducibility of Results, Treatment Outcome, Astatine, Carcinoma, Ovarian Epithelial immunology, Carcinoma, Ovarian Epithelial radiotherapy, Neoplasm Recurrence, Local, Ovarian Neoplasms immunology, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
Eliminating microscopic residual disease with α-particle radiation is theoretically appealing. After extensive preclinical work with α-particle-emitting
211 At, we performed a phase I trial with intraperitoneal α-particle therapy in epithelial ovarian cancer using211 At conjugated to MX35, the antigen-binding fragments-F(ab')2 -of a mouse monoclonal antibody. We now present clinical outcome data and toxicity in a long-term follow-up with individual absorbed dose estimations. Methods: Twelve patients with relapsed epithelial ovarian cancer, achieving a second complete or nearly complete response with chemotherapy, received intraperitoneal treatment with escalating (20-215 MBq/L) activity concentrations of211 At-MX35 F(ab')2. Results: The activity concentration was escalated to 215 MBq/L without any dose-limiting toxicities. Most toxicities were low-grade and likely related to the treatment procedure, not clearly linked to the α-particle irradiation, with no observed hematologic toxicity. One grade 3 fatigue and 1 grade 4 intestinal perforation during catheter implantation were observed. Four patients had a survival of more than 6 y, one of whom did not relapse. At progression, chemotherapy was given without signs of reduced tolerability. Overall median survival was 35 mo, with a 1-, 2-, 5-, and 10-y survival of 100%, 83%, 50%, and 25%, respectively. Calculations of the absorbed doses showed that a lower specific activity is associated with a lower single-cell dose, whereas a high specific activity may result in a lower central dose in microtumors. Individual differences in absorbed dose to possible microtumors were due to variations in administered activity and the specific activity. Conclusion : No apparent signs of radiation-induced toxicity or decreased tolerance to relapse therapy were observed. The dosimetric calculations show that further optimization is advisable to increase the efficacy and reduce possible long-term toxicity., (© 2019 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2019
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4. B7-H3-targeted 212 Pb radioimmunotherapy of ovarian cancer in preclinical models.
- Author
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Kasten BB, Arend RC, Katre AA, Kim H, Fan J, Ferrone S, Zinn KR, and Buchsbaum DJ
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- Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal therapeutic use, Cell Differentiation, Cell Line, Tumor, Cell Survival, Cell Transformation, Neoplastic, Female, Humans, Mice, Ovarian Neoplasms pathology, B7 Antigens immunology, Epitopes immunology, Lead Radioisotopes therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
Introduction: Novel therapies that effectively kill both differentiated cancer cells and cancer initiating cells (CICs), which are implicated in causing chemotherapy-resistance and disease recurrence, are needed to reduce the morbidity and mortality of ovarian cancer. These studies used monoclonal antibody (mAb) 376.96, which recognizes a B7-H3 epitope expressed on ovarian cancer cells and CICs, as a carrier molecule for targeted α-particle radioimmunotherapy (RIT) in preclinical models of human ovarian cancer., Methods: mAb 376.96 was conjugated to the chelate 2-(4-isothiocyanotobenzyl)-1,4,7,10-tetraaza-1,4,7,10-tetra-(2-carbamoylmethyl)-cyclododecane (TCMC) and radiolabeled with
212 Pb, a source of α-particles. In vitro Scatchard assays determined the specific binding of212 Pb-376.96 to adherent differentiated or non-adherent CIC-enriched ES-2 and A2780cp20 ovarian cancer cells. Adherent ovarian cancer cells and non-adherent CIC-enriched tumorspheres treated in vitro with212 Pb-376.96 or the irrelevant isotype-matched212 Pb-F3-C25 were assessed for clonogenic survival. Mice bearing i.p. ES-2 or A2780cp20 xenografts were injected i.p. with 0.17-0.70MBq212 Pb-376.96 or212 Pb-F3-C25 and were used for in vivo imaging, ex vivo biodistribution, and therapeutic survival studies., Results:212 Pb-376.96 was obtained in high yield and purity (>98%); Kd values ranged from 10.6-26.6nM for ovarian cancer cells, with 104 -105 binding sites/cell.212 Pb-376.96 inhibited the clonogenic survival of ovarian cancer cells up to 40 times more effectively than isotype-matched control212 Pb-F3-C25; combining212 Pb-376.96 with carboplatin significantly decreased clonogenic survival compared to either agent alone. In vivo imaging and biodistribution analysis 24h after i.p. injection of212 Pb-376.96 showed high peritoneal retention and tumor tissue accumulation (28.7% ID/g in ES-2 ascites, 73.1% ID/g in A2780cp20 tumors); normal tissues showed lower and comparable uptake for212 Pb-376.96 and212 Pb-F3-C25. Tumor-bearing mice treated with212 Pb-376.96 alone or combined with carboplatin survived 2-3 times longer than mice treated with212 Pb-F3-C25 or non-treated controls., Conclusion: These results support additional RIT studies with212 Pb-376.96 for future evaluation in patients with ovarian cancer., (Copyright © 2017 Elsevier Inc. All rights reserved.)- Published
- 2017
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5. Cure of Human Ovarian Carcinoma Solid Xenografts by Fractionated α-Radioimmunotherapy with 211 At-MX35-F(ab') 2 : Influence of Absorbed Tumor Dose and Effect on Long-Term Survival.
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Bäck T, Chouin N, Lindegren S, Kahu H, Jensen H, Albertsson P, and Palm S
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- Animals, Antibodies, Monoclonal pharmacokinetics, Body Weight radiation effects, Cell Line, Tumor, Cell Proliferation radiation effects, Female, Humans, Mice, Mice, Nude, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Radiometry, Survival Analysis, Time Factors, Tissue Distribution, Alpha Particles therapeutic use, Antibodies, Monoclonal therapeutic use, Astatine therapeutic use, Cell Transformation, Neoplastic, Ovarian Neoplasms radiotherapy, Radiation Dosage, Radioimmunotherapy methods
- Abstract
The goal of this study was to investigate whether targeted α-therapy can be used to successfully treat macrotumors, in addition to its established role for treating micrometastatic and minimal disease. We used an intravenous fractionated regimen of α-radioimmunotherapy in a subcutaneous tumor model in mice. We aimed to evaluate the absorbed dose levels required for tumor eradication and growth monitoring, as well as to evaluate long-term survival after treatment. Methods: Mice bearing subcutaneous tumors (50 mm
3 , NIH:OVCAR-3) were injected repeatedly (1-3 intravenous injections 7-10 d apart, allowing bone marrow recovery) with211 At-MX35-F(ab')2 at different activities (close to acute myelotoxicity). Mean absorbed doses to tumors and organs were estimated from biodistribution data and summed for the fractions. Tumor growth was monitored for 100 d and survival for 1 y after treatment. Toxicity analysis included body weight, white blood cell count, and hematocrit. Results: Effects on tumor growth after fractionated α-radioimmunotherapy with211 At-MX35-F(ab')2 was strong and dose-dependent. Complete remission (tumor-free fraction, 100%) was found for tumor doses of 12.4 and 16.4 Gy. The administered activities were high, and long-term toxicity effects (≤60 wk) were clear. Above 1 MBq, the median survival decreased linearly with injected activity, from 44 to 11 wk. Toxicity was also seen by reduced body weight. White blood cell count analysis after α-radioimmunotherapy indicated bone marrow recovery for the low-activity groups, whereas for high-activity groups the reduction was close to acute myelotoxicity. A decrease in hematocrit was seen at a late interval (34-59 wk after therapy). The main external indication of poor health was dehydration. Conclusion: Having observed complete eradication of solid tumor xenografts, we conclude that targeted α-therapy regimens may stretch beyond the realm of micrometastatic disease and be eradicative also for macrotumors. Our observations indicate that at least 10 Gy are required. This agrees well with the calculated tumor control probability. Considering a relative biological effectiveness of 5, this dose level seems reasonable. However, complete remission was achieved first at activity levels close to lethal and was accompanied by biologic effects that reduced long-term survival., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)- Published
- 2017
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6. Absorbed Doses and Risk Estimates of (211)At-MX35 F(ab')2 in Intraperitoneal Therapy of Ovarian Cancer Patients.
- Author
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Cederkrantz E, Andersson H, Bernhardt P, Bäck T, Hultborn R, Jacobsson L, Jensen H, Lindegren S, Ljungberg M, Magnander T, Palm S, and Albertsson P
- Subjects
- Alpha Particles therapeutic use, Electrons therapeutic use, Female, Gastric Mucosa metabolism, Humans, Kidney diagnostic imaging, Kidney metabolism, Lung diagnostic imaging, Lung metabolism, Neoplasm Recurrence, Local, Neoplasm, Residual, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Peritoneal Neoplasms secondary, Proton Therapy, Radiotherapy Dosage, Relative Biological Effectiveness, Risk Assessment, Stomach diagnostic imaging, Thyroid Gland diagnostic imaging, Thyroid Gland metabolism, Tissue Distribution, Tomography, Emission-Computed, Single-Photon methods, Urinary Bladder diagnostic imaging, Urinary Bladder metabolism, Antibodies, Monoclonal pharmacokinetics, Astatine pharmacokinetics, Immunoconjugates pharmacokinetics, Immunoglobulin Fab Fragments metabolism, Ovarian Neoplasms radiotherapy, Peritoneal Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
Purpose: Ovarian cancer is often diagnosed at an advanced stage with dissemination in the peritoneal cavity. Most patients achieve clinical remission after surgery and chemotherapy, but approximately 70% eventually experience recurrence, usually in the peritoneal cavity. To prevent recurrence, intraperitoneal (i.p.) targeted α therapy has been proposed as an adjuvant treatment for minimal residual disease after successful primary treatment. In the present study, we calculated absorbed and relative biological effect (RBE)-weighted (equivalent) doses in relevant normal tissues and estimated the effective dose associated with i.p. administration of (211)At-MX35 F(ab')2., Methods and Materials: Patients in clinical remission after salvage chemotherapy for peritoneal recurrence of ovarian cancer underwent i.p. infusion of (211)At-MX35 F(ab')2. Potassium perchlorate was given to block unwanted accumulation of (211)At in thyroid and other NIS-containing tissues. Mean absorbed doses to normal tissues were calculated from clinical data, including blood and i.p. fluid samples, urine, γ-camera images, and single-photon emission computed tomography/computed tomography images. Extrapolation of preclinical biodistribution data combined with clinical blood activity data allowed us to estimate absorbed doses in additional tissues. The equivalent dose was calculated using an RBE of 5 and the effective dose using the recommended weight factor of 20. All doses were normalized to the initial activity concentration of the infused therapy solution., Results: The urinary bladder, thyroid, and kidneys (1.9, 1.8, and 1.7 mGy per MBq/L) received the 3 highest estimated absorbed doses. When the tissue-weighting factors were applied, the largest contributors to the effective dose were the lungs, stomach, and urinary bladder. Using 100 MBq/L, organ equivalent doses were less than 10% of the estimated tolerance dose., Conclusion: Intraperitoneal (211)At-MX35 F(ab')2 treatment is potentially a well-tolerated therapy for locally confined microscopic ovarian cancer. Absorbed doses to normal organs are low, but because the effective dose potentially corresponds to a risk of treatment-induced carcinogenesis, optimization may still be valuable., (Copyright © 2015 Elsevier Inc. All rights reserved.)
- Published
- 2015
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7. Anti-L1CAM radioimmunotherapy is more effective with the radiolanthanide terbium-161 compared to lutetium-177 in an ovarian cancer model.
- Author
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Grünberg J, Lindenblatt D, Dorrer H, Cohrs S, Zhernosekov K, Köster U, Türler A, Fischer E, and Schibli R
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- Animals, Antibodies, Monoclonal pharmacokinetics, Cell Line, Tumor, Female, Humans, Lutetium pharmacokinetics, Mice, Terbium pharmacokinetics, Tissue Distribution, Tomography, Emission-Computed, Single-Photon, Antibodies, Monoclonal therapeutic use, Lutetium therapeutic use, Neural Cell Adhesion Molecule L1 immunology, Ovarian Neoplasms radiotherapy, Radioimmunotherapy, Radioisotopes therapeutic use, Terbium therapeutic use
- Abstract
Purpose: The L1 cell adhesion molecule (L1CAM) is considered a valuable target for therapeutic intervention in different types of cancer. Recent studies have shown that anti-L1CAM radioimmunotherapy (RIT) with (67)Cu- and (177)Lu-labelled internalising monoclonal antibody (mAb) chCE7 was effective in the treatment of human ovarian cancer xenografts. In this study, we directly compared the therapeutic efficacy of anti-L1CAM RIT against human ovarian cancer under equitoxic conditions with the radiolanthanide (177)Lu and the potential alternative (161)Tb in an ovarian cancer therapy model., Methods: Tb was produced by neutron bombardment of enriched (160)Gd targets. (161)Tb and (177)Lu were used for radiolabelling of DOTA-conjugated antibodies. The in vivo behaviour of the radioimmunoconjugates (RICs) was assessed in IGROV1 tumour-bearing nude mice using biodistribution experiments and SPECT/CT imaging. After ascertaining the maximal tolerated doses (MTD) the therapeutic impact of 50 % MTD of (177)Lu- and (161)Tb-DOTA-chCE7 was evaluated in groups of ten mice by monitoring the tumour size of subcutaneous IGROV1 tumours., Results: The average number of DOTA ligands per antibody was 2.5 and maximum specific activities of 600 MBq/mg were achieved under identical radiolabelling conditions. RICs were stable in human plasma for at least 48 h. (177)Lu- and (161)Tb-DOTA-chCE7 showed high tumour uptake (37.8-39.0 %IA/g, 144 h p.i.) with low levels in off-target organs. SPECT/CT images confirmed the biodistribution data. (161)Tb-labelled chCE7 revealed a higher radiotoxicity in nude mice (MTD: 10 MBq) than the (177)Lu-labelled counterpart (MTD: 12 MBq). In a comparative therapy study with equitoxic doses, tumour growth inhibition was better by 82.6 % for the (161)Tb-DOTA-chCE7 than the (177)Lu-DOTA-chCE7 RIT., Conclusions: Our study is the first to show that anti-L1CAM (161)Tb RIT is more effective compared to (177)Lu RIT in ovarian cancer xenografts. These results suggest that (161)Tb is a promising candidate for future clinical applications in combination with internalising antibodies.
