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公开(公告)号：US08232075B2
公开(公告)日：2012-07-31
申请号：US11936866
申请日：2007-11-08
申请人： Yen-Tung Luan , Wenge Wang , Ryan Nolan , Denis Drapeau
发明人： Yen-Tung Luan , Wenge Wang , Ryan Nolan , Denis Drapeau
CPC分类号： C12Q1/02 , C12N5/0018 , C12N2500/32
摘要： This invention relates to methods for rationally designing cell culture media for use in cell cultures, e.g., cell cultures employed in polypeptide production; cell culture media designed with the disclosed methods; methods of producing a polypeptide of interest, e.g., an antibody, using such media; polypeptides produced using the methods and media disclosed herein; and pharmaceuticals compositions containing such polypeptides. The rationally designed media contain a concentration of an amino acid that is calculated for use in cell mass, a concentration of the amino acid that is calculated for use in cell maintenance, and a concentration of the amino acid that is calculated for incorporation into the polypeptide of interest.
摘要翻译： 本发明涉及用于合理设计用于细胞培养物的细胞培养基的方法，例如用于多肽生产的细胞培养物; 用公开的方法设计的细胞培养基; 使用这种培养基生产感兴趣多肽的方法，例如抗体; 使用本文公开的方法和介质产生的多肽; 和含有这种多肽的药物组合物。 合理设计的培养基含有计算用于细胞质量的氨基酸浓度，计算用于细胞维持的氨基酸浓度，以及计算用于掺入多肽的氨基酸浓度 出于兴趣。
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公开(公告)号：US20090317867A1
公开(公告)日：2009-12-24
申请号：US12425056
申请日：2009-04-16
申请人： Yen-Tung Luan , Wenge Wang , Gregg Nyberg , Jose Manuel Gomes , Denis Drapeau , Terry Cardoza
发明人： Yen-Tung Luan , Wenge Wang , Gregg Nyberg , Jose Manuel Gomes , Denis Drapeau , Terry Cardoza
IPC分类号： C12P21/00
CPC分类号： C12P21/02 , A61K38/00 , C07K14/51 , C12N1/38 , C12N5/0037 , C12N2500/24 , C12N2500/38 , C12N2501/90 , C12N2510/02
摘要： Methods and processes for improved recombinant protein production are provided. The methods are useful for production of growth factors, particularly those of the TGF-β superfamily, including bone morphogenetic proteins (BMPs), such as BMP-2. Suitable host cells are cultured in media where iron is present at a concentration of at least 2.25 μM and if pyridoxal is present, it makes up less than 55% of the molar concentration of vitamin B6 in the media.
摘要翻译： 提供了改良重组蛋白生产的方法和方法。 该方法可用于生长生长因子，特别是TGF-β超家族的生长因子，包括骨形态发生蛋白（BMP），如BMP-2。 合适的宿主细胞在培养基中培养，其中铁以至少2.25μM的浓度存在，并且如果存在吡哆醛，则其占培养基中维生素B6的摩尔浓度的小于55％。
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公开(公告)号：US20080274507A1
公开(公告)日：2008-11-06
申请号：US12107533
申请日：2008-04-22
IPC分类号： C12P21/04
CPC分类号： C12P21/02 , C07K14/70578 , C12N2500/33 , C12N2510/02 , C12P21/005
摘要： Methods of producing a protein in cell culture comprising an anti-senescence compound, such as the antioxidant carnosine, are provided. According to teachings of the present invention, cells grown in a cell culture medium comprising an anti-senescence compound exhibit increased viability and productivity. Furthermore, cell cultures grown in the presence of an anti-senescence compound exhibit decreased levels of high molecular weight aggregates in the cell culture medium.
摘要翻译： 提供了包含抗衰老化合物如抗氧化肌肽的细胞培养物中产生蛋白质的方法。 根据本发明的教导，在包含抗衰老化合物的细胞培养基中生长的细胞表现出增加的活力和生产力。 此外，在抗衰老化合物存在下生长的细胞培养物在细胞培养基中表现出降低的高分子量聚集体的水平。
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公开(公告)号：US07429491B2
公开(公告)日：2008-09-30
申请号：US10847729
申请日：2004-05-17
IPC分类号： C12N5/02
CPC分类号： C12N5/0018 , C12N2500/34
摘要： Methods of improving protein production in animal cell cultures are provided. Cell culture methods are presented wherein glucose is fed in a restricted manner to cell culture; this restricted feeding of glucose to the cell culture results in lactate production being controlled to a low level. The restricted feeding of glucose in a fed-batch process is not accomplished through a constant-rate feeding of glucose, and the restricted feeding need not depend on sampling. Instead, restricted feeding of glucose to the culture is accomplished through feeding of glucose to the culture at a rate that is a function of an expected or a premodeled rate of glucose consumption by the animal cells when exposed to medium containing a high level of glucose. Because lactate production is controlled to low levels, recombinant protein production is increased.
