Large scale accelerator production of 225Ac: Effective cross sections for 78-192MeV protons incident on 232Th targets.

Actinium-225 and 213Bi have been used successfully in targeted alpha therapy (TAT) in preclinical and clinical research. This paper is a continuation of research activities aiming to expand the availability of 225Ac. The high-energy proton spallation reaction on natural thorium metal targets has been utilized to produce millicurie quantities of 225Ac. The results of sixteen irradiation experiments of thorium metal at beam energies between 78 and 192MeV are summarized in this work. Irradiations have been conducted at Brookhaven National Laboratory (BNL) and Los Alamos National Laboratory (LANL), while target dissolution and processing was carried out at Oak Ridge National Laboratory (ORNL). Excitation functions for actinium and thorium isotopes, as well as for some of the fission products, are presented. The cross sections for production of 225Ac range from 3.6 to 16.7mb in the incident proton energy range of 78-192MeV. Based on these data, production of curie quantities of 225Ac is possible by irradiating a 5.0gcm-2 232Th target for 10 days in either BNL or LANL proton irradiation facilities.

Production of Sn-117m in the BR2 high-flux reactor.

The BR2 reactor is a 100MW(th) high-flux 'materials testing reactor', which produces a wide range of radioisotopes for various applications in nuclear medicine and industry. Tin-117m ((117m)Sn), a promising radionuclide for therapeutic applications, and its production have been validated in the BR2 reactor. In contrast to therapeutic beta emitters, (117m)Sn decays via isomeric transition with the emission of monoenergetic conversion electrons which are effective for metastatic bone pain palliation and radiosynovectomy with lesser damage to the bone marrow and the healthy tissues. Furthermore, the emitted gamma photons are ideal for imaging and dosimetry.

67Cu-2IT-BAT-Lym-1 pharmacokinetics, radiation dosimetry, toxicity and tumor regression in patients with lymphoma.

UNLABELLED: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced therapeutic responses and prolonged survival in patients with non-Hodgkin's lymphoma when labeled with 1311. Radiometal-labeled antibodies provide higher tumor radiation doses than corresponding 1311 antibodies. 67Cu has an exceptional combination of properties desirable for radioimmunotherapy, including gamma and beta emissions for imaging and therapy, respectively, a biocompatible half-time and absence of pathways contributing to myelotoxicity. The radioimmunoconjugate, 67Cu-21T-BAT-Lym-1, has been shown to be efficacious in nude mice bearing human Burkitt's lymphoma (Raji) xenografts. Based on these results, a clinical study of the pharmacokinetics and dosimetry of 67Cu-21T-BAT-Lym-1 in patients with lymphoma was initiated. METHODS: Eleven patients with advanced stage 3 or 4 lymphoma were given a preload dose of unmodified Lym-1, then an imaging dose of 126-533 MBq (3.4-14.4 mCi) 67Cu-21T-BAT-Lym-1. Total Lym-1 ranged from 25 to 70 mg dependent on the specific activity of the radioimmunoconjugate and was infused at a rate of 0.5-1 mg/min. Imaging, physical examination, including caliper measurement of superficial tumors, and analysis of blood, urine and fecal samples were performed for a period of 6-13 d after infusion to assess pharmacokinetics, radiation dosimetry, toxicity and tumor regression. RESULTS: In 7 patients, in whom superficial tumors had been accurately measured, tumors regressed from 18% to 75% (mean 48%) within several days of 67Cu-21T-BAT-Lym-1 infusion. The uptake and biological half-time of 67Cu-21T-BAT-Lym-1 in tumors were greater than those of normal tissues, except the mean liver half-time exceeded the mean tumor half-time. The mean tumor-to-marrow radiation ratio was 32:1, tumor-to-total body was 24:1 and tumor-to-liver was 1.5:1. Images were of very good quality; tumors and normal organs were readily identified. Mild and transient Lym-1 toxicity occurred in 6 patients; 1 patient developed a human antimouse antibody. There were no significant changes in blood counts or serum chemistries indicative of radiation toxicity. CONCLUSION: Because of the long residence time of 67Cu-21T-BAT-Lym-1 in tumors, high therapeutic ratios were achieved and, remarkably, numerous tumor regressions were observed after imaging doses. The results indicate considerable therapeutic potential for 67Cu-21T-BAT-Lym-1.

