Publications
143 results found
Niu H, Leak DJ, Shah N, et al., 2014, Metabolic characterization and modelling of fermentation process of an engineered Geobacillus thermoglucosidasius strain for bioethanol production with gas stripping, Chemical Engineering Science, ISSN: 1873-4405
Polizzi KM, Kontoravdi C, 2014, Genetically-encoded biosensors for monitoring cellular stress in bioprocessing, Current Opinion in Biotechnology, Vol: 31, Pages: 50-56, ISSN: 1879-0429
Todri E, Amenaghawon AN, Jimenez del Val I, et al., 2014, Global sensitivity analysis and meta-modeling of an ethanol production process, Chemical Engineering Science, Vol: 114, Pages: 114-127
Traditional ethanol fermentation becomes inhibitory to microbial growth at ethanol concentrations that depend on the producer organism, leading to reduced ethanol productivity. Continuous ethanol removal from the fermenter could increase productivity and potentially reduce the cost of product recovery. In this work, continuous ethanol removal via in situ gas stripping in a stirred tank reactor has been investigated as a means of reducing growth inhibition and improving productivity. A dynamic mathematical model that couples ethanol fermentation with gas stripping has been developed. This has been linked to a flash separation model to represent the initial steps of product recovery. Global sensitivity analysis was used to reduce the number of uncertain parameters, the values of which were estimated with satisfactory accuracy using experimental data for ethanol production from a metabolically engineered strain of the thermophile Geobacillus thermoglucosidasius growing on cellobiose. Simulation results show that continuous ethanol fermentation with product removal by gas stripping is feasible, with the associated energy requirement, costs of gas compression and fermenter agitation being a function of the stripping gas flow rate. Finally, the conditions under which gas stripping is a practical product recovery method were established.
Jedrzejewski PM, Jimenez del Val I, Constantinou A, et al., 2014, Towards controlling the glycoform: a model framework linking extracellular metabolites to antibody glycosylation, International Journal of Molecular Sciences, Vol: 15, Pages: 4492-4522, ISSN: 1422-0067
Glycoproteins represent the largest group of the growing number of biologically-derived medicines. The associated glycan structures and their distribution are known to have a large impact on pharmacokinetics. A modelling framework was developed to provide a link from the extracellular environment and its effect on intracellular metabolites to the distribution of glycans on the constant region of an antibody product. The main focus of this work is the mechanistic in silico reconstruction of the nucleotide sugar donor (NSD) metabolic network by means of 34 species mass balances and the saturation kinetics rates of the 60 metabolic reactions involved. NSDs are the co-substrates of the glycosylation process in the Golgi apparatus and their simulated dynamic intracellular concentration profiles were linked to an existing model describing the distribution of N-linked glycan structures of the antibody constant region. The modelling framework also describes the growth dynamics of the cell population by means of modified Monod kinetics. Simulation results match well to experimental data from a murine hybridoma cell line. The result is a modelling platform which is able to describe the product glycoform based on extracellular conditions. It represents a first step towards the in silico prediction of the glycoform of a biotherapeutic and provides a platform for the optimisation of bioprocess conditions with respect to product quality.
Kyriakopoulos S, Polizzi KM, Kontoravdi C, 2013, Dynamic profiling of amino acid transport and metabolism in Chinese hamster ovary cell culture, 23rd European Society for Animal Cell Technology (ESACT) Meeting: Better Cells for Better Health
Jimenez del Val I, Constantinou A, Dell A, et al., 2013, A quantitative and mechanistic model for monoclonal antibody glycosylation as a function of nutrient availability during cell culture, 23rd European Society for Animal Cell Technology (ESACT) Meeting: Better Cells for Better Health
Chen N, Bennett MH, Kontoravdi C, 2013, Analysis of Chinese hamster ovary cell metabolism through a combined computational and experimental approach, Cytotechnology, Vol: Online First
Kontoravdi C, Samsatli NJ, Shah N, 2013, Development and design of bio-pharmaceutical processes, Current Opinion in Chemical Engineering
Behjousiar A, Constantinou A, Polizzi KM, et al., 2013, FIBS-enabled non-invasive metabolic profiling, Journal of Visualised Experiments (accepted)
A description of how to calibrate Förster Resonance Energy Transfer integrated biological sensors (FIBS) for in situ metabolic profiling is presented. The FIBS can be used to estimate intracellular metabolite concentrations non-invasively aiding in the development of metabolic models and high throughput screening of bioprocess conditions.
