Correlation of FcyRIIIa polymorphisms and the response to rituximab in thai population

Abstract

Rituximab is the chimeric IgG1 monoclonal antibody against CD20 which has been approved for B-cell non-Hodgkins lymphomas (NHLs) treatment. Antibody dependent cellular cytotoxicity (ADCC) by rituximab-activated NK cells has been suggested to be an important mechanism of rituximab via the Fc gamma IIIa receptor (FCyRIIIa) binding on natural killer (NK) cells. FCyRIIIa has two expressed alleles that differ at amino acid position 158 in the extracellular domain; valine (V158) and phenylalanine (F158). These allelic variants have been demonstrated to differ in IgG1 binding and ADCC. V/V homozygotes and V/F heterozygotes bind IgG high affinity than F/F homozygotes. The RFLP-Nested PCR and allele specific amplification was used to identify the FCyRIIIa polymorphism in the study. The correlation of FCyRIIIa polymorphism and rituximab response both in vitro and in vivo was also studied. The results showed the distributions of FCyRIIIa-158 polymorphism in these subjects were as followed: V/V 40.25%, V/F 16.88% and F/F 42.85%. Higher rituximab-induced Ramos cell cytotoxicity (mean rank 33.16%, 36.87%) was observed in the subjects with VV and VF genotypes, respectively; meanwhile the lower cytotoxicity (mean rank 20.07%) was determined in the subjects with FF genotype. For the in vivo study, the NHL patients with V/V or V/F genotypes had a primary response as complete response; meanwhile the NHL patients with F/F genotype had a primary response as partial response. The correlation of FCyRIIIa polymorphism and the primary response in NHL patients is unclear that causing the less number of subjects. The higher number of patients is necessary for the further study. However, these results may provide useful information to understand beneficial response of rituximab as well as other IgG1 therapeutic antibody in Thai patients.