A genome-wide association study identifies a novel susceptibility locus for the immunogenicity of polyethylene glycol

Chia-Jung Chang,Ming-Ta Michael Lee,Ying-Ting Chen,Bing-Mae Chen,Michael S Hershfield,Chien-Hsiun Chen,Jer-Yuarn Wu,Tian-Lu Cheng,Yuan-Tsong Chen,Steve R Roffler,Yu-Cheng Su

doi:10.1038/s41467-017-00622-4

Abstract

Conjugation of polyethylene glycol (PEG) to therapeutic molecules can improve bioavailability and therapeutic efficacy. However, some healthy individuals have pre-existing anti-PEG antibodies and certain patients develop anti-PEG antibody during treatment with PEGylated medicines, suggesting that genetics might play a role in PEG immunogenicity. Here we perform genome-wide association studies for anti-PEG IgM and IgG responses in Han Chinese with 177 and 140 individuals, defined as positive for anti-PEG IgM and IgG responses, respectively, and with 492 subjects without either anti-PEG IgM or IgG as controls. We validate the association results in the replication cohort, consisting of 211 and 192 subjects with anti-PEG IgM and anti-PEG IgG, respectively, and 596 controls. We identify the immunoglobulin heavy chain (IGH) locus to be associated with anti-PEG IgM response at genome-wide significance (P = 2.23 × 10−22). Our findings may provide novel genetic markers for predicting the immunogenicity of PEG and efficacy of PEGylated therapeutics.

Highlights

Conjugation of polyethylene glycol (PEG) to therapeutic molecules can improve bioavailability and therapeutic efficacy
We aimed to identify genetic variations that predispose individuals toward producing anti-PEG antibodies in a Han Chinese population residing in Taiwan
We identified 7 novel single-nucleotide polymorphisms (SNPs) within the immunoglobulin heavy chain region (IGH) that reached genome-wide association significance for the presence of anti-PEG IgM

Summary

Introduction

Conjugation of polyethylene glycol (PEG) to therapeutic molecules can improve bioavailability and therapeutic efficacy. PEG-therapeutics are capable of priming immune responses and inducing the accelerated blood clearance of a subsequent infusion[6, 7] This might compromise therapeutic efficacy and safety of administered PEGylated medicines by influencing their pharmacokinetics and increasing risk of infusion reactions, raising questions on the clinical impact of anti-PEG antibodies[9, 12]. We aim to identify novel susceptibility loci that might predispose individuals toward inducing antibody responses against PEG by utilizing a genome-wide association study (GWAS) scan in a Han Chinese population residing in Taiwan and to elucidate the immunological mechanisms underlying anti-PEGylated medicine antibody production. We demonstrate that the risk allele of rs12590237 is significantly correlated with higher prevalence and concentrations of anti-PEG IgM in the plasma These findings shed new light on the genetic basis for the immunogenicity of PEG and reveal potential genetic markers likely used for PEGylated drug therapeutics’ efficacy prediction

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