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Pretargeting with Bispecific Anti-Renal Cell Carcinoma x Anti-DTPA(In) Antibody in 3 RCC Models

¹ Department of Nuclear Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands
² Department of Experimental Urology, University Medical Center Nijmegen, Nijmegen, The Netherlands
³ Immunomedics, Inc., Morris Plains, New Jersey

We have developed an efficient pretargeting strategy for renal cell carcinoma (RCC) based on a biologically produced bispecific monoclonal antibody (bs-mAb). Tumor targeting with this 2-step pretargeting strategy in the NU-12 mouse RCC model was very efficient compared with other pretargeting strategies, possibly due to unique characteristics of the NU-12 tumor used in our studies. Here we describe the bs-mAb G250xDTIn-1 pretargeting strategy in 3 different RCC nude mouse models. Methods: Three different human RCC xenografts in nude mice (NU-12, SK-RC-1, and SK-RC-52 tumors) were pretargeted with 100 pmol bs-mAb G250xDTIn-1. Three days after administration of the bs-mAb, mice were injected intravenously with 4 pmol ¹¹¹In-labeled bivalent peptide, diDTPA-FKYK (DTPA is diethylenetriaminepentaacetic acid). At 1, 4, 24, 48, and 72 h after injection of the radiolabeled peptide, the biodistribution of the radiolabel was determined. The 3 RCC tumors were characterized in vivo and in vitro for G250 antigen expression, vessel density, vascular volume, and vascular permeability and by targeting with ¹¹¹In-/¹²⁵I-labeled cG250 mAb. Results: Using the pretargeting strategy, relatively high uptake of the radiolabel was observed in all 3 tumor models (maximum uptake: SK-RC-1 [278 ± 130 %ID/g (percentage injected dose per gram), 1 h after injection] > NU-12 [93 ± 41 %ID/g, 72 h after injection] > SK-RC-52 [54 ± 9 %ID/g, 4 h after injection]). Remarkably, uptake of the radiolabel in the tumor did not correlate with G250 antigen expression. The kinetics of the radiolabel in the tumor varied largely in the 3 RCC tumors: SK-RC-1 and SK-RC-52 tumors showed a washout of the ¹¹¹In label from the tumor with time: only 30% of the radiolabel was retained in the tumor 3 d after injection, whereas the ¹¹¹In label was fully retained in NU-12 tumors. Physiologic characteristics (vessel density, vascular volume, and vascular permeability) of the tumors may explain these differences. Conclusion: G250 antigen–expressing tumors can be pretargeted very efficiently with the bs-mAb G250xDTIn-1. There was no correlation between G250 antigen expression and uptake of the radiolabel in the tumor using the pretargeting strategy or with directly labeled mAbs. Therefore, these studies show that physiologic characteristics of the tumor, such as vascular permeability, play a significant role in pretargeting.

Key Words: pretargeting strategy • bispecific antibody G250xDTIn-1 • G250 antigen • renal cell carcinoma

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