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Clinical Cancer Research Vol. 9, 3827S-3830S, September 1, 2003
© 2003 American Association for Cancer Research

Session I: ANTIBODIES AND NON-ISOTOPIC IMMUNOCONJUGATES

The New Tie-1 Monoclonal Antibodies Detect Angiogenesis in Metastatic Malignancies1

Päivi Karnani and Kalevi Kairemo2

Department of Pharmacology, Institute of Biomedicine [P. K.] and Department of Clinical Chemistry, Institute of Clinical Medicine [K. K.], University of Helsinki, FIN-00014 Helsinki, Finland


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Tie-1 is a transmembrane receptor expressed in vascular endothelium during angiogenic events and during embryonal growth in most mammalian species. The monoclonal antibodies (mAbs) used here are generated against the extracellular part of the Tie-1 receptor protein. We analyzed the specific binding of 125I-labeled Tie-1 mAbs in the metastatic tumor model in mouse and in human serum samples to determine the possible use of the Tie-1 mAbs in detecting malignant growth. The in vivo biodistribution of 125I-Tie-1 mAbs (IgG1) was evaluated in the mouse model. The same Tie-1 mAbs were used to analyze Tie-1 in patient serum samples. A high accumulation of two 125I-Tie-1 mAbs, clones 10f11g6 and 3c4c7, was detected in the lung metastases of mouse tumor model. The uptake in the metastases is 12% injected dose/gram (ID/g; 10f11g6) and 7.8% ID/g (3c4c7) at 96 h after the injections of 125I-Tie-1 mAbs, and the accumulation to the blood is 7% and 5% ID/g with the two mAbs, respectively. The finding directed us to analyze serum samples from lung, ovarian, and breast cancer patients. High levels of Tie-1 were detected in samples related to new pelvic or thoracic metastases in patients. Here we connect the Tie-1 levels in serum to tumor progression. The results suggest that Tie-1 mAbs can be used as a surrogate marker of progressive disease.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
The importance of angiogenesis for tumor growth and progression is emphasized in many studies (1 , 2) . Tie-1, tyrosine kinase with immunoglobulin and epidermal growth factor homology domains (3) , and Tie-2/Tek, tunica interna endothelial cell kinase (4 , 5) , are receptor tyrosine kinases with key roles in signal transduction of epithelial cells (6) . Studies with transgenic mice demonstrate the importance of Tie-1 in the maturation of vasculature during the growth period. The gene deletion of Tie-1(-/-) in mice leads to extensive edemas and disruption of vascular integrity in mid-gestation. These effects finally end in embryonic lethality by day 13.5 of the embryonic growth period (7) .

Tie-1mRNA distribution is detected overall embryonic endothelium reflecting the important role of Tie-1 in the development of vasculature (8) . Strong signals of Tie-1mRNA persist in the lung capillaries in the perialveolar septa. In adult tissues, the Tie-1mRNA signal is found in lung, heart capillaries, and placenta (9 , 10) . In adults, the endothelial cell turnover is slow, except during neovascularization, and enhanced expression is detected only during neovascularization-associated processes. Up-regulation of Tie-1is detected by Tie-1mRNA analyses in the neovascularization accompanying wound healing and ovulation (9) . The Tie-1mRNA signal is strongest at the seventh day after the injuries, indicating prominent angiogenesis in the rebuilding endothelium. The mRNA signal from the normal skin near the wound is less intense or undetectable. The in vivo usability of the Tie-1mAbs3 to detect enhanced endothelial growth was evaluated previously by detecting tissue growth in a healing wound of mouse skin (11) , and the Tie-1 mAbs were found to target the rebuilding endothelium in vivo.

The Tie-1 mAbs are used to detect Tie-1 protein in human samples by immunohistochemical methods. The binding to Tie-1 in vascular endothelial cells is used to determine the microvessel density of human breast cancer samples (12) and to detect angiogenesis in arteriovenous malformations and in the surrounding brain tissue (13) .