- Published
- 2014
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8. Targeted radionuclide therapy with A 177Lu-labeled anti-HER2 nanobody.
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D'Huyvetter M, Vincke C, Xavier C, Aerts A, Impens N, Baatout S, De Raeve H, Muyldermans S, Caveliers V, Devoogdt N, and Lahoutte T
- Subjects
- Animals, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized pharmacokinetics, Cell Line, Tumor, Female, Humans, Lutetium adverse effects, Lutetium pharmacokinetics, Male, Mice, Mice, Nude, Radioisotopes adverse effects, Radioisotopes pharmacokinetics, Radiopharmaceuticals adverse effects, Radiopharmaceuticals pharmacokinetics, Rats, Rats, Wistar, Single-Chain Antibodies adverse effects, Single-Chain Antibodies pharmacokinetics, Single-Chain Antibodies therapeutic use, Trastuzumab, Antibodies, Monoclonal, Humanized therapeutic use, Lutetium therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods, Radioisotopes therapeutic use, Radiopharmaceuticals therapeutic use, Receptor, ErbB-2 immunology
- Abstract
RIT has become an attractive strategy in cancer treatment, but still faces important drawbacks due to poor tumor penetration and undesirable pharmacokinetics of the targeting vehicles. Smaller radiolabeled antibody fragments and peptides feature highly specific target accumulation, resulting in low accumulation in healthy tissue, except for the kidneys. Nanobodies are the smallest (MW<15 kDa) functional antigen-binding fragments that are derived from heavy chain-only camelid antibodies. Here, we show that the extend of kidney retention of nanobodies is predominantly dictated by the number of polar residues in the C-terminal amino acid tag. Three nanobodies were produced with different C-terminal amino-acid tag sequences (Myc-His-tagged, His-tagged, and untagged). Dynamic planar imaging of Wistar rats with 111In-DTPA-nanobodies revealed that untagged nanobodies showed a 70% drop in kidney accumulation compared to Myc-His-tagged nanobodies at 50 min p.i.. In addition, coinfusion of untagged nanobodies with the plasma expander Gelofusin led to a final reduction of 90%. Similar findings were obtained with different 177Lu-DTPA-2Rs15d nanobody constructs in HER2pos tumor xenografted mice at 1 h p.i.. Kidney accumulation decreased 88% when comparing Myc-His-tagged to untagged 2Rs15d nanobody, and 95% with a coinfusion of Gelofusin, without affecting the tumor targeting capacity. Consequently, we identified a generic method to reduce kidney retention of radiolabeled nanobodies. Dosimetry calculations of Gelofusin-coinfused, untagged 177Lu-DTPA-2Rs15d revealed a dose of 0.90 Gy/MBq that was delivered to both tumor and kidneys and extremely low doses to healthy tissues. In a comparative study, 177Lu-DTPA-Trastuzumab supplied 6 times more radiation to the tumor than untagged 177Lu-DTPA-2Rs15d, but concomitantly also a 155, 34, 80, 26 and 4180 fold higher radioactivity burden to lung, liver, spleen, bone and blood. Most importantly, nanobody-based targeted radionuclide therapy in mice bearing small estiblashed HER2pos tumors led to an almost complete blockade of tumor growth and a significant difference in event-free survival between the treated and the control groups (P<0.0001). Based on histology analyses, no evidence of renal inflammation, apoptosis or necrosis was obtained. In conclusion, these data highlight the importance of the amino acid composition of the nanobody's C-terminus, as it has a predominant effect on kidney retention. Moreover, we show successful nanobody-based targeted radionuclide therapy in a xenograft model and highlight the potential of radiolabeled nanobodies as a valuable adjuvant therapy candidate for treatment of minimal residual and metastatic disease.
- Published
- 2014
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9. Modifications in dynamic contrast-enhanced magnetic resonance imaging parameters after α-particle-emitting ²²⁷Th-trastuzumab therapy of HER2-expressing ovarian cancer xenografts.
- Author
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Heyerdahl H, Røe K, Brevik EM, and Dahle J
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- Animals, Extracellular Space metabolism, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Plasma metabolism, Random Allocation, Time Factors, Transplantation, Heterologous, Trastuzumab, Alpha Particles therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Capillary Permeability radiation effects, Contrast Media pharmacokinetics, Ovarian Neoplasms blood supply, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods, Receptor, ErbB-2 metabolism, Thorium therapeutic use
- Abstract
Purpose: The purpose of this study was to investigate the effect of α-particle-emitting (227)Th-trastuzumab radioimmunotherapy on tumor vasculature to increase the knowledge about the mechanisms of action of (227)Th-trastuzumab., Methods and Materials: Human HER2-expressing SKOV-3 ovarian cancer xenografts were grown bilaterally in athymic nude mice. Mice with tumor volumes 253 ± 36 mm(3) (mean ± SEM) were treated with a single injection of either (227)Th-trastuzumab at a dose of 1000 kBq/kg body weight (treated group, n=14 tumors) or 0.9% NaCl (control group, n=10 tumors). Dynamic T1-weighted contrast-enhanced magnetic resonance imaging (DCEMRI) was used to study the effect of (227)Th-trastuzumab on tumor vasculature. DCEMRI was performed before treatment and 1, 2, and 3 weeks after therapy. Tumor contrast-enhancement curves were extracted voxel by voxel and fitted to the Brix pharmacokinetic model. Pharmacokinetic parameters for the tumors that underwent radioimmunotherapy were compared with the corresponding parameters of control tumors., Results: Significant increases of kep, the rate constant of diffusion from the extravascular extracellular space to the plasma (P<.05), and kel, the rate of clearance of contrast agent from the plasma (P<.01), were seen in the radioimmunotherapy group 2 and 3 weeks after injection, compared with the control group. The product of kep and the amplitude parameter A, associated with increased vessel permeability and perfusion, was also significantly increased in the radioimmunotherapy group 2 and 3 weeks after injection (P<.01)., Conclusions: Pharmacokinetic modeling of MRI contrast-enhancement curves evidenced significant alterations in parameters associated with increased tumor vessel permeability and tumor perfusion after (227)Th-trastuzumab treatment of HER2-expressing ovarian cancer xenografts., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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10. Targeted alpha therapy with 227Th-trastuzumab of intraperitoneal ovarian cancer in nude mice.
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Heyerdahl H, Abbas N, Sponheim K, Mollatt C, Bruland Ø, and Dahle J
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- Animals, Antibodies, Monoclonal, Humanized pharmacokinetics, Female, Mice, Mice, Nude, Neoplasms, Experimental metabolism, Organometallic Compounds pharmacokinetics, Ovarian Neoplasms metabolism, Radiopharmaceuticals pharmacokinetics, Receptor, ErbB-2, Tissue Distribution, Trastuzumab, Treatment Outcome, Alpha Particles therapeutic use, Antibodies, Monoclonal, Humanized therapeutic use, Neoplasms, Experimental radiotherapy, Organometallic Compounds therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods, Radiopharmaceuticals therapeutic use
- Abstract
Unlabelled: The aim of the current study was to investigate the therapeutic effect of 227Th-radioimmunotherapy on intraperitoneally growing human bioluminescent HER2 positive ovarian cancer cells., Methods: In vitro toxicity of 227Th-trastuzumab in bioluminescent SKOV3-luc-D3 ovarian cancer cells was assessed in a growth assay. The biodistribution of intraperitoneally administrated 227Th-trastuzumab in athymic nude mice without tumor cells was determined. For in vivo therapy, seventy female athymic nude mice were intraperitoneally inoculated with tumor cells 17 days prior to injection of single 227Th-trastuzumab doses of 1000 kBq/kg, 600 kBq/kg or 400 kBq/kg, or three injections with 400 kBq/kg 227Th-trastuzumab separated by 4 weeks. Two control groups were given either 20 µg unlabeled trastuzumab or 0.9% NaCl. In vivo bioluminescence imaging was performed weekly before and after onset of therapy. Tumor growth, survival and toxicity were compared., Results: There was a statistically significant therapeutic effect of the 227Th-trastuzumab treatment both with respect to survival and tumor growth. The maximum tolerated dosage was 600 kBq/kg 227Th-trastuzumab. In the in vitro study, two hours incubation with 20 kBq/ml of 227Th-trastuzumab, followed by washing, and subsequent culture of the cells resulted in an average absorbed radiation dose of 6 Gy after 11 days and complete growth inhibition., Conclusion: Targeted alpha therapy with 227Th-trastuzumab of human SKOV3-luc-D3 cells growing intraperitoneally in nude mice was clearly superior to unlabeled trastuzumab therapy. The results warrant further studies of 227Th-radioimmunotherapy used as adjuvant treatment and for metastatic cancer.
- Published
- 2013
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11. Comparison of 211At-PRIT and 211At-RIT of ovarian microtumors in a nude mouse model.
- Author
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Frost SH, Bäck T, Chouin N, Hultborn R, Jacobsson L, Elgqvist J, Jensen H, Albertsson P, and Lindegren S
- Subjects
- Animals, Antibodies, Monoclonal pharmacokinetics, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Ovarian Neoplasms diagnostic imaging, Ovarian Neoplasms immunology, Radionuclide Imaging, Tissue Distribution, Alpha Particles therapeutic use, Antibodies, Monoclonal therapeutic use, Astatine administration & dosage, Avidin therapeutic use, Disease Models, Animal, Ovarian Neoplasms radiotherapy, Radioimmunotherapy
- Abstract
Unlabelled: Abstract Purpose: Pretargeted radioimmunotherapy (PRIT) against intraperitoneal (i.p.) ovarian microtumors using avidin-conjugated monoclonal antibody MX35 (avidin-MX35) and (211)At-labeled, biotinylated, succinylated poly-l-lysine ((211)At-B-PLsuc) was compared with conventional radioimmunotherapy (RIT) using (211)At-labeled MX35 in a nude mouse model., Methods: Mice were inoculated i.p. with 1×10(7) NIH:OVCAR-3 cells. After 3 weeks, they received PRIT (1.0 or 1.5 MBq), RIT (0.9 MBq), or no treatment. Concurrently, 10 additional animals were sacrificed and examined to determine disease progression at the start of therapy. Treated animals were analyzed with regard to presence of tumors and ascites (tumor-free fraction; TFF), 8 weeks after therapy., Results: Tumor status at baseline was advanced: 70% of sacrificed animals exhibited ascites. The TFFs were 0.35 (PRIT 1.0 MBq), 0.45 (PRIT 1.5 MBq), and 0.45 (RIT). The 1.5-MBq PRIT group exhibited lower incidence of ascites and fewer tumors >1 mm than RIT-treated animals., Conclusions: PRIT was as effective as RIT with regard to TFF; however, the size distribution of tumors and presence of ascites indicated that 1.5-MBq PRIT was more efficient. Despite advanced disease in many animals at the time of treatment, PRIT demonstrated good potential to treat disseminated ovarian cancer.
- Published
- 2013
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12. Predictors of long-term outcome from intraperitoneal radioimmunotherapy for ovarian cancer.
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Meredith R, You Z, Alvarez R, Partridge E, Grizzle W, and LoBuglio A
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- Adult, Aged, Animals, Antibodies, Neoplasm administration & dosage, Antibodies, Neoplasm immunology, Disease-Free Survival, Female, Humans, Immunotoxins administration & dosage, Immunotoxins immunology, Infusions, Parenteral, Mice, Middle Aged, Ovarian Neoplasms immunology, Prognosis, Radiopharmaceuticals immunology, Lutetium administration & dosage, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods, Radiopharmaceuticals administration & dosage, Yttrium Radioisotopes administration & dosage
- Abstract
Data was analyzed from 92 patients > 5 years after intraperitoneal (IP) radionuclide therapy (RIT) with (90)Y- or (177)Lu-CC49 to determine prognostic factors. Patients had CC49 antibody-reactive ovarian cancer confined to the abdominal cavity after primary debulking and chemotherapy. The first 27 patients received IP (177)Lu-CC49 alone; the remainder received Interferon (IFN), to increase the expression of the tumor-associated glycoprotein-72 (TAG-72) antigen, +/- IP paclitaxel (25-100 mg/m(2)) 2 days before RIT. Factors assessed by univariate (and some multivariate) analysis included age, race, body size, interval between initial diagnosis and RIT, interval between 2nd look surgery and RIT, (90)Y versus (177)Lu, MBq dose, paclitaxel dose, grade of tumor, extent of initial surgery, size of disease deposits prior to RIT, intensity of TAG reactivity, the addition of unlabeled antibody, and the development of human anti-mouse antibody and/or serum sickness after murine antibody. A statistically significant improvement in progression-free survival (p ≤ 0.05) was noted for less bulky disease and younger age. Administration of paclitaxel plus IFN, an immune response, and use of (90)Y showed a favorable nonsignificant trend. Dose escalation of radionuclide did not change risk of progression; thus, this therapy may have therapeutic efficacy at modest dose levels.
- Published
- 2012
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13. In vivo distribution of avidin-conjugated MX35 and (211)At-labeled, biotinylated poly-L-lysine for pretargeted intraperitoneal α-radioimmunotherapy.
