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[Cancer Research 59, 1615-1619, April 1, 1999]
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[Cancer Research 59, 1615-1619, April 1, 1999]
© 1999 American Association for Cancer Research

Tumor Biology

Intratumoral Distribution of Two Consecutive Injections of Chimeric Antibody G250 in Primary Renal Cell Carcinoma

Implications for Fractionated Dose Radioimmunotherapy1

Martijn G. Steffens2, Otto C. Boerman, Wim J. G. Oyen, Paul H. M. Kniest, J. Alfred Witjes, Gosse O. N. Oosterhof, Geert J. L. H. van Leenders, Frans M. J. Debruyne, Frans H. M. Corstens and Egbert Oosterwijk

Departments of Urology [M. G. S., J. A. W., G. O. N. O., F. M. J. D., E. O.], Nuclear Medicine [O. C. B., W. J. G. O., P. H. M. K., F. H. M. C.], and Pathology [G. J. L. H. v. L.], University Hospital Nijmegen, 6500 HB, Nijmegen, The Netherlands


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Tumor uptake of the chimeric G250 (cG250) monoclonal antibody (mAb) in patients with primary renal cell carcinoma (RCC) is among the highest reported in solid tumors. However, as observed in other tumor types, the intratumoral distribution of the antibody is highly heterogeneous, which may limit the efficacy of radioimmunotherapy. A number of highly dynamic physiological factors have been postulated that may contribute to heterogeneous tumor uptake of antibodies. Their impact on tumor uptake of antibodies may vary from one tumor region to another as well as from one day to the next. Here, we report on a clinical study that was designed to investigate whether the pattern of mAb cG250 uptake within RCC tumors is altered with subsequent injections.

Ten patients with a clinical diagnosis of primary RCC were studied. Nine days before surgery, patients received 125I-cG250 (5 mg of cG250, 50 µCi of 125I), followed by a second injection of 131I-cG250 (5 mg of cG250, 3.5 mCi of 131I) 4 days later. Postsurgery, the tumor was cut into (1-cm) thick slices. Slices were imaged on a gamma camera, and the slice with the most pronounced heterogeneity in 131I-cG250 distribution was selected and cut into 1-cm3 cubes. Each cube was analyzed for 125I-cG250 and 131I-cG250 uptake, and the 131I/125I ratio was determined. For each tumor slice, the distribution patterns of both isotopes were reconstructed and compared with each other.

All tumors analyzed showed a heterogeneous distribution of both isotopes throughout the tumor slice; focal uptake in some areas of a tumor reached very high levels (up to 0.19% injected dose/g), whereas other tumorous areas of the same slice showed much lower uptake (as low as 0.0047% injected dose/g). Remarkably, in all tumors, the distribution pattern of both injections was identical: without exception, in all samples analyzed (n = 692), the uptake of 125I-cG250 was similar to 131I-cG250 uptake. Overall, the 131I/125I ratio was 1.64 ± 0.31 (mean ± SD).

The constant 131I/125I ratios, observed in all tumor samples investigated, indicate that the tumor parameters governing cG250 mAb uptake were not altered significantly within the time period studied. In addition, the results of this study suggest that multiple radiolabeled antibody injections, administered within short time periods, will target the same areas within a tumor and, thus, will not solve the problem of heterogeneous tumor uptake of antibody.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although the initial expectations of radioimmunotherapy with radiolabeled monoclonal antibodies have not yet been fulfilled (for review see Ref. 1 ), this therapy regimen could still be a useful tool in the management of cancer. Recent studies have shown that radioimmunotherapy in hematological malignancies can lead to complete and lasting responses in the majority of patients (2 , 3) . However, more modest results have been reported in solid tumors (1) . Heterogeneous intratumoral antibody distribution, i.e., suboptimal targeting of some tumor regions, is one of the factors that may explain the poor therapeutic efficacy of radioimmunotherapy in solid tumors. A number of factors, e.g., heterogeneity of expression of the tumor-associated antigen (1) , tumor necrosis, vascular volume, blood flow rate, and vascular permeability, might account for the heterogeneous distribution of antibody throughout a tumor (4) . In addition, Jain and coworkers (5, 6, 7, 8) have postulated a number of physiological barriers that may contribute to poor tumor localization of antibodies: heterogeneous blood supply, (centrally) elevated IFP,3 and large transport distances in the interstitium. Due to macro- and microscopic tumor heterogeneity, the influence of the factors mentioned above were postulated to vary from one location to another in the same tumor and from one day to the next (5) .

