The therapeutic effects of the low and high affinity mAbs 17-1A and 323/A3 were investigated in nude mice xenografted with LS 180 human colorectal carcinoma cells. Treatment of mice grafted with dispersed tumor cells, before formation of a tumor nodule, was started 1 day after s.c. injection of tumor cells and consisted of a single i.p. injection of murine 17-1A or 323/A3 mAb. Tumor appearance after a single injection of either 17-1A or 323/A3 was delayed as compared to injection of an irrelevant mAb. Both 17-1A and 323/A3 reduced the tumor growth rate, and both mAbs decreased the total number of mice that eventually developed a tumor. In all experiments, 323/A3 showed consistently better treatment effects on xenografted mice than mAb 17-1A. For treatment of established tumors with mAb 17-1A or 323/A3 therapy was delayed until a tumor nodule was macroscopically detectable. One single i.p. injection of mAb 17-1A had no effect on further tumor growth and mean tumor size as compared to the control group injected with irrelevant mAb. One single i.p. injection with mAb 323/A3 reduced the tumor growth rate in some mice with established tumors and resulted in a significant difference of mean tumor size of this group as compared to the 17-1A treated mice and the control groups. Multiple injections with mAb 17-1A also had no effects on established tumors, in contrast to mAb 323/A3, where serial injections resulted in tumor growth reduction and, eventually, in some mice reduction in tumor size. In summary, we showed that in nude mice mAb 323/A3 (Ka = 2 × 109 m-1) is much more potent than mAb 17-1A (Ka = 5 × 107 m-1) in eradication of nonestablished tumor cells and treatment of small established tumors. These results suggest that high affinity mAbs like 323/A3 might dramatically improve the clinical results obtained thus far with the low affinity mAb 17-1A in the adjuvant treatment of surgically resected Dukes C colorectal cancer patients with minimal residual disease.
This research was supported by the Technology Foundation (Grant LBI 002398) and the Dutch Cancer Society (Grant RUL 94-762).