- Author
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Frost SH, Bäck T, Chouin N, Jensen H, Hultborn R, Jacobsson L, and Lindegren S
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal chemistry, Astatine administration & dosage, Astatine chemistry, Avidin administration & dosage, Avidin chemistry, Biotinylation methods, Bone Marrow drug effects, Female, Iodine Isotopes administration & dosage, Iodine Isotopes chemistry, Iodine Isotopes pharmacokinetics, Isotope Labeling methods, Kidney drug effects, Lysine administration & dosage, Lysine chemistry, Mice, Mice, Inbred BALB C, Mice, Nude, Ovarian Neoplasms drug therapy, Ovarian Neoplasms radiotherapy, Polymers administration & dosage, Polymers chemistry, Polymers pharmacokinetics, Tissue Distribution, Antibodies, Monoclonal pharmacokinetics, Astatine pharmacokinetics, Avidin pharmacokinetics, Lysine pharmacokinetics, Radioimmunotherapy methods
- Abstract
Purpose: Avidin-coupled monoclonal antibody MX35 (avidin-MX35) and astatine-211-labeled, biotinylated, succinylated poly-l-lysine ((211)At-B-PL(suc)) were administered in mice to assess potential efficacy as an intraperitoneal (i.p.) therapy for microscopic tumors. We aimed to establish a timeline for pretargeted radioimmunotherapy using these substances, and estimate the maximum tolerable activity., Methods: (125)I-avidin-MX35 and (211)At-B-PL(suc) were administered i.p. in nude mice. Tissue distributions were studied at various time points and mean absorbed doses were estimated from organ uptake of (211)At-B-PL(suc). Studies of myelotoxicity were performed after administration of different activities of (211)At-B-PL(suc)., Results: We observed low blood content of both (125)I-avidin-MX35 and (211)At-B-PL(suc), indicating fast clearance. After sodium perchlorate blocking, the highest (211)At uptake was found in kidneys. Red bone marrow (RBM) accumulated some (211)At activity. Mean absorbed doses of special interest were 2.3 Gy/MBq for kidneys, 0.4 Gy/MBq for blood, and 0.9 Gy/MBq for RBM. An absorbed dose of 0.9 Gy to the RBM was found to be safe. These values suggested that RBM would be the key dose-limiting organ in the proposed pretargeting scheme, and that blood data alone was not sufficient for predicting its absorbed dose., Conclusions: To attain a favorable distribution of activity and avoid major toxicities, at least 1.0 MBq of (211)At-B-PL(suc) can be administered 24 hours after an i.p. injection of avidin-MX35. These results provide a basis for future i.p. therapy studies in mice of microscopic ovarian cancer.
- Published
- 2011
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14. Tumor cure probability during alpha-RIT of ovarian cancer with different radiation sensitivity.
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Elgqvist J, Johansson BR, Partheen K, and Danielsson A
- Subjects
- Animals, Cell Growth Processes physiology, Cell Line, Tumor, Female, Humans, Mice, Models, Statistical, Neoplasm Metastasis, Ovarian Neoplasms pathology, Radiation Tolerance, Xenograft Model Antitumor Assays, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
Purpose: To calculate the tumor cure probability (TCP) and metastatic cure probability (MCP) during alpha-radioimmunotherapy (alpha-RIT) of small ovarian cancer tumors with cells of different radiation sensitivity., Materials and Methods: An in-house-developed biokinetic model and a Monte-Carlo program were used to calculate the cumulative activity on tumor cell surfaces and the specific energy to tumor cell nuclei, respectively. An in-house-developed computational model was used to calculate the TCP and MCP as a function of assumed radiation sensitivities, expressed as D(37), of the tumor cells. The calculations were performed using various assumptions regarding the activity distribution in measured tumors and used the alpha-particle energies emitted from astatine-211 ((211)At). Regarding the calculations of the cumulative activity on each cell surface, the number of antigenic sites expressed by NIH:OVCAR-3 cells for the mAb MX35 F(ab')2 was used. To illustrate the tumor growth at the peritoneum in nude mice, scanning electron microscopy images were used., Results: In the case of a maximum diffusion depth of 30 mum for the activity in the tumors, the TCP was high for D(37) values not exceeding approximately 4.3, approximately 2.9, approximately 1.8, and approximately 0.8 Gy for 200, 100, 50, and 25 kBq (211)At-MX35 F(ab')2 four weeks after cell inoculation, respectively. In order to achieve complete remission of the metastatic disease in mice (i.e. MCP=1), the D(37) value should not exceed approximately 2.2, approximately 1.3, approximately 0.6, and approximately 0.3 Gy when injecting 200, 100, 50, or 25 kBq, respectively, assuming a maximum diffusion depth of 30 mum for the activity in the tumors., Conclusion: The radiation sensitivity, expressed as D(37), of tumor cells subjected to alpha-RIT could be decisive for therapeutic outcome, expressed as TCP or MCP, when treating small tumors of ovarian cancer.
- Published
- 2010
15. Intraperitoneal alpha-radioimmunotherapy in mice using different specific activities.
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Elgqvist J, Andersson H, Haglund E, Jensen H, Kahu H, Lindegren S, Warnhammar E, and Hultborn R
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal chemistry, Cell Line, Tumor, Disease Models, Animal, Female, Infusions, Parenteral, Mice, Ovarian Neoplasms immunology, Alpha Particles, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
Purpose: The aim of this study was to investigate the therapeutic efficacy of the alpha-radioimmunotherapy of ovarian cancer in mice, using different specific activities. This study was performed by using the monoclonal antibody, MX35 F(ab')(2), labeled with the alpha-particle-emitter, 211At., Methods: Animals were intraperitoneally inoculated with approximately 1 x 10(7) cells of the cell line, NIH:OVCAR-3. Four (4) weeks later, five groups of animals were given 400 kBq of 211At-MX35 F(ab')(2) with specific activities equal to 130, 65, 32, 16, or 4 kBq/microg, respectively (n = 18 in each group). As controls, animals were given unlabeled MX35 F(ab')(2) (n = 12). Eight (8) weeks after treatment, the animals were sacrificed and the presence of macro- and microscopic tumors and ascites was determined., Results: The tumor-free fractions (TFFs) of the animals, defined as the fraction of animals with no macro- and microtumors and no ascites, were 0.67, 0.73, 0.50, 0.50, and 0.17 when treated as above. Only the TFF of 0.17, for the specific activity of 4 kBq/microg, was significantly less, compared to that of the specific activity of 130 kBq/microg. The TFF for the specific activity of 4 kBq/microg showed a significant lowering, compared to the specific activity of 130 kBq/microg (p < 0.05). Treatment with unlabeled MX35 F(ab')(2) resulted in a TFF of zero., Conclusions: A specific activity-dependent therapeutic outcome could not be shown in the interval of 130- to 16 kBq/mug. For lower specific activities (i.e., 4 kBq/microg), the therapeutic efficacy was significantly lowered.
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- 2009
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16. Alpha-particle radioimmunotherapy with astatine-211 and bismuth-213.
- Author
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Lucignani G
- Subjects
- Animals, Antineoplastic Agents metabolism, Antineoplastic Agents pharmacokinetics, Antineoplastic Agents pharmacology, Brain Neoplasms radiotherapy, Cell Line, Tumor, Female, Humans, Mice, Ovarian Neoplasms radiotherapy, Radioisotopes, Alpha Particles therapeutic use, Astatine therapeutic use, Bismuth therapeutic use, Radioimmunotherapy methods
- Published
- 2008
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17. Bismuth-213 radioimmunotherapy with C595 anti-MUC1 monoclonal antibody in an ovarian cancer ascites model.
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Song EY, Qu CF, Rizvi SM, Raja C, Beretov J, Morgenstern A, Apostolidis C, Bruchertseifer F, Perkins A, and Allen BJ
- Subjects
- Alpha Particles, Animals, Cell Line, Tumor, Female, Humans, Kidney metabolism, Mice, Mice, Inbred BALB C, Mucin-1 analysis, Ovarian Neoplasms mortality, Tissue Distribution, Xenograft Model Antitumor Assays, Antibodies, Monoclonal therapeutic use, Bismuth therapeutic use, Mucin-1 immunology, Ovarian Neoplasms radiotherapy, Radioimmunotherapy adverse effects
- Abstract
Purpose: Control of ovarian cancer (OC) ascites remains a major objective in post-surgical treatment. The aim of this study was to investigate the effect of targeted alpha therapy (TAT) for the control of ascites in an OC ascites mouse model; the biodistribution of (213)Bi-C595 and its long term toxicity., Methods: The expression of tumor-associated antigen mucin-1 (MUC-1) in OVCAR3 ascites cells in mice and OC cancer tissues in patients was detected by indirect immmunostaining. The monoclonal antibody (MAb) C595 was labeled with (213)Bi using the chelator cDTPA to form the alpha-immunoconjugate (AIC). Mice were injected with different concentrations of AIC by i.p administration. Changes in tumor progression were assessed by measurement of the circumference of the abdomen., Results: MUC-1 is strongly expressed in 73% of OC tissues. At 9 days post-cell inoculation in mice, a single injection of 355 MBq/kg of (213)Bi-C595 can prolong survival by 25 days. A high tumor: blood ratio (5.8) was found in biodistribution study. The maximum tolerance dose (MTD) was more than 1180 MBq/kg up to 21 weeks., Conclusions: C595 is a specific targeting vector for ovarian cancer cells, which show a high percentage of expression of MUC1. (213)Bi-C595 can effectively target and kill ovarian cancer cells in vitro and in vivo. (213)Bi-C595 is the recommended alpha conjugate for a Phase I clinical trial for ovarian cancer.
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- 2008
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18. Targeting the human MUC1 oncoprotein: a tale of two proteins.
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Kufe DW
- Subjects
- Amino Acid Sequence, Animals, Female, Humans, Mice, Molecular Sequence Data, Mucin-1 chemistry, Mucin-1 drug effects, Protein Subunits, Antibodies, Monoclonal therapeutic use, Bismuth therapeutic use, Mucin-1 physiology, Oncogene Proteins physiology, Ovarian Neoplasms radiotherapy, Radioimmunotherapy
- Published
- 2008
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19. Therapeutic efficacy of astatine-211-labeled trastuzumab on radioresistant SKOV-3 tumors in nude mice.
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Palm S, Bäck T, Claesson I, Danielsson A, Elgqvist J, Frost S, Hultborn R, Jensen H, Lindegren S, and Jacobsson L
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal, Humanized, Antineoplastic Agents administration & dosage, Astatine administration & dosage, Cell Line, Tumor, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Ovarian Neoplasms chemistry, Ovarian Neoplasms pathology, Radiotherapy Dosage, Receptor, ErbB-2, Trastuzumab, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Astatine therapeutic use, Ovarian Neoplasms radiotherapy, Radiation Tolerance, Radioimmunotherapy methods
- Abstract
Purpose: To investigate the potential use of astatine-211 (211At)-labeled trastuzumab for the treatment of HER-2-positive, radioresistant ovarian carcinoma., Methods and Materials: Four-week-old nude mice were inoculated intraperitoneally with 5 . 10(6) SKOV-3 cells in 0.4 mL saline on Day 0. The endpoint was the total tumor weight in each mouse on Day 63. Three experiments were performed in which the response to single-dose and fractionated treatment with unlabeled and 211At-labeled antibody was evaluated., Results: Experiment 1 showed, for the same total amount of trastuzumab, a dose-response relationship between 211At activity (0-400 kBq on Day 7) and therapeutic efficacy (p = 0.001). The effect of varying the amount of unlabeled trastuzumab was studied in Experiment 2. All mice, except for the controls, received 400 kBq 211At-trastuzumab, and different groups received 5, 50, or 500 microg trastuzumab on Day 7. The increase from 5 to 50 microg trastuzumab reduced the tumors by 78% in weight. No tumors were present in mice given 500 microg trastuzumab. In Experiment 3, the effect of a fractionated treatment regimen was studied. Mice that received 100 kBq 211At-trastuzumab on Days 7 and 8 had a 42% smaller tumor burden than did controls. Groups of mice injected with 200 + 100 kBq on Days 7 and 21 and mice injected with 100 kBq on Days 7, 8, and 21 both had 24% less tumor weight than the corresponding controls., Conclusion: The combination of 500 microg trastuzumab and 400 kBq 211At-trastuzumab had the greatest effect, with complete eradication of the tumors in this nude mouse model.
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- 2007
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20. Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with 211At-MX35 F(ab')2.
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Elgqvist J, Andersson H, Bernhardt P, Bäck T, Claesson I, Hultborn R, Jensen H, Johansson BR, Lindegren S, Olsson M, Palm S, Warnhammar E, and Jacobsson L
- Subjects
- Animals, Data Interpretation, Statistical, Dose Fractionation, Radiation, Female, Mice, Mice, Inbred BALB C, Mice, Nude, Ovarian Neoplasms pathology, Radiation Dosage, Radiopharmaceuticals therapeutic use, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Astatine therapeutic use, Ovarian Neoplasms radiotherapy, Ovarian Neoplasms secondary, Radioimmunotherapy methods
- Abstract
Purpose: To elucidate the therapeutic efficacy of alpha-radioimmunotherapy of ovarian cancer in mice. This study: (i) estimated the minimum required activity (MRA), giving a reasonable high therapeutic efficacy; and (ii) calculated the specific energy to tumor cell nuclei and the metastatic cure probability (MCP) using various assumptions regarding monoclonal-antibody (mAb) distribution in measured tumors. The study was performed using the alpha-particle emitter Astatine-211 (211At) labeled to the mAb MX35 F(ab')2., Methods and Materials: Animals were inoculated intraperitoneally with approximately 1 x 10(7) cells of the cell line NIH:OVCAR-3. Four weeks later animals were treated with 25, 50, 100, or 200 kBq 211At-MX35 F(ab')2 (n = 74). Another group of animals was treated with a nonspecific mAb: 100 kBq 211At-Rituximab F(ab')2 (n = 18). Eight weeks after treatment the animals were sacrificed and presence of macro- and microscopic tumors and ascites was determined. An MCP model was developed and compared with the experimentally determined tumor-free fraction (TFF)., Results: When treatment was given 4 weeks after cell inoculation, the TFFs were 25%, 22%, 50%, and 61% after treatment with 25, 50, 100, or 200 kBq (211)At-MX35 F(ab')2, respectively, the specific energy to irradiated cell nuclei varying between approximately 2 and approximately 400 Gy., Conclusion: As a significant increase in the therapeutic efficacy was observed between the activity levels of 50 and 100 kBq (TFF increase from 22% to 50%), the conclusion was that the MRA is approximately 100 kBq (211)At-MX35 F(ab')2. MCP was most consistent with the TFF when assuming a diffusion depth of 30 mum of the mAbs in the tumors.
- Published
- 2006
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21. Fractionated radioimmunotherapy of intraperitoneally growing ovarian cancer in nude mice with 211At-MX35 F(ab')2: therapeutic efficacy and myelotoxicity.
