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Production for Biologically Active Polypeptide

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Production for Biologically Active Polypeptide Europaisches Patentamt J European Patent Office Oy Publication number: 0 625 574 A1 Office europeen des brevets EUROPEAN PATENT APPLICATION © Application number: 94107586.3 © int. ci.5;C12N 15/12, C12N 15/85, C12N 15/18, C12P 21/00, @ Date of filing: 17.05.94 C12N 5/06, C12N 5/16 Priority: 19.05.93 JP 117283/93 © Applicant: Takeda Chemical Industries, Ltd. 14.04.94 JP 75553/94 1-1 Doshomachi 4-chome, Chuo-ku Date of publication of application: Osaka-shi, Osaka 541 (JP) 23.11.94 Bulletin 94/47 © Inventor: Sawada, Hidekazu Designated Contracting States: 531 -Oaza-takamiya AT BE CH DE DK ES FR GB GR IE IT LI LU NL Neyagawa, Osaka 572 (JP) PTSE Inventor: Takekawa, Shiro 5-3-B305, Umezono 2-chome Tsukuba, Ibaraki 305 (JP) Inventor: Nishimura, Osamu 54-16, Daiwanishi 1-chome Kawanishi, Hyogo 666-01 (JP) © Representative: von Kreisler, Alek, Dipl.-Chem. et al Patentanwalte von Kreisler-Selting-Werner Bahnhofsvorplatz 1 (Deichmannhaus) D-50667 Koln (DE) Production for biologically active polypeptide. © The present invention provides a method of producing a biologically active polypeptide by culturing animal cells capable of producing the polypeptide, adapted to agitation culture in suspension in serum-free medium, and Chinese hamster ovarian cells, capable of proliferation in suspension in serum-free medium, which produce a polypeptide belonging to the human nerve growth factor family and is useful for industrial mass production of a biologically active polypeptide in high purity. ID ID CM CO UJ Rank Xerox (UK) Business Services (3.10/3.09/3.3.4) EP 0 625 574 A1 Field of the invention The present invention relates to a method of efficiently producing a eukaryotic biologically active polypeptide by culturing recombinant animal cells in suspension in serum-free medium, and cells capable 5 of producing the biologically active polypeptide by the culture of the present invention. Background of the invention The mass-culture of recombinant animal cells is very important for the production of biologically active w polypeptides such as interferons, erythropoietin, tissue plasminogen activator, granulocyte colony stimulat- ing factors and nerve growth factors. For example, the nerve growth factor (hereinafter sometimes abbreviated to as NGF) family is known to play a key role in the survival of cholinergic neurons in the procephalic basal field in the central nervous system, as well as being essential for the survival of sensory or sympathetic nerve ganglion cells in the 75 peripheral nervous system. Since NGF acts to enhance neuron survivability as stated above; since intracerebral administration of NGF improved memory disorder in aged rats [W. Fischer et al., Nature, Vol. 329, p. 65 (1887)]; and since research has advanced drug delivery systems for intracerebral transportation of intravenously administered NGF [P.M. Friden et al., Science, Vol. 259, p. 373 (1993)], there is a need for industrial production of NGF with the expectation that it is applicable to Pharmaceuticals for senile 20 dementia. For producing biologically active polypeptides by animal cell, both suspensive and adherent types of cells can be used for host cells: suspensive cells such as human Burkitt's lymphoma (Namalwa) cells and mouse myeloma (Sp2/0) cells, and adhesive cells such as Chinese hamster ovary (CHO) cells, baby hamster kidney (BHK) cells, human uterocervical epitheloid carcinoma (HeLa) cells, mouse mammary tumor 25 (C127) cells and mouse fibroblast (NIH/3T3) cells. CHO cells, in particular, are commonly used [C. Bebbington and C. Hentschel, Trends in Biotechnology, Vol. 3, p. 314 (1985); D. Broad et al., Cytotech- nology, Vol. 5, p.47 (1991)]. Suspensive cells usually permit agitation culture in suspension, while adhesive cells, not easy to culture in suspension, are usually cultured by roller bottle culture, microcarrier culture or culture in which cells are 30 immobilized on an immobilizing bed. For industrial mass production of valuable substances, however, suspension culture is advantageous over immobilized culture from the viewpoint of operation and scale-up feasibility. Recently it was reported that the erythroblast differentiation factor (EDF) gene introduced adhesive CHO cells were adapted to suspension culture by forcedly repeating culture in suspension [M. Murata et al., Journal of Fermentation Technology, Vol. 66, p. 501 (1988)], but these cells were only viable 35 for five days in serum-free medium. The above-mentioned host cells all require serum for their proliferation, and are usually incapable of proliferating in serum-free medium. Serum contains various unknown protein substances and its quality fluctuates among lots. Because of these features, serum