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Title: | Mono-PEGylation of a thermostable Arginine-depleting enzyme for the treatment of lung cancer | Authors: | Chung, SF Kim, CF Kwok, SY Tam, SY Chen, YW Chong, HC Leung, SL So, PK Wong, KY Leung, YC Lo, WH |
Issue Date: | 2020 | Source: | International journal of molecular sciences, 2020, v. 21, no. 12, | Abstract: | L-arginine (L-Arg) depletion induced by randomly PEGylated arginine deiminase (ADI-PEG20) can treat arginosuccinate synthase (ASS)-negative cancers, and ADI-PEG20 is undergoing phase III clinical trials. Unfortunately, ASS-positive cancers are resistant to ADI-PEG20. Moreover, the yield of ADI production is low because of the formation of inclusion bodies. Here, we report a thermostable arginine-depleting enzyme, Bacillus caldovelox arginase mutant (BCA-M: Ser161->Cys161). An abundant amount of BCA-M was easily obtained via high cell-density fermentation and heat treatment purification. Subsequently, we prepared BCA-M-PEG20, by conjugating a single 20 kDa PEG monomer onto the Cys161 residue via thio-chemistry. Unlike ADI-PEG20, BCA-M-PEG20 significantly inhibited ASS-positive lung cancer cell growth. Pharmacodynamic studies showed that a single intraperitoneal injection (i.p). administration of 250 U/mouse of BCA-M-PEG20 induced low L-Arg level over 168 h. The mono-PEGylation of BCA-M prolonged its elimination half-life from 6.4 to 91.4 h (a 14-fold increase). In an A549 lung cancer xenograft model, a weekly administration of 250 U/mouse of BCA-M-PEG20 suppressed tumor growth significantly. We also observed that BCA-M-PEG20 did not cause any significant safety issue in mouse models. Overall, BCA-M-PEG20 showed excellent results in drug production, potency, and stability. Thereby, it has great potential to become a promising candidate for lung cancer therapy. | Keywords: | L-Arg Mono-PEGylation Thermostable enzyme |
Publisher: | Molecular Diversity Preservation International (MDPI) | Journal: | International journal of molecular sciences | EISSN: | 1422-0067 | DOI: | 10.3390/ijms21124234 | Rights: | © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). The following publication Chung S-F, Kim C-F, Kwok S-Y, Tam S-Y, Chen YW, Chong H-C, Leung S-L, So P-K, Wong K-Y, Leung Y-C, Lo W-H. Mono-PEGylation of a Thermostable Arginine-Depleting Enzyme for the Treatment of Lung Cancer. International Journal of Molecular Sciences. 2020; 21(12):4234, is available at https://doi.org/10.3390/ijms21124234 |
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