Monoclonal antibodies targeting cancer: 'magic bullets' or just the trigger?

The first monoclonal antibodies (mAbs) approved for cancer therapy are now in Phase II and III trials, but the critical mechanism(s) determining effic acy and response in patients are still largely undefined. Both the direct a ntigen-binding (Fab) and constant (Fc) regions of mAbs can contribute to th eir biological activity. However, Clynes et al (Nat Med 2000, 6:443) recent ly suggested that the latter (at least in experimental models) might be the dominant component in vivo, triggering host responses to destroy cancer ce lls. Those workers showed that in mice lacking 'activation' Fc receptors (F c gamma RI and Fc gamma RIII), anti-tumour effects of certain mAbs were sig nificantly reduced. In contrast, mice deficient in the 'inhibitory' recepto r Fc gamma RIIB responded with tumour growth inhibition and enhanced antibo dy-dependent cellular cytotoxicity (ADCC). These observations suggest that mAbs might be engineered for preferential binding to Fc gamma RIII to maxim ise therapeutic benefit. However, further work is needed to establish a def initive cause-effect relationship in experimental models that are more clin ically relevant, to determine whether human Fc gammaR isoforms behave in a similar fashion, and to confirm that therapeutic mAbs and host cells can ad equately access solid tumour deposits to mediate effective ADCC in situ. Fi nally, the 'cost-benefit' ratio of such modified macromolecules will need t o be measured against mini-mAb constructs, antisense oligonucleotides, pept idomimetics and emerging drugs capable of inhibiting key tumour cell signal ling pathways.