摘要翻译： 提供了改善动物细胞培养物中蛋白质生产的方法。 提出了细胞培养方法，其中将葡萄糖以有限的方式加入到细胞培养物中; 这种限制性地将葡萄糖摄入细胞培养物导致乳酸生产被控制到低水平。 在补料分批过程中限制的葡萄糖喂养不能通过葡萄糖的恒定速率进料来实现，而限制进料不需要依赖于取样。 相反，通过将葡萄糖以暴露于含有高水平葡萄糖的培养基的动物细胞的葡萄糖消耗的预期或预先模拟速率的函数的速率供给到培养物中来实现葡萄糖向培养物的进食。 由于乳酸生产控制在低水平，因此重组蛋白质生产增加。
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公开(公告)号：US08192951B2
公开(公告)日：2012-06-05
申请号：US11934458
申请日：2007-11-02
申请人： Wenge Wang , Yen Tung Luan
发明人： Wenge Wang , Yen Tung Luan
CPC分类号： C12N5/0018 , C12N2500/34 , C12N2510/02
摘要： An improved system for large scale production of proteins and/or polypeptides in cell culture is provided. In accordance with the present invention, cells expressing the protein or polypeptide of interest are grown in media that comprise a glycolysis-inhibiting substance. Additionally and/or alternatively, cells expressing the protein or polypeptide of interest are grown in media in which glutamine is limited. The use of such a system allows high levels of protein or polypeptide production and lessens accumulation of undesirable metabolic waste products such as lactate. Proteins and polypeptides expressed in accordance with the present invention may be advantageously used in the preparation of pharmaceutical, immunogenic, agricultural or other commercial compositions.
摘要翻译： 提供了在细胞培养物中大规模生产蛋白质和/或多肽的改进系统。 根据本发明，表达目的蛋白或多肽的细胞在包含糖酵解抑制物质的培养基中生长。 另外和/或替代地，表达目的蛋白质或多肽的细胞在限制谷氨酰胺的培养基中生长。 使用这种系统允许高水平的蛋白质或多肽产生并减少不合需要的代谢废物（例如乳酸盐）的积累。 根据本发明表达的蛋白质和多肽可有利地用于制备药物，免疫原性，农业或其它商业组合物。
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公开(公告)号：US08039231B2
公开(公告)日：2011-10-18
申请号：US12425056
申请日：2009-04-16
申请人： Yen-Tung Luan , Wenge Wang , Gregg Nyberg , Jose Manuel Gomes , Denis Drapeau , Terry Cardoza
发明人： Yen-Tung Luan , Wenge Wang , Gregg Nyberg , Jose Manuel Gomes , Denis Drapeau , Terry Cardoza
IPC分类号： C12P21/06
CPC分类号： C12P21/02 , A61K38/00 , C07K14/51 , C12N1/38 , C12N5/0037 , C12N2500/24 , C12N2500/38 , C12N2501/90 , C12N2510/02
摘要： Methods and processes for improved recombinant protein production are provided. The methods are useful for production of growth factors, particularly those of the TGF-β superfamily, including bone morphogenetic proteins (BMPs), such as BMP-2. Suitable host cells are cultured in media where iron is present at a concentration of at least 2.25 μM and if pyridoxal is present, it makes up less than 55% of the molar concentration of vitamin B6 in the media.
