Dual Modification of Bioengineered Bacillus caldovelox Arginase Achieves Long-Lasting and Sustained Arginine Depletion for Gastric Cancer Treatment
Year: 2026
Type: article
Abstract: We have previously reported a mono-PEGylated thermostable Bacillus caldovelox arginase mutant (BCA-M-PEG20, also named as Mn-BCA-M-PEG20L), a Mn2+-enriched enzyme shown to be effective against gastric cancer xenograft mouse models. To further enhance the pharmacodynamics and efficacy of the drug, in this study, we applied a dual approach to modify the protein drug molecule. We introduced a V20P mutation (change of Val20 to Pro20) together with a metal substitution process (replacement of Mn2+ by Ni2+/Co2+), resulting in a novel enzyme drug named Ni/Co-V20P-PEG20L with high catalytic efficiency and excellent pharmacodynamic properties. Both Ni-V20P-PEG20L and Co-V20P-PEG20L demonstrated remarkable anti-cancer effects on gastric and lung cancer cell lines. Particularly, one injection of Co-V20P-PEG20L maintained a sustained arginine depletion for two weeks, outperforming Ni-V20P-PEG20L, and was therefore chosen for further anti-tumor in vivo studies. We found that the biweekly administration of Co-V20P-PEG20L at a dosage of 20 mg/kg resulted in over 50% suppression in tumor mass in a human MKN-45 gastric cancer xenograft mouse model. Although Co-V20P-PEG20L is a bacterial enzyme, mono-PEGylation technology could protect the drug molecule from anti-drug antibodies. In conclusion, our findings demonstrate that Co-V20P-PEG20L is a promising new arginine-depleting enzyme for the treatment of various cancer types.
Institution: Hong Kong Polytechnic University
Language: English
Topic: Bacterial Cancer Therapy
Subfield: Biotechnology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,499
OpenAlex ID: W7225778081