- Author
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Elgqvist J, Andersson H, Bäck T, Claesson I, Hultborn R, Jensen H, Lindegren S, Olsson M, Palm S, Warnhammar E, and Jacobsson L
- Subjects
- Animals, Antibodies, Monoclonal pharmacokinetics, Cell Line, Tumor, Female, Humans, Mice, Organometallic Compounds pharmacokinetics, Antibodies, Monoclonal therapeutic use, Bone Marrow radiation effects, Dose Fractionation, Radiation, Immunoglobulin Fab Fragments therapeutic use, Organometallic Compounds therapeutic use, Ovarian Neoplasms radiotherapy, Peritoneal Neoplasms radiotherapy, Radioimmunotherapy adverse effects
- Abstract
Objective: The aim of this study was to investigate the therapeutic efficacy and myelotoxicity during fractionated radioimmunotherapy of ovarian cancer in mice. The study was performed using the monoclonal antibody MX35 F(ab')(2) labeled with the alpha-particle emitter (211)At., Methods: Animals were intraperitoneally inoculated with approximately 1x10(7) cells of the cell line NIH:OVCAR-3. Four weeks later, the mice were given the first treatment. Six groups of animals were intraperitoneally injected with approximately 800, 3x approximately 267, approximately 400, 3x approximately 133, approximately 50 or 3x approximately 17 kBq (211)At-MX35 F(ab')(2) (n=18 in each group). The second and third injections for Groups 2, 4 and 6 were given 4 and 8 days after the first injection, respectively. As controls, animals were treated with unlabeled MX35 F(ab')(2) (n=12). Eight weeks after the last injection, the animals were sacrificed and the presence of macro- and microscopic tumors and ascites was determined. Blood counts were determined for each mouse in Groups 1 and 2 before the first injection and 3, 7, 11, 15 and 23 days after the first injection. The calculation of the mean absorbed dose to the bone marrow was based on the ratio between the (211)At-activity concentration in bone and blood [i.e., the bone-to-blood ratio (BBLR)] as well as that between the (211)At-activity concentration in bone marrow and blood [i.e., the bone-marrow-to-blood ratio (BMBLR)] and the cumulated activity and absorbed fraction of the alpha-particles emitted by (211)At in the bone marrow., Results: The tumor-free fractions of animals were 56% and 41% when treated with approximately 800 kBq and 3x approximately 267 kBq (211)At-MX35 F(ab')(2), respectively; 39% and 28% when treated with approximately 400 kBq and 3x approximately 133 kBq (211)At-MX35 F(ab')(2), respectively; and 17% and 22% when treated with approximately 50 kBq or 3x approximately 17 kBq (211)At-MX35 F(ab')(2), respectively. The nadir of the white blood cell (WBC) counts was decreased (from 46% to 19%, compared with the baseline WBC counts) and delayed (from Day 4 to Day 11 after the first injection) during the fractionated treatment compared with the single-dose treatment. The percentage of injected activity per gram (%IA/g) for blood, bone and bone marrow all peaked 6 h after injection at 13.80+/-1.34%IA/g, 4.00+/-0.69%IA/g and 8.28+/-1.38%IA/g, respectively. The BBLR and BMBLR were 0.20+/-0.04 and 0.58+/-0.01, respectively. The mean absorbed dose to bone marrow was approximately 0.4 Gy after intraperitoneally injecting approximately 800 kBq (211)At-MX35 F(ab')(2)., Conclusion: No advantage was observed in the therapeutic efficacy of using a fractionated regimen compared with a single administration, with the same total amount of administered activity. Alleviation of the myelotoxicity was observed during the fractionated regimen in terms of decreased suppression and delayed nadir of the WBC counts. No thrombocytopenia was observed during either regimen.
- Published
- 2006
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22. 211At radioimmunotherapy of subcutaneous human ovarian cancer xenografts: evaluation of relative biologic effectiveness of an alpha-emitter in vivo.
- Author
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Bäck T, Andersson H, Divgi CR, Hultborn R, Jensen H, Lindegren S, Palm S, and Jacobsson L
- Subjects
- Alpha Particles, Animals, Antibodies, Monoclonal chemistry, Cell Line, Tumor, Cobalt Radioisotopes, Dose-Response Relationship, Radiation, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Transplantation, Radiometry, Relative Biological Effectiveness, Time Factors, Astatine therapeutic use, Isotopes therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods, Radioisotopes pharmacology
- Abstract
Unlabelled: The use of alpha-particle emitters in radioimmunotherapy (RIT) appears to be promising. We previously obtained convincing results in the treatment of microscopic intraperitoneal ovarian cancer in nude mice by using the alpha-emitter 211At. This study was performed to evaluate the relative biological effectiveness (RBE) of 211At compared with that of 60Co gamma-irradiation in an RIT model. Our endpoint was growth inhibition (GI) of subcutaneous xenografts., Methods: GI after irradiation was studied with subcutaneous xenografts of the human ovarian cancer cell line NIH:OVCAR-3 implanted in nude mice. The animals received an intravenous injection of 211At-labeled monoclonal antibody MX35 F(ab')2 at different levels of radioactivity (0.33, 0.65, and 0.90 MBq). Control mice received unlabeled MX35 F(ab')2 only. To calculate the mean absorbed dose to tumor, a separate biodistribution study established the uptake of 211At in tumors and organs at different times after injection. External irradiation of the tumors was performed with 60Co. Tumor growth was monitored, and the normalized tumor volume (NTV) was calculated for each tumor. GI was defined by dividing the NTV values by the fitted NTV curve obtained from the corresponding control mice. To compare the biologic effects of the 2 radiation qualities, the mean value for GI (from day 8 to day 23) was plotted for each tumor as a function of its corresponding absorbed dose. From exponential fits of these curves, the doses required for a GI of 0.37 (D37) were derived, and the RBE of 211At was calculated., Results: The biodistribution study showed the uptake of the immunoconjugate by the tumor (amount of injected radioactivity per gram) to be 14% after 7 h. At 40 h, the ratio of uptake in tumors to uptake in blood reached a maximum value of 6.2. The administered activities of 211At corresponded to doses absorbed by tumors of 1.35, 2.65, and 3.70 Gy. The value (mean+/-SEM) for D37 was 1.59+/-0.08 Gy. Tumor growth after 60Co external irradiation showed a value for D37 of 7.65+/-1.0 Gy. The corresponding RBE of 211At irradiation was 4.8+/-0.7., Conclusion: Using a tumor GI model in nude mice, we were able to derive an RBE of alpha-particle RIT with 211At. The RBE was found to be 4.8+/-0.7.
- Published
- 2005
23. Pharmacokinetics, biodistribution, and radioimmunotherapy with monoclonal antibody 776.1 in a murine model of human ovarian cancer.
- Author
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Berger MA, Masters GR, Singleton J, Scully MS, Grimm LG, Soltis DA, and Albone EF
- Subjects
- Animals, CA-125 Antigen analysis, Female, Humans, Immunoglobulin G metabolism, Immunoglobulin G therapeutic use, Iodine Radioisotopes pharmacokinetics, Iodine Radioisotopes therapeutic use, Mice, Tissue Distribution, Transplantation, Heterologous, Yttrium Radioisotopes pharmacokinetics, Yttrium Radioisotopes therapeutic use, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
776.1 is a murine IgG1 monoclonal antibody to the human ovarian cancer antigen CA 125 that has the unique property of having a clear preference for binding to the cell-associated form of the antigen. We have examined the tumor localization properties and efficacy of 776.1 in a subcutaneous OVCAR-3 xenograft mouse model of human ovarian cancer. Biodistribution experiments using (125)I-labeled 776.1 demonstrated a peak uptake in tumors at 72 hours postinjection, with an average of 17.7% of injected dose per gram localized to the tumor. Little uptake in other organs was observed. Further experiments using CA 125-transfected syngeneic tumors, as well as an immunoprecipitation assay using human chimeric 776.1, both clearly demonstrated that 776.1 localizes to the tumor in a CA 125-dependent manner. DOTA-776.1 (1,4,7,10-tetraazacyclododecane-N,N',N",N'" tetraacetic acid-conjugated 776.1) was labeled with (90)Y and used in efficacy studies. [(90)Y-DOTA]776.1 at a single dose of 150 microCi was able to mediate efficient reduction of tumor growth, with regression observed in a subset of animals for a period ranging from 3 to 48 days, equivalent to 3 weekly administrations of cisplatin at 6 mg/kg. No significant regression was observed in groups receiving [(90)Y-DOTA]MOPC-21 control antibody at any dose. These results suggest that 776.1 may be a promising radioimmunotherapeutic agent for the treatment of human ovarian cancer.
- Published
- 2005
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24. Preliminary results of nanopharmaceuticals used in the radioimmunotherapy of ovarian cancer.
- Author
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McQuarrie S, Mercer J, Syme A, Suresh M, and Miller G
- Subjects
- Animals, Cell Line, Tumor, Female, Humans, Liposomes, Mice, Mice, Inbred BALB C, Mice, Nude, Xenograft Model Antitumor Assays methods, Antineoplastic Agents administration & dosage, Ovarian Neoplasms drug therapy, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
Purpose: The treatment of late stage ovarian cancer presents an unmet clinical need for women around the world. A multistep radioimmunotherapeutic (RIT) approach, exploiting the combination of a bispecific monoclonal antibody (BsMAb) with 90Y labelled biotinylated long-circulating liposomes was tested as a potential adjuvant treatment for epithelial ovarian carcinomatosis in an attempt to meet this need. This approach was used to overcome some of the major obstacles associated with conventional strategies, in particular, to increase the amount of radioactivity delivered to the tumor site compared with conventional monoclonal antibody (MAb) radionuclide delivery. We hypothesize that sequential intraperitoneal administration of the targeting and therapeutic moieties provides the basis for an enhanced therapeutic ratio., Methods: A BsMAb, with anti-CA 125 and anti-biotin epitopes was engineered for use with PEGylated liposomes coated with biotin to deliver the cytotoxic radionuclide 90Y to tumor sites. An in vivo therapy trial was used to test this RIT protocol with Balb/c nude mice (n=29) xenografted with the NIH:OVCAR-3 (CA 125+) human ovarian cancer cell line., Results: A median tumor growth delay of 91 days for the combined treatment group versus 77.7 days for the control group was observed., Conclusion: An ongoing tumor growth delay/control study using this model has indicated an appreciable delay in progress of tumor and ascites development in treated vs. control populations.
- Published
- 2005
25. Radioimmunotherapy in advanced ovarian cancer: is there a role for pre-targeting with (90)Y-biotin?
- Author
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Grana C, Bartolomei M, Handkiewicz D, Rocca P, Bodei L, Colombo N, Chinol M, Mangioni C, Malavasi F, and Paganelli G
- Subjects
- Adult, Aged, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal immunology, Biotin adverse effects, Biotin immunology, Female, Humans, Immunotoxins adverse effects, Immunotoxins immunology, Middle Aged, Ovarian Neoplasms immunology, Retrospective Studies, Salvage Therapy, Yttrium Radioisotopes adverse effects, Biotin administration & dosage, Immunotoxins administration & dosage, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods, Yttrium Radioisotopes administration & dosage
- Abstract
Objectives: Despite recent advances in the management of ovarian cancer, this tumor remains the leading cause of death among gynecologic malignancies. Moreover, advanced ovarian carcinoma has a poor prognosis, thus requiring new therapeutic modalities. Previous studies have indicated a survival advantage for ovarian cancer patients (pts) treated with radioimmunotherapy (RIT). Pre-targeting RIT, based on the avidin-biotin system, has been the objective of previous studies performed by our group., Patients and Methods: In the present study, the therapeutic efficacy and toxicity of RIT in 38 advanced ovarian cancer patients have been retrospectively evaluated. RIT was performed according to the following three-step protocol: biotinylated monoclonal antibodies (MoAb) and avidin were intraperitoneally (ip) injected (1st and 2nd step), and 12-18 h later (90)Y-labeled biotin either iv or ip was injected as 3rd step. Sixteen out of 38 patients were treated by intraperitoneal injection only, whereas other 22 pts received the combined treatment (ip + iv); the dose range was 10-100 mCi of (90)Y-biotin., Results: Both of the two therapy regimens were well tolerated; no acute side effects were observed. Two patients (5%) showed temporary hematological grade III-IV toxicity. As regards to the therapeutic efficacy, in the ip group we observed 6% of objective tumor reduction, stabilization in 31% of pts, and progression in 50%. In the group of combined treatment, 9% of patients achieved objective responses, 32% showed stable disease, and 41% had a progression., Conclusions: These data show the excellent tolerability (maximum tolerated dose (MTD) has not been determined yet) and the potential therapeutic role of RIT in advanced ovarian cancer. Patients with minimal residual disease would probably take the best advantages of RIT with (90)Y-biotin (electrons). These data warrant further prospective studies.
- Published
- 2004
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26. Tumor-specific dose scheduling of bimodal radioimmunotherapy and chemotherapy.
- Author
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Blumenthal RD, Leone E, and Goldenberg DM
- Subjects
- Drug Administration Schedule, Female, Humans, Ovarian Neoplasms pathology, Tumor Cells, Cultured, Yttrium Radioisotopes therapeutic use, Antineoplastic Agents therapeutic use, Combined Modality Therapy methods, Ovarian Neoplasms drug therapy, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
Introduction: Radioimmunotherapy (RAIT) has been shown to enhance the efficacy of chemotherapy in a variety of tumor models. When multiple drugs are available for a given tumor type, several questions arise, such as how one selects the appropriate drug to be used with RAIT, in what sequence to administer the two therapeutic agents and how to space the two modalities. Unique molecular characteristics affecting chemo- and radiosensitivity are found in every tumor. We postulated that the agents and dose scheduling of bimodal RAIT plus chemotherapy might have to be tailored to each tumor based on the expression of specific relevant genes., Materials and Methods: To determine whether a single choice of agents and sequence and spacing of agents would be effective in 4 established human ovarian cancer cell lines, the cytotoxic effect of four standard first- and second-line chemotherapeutic agents used to treat ovarian cancer (doxorubicin, carboplatin, paclitaxel, or topotecan) or radioimmunotherapy (90Y-RS-7 IgG anti-EGP1) were evaluated as single agents or as a bimodal therapy. The four human ovarian cancer lines differed with respect to expression of p53 and drug resistance proteins: SKOV3 (p53null, mdr-, mrp+), A2780 (p53wt, mdr+, mrp), IGROV-1 (p53mut, mdr, mrp+), and OVCAR3 (p53mut, mdr-, mrp-)., Results: The profile of chemo- and radiosensitivity for the 4 drugs and for RAIT was unique for each of the four tumor lines. As a result, combinations of radio-antibody and chemotherapy that resulted in good growth inhibition in one tumor line were ineffective in another. Several specific synergistic and antagonistic combinations were identified for each of the ovarian cancer cell lines studied., Conclusion: These studies provide evidence that individualized bimodal RAIT and chemotherapy has to be used for each tumor. Therefore, the influence of individual molecular traits on growth inhibition effects from different combinations of agents needs to be studied. This work should then permit rational choices of which drug to add to RAIT, which dose-schedule to use (sequential with RAIT first or sequential with drug first) and how to space the two modalities, based on certain phenotypic markers of the tumors.