interferes with purification of the desired biologically active polypeptide. In Pharmaceuticals, in particular, the use of serum-containing medium 40 requires painstaking tests concerning removal of serum-derived impurities for safety evaluation. In addition, serum is expensive. Accordingly, the serum-containing medium is variously problematic for industrial production of a substance, and the use of serum-free medium is desired. In recent years, there have been some reports of adaptation to serum-free medium of serum-dependent cells such as Namalwa cells or the antithrombin III gene transfected CHO cells [S. Hosoi et al., Cytotechnology, Vol. 5, p. 17 (1991); T. 45 Yamauchi et al., Biosci. Biotech. Biochem., Vol. 56, p. 600 (1990)]. It is necessary, however, to determine what kinds of medium are suitable to serum-free medium adaptation on a cell-by-cell basis because commonly used serum-free media are diverse. Also, cell lines adapted to serum-free medium do not always retain their original productivity; a highly productive strain must be bred again in the case of productivity reduction. 50 For efficient production of substances by cell culture, it is usually advantageous to continuously culture cells at high density for a long period of time. In culturing suspensive cells such as hybridomas for producing monoclonal antibodies and recombinant mouse myeloma cells encoding desired substance, high cell density perfusion culture in suspension has been attempted in which cells are continuously cultured for a long period of time while fresh medium is supplied to the culture vessel and culture supernatant 55 containing waste products is removed from the culture vessel [K. Kitano et al., Applied Microbiology and Biotechnology, Vol. 24, p. 282 (1986); Y. Takazawa and M. Tokashiki, Cytotechnology, Vol. 2, p. 95 (1989)]. However, there are no animal cells adapted to both of suspension culture and serum independence which were originally adhesive and serum-dependent. EP 0 625 574 A1 Although the development of mass production methods of various biologically active polypeptides is desired, as described above, no such production methods have been well established. For production of human NGF of high specific activity by cell culture, for instance, the use of the human NGF gene introduced CHO cells [Iwane et al., Biochemical and Biophysical Research Communication, Vol. 171, p. 116 5 (1990)] is best. This method, however, uses a medium containing about 5% fetal calf serum, and all proposed culture designs are of small laboratory scale and short term. For industrial mass production of biologically active polypeptides, it is necessary to improve production methods and increase the production scale. w Summary of the invention The present inventors investigated methods of efficiently producing the desired biologically active polypeptide using recombinant CHO cells that produce human NGF, and discovered a technique for very efficient production of biologically active polypeptides such as the human NGF family. The inventors made 75 further investigations based on this finding, and developed the present invention. Accordingly, the present invention relates to a method of producing a biologically active polypeptide for extended period of time which comprises adapting adhesion-dependent cells, i.e., adhesive animal cells, capable of producing said biologically active polypeptide, to be adhension-indepondent, i.e., adapted to agitation culture in suspension and adapting said cells to grow in serum-free medium. Preferably, the 20 extended period of time for production of the biologically active polypeptide is more than 20 days, more preferably, more than 40 days and most preferably, more than 60 days. The animal cells are preferably Chinese hamster ovary cells, and the biologically active polypeptide is preferably a peptide belonging to the human nerve growth factor family, especially NGF or NGF-2, further the culture method is preferably agitation culture in suspension and also perfusion culture. The present invention also relates to Chinese 25 hamster ovary cells which produce a peptide belonging to the human nerve growth factor family and which is capable of proliferation in serum-free medium with suspension for extended period of time, more specifically the polypeptide is NGF or NGF-2. Brief description of the drawings 30 Figure 1 shows the time course of serum-free batch culture in suspension of SF-K45 obtained in Example 4. Figure 2 shows the time course of serum-free perfusion culture in suspension of SF-K45 obtained in Example 4. 35 Figure 3 shows results of SDS-PAGE of the preparation of the purified human NGF obtained in Example 4. In these figures, M represents a molecular weight marker, A represents the preparation of purified human NGF obtained in Example 4 and B represents the preparation of mouse NGF
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