摘要翻译： 提供了改良重组蛋白生产的方法和方法。 该方法可用于生长生长因子，特别是TGF-β的生长因子; 超家族，包括骨形态发生蛋白（BMP），如BMP-2。 合适的宿主细胞在其中铁以至少2.25μM的浓度存在的培养基中培养，并且如果存在吡哆醛，则其占培养基中维生素B6的摩尔浓度的小于55％。
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公开(公告)号：US20080108553A1
公开(公告)日：2008-05-08
申请号：US11936866
申请日：2007-11-08
申请人： Yen-Tung Luan , Wenge Wang , Ryan Nolan , Denis Drapeau
发明人： Yen-Tung Luan , Wenge Wang , Ryan Nolan , Denis Drapeau
CPC分类号： C12Q1/02 , C12N5/0018 , C12N2500/32
摘要： This invention relates to methods for rationally designing cell culture media for use in cell cultures, e.g., cell cultures employed in polypeptide production; cell culture media designed with the disclosed methods; methods of producing a polypeptide of interest, e.g., an antibody, using such media; polypeptides produced using the methods and media disclosed herein; and pharmaceuticals compositions containing such polypeptides. The rationally designed media contain a concentration of an amino acid that is calculated for use in cell mass, a concentration of the amino acid that is calculated for use in cell maintenance, and a concentration of the amino acid that is calculated for incorporation into the polypeptide of interest. The rationally designed media may contain a baseline-adjusted concentration, A, of at least one amino acid that is calculated according to the formula A=[(M*X)+(N*P)+(Y*M*X)]*F, wherein X is the concentration of the amino acid that is used per unit of cell mass, P is the concentration of the amino acid that is used for incorporation into the polypeptide of interest per unit of polypeptide titer, M is the multiplier for the desired peak cell density of the cell culture, N is the multiplier for the desired concentration of the polypeptide of interest, Y is the cell maintenance factor; and F is the baseline factor. This rationally designed media may also be used to produce a starting cell culture medium comprising a concentration, B, of at least one amino acid according to the formula B=[A−(Z*V)]/(1−V), wherein Z is a concentration of the amino acid in the feeding cell culture medium, and V is a volume of the feeding culture medium as a proportion of the desired cell culture medium volume.
摘要翻译： 本发明涉及用于合理设计用于细胞培养物的细胞培养基的方法，例如用于多肽生产的细胞培养物; 用公开的方法设计的细胞培养基; 使用这种培养基生产感兴趣多肽的方法，例如抗体; 使用本文公开的方法和介质产生的多肽; 和含有这种多肽的药物组合物。 合理设计的培养基含有计算用于细胞质量的氨基酸浓度，计算用于细胞维持的氨基酸的浓度以及计算用于掺入多肽的氨基酸的浓度 出于兴趣。 合理设计的培养基可以含有根据公式A = [（M * X）+（N * P）+（Y * M * X）]计算的至少一个氨基酸的基线调整浓度A * F，其中X是每单位细胞质量使用的氨基酸的浓度，P是单位多肽滴度用于掺入感兴趣多肽的氨基酸的浓度，M是 细胞培养物所需的峰值细胞密度，N是感兴趣多肽所需浓度的乘数，Y是细胞维持因子; F是基线因子。 这种合理设计的培养基也可用于产生包含至少一种根据式B = [A-（Z * V）] /（1-V）的氨基酸的浓度B的起始细胞培养基，其中 Z是饲养细胞培养基中氨基酸的浓度，V是作为所需细胞培养基体积的比例的饲养培养基的体积。
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公开(公告)号：US20060160180A1
公开(公告)日：2006-07-20
申请号：US11213317
申请日：2005-08-25
申请人： Denis Drapeau , Yen-Tung Luan , James Mercer , Wenge Wang , Daniel Lasko
发明人： Denis Drapeau , Yen-Tung Luan , James Mercer , Wenge Wang , Daniel Lasko
CPC分类号： C07K16/28 , C07K16/00 , C07K16/18 , C07K16/22 , C07K2319/30 , C12N5/0018 , C12N2500/20 , C12N2500/32 , C12N2510/04 , C12P21/00
摘要： An improved system for large scale production of proteins and/or polypeptides in cell culture, particularly in media characterized by one or more of: i) a cumulative amino acid concentration greater than about 70 mM; ii) a molar cumulative glutamine to cumulative asparagine ratio of less than about 2; iii) a molar cumulative glutamine to cumulative total amino acid ratio of less than about 0.2; iv) a molar cumulative inorganic ion to cumulative total amino acid ratio between about 0.4 to 1; or v) a combined cumulative glutamine and cumulative asparagine concentration between about 16 and 36 mM, is provided. The use of such a system allows high levels of protein production and lessens accumulation of certain undesirable factors such as ammonium and/or lactate. Additionally, culture methods including a temperature shift, typically including a decrease in temperature when the culture has reached about 20-80% of it maximal cell density, are provided. Alternatively or additionally, the present invention provides methods such that, after reaching a peak, lactate and/or ammonium levels in the culture decrease over time.