In the present study, we investigated the biodistribution of Tie-1 antibodies in a mouse xenograft model to determine the possible use of the Tie-1 mAbs in detecting malignant growth in vivo. Additionally, we measured Tie-1 levels in serum samples of cancer patients to clarify the possible use of Tie-1 as a marker of disease progression. The aim of the study was to define the role of Tie-1in vascular angiogenesis related to tumor progression.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Antigen and mAbs.
Tie-1 is a transmembrane tyrosine kinase receptor with two extracellular immunoglobulin homology domains separated by three tandem epidermal growth factor homologies on the outer cell membrane (3) . Tie-1is abundantly expressed in vascular endothelia during embryonal vasculogenesis and in some leukemia and hematopoietic cells, including human erythroleukemia (HEL) and human megakaryoblastic leukemia (DAMI) cell lines (14) . The Tie-1 mAbs used here were generated against the recombinant tie protein (3) with traditional methods at the Biotechnology Institute at Turku University (11) . The mAbs are IgG1 subtype, and their binding/dissociation constants were defined with Biacor method before these experiments. The affinities are as follows: Tie-1 mAb clone 10f11g6, Kd = 3.8 x 107 M-1 and kdiss = 4.6 x 10-4s-1; and Tie-1 mAb clone 3c4c7, Kd = 6.6 x 107 M-1 and kdiss = 8.1 x 10-4s-1. The binding properties of the Tie-1 mAbs were characterized previously in time-resolved immunofluorometric assay (15) . The two clones 10f11g6 and 3c4c7 presented optimal binding in the sandwich-type assay. The Tie-1 mAbs did not inhibit binding of each other to the recombinant tie protein in a combination assay of two Tie-1 mAbs.

Radiolabeling.
Forty µg of Tie-1 mAbs were labeled with 37 MBq of Na125I (Amersham Plc, Little Chalfont, United Kingdom) using the chloramine-T method (16) . The radiolabeled antibodies were purified with Sephadex-G25 (Pharmacia AB, Uppsala, Sweden), resulting in a main fraction of 1.8 ml. The specific activity was 20 µCi/µg. Before the biodistribution experiments with the labeled antibodies, specific binding was confirmed in the cell assay (17) . The transfected mouse endothelial LE GD 14-2 cells expressing the Tie-1 receptor (18) were used. The cells were grown in DMEM with 10% FCS and harvested with 10 mM PBS. The cell assay was performed in duplicate with more than 1 million cells suspended in each assay vial. The competitive binding method with serial dilutions (from 20 to 2000 ng) of the corresponding unlabeled Tie-1 mAbs was applied, and the assays were performed at room temperature (20°C).

Animal Model and Biodistribution.
Female 6–8-week-old mice (C57Bl/6; Bomholtgaard) bearing LLC xenografts were used in the study. The xenografts were initiated by injecting 1 M cells (LLC1/2 from American Type Culture Collection, Manassas, VA) in 0.25 ml/animal to right limb i.m. The study was approved by the local ethical committees for animal research and by the County Administration Board of Western Finland.

Thyroid blockade of the mice was started 1 day before injections of labeled antibodies and continued throughout the experiment with potassium iodide solution (400 mg/100 ml) ad libitum. The radioactivities in main organs were measured in a gamma counter (gamma master 1277; Wallac). The biodistribution of 125I-Tie-1 mAbs was evaluated at 24, 48, 72, 96, and 120 h after the i.v. injections of 30 ng of mAbs in 20 mM PBS. For the control, we used a nonrelevant mAbs/Fc3001 against prostatic acid phosphatase (Orion Diagnostica, Oulunsalo, Finland). The same method was used to label the control antibodies of IgG1 subtype with 125I.

IRMA.
The IRMA is a sandwich-type of assay (19) to analyze soluble proteins with two mAbs. The assay presents a good linearity with the selected Tie-1 mAbs. The analyses were done in Orion Diagnostica, according to the Spectria instructions. Heparinized vials were used to collect the blood, and the samples were centrifuged without delay and stored at -20°C until analysis. The catching Tie-1 mAbs were immobilized on the inner surface of the polystyrene assay tubes, and the detecting Tie-1 mAbs were radiolabeled with 125I. Recombinant tie protein is used as a standard in the assay (19) , and the sensitivity of the assay was 5 µg/liter. The catching and labeled Tie-1 clones are 3c4c7 and 10f11g6, respectively. The same recombinant tie protein was used as a standard in the immunofluorometric assay to analyze Tie-1 in human blood samples (15) .

