Anti-PEG antibodies in the clinic: Current issues and beyond PEGylation

Abstract

The technique of attaching the polymer polyethylene glycol (PEG), or PEGylation, has brought more than ten protein drugs into market. The surface conjugation of PEG on proteins prolongs their blood circulation time and reduces immunogenicity by increasing their hydrodynamic size and masking surface epitopes. Despite this success, an emerging body of literature highlights the presence of antibodies produced by the immune system that specifically recognize and bind to PEG (anti-PEG Abs), including both pre-existing and treatment-induced Abs. More importantly, the existence of anti-PEG Abs has been correlated with loss of therapeutic efficacy and increase in adverse effects in several clinical reports examining different PEGylated therapeutics. To better understand the nature of anti-PEG immunity, we summarize a number of clinical reports and some critical animal studies regarding pre-existing and treatment-induced anti-PEG Abs. Various anti-PEG detection methods used in different studies were provided. Several protein modification technologies beyond PEGylation were also highlighted.

Keywords: Anti-PEG antibody; Antibody detection; Immunogenicity; PEGylation; Polymer conjugation; Protein therapeutics.

Figure 1

Mean anti-pegloticase antibody titers over time among serum uric acid responders and NR receiving biweekly (a) and monthly (b) pegloticase. (d). Reprinted with permission from ref[19]. Anti-PEG antibody vs. asparaginase activity for patients treated with PEG-asparaginase tested by serological identification (c) and flow cytometry (d). Reprinted with permission from ref[16].

Figure 2

Detection of anti-PEG Abs by an SPR sensor. (a) Scheme showing the detection setup. The gold chip surface was modified with PEG-based polymer brushes. The polymer brush serves dual functions, providing a nonfouling background while serving as the investigated antigen. (b) Sensor signal-time curves when detecting. Reprinted with permission from ref[60].

Figure 3

Chemical structures of various synthetic polymers used for protein-polymer conjugation.

Figure 4

Antibody titer against either polymer detecting for a) IgM and b) IgG after three repeated administrations of polymer-conjugated proteins. As rat anti-PEG IgM is commercially available, the IgM titer over the course of the study is quantified in c). Reprinted with permission from ref[83].

Figure 5

a) Scheme shows the protein nanocapsule structure. b) Circulation profiles of the modified uricase after the first and third administrations. c) Anti-polymer Ab detected by SPR sensor. Reprinted with permission from ref[60].