Localization of monoclonal antibody G250 and bispecific monoclonal antibody CD3/G250 in human renal-cell carcinoma xenografts: relative effects of size and affinity

Abstract

A study was made of the relative effects of size and binding strength of various forms of the monoclonal antibody (MAb) G250, reacting with primary and metastatic human renal-cell carcinoma (RCC), on the localization in human RCC xenografts in nude mice. Preferential tumor localization was demonstrated after injection of 125I-labelled intact IgG, with increasing tumor/non-tumor ratios in time. Approximately 27.4% of the injected dose/gram (%ID/g) was localized in the xenograft 24 hr post-injection. A control MAb did not preferentially localize in xenografts. With F(ab')2 fragments, higher tumor/blood ratios were obtained, although a lower percentage of injected dose per gram was bound to the tumor, 24 and 48 hr post-injection. Using a bispecific MAb CD3/G250 F(ab')2 fragment, which reacts with CD3 on human T lymphocytes and binds monovalently to RCC, an enhanced accumulation in tumor tissue was also observed. The %ID/g tumor obtained with bispecific CD3/G250 F(ab')2 was comparable with %ID/g tumor found with G250 F(ab')2. The 10-fold lower binding affinity to RCC compared with intact IgG or F(ab')2 had only marginal effects on %ID/g tumor. These results show that MAb G250 preferentially localizes to RCC xenografts. Because injection of F(ab')2 fragments resulted in higher tumor/non-tumor ratios, G250 F(ab')2 may therefore be more suitable for diagnostic evaluation of RCC in patients. The tumor uptake is more dependent on size than on affinity. Furthermore, the data obtained with bispecific MAb CD3/G250 F(ab')2 support the hypothesis that this bispecific MAb may be able to target cytotoxic T lymphocytes to RCC in humans to mediate destruction of RCC.