A modified arginine-depleting enzyme NEI-01 inhibits growth of pancreatic cancer cells

Jeremy P H Chow,Yu-On Leung,Yun-Chung Leung,Alan W L Law,Raymond M H Wong,Ka-Ying Ng,Oscar M Leung,Sui-Yi Kwok,Daniel T L Chow,Yijun Cai,Steven H K Chung,Ka-Chun Chau,Irina V Lebedeva

doi:10.1371/journal.pone.0231633

Jeremy P H Chow, Yu-On Leung + Show 11 more

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https://doi.org/10.1371/journal.pone.0231633

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Abstract

Arginine deprivation cancer therapy targets certain types of malignancies with positive result in many studies and clinical trials. NEI-01 was designed as a novel arginine-depleting enzyme comprising an albumin binding domain capable of binding to human serum albumin to lengthen its half-life. In the present work, NEI-01 is shown to bind to serum albumin from various species, including mice, rat and human. Single intraperitoneal administration of NEI-01 to mice reduced plasma arginine to undetectable level for at least 9 days. Treatment of NEI-01 specifically inhibited cell viability of MIA PaCa-2 and PANC-1 cancer cell lines, which were ASS1 negative. Using a human pancreatic mouse xenograft model, NEI-01 treatment significantly reduced tumor volume and weight. Our data provides proof of principle for a cancer treatment strategy using NEI-01.

Highlights

Arginine is a nonessential amino acid for human cells as it can be generated through the urea cycle by argininosuccinate sythethase (ASS1) and argininosuccinate lyase (ASL) in normal cells
Some tumor cells are deficient in ASS1, which can result in arginine auxotrophy
We found that single administration of NEI-01 depleted mouse plasma arginine to undetectable level for at least 9 days, showing an extended circulating half-life

Summary

Introduction

Arginine is a nonessential amino acid for human cells as it can be generated through the urea cycle by argininosuccinate sythethase (ASS1) and argininosuccinate lyase (ASL) in normal cells. It has been reported that ADI inhibits the growth of several ASS1-negative tumors, such as melanoma and hepatocellular carcinoma (HCC) [1, 2], suggesting that it has potential as an anti-cancer agent. Several chemically modified arginine-depleting enzymes are in different phases of clinical trials [3,4,5,6]. The in vivo application of arginine-depleting enzymes face two major problems: short circulating half-life in plasma and high immunogenicity [7]. One strategy for overcoming these problems is the covalent linkage of a well-known chemical modifier, polyethelene glycol (PEG), to the amino group of the proteins, providing a number of advantages such as low antigenicity, low toxicity and extended circulating half-life [8].

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