- Published
- 2003
27. [Radioimmunotherapy in patients with ovarian cancer in complete remission after the first line surgery and chemotherapy after second look laparoscopy procedure].
- Author
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Markowska J, Madry R, Kierzkowski J, Malicki J, Roszak A, Lubin J, and Bratos K
- Subjects
- Female, Humans, Remission Induction, Retrospective Studies, Time Factors, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Iodine Radioisotopes therapeutic use, Laparoscopes, Ovarian Neoplasms radiotherapy, Ovarian Neoplasms surgery, Radioimmunotherapy methods, Second-Look Surgery instrumentation
- Abstract
Objectives: The aim of the study was analysed a chance to successful radioimmunotherapy in patients with ovarian cancer as a consolidation procedure., Design: Between 2000 and 2002 we introduced 56 patients into consolidation study with radioimmunotherapy after second look laparoscopy., Materials and Methods: 17 patients during screening procedure have failed--mostly with positive CT scans (9/17). We have done 39 laparoscopies. Among 11 patients during laparoscopy we have found in 6 cases a residual disease and in 5 cases adhesions in abdomen or pelvis and this group was excluded from study. The remaining 28 patients were divided into two groups--14 in active and 14 in control arm., Results: Only 50% of patients with ovarian cancer in complete clinical remission after first line surgery and chemotherapy can be candidates to consolidation therapy. Among patients subjected to laparoscopy in 70% there was no evidence of macroscopic disease and adhesions., Conclusions: Only 50% patients in complete clinical remission after first line surgery and chemotherapy have chance to successful radioimmunotherapy.
- Published
- 2003
28. Astatine-211-labeled antibodies for treatment of disseminated ovarian cancer: an overview of results in an ovarian tumor model.
- Author
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Andersson H, Elgqvist J, Horvath G, Hultborn R, Jacobsson L, Jensen H, Karlsson B, Lindegren S, and Palm S
- Subjects
- Animals, Antibodies, Monoclonal therapeutic use, Benzoates therapeutic use, Cell Division, Cell Line, Tumor, Cell Survival, Clinical Trials as Topic, Dose-Response Relationship, Radiation, Female, Humans, Mice, Mice, Inbred BALB C, Mice, Nude, Monte Carlo Method, Neoplasm Transplantation, Radiometry, Time Factors, Tissue Distribution, Trimethyltin Compounds therapeutic use, Astatine therapeutic use, Isotopes therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
Purpose: The aim of the study was to establish and refine a preclinical model to alpha-immunoradiotherapy of ovarian cancer., Experimental Design: At-211 was produced by cyclotron irradiation of a bismuth-209 target and isolated using a novel dry distillation procedure. Monoclonal antibodies were radiohalogenated with the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate and characterized in terms of radiochemical yield and in vitro binding properties. In vitro OVCAR-3 cells were irradiated using an external Cobalt-60 beam, as reference, or At-211-albumin and labeled antibody. Growth assays were used to establish cell survival. A Monte Carlo program was developed to simulate the energy imparted and the track length distribution. Nude mice were used for studies of WBC depression, with various activities of Tc-99m antibodies, as reference, and At-211 antibodies. In efficacy studies, OVCAR-3 cells were inoculated i.p., and animals were treated 2 weeks later. The animals were either dissected 6 weeks later or followed-up for long-term survival., Results: A rapid distillation procedure, as well as a rapid and high-yield, single-pot labeling procedure, was achieved. From growth inhibition data, the relative biological effectiveness of the alpha-emission for OVCAR-3 cells was estimated to be approximately 5, which is in the same range as found in vivo for hematological toxicity. At-211 MOv18 was found to effectively inhibit the development of tumors and ascites, also resulting in long-term survival without significant toxic effect., Conclusions: Use of the short-range, high-linear energy transfer alpha-emitter At-211 conjugated to a surface epitope-recognizing monoclonal antibody appears to be highly efficient without significant toxicity in a mouse peritoneal tumor model, urging a Phase I clinical trial.
- Published
- 2003
29. Targeted actinium-225 in vivo generators for therapy of ovarian cancer.
- Author
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Borchardt PE, Yuan RR, Miederer M, McDevitt MR, and Scheinberg DA
- Subjects
- Animals, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Dimerization, Female, Humans, Indium Radioisotopes, Mice, Neoplasm Transplantation, Tissue Distribution, Transplantation, Heterologous, Trastuzumab, Tumor Cells, Cultured, Actinium therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods
- Abstract
Advanced ovarian cancer is largely incurable, but initially it is frequently confined to the i.p. space. We explored i.p. radioimmunotherapy in a mouse model of human ovarian cancer. Use of a targeted actinium-225 ((225)Ac) in vivo generator of alpha particles exploits the extreme, selective cytotoxicity of alpha particles, while providing a feasible half-life to enable delivery to tumor. (225)Ac chelated with 2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid was conjugated to trastuzumab, an anti-HER-2/neu antibody. The radioimmunoconjugate was tested for immunoreactivity, internalization, and cytotoxicity using a human ovarian carcinoma cell line, SKOV3. (225)Ac-labeled trastuzumab retained immunoreactivity (50-90%), rapidly internalized into cells (50% at 2 h), and had an ED(50) of 1.3 nCi/ml after 4 days of incubation in vitro. i.p. administered (225)Ac- or (111)In-labeled trastuzumab behaved similarly with high tumor uptake [56-60% injected dose per gram (% ID/g) at 4 h, which increased to 65-70% ID/g at 24 h]. Tumor uptake was 3-5-fold higher than liver and spleen, the normal organs with the highest uptake. i.v. administration of (111)In-labeled trastuzumab produced slightly higher normal organ uptake compared with i.p.-administered (111)In-labeled trastuzumab. However, tumor uptake was low, 5%-26% ID/g. Therapy was examined with native trastuzumab and 220, 330, and 450 nCi of (225)Ac-labeled trastuzumab or (225)Ac-labeled control antibody at different dosing schedules. Therapy was initiated 9 days after tumor seeding. Groups of control mice and those administered native trastuzumab had median survivals of 33 and 37 or 44 days, respectively. Median survival was 52-126 days with (225)Ac-labeled trastuzumab at various doses and schedules, and 48-64 days for (225)Ac-labeled control the same schedules. Deaths from toxicity occurred with the highest activity levels. In conclusion, i.p. administration with a (225)Ac-labeled internalizing anti-HER-2/neu antibody can extend survival significantly in a nude mouse model of human ovarian cancer at levels that produce no apparent gross toxicity.
- Published
- 2003
30. Dosimetric model for intraperitoneal targeted liposomal radioimmunotherapy of ovarian cancer micrometastases.
- Author
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Syme AM, McQuarrie SA, Middleton JW, and Fallone BG
- Subjects
- Biophysical Phenomena, Biophysics, CA-125 Antigen metabolism, Computer Simulation, Female, Humans, Injections, Intraperitoneal, Liposomes, Models, Biological, Ovarian Neoplasms immunology, Peritoneal Neoplasms immunology, Radioimmunotherapy statistics & numerical data, Radioisotopes therapeutic use, Radiotherapy, Adjuvant, Rhenium therapeutic use, Ovarian Neoplasms radiotherapy, Peritoneal Neoplasms radiotherapy, Peritoneal Neoplasms secondary, Radioimmunotherapy methods, Radiotherapy Planning, Computer-Assisted statistics & numerical data
- Abstract
A simple model has been developed to investigate the dosimetry of micrometastases in the peritoneal cavity during intraperitoneal targeted liposomal radioimmunotherapy. The model is applied to free-floating tumours with radii between 0.005 cm and 0.1 cm. Tumour dose is assumed to come from two sources: free liposomes in solution in the peritoneal cavity and liposomes bound to the surface of the micrometastases. It is assumed that liposomes do not penetrate beyond the surface of the tumours and that the total amount of surface antigen does not change over the course of treatment. Integrated tumour doses are expressed as a function of biological parameters that describe the rates at which liposomes bind to and unbind from the tumour surface, the rate at which liposomes escape from the peritoneal cavity and the tumour surface antigen density. Integrated doses are translated into time-dependent tumour control probabilities (TCPs). The results of the work are illustrated in the context of a therapy in which liposomes labelled with Re-188 are targeted at ovarian cancer cells that express the surface antigen CA-125. The time required to produce a TCP of 95% is used to investigate the importance of the various parameters. The relative contributions of surface-bound radioactivity and unbound radioactivity are used to assess the conditions required for a targeted approach to provide an improvement over a non-targeted approach during intraperitoneal radiation therapy. Using Re-188 as the radionuclide, the model suggests that, for microscopic tumours, the relative importance of the surface-bound radioactivity increases with tumour size. This is evidenced by the requirement for larger antigen densities on smaller tumours to affect an improvement in the time required to produce a TCP of 95%. This is because for the smallest tumours considered, the unbound radioactivity is often capable of exerting a tumouricidal effect before the targeting agent has time to accumulate significantly on the tumour surface.
- Published
- 2003
- Full Text
- View/download PDF
31. A Phase I study of combined modality (90)Yttrium-CC49 intraperitoneal radioimmunotherapy for ovarian cancer.
- Author
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Alvarez RD, Huh WK, Khazaeli MB, Meredith RF, Partridge EE, Kilgore LC, Grizzle WE, Shen S, Austin JM, Barnes MN, Carey D, Schlom J, and LoBuglio AF
- Subjects
- Adult, Aged, Animals, Antibodies, Heterophile biosynthesis, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal immunology, Antibodies, Neoplasm administration & dosage, Antibodies, Neoplasm immunology, Combined Modality Therapy, Disease-Free Survival, Female, Humans, Immunoconjugates administration & dosage, Injections, Intraperitoneal, Maximum Tolerated Dose, Mice, Middle Aged, Treatment Outcome, Yttrium Radioisotopes administration & dosage, Adenocarcinoma radiotherapy, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Immunoconjugates therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy, Yttrium Radioisotopes therapeutic use
- Abstract
Purpose: The purpose of this study was to determine the feasibility and maximum tolerated dose of (90)Yttrium-CC49 ((90)Y-CC49) as the radioimmunotherapy (RIT) component of an i.p. combined modality treatment for recurrent ovarian cancer., Experimental Design: A Phase I trial of (90)Y-CC49 RIT was conducted in ovarian cancer patients who had persistent or recurrent intra-abdominal disease, had failed one or two prior chemotherapy regimens, and demonstrated TAG-72 expression. Patients were treated with a previously established combined modality treatment protocol of s.c. IFN alpha2b, i.p. paclitaxel, and increasing dosages of i.p. (90)Y-CC49. Patients were monitored for toxicity, generation of human antimouse antibody response, and clinical efficacy., Results: Twenty eligible patients were treated per study specifications. All patients had been treated with debulking and paclitaxel/carboplatin-based chemotherapy at initial diagnosis. The patients included 11 patients with persistent disease at the time of second look laparotomy and 9 patients with delayed recurrence. Patients were treated with i.p. (90)Y-CC49 given in combination with s.c. IFN alpha2b (dose of 3 x 10(6) units for a total of four doses) and i.p. paclitaxel (dose of 100 mg/m(2)). RIT treatment was associated with primarily hematological toxicity. The maximum tolerated dose of i.p. (90)Y-CC49 was established at 24.2 mCi/m(2) in this combined regimen. Of nine patients with measurable disease, two had partial responses lasting 2 and 4 months. Of 11 patients with nonmeasurable disease, median time to progression was 6 months in 7 patients who recurred; 4 of these patients remain no evidence of disease at 9+, 18+, 19+, and 23+ months., Conclusions: (90)Yttrium-CC49-based RIT in combination with IFN alpha2b and i.p. paclitaxel is feasible and well tolerated at a dose of < or =24.2 mCi/m(2).
- Published
- 2002
32. Targeted therapy of cancer with radiolabeled antibodies.
- Author
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Goldenberg DM
- Subjects
- Brain Neoplasms radiotherapy, Breast Neoplasms radiotherapy, Colorectal Neoplasms radiotherapy, Female, Hodgkin Disease radiotherapy, Humans, Leukemia, Myeloid radiotherapy, Lymphoma, Non-Hodgkin radiotherapy, Lymphoma, T-Cell radiotherapy, Male, Ovarian Neoplasms radiotherapy, Prostatic Neoplasms radiotherapy, Radiotherapy Dosage, Neoplasms radiotherapy, Radioimmunotherapy
- Abstract
This review focuses on the use of radiolabeled antibodies in the therapy of cancer, termed radioimmunotherapy (RAIT). Basic problems concerning the choice of antibody and radionuclide and the physiology of tumor and host are discussed. Then follows a review of pertinent clinical publications on various radioantibody constructs in the treatment of hematopoietic and solid tumors of diverse histopathologies, grades, and stages, and in different clinical settings. Factors such as dose rate delivered, tumor size, and radiosensitivity play a major role in determining therapeutic response, while target-to-nontarget ratios and, particularly, circulating radioactivity to the bone marrow determine the major dose-limiting toxicities. RAIT appears to be gaining a place in the therapy of hematopoietic neoplasms, such as non-Hodgkin's lymphoma, with several agents advancing in clinical trials toward registration, of which one has just been approved by the FDA. Although RAIT of solid tumors has shown less progress, pretargeting strategies, such as an affinity-enhancement system consisting of bispecific antibodies separating targeting from delivery of the radiotherapeutic, appear to enhance tumor-to-nontumor ratios and may increase rad doses to tumor more selectively than directly labeled antibodies.
