Monoclonal Antibody Process Development Using Medium Concentrates

Bibila, Theodora A.; Ranucci, Colette S.; Glazomitsky, Konstantin; Buckland, Barry C.; Auniņš, John G.

doi:10.1021/bp00025a011

Cited by 89 publications

(71 citation statements)

References 13 publications

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“…Then the early nineties were marked by the development of recombinant GS-NS0 technology (by Celltech) leading a few years later to the possibility of producing 1-2 g/l of monoclonal antibodies in a fed batch process (Bibila et al 1994). Today we see antibody titers at an industrial scale of 5 g/l and more (Birch 2005).…”

mentioning

confidence: 99%

Introduction to animal cell culture technology—past, present and future

Merten

2006

Cytotechnology

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mentioning

confidence: 99%

Introduction to animal cell culture technology—past, present and future

Merten

2006

Cytotechnology

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“…Feeding medium concentrates has been reported to dramatically increase cell densities and final product titers in recombinant CHO [17] and NS0 cell cultures [3]. Figure 3 shows the consumption and production profiles for the most important biochemical components in the growth medium namely Glucose, Lactate, Glutamine and Ammonia.…”

Section: Fed-batch Runsmentioning

confidence: 99%

“…However, for the choice of the appropriate cell line, certain key criteria have to be considered which include: the ability to provide a close to human glycosylation pattern, the capability to produce high mAb concentrations in the chosen production system, the ability to consistently produce a product of uniform characteristics (stability), and the speed with which a high yielding cell line can be obtained [1,2]. NS0, a murine myeloma cell line, has been adopted by a number of biotechnology companies for the expression of therapeutic antibodies [3][4][5][6][7]. The successful use of NS0 cells in several fusion, transfection, selection and production approaches are among the few properties of this cell line that make it a perfect candidate for the expression of the desired product [8].…”

Section: Introductionmentioning

confidence: 99%

“…Fed batch cultures have been developed with the objective of achieving maximal increase in the culture viable cell concentrations and prolonging the culture lifetime for increased product concentrations [3,5,[11][12][13][14][15] Strategies such as development of the feeding solutions, feeding rate control, maintaining low residual glucose and/or glutamine concentrations, employing dialysis membranes to remove low molecular weight components from the culture, feeding based on Oxygen UptakeHence, based on the hypothesis that none of the factors affecting the production process can really be independent, fractional factorial design using design expert software was carried out to find the interaction between the batch (Dissolved Oxygen, Temperature and Seeding Density) and fed-batch (post-feed Glucose concentration) process parameters. The usage of design of experiments also facilitates shorter development time, hence more cost effective.…”

Section: Introductionmentioning

confidence: 99%

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Study on Interactions between Fed-Batch and Batch Operating Parameters for the Development of Monoclonal Antibody Fed-Batch using Design of Experiments

Raja¹,

Anuar²,

Rahman³

et al. 2014

J Bioprocess Biotech

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In conventional fed batch process development approaches, batch operating parameters (such as pH, temperature, seeding density, dissolved oxygen concentration) are kept constant and only feeding parameters such as feeding time, post-feed concentration are manipulated. The batch and fed batch operating parameters are assumed to be independent of each other. This approach to process development ignores any interactions that might exist between the batch and fed-batch operating parameters are therefore not evaluated. However in a complex bioprocess, none of the factors affecting the process can be assumed to be independent of each other and mutually exclusive. Therefore in this study an attempt was made to study the interaction between fed-batch operating parameter-post feed glucose concentration (A) and batch operating parameters-seeding density (B), temperature (C), and dissolved oxygen concentration (D) by their simultaneous manipulation, as well as the effect of these interactions on cell growth and monoclonal antibody (mAb) production. NS0 cell line producing the mAb's against carcino-embryogenic antigen (Anti-CEA) was used. The final mAb concentration, viable cell density and integral of viable cell concentration (IVCC) were the responses evaluated. Statistical analysis experimental data showed that parameter (A) and its interaction with parameter (B) were the main factors affecting both the response variables. In comparison to the batch run which yielded 5.21 mg/L mAb, the developed fed batch process increased the mAb titer by 10 fold (59.40 mg/mL), and the IVCC was increased by 7 fold. The maximum VCD value (3.46×10 6 cells/mL) of the developed fed batch process was 1.25 over fold the value for batch.