Radiochemical purification of no-carrier-added scandium-47 for radioimmunotherapy.

A procedure, adaptable to large-scale remote operation, was developed to purify no-carrier-added (NCA) 47Sc from irradiated Ti targets. Methods based on extraction chromatography and cation-exchange chromatography were compared. Results of this comparison led to the development of an optimized procedure based on cation-exchange with Dowex AG 50W-X4 and 47Sc elution with HCl/HF. This method gave 90-97% overall 47Sc recovery, with a Ti separation factor greater than 2.4 x 10(-5), and specific activities > or = 0.9 GBq microgram-1. Use of the 47Sc product, for labeling monoclonal antibodies, resulted in consistent labeling yields of > or = 90%.

Maximum tolerated dose of 67Cu-2IT-BAT-LYM-1 for fractionated radioimmunotherapy of non-Hodgkin's lymphoma: a pilot study.

PURPOSE: Lym-1, a monoclonal antibody (MoAb) that preferentially targets malignant lymphocytes, has induced therapeutic responses in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine-131 (131I). Radiometal labeled antibodies provide a higher tumor radiation dose than the corresponding 131I labeled antibodies. Based on the strategy of fractionating the total radiation dose, this study was designed to define the maximum tolerated dose (MTD) of the first 2, of a maximum of 4, doses of 67Cu-2IT-BAT-Lym-1 given 4 weeks apart. Additionally, toxicity, radiation dosimetry and efficacy were assessed. MATERIALS AND METHODS: Patients had Ann Arbor stage IVB NHL, resistant to standard therapy, including multiple chemotherapy regimens. Each dose of 67Cu-2IT-BAT-Lym-1 was given after a preload of unmodified Lym-1. A 10 mCi imaging dose of 67Cu-2IT-BAT-Lym-1 was given in order to assess pharmacokinetics and radiation dosimetry prior to therapy. Based on the MTD for 131I-Lym-1 and comparative dosimetry for 131I-Lym-1 and 67Cu-2IT-BAT-Lym-1, the trial was initiated at 60 millicuries per square meter of body surface area (mCi/m2) in cohorts of 3 patients. RESULTS: A single cohort of patients proved sufficient to define the MTD as 60 mCi/m2 for each of the first 2 doses of 67Cu-2IT-BAT-Lym-1. The dose-limiting toxicities were grade 3-4 thrombocytopenia and neutropenia. Neutropenic sepsis and bleeding did not occur. Mean radiation dose contributed to the bone marrow by 67Cu in the body and blood was 0.2 (range, 0.2 to 0.3) rads/mCi. Copper-67 incorporated into ceruloplasmin contributed 25% of the dose to marrow from blood. Non-hematologic toxicities did not exceed grade 2. The three patients had substantial tumor regression even after imaging doses of 67Cu-2IT-BAT-Lym-1. After therapy, one response was complete with a duration of 12 months. Radiation doses to tumors in this patient varied from 7.0-21.9 rads/mCi or 5420-7000 total rads from the course of therapy. CONCLUSION: 67Cu-2IT-BAT-Lym-1 provided good imaging, favorable radiation dosimetry and a remarkably high therapeutic index (ratio of tumor to marrow radiation doses). The non-myeloablative MTD for each of 2 doses was 60 mCi/m2.

Treatment of metastatic bone pain with tin-117m Stannic diethylenetriaminepentaacetic acid: a phase I/II clinical study.

The physical characteristics of Sn-117m combined with the biodistribution of the compound tin-117m (Stannic, 4+) diethylenetriaminepentaacetic acid (Sn-117m DTPA) suggest that it should be an excellent agent for the palliation of pain from bony metastases. Prior work has established the dosimetry and the safety for the material in human beings. The presence of low-energy conversion electrons should result in the relative sparing of the bone marrow while delivering a high radiation dose to sites of bony metastatic disease. Forty-seven patients with painful bone metastases from various malignancies were treated with Sn-117m DTPA. The patients were assigned to five different dose levels ranging from 2.64 to 10.58 MBq (71-286 microCi) per kg of body weight. Follow-up included review of pain diaries, performance scores, analgesic requirements, blood chemistries, and hematological assessment. Three patients received a second treatment. There was an overall response rate for relief of pain of 75% (range, 60-83%) in the 40 treatments that could be evaluated. No correlation was apparent in this limited series between response rate and the five dose levels used. The relief was complete in 12 patients (30%). The time to onset of pain relief was 19 +/- 15 days with doses < or = 5.29 MBq/kg and 5 +/- 3 days with doses > or = 6.61 MBq/kg. Myelotoxicity was minimal, with only one patient having a marginal grade 3 WBC toxicity. On the basis of our data, Sn-117m DTPA should be an effective and safe radiopharmaceutical for palliation of painful bony metastases. A large-scale trial is warranted to evaluate it in comparison to other similar agents.