- Published
- 2002
33. Modern trends in radioimmunotherapy of cancer: pretargeting strategies for the treatment of ovarian cancer.
- Author
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McQuarrie SA, Xiao Z, Miller GG, Mercer JR, and Suresh MR
- Subjects
- Antibodies, Monoclonal therapeutic use, Female, Fluorescein-5-isothiocyanate, Humans, Liposomes, Tumor Cells, Cultured, Ovarian Neoplasms radiotherapy, Radioimmunotherapy
- Abstract
A review of published data on some of the problems associated in treating cancer using radioimmunotherapy is presented. Potential improvements for this type of therapy using pretargeting strategies are discussed and preliminary results on a novel multistep regimen to treat human ovarian cancer are presented. A pretargeting strategy using a biotinylated, anti-CA125 monoclonal antibody (MAb) to attract biotinylated long-circulating liposomes to the surface of CA125-expressing ovarian cancer cells, was employed. Confocal laser scanning microscopy and fluorescent labels were used to establish the biodistribution patterns in NIH:OVCAR-3 (CA-125 positive) and SK-OV-3 (CA-125 negative) human ovarian cancer cells. Shedding kinetics of the pretargeted stage were measured using 125I labeled MAbs. No significant internalization of the MAb used in the pretargeting step was observed by 4 hrs. The antibody was gradually internalized starting at 6 hrs, and most of the labelled MAb was detected in cytoplasm by 24 hrs. Shedding and exocytosis of the antigen-MAb complex was not significant for up to 6-hours following administration of the iodinated MAb. Biotinylated liposomes were shown to specifically target the biotinylated MAb/streptavidin complex on the cell surface. We have demonstrated that by a three-step pretargeting approach, biotinylated liposomes can be specifically delivered to cells pretargeted with biotinylated MAb/SAv complex. The slow internalization and shedding properties of the two MAbs are ideal for multistep pretargeting methods. A successful multistep linkage was established with the biotinylated MAb B27.1, streptavidin and biotinylated liposomes to OVCAR-3 cells, but not to SK-OV-3 cells.
- Published
- 2001
34. Influence of the route of administration on targeting of ovarian cancer with the chimeric monoclonal antibody MOv18: i.v. vs. i.p.
- Author
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van Zanten-Przybysz I, Molthoff CF, Roos JC, Verheijen RH, van Hof A, Buist MR, Prinssen HM, den Hollander W, and Kenemans P
- Subjects
- Adult, Aged, Antibodies, Monoclonal pharmacokinetics, Biopsy, Female, Humans, Immunohistochemistry, Iodine Radioisotopes pharmacokinetics, Iodine Radioisotopes therapeutic use, Isotope Labeling, Kinetics, Middle Aged, Neoplasm Recurrence, Local, Ovarian Neoplasms diagnostic imaging, Ovarian Neoplasms surgery, Ovary metabolism, Tissue Distribution, Tomography, Emission-Computed, Single-Photon, Antibodies, Monoclonal administration & dosage, Iodine Radioisotopes administration & dosage, Ovarian Neoplasms radiotherapy, Radioimmunotherapy
- Abstract
MOv18 antibody binds the membrane folate receptor highly expressed on ovarian carcinoma cells. Since ovarian cancer is mainly limited to the peritoneal cavity, locoregional delivery of therapeutics can be an option. The same patient was injected i.v. and i.p. with c-MOv18 IgG labeled with different radionuclides. To study the kinetics of c-MOv18, patients were divided into 2 groups. Fifteen patients received c-MOv18 labeled with (131)I, (125)I and (123)I (for imaging). Seven patients were operated 2 days, 7 patients 6 days and 1 patient 3 days post-injection. Radioactivity was determined in blood, ascites and biopsies of tumor and of several normal tissues. No adverse events occurred. No anti-MOv18 responses were observed. The area under the blood activity vs. time curve (AUC) was significantly lower after i.p. injection for 2 and 6 days post-injection (p = 0.01 and p = 0.02, respectively). At 2 days post-injection, a significant difference in tumor uptake was found in favor of the i.v. route of administration (4.9% and 2.4%ID/kg for i.v. and i.p., respectively; p < 0.0001). Uptake in solid tumor tissue in ovarian cancer patients operated 6 days post-injection was not significantly different (p = 0.79) for both routes (3.8% and 3.9%ID/kg for i.v. and i.p., respectively). In conclusion, no advantage could be demonstrated for the i.p. route with respect to tumor uptake. The i.p. route could be advantageous with respect to bone marrow toxicity since the AUC was significantly lower for the i.p. route. However, within 2 days post-injection, the blood clearance followed the same pattern for both routes., (Copyright 2001 Wiley-Liss, Inc.)
- Published
- 2001
35. Optimal quality (131)I-monoclonal antibodies on high-dose labeling in a large reaction volume and temporarily coating the antibody with IODO-GEN.
- Author
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Visser GW, Klok RP, Gebbinck JW, ter Linden T, van Dongen GA, and Molthoff CF
- Subjects
- Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacokinetics, Carrier Proteins immunology, Female, Folate Receptors, GPI-Anchored, Iodine Radioisotopes pharmacokinetics, Mice, Mice, Nude, Neoplasm Proteins immunology, Ovarian Neoplasms immunology, Ovarian Neoplasms radiotherapy, Tissue Distribution, Antibodies, Monoclonal therapeutic use, Indicators and Reagents, Iodine Radioisotopes therapeutic use, Radioimmunotherapy, Receptors, Cell Surface, Urea analogs & derivatives
- Abstract
Unlabelled: A novel, facile procedure for efficient coupling of high doses of (131)I to monoclonal antibodies (MAbs) was developed with minimal chemical and radiation damage., Methods: To diminish the radiation and chemical burden during labeling, iodination was performed in a large reaction volume and by temporarily coating the MAb with a minimal amount of IODO-GEN. The MAb was coated by injection of IODO-GEN (dissolved in acetonitrile [MeCN]) into the aqueous MAb solution, and the coating was subsequently removed by addition of ascorbic acid. For chemoprotection before, during, and after PD-10 purification of the (131)I-MAbs, ascorbic acid and human serum albumin were used. The effects of autoradiolysis in the starting (131)I solution were countered by treatment with NaOH and ascorbic acid. For this so-called IODO-GEN-coated MAb method, the sensitive chimeric MAb MOv18 (c-MOv18) and the more robust murine MAbs K928 and E48 were used. The high-dose (131)I-labeled MAbs were characterized for radiochemical purity and MAb integrity by thin-layer chromatography, high-performance liquid chromatography, and sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by phosphor imager quantification. The high-dose (131)I-labeled MAbs were also characterized for immunoreactivity. The radiopharmacokinetics and biodistribution of (131)I-c-MOv18 were analyzed in human tumor-bearing nude mice. For comparison, (131)I-c-MOv18 batches were made using the conventional chloramine-T or IODO-GEN-coated vial method., Results: Conventional high-dose labeling of 5 mg c-MOv18 with 4.4 GBq (131)I resulted in a labeling yield of 60%, a radiochemical purity of 90%, an immunoreactive fraction of 25% (72% being the maximum in the assay used), and the presence of aggregation and degradation products. Using similar amounts of (131)I and MAb in the IODO-GEN-coated MAb method, 85%-89% overall radiochemical yield, at least 99.7% radiochemical purity, and full preservation of MAb integrity and immunoreactivity were achieved. For this labeling, 5 mg MAb were coated with 35 microg IODO-GEN during 3 min in a reaction volume of 6 mL. Also, biodistribution was optimal, and tumor accumulation was superior to that of coinjected (125)I-c-MOv18 labeled according to the conventional IODO-GEN-coated vial method., Conclusion: A new, facile, high-dose (131)I-labeling method was developed for production of (131)I-labeled MAbs with optimal quality for use in clinical radioimmunotherapy.
- Published
- 2001
36. Comparison of the therapeutic efficacy of 211At- and 131I-labelled monoclonal antibody MOv18 in nude mice with intraperitoneal growth of human ovarian cancer.
- Author
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Andersson H, Palm S, Lindegren S, Bäck T, Jacobsson L, Leser G, and Horvath G
- Subjects
- Alpha Particles therapeutic use, Animals, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal, Murine-Derived, Beta Particles therapeutic use, Bone Marrow radiation effects, Cell Division radiation effects, Female, Humans, Immunoconjugates pharmacokinetics, Iodine Radioisotopes therapeutic use, Mice, Mice, Nude, Ovarian Neoplasms metabolism, Ovarian Neoplasms pathology, Peritoneal Neoplasms metabolism, Peritoneal Neoplasms secondary, Radiotherapy Dosage, Tumor Cells, Cultured, Antibodies, Monoclonal therapeutic use, Astatine therapeutic use, Immunoconjugates therapeutic use, Ovarian Neoplasms radiotherapy, Peritoneal Neoplasms radiotherapy, Radioimmunotherapy
- Abstract
The purpose of the present study was to compare the therapeutic efficacy of the alpha-emitter Astatine-211 with the beta-emitter Iodine-131 bound to the specific monoclonal antibody MOv18. The measurements were performed in an ovarian cancer cell line (NIH:OVCAR 3) growing intraperitoneally in nude mice. Two weeks after the intraperitoneal inoculation of 1 x 10(7) cells of the human ovarian cancer cell line NIH:OVCAR-3 twenty mice were treated intraperitoneally with the specific monoclonal antibody MOv-18 labelled with either 211At (310-400 kBq) or 131I (5100-6200 kBq). The pharmacokinetics and biodistribution of labelled antibody in tumour-free animals were studied and the resulting bone marrow dose was estimated. When the mice were treated with 211At-labelled antibody 9 out of 10 mice were free of macro- and microscopic tumour compared to 3 out of 10 when Iodine-131 was used. The equivalent dose to the bone marrow was 2.4-3.1 Sv from 211At- and 3.4-4.1 Sv from 131I-irradiation. The therapeutic efficacy of 211At-labelled specific antibody is very good and, at approximately equivalent bone marrow doses, better than that of 131I.
- Published
- 2001
37. Radioimmunotherapy with intravenously administered 131I-labeled chimeric monoclonal antibody MOv18 in patients with ovarian cancer.
- Author
-
van Zanten-Przybysz I, Molthoff CF, Roos JC, Plaizier MA, Visser GW, Pijpers R, Kenemans P, and Verheijen RH
- Subjects
- Antibodies, Monoclonal pharmacokinetics, Female, Humans, Immunoglobulin G, Injections, Intravenous, Iodine Radioisotopes pharmacokinetics, Iodine Radioisotopes therapeutic use, Middle Aged, Ovarian Neoplasms diagnostic imaging, Radionuclide Imaging, Radiotherapy Dosage, Antibodies, Monoclonal administration & dosage, Iodine Radioisotopes administration & dosage, Ovarian Neoplasms radiotherapy, Radioimmunotherapy adverse effects
- Abstract
Unlabelled: We investigated the safety and pharmacokinetics of (131)I-labeled chimeric monoclonal antibody MOv18 ((131)I-c-MOv18 IgG) in patients with ovarian cancer and the estimated radiation dose to cancer-free organs and tumor., Methods: Three patients were injected intravenously with 3 GBq (131)I-c-MOv18. Toxicity was evaluated according to the World Health Organization toxicity scales. Blood sampling was performed for 12 wk after injection. Whole-body and SPECT imaging was performed frequently. Dose rates were obtained with a portable dose-rate measure. Quantitative activity analysis of several organs was performed with the region-of-interest technique. Absorbed doses were calculated using MIRDOSE3., Results: Transient changes in hematologic profiles were seen in 2 patients. Pancytopenia developed in 1 patient; on analysis, she entered the study probably with exhausted bone marrow reserves. Nonhematologic toxicity was mild. No human antichimeric antibody responses were observed. Mean isolation time was 12 d. The plasma elimination half-life increased almost 3-fold compared with that after tracer doses of c-MOv18. Dosimetry showed mean absorbed doses of 163, 380, 276, 338, 781, and 216 cGy, for whole-body, liver, kidney, spleen, lung, and red marrow, respectively. Tumor-absorbed doses ranged from 600 to 3800 cGy. All patients achieved a stable disease state, as confirmed by CT and carcinoma-associated antigen CA 125, lasting from 2 to >6 mo., Conclusion: (131)I-labeled c-MOv18 can safely be given to patients with noncompromised bone marrow reserves and may have therapeutic potential particularly in patients with minimal residual disease.
- Published
- 2000
38. Absorbed dose estimates for 131I-labelled monoclonal antibody therapy in patients with intraperitoneal pseudomyxoma.
- Author
-
Laitinen JO, Tenhunen M, and Kairemo KJ
- Subjects
- Antibodies, Monoclonal pharmacokinetics, Antibodies, Neoplasm metabolism, Appendiceal Neoplasms radiotherapy, Female, Humans, Iodine Radioisotopes pharmacokinetics, Models, Biological, Ovarian Neoplasms radiotherapy, Radiotherapy Dosage, Tissue Distribution, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Iodine Radioisotopes therapeutic use, Peritoneal Neoplasms radiotherapy, Pseudomyxoma Peritonei radiotherapy, Radioimmunotherapy
- Abstract
Seven patients with intraperitoneal pseudomyxoma originating from the appendix (4 cases) and from the ovary (3 cases) were treated with radioimmunotherapy. During the therapy, nine infusions of 3.0-4.2 GBq of 131I-labelled B72.3 monoclonal antibody were administered. We developed three-dimensional dose calculation software that can utilize activity maps based on SPET images to calculate the absorbed dose distribution using point source kernels. The dose calculation program was employed to calculate absorbed doses to various organs. The calculated dose distributions enable us to evaluate the variation in dose within the organs, which is normally not available using approaches based on geometric models. The patient-specific absorbed dose calculations were compared with doses based on a model that uses photon S-factors derived from a standard phantom. The compared doses agreed well on average, but in some organs showed large discrepancies.
