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PET Imaging of ⁸⁶Y-Labeled Anti-Lewis Y Monoclonal Antibodies in a Nude Mouse Model: Comparison Between ⁸⁶Y and ¹¹¹In Radiolabels

Nuclear Medicine Service, Departments of Radiology and Medical Physics, Memorial Sloan-Kettering Cancer Center, New York; Ludwig Institute for Cancer Research, New York, New York; Ludwig Institute for Cancer Research, Austin and Repatriation Medical Center, Heidelberg, Victoria, Australia; and Radioimmune and Inorganic Chemistry Section, Radiation Oncology Branch, Division of Clinical Sciences, National Cancer Institute, Bethesda, Maryland

	ABSTRACT

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Absorbed doses in ⁹⁰Y radioimmunotherapy are usually estimated by extrapolating from ¹¹¹In imaging data. PET using ⁸⁶Y (ß⁺ 33%; half-life, 14.7 h) as a surrogate radiolabel could be a more accurate alternative. The aim of this study was to evaluate an ⁸⁶Y-labeled monoclonal antibody (mAb) as a PET imaging agent and to compare the biodistribution of ⁸⁶Y- and ¹¹¹In-labeled mAb. Methods: The humanized anti-Lewis Y mAb hu3S193 was labeled with ¹¹¹In or ⁸⁶Y through CHX-A''-diethylenetriaminepentaacetic acid chelation. In vitro cell binding and cellular retention of radiolabeled hu3S193 were evaluated using HCT-15 colon carcinoma cells, a cell line expressing Lewis Y. Nude mice bearing HCT-15 xenografts were injected with ⁸⁶Y-hu3S193 or ¹¹¹In-hu3S193. The biodistribution was studied by measurements of dissected tissues as well as by PET and planar imaging. Results: The overall radiochemical yield in hu3S193 labeling and purification was 42% ± 2% (n = 2) and 76% ± 3% (n = 6) for ⁸⁶Y and ¹¹¹In, respectively. Both radioimmunoconjugates specifically bound to HCT-15 cells. When cellular retention of hu3S193 was studied using ¹¹¹In-hu3S193, 80% of initially cell-bound ¹¹¹In activity was released into the medium as high-molecular-weight compounds within 8 h. When coadministered, in vivo tumor uptake of ⁸⁶Y-hu3S193 and ¹¹¹In-hu3S193 reached maximum values of 30 ± 6 and 29 ± 6 percentage injected dose per gram and tumor sites were easily identifiable by PET and planar imaging, respectively. Conclusion: At 2 d after injection of ¹¹¹In-hu3S193 and ⁸⁶Y-hu3S193 radioimmunoconjugates, the uptake of ¹¹¹In and ⁸⁶Y activity was generally similar in most tissues. After 4 d, however, the concentration of ⁸⁶Y activity was significantly higher in several tissues, including tumor and bone tissue. Accordingly, the quantitative information offered by PET, combined with the presumably identical biodistribution of ⁸⁶Y and ⁹⁰Y radiolabels, should enable more accurate absorbed dose estimates in ⁹⁰Y radioimmunotherapy.

Key Words: ⁸⁶Y • PET imaging • radioimmunotherapy • Lewis Y • 3S193 antibody

	INTRODUCTION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
Nuclear medicine has extensively used ⁹⁰Y as a therapeutic agent because of its physical properties. It is a high-energy (maximum, 2.27 MeV) pure ß^--emitter. The nonpenetrating ß^--emissions have a maximum range of approximately 10 mm with a mean range of 3.9 mm in soft tissue, and the lack of penetrating photon emissions minimizes the indiscriminate whole-body radiation absorbed dose burden. Primarily, ⁹⁰Y has been used for bone pain palliation (1–3) and in radiolabeled monoclonal antibody (mAb) therapies (4–8). The paucity of -ray emissions, however, renders this isotope extremely difficult to image. Attempts have been made to image the Bremsstrahlung radiation (9–12) generated by the slowing down of high-energy electrons in tissue. However, the low photon yield and the polychromatic nature of the Bremsstrahlung spectrum result in limited quantitative accuracy with ⁹⁰Y. To avoid complex and inaccurate Bremsstrahlung imaging methods, it has been customary to use ¹¹¹In as a surrogate for ⁹⁰Y. ¹¹¹In has an almost identical half-life to ⁹⁰Y, emits 2 -rays of 171 and 245 keV, and is readily incorporated into the same metal chelating agents as yttrium. For these reasons, ¹¹¹In has been considered an excellent analog for ⁹⁰Y.

