The effect of antibody protein dose of anti-renal cell carcinoma monoclonal antibodies in nude mice with renal cell carcinoma xenografts.

Abstract

Antibodies preferentially can direct radionuclides to solid tumors. However, antibody uptake in tumors is often highly heterogeneous. This heterogeneity may be overcome by increasing antibody protein dose. The biodistribution of increasing protein doses of radioiodinated antirenal cell carcinoma (RCC) monoclonal antibodies (MoAbs) G250 and RC 38 was studied in mice with NU-12 or SK-RC-52 RCC xenografts. In addition, MoAb affinity constants and antigen densities (Scatchard analysis) and MoAb processing (internalization) were determined in vitro. The relative uptake of G250 in NU-12 tumors was very high at low protein doses (125% injected dose/g [%ID/g]), but decreased at higher doses, suggesting tumor saturation. Indeed, saturation of G250 antigen occurred at 3 microg protein. In this model, 9200 G250 determinants per NU-12 cell could be targeted, which is only 6.1% of the 150,000 G250 determinants per NU-12 cell as determined in vitro. The RC 38 uptake in NU-12 tumors remained constant up to the 10 microg dose level (40% ID/g) and decreased at higher doses. RC 38 antigens were saturated at 25 microg of RC 38. With RC 38, 15% of the available RC 38 antigens per NU-12 tumor cell were targeted. In contrast, G250 uptake in SK-RC-52 tumors was very low at low antibody dose (4% ID/g at 1 microg) and increased with increasing protein dose. These differences in G250 biodistribution might be related to differences in the processing of G250 by the tumor cells. Our studies show that some RCC tumors can be saturated with anti-RCC MoAbs at low (25 microg) to very low (3 microg) protein doses. At nonsaturated doses relatively high tumor uptake can be achieved. Surprisingly, in NU-12 tumors only 6.1% and 15% of the available antigenic sites were targeted at the saturating dose levels with G250 and RC 38, respectively.