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Targeting Superficial Bladder Cancer by the Intravesical Administration of Copper-67–Labeled Anti-MUC1 Mucin Monoclonal Antibody C595

From the Departments of Urology and Pathology, City Hospital; Departments of Medical Physics and Radiology, University Hospital; and Cancer Research Laboratory, School of Pharmaceutical Sciences, University of Nottingham, Nottingham, United Kingdom; and Centre for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland.

Address reprint requests to Prof A.C. Perkins, Department of Medical Physics, University Hospital, Nottingham NG7 2UH, United Kingdom; email alan.perkins{at}nottingham.ac.uk

	ABSTRACT

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PURPOSE: More effective intravesical agents are required to limit the recurrence and progression of superficial bladder cancer. This study assessed the ability of copper-67 (⁶⁷Cu)-C595 murine antimucin monoclonal antibody to bind selectively to superficial bladder tumors when administered intravesically, with a view to its development for therapy.

PATIENTS AND METHODS: Approximately 20 MBq of ⁶⁷Cu-C595 monoclonal antibody was administered intravesically to 16 patients with a clinical indication of superficial bladder cancer. After 1 hour, the bladder was drained and irrigated. Tissue uptake was assessed by imaging and by the assay of tumor and normal tissues obtained by endoscopic resection.

RESULTS: Tumor was correctly identified in the images of 12 of 15 patients who were subsequently found to have tumors. Assay of biopsy samples at 2 hours showed a mean tumor uptake of 59.4% of the injected dose per kilogram (SD = 48.0), with a tumor-to-normal tissue ratio of 14.6:1 (SD = 20). After 24 hours (n = 5), this decreased to 4.3% of the injected dose per kilogram (SD = 2.9), with a tumor-to-normal tissue ratio of 1.8:1 (SD = 0.8).

CONCLUSION: This study indicates a promising method for the treatment of superficial bladder cancer. Although the mean initial tumor uptake was high, effective therapy of bladder tumors will require an increased retention of the cytotoxic radionuclide in tumor tissue.

	INTRODUCTION

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BLADDER CANCER is the fifth most common cancer in men and the fifth most common cause of death from cancer in men in the United Kingdom. The incidence in women is lower, but the disease still accounts for some 1,000 deaths per year among women in the United Kingdom. The majority of patients with bladder cancer present with superficial disease that is confined to the mucosa. However, 70% of these superficial bladder tumors will recur after endoscopic resection, and 20% progress to life-threatening invasive disease.¹ Intravesical chemotherapy or immunotherapy is a promising approach, but studies to date have shown limited efficacy, particularly in preventing tumor progression, and significant side effects.² Patients with poor prognostic factors or muscle-invasive disease need more radical treatment in the form of external-beam radiotherapy or cystectomy, both of which carry significant morbidity and mortality. More effective local treatments would reduce the recurrence rate of superficial tumors and decrease the number of patients for whom aggressive treatment for invasive disease is required. Radiation has been shown to be of value in treating patients with superficial tumors,^3-6 and by using a suitable carrier for a radionuclide to target the therapeutic effect, damage to normal structures may be limited.

MUC1 mucin is a glycoprotein present on normal urothelium that is aberrantly expressed in bladder cancer.^7,8 Monoclonal antibody C595 (also known as NCRC48) is reactive with the protein core of MUC1 mucin.⁹ The target epitope of the C595 antibody is the tetrameric motif Arg-Pro-Ala-Pro that is repeated many times within the MUC1 protein core. The reactivity of the C595 antibody with synthetic peptides containing this motif permits efficient antibody purification using peptide-epitope affinity chromatography, which, unlike other methodologies, enables exclusion recovery of functionally active antibody. We have previously shown antibody localization of bladder tumors after intravesical administration of indium-111 (¹¹¹In)–labeled C595 with a mean tumor uptake to normal tissue ratio of 12:1.^{10 111}In is suitable for imaging, but with no beta emission, it is poorly suited for therapy. We have sought an alternative radiolabel with both a gamma emission for external imaging and also a beta emission with suitable characteristics for therapy. Most clinical studies for radioimmunotherapy (RIT) have used yttrium-90 or iodine-131 (¹³¹I) as the therapeutic moiety. As a pure beta emitter, yttrium-90 is unsuitable for imaging. Although ¹³¹I is inexpensive, widely available, and well established as a radiolabel, it has several major drawbacks, including a predominant gamma emission of 364 keV (82% abundance), which accounts for two thirds of the absorbed dose equivalent of this nuclide, and a relatively long physical half-life (8 days).¹¹ To achieve higher tumor doses without compromising patient or staff, radionuclides with better physical characteristics are required.

