High MW polyethylene glycol prolongs circulation of pegloticase in mice with anti-PEG antibodies

Pegloticase is an enzyme used to reduce serum uric acid levels in patients with chronic, treatment-refractory gout. Clinically, about 40% of patients develop high titers of anti-PEG antibodies (APA) after initial treatment, which in turn quickly eliminate subsequent doses of pegloticase from the systemic circulation and render the treatment ineffective. We previously found that pre-infusion with high MW free PEG (40 kDa) can serve as a decoy to saturate circulating APA, preventing binding to a subsequently administered dose of PEG-liposomes and restoring their prolonged circulation in mice, without any detectible toxicity. Here, we investigated the use of 40 kDa free PEG to restore the circulation of radio-labeled pegloticase in mice using longitudinal Positron Emission Tomography (PET) imaging over 4 days. Mice injected with pegloticase developed appreciable APA titers by Day 9, which further increased through Day 14. Compared to naive mice, mice with pegloticase-induced APA rapidly cleared 89Zr-labeled pegloticase, with -75% lower pegloticase concentrations in the circulation at four hours after treatment. The 96-h AUC in APA+ mice was less than 30% of the AUC in naive mice. In contrast, preinfusion of free PEG into PEG-sensitized mice restored the AUC of pegloticase to -80% of that seen in naive mice, resulting in a similar biodistribution to pegloticase in naive mice over time. These results suggest that preinfusion of free PEG may be a promising strategy to enable the safe and efficacious use of pegloticase and other PEGylated drugs in patients that have previously failed therapy due to induced APA.

Automated summary

Pre-infusion of high MW free PEG (40 kDa) can serve as a decoy to saturate circulating APA, preventing subsequent doses of pegloticase from being eliminated from the circulation rapidly by APA. This strategy may offer a promising approach to enable safe and effective use of pegloticase in patients with treatment-refractory gout who have developed anti-PEG antibodies.