In a Phase I protein dose escalation study with 131I-labeled mAb cG250 in patients with primary RCC, excellent tumor targeting was observed. In this study, tumor uptake as high as 0.52% ID/g and tumor:blood ratios as high as 855:1 (8 days p.i.) have been observed (9) . However, the distribution of the mAb cG250 throughout the tumors was highly heterogeneous: in some cases, regional differences in intratumoral mAb cG250 uptake exceeded a factor of 100 (9) . In a subsequent study, we showed that this heterogeneous mAb cG250 distribution could not be attributed solely to (a) antigen expression, (b) blood vessel density, (c) reactive stromal tissue, or (d) necro-sis (10) .

To further analyze the heterogeneous mAb cG250 tumor uptake, we designed a study to investigate whether this tumor uptake is influenced by the dynamic factors mentioned above. If, indeed, these factors determine intratumoral distribution of antibodies, the mAb cG250 distribution over an RCC tumor is likely to change with time. As a consequence, dose fractionation might circumvent heterogeneous tumor uptake of antibodies and prove to be more effective than single-dose radioimmunotherapy. Here, we present the results of a clinical study in patients with primary RCC in which the distribution of two consecutive injections of mAb cG250, with a time interval of 4 days, has been analyzed.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Characteristics.
Tumors of 10 patients with a clinical diagnosis of primary RCC were studied. The group of patients included eight men, ages 42–70 years (median age, 61 years), and two women, ages 51 and 52 years. Patient characteristics and tumor diameters are listed in Table 1Citation . All patients underwent a radical tumor nephrectomy 9 days after the first mAb cG250 injection as part of their treatment plan. The study protocol and informed consent forms were approved by the Institutional Review Board of the University Hospital Nijmegen. Prior to study entry, all patients agreed to participate by written informed consent.


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  		Table 1 Patient and tumor characteristics, range in uptake of 125I-cG250 and 131I-cG250, 95% confidence interval of the 131I/125I ratio, and the correlation coefficient between 125I-cG250 and 131I-cG250 uptake

 
Chimeric mAb cG250.
The generation, characteristics, and reactivity of chimeric mAb cG250 and its murine progenitor have already been described elsewhere (9 , 11) . Chimeric mAb cG250 has been produced by DNA recombinant technology, as described by Velders et al. (12) . Briefly, the constant regions of heavy and light chains of murine mAb G250 were substituted by their human analogues. mAb cG250 is reactive with the antigen G250, which is expressed in all clear cell RCC and in the majority of non-clear cell RCC. Expression in normal organs is restricted to the gastric mucosal cells and the larger bile ducts. Recently, the G250 antigen has been cloned and was found to be homologous to the MN antigen, which is expressed in cervical carcinomas (13) .

Radiolabeling and Quality Control.
Sterile vials with purified and pyrogen-free clinical-grade mAb cG250 were generously provided by Centocor Europe (Leiden, The Netherlands). mAb cG250 was radiolabeled according to the iodogen method (14) . Briefly, 1.0 ml of cG250 (5 mg/ml) and 100 µl 0.5 M sodium phosphate (pH 7.2) were added to a iodogen-coated tube (50 µg). Subsequently, 200 µCi of Na125I (Amersham-Cygne, 's-Hertogenbosch, The Netherlands; first mAb cG250 administration) or 8 mCi of Na131I (Nordion, Fleurus, Belgium; second mAb cG250 administration) were added. After 15 min of incubation at room temperature, the reaction mixture was applied on a PD-10 column (Pharmacia, Woerden, The Netherlands) and eluted with a phosphate buffered NaCl solution (pH 7.4; 8.2 g/liter NaCl, 1.9 g/liter Na2HPO4·2H2O, and 0.3 g/liter NaH2PO4·2H2O). The first activity peak eluted from the PD-10 column was collected, and cold cG250 was added to obtain a mAb cG250 solution with a specific activity of 10 µCi 125I/mg mAb cG250 or a specific activity of 0.7 mCi 131I/mg mAb cG250.

ITLC was used to determine the presence of free radioiodine using Gelman ITLC-SG strips (Gelman Sciences, Inc., Ann Arbor, MI) and 0.15 M sodium citrate (pH 5.5) as the mobile phase (release criterion: <5% free radioiodine).

Prior to each antibody administration, the immunoreactivity of each preparation was determined on freshly trypsinized SK-RC-52 (15) cells, as described previously (16) .

