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.

Development of Sialic Acid-coated Nanoparticles for Targeting Cancer and Efficient Evasion of the Immune System

“…Among these, PEG is the most widely used material to reduce uptake by the mononuclear phagocyte system (MPS) for improving the stealth effect because of its low cost and ease of modification 7-9. However, PEGylated nanoparticles have a potential drawback in diagnostic and therapeutic efficacy due to the production of PEG-specific antibodies 10-13. In addition, PEG coating onto nanoparticles has been reported to mitigate the drug release and target cell interaction, thus compromising the diagnostic and therapeutic goals 14, 15.…”

Particle Targeting in Complex Biological Media

“…Although PEG remains the most established low-fouling material used for modifying drug carriers, alternative materials and strategies have been explored for the development of particles with enhanced biocompatibility and improved in vivo performance (Table 2). [151] For example, low-fouling capsules can be prepared using poly(N-vinyl pyrrolidone) (PVPON) as the building block via LbL assembly. [14,136b,137] The neutral PVPON is both highly biocompatible and low-fouling.…”

“…[154] Zwitterionic poly(carboxybetaine) (PCB)-based nanomaterials, as demonstrated by Yang et al, showed prolonged circulation time after both the first and the second administration, indicating negligible production of polymer-specific Abs, which can be an issue for PEG. [139,151] This indicated that PCB could be an alternative to PEG to resist activation of immune responses as well as rapid clearance from blood circulation. [139] Many other synthetic or biological molecules, including poly[N -(2-hydroxypropyl)-methacrylamide], poly(vinyl alcohol), poly(4-acryloylmorpholine), poly(amino acids), and polysaccharides, have also been explored as alternative choices to PEG to develop stealth drug carriers (Table 2).…”

Responsive hybrid (poly)peptide–polymer conjugates

“…43 Within the past decade there has been a push to advance beyond PEGylation, as recent literature has documented anti-PEG antibodies that have a detrimental effect on drug efficacy. 44 A range of PEG-alternatives such as poly(N-vinylpyrrolidone), 45 poly(glycerol), 46 poly(zwitterions), 47 poly(carbonates), 48 poly(oxazolines), 49 and poly(sacharrides), 50 have shown promise, and have been reviewed elsewhere. 51,52 In addition, polyphosphoesters (PPE) represent an important alternative to PEG because of their biocompatibility, biodegradability, similar architecture to biomolecules, and ability to be functionalized.…”