Antilymphoma mouse monoclonal antibody (MoAb) Lym-1, labeled with 67Cu or 131I, has demonstrated promising results in radioimmunotherapy (RIT) for lymphoma. Although 131I has played a central role in RIT thus far, some properties of 67Cu are preferable. A subset of our patients received both 67Cu- and 131I-labeled Lym-1, allowing a comparative evaluation of the two radiopharmaceuticals administered to a matched population of patients. Four patients with B-lymphocytic non-Hodgkin’s lymphoma that had progressed despite standard therapy entered trials of 67Cu- and 131I-labeled Lym-1, which were injected 3–26 days apart. Lym-1 was conjugated to 6-[p-(bromoacetamido)benzyl]-1,4,7,11-tetraazacyclotetradecane-N,N′,N″,N‴-tetraacetic acid (BAT) via 2-iminothiolane (2IT) and radiolabeled with 67Cu to prepare 67Cu-2IT-BAT-Lym-1; 131I-Lym-1 was preparred by the chloramine-T reaction. Planar imaging was used to quantitate 67Cu-2IT-BAT-Lym-1 or 131I-Lym-1 in organs and tumors daily for 3 days or longer. 67Cu-2IT-BAT-Lym-1 exhibited higher peak concentration in 92% (12 of 13) of tumors and a longer biological half-time in every tumor than 131I-Lym-1. The mean tumor concentration (%ID/g) of 67Cu-2IT-BAT-Lym-1 was 1.7, 2.2, and 2.8 times that of 131I-Lym-1 at 0, 24, and 48 h after injection, respectively. The mean biological half-times of 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 in tumor were 8.8 and 2.3 days, respectively. Consequently, the mean tumor radiation dose delivered by 67Cu-2IT-BAT-Lym-1 was twice that of 131I-Lym-1, 2.8 (range 0.8–6.7), and 1.4 (range 0.4–3.5) Gy/GBq, respectively. 67Cu-2IT-BAT-Lym-1 delivered a lower marrow radiation dose than 131I-Lym-1; hence, the tumor:marrow therapeutic indices were 29 and 9.7, respectively. Radiation doses from 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 to normal tissues were similar except for liver, which received a higher dose from 67Cu-2IT-BAT-Lym-1. Images obtained with 67Cu-2IT-BAT-Lym-1 were superior. Radiation dosimetry data for 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 agreed with corresponding data from the larger populations of patients from which the matched population for the current study was drawn. In conclusion, 67Cu-2IT-BAT-Lym-1 given to non-Hodgkin’s lymphoma patients in close temporal proximity to 131I-Lym-1 exhibited greater uptake and longer retention in tumor, resulting in higher radiation dose and therapeutic index than 131I-Lym-1. These as well as other factors suggest that 67Cu-2IT-BAT-Lym-1 may be superior to 131I-Lym-1 for RIT.

67Cu has excellent properties for RIT3 of lymphoma, but clinical investigation has been limited by availability of the radionuclide. 131I continues to play a central role in RIT because of its routine availability and relatively low cost. We have reported previously our clinical experience with 67Cu- and 131I-labeled Lym-1 for pharmacokinetic/dosimetry studies and therapy of lymphoma (1, 2, 3, 4). A subset of our patients have received both 67Cu- and 131I-labeled Lym-1, allowing a comparative evaluation of the two radiopharmaceuticals administered to a matched population of patients.

A comparison of the physical properties of 67Cu and 131I (Table 1) reveals their therapeutic β emissions are similar (Fig. 1) and approximately equally well suited to the treatment of small or diffuse tumors 1–5 mm in diameter (5, 6). The chief differences are in their half-lives and γ emissions, which contribute to a higher therapeutic index, better imaging, radiation dose estimation, and other factors that favor 67Cu for RIT (Table 2). Biological factors have also been found to favor 67Cu, particularly in the case of internalizing antibodies. Whereas 131I-MoAbs are rapidly degraded after endocytosis by cells with subsequent rapid release of 131I-tyrosine, MoAbs labeled with radiometals including 67Cu exhibit prolonged retention in target cells, as demonstrated in comparative studies in cell culture (7, 8, 9, 10, 11) and in mice (12, 13).

To develop 67Cu as a therapeutic agent for RIT, the macrocyclic chelating agent TETA was specifically designed to stably bind copper (14). TETA is incorporated in the immunoconjugate 2IT-BAT-Lym-1, which, under well-characterized conditions, binds 67Cu rapidly, selectively, with high specific activity, and with complete retention of structural and functional integrity (15, 16, 17). Labeling of 67Cu-2IT-BAT-Lym-1 has been optimized to the extent that product yield and quality are comparable to those of 131I-Lym-1 (17).

Four patients concurrently enrolled in 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 trials were evaluable for directly comparative data on the pharmacokinetics and dosimetry of 67Cu-2IT-BAT-Lym-1 versus131I-Lym-1 injected in close temporal proximity.

