WO2002076578A1 - Control of glycoforms in igg - Google Patents
Control of glycoforms in igg Download PDFInfo
- Publication number
- WO2002076578A1 WO2002076578A1 PCT/US2002/009998 US0209998W WO02076578A1 WO 2002076578 A1 WO2002076578 A1 WO 2002076578A1 US 0209998 W US0209998 W US 0209998W WO 02076578 A1 WO02076578 A1 WO 02076578A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- nghc
- culture
- osmolality
- temperature
- batched
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
- C07K2317/41—Glycosylation, sialylation, or fucosylation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
Definitions
- This invention relates to processes for controlling glycoforms in recombinantly produced IgG.
- Monoclonal antibodies (IgG isotypes) are produced using a variety of expression systems.
- the majority of the expression systems used for production of monoclonal antibodies are mammalian and include host systems such as Chinese hamster ovary (CHO) , hybridoma and myeloma cells or their derivatives .
- Antibodies significantly differ from other recombinant proteins in their glycosylation patterns . Glycosylation tends to be highly conserved in IgG molecules with a single N-linked biantennary structure at Asn297, which is buried between the CH2 domains, forming extensive contacts with the amino acid residues within CH2. Typically, in recombinantly produced IgG, there is heterogeneous processing of the core oligosaccharide structures attached at the Asn297 site and the IgGs exist in multiple glycoforms. In contrast, non-IgG proteins produced in CHO cells may have multiple N-linked glycosylation sites.
- IgG N-linked glycoforms can vary by site occupancy of the Asn site, i.e., macroheterogeneity, or by variation in the oligosaccharide structure at the glycosylation site, i.e., microheterogeneity. This includes variations in sugar residues, in the length of the oligosaccharide or in the number of branches making up the oligosaccharide (biantennary and triantennary structures). See Jenkins, Parekh, James, (1996) Nature Biotechnology, 14:975-981.
- NGHC non-glycosylated heavy chain
- 5,705,364 describes a process for controlling sialic acid content in a glycoprotein produced in a mammalian host cell such as CHO by controlling temperature and osmolality in the presence of an alkanoic acid.
- a mammalian host cell such as CHO
- culture pH and ammonia concentration affected glycosylation of recombinant mouse placental lactogen proteins produced in CHO cells. See Borys, inzer, Papoutsakis, (1993) Bio/Technology, 11:720-724 and Borys, Linzer, Papoutsakis, (1993) Biotechnology and Bioengineering, 43:505-514.
- Primatone RL an animal tissue hydrolysate, affects sialylation of IFN- ⁇ in batch and fed-batch mode. See Gu, Zie, Harmon, Wang, (1997) Biotechnology and Bioengineering, 56:353-360. Glucose limitation is suggested to affect site occupancy of IFN- ⁇ due to a reduction in nucleotide biosynthesis. See Nyberg, Balcarcel, Follstad, Stephanopoulos, Wang, (1998) Biotechnology and Bioengineering, 62:336-347. The contribution of the oligosaccharide side chain to IgG function has been greatly debated. One of the key functions of the carbohydrate structure is in the complement fixation pathway and the extent of glycosylation has been directly correlated to antibody-dependent cellular cytotoxicity (ADCC) and recruitment of complement. See
- Fig. 1 is a graph of experimental results demonstrating the effect of culture temperature on NGHC formation.
- Fig. 2 is a graph of experimental results demonstrating the effect of culture temperature and batched medium osmolality on NGHC formation.
- Fig. 3 is a graph of a statistical regression of experimental results predicting the effect of culture temperature and batched medium osmolality on NGHC formation.
- Fig. 4 is a graph of experimental results demonstrating the reduction of NGHC in two 1200 L pilot plant batches by increasing culture temperature and reducing batched medium osmolality.
- Fig. 5 is a graph of experimental results demonstrating the reduction of NGHC using an in-house and two commercially available media by manipulating temperature and batched medium osmolality. Detailed Description of the Invention
- the present invention provides a method to control the level of IgG non-glycosylated heavy chain (NGHC) in a cell culture process producing a recombinant monoclonal antibody.