Patient Samples.
Human serum samples from breast, ovarian, and lung cancer patients were analyzed, and the Tie-1 level was compared with that of the normal samples. A total of 65 samples were analyzed, the normal biodistribution of the values was counted, and the means with SDs were compared with 20 control samples. The control samples were from 20 healthy individuals. The patients had histologically verified diseases, were treated for their disease and cured, and are outpatients visiting for regular controls. The samples were collected at 2–6-month intervals, and the possible progression was verified clinically. The study was approved by the local ethical committees and by the institutional review boards of the local hospitals.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Before the in vivo biodistribution experiments, we determined the affinities of the labeled antibodies. The maximal amount of Tie-1 mAb clone 10f11g6 bound to LE cells is higher than that seen with Tie-1 mAb clone 3c4c7. The competitive binding results are 21 pmol of 10f11g6 to 100,000 LE cells compared with 6–7 pmol of 3c4c7 to 100,000 LE cells (Fig. 1)Citation .



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  		Fig. 1. The specific binding of the two Tie-1 mAbs to LE cells expressing the transfected Tie-1 receptor construct. Specific binding with 3c4c7 (top) and 10f11g6 (bottom). The amount of Tie-1 mAb bound to LE cells is three times greater with Tie-1 mAb clone 10F11 than with clone 3c4c7.

 
Biodistribution of the Tie-1 mAb clones 3c4c7 and 10f11g6 was evaluated in the mouse model (Fig. 2)Citation . The uptake to lung metastases (12% ID/g, 10f11g6) is higher than that to the blood (7% ID/g, 10f11g6) at 96 h after injection of radiolabeled mAbs. Lung metastases were detected in 14 animals; 3 received injection with Tie-1 mAb clone 3c4c7, and 11 received injection with clone 10f11g6. The metastases were found at 48, 72, and 96 h after the injections (in three mice in each point) and in four mice at the later time point.



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  		Fig. 2. The biokinetics of Tie-1 mAbs in the LLC model. The blood clearance of Tie-1 mAbs is slow, and the uptake of Tie-1 mAbs to the metastases is higher than that to the tumor xenografts.

 
The accumulation of activity in the lung metastases is 12% ID/g with the clone 10f11g6 and 7.8% ID/g with 3c4c7 at 96 h. The high blood accumulation limits the usability of the Tie-1 mAbs in the biodistribution studies. The target:liver ratios are used to compare organ activities between the Tie-1 mAbs (Fig. 3Citation ; Table 1Citation ). Tie-1 is not markedly expressed in the vascular endothelium of liver, and the accumulation of 125I-Tie-1 mAbs represents mostly the activity in the blood flow.



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  		Fig. 3. Target:liver ratios of the Tie-1 mAbs in LLC model. The metastases:liver ratios of Tie-1 mAbs are best with clone 3c4c7 at 4 days, but the tumor:liver ratio is higher with the Tie-1 mAb 10f11g6 at 4 days.

 

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  		Table 1 Target: liver ratios in the main organs at 96 h after injection of 125I-Tie-1 mAbs

 
The 65 serum samples of patients do not differ from the control samples when the mean values of Tie-1 in serum are compared. The mean of controls is 150 µg/liter, and the lowest value is 110 µg/liter, and the highest value is 220 µg/liter. There were, however, samples with elevated values in the assay, and they were connected to new metastatic formation. Altogether, 13 serum samples had values above the highest value of the control samples. The levels of Tie-1 in these serum samples of lung, ovarian, and breast cancer patients are presented in Table 2Citation . The ranges of the elevated values measured in the various cancer types do not overlap. The highest values of Tie-1 are found in small cell lung carcinomas (293 µg/liter) and in breast carcinomas with lung metastases (372 µg/liter).


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  		Table 2 Tie-1 protein levels in the blood samples of normal controls and cancer patients

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Tie-1 protein expression is a potential marker directly correlated to endothelial cells and to the growth process in neovascularization (20) . The real-time quantitative reverse transcription-PCR analyses of angiogenic markers in various tumor types have raised the capacity of research for specific markers of tumor growth. Tie-1 and Tie-2mRNAs are enhanced in prostate tumor and in angiogenesis models, indicating the active level of gene expressions in the particular tissues (20) .