Patient Population

Patients with B-lymphocyte NHL that had progressed despite standard therapy entered trials of 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1. The patients were 43–64 years of age. Pathological material was obtained from all of the patients before therapy to classify the NHL according to the Working Formulation (18) and to determine reactivity with Lym-1. All of the patients had Ann Arbor stage IV and extranodal low, intermediate, or high-grade NHL. Their Karnofsky performance status ranged from 70 to 90. Lym-1 reactivity, defined as percent positive staining of fresh or frozen tumor tissue, was 39–80%. Patients were eligible if their malignant tissue reacted with Lym-1, serum was negative for human antimouse antibody, they had received no other cancer therapy for at least 4 weeks, they had measurable disease at the time of entry, and they met additional trial-specific criteria. Before trial entry, patients signed an informed consent that was approved by the University of California at Davis Human Subjects and Radiation Use Committees under an Investigational New Drug authorization from the United States Food and Drug Administration.

Four evaluable patients were enrolled in trials of both 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 (1, 2, 3, 4). Each patient received a dose of 67Cu-2IT-BAT-Lym-1 (0.14–0.53 GBq) and 131I-Lym-1 (0.47–4.3 GBq), 3–26 days apart.

Pharmaceuticals

Lym-1 (Damon Biotechnology, Needham Heights, MA, or Techniclone, Inc., Tustin, CA) is a nonshedding, noninternalizing IgG2a mouse MoAb with high affinity for a discontinuous epitope on the β subunit of the human leukocyte antigen-Dr located on the surface membrane of malignant B-lymphocytes (19). Lym-1 has antibody dependent cellular cytotoxicity and complement dependent cytotoxicity against Raji human lymphoma cells in vitro but little effectiveness in vivo(20). Lym-1 was specified as greater than 95% pure monomeric IgG by PAGE and met FDA mouse MoAb production guidelines for murine viral, mycoplasma, fungal, and bacterial contamination, endotoxin, pyrogen, and DNA content, and general safety testing in animals.

Lym-1 was labeled with 67Cu (Brookhaven National Laboratory, Upton, NY, or Los Alamos National Laboratory, Los Alamos, NM), as previously described (1, 2). Briefly, the immunoconjugate 2IT-BAT-Lym-1 was prepared by conjugating BAT to Lym-1 via 2IT (Sigma Chemical Co., St. Louis, MO) as described previously (16). Four conjugations were performed. The chelate to antibody ratios of 2IT-BAT-Lym-1, assayed by cobalt binding, ranged from 1.1 to 3.0, ratios associated with little or no change in immunoreactivity or biodistribution relative to unmodified Lym-1 (16). 67Cu and 2IT-BAT-Lym-1 were combined at a mean ratio of 0.045 GBq:1 mg. After radiolabeling, EDTA (Fisher Scientific, Pittsburgh, PA) was added to scavenge nonspecifically bound 67Cu, then 67Cu-2IT-BAT-Lym-1 was purified by Sephadex G25 molecular sieving chromatography (Sigma) and formulated in 4% human serum albumin/saline at a concentration of approximately 0.037 GBq/ml.

Lym-1 was labeled with 131I (ICN Radiochemicals, Irvine, CA) by the chloramine-T method as described previously (3, 4) using ratios of 0.37 GBq 131I:0.02 mg chloramine-T:0.02 mg sodium metabisulfite:1.0 mg Lym-1 (molar ratios 0.1:70:80:1). After radiolabeling, 131I-Lym-1 was purified by Sephadex G25 molecular sieving chromatography and formulated in 4% human serum albumin/saline at a concentration of approximately 0.037 GBq/ml.

67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 were examined for structural and functional integrity by cellulose acetate electrophoresis (Gelman Sciences, Inc., Ann Arbor, MI), molecular sieving high-performance liquid chromatography (Beckman, Fullerton, CA), and radioimmunoassay as described previously (1).

Antibody Injection

Unmodified Lym-1 (20 mg) was given before 67Cu-2IT-BAT-Lym-1 or 131I-Lym-1 to block nonspecific binding sites and provide stable pharmacokinetics (21). Lym-1, 67Cu-2IT-BAT-Lym-1, and 131I-Lym-1 were injected at about 0.5–1.0 mg/min.

Blood and Urine Clearance

Blood samples were obtained immediately, during the next 6 h, and daily for up to 13 days after the injection of 67Cu-2IT-BAT-Lym-1 or 131I-Lym-1. Blood samples were assayed in a gamma well counter (Pharmacia LKB, Piscataway, NJ) to obtain the concentration of 67Cu or 131I in the blood. All of the urine was collected for 4–13 days after infusion of 67Cu-2IT-BAT-Lym-1 or 131I-Lym-1. Aliquots of urine were assayed in a gamma well counter and then multiplied by the measured urine volume to calculate the output of 67Cu or 131I.