Radionuclide development at BNL for nuclear medicine therapy.

Radionuclides with medium energy beta emission and a several day half-life have often been viewed as attractive candidates for radioimmunotherapy. Among the most promising in this category are 47Sc, 67Cu, 153Sm, 188Re, and 199Au. The production of 67Cu, 153Sm, 199Au at BNL is summarized and the development of the latest candidate for this application, 47Sc, is described in detail. We also summarize the development of another important therapeutic radionuclide, 117mSn for bone pain palliation.

Enhancement of 67Cu-2IT-BAT-LYM-1 therapy in mice with human Burkitt's lymphoma (Raji) using interleukin-2.

BACKGROUND: Lymphomas have been shown to be responsive to 131I immunoconjugates in studies conducted in mice and patients. We have observed that copper 67 (67Cu)-labeled Lym-1 remains in lymphomatous tissue longer than 131I-Lym-1 and, consequently, results in higher absorbed radiation doses to tumors. In addition, recombinant interleukin-2 (rIL-2) has been reported to increase tumor uptake of radiolabeled antibody. Therefore, we examined the efficacy of 67Cu-labeled Lym-1 and the ability of rIL-2 to enhance this efficacy in athymic mice implanted with Raji xenografts. METHODS: 6[p-(bromoacetamido) benzyl]-1,4,8,11-tetraazacyclotetradecane-N,N', N'',N'''-tetraacetic acid (BAT) was conjugated to Lym-1 via 2-iminothiolane (2IT) to prepare 2IT-BAT-Lym-1, which was labeled with 67Cu. Mice with Raji xenografts were treated with 335-500 microCi (12.4-18.0 MBq) of 67Cu-2IT-BAT-Lym-1 with or without 48,000-144,000 IU of rIL-2 once or were treated b.i.d. for 5 days beginning simultaneously with 67Cu-2IT-BAT-Lym-1. Mouse weight, blood counts, and mortality were monitored to assess toxicity, and tumor size was measured to assess efficacy. In addition, groups of mice were sacrificed to assess the biodistribution of 67Cu-2IT-BAT-Lym-1 with and without rIL-2. RESULTS: In mice treated with 335 microCi of 67Cu-2IT-BAT-Lym-1 alone, 28% of tumors were cured. When 48,000 IU of rIL-2 were added, 50% were cured. The overall response-rate was 50% for both regimens. In mice treated with 400 microCi of 67Cu-2IT-BAT-Lym-1 alone, 42% responded, all of which were cured. When 48,000 IU of rIL-2 were added, 77% of tumors responded, and 38% were cured. Larger or multiple doses of rIL-2 did not result in additional therapeutic enhancement. The tumor uptake and radiation dose after 67Cu-2IT-BAT-Lym-1 were about two times greater when a single dose of rIL-2 was added: This may be the basis for enhanced therapeutic efficacy. Mortality was not altered for 335 microCi or 400 microCi doses of 67Cu-2IT-BAT-Lym-1 by rIL-2 nor were other toxicity parameters. Mortality was increased at 500 microCi by the addition of rIL-2. CONCLUSIONS: 67Cu-2IT-BAT-Lym-1 provided a therapeutic and frequently curative dose of radiation to tumored mice at tolerated doses. The therapeutic effectiveness of 67Cu-2IT-BAT-Lym-1 may have been enhanced by rIL-2.

Efficacy and toxicity of 67Cu-2IT-BAT-Lym-1 radioimmunoconjugate in mice implanted with human Burkitt's lymphoma (Raji).

