Elsevier

Genomics

Volume 109, Issues 3–4, July 2017, Pages 251-257
Genomics

Correlation of FCGRT genomic structure with serum immunoglobulin, albumin and farletuzumab pharmacokinetics in patients with first relapsed ovarian cancer

https://doi.org/10.1016/j.ygeno.2017.04.006Get rights and content
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Highlights

  • PK analysis of farletuzumab was associated with endogenous high albumen/low IgG1

  • fcgrt structural analysis found no association with farletuzumab, albumin or IgG PK

  • fcgrt analysis identified novel VNTRs in the promoter and SNVs in the coding region

Abstract

Farletuzumab (FAR) is a humanized monoclonal antibody (mAb) that binds to folate receptor alpha. A Ph3 trial in ovarian cancer patients treated with carboplatin/taxane plus FAR or placebo did not meet the primary statistical endpoint. Subgroup analysis demonstrated that subjects with high FAR exposure levels (Cmin > 57.6 μg/mL) showed statistically significant improvements in PFS and OS. The neonatal Fc receptor (fcgrt) plays a central role in albumin/IgG stasis and mAb pharmacokinetics (PK). Here we evaluated fcgrt sequence and association of its promoter variable number tandem repeats (VNTR) and coding single nucleotide variants (SNV) with albumin/IgG levels and FAR PK in the Ph3 patients. A statistical correlation existed between high FAR Cmin and AUC in patients with the highest quartile of albumin and lowest quartile of IgG1. Analysis of fcgrt identified 5 different VNTRs in the promoter region and 9 SNVs within the coding region, 4 which are novel.

Abbreviations

FAR
farletuzumab
PK
pharmacokinetics
FcRn
neonatal Fc receptor
IgG
immunoglobulin G
mAb
monoclonal antibody
AUC
area under the curve
Cmin
trough concentration
HR
hazard ratio
EOC
epithelial ovarian cancer
SOC
standard of care
Ph3
Phase 3
VNTR
variable number tandem repeat
SNV
single nucleotide variation

Keywords

Neonatal Fc receptor
FcRn
Fcgrt
IgG
Albumin
Farletuzumab
Ovarian cancer
Pharmacokinetics
Monoclonal antibody

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