Radiation Dosimetry

Methods for obtaining pharmacokinetic data for 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 have been described previously (22, 23, 24). Briefly, planar images of conjugate views were acquired immediately, during the next 6 h, and daily for 3 days or longer after the injection of radiolabeled Lym-1 and used to quantitate 67Cu-2IT-BAT-Lym-1 or 131I-Lym-1 in organs and tumors (24, 25) except in one patient, the first tumor images were taken a day after the injection of 67Cu-2IT-BAT-Lym-1. Appropriate corrections were performed to ensure that the radiopharmaceutical dose had no effect on the radiation dosimetry; previous studies have demonstrated that such corrections provide consistent radiation dosimetry over a radiopharmaceutical dose range of 0.1–5.6 GBq of 131I-MoAb (23).

The radiation dose to tissues was calculated as the sum of radiation contributed by radioactivity in the tissue (nonpenetrating and penetrating) and the remainder of the body (penetrating), using the MIRD Committee formula (26). Pharmacokinetic data in tissues were fit to a monoexponential function to calculate cumulated activity. The MIRD S values and reference man masses (27) were used for all of the organs except for the spleen. Because of the large variation in spleen volumes, patient-specific splenic radiation dose was determined using actual spleen volume measured by CT images (28). Tumor radiation dose was determined for nonpenetrating emissions in the tumor and penetrating emissions from the total body (27, 29). The masses of palpable and nonpalpable tumors were determined using calipers and CT images or magnetic resonance imaging, respectively. Tumors less than 2 g by caliper measurement or less than 10 g by CT measurement were excluded from the analysis to assure accuracy; 13 tumors from our matched patient population were evaluated. The tumor radiation dose rate (Gy/h/GBq) was calculated in the same manner as the total dose but for each time point.

The marrow radiation dose was estimated as the sum of nonpenetrating radiation from the blood and penetrating radiation from the total body (30). Pharmacokinetic data in blood were fit to a biexponential function to calculate cumulated activity. To calculate marrow radiation from blood, it was assumed that the specific activity of the blood in the marrow was 25% of that of blood (30). To calculate marrow radiation from the total body, it was assumed that radionuclide was uniformly distributed in the body. S values for penetrating emissions were obtained by subtracting the S values for nonpenetrating emissions from the S values for penetrating and nonpenetrating emissions using MIRD data (30).

RESULTS

67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 were prepared in 95% or greater radiochemical purity on monomeric MoAb, as assessed by high-performance liquid chromatography and cellulose acetate electrophoresis with mean radiolabeling efficiencies of 83 ± 13 and 98 ± 1%, respectively. 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 exhibited immunoreactivity of 85 ± 6 and 88 ± 13% relative to unmodified Lym-1, respectively.

67Cu-2IT-BAT-Lym-1 exhibited greater tumor uptake and retention (after correction for radioactive decay) than 131I-Lym-1 (Fig. 2). The mean tumor concentration (%ID/g) of 67Cu was 1.7, 2.2, and 2.8 times that of 131I at 0, 24, and 48 h after injection, respectively. 67Cu-2IT-BAT-Lym-1 exhibited higher peak concentration in 92% (12 of 13) of tumors and a longer biological half-time in every tumor than 131I-Lym-1. The mean peak tumor concentration of 67Cu-2IT-BAT-Lym-1 and 131I Lym-1 was 0.048 (range, 0.014–0.094) and 0.029 (range, 0.006–0.098) %ID/g, respectively. The mean tumor clearance half-time of 67Cu-2IT-BAT-Lym-1 and 131I Lym-1 was 8.8 (range, 3.2–18.1) and 2.3 (range, 0.8–5.3) days, respectively. The mean peak tumor dose rate of 67Cu-2IT-BAT-Lym-1 and 131I Lym-1 was 0.036 (range, 0.008–0.084) and 0.026 (range, 0.004–0.098) Gy/h/GBq, respectively.

Blood clearances of 67Cu and 131I were similar for both radionuclides until 2 days after injection, when 67Cu demonstrated slower clearance (Fig. 3)). The results are consistent with the incorporation of 67Cu in ceruloplasmin in the liver, followed by the recirculation of 67Cu in the blood as 67Cu-ceruloplasmin, as indicated by previous studies (2). Total body clearance was monoexponential with half-times of 8.0 (range, 6.0–12.2) and 1.7 (range, 1.4–2.2) h for 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1, respectively. Urine clearance accounted for virtually all of the total body clearance of both radionuclides.

Because the photon energies of 67Cu are better suited for gamma camera imaging, the images of patients receiving 67Cu-2IT-BAT-Lym-1 were superior to those of the same patients receiving 131I-Lym-1 (Figs. 4, 5, and 6). The higher tumor concentration of 67Cu-2IT-BAT-Lym-1 resulted in better tumor image contrast. 67Cu-2IT-BAT-Lym-1 provided approximately twice the counting efficiency (counts/s/GBq injected) as 131I-Lym-1 when imaging the same tumor at the same time point.

Radiation dosimetry for tumor and normal tissues (Fig. 7) revealed that 67Cu-2IT-BAT-Lym-1 delivered twice the radiation dose to tumor as 131I-Lym-1, 2.8 (range, 0.8–6.7) and 1.4 (range, 0.4–3.5) Gy/GBq, respectively. 67Cu-2IT-BAT-Lym-1 delivered a lower dose to marrow than 131I-Lym-1, resulting in tumor:marrow therapeutic indices of 29 and 9.7, respectively. 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 delivered similar radiation doses to the normal tissues examined, except the liver, which received a higher radiation dose from 67Cu-2IT-BAT-Lym-1 (Table 3) due to higher uptake and retention of 67Cu.