Radioimmunotherapy has shown promising results for treatment of radiosensitive malignancies such as lymphoma. Positive responses have been reported in patients with non-Hodgkin's lymphoma treated with 131I-radiolabeled Lym-1, a mouse anti-lymphoma monoclonal antibody. In this study, the efficacy of 67Cu-radiolabeled Lym-1 was examined. Nude mice bearing human Burkitt's lymphoma (Raji) tumors (20-524 mm3) were treated with 12.4, 14.8, 18.5, and 23.3 MBq of 67Cu-2IT-BAT-Lym-1. Tumor size was measured to assess efficacy, and mouse weight, blood counts, and mortality were monitored to assess toxicity. In mice treated with 12.4, 14.8, and 18.5 MBq of 67Cu-2IT-BAT-Lym-1, 50% (9 of 18), 42% (5 of 12), and 50% (3 of 6) of tumors achieved remission or cure; 33% of tumors were cured overall; and significant regrowth delay was observed. The 23.3 MBq dose group did not yield meaningful efficacy data because of high mortality. In control groups receiving 14.8 and 18.5 MBq of the isotype-matched nonspecific monoclonal antibody radioimmunoconjugate, 67Cu-2IT-BAT-L6, 0% (0 of 15) and 17% (2 of 12) of tumors achieved a response; hence, targeted delivery of radiation was the dominant antitumor mechanism of 67Cu-2IT-BAT-Lym-1. LD50/30 for mice treated with 67Cu-2IT-BAT-Lym-1 and -L6 were 21.6 and 20.6 MBq, respectively. In conclusion, 67Cu-2IT-BAT-Lym-1 provided a therapeutic and frequently curative dose of radiation to tumored mice with modest toxicity.

Tin-117m(4+)-DTPA for palliation of pain from osseous metastases: a pilot study.

UNLABELLED: The physical and biological attributes of 117mSn(4+)-DTPA indicate that it should be an effective agent for palliative therapy of painful bony metastatic disease. The aim of this study was to evaluate whether or not this agent could effectively reduce pain while sparing the hemopoietic marrow from adverse effects. METHODS: Fifteen patients (10 males and 5 females) with painful bony metastases from various primary cancers were included in the study. Seven patients received 1.22 to 3.11 MBq/kg of 117mSn intravenously (Group 1) and eight patients received 4.85 to 5.77 MBq/kg (Group 2). All but one were treated as outpatients and followed for a minimum of 2 mo. RESULTS: In the first group, pain relief was non-assessable in four patients because of death or additional treatment of soft-tissue disease by another modality. One patient had no relief of pain, one had complete relief of pain and one had transient relief of pain. No myelotoxicity was observed. For Group 2, three patients achieved complete relief of pain, two good relief, two partial relief and one began to experience pain relief when he suffered a pathological fracture 2 mo post-treatment. None of these patients had myelotoxicity. CONCLUSION: Tin-117m(4+)-DTPA can reduce pain from metastatic disease to bone without inducing adverse reactions related to bone marrow. Further studies are needed to assess tolerance levels for the bone marrow and to evaluate response rates and duration of effect.

Production of no-carrier-added 199Au for gold cluster-labelled antibodies.

The production of no-carrier-added (NCA) 199Au by neutron activation of 198Pt was developed and the radiochemical separation of 199Au from Pt targets was investigated. Three different procedures, based on anion exchange in mixed solvent media, solvent extraction and extraction chromatography, are reported. The extraction chromatography method was superior in terms of yield (> 95%), Pt separation factor (< or = 10(-5)), and separation time (approximately 1 hr). This scheme has been used to successfully process large amounts (> 30 GBq) of 199Au, with an average specific activity of 7.59 GBq/micrograms (205 mCi/micrograms).

Biodistribution of Sn-117m(4+)DTPA for palliative therapy of painful osseous metastases.

Tin-117 has certain physical characteristics (half-life of 13.6 days, low-energy-conversion electrons, gamma photon of 158.6 keV) that suggest that it may be a favorable agent for radionuclide therapy. It has been shown in animal models that Sn-117m in the chemical form Sn(4+)diethylenetriaminepentaacetic acid localizes selectively in bone. The authors therefore studied its whole-body distribution in 10 patients to obtain absorbed dose estimates for therapy. The results showed that more than 50% of the administered activity was absorbed in the bones of patients with metastatic carcinoma. Retention was determined primarily by radioactive decay. For adult men, the radiation absorbed dose estimate averaged 54.8 mGy/MBq (203 rad/mCi) to bone surfaces and 6.1 mGy/MBq (22.6 rad/mCi) to the red marrow. All other tissues received less than 1/10 of the dose received by red marrow. These results suggest that a clinical therapeutic trial should be attempted.

