TY  - JOUR
AU  - Tseng, Yi-Han
AU  - Lin, Hsuan-Pei
AU  - Lin, Sung-Yao
AU  - Chen, Bing-Mae
AU  - Vo, Thanh Nguyet Nguyen
AU  - Yang, Shih-Hung
AU  - Lin, Yi-Chen
AU  - Prijović, Željko
AU  - Czosseck, Andreas
AU  - Leu, Yu-Lin
AU  - Roffler, Steve R.
PY  - 2024
UR  - https://vinar.vin.bg.ac.rs/handle/123456789/12961
AB  - Engineering human enzymes for therapeutic applications is attractive but introducing new amino acids may adversely affect enzyme stability and immunogenicity. Here we used a mammalian membrane-tethered screening system (ECSTASY) to evolve human lysosomal beta-glucuronidase (hBG) to hydrolyze a glucuronide metabolite (SN-38G) of the anticancer drug irinotecan (CPT-11). Three human beta-glucuronidase variants (hBG3, hBG10 and hBG19) with 3, 10 and 19 amino acid substitutions were identified that display up to 40-fold enhanced enzymatic activity, higher stability than E. coli beta-glucuronidase in human serum, and similar pharmacokinetics in mice as wild-type hBG. The hBG variants were two to three orders of magnitude less immunogenic than E. coli beta-glucuronidase in hBG transgenic mice. Intravenous administration of an immunoenzyme (hcc49-hBG10) targeting a sialyl-Tn tumor-associated antigen to mice bearing human colon xenografts significantly enhanced the anticancer activity of CPT-11 as measured by tumor suppression and mouse survival. Our results suggest that genetically-modified human enzymes represent a good alternative to microbially-derived enzymes for therapeutic applications.
T2  - Journal of Controlled Release
T1  - Engineering stable and non-immunogenic immunoenzymes for cancer therapy via in situ generated prodrugs
VL  - 369
SP  - 179
EP  - 198
DO  - 10.1016/j.jconrel.2024.02.026
ER  - 

@article{
author = "Tseng, Yi-Han and Lin, Hsuan-Pei and Lin, Sung-Yao and Chen, Bing-Mae and Vo, Thanh Nguyet Nguyen and Yang, Shih-Hung and Lin, Yi-Chen and Prijović, Željko and Czosseck, Andreas and Leu, Yu-Lin and Roffler, Steve R.",
year = "2024",
abstract = "Engineering human enzymes for therapeutic applications is attractive but introducing new amino acids may adversely affect enzyme stability and immunogenicity. Here we used a mammalian membrane-tethered screening system (ECSTASY) to evolve human lysosomal beta-glucuronidase (hBG) to hydrolyze a glucuronide metabolite (SN-38G) of the anticancer drug irinotecan (CPT-11). Three human beta-glucuronidase variants (hBG3, hBG10 and hBG19) with 3, 10 and 19 amino acid substitutions were identified that display up to 40-fold enhanced enzymatic activity, higher stability than E. coli beta-glucuronidase in human serum, and similar pharmacokinetics in mice as wild-type hBG. The hBG variants were two to three orders of magnitude less immunogenic than E. coli beta-glucuronidase in hBG transgenic mice. Intravenous administration of an immunoenzyme (hcc49-hBG10) targeting a sialyl-Tn tumor-associated antigen to mice bearing human colon xenografts significantly enhanced the anticancer activity of CPT-11 as measured by tumor suppression and mouse survival. Our results suggest that genetically-modified human enzymes represent a good alternative to microbially-derived enzymes for therapeutic applications.",
journal = "Journal of Controlled Release",
title = "Engineering stable and non-immunogenic immunoenzymes for cancer therapy via in situ generated prodrugs",
volume = "369",
pages = "179-198",
doi = "10.1016/j.jconrel.2024.02.026"
}

Tseng, Y., Lin, H., Lin, S., Chen, B., Vo, T. N. N., Yang, S., Lin, Y., Prijović, Ž., Czosseck, A., Leu, Y.,& Roffler, S. R.. (2024). Engineering stable and non-immunogenic immunoenzymes for cancer therapy via in situ generated prodrugs. in Journal of Controlled Release, 369, 179-198.
https://doi.org/10.1016/j.jconrel.2024.02.026

Tseng Y, Lin H, Lin S, Chen B, Vo TNN, Yang S, Lin Y, Prijović Ž, Czosseck A, Leu Y, Roffler SR. Engineering stable and non-immunogenic immunoenzymes for cancer therapy via in situ generated prodrugs. in Journal of Controlled Release. 2024;369:179-198.
doi:10.1016/j.jconrel.2024.02.026 .

Tseng, Yi-Han, Lin, Hsuan-Pei, Lin, Sung-Yao, Chen, Bing-Mae, Vo, Thanh Nguyet Nguyen, Yang, Shih-Hung, Lin, Yi-Chen, Prijović, Željko, Czosseck, Andreas, Leu, Yu-Lin, Roffler, Steve R., "Engineering stable and non-immunogenic immunoenzymes for cancer therapy via in situ generated prodrugs" in Journal of Controlled Release, 369 (2024):179-198,
https://doi.org/10.1016/j.jconrel.2024.02.026 . .