- Published
- 2000
- Full Text
- View/download PDF
39. Intraperitoneal radioimmunotherapy with human monoclonal IGM in nude mice with peritoneal carcinomatosis.
- Author
-
Borchardt PE, Quadri SM, Freedman RS, and Vriesendorp HM
- Subjects
- Animals, Antibodies, Monoclonal, Dose Fractionation, Radiation, Female, Humans, Immunoglobulin M, Mice, Mice, Nude, Survival, Time Factors, Transplantation, Heterologous, Tumor Cells, Cultured, Yttrium Radioisotopes administration & dosage, Yttrium Radioisotopes therapeutic use, Ovarian Neoplasms radiotherapy, Peritoneal Neoplasms radiotherapy, Radioimmunotherapy
- Abstract
Unlabelled: In an effort to improve loco-regional control of ovarian cancer, intraperitoneal (i.p.) administration of an yttrium-90 (90Y) labeled human IgM was studied in a nude mouse model of the disease., Methods: Athymic nude mice bearing i.p. nodules of SKOV3 NMP2, a human ovarian carcinoma cell line, received single (50-400 microCi) or fractionated (150-510 microCi) administrations of 90Y-labeled 2B12. Untreated mice and mice treated with unlabeled immunoconjugate served as controls. Mice were monitored for weight loss, blood counts and survival., Results: Mice that received at least 300 microCi of 90Y-labeled 2B12 in a single administration lost more than 10% of their body weight with some early deaths, both of which were prevented with fractionated administration. Granulocytes and lymphocytes declined with treatment while red blood cell counts were relatively stable. Untreated mice and mice treated with unlabeled immunoconjugate had a median survival time of 20 and 17 days respectively. Treatment with 90Y-labeled 2B12 increased median survival by 11-12 days per 100 microCi for single (50-300 microCi) and fractionated administrations (150-510 microCi). The highest fractionated activity produced over three logs of tumor cell kill without significant toxicity., Conclusion: Intraperitoneal RIT with 90Y-labeled 2B12 appears to be an attractive modality to treat peritoneal carcinomatosis and warrants further development.
- Published
- 2000
- Full Text
- View/download PDF
40. Radioimmunotherapy of nude mice with intraperitoneally growing ovarian cancer xenograft utilizing 211At-labelled monoclonal antibody MOv18.
- Author
-
Andersson H, Lindegren S, Back T, Jacobsson L, Leser G, and Horvath G
- Subjects
- Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Neoplasm administration & dosage, Antigens, Neoplasm immunology, Ascites etiology, Ascites radiotherapy, Astatine administration & dosage, Carcinoma immunology, Carcinoma pathology, Carrier Proteins immunology, Female, Folate Receptors, GPI-Anchored, Humans, Injections, Intraperitoneal, Injections, Intravenous, Membrane Glycoproteins immunology, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Proteins immunology, Neoplasm Transplantation, Neoplasm, Residual, Ovarian Neoplasms immunology, Ovarian Neoplasms pathology, Peritoneal Neoplasms immunology, Peritoneal Neoplasms pathology, Transplantation, Heterologous, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Astatine therapeutic use, Carcinoma radiotherapy, Immunoconjugates therapeutic use, Ovarian Neoplasms radiotherapy, Peritoneal Neoplasms radiotherapy, Radioimmunotherapy, Receptors, Cell Surface
- Abstract
The aim of this study was to investigate the therapeutic efficacy of 211At-labelled monoclonal antibody given intraperitoneally to nude mice with intraperitoneal growth of a human ovarian cancer cell line. Female nude mice were inoculated intraperitoneally with 1 x 10(7) cells of the human ovarian cancer cell line NIH:OVCAR 3. After about two weeks they were injected with the 211At-labelled specific monoclonal antibody MOv18 intraperitoneally. For comparison, other groups of mice were given the same labelled antibody intravenously, 211At-labelled unspecific antibody C242 intraperitoneally or unalbelled MOv18 intraperitoneally. Six weeks later the animals were sacrificed and the occurrence of tumour and ascites was determined. When the mice were treated with 211At-labelled MOv18 intraperitoneally 9 out of 10 were apparently free of both ascites and tumour compared to none of the mice given unlabelled antibody. 211At-labelled MOv18 given intravenously or 211At-labelled unspecific antibody given intraperitoneally were less effective. Regional radioimmunotherapy with the alpa-emitter 211Astatine seems to be an effective treatment of nude mice with intraperitoneally growing human ovarian cancer. Hopefully this treatment can be given in an adjuvant setting to women with minimal residual ovarian cancer in the future.
- Published
- 2000
41. A phase II study of intraperitoneal radioimmunotherapy with iodine-131-labeled monoclonal antibody OC-125 in patients with residual ovarian carcinoma.
- Author
-
Mahé MA, Fumoleau P, Fabbro M, Guastalla JP, Faurous P, Chauvot P, Chetanoud L, Classe JM, Rouanet P, and Chatal JF
- Subjects
- Aged, Animals, Female, Humans, Injections, Intraperitoneal, Mice, Middle Aged, Neoplasm, Residual, Antibodies, Monoclonal therapeutic use, Iodine Radioisotopes therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy
- Abstract
Standard treatment of advanced ovarian cancer is a combination of surgery and chemotherapy. Additional therapies using the i.p. route are considered as a potential means of improving the locoregional control rate. This Phase II study evaluated the efficacy of i.p. radioimmunotherapy (RIT) in patients with minimal residual ovarian adenocarcinoma after primary treatment with surgery and chemotherapy. Between February 1995 and March 1996, six patients with residual macroscopic (<5 mm) or microscopic disease as demonstrated by laparotomy and multiple biopsies received i.p. RIT. All had initial stage III epithelial carcinoma and were treated with debulking surgery and one line (four patients) or two lines (two patients) of chemotherapy. RIT was performed with 60 mg of OC 125 F(ab')2 monoclonal antibody labeled with 4.44 GBq (120 mCi) of 131I injected 5-10 days after the surgical procedure. Systematic laparoscopy or laparotomy with multiple biopsies performed 3 months after RIT in five patients (clinical progression was seen in one patient) showed no change in three patients and progression in two patients. Toxicity was mainly hematological, with grade III neutropenia and thrombocytopenia in two patients. Human antimouse antibody production was demonstrated in all six patients. This study showed little therapeutic benefit from i.p. RIT in patients with residual ovarian carcinoma.
- Published
- 1999
42. A new era for radiolabeled antibodies in cancer?
- Author
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DeNardo SJ, Kroger LA, and DeNardo GL
- Subjects
- Clinical Trials as Topic, Female, Humans, Leukemia radiotherapy, Lymphoma radiotherapy, Ovarian Neoplasms radiotherapy, Antibodies, Neoplasm therapeutic use, Neoplasms radiotherapy, Radioimmunotherapy methods, Radiopharmaceuticals therapeutic use
- Abstract
Radioimmunotherapy (RIT), a therapy targeted to tumor cells, is a modality that can currently deliver radiation to tumor cells at levels 3-50-times higher than to the normal tissue with the next highest dose. RIT appears promising for future cancer therapy. Clinical responses in patients with advanced cancer have frequently been achieved with RIT as a single agent. Extended complete remissions and even increased survival have been achieved in lymphoma. Similar results in other cancers seem likely with RIT in combination therapy.
- Published
- 1999
- Full Text
- View/download PDF
43. Phase I study of 90Y-labeled B72.3 intraperitoneal administration in patients with ovarian cancer: effect of dose and EDTA coadministration on pharmacokinetics and toxicity.
- Author
-
Rosenblum MG, Verschraegen CF, Murray JL, Kudelka AP, Gano J, Cheung L, and Kavanagh JJ
- Subjects
- Adult, Aged, Animals, Antibodies, Monoclonal administration & dosage, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacokinetics, Antibodies, Neoplasm administration & dosage, Antibodies, Neoplasm immunology, Ascites radiotherapy, Ascitic Fluid chemistry, Bone Marrow chemistry, Bone Marrow radiation effects, Bone Marrow Diseases chemically induced, Bone and Bones chemistry, Carcinoma pathology, Carcinoma secondary, Carcinoma therapy, Chelation Therapy, Dose-Response Relationship, Immunologic, Dose-Response Relationship, Radiation, Edetic Acid administration & dosage, Edetic Acid pharmacology, Fallopian Tube Neoplasms pathology, Fallopian Tube Neoplasms radiotherapy, Fallopian Tube Neoplasms therapy, Female, Half-Life, Humans, Injections, Intraperitoneal, Mice, Middle Aged, Neoplasm, Residual, Ovarian Neoplasms pathology, Ovarian Neoplasms therapy, Peritoneal Neoplasms radiotherapy, Peritoneal Neoplasms secondary, Peritoneal Neoplasms therapy, Radiation Injuries chemically induced, Radioisotopes administration & dosage, Radioisotopes adverse effects, Radioisotopes pharmacokinetics, Radiotherapy Dosage, Tissue Distribution, Treatment Outcome, Ytterbium administration & dosage, Ytterbium adverse effects, Ytterbium pharmacokinetics, Antibodies, Monoclonal therapeutic use, Antibodies, Neoplasm therapeutic use, Antigens, Neoplasm immunology, Bone Marrow Diseases prevention & control, Carcinoma radiotherapy, Chelating Agents therapeutic use, Edetic Acid therapeutic use, Glycoproteins immunology, Ovarian Neoplasms radiotherapy, Radiation Injuries prevention & control, Radioimmunotherapy adverse effects, Radioisotopes therapeutic use, Ytterbium therapeutic use
- Abstract
The tumor-associated glycoprotein 72 (TAG-72) antigen is present on a high percentage of tumor types including ovarian carcinomas. Antibody B72.3 is a murine monoclonal recognizing the surface domain of the TAG-72 antigen and has been widely used in human clinical trials. After our initial encouraging studies (M. G. Rosenblum et al., J. Natl. Cancer Inst., 83: 1629-1636, 1991) of tissue disposition, metabolism, and pharmacokinetics in 9 patients with ovarian cancer, we designed an escalating dose, multi-arm Phase I study of 90Y-labeled B72.3 i.p. administration. In the first arm of the study, patients (3 pts/dose level) received an i.p. infusion of either 2 or 10 mg of B72.3 labeled with either 1, 10, 15, or 25 mCi of 90Y. Pharmacokinetic studies demonstrated that concentrations of 90Y-labeled B72.3 persist in peritoneal fluid with half-lives >24 h after i.p. administration. In addition, 90Y-labeled B72.3 was absorbed rapidly into the plasma with peak levels achieved within 48 h, and levels declined slowly thereafter. Cumulative urinary excretion of the 90Y label was 10-20% of the administered dose which suggests significant whole-body retention of the radiolabel. Biopsy specimens of bone and marrow obtained at 72 h after administration demonstrated significant content of the label in bone (0.015% of the dose/g) with relatively little in marrow (0.005% of the dose/g). The maximal tolerated dose was determined to be 10 mCi because of hematological toxicity and platelet suppression. This typically occurred on the 29th day after administration and was thought to be a consequence of the irradiation of the marrow from the bony deposition of the radiolabel. In an effort to suppress the bone uptake of 90Y, patients were treated with a continuous i.v. infusion of EDTA (25 mg/kg/12 h x 6) infused immediately before i.p. administration of the radiolabeled antibody. Patients (3 pts/dose level) were treated with doses of 10, 15, 20, 25, 30, 35, 40, or 45 mCi of 90Y-labeled B72.3 for a total of 38 patients. EDTA administration resulted in significant myeloprotection, which allowed escalation to the maximal tolerated dose of 40 mCi. Dose-limiting toxicity was thrombocytopenia and neutropenia. Studies of plasma and peritoneal fluid pharmacokinetics demonstrate no changes compared with patients without EDTA pretreatment. Cumulative urinary excretion of the radiolabel was not increased in patients pretreated with EDTA compared with the untreated group. However, analysis of biopsy specimens of bone and marrow demonstrated that bone and marrow content of the 90Y label was 15-fold lower (<0.001% injected dose/g) than a companion group without EDTA. Four responses were noted in patients who received 15-30 mCi of 90Y-labeled B72.3 with response durations of 1-12 months. These results demonstrate the myeloprotective ability of EDTA, which allows safe i.p. administration of higher doses of 90Y-labeled B72.3 and, therefore, clearly warrant an expanded Phase II trial in patients with minimal residual disease after standard chemotherapy or for the palliation of refractory ascites.
- Published
- 1999
44. Radiation absorbed dose estimates for indium-111-labeled B72.3, an IgG antibody to ovarian and colorectal cancer: MIRD dose estimate report No. 18.
- Author
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Mardirossian G, Brill AB, Harwood SJ, Olsen J, Dwyer KA, and Siegel JA
- Subjects
- Female, Humans, Male, Pentetic Acid pharmacokinetics, Radiotherapy Dosage, Tissue Distribution, Antibodies, Monoclonal pharmacokinetics, Colorectal Neoplasms radiotherapy, Indium Radioisotopes pharmacokinetics, Oligopeptides pharmacokinetics, Ovarian Neoplasms radiotherapy, Pentetic Acid analogs & derivatives, Radioimmunotherapy
- Published
- 1998
45. Indium-111- and yttrium-90-labeled human monoclonal immunoglobulin M targeting of human ovarian cancer in mice.
- Author
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Borchardt PE, Quadri SM, Freedman RS, and Vriesendorp HM
- Subjects
- Animals, Female, Humans, Immunoconjugates pharmacokinetics, Immunoconjugates therapeutic use, Immunoglobulin M metabolism, Immunoglobulin M therapeutic use, Mice, Mice, Nude, Neoplasm Transplantation, Ovarian Neoplasms metabolism, Peritoneal Neoplasms radiotherapy, Peritoneal Neoplasms secondary, Tissue Distribution, Indium Radioisotopes therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy, Yttrium Radioisotopes therapeutic use
- Abstract
Unlabelled: Most patients with ovarian cancer have disease in the peritoneal cavity. Treatment of this region is inadequate because recurrences are frequent. Increased radiation doses to tumor and, hence, greater tumor control may be possible with intraperitoneal (i.p.) administration of radiolabeled human monoclonal immunoglobulin M (IgM), which is reactive with tumor-associated antigens., Methods: Biodistribution studies were performed in nude mice bearing i.p. nodules of human ovarian cancer after administration of human monoclonal IgMlambda (AC6C3-2B12), labeled with 111In or 90Y. Irrelevant 111In-labeled human IgMlambda (CH-1B9) and 90Y-aggregate served as specificity controls., Results: Intravenous administration of 111In-labeled AC6C3-2B12 produced low tumor and high liver and spleen uptake. Intraperitoneal administration of AC6C3-2B12 labeled with 111In or 90Y resulted in rapid, high tumor uptake (>45% of injected dose per gram of tumor at 3 hr) that was at least three-fold higher than any normal organ. Biodistribution results were similar for 111In- and 90Y-labeled IgM. Tumor uptake of 111In-labeled AC6C3-2B12 was two-fold greater than that of 111In-labeled CH-1B9. Normal organ uptakes were similar for tumor-reactive and irrelevant IgM. Radioimmunoconjugates were retained in the peritoneal cavity for a prolonged period of time. Yttrium-90 aggregate demonstrated high tumor and bone uptake., Conclusion: Higher tumor uptake was observed after i.p. administration of tumor-reactive IgM than after irrelevant IgM. The in vivo behavior of tumor-reactive IgM was similar when it was radiolabeled with either 111In or 90Y. Therefore, 111In-based imaging studies can be used to predict the biodistribution of subsequently administered 90Y-labeled IgM. Further development of radiolabeled AC6C3-2B12 as a diagnostic and therapeutic agent for patients with advanced ovarian carcinoma is warranted.
