Characterization, efficacy, pharmacokinetics, and biodistribution of 5 kDa mPEG modified tetrameric canine uricase variant

Abstract

PEGylated uricase is a promising anti-gout drug, but the only commercially marketed 10kDa mPEG modified porcine-like uricase (Pegloticase) can only be used for intravenous infusion. In this study, tetrameric canine uricase variant was modified by covalent conjugation of all accessible ɛ amino sites of lysine residues with a smaller 5kDa mPEG (mPEG-UHC). The average modification degree and PEGylation homogeneity were evaluated. Approximately 9.4 5kDa mPEG chains were coupled to each monomeric uricase and the main conjugates contained 7–11 mPEG chains per subunit. mPEG-UHC showed significantly therapeutic or preventive effect on uric acid nephropathy and acute urate arthritis based on three different animal models. The clearance rate from an intravenous injection of mPEG-UHC varied significantly between species, at 2.61mL/h/kg for rats and 0.21mL/h/kg for monkeys. The long elimination half-life of mPEG-UHC in non-human primate (191.48h, intravenous injection) indicated the long-term effects in humans. Moreover, the acceptable bioavailability of mPEG-UHC after subcutaneous administration in monkeys (94.21%) suggested that subcutaneous injection may be regarded as a candidate administration route in clinical trails. Non-specific tissue distribution was observed after administration of 125I-labeled mPEG-UHC in rats, and elimination by the kidneys into the urine is the primary excretion route.