The mean dose rates to tumor from 67Cu-2-IT-BAT-Lym-1 were 1.4 to 2.7 times those from 131I-Lym-1 for up to 3 days after injection (Fig. 8). The initial dose rates were 0.036 and 0.026 Gy/h/GBq and the dose rates at 3 days were 0.016 and 0.006 Gy/h/GBq for 67Cu and 131I, respectively.

As noted previously, 67Cu has exhibited potential advantages for RIT in preclinical studies. In SW2-xenografted mice, 67Cu- and 131I-labeled noninternalizing MoAb SEN7 demonstrated similar tumor uptake, but 67Cu-SEN7 achieved a higher tumor:blood ratio because of lower blood levels (11). In studies of 67Cu- and 125I-labeled chCE7 in mice with human neuroblastoma xenografts (12), 67Cu-chCE7 exhibited a prolonged retention in tumor compared with 125I-chCE7. The results were attributed to longer cellular retention of 67Cu-chCE7 degradation products after endocytosis and catabolysis (8). Similarly, 67Cu-MAb35 had twice the tumor concentration (%ID/g) of 131I-MAb35 after coinjection in the LoVo xenografted nude mouse model (13). In a clinical setting, similar results were recently reported by Bischof Delaloye et al.(31). The comparative biokinetics of simultaneously injected 67Cu- and 125I-labeled MAb35 were examined in six patients scheduled for surgery for primary colorectal cancer. Tumor samples were counted after surgical removal 2–8 days after injection. Tumor uptake of 67Cu-MAb35 was nearly twice that of 125I-MAb35, and blood clearance of 67Cu-MAb35 was faster.

Our aim in this study was to compare the pharmacokinetics and dosimetry of 67Cu- and 131I-labeled Lym-1 in lymphoma patients, each of whom received both radiopharmaceuticals. The MoAb Lym-1 was of particular interest because it is a noninternalizing MoAb. Unlike internalizing MoAbs, noninternalizing MoAbs have not demonstrated a significant advantage in uptake or retention of 67Cu-MoAb in tumor in the mouse model (11), although we had reported preliminary observations of more prolonged retention of 67Cu-2IT-BAT-Lym-1 in the tumors of NHL patients than previously observed in patients receiving 131I-Lym-1 (22). In the present study, we investigated this observation further by injecting both radiopharmaceuticals 26 days apart or less in a matched set of patients to eliminate patient to patient variation. The results demonstrated markedly greater uptake and retention—and, hence, radiation dose—in tumor with 67Cu-2IT-BAT-Lym-1 compared with 131I-Lym-1, which indicated that the pharmacokinetic advantage of 67Cu-MoAbs is not limited to internalizing antibodies. It is beyond the scope of this study to determine the cause at the cellular level of greater uptake and/or retention of 67Cu-2IT-BAT-Lym-1, but the results probably reflect that the terms “internalizing” and “noninternalizing” are convenient descriptions of two ranges in a continuum of internalization rates.

The pharmacokinetic and dosimetric results of this study varied from patient to patient and tumor to tumor. However, the comparative pharmacokinetic results and relative radionuclide kinetics for each individual tumor were remarkably consistent. 67Cu-2IT-BAT-Lym-1 exhibited higher peak concentration in almost every tumor and a longer biological half-time in every tumor (Fig. 2) and provided a greater radiation dose to every tumor than 131I-Lym-1.

The matched population of 4 patients receiving 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 were concurrently enrolled in separate studies of 67Cu-2IT-BAT-Lym-1 (14 patients) and 131I-Lym-1 (46 patients; Table 3). In the matched population, the tumor radiation dose from 67Cu (2.83 Gy/GBq) was approximately twice that from 131I (1.44 Gy/GBq). Similarly, comparing all of the 67Cu-2IT-BAT-Lym-1 patients to all of the 131I-Lym-1 patients, the tumor radiation dose from 67Cu (2.44 Gy/GBq) was approximately twice that from 131I (1.04 Gy/GBq; Table 3). Hence, the results favor 67Cu-2IT-BAT-Lym-1 among relatively large groups of patients and in a matched population, thereby eliminating patient-to-patient variation.

In the matched population, three patients received 67Cu-2-IT-BAT-Lym-1 (0.14–0.37 GBq) and then 131I-Lym-1 after intervals of 5, 15, and 26 days; one patient received 131I-Lym-1 (0.47 GBq) and then 67Cu-2IT-BAT-Lym-1 after an interval of 3 days. The matched population exhibited similar 67Cu dosimetry compared with all of the patients receiving 67Cu-2IT-BAT-Lym-1 and similar 131I dosimetry compared with all of the patients receiving 131I-Lym-1 (Table 3), which suggests that in the matched population, the first dose of radiopharmaceutical had no appreciable effect on the radiation dosimetry of the second radiopharmaceutical. This observation is consistent with a previous study demonstrating that tracer doses of 131I-Lym-1 had no effect on the biodistribution or radiation dosimetry of subsequent doses of 131I-Lym-1 (23).

