Results were analyzed with LightCycler Software using the Ct method. == Southern blot == Ten g of genomic DNA extracted from either Jurkat cells, FcRn expressing Jurkat cells, FcRn expressing Jurkat cells or peripheral blood from healthy individual used as internal control were digested by HindIII and XbaI for 6 h at 37C. experienced 3 copies ofFCGRT. The PK guidelines of this individual did not differ from those of individuals with 2 copies. TheFCGRTpromoter VNTR may influence mAbs distribution in the body. CNV ofFCGRTcannot be used as a relevant pharmacogenetic marker because of its low rate of recurrence. Keywords:FcRn, neonatal Fc receptor, DNA Copy Number Variation, restorative monoclonal antibodies, pharmacokinetics, restorative drug monitoring, cetuximab, genetic polymorphism == Intro == Pharmacokinetics (PK) of monoclonal antibodies (mAbs) progressively appears as a critical determinant of individuals restorative response. There is growing evidence that their concentrations are highly variable and that Micafungin the degree of exposure to these biopharmaceuticals is definitely associated with the response rate to infliximab,1adalimumab,2rituximab,3cetuximab,4trastuzumab.5Based about these observations, empirical attempts to increase doses have led to mixed results. It is therefore of the highest importance to better determine the sources of PK variability in humans to propose fresh dosing strategies. Body mass or body surface area,6sex6,7and the antigenic burden8,9are well-known factors that contribute to mAb interindividual PK variability. Another element responsible for this variability could be FcRn, a widely expressed MHC class I-like receptor that binds IgG and albumin with a higher affinity at acidic pH (< 6.5) than at neutral pH.10-12FcRn permits the recycling and transcytosis of endogenous IgG, as reviewed by Roopenian et al.13FcRn is likely to have a crucial part in mAb PK in human being, but, to our knowledge, there is no direct proof. We recently reported that serum albumin concentration influences cetuximab clearance,4suggesting the involvement of FcRn. Another indirect proof of the part of FcRn in humans treated with mAbs resides in the better PK profile and restorative activity of chimeric or humanized mAbs in comparison to murine mAbs, which bind poorly to human being FcRn.14 An interesting, but not yet documented, approach to understand mAb PK Micafungin interindividual variability would be to study genetic polymorphisms responsible of variations in FcRn expression. In human being, FcRn is encoded byFCGRT,a 14 kb gene located on the long arm of chromosome 19 and comprising 7 exons.15Few data are available about potential polymorphisms of this gene that are of interest. A VNTR ofFCGRTpromoter region was explained by Sachs et al.16They observed that homozygous individuals for 3 repetitions of a 37 base pair (bp) VNTR (VNTR3) express 1.66-fold moreFCGRTtranscripts in their monocytes than heterozygous individuals for 2 and 3 repetitions (VNTR2/VNTR3). Furthermore, they reported a functional effect of this polymorphism, which was that monocytes from VNTR3 homozygous individuals bound IgG at acidic pH more efficiently than heterozygous individuals. In another study, despite the fact that a relationship with the VNTR polymorphism was not APAF-3 observed, common variable immunodeficiency (CVID) individuals with low FcRn mRNA level and treated with intravenous immunoglobulins (IVIg) were shown Micafungin to possess a more quick decrease of IgG concentration than individuals with higher mRNA level.17These results were corroborated by our group in recent work showing that IVIg therapy is more efficient in VNTR3/VNTR3 homozygous CVID patients than in VNTR2/VNTR3 patients.18Nevertheless, to our knowledge the affect of this polymorphism about mAb PK has not yet been studied. Besides VNTR, copy number variance (CNV) ofFCGRThas not been reported yet. CNV has been described as a repetition or deletion of 1kb genetic region that potentially leads to a variable copy number of a gene.19,20CNV may impact the protein level and lead to functional effects. As examined by He et al., some CNV are used mainly because pharmacogenetic markers.21A study using bovineFCGRTtransgenic mouse showed that additional copies ofFCGRTled to an increase of FcRn mRNA and protein levels and to a lengthening of IgG half-life.22This suggests that naturally occurring supplemental copies of the gene Micafungin could have an effect on IgG half-life. Taken collectively, these data suggest that the recognition of genetic polymorphisms responsible for a variance inFCGRTgene expression is definitely of great interest, particularly in the case of restorative mAbs. In this work, we focused on analyzing the influence of VNTR polymorphism and CNV ofFCGRTon interindividual PK variability of cetuximab. == Results == == VNTR and cetuximab PK == Micafungin The VNTR polymorphism explained by Sachs etal.16in 2006 was investigated.