Engineering stable and non-immunogenic immunoenzymes for cancer therapy via in situ generated prodrugs
Само за регистроване кориснике
2024
Аутори
Tseng, Yi-HanLin, 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.
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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.
Кључне речи:
Beta-glucuronidase / Immunogenicity / SN-38G / CPT-11 / Irinotecan / Antibody-directed enzyme prodrug therapyИзвор:
Journal of Controlled Release, 2024, 369, 179-198Финансирање / пројекти:
- National Science and Technology Council, Taipei, Taiwan [112-2320-B-001-003]
- Academia Sinica Core Facility and Innovative Instrument [Project AS-CFII-111-212]
- Academia Sinica Core Facility and Innovative Instrument [Project AS-CFII-111- 201]
Колекције
Институција/група
VinčaTY - 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 . .