期刊
MICROBIAL CELL FACTORIES
卷 15, 期 -, 页码 -出版社
BIOMED CENTRAL LTD
DOI: 10.1186/s12934-016-0508-5
关键词
Trichoderma reesei; Filamentous fungi; Interferon; Therapeutic proteins; Proteases; Cytokines
资金
- Novartis Pharma AG
- Glykos Finland Oy
Background: The filamentous fungus Trichoderma reesei has tremendous capability to secrete over 100 g/L of proteins and therefore it would make an excellent host system for production of high levels of therapeutic proteins at low cost. We have developed T. reesei strains suitable for production of therapeutic proteins by reducing the secreted protease activity. Protease activity has been the major hindrance to achieving high production levels. We have constructed a series of interferon alpha-2b (IFN alpha-2b) production strains with 9 protease deletions to gain knowledge for further strain development. Results: We have identified two protease deletions that dramatically improved the production levels. Deletion of the subtilisin protease slp7 and the metalloprotease amp2 has enabled production levels of IFN alpha-2b up to 2.1 and 2.4 g/L, respectively. With addition of soybean trypsin protease inhibitor the level of production improved to 4.5 g/L, with an additional 1.8 g/L still bound to the secretion carrier protein. Conclusions: High levels of IFN alpha-2b were produced using T. reesei strains with reduced protease secretion. Further strain development can be done to improve the production system by reducing protease activity and improving carrier protein cleavage.
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