Copper-67 (⁶⁷Cu) has a gamma emission of 185 keV (42% abundance) that is suitable for imaging and, together with a physical half-life of 2.6 days, results in a lower systemic radiation burden to the patient and staff. Its beta particle emission with a maximum range in tissue of 2.2 mm is appropriate for the treatment of small tumor deposits.¹² The present study was performed to assess the ability of ⁶⁷Cu-labeled C595 monoclonal antibody to bind preferentially to superficial bladder tumors when administered intravesically, with a view to its development for therapy.

	PATIENTS AND METHODS

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Monoclonal Antibody
The monoclonal antibody C595 (murine IgG3 immunoglobulin) was labeled with ⁶⁷Cu using the 14N4 macrocycle. The antibody production, purification, radiolabeling method, and preclinical testing have previously been described in detail.¹³ The immunoreactive fraction of the labeled antibody for each administration was assessed by its capacity to rebind to peptide-epitope–conjugated Sepharose beads (Pharmacia Biotech, Uppsala, Sweden).¹³

Patients, Imaging, and Surgery
Sixteen patients suspected to have bladder cancer on the basis of preoperative radiology (intravenous urography or ultrasound) or flexible cystoscopy were recruited and entered onto the study after giving written informed consent. Approval was obtained from the local Hospitals Ethics Committee and the Administration of Radioactive Substances Advisory Committee (ARSAC) of the United Kingdom Department of Health. Fifteen patients had tumors confirmed at cystoscopy; one patient had cystitis. Patients were catheterized and bladders were drained. A 50-mL solution containing 0.5 mg of C595 antibody labeled with approximately 20 MBq of ⁶⁷Cu was instilled into the bladder. After incubation for 1 hour, this was washed out with three 50-mL volumes of 0.9% saline and replaced with a further 50 mL of saline. Anterior planar gamma camera images were taken immediately after instillation and post washout using a large field-of-view gamma camera fitted with a medium energy collimator (IGE Starport, IGE, Slough, United Kingdom). Images were acquired in a 128 x 128–pixel matrix and stored onto optical disc using a dedicated nuclear medicine computer (Hermes, Nuclear Diagnostics Ltd, Gravesend, United Kingdom). Cystoscopy was then performed, with patients under general anaesthesia. Biopsies of bladder tumor and normal urothelium were removed by transurethral resection. Six patients were examined by cystoscopy at 24 hours, and the remaining 10 were examined at 2 hours. At cystoscopy, the position and number of tumors were noted before biopsy of normal urothelium and resection of tumor. Normal and tumor specimens were blot-dried and weighed, and the emission of ⁶⁷Cu was measured in a gamma counter. Tumor localization was therefore assessed both by scintigraphy and direct tissue counting, and the proportion of the injected dose taken up by tumor and normal urothelium was calculated.