Radiometal-labeled MoAbs, such as 67Cu-2IT-BAT-Lym-1, are retained in the liver longer than 131I-MoAbs. In the current study, the radiation dose to the liver from 67Cu was greater than that from 131I (Table 3). One approach to reducing radiation dose to the liver is to attach the radiometal chelate to the MoAb through a readily metabolizable peptide linker. In a study of 90Y-labeled chimeric L6 (ChL6) MoAb in mice with breast cancer xenografts, the use of such a linker reduced the radiation dose to liver by about one-half when compared with 90Y-ChL6 with a nonmetabolizable 2IT linker (32). A similar modification could be incorporated readily in 67Cu-labeled Lym-1.

The results of this study suggest the potential for improved therapeutic response or cure of NHL. One advantage of 67Cu therapy is that it provides a more prolonged radiation exposure at a higher radiation dose rate and thus provides a greater total radiation dose to tumor. The relationship between absorbed dose and response rate is a fundamental principle in conventional external-beam radiotherapy, and there is evidence of a similar correlation in RIT (5). Dose rates as low as 0.05 Gy/h can stop the growth of lymphoma cells in vitro(33). Because tumor cells double more slowly in vivo than in vitro, dose rates as low as 0.02 to 0.03 Gy/h should barely counteract proliferation of malignant epithelial cells in vivo(34). In the vicinity of this critical value, relatively small changes in the dose rate result in significant changes in the viable tumor-cell population (33, 34, 35). Three days after the injection of 67Cu-2IT-BAT-Lym-1, the mean radiation dose rate to tumors per unit activity decreased from 0.036 to 0.016 Gy/h/GBq; hence, given a hypothetical 3.7 GBq dose, tumors would receive a radiation dose rate of 0.13 to 0.06 Gy/h. Comparatively, tumors in a patient receiving a 3.7 GBq dose of 131I-Lym-1 would receive a radiation dose rate of 0.10 to 0.02 Gy/h. Therefore, 67Cu-2IT-BAT-Lym-1 provides a higher dose rate to tumor than 131I-Lym-1 in the vicinity of the critical value of dose rate to counteract proliferation of malignant cells, which suggests a greater potential for therapeutic response or cure.

Because 67Cu is a novel radionuclide under development, it is not routinely available in quantities sufficient for RIT. 67Cu for this study was produced by high energy spallation reactions in the Brookhaven Linac Isotope Producer (BLIP) and Brookhaven National Laboratory (36) and the Los Alamos Meson Physics Facility (LAMPF) at Los Alamos National Laboratory and could be made continuously available by these institutions. The fast neutron reaction on enriched 67Zn can be used to fill in the gaps in the operating schedules of the large accelerators (37). Simply stated, millicurie production is possible on existing accelerators and reactors if clinical demand mandated (38). In this study, superior imaging, substantially greater radiation dosimetry to tumor, and a 3-fold improvement in tumor:marrow therapeutic index was achieved with 67Cu-2IT-BAT-Lym-1 compared with 131I-Lym-1. The results were consistent with the exceptional combination of desirable physical and biochemical properties of 67Cu for RIT. A sustained commitment to 67Cu production and continuing studies of 67Cu for RIT is warranted by this and previous studies of 67Cu-2IT-BAT-Lym-1.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

        
1

Supported by National Cancer Institute Grant CA47829 and Department of Energy Grant DE FG03–84ER60233.

                
3

The abbreviations used are: RIT, radioimmunotherapy; MoAb, monoclonal antibody; TETA, 1,4,7,11-tetraazacyclotetradecane-N,N′,NN‴-tetraacetic acid; NHL, non-Hodgkin’s lymphoma; MIRD, medical internal radiation dosimetry; CT, computed tomography; 2IT, 2-iminothiolane; BAT, 6-[p-(bromoacetamido)benzyl]-TETA.

Fig. 1.

Radiation absorbed dose rate as a function of distance from a point source for 67Cu (•) and 131I (○). The energy deposition of both radionuclides is similar, and their moderate β emissions are approximately equally well suited to the treatment of small (1–5-mm diameter) tumors. The figure illustrates the amount of energy deposited per unit thickness of a sphere of radius (r) per unit time per unit activity, according to a calculation by Jungerman et al.(43); the purpose of the calculation is to nullify the 1/r2 dependence that tends to mask differences among radionuclides.

Fig. 1.

Radiation absorbed dose rate as a function of distance from a point source for 67Cu (•) and 131I (○). The energy deposition of both radionuclides is similar, and their moderate β emissions are approximately equally well suited to the treatment of small (1–5-mm diameter) tumors. The figure illustrates the amount of energy deposited per unit thickness of a sphere of radius (r) per unit time per unit activity, according to a calculation by Jungerman et al.(43); the purpose of the calculation is to nullify the 1/r2 dependence that tends to mask differences among radionuclides.