Kyriakopoulos S, Polizzi KM, Kontoravdi C, 2013, Comparative analysis of amino acid metabolism and transport in CHO variants with different levels of productivity, Journal of Biotechnology, Vol: 168, Pages: 543-551
Jimenez del Val I, Kyriakopoulos S, Polizzi KM, et al., 2013, An optimised method for extraction and quantification of nucleotides and nucleotide sugars from mammalian cells, Analytical Biochemistry, Vol: 443, Pages: 172-180
Royle KE, Jimenez del Val I, Kontoravdi C, 2013, Integration of models and experimentation to optimise the production of potential biotherapeutics, Drug Discovery Today, Vol: In Press
Royle KE, Kontoravdi C, 2013, A systems biology approach to optimising hosts for industrial protein production, Biotechnology Letters
The vast number of expression hosts available for recombinant protein production have a variety of advantages and disadvantages; none, however, is globally optimal and host selection is frequently a compromise. Strain development requires a holistic approach, which systems biology can supply by delineating experimental data sets with computational modelling. Here, we review recent advances in computational models, in parallel with an expansion of the molecular toolbox, in the pursuit of optimal host strains for industrial protein production.
Stefani I, Kontoravdi C, Polizzi K, 2013, O1–08–04: Analysis of the profile of unfolded protein response (UPR) markers in model‐systems of Alzheimer's disease, Alzheimer's & Dementia, Vol: 9, ISSN: 1552-5260
Jedrzejewski PM, Jimenez del Val I, Polizzi KM, et al., 2013, Applying quality by design to glycoprotein therapeutics: experimental and computational efforts of process control, Pharmaceutical Bioprocessing, Vol: 1, Pages: 51-69, ISSN: 2048-9145
Therapeutic glycoproteins represent one of the most important classes of products in the pharmaceutical industry, accounting for 77 high-value drugs out of 642 pharmaceuticals approved by the European Medicines Agency. Their therapeutic efficacy, serum half-life and immunogenicity depend on glycosylation, a complex and prominent post-translational event, which in turn is influenced by manufacturing process conditions. For this reason, protein glycosylation is a critical quality attribute for these drugs. Herein, we review the impact of glycosylation on product function, and the role of manufacturing conditions on the resulting glycoform distribution. We further present promising developments in terms of alternative, genetically engineered hosts, as well as advances in process operation that influence the glycan profile of the recombinant product. Finally, we review work on dynamic mathematical modeling for protein glycosylation that allows researchers to evaluate genetic engineering and process operation strategies in silico, with the aim of guiding experimentation. We demonstrate that such model-based approaches, when substantiated by experimental evidence, can support the quality by design initiative and expedite process development.