Immunohistochemistry
Immunohistochemistry was performed on the resected tumor specimens indirectly to assess MUC1 expression. Paraffin blocks were sectioned at 3 µm and endogenous peroxidase activity was blocked with 1% hydrogen peroxide in methanol for 10 minutes. Nonspecific binding was blocked with a 1-in-10 dilution of normal swine serum for 10 minutes. Immunostaining was performed using a Shandon Sequenza semiautomatic immunostainer (Shandon, Pittsburgh, PA). Monoclonal antibody C595 was diluted in normal swine serum to 12 µg/mL, and this primary antibody layer was applied for 1 hour. Appropriate controls, including irrelevant antibodies and diluent alone, were included. Detection of antibody binding was performed using biotinylated goat antimouse/rabbit immunoglobulins followed by streptavidin-conjugated horseradish-peroxidase complex as specified by the manufacturer (Dako Corp, Copenhagen, Denmark). Visualization was performed using a solution of 0.025% 3,3 diaminobenzidine as the chromogen diluted in Tris buffer (pH 7.6; Signa Chemical Co, Poole, United Kingdom), with hydrogen peroxide as the substrate. Tissue sections were counterstained with hematoxylin, dehydrated in graded alcohol solutions, cleared in xylene, and mounted in DPX mountant. Immunostaining was performed without any form of antigen retrieval. All sections were assessed by one observer without prior knowledge of the tumor grade or stage.

Assessment of Systemic Absorption
Systemic absorption of radiolabeled antibody was assessed using two methods. First, ⁶⁷Cu activity was measured in whole blood samples taken 12 hours after antibody administration. Second, because C595 is of murine origin, if it is absorbed systemically, it will induce an immune response with the production of human antimouse antibodies (HAMA). Serum taken from patients before and 3 weeks after antibody administration was measured for a specific IgG HAMA response using enzyme-linked immunoadsorbent assay.

Monoclonal antibody C595 (50 µL at 5 µg/mL) was applied to one half of a 96-well plate and allowed to adsorb overnight at 4°C, with the other one half coated with phosphate-buffered saline (PBS; pH 7.3) as control. Plates were washed three times with PBS, 0.02% (weight-to-volume ratio) Tween-20 (Sigma Chemical Co, Poole, United Kingdom) and then blocked with 1% bovine serum albumin in PBS. Serum samples taken from patients before and 3 weeks after antibody administration were diluted 1/30 in 1% bovine serum albumin in PBS for assay and applied in triplicate to each side of the plate. Positive control serum was obtained from a patient who was known to have developed an antimouse response after previous systemic administration of the C595 antibody in a prior study.¹⁴ The sample obtained from each patient before antibody administration was used as the negative control for the respective postinjection sample. The plates were washed again three times before adding 50 µL of horseradish-peroxidase conjugated rabbit anti-IgM/G immunoglobulins (Dako), diluted 1/1,000 with PBS. After a further wash at 1 hour, the reaction was developed with 2,2 azinodi(3-ethylbenz-thiazoline-6-sulfonic acid) (ABTS; Sigma Chemical Co) in citrate phosphate buffer (pH 4.0) and 0.1% (volume-to-volume ratio) hydrogen peroxide. Plates were read on a spectrophotometer at 405 nm. HAMA levels between the pre- and postdose group as a whole were compared using the Wilcoxon signed-rank test. Individual pre- to postinjection samples were compared using an unpaired t test.

	RESULTS

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Radiolabeling
The mean labeling efficiency of ⁶⁷Cu incorporation to the antibody protein was 55%. The mean activity administered to patients was 15.8 MBq (SD = 3.6; n = 16), conjugated to 0.5 mg of C595 antibody. The mean immunoreactive fraction of the ⁶⁷Cu labeled antibody was 87.6% (SD = 12.5; n = 10).

Immunoscintigraphy
The details of the 16 patients studied and the results from imaging and biopsy counts are listed in Table 1. The presence and position of tumor was demonstrated correctly in 12 of 15 patients with tumor, although in two patients with bladder diverticula, delayed imaging at 6 to 8 hours was required to show tumor localization in view of the high initial background activity. The three patients with false-negative scans all had low-grade pTa tumors, and the one nontumor control had a negative scan. There were no false-positive results from imaging. Examples of bladder tumor localization by immunoscintigraphy are shown in Fig 1. The negative control scan in the patient with no bladder tumor is shown for comparison in Fig 2.

View larger version (61K): [in this window] [in a new window]   Fig 1. (A) Intravenous urography and (B) gamma camera image from patient showing left-sided bladder tumor and corresponding area of activity after washout of 67Cu-C595 antibody.