Study Design.
On day 0, patients received a first i.v. infusion of 5 mg of mAb cG250 tracer labeled with 50 µCi of 125I. Four days later, a second i.v. infusion of 5 mg of mAb cG250 tracer labeled with 3.5 mCi of 131I was administered (day 4). Whole-body images were recorded 1 h (day 4), 2 days (day 6), and 4 days (day 8) after the second infusion, using a dual-headed gamma camera equipped with a high-energy collimator (Multispect 2; Siemens Inc., Hoffman Estates, IL). A tumor nephrectomy was performed on day 9. An interval of 4 days between both administrations (days 0 and 4) followed by surgery on day 9 allowed adequate tumor targeting of both injections. There were no deviations from the study protocol in any patient.

Tumor Analysis.
Immediately after surgery (day 9), the tumor specimens were cut into slices of 1-cm thickness. Slices were imaged on a single-head gamma camera (Orbiter; Siemens) equipped with a high-energy collimator. Using the images, the slice displaying the most pronounced heterogeneity was selected, mapped, and cut into 1-cm3 cubes. Each 1-cm3 tumor sample was then weighed and the uptake of both 125I-cG250 and 131I-cG250 was determined in a gamma counter (1480 Wizard 3''; Wallac Oy, Turku, Finland) using the different energy peaks of 125I and 131I. Samples were counted at two time points, directly after surgery and seven half-lives of 131I (8 weeks) later, to check for proper correction of 131I-scatter in the 125I channel of the gamma counter. After seven half-lives, the faster decay of 131I had resulted in well-balanced amounts of radioactivity from both isotopes in the tumor samples. Uptake in tumor samples was expressed as % ID/g. For each 1-cm3 tumor sample, the 131I/125I ratio was calculated. Differences in the distribution pattern of 125I-cG250 and 131I-cG250 over the tumor would reflect a change in factors governing tumor uptake dynamics within the four day time interval between the two administrations.

Three-Dimensional Display of Tumor Uptake.
A computerized reconstruction of the distribution pattern of both injections over the tumor slice was generated from the uptake of 125I-cG250 and 131I-cG250, as measured in the 1-cm3 tumor samples. To allow visual comparison of both distribution patterns, the data were rendered as a three-dimensional display. Cubic spline interpolation was used to create a smooth surface. Standard perspective projection, hidden surface removal, and the simulation of a light source completed the final image and gave a proper sense for the distribution of the uptake. Data on the grid outside the kidney were rendered in a dark gray color.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Radiolabeling and Quality Control.
The labeling efficiency of the radioiodination ranged between 65 and 85%. After PD-10 elution, >98% of the pooled radioactivity was protein bound (release criterion: >=95%), as measured by ITLC. The immunoreactivity of the 125I-cG250 and 131I-cG250 preparations was always >95%.

Tumor Analysis.
Counting of radioactivity in the tumor samples after seven half-lives of 131I revealed results that were identical to those obtained by counting of the samples directly after surgery, indicating that cross-over correction was carried out correctly.

A total of 692 tumor samples (1-cm3) from 10 tumors were investigated for the uptake of 125I-cG250 and 131I-cG250. All tumors analyzed showed a heterogeneous distribution of both isotopes throughout the tumor slice. An example of such heterogeneous distribution is shown in Fig. 1ACitation (tumor patient 8). The corresponding tumor slice is shown in Fig. 1BCitation . Focal uptake in some areas of this tumor reached very high levels (e.g., Fig. 1Citation , block 1, 131I-cG250 uptake, 0.19% ID/g; block 21, 131I-cG250 uptake, 0.18% ID/g), whereas other areas showed much lower uptake (e.g., Fig. 1Citation , block 18, 131I-cG250 uptake, 0.0047% ID/g). In all slices analyzed, the uptake of either 131I-cG250 or 125I-cG250 in the remaining normal kidney tissue did not exceed 0.0019% ID/g.



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  		Fig. 1. A, uptake of 125I-cG250 and 131I-cG250 in the 1-cm3 samples of a tumor slice (patient 8). Indicated within the blocks are: the sample number (top), 125I-cG250 uptake (middle), and 131I-cG250 uptake (bottom). Uptake is expressed as % ID/g tissue. B, corresponding tumor slice of A. Indicated is the grid pattern according to which the tumor slice was cut and the contour of the tumorous kidney (- - - - -). Note the sharply delineated tumor in the upper pole of the kidney.

