2437

Antibody-based cancer immunotherapies may be generalized into two categories. The first category encompasses those antibodies which are designed to specifically target the tumor. Here the therapeutic effect comes as a result of the antibody binding to tumor cells and eliciting direct and/or indirect killing mechanisms. The second category includes those antibodies which mediate their effects not by targeting cancers directly, but rather by binding and modulating immune effector cells. Anti-CTLA-4 antibodies are a classic example of the latter category and although results from preclinical studies have proven the concept for their use, two major obstacles have prevented their successful application for human cancer therapy. First, the lack of in vitro correlates of the anti-tumor effect of the antibodies makes it difficult to screen for the most efficacious antibody by in vitro analysis. Moreover, significant autoimmune side-effects have been observed in a recent clinical trial. In order to address these two issues, we have generated human CTLA-4 gene knock-in mice and used them to compare a panel of anti-human CTLA-4 antibodies for their ability to induce tumor rejection and autoimmunity. Surprisingly, while all antibodies induced protection against cancer and demonstrated some autoimmune side effects, the antibody that induced the strongest protection also induced the least autoimmune side effect. These results demonstrate that autoimmune disease is not a necessary price for cancer immunity. Our approach may be generally applicable to the development of human therapeutic antibodies.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]