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(12) Patent Application Publication (10) Pub. No.: US 2008/0108115 A1 Bringi Et Al US 2008O108115A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0108115 A1 Bringi et al. (43) Pub. Date: May 8, 2008 (54) ENHANCED PRODUCTION OF TAXOL AND application No. 08/370,494, filed on Jan. 9, 1995, now TAXANES BY CELL CULTURES OF TAXUS abandoned, which is a division of application No. SPECIES 07/874,344, filed on Apr. 24, 1992, now Pat. No. 5,407, 816, which is a continuation-in-part of application No. (75) Inventors: Venkataraman Bringi, Ithaca, NY 07/839,144, filed on Feb. 20, 1992, now abandoned. (US); Prakash Kadkade, Marlboro, MA (US); Christopher Prince, Lansing, NY Publication Classification (US); Braden Roach, Interlaken, NY (US) (51) Int. Cl. CI2P 17/02 (2006.01) Correspondence Address: (52) U.S. Cl. .............................................................. 435/123 HUNTON & WILLIAMS LLP INTELLECTUAL PROPERTY DEPARTMENT (57) ABSTRACT 1900 KSTREET, N.W. This invention provides methods whereby taxol, baccatin III, SUTE 12OO and other taxol-like compounds, or taxanes, can be produced WASHINGTON, DC 20006-1109 (US) in very high yield from all known Taxus species, e.g., brevi folia, Canadensis, cuspidata, baccata, globosa, floridana, (73) Assignee: DFB BIOTECH, INCORPORATED, wallichiana, media and chinensis. Particular modifications of Fort Worth, TX culture conditions (i.e., media composition and operating modes) have been discovered to enhance the yield of various (21) Appl. No.: 11/836,604 taxanes from cell culture of all species of Taxus. Particularly (22) Filed: Aug. 9, 2007 preferred enhancement agents include silver ion or complex, jasmonic acid (especially the methyl ester), auxin-related Related U.S. Application Data growth regulators, and inhibitors of the phenylpropanoid pathway, Such as 3.4-methylenedioxy-6-nitrocinnamic acid. (60) Division of application No. 09/083, 198, filed on May These enhancement agents may be used alone or in combi 22, 1998, now Pat. No. 7,264,951, which is a continu nation with one another or other yield-enhancing conditions. ation-in-part of application No. PCT/US97/08907, While the yield of taxanes from plant cell culture of T. chin filed on May 27, 1997, which is a continuation-in-part ensis is particularly enhanced by use of one or more of these of application No. 08/653,036, filed on May 24, 1996, conditions, yield of taxanes for all Taxus species has been now abandoned, which is a continuation-in-part of found to benefit from use of these conditions. 180 160 140 120 s OO 000 80 DAYS Patent Application Publication May 8, 2008 Sheet 1 of 11 US 2008/0108115 A1 (bu) H93M AO 39WWW UPO ONO S S3 t Upon quo go 3 & 8 8 (6u) H93A HS3 39WAW Patent Application Publication May 8, 2008 Sheet 2 of 11 US 2008/0108115 A1 Ore O. 0-ts CES MEDIUM CES MEDU CONTROL TREATENT F. G. 2A O.On so s O mo O CES MEDU CES MEDIUM CONTROL TREATMENT FG.2B Patent Application Publication May 8, 2008 Sheet 3 of 11 US 2008/0108115 A1 3 CA l 2 l 3 l D - up l - 9. 3 O L) r O 3 ONV8 33WONVNO. 3 SWM Patent Application Publication May 8, 2008 Sheet 4 of 11 US 2008/0108115 A1 0000'O+ Patent Application Publication May 8, 2008 Sheet 5 of 11 US 2008/0108115 A1 +0.7000 SCAN: 26.85 AU +0.0022 90 n 3OO 7-xylosyl 0-deacetyl loxol F.G. 4B SCAN: 33.48 Patent Application Publication May 8, 2008 Sheet 7 of 11 US 2008/0108115 A1 Patent Application Publication May 8, 2008 Sheet 8 of 11 US 2008/0108115 A1 8 s 3 s S. K O (...) ALISNN 3AJW3 Patent Application Publication May 8, 2008 Sheet 9 of 11 US 2008/0108115 A1 re Co f 3 gr 2-3 N 13 3 3 CN 8 8 'm N CN 8 G to s LL s:- S. Sp s S. 8- stages s N s 3 s is a (6) ALISN3LN 3AW13 Patent Application Publication May 8, 2008 Sheet 10 of 11 US 2008/0108115 A1 3 :- Rs s es ( ) se 3 G 2 s c & s S. g 2 N. --8 N : 3 (6) ALSN3LN 3AY3 Patent Application Publication May 8, 2008 Sheet 11 of 11 US 2008/0108115 A1 r CO rf g S 8 8 N to N 8 us CS is 8 .T S3 3 sa $ 3 3 s S O (). ASN3LN 3AW3 US 2008/0108115 A1 May 8, 2008 ENHANCED PRODUCTION OF TAXOLAND other derivatives is baccatin III. Baccatin III is normally not TAXANES BY CELL CULTURES OF TAXUS accumulated as a major taxane in planta, and hence there is no SPECIES facile large-scale natural source for this molecule. However, it 0001. This application is a continuation-in-part of Inter is a very desirable starting point for semi-synthesis because of national application PCT/US97/08907, designating the U.S. its chemical closeness to taxol; for example, the steps that are filed May 27, 1997, and a continuation-in-part of U.S. Ser. required for acetylation of the 10 position of 10-deacetylbac No. 08/653,036, filed May 24, 1996, which is a continuation catin III are