Characterization and therapeutic management of anti-PEG antibodies

For nearly three decades, polyethylene glycol (PEG) has been conjugated to therapeutics or therapeutic delivery vehicles as a means of providing protection from the immune system and extending the pharmacokinetic profile of the drugs. However, recent clinical evidence has made it clear that anti-PEG antibodies (APA) can critically reduce the efficacy and safety of PEGylated therapeutics. For some PEGylated drugs, up to ~40% of patients can develop APA, increasing their rate of clearance from circulation as well as the risk for serious adverse events. In this dissertation, I worked to 1) clarify the extent to which clinicians are aware of APA, 2) develop a minimal physiologically based pharmacokinetic (mPBPK) model to predict the impacts of APA in vivo, 3) characterize the ability of high molecular weight free PEG to saturate APA, in order to restore the long-lived circulation of PEGylated drugs, and 4) study the ability of pre-treatment with free PEG or tolerogenic nanoparticles to reduce the APA response to a subsequent dose of PEGylated drug. Our results indicated that although 91% of physicians who regularly prescribe PEGylated drugs were aware of antidrug antibodies in general, only 22% were aware of APA responses. Our mPBPK model predicted that the prolonged circulation of PEGylated drugs will be compromised only at APA concentrations much greater than typical pre-existing concentrations, suggesting that induced APA responses play the largest role in clinical impacts. Also, I found that pre-administration of 40 kDa free PEG effectively restored the prolonged circulation of PEGylated liposomes in the presence of high titers of pre-existing APA for at least 48 hours in mice, with no measurable systemic or organ-specific toxicities. In our studies of potential strategies to reduce anti-PEG immune responses, I found that pre-dosing with free PEG alone was capable of markedly reducing subsequent APA responses to PEG-liposomes; this effect was comparable to, and in several cases exceeded, tolerogenic liposomes with cytotoxic cargo. I expect that the modeling methods and therapeutic interventions described here may inform future studies of methods to predict, characterize, and manage the clinical impacts of APA.Doctor of Philosoph