Targeting of human gamma-glutamyltransferase with mAb 138H11 in a new renal cell carcinoma mouse model

Renal cell carcinoma (RCC) belongs to the 12 most frequent tumors in Germany. Its incidence increases worldwide. 30% to 40% of patients already have metastases when the tumor is diagnosed and further 50% develop metastases after tumor resection. Radiotherapy or chemotherapy have no therapeutic effect against RCC. Systematic therapy of RCC with immunostimulatory cytokines is limited by dose due to serious side effects. A tumor targeting antibody offers the possibility to achieve efficient local doses of cytotoxic or immunostimulating reagents within the tumor without high systemic burden.

Our approach is to treat metastatic RCC with immunoactive agents coupled to our mAb 138H11 specific for human GGT (gamma-glutamyltransferase) which has the ability to target human clear cell and papillary RCC. In extracorporeal transfusion experiments with human RCC-bearing kidney 99m-Tc-labeled 138H11 was enriched up to 20-fold in the tumor. Treatment of nude mice bearing human RCC xenografts with a highly cytotoxic drug (Calicheamicin theta) conjugated to mAb 138H11 led to a significant shrinkage of tumor mass (Cancer Res. 2000, 60, 6089-6094). However, these nude mice are not useful for evaluating ADCC of naked 138H11 or immunoactive conjugates.

For creating a syngeneic immunocompetent mouse model bearing a tumor sensitive to mAb 138H11, we stably transfected the murine RCC RENCA cell line with the human GGT-gene. FACS-analyses revealed that transfected cells were positive for mAb 138H11, in contrast to wild type cells. The transfected cells were growing s.c. in Balb/c Mice without signs of rejection by the host. The mice showed a higher uptake of 99m-Tc-labeled 138H11 in the GGT positive RENCA tumors compared to the wild type tumors.