B-cell killing by rituximab depends on antibody-dependent cellular cytotoxicity (ADCC). A genetic polymorphism in the Fc Gamma Receptor (FcγR) with an increased affinity for IgG1 could influence response. The study objectives were to assess the effect of the full range of FcγR variants on depletion, clinical response and functional effect on NK-cell-mediated killing.
A prospective longitudinal study was conducted in a UK rituximab registry. Major clinical response (MCR) was defined as improvement of active BILAG-2004 domains to grade C/better at 6 months. Partial Clinical response (PCR) allowed 1 persistent B. B-cell depletion was evaluated by highly-sensitive flow cytometry. Qualitative and quantitative polymorphisms for five major FcγRs were measured using multiplex ligation-dependent probe amplification. NK-cell degranulation (CD107a) in the presence of rituximab-coated Raji cells were assessed using flow cytometry.
262 patients were studied. In cycle 1 rituximab, 177/262 (67.6%) achieved BILAG response [MCR=34.4%; PCR=33.2%]. No clinical/serological feature consistently predicted depletion and response. At the genotypic level, complete depletion was associated with carriage of FCGR3A-158V allele, OR 2.95 (95% CI 1.16-7.51) and FCGR2C-ORF allele 3.3 (1.12-9.72). By integrating copy number and functional SNP analysis, MCR was associated with higher number copies of FCGR3A-158V allele, 1.64 (1.12-2.41) and FCGR2C-ORF allele 1.93 (1.09-3.40). For FCGR3A, degranulation activity was higher in the V allele carriers vs FF; p=0.024.
ADCC-enhancing FcγRIIIa and FcγRIIc variants were associated with complete B-cell depletion and MCR in SLE. This was supported by functional data on NK-cell-mediated cytotoxicity. These results may guide stratification and development of more effective B-cell targeted strategies.