Isotype-dependent inhibition of tumor growth in vivo by monoclonal antibodies to death receptor 4

To explore an approach for death receptor targeting in cancer, we developed murine mAbs to human death receptor 4 (DR4). The mAb 4H6 (IgG1) competed w ith Apo2L/TNF-related apoptosis-inducing ligand (DR4's ligand) for binding to DR4, whereas mAb 4G7 (IgG2a) did not. In vitro, both mAbs showed minimal intrinsic apoptosis-inducing activity, but each triggered potent apoptosis upon cross-linking. In a colon tumor nude mouse model in vivo, mAb 4H6 tre atment without addition of exogenous linkers induced apoptosis in tumor cel ls and caused complete tumor regression, whereas mAb 4G7 partially inhibite d tumor growth. An IgG2a isotype switch variant of mAb 4H6 was much less ef fective in vivo than the parent IgG1-4H6, despite similar binding affinitie s to DR4. The same conclusion was obtained by comparing other IgG1 and IgG2 mAbs to DR4 for their anti-tumor activities in vivo. Thus, the isotype of anti-DR4 mAb may be more important than DR4 binding affinity for tumor elim ination in vivo. Anti-DR4 mAbs of the IgG1 isotype may provide a useful too l for investigating the therapeutic potential of death receptor targeting i n cancer.