Poly(ethylene glycol)(PEG) is commonly used for extending plasma half-lives of biologics but has significant drawbacks; for example, immunogenicity has led to market withdrawal of peginesatide (Omontys), pegloticase (Krystexxa) and the cessation of pegnivacogin (Revolixys) trials, while dozens of other PEG formulations present antiPEG antibodies, accelerated blood clearance (ABC), infusion reactions and reduced efficacy overtime. Furthermore, PEG offer no inherent protection from environmental stressors, despite biologics being highly susceptible to chemical modification along the manufacturing chain (production, sterilization, lyophilization), as well as in vivo after administration. Excipients (e.g. antioxidants, cryo/lyoprotectants) can partially address this issue but their protective functions cease after administration.<br/>Herein we have rationally designed a new ‘active-stealth’ polymer, poly(thioglycidyl glycerol)(PTGG), composed of a cryo/lyoprotective glycerol-derived side-chain and an antioxidant polysulfide backbone. In human plasma, PTGG was significantly less immunogenic than PEG (~35% less complement activation), but also features a potent ROS-scavenging and anti-inflammatory action. When conjugated to proteins in a one-pot processes; molar mass- and grafting density-matched PTGG-lysozyme conjugates demonstrated superiority over PEG analogs both in terms of enzyme activity as well as stability (to freezedrying and oxidation). In mice and rats, PTGG-ovalbumin conjugates displayed circulation half-lives up to twice as long as PEG-ovalbumin, but most importantly – and differently from PEG - without any associated ABC or anti-polymer immunogenicity. PTGG’s ‘active-stealth’ character make it a highly promising alternative to PEG for conjugation to biologics or nanocarriers.

ROS-scavenging ‘stealth’ polymer, poly(thioglycidyl glycerol)(PTGG), outperforms PEG in protein conjugates and nanocarriers, and enhances protein stability to environmental and biological stressors

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