摘要翻译： 特别是在以下一个或多个特征的介质中大规模生产蛋白质和/或多肽的改进系统：i）累积的氨基酸浓度大于约70mM; ii）累积谷氨酰胺的累积天冬酰胺摩尔比小于约2; iii）累积谷氨酰胺与累积总氨基酸的摩尔比小于约0.2; iv）摩尔累计无机离子与累积总氨基酸比例在约0.4至1之间; 或v）组合的累积谷氨酰胺和约16至36mM之间的累积天冬酰胺浓度。 使用这样的系统允许高水平的蛋白质产生并减少某些不需要的因素例如铵和/或乳酸盐的积累。 此外，提供包括温度变化的培养方法，通常包括当培养物达到其最大细胞密度的约20-80％时的温度降低。 或者或另外，本发明提供了在达到峰值之后，培养物中的乳酸盐和/或铵水平随时间降低的方法。
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公开(公告)号：US20060121568A1
公开(公告)日：2006-06-08
申请号：US11213308
申请日：2005-08-25
申请人： Denis Drapeau , Yen-Tung Luan , James Mercer , Wenge Wang , Daniel Lasko
发明人： Denis Drapeau , Yen-Tung Luan , James Mercer , Wenge Wang , Daniel Lasko
IPC分类号： C12P21/06 , C07K14/705 , C12N5/06
CPC分类号： C12P21/02 , C07K16/18 , C07K16/22 , C07K16/2896 , C07K2317/24 , C12N5/0037 , C12N2500/22 , C12N2500/32 , C12N2500/38 , C12N2500/60 , C12N2510/02
摘要： An improved system for large scale production of proteins and/or polypeptides in cell culture, particularly in media characterized by one or more of: i) a cumulative amino acid concentration greater than about 70 mM; ii) a molar cumulative glutamine to cumulative asparagine ratio of less than about 2; iii) a molar cumulative glutamine to cumulative total amino acid ratio of less than about 0.2; iv) a molar cumulative inorganic ion to cumulative total amino acid ratio between about 0.4 to 1; or v) a combined cumulative glutamine and cumulative asparagine concentration between about 16 and 36 mM, is provided. The use of such a system allows high levels of protein production and lessens accumulation of certain undesirable factors such as ammonium and/or lactate. Additionally, culture methods including a temperature shift, typically including a decrease in temperature when the culture has reached about 20-80% of it maximal cell density, are provided. Alternatively or additionally, the present invention provides methods such that, after reaching a peak, lactate and/or ammonium levels in the culture decrease over time.
摘要翻译： 特别是在以下一个或多个特征的介质中大规模生产蛋白质和/或多肽的改进系统：i）累积的氨基酸浓度大于约70mM; ii）累积谷氨酰胺的累积天冬酰胺摩尔比小于约2; iii）累积谷氨酰胺与累积总氨基酸的摩尔比小于约0.2; iv）摩尔累计无机离子与累积总氨基酸比例在约0.4至1之间; 或v）组合的累积谷氨酰胺和约16至36mM之间的累积天冬酰胺浓度。 使用这样的系统允许高水平的蛋白质产生并减少某些不需要的因素例如铵和/或乳酸盐的积累。 此外，提供包括温度变化的培养方法，通常包括当培养物达到其最大细胞密度的约20-80％时的温度降低。 或者或另外，本发明提供了在达到峰值之后，培养物中的乳酸盐和/或铵水平随时间降低的方法。
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公开(公告)号：US20050070013A1
公开(公告)日：2005-03-31
申请号：US10847729
申请日：2004-05-17
申请人： Yen-Tung Luan , Terry Stanek , Denis Drapeau
发明人： Yen-Tung Luan , Terry Stanek , Denis Drapeau
CPC分类号： C12N5/0018 , C12N2500/34
摘要： Methods of improving protein production in animal cell cultures are provided. Cell culture methods are presented wherein glucose is fed in a restricted manner to cell culture; this restricted feeding of glucose to the cell culture results in lactate production being controlled to a low level. The restricted feeding of glucose in a fed-batch process is not accomplished through a constant-rate feeding of glucose, and the restricted feeding need not depend on sampling. Instead, restricted feeding of glucose to the culture is accomplished through feeding of glucose to the culture at a rate that is a function of an expected or a premodeled rate of glucose consumption by the animal cells when exposed to medium containing a high level of glucose. Because lactate production is controlled to low levels, recombinant protein production is increased.
摘要翻译： 提供了改善动物细胞培养物中蛋白质生产的方法。 提出了细胞培养方法，其中将葡萄糖以有限的方式加入到细胞培养物中; 这种限制性地将葡萄糖摄入细胞培养物导致乳酸生产被控制到低水平。 在补料分批过程中限制的葡萄糖喂养不能通过葡萄糖的恒定速率进料来实现，而限制进料不需要依赖于取样。 相反，通过将葡萄糖以暴露于含有高水平葡萄糖的培养基的动物细胞的葡萄糖消耗的预期或预先模拟速率的函数的速率供给到培养物中来实现葡萄糖向培养物的进食。 由于乳酸生产控制在低水平，因此重组蛋白质生产增加。
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