Close modal
Fig. 2.

Tumor concentration of 67Cu (•, ▪, ▴, ♦) and 131I (○, □, ▵, ⋄) in lymphoma patients receiving 67Cu-2-IT-BAT-Lym-1 and 131I-Lym-1 after correction for radioactive decay. Comparative data for the same tumor are denoted by corresponding symbols; e.g., patient 1 had four tumors, and the concentrations in one tumor are denoted as 67Cu (•) and 131I (○). 67Cu-2-IT-BAT-Lym-1 exhibited higher concentration and longer retention in tumors than 131I-Lym-1.

Fig. 2.

Tumor concentration of 67Cu (•, ▪, ▴, ♦) and 131I (○, □, ▵, ⋄) in lymphoma patients receiving 67Cu-2-IT-BAT-Lym-1 and 131I-Lym-1 after correction for radioactive decay. Comparative data for the same tumor are denoted by corresponding symbols; e.g., patient 1 had four tumors, and the concentrations in one tumor are denoted as 67Cu (•) and 131I (○). 67Cu-2-IT-BAT-Lym-1 exhibited higher concentration and longer retention in tumors than 131I-Lym-1.

Close modal
Fig. 3.

Blood clearance of 67Cu and 131I in lymphoma patients treated with 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1. The mean decay corrected blood clearance (large symbols) of 67Cu (•) and 131I (○) were similar for up to 2 days after treatment; the subsequent slower clearance of 67Cu has been attributed to recirculation of catabolized 67Cu as 67Cu-ceruloplasmin. The upper and lower ranges of data are shown by the corresponding smaller symbols above and below each data point.

Fig. 3.

Blood clearance of 67Cu and 131I in lymphoma patients treated with 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1. The mean decay corrected blood clearance (large symbols) of 67Cu (•) and 131I (○) were similar for up to 2 days after treatment; the subsequent slower clearance of 67Cu has been attributed to recirculation of catabolized 67Cu as 67Cu-ceruloplasmin. The upper and lower ranges of data are shown by the corresponding smaller symbols above and below each data point.

Close modal
Fig. 4.

Planar anterior images of the pelvis of a patient 4 h (upper left) and 24 h (upper right) after an injection of 0.16 GBq of 67Cu-2IT-BAT-Lym-1 and 6 h (lower left) and 24 h (lower right) after an injection of 1.1 GBq of 131I-Lym-1 given to the same patient 5 days later. The images reveal bilateral iliofemoral NHL. 67Cu-2IT-BAT-Lym-1 provided better tumor image contrast than 131I-Lym-1 at every time point. Count acquisition was faster with 67Cu; at 24 h after injection, 67Cu and 131I counts were acquired at the rate of 10,100 and 4,100 counts/s/GBq injected, respectively. Open arrows, NHL; solid arrows, bladder.

Fig. 4.

Planar anterior images of the pelvis of a patient 4 h (upper left) and 24 h (upper right) after an injection of 0.16 GBq of 67Cu-2IT-BAT-Lym-1 and 6 h (lower left) and 24 h (lower right) after an injection of 1.1 GBq of 131I-Lym-1 given to the same patient 5 days later. The images reveal bilateral iliofemoral NHL. 67Cu-2IT-BAT-Lym-1 provided better tumor image contrast than 131I-Lym-1 at every time point. Count acquisition was faster with 67Cu; at 24 h after injection, 67Cu and 131I counts were acquired at the rate of 10,100 and 4,100 counts/s/GBq injected, respectively. Open arrows, NHL; solid arrows, bladder.

Close modal
Fig. 5.

Transverse single-photon emission CT through the inguinal region of the pelvis (1.9-cm section) of a patient 24 h after an injection of 0.16 GBq of 67Cu-2IT-BAT-Lym-1 (left) and 24 h after an injection of 1.1 GBq of 131I-Lym-1 (right) given to the same patient 5 days later. 67Cu-2IT-BAT-Lym-1 provided better image contrast of the left femoral NHL. Open arrows, NHL; solid arrows, bladder.

Fig. 5.

Transverse single-photon emission CT through the inguinal region of the pelvis (1.9-cm section) of a patient 24 h after an injection of 0.16 GBq of 67Cu-2IT-BAT-Lym-1 (left) and 24 h after an injection of 1.1 GBq of 131I-Lym-1 (right) given to the same patient 5 days later. 67Cu-2IT-BAT-Lym-1 provided better image contrast of the left femoral NHL. Open arrows, NHL; solid arrows, bladder.

Close modal
Fig. 6.

Planar anterior images of the pelvis of a patient, 24 h after an injection of 0.37 GBq of 67Cu-2IT-BAT-Lym-1 (left) and 24 h after an injection of 2.2 GBq of 131I-Lym-1 (right), given to the same patient 14 days later. The images reveal bilateral iliofemoral NHL and mid-abdominal NHL with 67Cu-2IT-BAT-Lym-1 providing superior contrast. Count acquisition was faster with 67Cu; at 24 h after injection, 67Cu and 131I counts were acquired at the rate of 9100 and 4200 counts/s/GBq injected, respectively. Open arrows, NHL; solid arrows, bladder.

