Zwitterlation - A Promising Strategy beyond PEGylation

S. Jiang
University of Washington,
United States

Keywords: PEG, protein therapy


Advances in protein therapy are hindered by the poor stability, inadequate pharmacokinetic (PK) profiles, and immunogenicity of many therapeutic proteins. Poly(ethylene glycol) conjugation (PEGylation) is the most successful strategy to date to overcome these shortcomings, and more than 10 PEGylated proteins have been brought to market. However, induced and pre-existing anti-PEG antibodies raise serious concerns about the future of PEGylated therapeutics. Here, we demonstrate a new protein conjugation technology based on zwitterionic polycarboxybetaine(PCB) polymers (Zwitterlation). PCB polymers are derived from naturally occurring glycine betaine, which is also used as a protein stabilizer. While PEG is amphiphilic with both hydrophilic and hydrophobic characteristics, PCB polymers are superhydrophilic via electrostatic-induced hydration and are invisible in complex media. This technology can be realized via polymer conjugation or nanogel encapsulation and effectively enhances protein stability, PK and pharmacodynamics (PD) while mitigating the immune response. Several immunogenic proteins such as uricase conjugated with PEG and PCB are compared. While anti-PEG antibodies were observed, no antibodies against PCB polymers were detected for all of these studies after 3-5 weekly injections in a rat model. We also demonstrate a PCB-protected bioscavenger that offers long-term protection against organophosphates (OP) intoxication in guinea pigs. This technology is applicable to a variety of proteins and unlocks the possibility of adopting highly immunogenic proteins for therapeutic or protective applications. In addition to proteins, this technology has been also demonstrated to have superior performance over PEGylation for micelles, liposomes, nanogels and solid nanoparticles (e.g., quantum dots, silica, iron oxides and gold nanoparticles) for nanomedicine and nanodiagnostics.