 
Table 1Citation summarizes the results of the tumor analyses. The intratumoral uptake of the same mAb G250 injection varied dramatically, in some cases exceeding a factor of 50. However, the behavior of both consecutive mAb G250 injections was identical; the 131I/125I ratios, calculated for all samples (n = 692), ranged from 0.94 to 3.16. In Table 1Citation , the 95% confidence interval of the mean 131I/125I ratio for the individual tumors is shown, ranging between 0.69 and 3.20. This identical behavior is further emphasized by the correlation coefficient (r) between the 125I-cG250 uptake and the 131I-cG250 uptake in the samples of a tumor slice (Table 1)Citation : correlation coefficients ranged between 0.968 (tumor 5) and 0.998 (tumor 1).

Overall, the 131I-cG250 uptake (5 days p.i.) in the tumor samples (n = 692) was 1.64 ± 0.31 (mean ± SD) higher than the 125I-cG250 uptake (9 days p.i.; overall mean 131I/125I ratio).

131I-cG250 Immunoscintigraphy.
Excellent visualization of the primary tumors was obtained in all 10 patients. The tumors were first visualized on the second scan (48 h p.i.). As a result of background clearance, image quality improved with time. In Fig. 2Citation , an example of the immunoscintigrams is shown (patient 8, 4 days p.i.). Both the anterior and the posterior scan show a clear visualization of the tumor in the right kidney. In the lateral part of the tumor, an area with high 131I-cG250 uptake can be delineated from the medial part of the tumor, which shows lower 131I-cG250 uptake.



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  		Fig. 2. Immunoscintigrams of a 56-year-old male patient (patient 8), recorded 4 days after the 131I-cG250 injection. In the right kidney, a sharply delineated tumor is visualized. The lateral zone of the tumor shows higher uptake than the medial part.

 
Three-Dimensional Display of Tumor Uptake.
The identical behavior of both injections was best illustrated by the three-dimensional reconstruction of the uptake of 125I-cG250 and 131I-cG250 throughout a tumor slice.

Two typical examples of these reconstructions are shown in Fig. 3Citation (A and B, patient 7; C and D, patient 8). The intratumoral distribution of 125I-cG250 is virtually identical to the 131I-cG250 distribution.



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  		Fig. 3. Three-dimensionally displayed reconstructions of the distribution of 125I-cG250 (9 days p.i.; A and C) and 131I-cG250 (5 days p.i.; B and D) throughout the tumors slices of two patients. Uptake of radiolabeled mAb cG250 is displayed vertically. A and B, patient 7, tumor in the lower pole of the right kidney; C and D, patient 8, tumor in the upper pole of the right kidney.

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although radioimmunotherapy with monoclonal antibodies has been successful in several malignancies, a number of limitations have been encountered that hamper the efficacy of this therapeutic approach. One major obstacle appears to be the heterogeneity of the antibody uptake in a tumor. In general, the mechanisms governing and factors influencing antibody uptake in solid tumors are largely unknown. Insight in these factors is important because it may lead to approaches resulting in more homogeneous tumor uptake of antibodies.

In a previous study, we investigated whether tumor uptake of mAb cG250 correlated with antigen expression, (neo)vascularization, reactive stromal tissue, or necrosis (10) . This study showed that high antigen expression is a prerequisite for high antibody uptake. However, regional differences in antibody uptake within a tumor could not be explained by antigen expression alone. Similar results in different tumor types were obtained by several other investigators (17 , 18) ; antigen expression is an important factor, but the mechanism governing tumor uptake cannot be explained by antigen expression alone.

The observed heterogeneity in mAb cG250 uptake by the RCC tumors might be reduced by using tumor-saturating protein doses (9) . However, at tumor-saturating protein doses, the uptake of mAb cG250 in terms of % ID/g is highly reduced, which will hamper effective radioimmunotherapy (9) .

Over the last decade, Jain and coworkers (5, 6, 7, 8) investigated the tumor physiological factors that may hamper the delivery of macromolecules to tumors. This group of investigators especially focused on factors influencing the (micro)circulation, such as the nature of tumor vasculature, IFP, and (trans)vascular transport mechanisms. From this extensive work, several main conclusions were drawn: (a) the elevated IFP in tumors has been identified as a significant cause of the poor delivery of macromolecules (19) ; (b) microvascular pressure is the principle driving force for elevated IFP (20) ; (c) elevated IFP is associated with the development of the neovasculature (21) ; (d) elevated IFP coupled with high vascular permeability may contribute to blood flow reduction and alteration of the blood flow pattern (7 , 8) ; and (e) transient collapse of tumor vessels may occur as a result from locally higher mean IFP compared to the microvascular pressure (7) . From these conclusions, the authors postulated that the (micro)circulation in a tumor has an unstable character with possible reversal of blood flow directions. Most likely, this contributes significantly to the reported temporal and spatial heterogeneities in blood flow (22, 23, 24) .

