Application of monoclonal antibody G250 recognizing carbonic anhydrase IX in renal cell carcinoma

Abstract

Monoclonal antibody G250 (mAbG250) recognizes a determinant on carbonic anhydrase IX (CAIX). CAIX is expressed by virtually all renal cell carcinomas of the clear cell type (ccRCC), but expression in normal tissues is restricted. The homogeneous CAIX expression in ccRCC and excellent targeting capability of mAbG250 in animal models led to the initiation of the clinical evaluation of mAbG250 in (metastatic) RCC (mRCC) patients. Clinical studies confirmed the outstanding targeting ability of mAbG250 and cG250 PET imaging, as diagnostic modality holds great promise for the future, both in detecting localized and advanced disease. Confirmation of the results obtained in the non-randomized clinical trials with unmodified cG250 is needed to substantiate the value of cG250 treatment in mRCC. cG250-Based radio immuno-therapy (RIT) holds promise for treatment of patients with small-volume disease, and adjuvant treatment with unmodified cG250 may be of value in selected cases. In the upcoming years, ongoing clinical trials should provide evidence for these assumptions. Lastly, whether cG250-based RIT can be combined with tyrosine kinase inhibitors, which constitutes the current standard treatment for mRCC, needs to be established.

Figure 1

Schematic representation of regulation of carbonic anhydrase IX expression (CAIX) in kidney. In normal kidney tissue, hypoxia inducible factor-1α (HIF-1α) is hydroxylated by prolyl hydroxylase domain proteins (PHD) and bound by Von Hippel-Lindau protein (pVHL). Subsequently, the complex is ubiquitinated, which causes degradation of HIF-1α. In clear cell renal cell carcinoma (ccRCC), pVHL is mutated and binding with HIF-1α is prohibited. Subsequently HIF-1α forms a heterodimeric complex with HIF-1β, translocates to the nucleus, where it activates hypoxia inducible genes, such as vascular endothelial growth factor and CAIX, which is expressed on the tumor cell membrane. Reproduced with permission from Stillebroer et al., European Urology, published by Elsevier, July, 2010; 58(1): 75–83 [20].

Figure 2

Whole body scan of a patient with multiple RCC metastases two weeks after infusion of 4144 MBq ¹³¹I-cG250. Ant.: Anterior view; Post.: Posterior view. Note: thyroid uptake is due to non-specific accumulation, despite attempts to block thyroid uptake with intake of saturated potassium iodine.

Figure 3

Images of a patient with metastatic RCC. Conventional CT (A) and ¹¹¹In-girentuximab immunoSPECT (B) images of a patient with metastatic ccRCC. Clear and preferential uptake of the radiolabeled antibody was observed in mediastinal and pleural lesions (arrows). The patient was enrolled in the phase II ¹⁷⁷Lu-girentuximab RIT trial.