PEGylation and pharmacological characterization of a potential anti-tumor drug, an engineered arginine deiminase originated from Pseudomonas plecoglossicida

Arginine deiminase (ADI) has been studied as a potential anti-cancer agent for arginine-auxotrophic tumors. PEGylation is one of the best methods to formulate a bioconjugated protein with extended physical stability and reduced immunogenicity. Here, PEGylation and pharmacological properties of an engineered ADI originated from Pseudomonas plecoglossicida were studied. Among polyethylene glycol (PEG) reagents with succinimidyl ester groups varying in size and linkers, three PEGylated products with high yield and catalytic activity were further characterized, named ADI-SS20 kDa, ADI-SC20 kDa, and ADI-SPA20 kDa. In the pharmacodynamic/pharmacokinetic (PD/PK) studies with ADI-SPA20 kDa, a remarkable improvement in circulating half-life compared with native ADI was observed. ADI-SPA20 kDa injections via intravenous, intramuscular and subcutaneous routes all exhibited superior efficacy than native ADI on depleting serum arginine. Additionally, our results demonstrated that single ADI-SPA20 kDa administration of 5 U/mouse via intravenous injection could maintain serum arginine at an undetectable level for 5 days with a half-life of 53.2 h, representing 11-fold improvement in half-life than that of the native ADI. In a mice H22 hepatocarcinoma model, ADI-SPA20 kDa dosage of 5 U per 5 days showed an inhibition rate of 95.02% on tumor growth during 15-day treatments.

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