- NGHC IgG non-glycosylated heavy chain
- the level of NGHC can be decreased or increased.
- Batched medium osmolality of a final seed culture used to inoculate a production culture can optionally be adjusted to match that of the production culture.
- NGHC can be decreased by increasing the temperature of the cell culture. Likewise, NGHC can be increased by decreasing the temperature of the cell culture. Preferred temperatures for the process are within a range of about 33 °C to about 35°C.
- NGHC can be decreased by decreasing the batched medium osmolality in the cell culture.
- NGHC can be increased by increasing the batched medium osmolality of the cell culture.
- Preferred osmolalities for the process are within a range of about 285 mOsm to about 417 mOsm.
- NGHC level can be decreased by combining increased temperature and low batched medium osmolality of the cell culture. In yet another embodiment of the invention, NGHC level can be increased by combining decreased temperature and increased batched medium osmolality of the cell culture.
- the process of the invention provides for NGHC control at a constant level at any temperature within the preferred range if batched medium osmolality is constant.
- NGHC can be controlled at a constant level at any batched medium osmolality within the preferred range if temperature is held constant.
- media compositions consisted of a basal formulation containing amino acids, salts, trace elements, and vitamins similar to those described in PCT
- Yeast hydrolysate such as TC yeastolate was added in an amount of 5 g/L or 10 g/L. Supplemental glucose was added at either 4.5 g/L or 9 g/L. The medium was supplemented with ferric fructose or ferric EDTA, recombinant insulin and a lipid mixture. Sodium bicarbonate was added to batched media as a buffer and methotrexate was added to batched media as a selective agent to maintain expression of the recombinant protein. The surfactant Lutrol F68 was also added to batched media. Batched medium osmolality for seed and production bioreactors are stated in each Example. Osmolality of the batched medium was adjusted by adding NaCl and KC1. During cultivation in bioreactors, sodium carbonate was added as needed for pH control. Media was sterilized by either 0.1 or 0.2 micron filtration.
- Example 7 proprietary medium as described above was used. Additionally, cells were adapted to two commercially available media, CD-CHO (Invitrogen, Rockville, MD) and EX- CELL 325 (JRH Biosciences, Lenexa, KS) . All cultures were then evaluated for NGHC production at various temperatures and batched medium osmolalities.
- Data was generated by cultivation of a recombinant CHO cell line producing an IgGl anti-CD4 monoclonal antibody in shake flasks and 3L Applikon bioreactors. This antibody is described as CE9.1 in U.S. Pat. No. 6,136,310.
- Shake flask scale-up cultures were grown in medium with an osmolality in the range of 370-380 mOsm and shaken at 150 RPM in a 5% carbon dioxide incubator at 37°C. Cells were passed on a 3-4 day schedule with a target seeding density of 600,000 viable cells/mL.
- 3L production bioreactors were operated the same as seed reactors except for temperature and pH setpoints which varied depending on the example. Every one or two days, cells in seed and production bioreactors were trypsinized and counted using trypan blue exclusion and a hemacytometer for percent viability and a ZM Coulter Counter for total cell count. Batched media osmolalities were as specified in each example.
- the 300 L was used to inoculate a 1500 L ABEC production bioreactor with a 1200 L culture volume.
- the production reactor was operated at temperatures specified in the example and pH 6.9-7.0 with dissolved oxygen of 48 mm Hg.
- Batched medium osmolality for the 80 L seed reactor was 370-380 mOsm.
- Batched medium osmolality for the 750 L ABEC seed reactor and the 1500 L ABEC production reactor was as specified in the Example.
- Shake flask scale-up cultures of the recombinant cell line were shaken at 150 RPM, in a 5% carbon dioxide incubator at 37°C. Cells were passed on a 3-4 day schedule with a target seeding density of 800,000 VCC/mL. On passage days, cells were trypsinized and counted using trypan blue exclusion and a hemacytometer for percent viability and a Zl Coulter Counter for total cell count.
