Rational design, engineer, and characterization of a novel pegylated single isomer human arginase for arginine depriving anti-cancer treatment
| Autor: | Sai Fung Chung, Murray Cutler, Lynn Y L Huang, Thomas Wai-hung Lo, Johnson Y.N. Lau, Kuo-Ming Yu, Tammy Pui-shi Pang, Thomas Yun-Chung Leung, Min Tian |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Arginine Mice Nude Antineoplastic Agents Pharmacology 030226 pharmacology & pharmacy Protein Structure Secondary General Biochemistry Genetics and Molecular Biology Polyethylene Glycols Rats Sprague-Dawley Mice 03 medical and health sciences 0302 clinical medicine Pharmacokinetics PEG ratio medicine Animals Humans General Pharmacology Toxicology and Pharmaceutics Cytotoxicity Mice Inbred BALB C Arginase Dose-Response Relationship Drug Chemistry In vitro toxicology Cancer General Medicine Chemical Engineering medicine.disease Xenograft Model Antitumor Assays Rats Isoenzymes Treatment Outcome 030104 developmental biology Drug Design Toxicity |
| Zdroj: | Life Sciences. 264:118674 |
| ISSN: | 0024-3205 |
| Popis: | Aims Arginine depleting enzymes are found effective to treat arginine-auxotrophic cancers and therapy-resistant malignancies, alone or in combination with cytotoxic agents or immune checkpoint inhibitors. We aim to select and validate a long-lasting, safe and effective PEGylated and cobalt-chelated arginase conjugated at the selective cysteine residue as a therapeutic agent against cancers. Main methods Exploring pharmacokinetic and pharmacodynamic properties of the three arginase conjugates with different PEG modality (20 kDa linear as A20L, 20 kDa branched as A20Y, and 40 kDa branched as A40Y) by cell-based and animal studies. Key findings Arginase conjugates showed comparable systemic half-lives, about 20 h in rats and mice. The extended half-life of PEGylated arginase was concurrent with the integrity of conjugates of which PEG and protein moieties remain attached in bloodstream for 72 h after drug administration. Arginase modified with a linear 20 kDa PEG (A20L) was chosen as the lead candidate (PT01). In vitro assays confirmed the very potent cytotoxicity of PT01 against cancer cell lines of breast, prostate, and pancreas origin. In MIA PaCa-2 pancreatic and PC-3 prostate tumor xenograft models, weekly infusion of the PT01 at 5 and 10 mg/kg induced significant tumor growth inhibition of 44–67%. All mice experienced dose-dependent but rapidly reversible weight loss following each weekly dose, suggesting tolerable toxicity. Significance These non-clinical data support PT01 as the lead candidate for clinical development that may benefit cancer patients by providing an alternative cytotoxic mechanism. |
| Databáze: | OpenAIRE |
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