Another piece of the puzzle

Carton and colleagues (page 754) have added to the controversy regarding the dominant mechanism of action of rituximab in vivo. They determined the effect of a FcγRIIIa-158V/F receptor polymorphism in patients treated with 4 infusions of rituximab as initial therapy for low-risk follicular NHL. Twenty percent were homozygous for valine (158V), 35% homozygous for phenylalanine (158F), and 45% heterozygous. Patients with homogenous 158V were found to have a greater response rate and a greater molecular response at 1 year compared with patients with either the homozygous 158F or the heterozygous patients with 158F/V genotype. Despite these findings, the time-to-tumor progression did not differ between the 2 groups, likely due to the small numbers of patients. FcγRIIIa-158V/V receptors have higher affinity interaction with IgG1, promoting more efficient antibody-dependent cell-mediated cytotoxicity (ADCC). These results are consistent with other observations that point to the importance of ADCC as a mechanism of rituximab killing. Interestingly, there was not a clear gene-dose relationship, as the patients with homozygous 158F had a similar response rate to the patients with 158V/F. Ultimately, whether this observation is actually due to FcγRIIIa genotype or to another closely linked gene remains to be settled.

But this is not the whole story, as 67% of the 158F carriers with less efficient interaction with IgG1 had remissions and patients homozogous for 158V continue to relapse. Possible factors include other Fc receptors, complement-mediated cytotoxicity, and direct effects of antibody binding. Longer follow-up, a larger series of patients, and extension of these observations to patients receiving rituximab for relapsed disease or concurrently with chemotherapy will be important. Nevertheless, these observations may lead to strategies to augment ADCC. Options include engineering a better IgG1 antibody that allows more efficient interaction with 158F carrier genotype or increasing the number of or activation of the ADCC effector cells through administration of cytokines. Ultimately, a better understanding of these mechanisms of action and resistance will provide the rationale for new approaches that will increase response rates to antibody therapy.