- a vial of cells was thawed and scaled using medium as described above for 4 passages .
- a subset of these cells continued to be scaled using this medium and two other portions were adapted to two commercial media, CD-CHO (Invitrogen) and EXCELL-325 (JRH Biosciences) , using the following ratios of in-house media to vendor media over 5 passages: 100/0, 50/50, 0/100.
- Batched medium osmolalities for scale-up and adaptation were 358 mOsm for in-house medium and 353 mOsm for the commercial media.
- cells in each medium were subcultured into like media batched at low, mid, and high osmolalities.
- Example 1 cells were filtered from the production cultures. For each batch, product was captured and concentrated on a protein A affinity column. The product eluate was then analyzed for % NGHC by densitometry scans of reduced SDS-PAGE gels. NGHC was reported as percentage of the total heavy chain or as percentage of total heavy and light chain as specified in each example.
- Example 6 cells were filtered from the production cultures. For each batch, product underwent capture and concentration on an affinity column and then was processed through 2 more chromatography steps . Final product was then analyzed for % NGHC by densitometry scans of SDS-PAGE gels.
- Example 7 cells were filtered from the production cultures. For each batch, product was captured and concentrated on an affinity column. The product eluate was then analyzed for % NGHC by a capillary SDS-PAGE separation performed on a micro-capillary array using an Agilant Bioanalyzer .
- Figure 2 illustrates NGHC versus temperature and osmolality.
- NGHC could be reduced in 1200L bioreactor cultures by increasing culture temperature and reducing batched medium osmolality.
- Standard production bioreactor culture temperature was 33.9°C and osmolality for seed flasks, seed bioreactors and the production reactor was 370-380 mOsm.
- the culture temperature of the production bioreactor was increased to 34.5°C and batched medium osmolality reduced to 305-315 mOsm.
- the batched osmolality of the final 750L seed bioreactor was also reduced to 305-315 mOsm.
- Average NGHC for the 18 standard batches was 5.7%.
- NGHC values as percent of total protein for the 2 "low NGHC" batches were 1.7% and
- Figure 4 illustrates NGHC levels as percent of total protein in all batches.
- NGHC could be reduced using in- house medium and two commercially available media, CD-CHO (Invitrogen) and EXCELL-325 (JRH Biosciences) by adjusting temperature and osmolality.
- CD-CHO Invitrogen
- EXCELL-325 JRH Biosciences
- Osmolalities for the proprietary medium were 310, 358, and 405 mOsm.
- Osmolalities for the commercial medium were 300, 353, and 405 mOsm.
- Table 6 and Figure 5 indicate a trend similar to that demonstrated in previous examples. At low temperature, NGHC formation as % of total protein is higher and more sensitive to batched medium osmolality than at mid and high temperatures. Glucose was not depleted in any of the tested conditions. Table 6
Abstract
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2002575087A JP2005509403A (en) | 2001-03-27 | 2002-03-27 | Control of glycoforms in IgG |
EP02725443A EP1373547A4 (en) | 2001-03-27 | 2002-03-27 | Control of glycoforms in igg |
AU2002256005A AU2002256005A1 (en) | 2001-03-27 | 2002-03-27 | Control of glycoforms in igg |
Applications Claiming Priority (2)
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US27902601P | 2001-03-27 | 2001-03-27 | |
US60/279,026 | 2001-03-27 |
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WO2002076578A1 true WO2002076578A1 (en) | 2002-10-03 |
WO2002076578A9 WO2002076578A9 (en) | 2003-03-06 |
