Since Fc-gamma receptors (FcgRs) are involved in the degradation of IgG complexes, we assessed whether a modification in FcgRs' affinity to Fc portion, caused by single nucleotide polymorphisms such as rs1801274-R131H FcgRIIa, rs396991-F158V FcgRIIIa and NA1/NA2-FcgRIIIb, might impact clearance of therapeutic monoclonal antibodies and thus, serum drug levels and the development of anti-drug antibodies.
A cross sectional, multicentral and non-interventional study was conducted in Tunisian RA patients treated with rituximab (RTX), etanercept (ETA), infliximab (IFX) and adalimumab (ADL). Serum drug level (SDL) of the different biologics and ADA against them were measured. All patients were genotyped for the three FCGR SNPs.
A total of 81 patients were included: 47 were under TNF-inhibitors (18 ETA, 13 ADL and 16 IFX) and 34 were under RTX. Regardless of the type of biotherapy, SDL was in therapeutic range, in 35 patients (43.2%) of whom only one was treated with RTX. Fourteen patients (22.2%) developed ADA but none of the patients treated with ETA had detectable ADA levels. There was no association between SDL positivity and FCGR polymorphisms. However, the high affinity FCGR2A 131 H/H receptor was statistically more prevalent in patients with detectable ADA treated with ADL, IFX and RTX (p=0.018). The same result was obtained in mAb TNFi subgroup (n=29, p=0.022) as well as in patients treated only with IFX (n=16, p=0.029).
Our work supports the hypothesis of an impact of FCGR SNPs on biologics' immunogenicity, particularly FCGR R131H polymorphism, but further studies with larger cohorts needs to be undertaken to confirm these results.