The use of a new radiopharmaceutical, 97Ru-DISIDA, and of 99Tcm-sulphur colloid for the simultaneous evaluation of duodenogastric reflux and gastric emptying.

There is no consensus or a uniform technique for measuring gastric emptying and numerous modalities have been reported. We report here the results obtained using a modification of the published techniques for the simultaneous measurement of duodenogastric reflux and gastric emptying utilizing simultaneously the recently developed radiopharmaceutical 97Ru-DISIDA, intravenously, and the oral administration of 99Tcm-sulphur colloid incorporated in a 'solid' test meal.

Development of a new radiolabel (203Pb) and new chelating agents for labeling monoclonal antibodies for imaging.

High liver uptake and slow body clearance presently limit the usefulness of 111In labeled antibodies for tumor imaging. We have investigated 203Pb as an alternative and better antibody label. The DTPA and cyclohexyl EDTA (CDTA) conjugates of an anticolon carcinoma antibody, 17-1A, were labeled (bicyclic anhydride method) with 203Pb and 111In with 60 and 90 per cent labeling yields, respectively. The biodistribution of 203Pb-17-1A conjugates was compared with the corresponding 111In-labeled preparations and with 203Pb-DTPA, 203Pb-nitrate and nonrelevant antibody controls in normal and human tumor (SW948) xenografted nude mice at 24 and 96 h. 203Pb labeled CDTA and DTPA antibody conjugates gave similar in vivo distributions. Even though the lead bound to these chelate-antibody conjugates was more labile in serum and in vivo, compared with indium, it cleared much faster from the liver and the whole body. A new series of chelating agents based on the incorporation of a trans-1,2-diaminocyclohexane moiety into the carbon backbone of polyaminocarboxylates is being synthesized. These are expected to provide stronger complexing ability for lead and produce greater in vivo stability. These ligands are also expected to be superior to EDTA and DTPA for labeling antibodies with other radiometals, including indium.

Radioactive gold cluster immunoconjugates: potential agents for cancer therapy.

An 11 gold atom (undecagold) cluster was covalently attached to specific sites on Fab', F(ab')2 and whole IgG molecules such that each carried 11-33 gold atoms without significant loss of native immunospecificity. Gold cluster labeled 17-1A monoclonal F(ab')2 antibody fragments showed 80% immunoreactivity compared to native antibody fragments in binding to human colon carcinoma cells in vitro. Radioactive gold in vivo biodistributions in nude mice with human tumors are also reported. By using clusters, potentially a larger destructive payload can be carried per antibody.

A new cholescintigraphic agent: ruthenium-97-DISIDA.

These are the first human experiments with 97Ru-DISIDA, a potentially new alternative to 131I-rose bengal where delayed imaging is indicated. 97Ru has a convenient half life. A DISIDA labeling kit was utilized to prepare the radiotracer for 17 patients (age 6 weeks-84 years). The cholescintigraphic data correlated well with other imaging procedures and with clinical findings. Dosimetric calculations were carried out and were compared with the radiation burden associated with the use of 99mTc-DISIDA and 131I-rose bengal.

Production of no-carrier added 67Cu.

Copper-67 has been produced at the BLIP by 68Zn(p, 2p) and 70Zn(p, alpha) reactions with 193 MeV protons and at the HFBR using the 67Zn(n, p) route. The effective cross-sections of natZn(p, 2pxn)61,64,67Cu reactions were measured at 200 MeV and compared with predicted values obtained from semi-empirical formulae given by Silberberg and Tsao. From these cross-sections, the fraction of 64Cu in the final 67Cu preparations was estimated and compared with the experimental values. A procedure has been developed consisting of electrodeposition and ion-exchange for isolation of no-carrier-added radiocopper from a Zn target. The method is adaptable for remote hot cell operation. The overall radiochemical yield of 67Cu and the separation factors from a Zn target and other radionuclides were evaluated. The saturation yield of 67Cu produced by the fast neutron 67Zn(n, p) reaction and the corresponding cross-section were remeasured. Experiments have been initiated to attach 67Cu to monoclonal antibodies for immunotherapy applications.