Fig. 6.

Planar anterior images of the pelvis of a patient, 24 h after an injection of 0.37 GBq of 67Cu-2IT-BAT-Lym-1 (left) and 24 h after an injection of 2.2 GBq of 131I-Lym-1 (right), given to the same patient 14 days later. The images reveal bilateral iliofemoral NHL and mid-abdominal NHL with 67Cu-2IT-BAT-Lym-1 providing superior contrast. Count acquisition was faster with 67Cu; at 24 h after injection, 67Cu and 131I counts were acquired at the rate of 9100 and 4200 counts/s/GBq injected, respectively. Open arrows, NHL; solid arrows, bladder.

Close modal
Fig. 7.

Mean radiation doses to tumor and major organs in lymphoma patients treated with 67Cu-2IT-BAT-Lym-1 (▪▪) and 131I-Lym-1 (▭); gray bars, range of radiation dose. The mean radiation dose to tumor from 67Cu was more than twice that from 131I; both of the radionuclides delivered similar radiation doses to normal organs, except for the liver.

Fig. 7.

Mean radiation doses to tumor and major organs in lymphoma patients treated with 67Cu-2IT-BAT-Lym-1 (▪▪) and 131I-Lym-1 (▭); gray bars, range of radiation dose. The mean radiation dose to tumor from 67Cu was more than twice that from 131I; both of the radionuclides delivered similar radiation doses to normal organs, except for the liver.

Close modal
Fig. 8.

Mean dose rate to tumor in lymphoma patients given 67Cu-2IT-BAT-Lym-1 (•) and 131I-Lym-1 (○). Because of the biocompatible half-life of 67Cu and the greater uptake and retention in tumor, 67Cu-2IT-BAT-Lym-1 delivered radiation to tumor at 1.4–2.7 times the dose rate delivered by 131I-Lym-1 during the first 72 h after treatment.

Fig. 8.

Mean dose rate to tumor in lymphoma patients given 67Cu-2IT-BAT-Lym-1 (•) and 131I-Lym-1 (○). Because of the biocompatible half-life of 67Cu and the greater uptake and retention in tumor, 67Cu-2IT-BAT-Lym-1 delivered radiation to tumor at 1.4–2.7 times the dose rate delivered by 131I-Lym-1 during the first 72 h after treatment.

Close modal
Table 1

Physical characteristics of 67Cu and 131I

67Cu131I
Half-life 2.58 days 8.04 days 
β energy (abundance) 577 keV (20%) 807 keV (1%) 
 484 keV (35%) 606 keV (86%) 
 395 keV (45%) 336 keV (13%) 
γ energy (abundance) 184 keV (49%) 723 keV (2%) 
 93 keV (16%) 637 keV (7%) 
 91 keV (7%) 364 keV (81%) 
  284 keV (6%) 
x90a 0.57 mm 0.71 mm 
67Cu131I
Half-life 2.58 days 8.04 days 
β energy (abundance) 577 keV (20%) 807 keV (1%) 
 484 keV (35%) 606 keV (86%) 
 395 keV (45%) 336 keV (13%) 
γ energy (abundance) 184 keV (49%) 723 keV (2%) 
 93 keV (16%) 637 keV (7%) 
 91 keV (7%) 364 keV (81%) 
  284 keV (6%) 
x90a 0.57 mm 0.71 mm 
a

x90 is the distance within which 90% of the energy is deposited assuming a point source.