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PCT/US2002/009998 WO2002076578A1 (en) | 2001-03-27 | 2002-03-27 | Control of glycoforms in igg |
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EP (1) | EP1373547A4 (en) |
JP (1) | JP2005509403A (en) |
AU (1) | AU2002256005A1 (en) |
WO (1) | WO2002076578A1 (en) |
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EP2527367A1 (en) | 2007-08-20 | 2012-11-28 | Glaxo Group Limited | Production method |
WO2015004679A1 (en) * | 2013-07-06 | 2015-01-15 | Cadila Healthcare Limited | Improved process for production of monoclonal antibodies |
US9499616B2 (en) | 2013-10-18 | 2016-11-22 | Abbvie Inc. | Modulated lysine variant species compositions and methods for producing and using the same |
US9499614B2 (en) | 2013-03-14 | 2016-11-22 | Abbvie Inc. | Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides |
US9505833B2 (en) | 2012-04-20 | 2016-11-29 | Abbvie Inc. | Human antibodies that bind human TNF-alpha and methods of preparing the same |
US9505834B2 (en) | 2011-04-27 | 2016-11-29 | Abbvie Inc. | Methods for controlling the galactosylation profile of recombinantly-expressed proteins |
US9512214B2 (en) | 2012-09-02 | 2016-12-06 | Abbvie, Inc. | Methods to control protein heterogeneity |
US9522953B2 (en) | 2013-10-18 | 2016-12-20 | Abbvie, Inc. | Low acidic species compositions and methods for producing and using the same |
US9550826B2 (en) | 2013-11-15 | 2017-01-24 | Abbvie Inc. | Glycoengineered binding protein compositions |
US9598667B2 (en) | 2013-10-04 | 2017-03-21 | Abbvie Inc. | Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins |
US9683033B2 (en) | 2012-04-20 | 2017-06-20 | Abbvie, Inc. | Cell culture methods to reduce acidic species |
US9688752B2 (en) | 2013-10-18 | 2017-06-27 | Abbvie Inc. | Low acidic species compositions and methods for producing and using the same using displacement chromatography |
US9708400B2 (en) | 2012-04-20 | 2017-07-18 | Abbvie, Inc. | Methods to modulate lysine variant distribution |
US9708399B2 (en) | 2013-03-14 | 2017-07-18 | Abbvie, Inc. | Protein purification using displacement chromatography |
US9879229B2 (en) | 2011-03-14 | 2018-01-30 | National Research Council Of Canada | Method of viral production in cells |
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US10450361B2 (en) | 2013-03-15 | 2019-10-22 | Momenta Pharmaceuticals, Inc. | Methods related to CTLA4-Fc fusion proteins |
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US10501769B2 (en) | 2009-10-26 | 2019-12-10 | Hoffmann-La Roche Inc. | Method for the production of a glycosylated immunoglobulin |
US11661456B2 (en) | 2013-10-16 | 2023-05-30 | Momenta Pharmaceuticals, Inc. | Sialylated glycoproteins |
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US20100113294A1 (en) * | 2007-04-16 | 2010-05-06 | Momenta Pharmaceuticals, Inc. | Defined glycoprotein products and related methods |
MX2012011648A (en) | 2010-04-07 | 2012-11-29 | Momenta Pharmaceuticals Inc | High mannose glycans. |
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US9170249B2 (en) | 2011-03-12 | 2015-10-27 | Momenta Pharmaceuticals, Inc. | N-acetylhexosamine-containing N-glycans in glycoprotein products |
US9695244B2 (en) | 2012-06-01 | 2017-07-04 | Momenta Pharmaceuticals, Inc. | Methods related to denosumab |
AU2015211514B2 (en) * | 2014-01-29 | 2018-05-10 | Lg Chem, Ltd. | Method for modulating galactosylation of recombinant protein through optimization of culture medium |
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2002
- 2002-03-27 AU AU2002256005A patent/AU2002256005A1/en not_active Abandoned
- 2002-03-27 WO PCT/US2002/009998 patent/WO2002076578A1/en active Application Filing
- 2002-03-27 EP EP02725443A patent/EP1373547A4/en not_active Ceased
