Schematic representation of initial clinical attempts to use recombinant TRAIL, its derivatives, and IgG antibodies targeting DR4 or DR5 as anti-cancer drugs. (a) Targeting cancer cells with APO2/TRAIL. Its mode of action (MOA), the crosslinking of DR5, may be limited to clustering only three DR5 molecules. The lack of effective crosslinking of DR5 is likely a major reason for the poor or absent anti-tumor activity of these agents in patients. (b) IgG anti-DR5 antibodies, being bivalent, are unable to cluster DR5 without secondary crosslinking. In nude mice, mouse B cells provide this secondary crosslinking by engaging IgG via their Fc gamma receptor II. In human patients, this secondary crosslinking may not be efficient enough to eradicate tumors because (i) unlike young nude mice used in experiments, humans have a very high concentration of their own IgG in blood, blocking the Fc gamma receptor II, and (ii) tumor infiltration by B cells in patients may be insufficient.