Influence of FCGRT gene polymorphisms on pharmacokinetics of therapeutic antibodies

• Published in: mAbs 2013-07, Vol.5 (4), p.614-619
• Main Authors: Passot, Christophe, Azzopardi, Nicolas, Renault, Sylvaine, Baroukh, Nadine, Arnoult, Christophe, Ohresser, Marc, Boisdron-Celle, Michèle, Gamelin, Erick, Watier, Hervé, Paintaud, Gilles, Gouilleux-Gruart, Valérie
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Cetuximab; Cohort Studies; DNA Copy Number Variation; FcRn; Female; Gene Dosage - genetics; genetic polymorphism; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - metabolism; Humans; Jurkat Cells; Life Sciences; Male; Medication; neonatal Fc receptor; Pharmaceutical sciences; pharmacokinetics; Polymorphism, Genetic; Promoter Regions, Genetic - genetics; Receptors, Fc - genetics; Receptors, Fc - metabolism; Tandem Repeat Sequences - genetics; therapeutic drug monitoring; therapeutic monoclonal antibodies
• ISSN: 1942-0862; 1942-0870
• DOI: 10.4161/mabs.24815

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.