- 2002-03-27 JP JP2002575087A patent/JP2005509403A/en active Pending
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EP2527367A1 (en) | 2007-08-20 | 2012-11-28 | Glaxo Group Limited | Production method |
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US10501769B2 (en) | 2009-10-26 | 2019-12-10 | Hoffmann-La Roche Inc. | Method for the production of a glycosylated immunoglobulin |
US11021728B2 (en) | 2009-10-26 | 2021-06-01 | Hoffmann-La Roche Inc. | Method for the production of a glycosylated immunoglobulin |
US11136610B2 (en) | 2009-10-26 | 2021-10-05 | Hoffmann-La Roche Inc. | Method for the production of a glycosylated immunoglobulin |
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US9505834B2 (en) | 2011-04-27 | 2016-11-29 | Abbvie Inc. | Methods for controlling the galactosylation profile of recombinantly-expressed proteins |
US9505833B2 (en) | 2012-04-20 | 2016-11-29 | Abbvie Inc. | Human antibodies that bind human TNF-alpha and methods of preparing the same |
US9957318B2 (en) | 2012-04-20 | 2018-05-01 | Abbvie Inc. | Protein purification methods to reduce acidic species |
US9683033B2 (en) | 2012-04-20 | 2017-06-20 | Abbvie, Inc. | Cell culture methods to reduce acidic species |
US9708400B2 (en) | 2012-04-20 | 2017-07-18 | Abbvie, Inc. | Methods to modulate lysine variant distribution |
US9512214B2 (en) | 2012-09-02 | 2016-12-06 | Abbvie, Inc. | Methods to control protein heterogeneity |
US9499614B2 (en) | 2013-03-14 | 2016-11-22 | Abbvie Inc. | Methods for modulating protein glycosylation profiles of recombinant protein therapeutics using monosaccharides and oligosaccharides |
US9708399B2 (en) | 2013-03-14 | 2017-07-18 | Abbvie, Inc. | Protein purification using displacement chromatography |
US10450361B2 (en) | 2013-03-15 | 2019-10-22 | Momenta Pharmaceuticals, Inc. | Methods related to CTLA4-Fc fusion proteins |
US10464996B2 (en) | 2013-05-13 | 2019-11-05 | Momenta Pharmaceuticals, Inc. | Methods for the treatment of neurodegeneration |
US11352415B2 (en) | 2013-05-13 | 2022-06-07 | Momenta Pharmaceuticals, Inc. | Methods for the treatment of neurodegeneration |
US10168326B2 (en) | 2013-07-04 | 2019-01-01 | F. Hoffmann-La Roche Inc. | Interference-suppressed immunoassay to detect anti-drug antibodies in serum samples |
US10761091B2 (en) | 2013-07-04 | 2020-09-01 | Hoffmann-La Roche, Inc. | Interference-suppressed immunoassay to detect anti-drug antibodies in serum samples |
WO2015004679A1 (en) * | 2013-07-06 | 2015-01-15 | Cadila Healthcare Limited | Improved process for production of monoclonal antibodies |
US9598667B2 (en) | 2013-10-04 | 2017-03-21 | Abbvie Inc. | Use of metal ions for modulation of protein glycosylation profiles of recombinant proteins |
US11661456B2 (en) | 2013-10-16 | 2023-05-30 | Momenta Pharmaceuticals, Inc. | Sialylated glycoproteins |
US9522953B2 (en) | 2013-10-18 | 2016-12-20 | Abbvie, Inc. | Low acidic species compositions and methods for producing and using the same |
US9499616B2 (en) | 2013-10-18 | 2016-11-22 | Abbvie Inc. | Modulated lysine variant species compositions and methods for producing and using the same |
US9688752B2 (en) | 2013-10-18 | 2017-06-27 | Abbvie Inc. | Low acidic species compositions and methods for producing and using the same using displacement chromatography |
US9550826B2 (en) | 2013-11-15 | 2017-01-24 | Abbvie Inc. | Glycoengineered binding protein compositions |
Also Published As
Publication number | Publication date |
---|---|
EP1373547A1 (en) | 2004-01-02 |
WO2002076578A9 (en) | 2003-03-06 |
AU2002256005A1 (en) | 2002-10-08 |
JP2005509403A (en) | 2005-04-14 |
EP1373547A4 (en) | 2006-01-18 |
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