title: Influence of FCGRT gene polymorphisms on pharmacokinetics of therapeutic antibodies.
abstract: The neonatal Fc receptor (FcRn) encoded by FCGRT is known to be involved in the pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs). Variability in the expression of FCGRT gene and consequently in the FcRn protein level could explain differences in PK observed between patients treated with mAbs. We studied whether the previously described variable number tandem repeat (VNTR) or copy number variation (CNV) of FCGRT are associated with individual variations of PK parameters of cetuximab. VNTR and CNV were assessed on genomic DNA of 198 healthy individuals and of 94 patients treated with the therapeutic mAb. VNTR and CNV were analyzed by allele-specific PCR and duplex real-time PCR with Taqman (®) technology, respectively. The relationship between FCGRT polymorphisms (VNTR and CNV) and PK parameters of patients treated with cetuximab was studied. VNTR3 homozygote patients had a lower cetuximab distribution clearance than VNTR2/VNTR3 and VNTR3/VNTR4 patients (p = 0.021). We observed no affects of VNTR genotype on elimination clearance. One healthy person (0.5%) and 1 patient (1.1%) had 3 copies of FCGRT. The PK parameters of this patient did not differ from those of patients with 2 copies. The FCGRT promoter VNTR may influence mAbs' distribution in the body. CNV of FCGRT cannot be used as a relevant pharmacogenetic marker because of its low frequency.
authors.affiliation: CNRS, UMR 7292, Université François Rabelais de Tours, Tours, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Passot
authors.forename: Nicolas
authors.initials: N
authors.lastname: Azzopardi
authors.forename: Sylvaine
authors.initials: S
authors.lastname: Renault
authors.forename: Nadine
authors.initials: N
authors.lastname: Baroukh
authors.forename: Christophe
authors.initials: C
authors.lastname: Arnoult
authors.forename: Marc
authors.initials: M
authors.lastname: Ohresser
authors.forename: Michèle
authors.initials: M
authors.lastname: Boisdron-Celle
authors.forename: Erick
authors.initials: E
authors.lastname: Gamelin
authors.forename: Hervé
authors.initials: H
authors.lastname: Watier
authors.forename: Gilles
authors.initials: G
authors.lastname: Paintaud
authors.forename: Valérie
authors.initials: V
authors.lastname: Gouilleux-Gruart
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068818:Cetuximab; D015331:Cohort Studies; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008297:Male; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011961:Receptors, Fc / Q000235:genetics* / Q000378:metabolism; D020080:Tandem Repeat Sequences / Q000235:genetics
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D015395:Histocompatibility Antigens Class I; D011961:Receptors, Fc; D000068818:Cetuximab; C100688:Fc receptor, neonatal
keywords: DNA Copy Number Variation; FcRn; cetuximab; genetic polymorphism; neonatal Fc receptor; pharmacokinetics; therapeutic drug monitoring; therapeutic monoclonal antibodies