Subtle differences in radionuclide retention of the metal chelating agent used for ¹¹¹In and ⁹⁰Y mAb labeling can result in a differential release between the 2 radiometals. Despite possible differences in the biodistributions of ¹¹¹In and ⁹⁰Y, ¹¹¹In is widely used as an analog for ⁹⁰Y in radioimmunotherapy trials. Of particular importance is the affinity of yttrium for bone. Loss of ⁹⁰Y from the chelating agent can result in a higher dose to bone and bone marrow, which would not be anticipated from biodistribution data derived from ¹¹¹In. Because bone marrow is the dose-limiting tissue in most radionuclide therapies, pretherapy tracer scans with ¹¹¹In-labeled mAb could underestimate the bone marrow dose.

A more suitable isotope for accurately imaging the biodistribution of ⁹⁰Y would be an alternative isotope of the yttrium metal. Recently, 2 alternative isotopes have been proposed. The first is the electron capture decaying ⁸⁷Y isotope, which emits a 485-keV -ray with a 92.2% yield and has a half-life of 3.3 d (13). This isotope can be visualized by planar or SPECT gamma camera imaging on many modern cameras, using a high-energy, high-resolution collimator. The second, ⁸⁶Y, is a positron emitter (33%) with a 14.7-h half-life that can be imaged on a PET camera (14). ⁸⁶Y has been used to estimate the radiation doses from ⁹⁰Y in patients administered ⁹⁰Y for bone pain palliation (3).

The mAb (3S193) used in this study binds to the Lewis Y antigen (Le^y), an antigen expressed on several human carcinomas of epithelial origin, including colon, lung, ovarian, and breast carcinomas. This mAb has been well characterized by Kitamura et al. (15) and Scott et al. (16) in its murine and humanized forms. Clinical radioimmunotherapy trials with this mAb are currently in progress to evaluate treatment efficacy in breast, colon, and ovarian carcinomas.

The objective of this study was to compare the biodistributions of ¹¹¹In with ⁸⁶Y-labeled anti-Le^y mAb and to test the feasibility of imaging tumors with ⁸⁶Y-anti Le^y in a rodent xenograft model.

	MATERIALS AND METHODS

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Materials
The characterization of the originally murine mAb 3S193, its association with Le^y, and its humanization have been described by Kitamura et al. (15). Humanized 3S193 (hu3S193) was produced and conjugated to CHX-A''-diethylenetriaminepentaacetic acid (DTPA), as has been described (17,18). [¹¹¹In]InCl₃ in 50 mmol/L HCl was purchased from NEN (Billerica, MA). All solutions were made using distilled deionized water (Milli-RO Plus; Millipore Inc., Bedford, MA) and all buffers were purified on a 200–400 mesh Chelex 100 column (Bio-Rad, Hercules, CA). All other chemicals were from commercial sources. NAP-5 desalting columns were purchased from Pharmacia (Piscataway, NJ), and 10-DG gel filtration columns were purchased from Bio-Rad. A fast protein liquid chromatography (FPLC) gel filtration column (Superdex 200HR; Pharmacia) coupled to a Waters high-performance liquid chromatography system (two 501 pumps, 486 UV detector), a radiodetector (Radiomatic flow scintillation analyzer; Packard Instrument Co., Meriden, CT), and a FRAC-100 fraction collector (Pharmacia), was used for chromatographic analysis. Instant thin-layer chromatography silica plates were purchased from Gelman Sciences Inc. (Ann Arbor, MI). All radioactive samples were measured in a well scintillation LKB Wallac gamma counter (1282 Compugamma CS), correcting for the ⁸⁶Y contribution in the ¹¹¹In window and the ¹¹¹In contribution in the ⁸⁶Y window in the double-isotope experiments described below. The PET camera used for ⁸⁶Y imaging was an Advance whole-body scanner (General Electric, Milwaukee, WI). The ¹¹¹In biodistribution was imaged using a Genesys gamma camera (ADAC, Milpitas, CA). Nude mice were purchased from Harlan Sprague-Dawley (Indianapolis, IN) and were kept in a controlled environment where cages, food, and water had been autoclaved. To prevent the development of hyperkeratosis associated with corynea bacteria, 1 mL Augmentin (Amoxycillin/Clavulanate potassium) was added per 500 mL drinking water.

