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Carbonic Anhydrase IX Expression in Clear Cell Renal Cell Carcinoma and Normal Tissues: Experiences From (Radio) Immunotherapy

Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, the Netherlands

Peter F.A. Mulders

Department of Urology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

Wim J.G. Oyen

Department of Nuclear Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

To the Editor:

Recently, Leibovich et al¹ published the results of a large cohort of patients (n = 730) with sporadic clear cell renal cell carcinoma (ccRCC) that was analyzed for the possible relationship between expression of carbonic anhydrase IX (CAIX) and outcome. Although they used the cut point criteria for CAIX tumor expression identified previously by Bui et al,^2,3 they could not confirm the results of the University of California, Los Angeles group, who reported that in metastatic RCC low ( 85%) CAIX staining is an independent poor prognostic factor for survival.² Although low CAIX expression was associated with increased risk of death as a result of RCC in an univariate analysis, after adjusting for nuclear grade or coagulative tumor necrosis, this was no longer the case.¹

Also in their study, Leibovich et al¹ determined CAIX expression in a wide variety of normal tissues and a few other tissues. They report, "CAIX expression was present in gastric mucosa, pancreatobiliary epithelium, and small intestine crypt base. Also, CAIX was seen in two specimens containing mesothelial cells, ovarian surface epithelium, and fetal rete testis." According to the authors, the CAIX expression levels in various normal tissues are high. Therefore, they raised the question of whether CAIX-directed therapeutic strategies will have a safe enough toxicity profile, while pointing also to the literature of anti-CAIX monoclonal antibody–based therapy that have not caused significant toxicities thus far.¹

We would like to comment on these two matters specifically. Regarding CAIX expression in normal tissues, it has been reported previously by other groups, in addition to the article by Leibovich et al¹ and the studies they refer to by Ivanov et al.^4-6 Furthermore, from the article, it does not become clear how the high expression in the various normal tissues is related to the high CAIX expression for which most ccRCC tumors are known. In our opinion, this is relevant information in light of a discussion on the toxicity profile. Several studies have shown, in direct comparison among numerous normal tissues, malignant cell lines, and ccRCCs, that in non-ccRCC malignant cells, the antigen expression is not as homogenous, nor is the antigen density per cell as high, and cytoplasmatic CAIX expression seems to be present more often than of membranous CAIX expression as compared with ccRCCs.^5-7 Furthermore, because CAIX expression is regulated by the transcription factor HIF-1 that in turn is regulated (among others) by the protein Von Hippel-Lindau (VHL), and because ccRCC is molecularly characterized by (functional) loss of the VHL gene, this explains the ubiquitous CAIX expression in ccRCC.^7,8 In contrast, the CAIX expression in non-RCC tumors is the result of locoregional hypoxia, leading to locoregional CAIX expression.⁸

Regarding the toxicity profile of anti-CAIX–directed therapy with monoclonal antibodies, we point out that we have ample experience with both unlabeled and radiolabeled versions of monoclonal antibody cG250, directed against the CAIX antigen. In the studies with unlabeled cG250, protein doses up to 50 mg per injection were administered to patients.^9,10 None of the serious (grade 3 or 4) adverse effects were attributed to cG250. However, grade 1 or 2 GI complaints were frequently noticed, but these were not attributed to the cG250 drug. In the radioimmunotherapy studies, where only protein doses of 5 mg per injection were given, the severe adverse effects were of hematologic origin, due to the high amounts of radioactivity attached to the antibody.^11,12 Therefore, we do not share the opinion of Leibovich et al¹ that exploitation of CAIX as a prognostic or therapeutic target will result in unacceptable toxicity.

Lastly, we regret that the authors state that CAIX-based imaging has yielded minimal sensitivity for detection of metastatic ccRCC, thereby referring to only one of our numerous studies.¹³ In this study, for unexplained reasons, indeed the diagnostic value of radioimmunoscintigraphy with ¹³¹I-cG250 was low. However, our experience in other studies with radiolabeled cG250 showed mostly excellent visualization of known metastatic lesions and frequently, new lesions were detected in patients.^11,12,14

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Leibovich BC, Sheinin Y, Lohse CM, et al: Carbonic anhydrase IX is not an independent predictor of outcome for patients with clear cell renal cell carcinoma. J Clin Oncol 25:4757-4664, 2007[Abstract/Free Full Text]

2. Bui MH, Seligson D, Han KR, et al: Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: Implications for prognosis and therapy. Clin Cancer Res 9:802-811, 2003[Abstract/Free Full Text]

3. Bui MH, Visapaa H, Seligson D, et al: Prognostic value of carbonic anhydrase IX and KI67 as predictors of survival for renal clear cell carcinoma. J Urol 171:2461-2466, 2004[CrossRef][Medline]

4. Ivanov S, Liao SY, Ivanova A, et al: Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 158:905-919, 2001[Abstract/Free Full Text]

5. Oosterwijk E, Ruiter DJ, Hoedemaeker PJ, et al: Monoclonal antibody G 250 recognizes a determinant present in renal-cell carcinoma and absent from normal kidney. Int J Cancer 38:489-494, 1986[Medline]

6. Li G, Passebosc-Faure K, Lambert C, et al: The expression of G250/mn/CA9 antigen by flow cytometry: Its possible implication for detection of micrometastatic renal cancer cells. Clin Cancer Res 7:89-92, 2001[Abstract/Free Full Text]

7. Wykoff CC, Beasley NJ, Watson PH, et al: Hypoxia-inducible expression of tumor-associated carbonic anhydrases. Cancer Res 60:7075-7083, 2000[Abstract/Free Full Text]

8. Maxwell PH, Wiesener MS, Chang GW, et al: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271-275, 1999[CrossRef][Medline]

9. Bleumer I, Knuth A, Oosterwijk E, et al: A phase II trial of chimeric monoclonal antibody G250 for advanced renal cell carcinoma patients. Br J Cancer 90:985-990, 2004[CrossRef][Medline]

10. Bleumer I, Oosterwijk E, Oosterwijk-Wakka JC, et al: A clinical trial with chimeric monoclonal antibody WX-G250 and low dose interleukin-2 pulsing scheme for advanced renal cell carcinoma. J Urol 175:57-62, 2006[CrossRef][Medline]

11. Steffens MG, Boerman OC, de Mulder PH, et al: Phase I radioimmunotherapy of metastatic renal cell carcinoma with ¹³¹I-labeled chimeric monoclonal antibody G250. Clin Cancer Res 5:3268s-3274s, 1999 (suppl)[Abstract/Free Full Text]

12. Brouwers AH, Mulders PF, de Mulder PH, et al: Lack of efficacy of two consecutive treatments of radioimmunotherapy with ¹³¹I-cG250 in patients with metastasized clear cell renal cell carcinoma. J Clin Oncol 23:6540-6548, 2005[Abstract/Free Full Text]

13. Brouwers AH, Dorr U, Lang O, et al: ¹³¹I-cG250 monoclonal antibody immunoscintigraphy versus [¹⁸F]FDG-PET imaging in patients with metastatic renal cell carcinoma: A comparative study. Nucl Med Commun 23:229-236, 2002[CrossRef][Medline]

14. Brouwers AH, Buijs WCAM, Oosterwijk E, et al: Targeting of metastatic renal cell carcinoma with the chimeric monoclonal antibody G250 labeled with ¹³¹I or ¹¹¹In: An intrapatient comparison. Clin Cancer Res 9:3953s-3960s, 2003 (suppl)[Medline]

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