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“…Humanized IgG1-monoclonal antibodies (mAbs) were produced in two cultivation systems, CHO [16] and GS-NS0 [17] cells. A four-step purification platform involving solubility, size separation, charge separation, and filtering were used.…”

Section: Proteins and Materialsmentioning

confidence: 99%

Discrimination among IgG1-κ monoclonal antibodies produced by two cell lines using charge state distributions in nanoESI-TOF mass spectra

Zamani

Lindholm

Ilag

et al. 2009

J. Am. Soc. Mass Spectrom.

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Charge state distributions (CSDs) of proteins in nanoESI mass spectra are affected by the instrumental settings and experimental conditions, in addition to the conformations of the proteins in the analyzed solutions. In the presented study, instrumental and experimental parameters-the desolvation gas flow rate, temperature, pH, buffer (ammonium acetate), and organic modifier (methanol) concentrations-were optimized according to a reduced central composite face experimental design to maximize the separation of CSDs of monoclonal IgG1-antibodies produced by two production systems (CHO and GS-NS0 cell lines). Principal component analysis and Fisher linear discriminant analysis were then used to reduce the dimensions of the acquired dataset and quantify the separation of the protein classes, respectively. The results show that the IgG1-molecules produced by the two production systems can be clearly distinguished using the described approach, which could be readily applied to other proteins and production systems. E lectrospray ionization mass spectrometry (ESI-MS) is a highly suitable technique for structural analysis of various macromolecules, partly because of the possibility of analyzing multiply charged ions from biological molecules, e.g., proteins in solution [1,2]. Further advantages for such analyses are offered by nanoESI-MS [3] (compared with conventional ESI), including reductions in sample consumption, greater tolerance of nonvolatile salts, and the softness of the technique. However, although nanoESI is a preferable ionization method for structural MS analyses of biological macromolecules, nanoESI has been shown to be highly dependent upon the geometry of the nanoflow needle; thus some needle-to-needle irreproducibility is to be expected [4].Charge-state distributions (CSD) of biological macromolecules in ESI-MS are being increasingly employed for exploring their conformations in solutions [4,5]. Changes in protein conformation can result in changes in the CSD in an ESI mass spectrum [6,7]. The mechanism whereby (nearly) desolvated ions are generated from a charged droplet is not completely understood [8]. Proteins acquire more charges in solutions that promote unfolding than the same proteins in solutions that promote folded conformations [7], but it should be noted that other factors than protein compactness may also contribute to differences in CSD patterns [9 -11]. For instance, in addition to altering the conformation of proteins, changes in the solvent also affect the ionization process, i.e., proton-transfer reactions. Thus, the solvent and the operating conditions have different conformational effects on proteins with differing stability during the electrospray process. Hence, understanding the influence of experimental conditions on protein CSDs is important to extract the structural information they may contain.In this study, the effects of selected instrumental and experimental parameters on the CSDs of IgG1-monoclonal antibodies produced by two production systems [Chinese hamster ovary (CHO)...

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Monoclonal Antibody Process Development Using Medium Concentrates

Cited by 89 publications

References 13 publications

Introduction to animal cell culture technology—past, present and future

Introduction to animal cell culture technology—past, present and future

Study on Interactions between Fed-Batch and Batch Operating Parameters for the Development of Monoclonal Antibody Fed-Batch using Design of Experiments

Discrimination among IgG1-κ monoclonal antibodies produced by two cell lines using charge state distributions in nanoESI-TOF mass spectra

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