Production and Separation of ⁸⁶Y
The general procedure for ⁸⁶Y production and separation has been reported (17). Briefly, isotope-enriched ⁸⁶SrCO₃ (97.02% ⁸⁶Sr) was irradiated with 15-MeV protons in the MSKCC cyclotron (model CS-15; Cyclotron Corp., Berkeley, CA). After irradiation, the target was dissolved in 4 mol/L nitric acid containing 1 mg/mL Fe(III), diluted with metal-free water, and stirred for 5 min. The ⁸⁶Y hydroxide was coprecipitated with ferric hydroxide by the addition of dilute ammonium hydroxide. The ⁸⁶Y occluded ferric hydroxide precipitate was concentrated by centrifugation. The precipitate was redissolved and precipitated 3 additional times and finally washed with warm water. All solutions were combined and the enriched strontium was recovered as carbonate by bubbling carbon dioxide through the solution. Lastly, the precipitate was dissolved in 6 mol/L HCl and loaded onto a preconditioned analytic grade 1 x 8 anion ion-exchange column. The column was eluted with 15 mL 6 mol/L HCl. The solution was evaporated to dryness and the residue was dissolved in 0.5 mL 50 mmol/L HCl. For this study, 333 ± 111 MBq (n = 2) ⁸⁶YCl₃ in 0.5 mL 50 mmol/L HCl were obtained.

Radiolabeling
⁸⁶Y-acetate or ¹¹¹In-acetate was prepared by mixing an aliquot of the radionuclide preparations (51.8–148 MBq ⁸⁶Y, 18.5–55.5 MBq ¹¹¹In) with 3 mol/L ammonium acetate (final pH = approximately 5). After 5–15 min, hu3S193 (100–250 µg) was added, and the mixture incubated for 30 min at room temperature. The reaction was terminated by the addition of ethylenediaminetetraacetic acid (EDTA) (50 nmol), and the radiolabeled mAb separated from unreacted radiometal on a 10-DG desalting column equilibrated with 50 mmol/L phosphate-buffered saline (PBS).

The amount of protein-bound radioactivity in the purified preparations was determined by thin-layer chromatography, on silica gel, using 10 nmol/L EDTA (pH 4.5) as an eluent. In this system, radiometal-EDTA migrates with the solvent front (R_f = approximately 0.8–1), whereas labeled mAb remains at the application site (R_f = approximately 0–0.2). Preparations of ⁸⁶Y-hu3S193 and ¹¹¹In-hu3S193 were also analyzed by FPLC as described previously, and antigen-binding capacity determined in a cell-binding assay, as described later in this article.

A single batch of ¹²⁵I-hu3S193 was prepared for cell binding and retention by adding 1.48 MBq ¹²⁵I in 50 µL 0.3 mol/L phosphate buffer (pH 7.5) to a vial coated with IODO-GEN (10 µg; Pierce, Rockford, IL). After 5 min, the ¹²⁵I activity was transferred to a vial containing hu3S193 (100 µg). The mixture was incubated for 30 min at room temperature, after which ¹²⁵I-hu3S193 was separated from unreacted ¹²⁵I on an NAP-5 desalting column.