Here, we investigated in patients with primary RCC whether mAb cG250 uptake is influenced by dynamic processes, as mentioned above. If, indeed, mAb cG250 uptake is dependent on these dynamic processes, differences in the distribution of two consecutive injections would be expected. In other words, repetitive injections would target different areas within a tumor. The former might implicate that fractionated radioimmunotherapy may be more effective than single high-dose radioimmunotherapy. However, the results of several studies are conflicting. Buchegger et al. (25) investigated the antitumor effects of radioimmunotherapy in nude mice with a s.c. human colon carcinoma xenograft and obtained higher and longer lasting response rates with single-dose radioimmunotherapy compared to dose fractionation. Similarly, Ullen et al. (26) reported higher tumor uptake as well as a higher tumor dose for a single bolus injection compared to the equivalent of multiple injections. In contrast, several other investigators have reported that fractionated dose radioimmunotherapy might be preferential to single high-dose radioimmunotherapy. It has been shown in both preclinical as well as in clinical studies that dose fractionation may allow the administration of a higher total dose of radioactivity compared to single-dose radioimmunotherapy and may lead to higher response rates (27, 28, 29, 30, 31, 32) . In addition, Blumenthal et al. showed in various tumor models that a first gift radioimmunotherapy (high-dose radioactivity) may significantly alter the vascular permeability of the tumor and, thus, the uptake of a second gift of radiolabeled antibody in the tumor (33) . On the basis of a mathematical model, O’Donoghue et al. (34) designed a rapid fractionation protocol for radioimmunotherapy using data from a clinical Phase I/II trial with murine mAb G250 in RCC patients. Simulated treatment consisted of a series of administrations separated by gaps of 3 days. For a heterogeneous absorbed dose distribution, rapid fractionation was predicted to be better than a single high-dose administration. The model showed that the efficacy of repeated administrations improved with increasing heterogeneity and number of administered fractions.

The results of our study, however, clearly demonstrate the identical behavior of the two consecutive mAb cG250 injections, given 4 days apart. This is best shown by the observation that, in the investigated tumor samples (n = 692), the differences between 125I-cG250 and 131I-cG250 uptake never exceeded a factor 3, whereas regional differences (i.e., different samples) in uptake of the same antibody injection sometimes exceeded a factor 40 or more. The strikingly similar three-dimensionally displayed distribution patterns of both injections over a tumor nicely illustrate this identical behavior. This is an unexpected finding in view of the temporal and spatial blood flow heterogeneity, as demonstrated in previous studies. Differences in uptake between 125I-cG250 and 131I-cG250 might still be present on a millimeter scale or even at a cellular level. However, the observed heterogeneous distribution of each separate injection on a centimeter scale will limit effective radioimmunotherapy and, apparently, cannot be overcome by multiple injections.

In conclusion, the identical distribution of the two mAb injections spaced 4 days apart indicates that the tumor parameters governing mAb cG250 uptake do not significantly alter within the time frame studied. The results of this study suggest that multiple injections of radiolabeled antibodies (dose-fractionated radioimmunotherapy), administered within short periods of time, will target the same areas within a tumor and, thus, will not solve the problem of heterogeneity of antibody uptake by the tumor.


   ACKNOWLEDGMENTS
 
We thank W. Guijt (Department of Radiology, University Hospital Nijmegen) for generously providing materials and technical assistance with the production of the figures and P. Laverman (Department of Nuclear Medicine, University Hospital Nijmegen) for carefully proofreading the manuscript.


   FOOTNOTES
 
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 This study was supported by the Dutch Cancer Society/Koningin Wilhelmina Fonds Grant 94-738. Back

2 To whom requests for reprints should be addressed, at Department of Urology, University Hospital Nijmegen, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. Phone: 31-24-3613813; Fax: 31-24-3618942; Back

3 The abbreviations used are: IFP, interstitial fluid pressure; mAb, monoclonal antibody; cG250, chimeric G250; RCC, renal cell carcinoma; ID, injected dose; p.i., postinjection; ITLC, instant TLC. Back

Received 7/22/98. Accepted 2/ 3/99.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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