Kyriakopoulos S, Kontoravdi C, 2013, Analysis of the landscape of biologically-derived pharmaceuticals in Europe: dominant production systems, molecule types on the rise and approval trends, European Journal of Pharmaceutical Sciences, Vol: 48, Pages: 428-441
Polizzi KM, Hallett JP, Kontoravdi C, et al., 2013, Frontier manufacturing: Scaling up synthetic biology
Royle K, Kontoravdi C, Leak DJ, 2013, Understanding single-chain antibody fragment production in pichia pastoris
Royle K, Jimenez Del Val I, Miller A, et al., 2013, Designing a synthetic Golgi reactor, Pages: 341-342
Jimenez Del Val I, Constantinou A, Dell A, et al., 2013, An integrated mechanistic model for nucleotide sugar metabolism and monoclonal antibody glycosylation, Pages: 658-659
Sou SN, Sellick C, Lee K, et al., 2013, Experimental and computational analysis of Chinese hamster ovary stable transfectants grown in fed-batch culture, Pages: 669-670
Kontoravdi C, 2013, Systematic Methodology for the Development of Mathematical Models for Biological Processes, SYNTHETI C BIOLOGY, Vol: 1073, Pages: 177-190, ISSN: 1064-3745
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Polizzi KM, Kontoravdi C, 2013, Synthetic Biology Preface, SYNTHETI C BIOLOGY, Editors: Polizzi, Kontoravdi, Publisher: HUMANA PRESS INC, Pages: V-V, ISBN: 978-1-62703-624-5
Sou SN, Polizzi KM, Kontoravdi C, 2013, Evaluation of transfection methods for transient gene expression in Chinese hamster ovary cells, Advances in Bioscience and Biotechnology, Vol: 04, Pages: 1013-1019, ISSN: 2156-8456
Jimenez del Val I, Nagy JM, Kontoravdi C, 2012, A dynamic model for monoclonal antibody glycosylation in a maturing Golgi apparatus, INTERNATIONAL CONFERENCE ON CELLULAR & MOLECULAR BIOENGINEERING
Jimenez del Val I, Jedrzejewski PM, Exley K, et al., 2012, Application of Quality by Design paradigm to the manufacture of protein therapeutics, Glycosylation, Editors: Petrescu, ISBN: 980-953-307-130-0
Therapeutic glycoproteins represent one of the most important class products of the pharmaceutical industry, with 77 high-value drugs out of a total 642 approved by the European Medicines Agency. Their therapeutic efficacy, serum half-life and immunogenicity depends on the post-translational process of glycosylation, which is influenced by manufacturing process conditions. For this reason, protein glycosylation is a critical quality attribute for these drugs. Herein, we review the impact of glycosylation on product function, the role of manufacturing conditions in the resulting glycoform distribution and the current production systems employed industrially. We further present promising developments in terms of alternative, genetically engineered hosts, as well as advances in process operation that influence the glycan profile of the recombinant product. We finally present work on dynamic mathematical modeling for protein glycosylation that allows researchers to evaluate genetic engineering and process operation strategies in silico, with the aim of guiding experimentation. We demonstrate that such model-based approaches, when substantiated by experimental evidence, can support the Quality by Design initiative and expedite process development.
Behjousiar A, Kontoravdi C, Polizzi KM, 2012, In Situ Monitoring of Intracellular Glucose and Glutamine in CHO Cell Culture, PLOS One, Vol: 7
The development of processes to produce biopharmaceuticals industrially is still largely empirical and relies on optimizing both medium formulation and cell line in a product-specific manner. Current small-scale (well plate-based) process development methods cannot provide sufficient sample volume for analysis, to obtain information on nutrient utilization which can be problematic when processes are scaled to industrial fermenters. We envision a platform where essential metabolites can be monitored non-invasively and in real time in an ultra-low volume assay in order to provide additional information on cellular metabolism in high throughput screens. Towards this end, we have developed a model system of Chinese Hamster Ovary cells stably expressing protein-based biosensors for glucose and glutamine. Herein, we demonstrate that these can accurately reflect changing intracellular metabolite concentrations in vivo during batch and fed-batch culture of CHO cells. The ability to monitor intracellular depletion of essential nutrients in high throughput will allow rapid development of improved bioprocesses.
Stefani IC, Wright D, Polizzi KM, et al., 2012, The role of ER stress-induced apoptosis in neurodegeneration, Current Alzheimer Research, Vol: 9, Pages: 373-387
Behjousiar A, Kontoravdi C, Polizzi KM, 2012, In situ monitoring of intracellular glucose and glutamine in CHO cell culture, PLoS One
Stefani IC, Wright D, Polizzi KM, et al., 2012, The role of ER stress-induced apoptosis in neurodegeneration, Current Alzheimer Research, Vol: 9, Pages: 373-387
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