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Immunology |
1 Laboratoire d’Immunologie, 2 Laboratoire de Pharmacologie, and 3 Service d’Oncologie Médicale et Maladies du Sang, Centre Hospitalier Régional et Universitaire; 4 "Immuno-Pharmaco-Genetics of Therapeutic Antibodies" Université François Rabelais de Tours; and 5 IFR 135: Imagerie Fonctionnelles Tours, France
The FCGR3A gene dimorphism generates two allotypes: Fc
RIIIa-158V and FcRIIIa-158F. The genotype homozygous for FcRIIIa-158V (VV) is associated with higher clinical response to rituximab, a chimeric anti-CD20 IgG1 used in the treatment of B lymphoproliferative malignancies. Our objective was to determine whether this genetic association relates to rituximab-dependent cytotoxicity mediated by FcRIIIa/CD16a+ cells. The number of CD16+ circulating monocytes, T cells, and natural killer (NK) cells in 54 donors was first shown to be unrelated to FCGR3A polymorphism. We then demonstrated that FcRIIIa-158V displays higher affinity for rituximab than FcRIIIa-158F by comparing rituximab concentrations inhibiting the binding of 3G8 mAb (anti-CD16) with VV NK cells and NK cells homozygous for FcRIIIa-158F (FF). VV and FF NK cells killed Daudi cells similarly after FcRIIIa engagement by saturating concentrations of rituximab or 3G8. However, the rituximab concentration resulting in 50% lysis (EC50) observed with NK cells from VV donors was 4.2 times lower than that observed with NK cells from FF donors (on average 0.00096 and 0.00402 µg/ml, respectively, P = 0.0043). Finally, the functional difference between VV and FF NK cells was restricted to rituximab concentrations weakly sensitizing CD20. This study supports the conclusion that FCGR3A genotype is associated with response to rituximab because it affects the relationship between rituximab concentration and NK cell-mediated lysis of CD20+ cells. Rituximab administration could therefore be adjusted according to FCGR3A genotype.
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