- Published
- 1998
46. [186Re]-labeled mouse and chimeric monoclonal antibody 323/A3: a comparison of the efficacy in experimental human ovarian cancer.
- Author
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Kievit E, van Gog FB, Schlüper HM, van Dongen GA, Pinedo HM, and Boven E
- Subjects
- Animals, Antibodies, Monoclonal chemistry, Antibodies, Monoclonal pharmacokinetics, Chelating Agents chemistry, Combined Modality Therapy, Dose-Response Relationship, Drug, Female, Glycine analogs & derivatives, Glycine chemistry, Humans, Immunotoxins chemistry, Immunotoxins pharmacokinetics, Isoelectric Point, Mice, Mice, Nude, Neoplasm Transplantation, Ovarian Neoplasms metabolism, Recombinant Fusion Proteins chemistry, Recombinant Fusion Proteins pharmacokinetics, Tissue Distribution, Transplantation, Heterologous, Tumor Cells, Cultured, Antibodies, Monoclonal therapeutic use, Immunotoxins therapeutic use, Ovarian Neoplasms radiotherapy, Ovarian Neoplasms therapy, Radioimmunotherapy, Radioisotopes, Recombinant Fusion Proteins therapeutic use, Rhenium
- Abstract
We have investigated whether [186Re]-labeled chimeric monoclonal antibody 323/A3 (MAb c-323/A3) is as effective as [186Re]-labeled mouse 323/A3 (m-323/A3) in the growth inhibition of human ovarian cancer xenografts OVCAR-3 and FMa. [186Re] was conjugated to MAbs with the use of the chelate S-benzoylmercaptoacetyltriglycine (S-benzoyl-MAG3). The maximum number of metal-MAG3 groups that could be conjugated to one MAb molecule accepting a minimal initial increase of the blood clearance (15%) was 8.5 and 2.9 for c-323/A3 and m-323/A3, respectively. With these molar ratios the immunoreactivity of both MAbs was maintained. An inverse relationship was observed between the protein dose of c-323/A3 and its blood clearance. Both [186Re]-c-323/A3 and [186Re]-m-323/A3 were comparable in the inhibition of the tumor growth when higher protein doses were used. Together with the expected lower immunogenicity, our results imply that c-323/A3 is preferable for use in [186Re]-radioimmunotherapy in ovarian cancer patients.
- Published
- 1998
- Full Text
- View/download PDF
47. Radioimmunotherapy after chemotherapy compared to chemotherapy alone in the treatment of advanced ovarian cancer: a matched analysis.
- Author
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Nicholson S, Gooden CS, Hird V, Maraveyas A, Mason P, Lambert HE, Meares CF, and Epenetos AA
- Subjects
- Adult, Aged, Animals, Antibodies, Monoclonal, Cohort Studies, Combined Modality Therapy, Female, Follow-Up Studies, Humans, Mice, Middle Aged, Neoplasm Staging, Ovarian Neoplasms mortality, Ovarian Neoplasms pathology, Patient Selection, Proportional Hazards Models, Regression Analysis, Survival Rate, Time Factors, Yttrium Radioisotopes therapeutic use, Ovarian Neoplasms drug therapy, Ovarian Neoplasms radiotherapy, Radioimmunotherapy
- Abstract
Ovarian cancer has an overall five-year survival of around 30% in spite of complete remissions being obtained after optimal surgery and platinum-based chemotherapy. Previous studies have indicated a survival advantage for patients treated with radiolabelled monoclonal antibodies (radioimmunotherapy). We report here on the survival of patients who received single-dose intraperitoneal radioimmunotherapy after having achieved complete remission with standard management. Twenty-five patients with epithelial ovarian cancer, stages Ic-IV, received adjuvant intraperitoneal radioimmunotherapy following completion of conventional chemotherapy. On achieving complete remission they receive once 25 mg of HMFG1 labelled with 18 mCi/m2. Controls for cases were sought from the database of the North Thames ovary group (NTOG). Controls were selected on the basis of stage, histological grade and type, and age of patient at diagnosis. Kaplan-Meier survival plots were constructed for cases and controls and subjected to statistical analysis with the log-rank test. Additionally, using a database of 84 NTOG patients known to be disease-free at the end of chemotherapy, estimated survival curves were constructed using Cox's proportional hazards regression model. Close matches were found for 20 of the 25 patients. Median survival has not been reached at a median follow-up of 59 months for cases and 27 months for controls. Survival at five years is 80% for cases and 55% for controls (p=0.0035). The Cox model estimates long-term (10-year) survival of 70% for patients who received radioimmunotherapy, compared to 32% for those that did not (p=0.003). All patients developed serological evidence of human anti-mouse antibody (HAMA). This study shows a likely survival benefit for patients with ovarian cancer who receive intraperitoneal radioimmuno-therapy in the adjuvant setting.
- Published
- 1998
- Full Text
- View/download PDF
48. Escalating protein doses of chimeric monoclonal antibody MOv18 immunoglobulin G in ovarian carcinoma patients: a phase I study.
- Author
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Molthoff CF, Prinssen HM, Kenemans P, van Hof AC, den Hollander W, and Verheijen RH
- Subjects
- Adult, Aged, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal pharmacokinetics, Female, Humans, Iodine Radioisotopes therapeutic use, Middle Aged, Tissue Distribution, Antibodies, Monoclonal therapeutic use, Immunoglobulin G therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy, Recombinant Fusion Proteins therapeutic use
- Abstract
Background: Successful first-line treatment of ovarian cancer does not incite cure. Recurrent disease often shows an increased resistance to chemotherapeutic agents. Therefore, other treatment modalities, like (radio)immunotherapy using tumor-associated monoclonal antibodies, should be considered. Chimeric MOv18 (c-MOv18) localizes well in ovarian carcinoma tissue. We investigated the safety of a single intravenous (i.v.) infusion of increasing doses of c-MOv18 in ovarian carcinoma patients., Methods: Fifteen patients received c-MOv18 (from 5 mg to 75 mg). Safety was determined by recording vital signs; by hematological, biochemical, and urinary analyses; and by the human-antichimeric antibody (HACA) response. Five patients received c-MOv18 labeled with a tracer dose of iodine-131 to analyze the pharmacokinetics and biodistribution in blood, urine, and tissue biopsies at surgery., Results: Administration of c-MOv18 IgG was uneventful. No significant changes in hematological, biochemical, or urine profiles were noted at any time postinjection (p.i). Starting with a dose of 50 mg, all patients experienced side effects, like fever, headache, and nausea/vomiting, maximally Grade II (World Health Organization toxicity scale). No HACA response was found up to 12 weeks p.i. The mean elimination half-life after infusion of 30-75 mg c-MOv18 was significantly higher compared with infusion of 1 mg. Absolute amount of c-MOv18 in carcinoma tissue increased with increasing c-MOv18 doses., Conclusions: Intravenous administration of c-MOv18 IgG in a dose up to 75 mg is safe, inducing only minor side effects at doses of 50 mg or higher. In view of the characteristics of c-MOv18, this antibody might be applicable as an unmodified antibody or as an immunoconjugate in the treatment of ovarian carcinomas.
- Published
- 1997
- Full Text
- View/download PDF
49. Radioimmunotherapy targeting of HER2/neu oncoprotein on ovarian tumor using lead-212-DOTA-AE1.
- Author
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Horak E, Hartmann F, Garmestani K, Wu C, Brechbiel M, Gansow OA, Landolfi NF, and Waldmann TA
- Subjects
- Animals, Antibodies, Monoclonal pharmacokinetics, Antibodies, Monoclonal therapeutic use, Female, Humans, Lead Radioisotopes pharmacokinetics, Mice, Mice, Nude, Neoplasm Transplantation, Ovarian Neoplasms metabolism, Proto-Oncogene Mas, Tissue Distribution, Lead Radioisotopes therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy, Receptor, ErbB-2 metabolism
- Abstract
Unlabelled: The specificity, toxicity and efficacy of lead (212Pb) radioimmunotherapy were evaluated in nude mice bearing the SK-OV-3 human ovarian tumor cell line expressing the HER2/neu proto-oncogene., Methods: The therapeutic agent used was the tumor-specific anti-HER2/neu monoclonal antibody AE1 conjugated to 212Pb, 212Bi being the daughter and thus the source of the alpha-particle and beta emissions. A bifunctional derivative of tetraazacyclododecanetetraacetic acid (p-SCN-Bz-DOTA) was used to couple 212Pb to the anti-HER2/neu monoclonal antibody AE1. The chelating agent did not alter the binding affinity to its antigenic target or the pharmacokinetics and tissue distribution of the AE1 antibody. Toxicity and therapeutic efficacy of 212Pb-AE1 were evaluated in nude mouse ascites or solid tumor models, wherein SK-OV-3 cells were administered i.p. or s.c., respectively., Results: The dose-limiting acute toxicity after i.v. administration of 212Pb-AE1 was bone marrow suppression, which was observed at doses above 25 microCi. Therefore, doses of 10 and 20 microCi were used in efficacy trials. The i.p. administration of 212Pb-AE1 3 days after i.p. tumor inoculation led to a significant (P2 = 0.015) prolongation of tumor-free survival. In a second model, i.v. treatment with 212Pb-AE1 3 days after s.c. tumor inoculation prevented subsequent tumor development in all animals treated with 10 or 20 microCi of 212Pb-AE1 (P2 = 0.002 compared to control groups). This efficacy in the adjuvant setting was antibody specific because treatments with equivalently labeled control antibody or unlabeled AE1 antibody or no treatment were less effective. The rate of growth of small (mean tumor volume, 15 mm3) SK-OV-3 tumors was modestly inhibited. However, tumor growth was not inhibited in mice bearing larger (mean tumor volume, 146 mm3) SK-OV-3 tumors by the administration of a single dose of 10 or 20 microCi of 212Pb-AE1., Conclusion: Lead-212-AE1 as an intact radiolabeled monoclonal antibody may be of only modest value in the therapy of bulky solid tumors due to the short physical half-life of 212Pb and time required to achieve a useful tumor-to-normal tissue ratio of radionuclide after administration. However, the radiolabeled monoclonal antibody may be useful in therapy of tumors in the adjuvant setting. Furthermore, 212Pb may be of value in select situations, including treatment of leukemia, intercavitary therapy or strategies that target vascular endothelial cells of tumors.
- Published
- 1997
50. Comparison of the biodistribution and the efficacy of monoclonal antibody 323/A3 labeled with either 131I or 186Re in human ovarian cancer xenografts.
- Author
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Kievit E, van Gog FB, Schlüper HM, van Dongen GA, Pinedo HM, and Boven E
- Subjects
- Animals, Antibodies, Monoclonal pharmacokinetics, Female, Humans, Iodine Radioisotopes pharmacokinetics, Mice, Mice, Nude, Organotechnetium Compounds pharmacokinetics, Ovarian Neoplasms metabolism, Radioisotopes pharmacokinetics, Radiopharmaceuticals pharmacokinetics, Radiotherapy Dosage, Rhenium pharmacokinetics, Tissue Distribution, Transplantation, Heterologous, Tumor Cells, Cultured, Antibodies, Monoclonal therapeutic use, Iodine Radioisotopes therapeutic use, Organotechnetium Compounds therapeutic use, Ovarian Neoplasms radiotherapy, Radioimmunotherapy methods, Radioisotopes therapeutic use, Radiopharmaceuticals therapeutic use, Rhenium therapeutic use
- Abstract
Purpose: The radionuclide 186Re has favorable physical characteristics for use in radioimmunotherapy, including the emission of beta-particles of a high-energy and a low-abundance of gamma-emission. The gamma-emission, in particular, is ideal for tumor imaging and poses less hazards to the patient and the medical personnel when compared with the gamma-emission of the widely used radionuclide 131I. In the present study, we determined whether 186Re-labeled monoclonal antibody 323/A3 may be better suited for the treatment of ovarian cancer than 131I-323/A3., Methods and Materials: We compared the biodistribution and the efficacy of 186Re- and 131I-labeled 323/A3 in nude mice bearing s.c. the human ovarian cancer xenografts FMa, OVCAR-3 and Ov.Pe. 186Re was conjugated to 323/A3 with the use of the S-benzoylmercaptoacetyltriglycine (S-benzoyl-MAG3) chelate., Results: A molar ratio of Re-MAG3:323/A3 of 3:1 did not affect the integrity and the pharmacokinetic behaviour of the MAb. The tumor uptake and the retention of 186Re- and 131I-labeled 323/A3 were comparable, but the cumulative absorbed radiation dose in the tumor delivered by 186Re-323/A3 was 1.3-fold higher than that of 131I-323/A3. When mice were treated with equivalent radionuclide doses, the tumor growth inhibition induced by 186Re-323/A3 was similar or slightly better when compared with the efficacy of 131I-323/A3. When mice were treated with radionuclide doses that were adjusted to obtain equal cumulative absorbed radiation doses in the tumor for both conjugates, 131I-323/A3 was slightly more effective in the inhibition of the growth of FMa and OVCAR-3 xenografts., Conclusions: The favorable physical characteristics of 186Re as well as its efficacy when conjugated to a MAb indicate 186Re as an attractive radionuclide in radioimmunotherapy of ovarian cancer patients.
- Published
- 1997
- Full Text
- View/download PDF
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