Radiolabeled monoclonal antibody G250 in renal-cell carcinoma

Summary

The current status of iodine 131-radiolabeled monoclonal antibody G250 (mAb G250) in renal-cell carcinoma (RCC) is described. This mAb recognizes a tumor-associated antigen that is expressed on the cell surface of almost all RCC but is not expressed on normal tissues, with the exception of gastric mucosa and larger bile ducts. On the basis of these favorable characteristics, this mAb seemed a prime candidate for clinical investigations. Preclinical animal studies and ex vivo perfusion experiments in tumor-bearing kidneys showed excellent targeting of mAb G250 to RCC tumors. Supported by these investigations, a phase I study was initiated to define the imaging and biodistribution characteristics of ¹³¹I-labeled mAb G250 in RCC patients. Specific localized of [¹³¹I]-mAb G250 to G250-antigen-positive primary and metastatic RCC was observed. In several patients, [¹³¹I]-mAb G250 imaging revealed thus far unrecognized, i.e., occult, disease. Values obtained for [¹³¹I]-mAb G250 uptake, relative as well as absolute, were among the highest reported for tumor biopsies obtained 8 days after intravenous mAb administration. The specific localization and high accumulation encouraged us to begin a phase I/II radiotherapy trial with [¹³¹I]-mAb G250. The maximal tolerable dose was reached at 90 mCi/m² [¹³¹I]-mAb G250. In the subsequent phase I/II radiotherapy study, we observed stable disease in a great number of patients as well as minor responses in a small number of patients. Multiple treatments seemed necessary to achieve better response rates. However, anti-mouse responses prevented multiple dosing with the murine mAb G250. Therefore, we developed a chimeric version of mAb G250 (cG250), in which constant regions of the mouse immunoglobulin have been exchanged for human immunoglobulin regions. A phase I clinical trial with cG250 is ongoing and very encouraging. The general imaging and targeting characteristics of cG250 seem comparable with those of murine mAb G250. In the near future the (radio)therapeutic possibilities of this promising mAb will be investigated.