Cell Binding
The antigen-binding capacity of radiolabeled hu3S193 was evaluated in a cell-binding assay. Labeled hu3S193 (10 ng) was added in triplicate to 5 x 10⁶ HCT-15 cells suspended in 200 µL Roswell Park Memorial Institute (RPMI) medium complemented with 0.1% human serum albumin (HSA) (RPMI + 0.1% HSA). In control vials, 100 µg hu3S193 were added to the cells before the labeled hu3S193 was added. The cell suspensions were incubated for 1 h on a rotating table at room temperature and washed twice by centrifugation and resuspension in RPMI + 0.1% HSA. Immunoreactive fraction was defined as radioactivity in pellet over total radioactivity.

For cellular retention analysis, HCT-15 cells were grown to confluence in a 96-well plate. A mixture of ¹¹¹In-hu3S193 (50 ng) and ¹²⁵I-hu3S193 (50 ng) in 200 µL RPMI + 0.1% HSA was added to each well. After incubation at 37°C for 2 h, cells were washed 3 times with RPMI + 0.1% HSA. Then, 200-µL culture medium was added to each well and the cells were further incubated at 37°C for 0, 1, 2, 4, 8, 16, and 24 h in triplicate samples. At each time point, the supernatant was removed and separated into high- and low-molecular-weight components on an NAP-5 desalting column. The cells were solubilized with 2 mol/L NaOH, and all fractions measured in a well counter using 2 windows selected to differentiate the ¹²⁵I x- and -ray peaks (25–35 keV) from the ¹¹¹In peaks (171 and 245 keV). ¹¹¹In standards were used to determine the down-scatter fraction into the ¹²⁵I window and all sample counts per min in the ¹²⁵I window appropriately corrected by the counts in the ¹¹¹In multiplied by the down-scatter factor (0.033 or 3.3%).

Biodistribution
Nude mice were injected subcutaneously in the left and right hind legs with 10⁶ HCT-15 cells suspended in 200 µL RPMI medium. Biodistribution experiments were performed 2–3 wk after tumor induction, at which time the mice weighed 18–27 g.

The general hu3S193 biodistribution kinetics in the current tumor model were investigated using ¹¹¹In-hu3S193. Mice were injected intravenously with 100 µL PBS containing 0.5% HSA (RPMI + 0.5% HSA) and 0.74 MBq ¹¹¹In-hu3S193 (3 µg). At various time points after injection, 6 mice were killed by exposure to CO₂ and then dissected.

For comparing ⁸⁶Y-hu3S193 and ¹¹¹In-hu3S193 biodistribution, mice were coinjected with 120 µL PBS containing 0.5% HSA, 1.48 MBq ⁸⁶Y-hu3S193, and 0.185 MBq ¹¹¹In-hu3S193 (total 100 µg) in 200 µL. Five mice were killed at 2 and 4 d after injection, respectively. The major organs were dissected, weighed, and counted on a well scintillation counter in 2 windows. For ⁸⁶Y, a single window was used, including both single 511-keV and 1.02-MeV coincident annihilation photons. For ¹¹¹In, a window encompassing both 171- and 245-keV -photons was used. Scintillation vials were filled with PBS to the same 3-mL volume. The cross-talk between the ¹¹¹In and ⁸⁶Y windows was derived from the counts in both windows using standards of each isotope. The cross-talk from ¹¹¹In into the ⁸⁶Y window was negligible (<2 times background) and, therefore, was assumed to be zero. The cross-talk factor from ⁸⁶Y into the ¹¹¹In window was 1.34 (134%), which was caused by the very large (polychromatic) emissions from ⁸⁶Y as well as the partial absorption of high-energy -rays in the sodium iodide detector. To convert counts in the ¹¹¹In window into ¹¹¹In activity, the counts in the ⁸⁶Y window were multiplied by 1.34 and subtracted from the counts in the ¹¹¹In window.

Imaging
The imaging studies were performed on mice administered ¹¹¹In- or ⁸⁶Y-labeled mAb only, because initial preliminary studies with coadministered ¹¹¹In and ⁸⁶Y showed severe degradation of the ¹¹¹In images from ⁸⁶Y photon down-scatter into the ¹¹¹In energy windows (data not shown).