The biodistribution of Tie-1 mAbs detected here generally follows the pattern that is expected for an endothelial marker. Accordingly, the level of Tie-1 in the blood samples of normal individuals is similar to the levels detected in stabilized disease. In the other study done with the same Tie-1 mAbs (15) , the blood levels of Tie-1 are similar in the normal samples. The detected levels are probably based on the shed Tie-1 fractions in the blood. According to many biodistribution studies, the Tie-1 mAbs also detect high levels of Tie-1 in the blood. The high blood accumulation of Tie-1 mAbs limits the use of these antibodies in in vivo targeting.

In the biodistribution studies, the level of activity is reduced slowly by metabolism in vivo. Targeting to the lung metastases is detected at 96 h after i.v. injections of the 125I-Tie-1 mAbs. In lung metastases, a similar biokinetics is recognized (Fig. 2)Citation . This tumor model does not typically form lung metastases in the mouse. Mostly, we detected uptake of the labeled Tie-1 mAbs to the primary xenografts only.

However, the biodistribution results indicate specific binding to the growing lung metastases with 125I-Tie-1 mAbs in mice in vivo. Tie-1 mRNA in adult mouse lung tissues (8) supports the specificity of the result, and additionally, the high Tie-1 levels in serum samples of progressive disease with lung metastases increase the value of these findings.

The considerably low uptake to the primary tumor in the mouse model is most possibly due to the low microvessel density in the tumor itself. There is no assumable transport barrier other than the low affinity for these antibodies. It is possible that the growth rate of the tumor xenografts is too rapid to allow reasonable targeting to the endothelial receptor Tie-1. The optimal expression of Tie-1 in neovascularization is strictly time-limited, and it is likely that the growth rate of metastases in this tumor model is more near the optimal timing. These differences in targeting between small and large tumors represent the know vascular effects in studying the mAb distribution in tumors of varying sizes (21) . The elevated interstitial pressure, an increase in intercapillary distance, and lower fluid extravasation are all named as possible explanations for low targeting to tumors.

The blood samples with high levels of Tie-1 are more carefully evaluated together with the patient clinical data. A recent progression in the disease was observed before elevation in the serum concentration of Tie-1 levels. The progression site was found either in lungs or in the pelvic soft tissues. The highest levels of Tie-1 are found in small cell lung carcinomas (293 µg/liter) and in breast carcinomas with lung metastases (372 µg/liter).

The Tie-1 level in the control samples is 150 µg/liter. The result of our study is in line with the earlier study (15) , where the control samples collected from 34 nonpregnant women resulted in a level of 173 ng/ml Tie-1 protein in the blood.

Malignant growth is targeted here with the new Tie-1 mAbs in the lung metastases. The biodistribution data in mouse and the data of serum samples, taken together, open a way to use Tie-1 mAbs in detecting malignancies. Tie-1 mAbs detect fractions of Tie-1 shed to the blood, and the progression of disease can be detected in its early state. Additionally, release of Tie-1 fractions from endothelial cells has recently been detected in connection with vascular endothelial growth factor stimulation (22) . The result supports a significant role for Tie-1in the vasculogenesis accompanying tumor progression.

Our results demonstrate that Tie-1 antibodies target metastatic disease in this animal model and may be used as a biomarker for progressive malignant disease, possibly as a surrogate marker for early detection of progression.


   ACKNOWLEDGMENTS
 
We thank Marjo Pihlaja (Orion Diagnostica) for help in preparing the IRMAs and Terhi Sten for guidance with the many radiolabeling processes. The help of Dr. Lasse Hautoniemi in performing the IRMAs is gratefully acknowledged. We highly appreciate the advice and help of Dr. Juha Partanen and Prof. Kari Alitalo, who donated the recombinant tie protein and the transfected LE cell line we used in the study.


   FOOTNOTES
 
1 Presented at the "Ninth Conference on Cancer Therapy with Antibodies and Immunoconjugates," October 24–26, 2002, Princeton, NJ. This work was supported by TEKES (National Technology Agency of Finland) and was a cooperative research project between Helsinki University, Turku Biotechnology Institute, and Orion Corporation in Finland. Back

2 To whom requests for reprints should be addressed. Present address: Department of Nuclear Medicine, Entrance 78, Uppsala University Hospital, S-751 85 Uppsala, Sweden. Phone: 46-18-6111006; Fax: 46-18-6114124. Back

3 The abbreviations used are: mAb, monoclonal antibody; ID/g, injected dose/gram; IRMA, immunoradiometric assay; LLC, Lewis lung carcinoma; LE, lung epithelial. Back


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
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