circumvented if baccatin III is the starting point in-part of U.S. Ser. No. 08/370,494, filed Jan. 9, 1995, which rather than 10-deacetylbaccatin III. is a divisional of U.S. Ser. No. 07/874,344, now U.S. Pat. No. 0009. This invention is related to the development of plant 5,407,816, filed Apr. 24, 1992, which is a continuation-in-part cell culture-based processes for the commercial production of of U.S. Ser. No. 07/839,144, filed Feb. 20, 1992. The text of taxol, baccatin III and other taxanes. each priority application is expressly incorporated herein by reference to the extent that the text of the respective priority Tissue Cultures as a Source of Plant-Derived Chemicals application differs from this application. 0010 The ability of plant cells to divide, grow, and pro duce secondary metabolites under a variety of different cul BACKGROUND OF THE INVENTION tural regimes has been amply demonstrated by a number of groups. At present, two compounds, shikonin (a red dye and 0002 A. Field of the Invention anti-inflammatory) and ginsengoside (a tonic in oriental 0003. This invention is directed to methods for the medicine) are produced by tissue-culture processes in Japan. enhanced production and recovery of taxol, baccatin III and Many other processes are reportedly close to commercializa other taxanes by cell cultures of Taxus species. tion, including Vanillin, berberine and roSmarinic acid (see Payne, et al. 1991, “Plant Cell and Tissue Culture in Liquid 0004 B. Related Art Systems. Hanser Publishers, Munich). The Taxane Supply Challenge 0011 The advantages of a plant cell culture process for 0005 Taxol is a diterpenoid alkaloid originally isolated taxol, baccatin III, and taxanes are many: (i) A cell culture from the bark of the pacific yew, Taxus brevifolia (Wani, et al. process ensures a limitless, continuous and uniform Supply of 1971, J. Am. Chem. Soc., 93, 2325-2327). Interest in taxol product, and is not subject to pests, disasters and seasonal began when the National Cancer Institute (NCI), in a large fluctuations, (ii) cell cultures can be cultivated in large biore scale screening program, found that crude bark extracts actors, and can be induced to overproduce the compound of exhibited anti-tumor activities. Since then, clinical trials have interest by manipulating environmental conditions, (iii) cell confirmed that taxol is extremely effective against refractory cultures produce a simpler spectrum of compounds compared ovarian cancers, and against breast and other cancers. Taxol to bark or needles, considerably simplifying separation and has been pronounced as a breakthrough in chemotherapy purification, (iv) a cell culture process can adapt quickly to because of its fundamentally different mechanism of cytotox rapid changes in demand better than agriculture-based pro icity, i.e., by inhibiting depolymerization of microtubules cesses, (v) besides Supplying taxol, baccatin III or other pre (see Rowinsky, et al., 1990, J. Natl. Cancer Inst., 82, 1247 cursors, a cell culture process could also produce taxane 1259). compounds that exhibit advantageous bioactivity profiles, or 0006 A daunting variable in the taxol equation has been that could be converted into other bioactive derivatives. supply. Bark-derived taxol has been discontinued as the pri 0012 Since aseptic, large-scale, plant cell cultivation is mary source of commercial drug; large-scale production has inherently expensive, a cell culture process becomes com been achieved by semi-synthesis, i.e., chemical attachment of mercially relevant only when these costs are offset by high a side chain to the plant-derived precursor, 10-deacetylbac productivity. Every plant species and target metabolite is catin III. Total synthesis, while accomplished by academic different, and different approaches are necessary for every laboratories, shows little promise as a viable commercial particular system. This invention focuses on creative and route to taxol. There is therefore an urgent need to develop skilled approaches for obtaining highly productive plant cell cost-effective, environmentally-benign, and consistent cultures for taxol, baccatin III, and taxane production. Sources of Supply to keep up with the growing demand for taxol. Problems with Tissue Cultures of Woody Plants and Conifers 0007. In addition to taxol, there is an urgent need to 0013 A historical survey of the literature suggests that develop processes for the commercial production of related whereas herbaceous plants have been relatively easily taxane molecules. Derivatives of taxol such as Taxotere have manipulated in culture, productive cultures of woody plants already been introduced into the world market.
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