The mice were injected with 3.7 MBq ¹¹¹In-hu3S193 (25 µg) in 200 µL PBS + 0.5% HSA. Animals were anesthetized with ketamine at 1 h, 24–26 h, and 48–50 h after injection and positioned on a Styrofoam (Dow Chemical Co., Midland, MI) base directly on the medium-energy, general purpose collimator of an ADAC Genesys gamma camera (ADAC, Milpitas, CA). A 20-min acquisition was performed with two 20% energy windows positioned at the 171- and 245-keV photopeaks of ¹¹¹In.

⁸⁶Y images were obtained on a whole-body Advance PET scanner (General Electric, Milwaukee, WI). The mice were injected with 3.7 MBq ⁸⁶Y-hu3S193 (20 µg) in 200 µL PBS + 0.5% HSA. The mice were anesthetized at 1 h, 24–26 h, and 48–50 h after injection and positioned on a circular Styrofoam (Dow Chemical) motel (Fig. 1) taped to the scanner couch. Acquisitions were performed for 20 min within a 300 to 650-keV energy window in 2-dimensional (2D) (septa-in) mode. Normalization, randoms, and scatter corrections were applied and the images were reconstructed by standard filtered backprojection using a Hanning filter with an 8-mm cutoff.

View larger version (114K): [in this window] [in a new window]   FIGURE 1. Animal set-up in Styrofoam motel on GE Advance PET scanner.

	RESULTS

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Radiolabeling Yields
The radiochemical yields for ⁸⁶Y- and ¹¹¹In-labeling and purification were 42% ± 2% (n = 2) and 76% ± 3% (n = 6), respectively. For ⁸⁶Y-hu3S193, the specific activity was 74 ± 37 MBq/mg (n = 2), the radiochemical purity was 96% ± 4% (n = 2), and the immunoreactive fraction was 44% (n = 1). For ¹¹¹In-hu3S193, the specific activity was 148 ± 74 MBq (n = 6), the radiochemical purity was 98% ± 3% (n = 6), and the immunoreactive fraction was 40% ± 14% (n = 5). In the FPLC radiochromatograms, only intact radiolabeled hu3S193 could be distinguished for both ⁸⁶Y- and ¹¹¹In-hu3S193. The lower labeling yield for ⁸⁶Y versus ¹¹¹In was assumed to be attributable to iron contamination. No assessment of the absolute chemical purity of ⁸⁶Y was performed. ¹²⁵I-labeling of hu3S193 resulted in 47% radiochemical yield and a specific activity of 74 MBq/mg (n = 1).

Cell Binding
After ¹¹¹In- and ¹²⁵I-hu3S193 binding to HCT-15 cells, 80% of the initially cell-bound radioactivity was recovered in the medium as high-molecular-weight species after an 8-h incubation. It was expected that a much higher yield of ¹²⁵I low-molecular-weight activity would be observed because of the digestion of mAb on internalization and release of the radioiodine. However, the results showed only a small difference between ¹¹¹In- and ¹²⁵I-hu3S193, suggesting that <20% internalization had occurred within the 8-h incubation (Fig. 2). The advantage of the radiometals, ¹¹¹In, and the isotopes of Y(III) is the nonspecific retention by cells upon intracellular disassociation of the metal from the chelate, leading to longer tumor retention relative to radiohalogenated immunoconjugates.

View larger version (19K): [in this window] [in a new window]   FIGURE 2. Cellular retention of 111In-hu3S193 (solid lines) and 125I-hu3S193 (dotted lines). Cell = cell-bound radioactivity; HM and LM = high- and low-molecular-weight radioactivity in supernatant. Error bars (n = 3) were omitted for clarity.

View larger version (29K): [in this window] [in a new window]   FIGURE 3. Biodistribution kinetics of 111In-hu3S193 in nude mice carrying HCT-15 xenografts (n = 6) at: 3, 18, 44, 72, 94, and 164 h.

Analysis of the serum stability of each radioimmunoconjugate, ⁸⁶Y-hu3S193, or ¹¹¹In-hu3S193 at 2 d after injection showed that the only radioactive component was intact mAb, as evaluated by FPLC chromatography (Fig. 4). However, it should be noted that "free" radiometals, unless associated with blood proteins, would not be detected in this assay.