View larger version (10K): [in this window] [in a new window]   Fig 2. Anterior gamma camera images from a patient with cystitis only and no evidence of bladder cancer. (A) Prewashout scan shows radioactivity in the bladder, and (B) postwashout scan shows no significant uptake in normal urothelium, with residual activity in the catheter spigot.

View larger version (24K): [in this window] [in a new window]   Fig 3. Tissue counts of tumor and normal urothelial specimens resected at 2 or 24 hours after intravesical administration of 67Cu-C595 antibody. The counts are expressed as a percentage of the total injected dose per kilogram of tissue.

There was a significant difference between the mean counts of tumor and normal specimens at 2 hours after instillation (P = .016), but the difference was no longer significant at 24 hours (P = .30).

Correlation of Uptake With Tumor Stage and Grade
The results of the assay of radioactivity in the tissue specimens obtained from the nine patients resected at 2 hours are listed according to tumor grade and stage in Tables 2 and 3. As the numbers in each group are small, statistical analysis was inappropriate, but it was observed that higher count rates were recorded in the higher-grade tumors.

View larger version (113K): [in this window] [in a new window]   Fig 4. Indirect immunohistochemistry with C595 antibody on a section from (A) normal urothelium showing expression on the luminal surface and (B) high-grade superficial bladder tumor with enhanced staining extending throughout the tumor.

	DISCUSSION

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Radioimmunotherapy, using the antibody-targeted approach, offers an attractive alternative to conventional chemotherapy. Although the results of therapeutic trials have been encouraging in the treatment of diffuse malignancies such as leukemia, there has been little progress toward the effective treatment of solid tumors. As a result, some researchers have adopted direct tumor injection or alternative routes of administration to optimize the treatment. In the case of superficial bladder cancer, the intravesical approach provides an attractive and well-tolerated route of administration.

In the present study, the production of radiolabeled antibody with a reproducibly high immunoreactive fraction confirms the reliability of the labeling method and suitability of the ⁶⁷Cu-C595 monoclonal antibody for radioimmunoscintigraphy. The mean tumor-to-normal ratio of almost 15:1 shown by this study is encouraging, although the SD of 20 is larger than would be hoped for, which indicates that this form of therapy may be more effective for some patients than for others. These results are similar to the 12:1 ratio previously shown by Kunkler et al¹⁰ using ¹¹¹In-C595. Nevertheless, both of these studies demonstrate the preferential reaction of C595 antibody for tumor relative to normal urothelium. It is possible that the C595 antibody possesses a higher affinity for bladder tumor–associated MUC1 than other anti-MUC1 antibodies that have been administered intravesically, such as HMFG1 and HMFG2.^15,16 Both the level of antibody uptake and the tumor-to-normal ratios were significantly higher in the present study in comparison with those reported in other intravesical studies using antimucin antibody^15,16 and the monoclonal antibody AUA1.¹⁷

We demonstrated positive bladder tumor imaging in 80% of patients, with the three false-negative scans occurring in patients with low-grade, noninvasive (G1pTa) tumors. These tumors have the lowest biologic potential for progression and invasion and are therefore of less clinical significance. Enhanced tumor localization in terms of tissue counts and imaging was seen in the higher-grade tumors. These have the greatest risk of recurrence and progression to invasive disease and would be the main target tumors for a therapeutic conjugate. Although there is high variation in MUC1 expression by different tumors, it is possible to determine the relative levels of expression and select those patients who are likely to respond to this form of therapy. This could achieved via immunostaining of tumor biopsies taken at the time of the diagnostic cystoscopy and also via immunoscintigraphy with a diagnostic rather than therapeutic dose of radionuclide.