Table 2

Comparison of 67Cu versus131I for RIT

67Cu131I
Relatively expensive, sporadic production Relatively inexpensive, routinely available 
Straightforward radiolabeling chemistry, high yields (17,39) Same 
Medium energy β emissions are suited to treatment of tumors 1 to 5 mm diameter (5,6) Same 
Half-life is matched to in vivo pharmacokinetics of MoAbs, providing superior imaging contrast (40) and better therapeutic ratio (41) Half-life is much longer than 0.5–3 days required for maximum tumor concentration of MoAb (38), hence normal organs inherit significant radiation dose (41) 
γ emissions are in ideal 75–250 keV range for imaging, providing superior dose estimation (5) γ emissions are higher in energy and abundance than desirable for imaging 
γ radiation of relatively low energy and abundance provides little radiation dose to nontarget organs γ emissions account for two-thirds of absorbed dose equivalent of 131I, contributing to radiation burden to marrow and other normal organs (13) 
Hospitalization is not required for doses less than 390 mCi (42) Radiation safety may require hospitalization for doses of 30 mCi or more (5) 
67Cu-MoAbs exhibit greater uptake and longer retention in tumor than 131I-MoAb analogs (40) 131I-MoAbs are rapidly degraded after endocytosis by cells with rapid release of 131I-tyrosine from cells (7) 
67Cu-MoAbs are retained in some nontarget organs, particularly the liver 131I-MoAbs are rapidly cleared from nontarget organs (37) 
The half-life of 67Cu is ideal in terms of dose rate for RIT (39) Due to longer half-life and lower concentration in the tumor, 131I-MoAbs provide a lower dose rate than 67Cu-MoAbs (37) 
67Cu131I
Relatively expensive, sporadic production Relatively inexpensive, routinely available 
Straightforward radiolabeling chemistry, high yields (17,39) Same 
Medium energy β emissions are suited to treatment of tumors 1 to 5 mm diameter (5,6) Same 
Half-life is matched to in vivo pharmacokinetics of MoAbs, providing superior imaging contrast (40) and better therapeutic ratio (41) Half-life is much longer than 0.5–3 days required for maximum tumor concentration of MoAb (38), hence normal organs inherit significant radiation dose (41) 
γ emissions are in ideal 75–250 keV range for imaging, providing superior dose estimation (5) γ emissions are higher in energy and abundance than desirable for imaging 
γ radiation of relatively low energy and abundance provides little radiation dose to nontarget organs γ emissions account for two-thirds of absorbed dose equivalent of 131I, contributing to radiation burden to marrow and other normal organs (13) 
Hospitalization is not required for doses less than 390 mCi (42) Radiation safety may require hospitalization for doses of 30 mCi or more (5) 
67Cu-MoAbs exhibit greater uptake and longer retention in tumor than 131I-MoAb analogs (40) 131I-MoAbs are rapidly degraded after endocytosis by cells with rapid release of 131I-tyrosine from cells (7) 
67Cu-MoAbs are retained in some nontarget organs, particularly the liver 131I-MoAbs are rapidly cleared from nontarget organs (37) 
The half-life of 67Cu is ideal in terms of dose rate for RIT (39) Due to longer half-life and lower concentration in the tumor, 131I-MoAbs provide a lower dose rate than 67Cu-MoAbs (37) 
Table 3

Radiation dosimetry data for the subset of patients receiving both 67Cu-2IT-BAT-Lym-1 and 131I-Lym-1 compared with the parent sets of patients receiving 67Cu-2IT-BAT-Lym-1 or 131I-Lym-1

67Cu-2IT-BAT-Lym-1 Dosimetry131I-Lym-1 Dosimetry
67Cu and 131I trial (current study)67Cu trialsa67Cu and 131I trial (current study)131I trialsb
Patients, n 14 46 
Tumors, n 13 38 13 98 
 67Cu radiation dose, mean ± 1 SD, Gy/GBq  131I radiation dose, mean ± 1 SD, Gy/GBq  
Tumor 2.83 ± 1.62 2.54 ± 1.46 1.44 ± 0.88 1.04 ± 0.75 
Total body 0.11 ± 0.01 0.10 ± 0.03 0.12 ± 0.02 0.11 ± 0.04 
Marrow 0.10 ± 0.04 0.09 ± 0.03 0.15 ± 0.06 0.11 ± 0.04 
Liver 1.68 ± 0.57 1.57 ± 0.47 0.35 ± 0.06 0.31 ± 0.09 
Lungs 0.48 ± 0.12 0.52 ± 0.08 0.58 ± 0.33 0.34 ± 0.12 
Kidneys 0.50 ± 0.19 0.62 ± 0.20 0.68 ± 0.18 0.30 ± 0.09 
Spleen 0.99 ± 0.32 0.97 ± 0.41 0.86 ± 0.22 0.58 ± 0.25 
67Cu-2IT-BAT-Lym-1 Dosimetry131I-Lym-1 Dosimetry
67Cu and 131I trial (current study)67Cu trialsa67Cu and 131I trial (current study)131I trialsb
Patients, n 14 46 
Tumors, n 13 38 13 98 
 67Cu radiation dose, mean ± 1 SD, Gy/GBq  131I radiation dose, mean ± 1 SD, Gy/GBq  
Tumor 2.83 ± 1.62 2.54 ± 1.46 1.44 ± 0.88 1.04 ± 0.75 
Total body 0.11 ± 0.01 0.10 ± 0.03 0.12 ± 0.02 0.11 ± 0.04 
Marrow 0.10 ± 0.04 0.09 ± 0.03 0.15 ± 0.06 0.11 ± 0.04 
Liver 1.68 ± 0.57 1.57 ± 0.47 0.35 ± 0.06 0.31 ± 0.09 
Lungs 0.48 ± 0.12 0.52 ± 0.08 0.58 ± 0.33 0.34 ± 0.12 
Kidneys 0.50 ± 0.19 0.62 ± 0.20 0.68 ± 0.18 0.30 ± 0.09 
Spleen 0.99 ± 0.32 0.97 ± 0.41 0.86 ± 0.22 0.58 ± 0.25 
a

Pooled data from pharmacokinetics/dosimetry and maximum tolerated dose trials reported by DeNardo et al.(1, 2).

b

Pooled data from maximum tolerated dose and low-dose therapy trials reported by DeNardo et al.(3, 4).

We thank Drs. Owen W. Lowe, Suresh C. Srivastava, Leonard F. Mausner, Kathleen L. Kolsky, and Eugene J. Peterson for facilitating the supply of 67Cu and for helpful discussions.

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