View larger version (14K): [in this window] [in a new window]   FIGURE 4. Serum analysis of animals 2 d after injection with 86Y-hu3S193 or 111In-hu3S193.

View larger version (21K): [in this window] [in a new window]   FIGURE 5. Serial coronal PET images of 2 mice injected with 86Y-hu3S193.

View larger version (29K): [in this window] [in a new window]   FIGURE 6. Serial planar images of 2 mice injected with 111In-hu3S193.

View larger version (94K): [in this window] [in a new window]   FIGURE 7. Four serial sections from HCT-15 tumor at 24 h after injection with 86Y-hu3S193. (A) Phosphor plate autoradiograph (100 x 100 µm2 resolution) showing spatial distribution of 86Y. (B) Horseradish peroxidase stain for injected hu3S193 mAb on adjacent section. (C) Horseradish peroxidase stain for Ley antigen on adjacent section. (D) Hematoxylin–eosin stain of adjacent section. Sections (B–D) were digitized frame-by-frame on microscope at x40 magnification using motorized scanning stage.

	DISCUSSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

The results of this study show that the biodistributions of ¹¹¹In-hu3S193 with ⁸⁶Y-hu3S193 anti-Le^y mAb are comparable within the 48-h time frame (>3.5 half-lives), indicating that PET imaging with ⁸⁶Y is feasible. Despite 7 half-lives, counts per minute in the tumor, which were obtained with the well scintillation counter, were still highly significant (>24,000) and >10 times background in all tissues (except muscle) at 96 h.

The advantage of using ⁸⁶Y is that the annihilation photon emissions detected by PET permit a more accurate determination of ⁸⁶Y than single-photon imaging devices. Furthermore, the use of this -emitting yttrium isotope permits the use of solid scintillation counting methods of tissue samples, thereby avoiding the quantification problems encountered with liquid scintillation counting of a pure ß^--emitter such as ⁹⁰Y.

This study confirmed that ¹¹¹In is a good analog for the isotopes of yttrium, especially at early time points (<48 h) after injection. However, the lower stability of the CHX-A''-DTPA chelate for ⁸⁶Y relative to ¹¹¹In results in a progressively higher ratio of the ⁸⁶Y radiometal to the parent compound. The marginally slower clearance kinetics of the yttrium radiometal resulted in a progressively higher %ID/g during a 4-d time period relative to ¹¹¹In. The implications of this departure between the pharmacokinetics of the 2 radiometals would lead to dosimetry estimates based on ¹¹¹In images that would underestimate the doses received by ⁹⁰Y. For this reason, ⁸⁶Y would be a more accurate surrogate for ⁹⁰Y. Furthermore, the ability to perform quantitative PET imaging with ⁸⁶Y radiopharmaceuticals offers a significant advantage over ¹¹¹In. Although the 14.7-h half-life of ⁸⁶Y is much lower than that of ¹¹¹In (2.7 d), the far higher sensitivity of PET cameras should permit clinical imaging to at least 4 half-lives.

	CONCLUSION

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 
This study has shown the feasibility of radiolabeling the hu3S193 anti-Le^y mAb with ⁸⁶Y to obtain tumor uptake (30 %ID/g) equivalent to ¹¹¹In and to obtain high-quality PET images at 48 h after injection with excellent tumor localization. Future studies will explore the utility of ⁸⁶Y-labeled mAbs to determine the biodistribution and dosimetry of ⁹⁰Y-labeled mAbs in patients.

	ACKNOWLEDGMENTS

 
The authors thank Chaitanya Divgi for contributing greatly to the experimental design. The authors also thank Andrew Scott from the Ludwig Institute for Cancer Research for many quality revisions of the manuscript. This study was funded by the Swedish Medical Research Council, the Swedish Institute, Department of Energy grant DE-FG02-95ER62039, and National Cancer Institute grants R01 CA78642 and 1R24CA83084.

	FOOTNOTES

 
Received Nov. 10, 2000; revision accepted Apr. 9, 2001.

For correspondence or reprints contact: John L. Humm, PhD, Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10021.

	REFERENCES

TOP ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS DISCUSSION CONCLUSION REFERENCES

 

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