One problem with the method of obtaining tumor biopsy material via an irrigating cystoscope in the bladder is that this procedure may wash off some of the bound antibody. As a result, the uptake shown in the images would appear to be higher than that shown by direct assay of radioactivity in tissues. To achieve a cytotoxic tumor dose, the residence time should be maximized. Further study is underway to identify the form of and reason for the loss of activity with time. We are also currently exploring a number of different strategies to deliver an effective therapeutic tumor dose, including increasing the specific activity of the radioimmunoconjugate, increasing the residence time to encourage internalization of radiolabeled antibody, and developing new antibody constructs. We have developed a single-chain fragment and diabody with the same epitope as the parent Mab, but the smaller molecular weight of these molecules should increase tissue penetration without causing systemic absorption.^18,19 An important finding from this study, which has also been demonstrated by others who have studied intravesical administration of antibody conjugates, is that no detectable amounts of antibody or radionuclide were absorbed systemically from the bladder. This will, therefore, allow the safe administration of multiple doses to achieve a cumulative therapeutic effect, in a manner that is similar to current intravesical therapies.

The findings of the immunohistochemistry confirm the heterogeneous MUC1 expression with areas of high and low staining and activity. With antibody-targeted chemotherapy, the whole tumor population needs to bind antibody for cytotoxic therapy to be successful, and for reasons of limited antibody penetration and low antigen expression in some areas of the tumor, this may not be likely. This supports the use of a therapeutic radionuclide as the "warhead" attached to the selective antibody carrier rather than a cytotoxic drug. By the use of an appropriate radionuclide with a suitable length of beta emission to produce a "bystander" effect, the problem of heterogeneous and low antigen expression may be reduced. Immunohistology demonstrated that the pattern of staining was more appropriate for targeting of a medium energy beta emitter than a cytotoxic drug. We selected ⁶⁷Cu on the basis of its suitable beta emission, stable radiolabeling, and favorable biodistribution. Previous in vivo studies using ⁶⁷Cu-labeled anti-CEA antibody in a nude mouse tumor xenograft system have indicated a distinct advantage to be gained from using this metallic nuclide, in that activity associated with ⁶⁷Cu accumulation in target tumors was found to be up to two times that observed with ¹³¹I.²⁰ In addition, antibody targeting of ⁶⁷Cu with a maximum tissue penetration of 2.2 mm should eliminate the extravesical complications that are associated with external-beam radiotherapy. Assuming that the complex is stable at the tumor site, extrapolation from the data obtained suggests that it is theoretically possible to deliver a therapeutic dose as great as 25 Gy to a 5-g superficial tumor. We therefore anticipate that, in practice, a course of repeated administration would be necessary for effective tumor therapy. Radiolabeling with therapeutic amounts of ⁶⁷Cu-C595 is in progress, and a dose-escalation study is planned to obtain additional patient data on tumor dosimetry.

One unique advantage of the natural access to the bladder via the urethra is not only the ease of introducing the conjugate directly into the bladder, but also the easy means of assessing the response to therapy. A therapeutic trial of this will first be tested using the marker tumor concept as recommended by the European Organization for Research and Treatment of Cancer²¹ to study the efficacy and incidence of side effects. Studies will use the ⁶⁷Cu-C595 radioimmunoconjugate as adjuvant treatment to transurethral resection of the tumor.

	ACKNOWLEDGMENTS

 
Funded by project grant no. 2168 from the Cancer Research Campaign United Kingdom and a grant from Trent Regional Health Authority United Kingdom.

Radionuclide production and antibody labeling was performed by the Paul Scherrer Institute research facility in Villigen, Switzerland.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Raghavan D, Shipley WU, Garnick MB, et al: Biology and management of bladder cancer. N Engl J Med 322:1129-1138, 1990[Medline]

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21. Van den Meijden APM, Haal RR, Kurth KH, et al: Phase II trials in Ta, T1 bladder cancer: The marker tumour concept. Br J Urol 77:634-637, 1996[Medline]

Submitted March 31, 1999; accepted August 24, 1999.

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This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hughes, O. D. M. Articles by Schubiger, P. A. Search for Related Content PubMed PubMed Citation Articles by Hughes, O. D. M. Articles by Schubiger, P. A. Social Bookmarking                            What's this?