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Continuing our strategy for a targeted therapy of metastatic renal cell carcinoma (RCC), a tumor which resists chemo- or radiotherapy, we now determined the primary structure of the antigen binding region of the monoclonal antibody 138H11. MAb 138H11, produced against human renal gamma-glutamyltransferase (GGT), stained over 99% clear cell and papillary RCC as well as other carcinomas on frozen sections, showing a membranous expression of the target antigen. In contrast, in normal kidneys GGT is restricted to the brush-border in the lumen of proximal tubules and thus not accessible to the circulation. Human tumor-bearing kidneys perfused in an extra-corporeal system with 99mTc-138H11 revealed a high, specific uptake into the tumor. In vivo, a 138H11-Calicheamicin theta conjugate was very effective in reducing the tumor size and preventing or significantly delaying the regrowth of residual tumor cells in xenografted nude mice (Cancer Res. 2000, 60, 6089-6094). However, these nude mice are not useful for evaluating ADCC of naked 138H11 or immunoactivating conjugates. For creating a syngenic, 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-analysis 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-labelled 138H11 into the GGT positive RENCA tumors compared to the wild type tumors. This new model will be usful in the future for evaluating therapeutic effects of potential constructs made with the newly cloned recombinant 138H11-derivatives such as stabilized scFv, diabodies and triabodies.

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.

We report the case of a 61-year-old man, with a rare combination of two advanced urological tumors: a concomitant spread of an adenocarcinomabeyond the kidney and a urothelial carcinoma beyond the bladder. Wesimultaneously performed a primary curative prostatovesiculectomy anda nephroureterectomy on the right with ileal neobladder. To ourknowledge, a case report of concomitant spread of an adenocarcinomabeyond the kidney (pT3 pN0 M0 G3) and a urothelial carcinoma beyondthe bladder (pT3a pN0 M0 G3) with subsequent curative therapy hasthus far not been published. A combination of the two diseasesdescribed here is obviously a remarkable rarity.