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Recent updates regarding and involving the AdBIOPRO competence centre

Update: 2021/03/16

Congratulations to Julia Scheffel and Sophia Hober on publishing their work with the title:" Highly selective Protein A resin allows for mild sodium chloride-mediated elution of antibodies ". 

The publication explores the use of milde elution conditions at neutral pH for antibodies mediated by sodium chloride on a platform based on a Protein A resin. The platform prevents the formation of aggregates and obtained a highly pure and concentrated elution pool with a recovery of 99%.

For more information: doi.org/10.1016/j.chroma.2020.461843

Update: 2021/02/05

Congratulations to Joaquín Gomis Fons and Bernt Nilsson on publishing their manuscript with the title: " An integrated continuous downstream process with real‐time control: A case study with periodic countercurrent chromatography and continuous virus inactivation " by Anton Löfgren, Joaquín Gomis-Fons, Niklas Andersson, Bernt Nilsson, Lotta Berghard, and Christine Lagerquist Hägglund. 

The publication disscuses the promising opportunity of combining a real-time controller, as a PAT, in combination with integrated continuous downstream processing. 

For more information: dx.doi.org/10.1002/bit.27681  

Update: 2021/01/29

Congratulations to Diogo Rodrigues, Elling W. Jacobsen, Véronique Chotteau, and Håkan Hjalmarsson for the publication of " An Integrated Approach for Modeling and Identification of Perfusion Bioreactors via Basis Flux Modes " by Diogo Rodrigues, Mohamed R. Abdalmoaty, Elling W. Jacobsen, Véronique Chotteau, and Håkan Hjalmarsson.

This paper discusses the challenges associated with the reliable and optimal operation of perfusion bioreactors and presents methods for modeling and identification of perfusion bioreactors as well as the vision for their integration.

Update: 2020/12/21

The AdBIOPRO competence centre wishes everyone a Merry Christmas and a Happy New Year

Update: 2020/12/10

Congratulations to Joaquín Gomis Fons and Bernt Nilsson for the publication of “ Optimal loading flow rate trajectory in monoclonal antibody capture chromatography ” by Joaquín Gomis-Fons, Mikael Yamanee-Nolin, Niklas Andersson, Bernt Nilsson, in the Journal of chromatography A.

The paper discusses the use of an optimal flow rate trajectory to improve process economics by increasing the productivity and resin utilization in a single-column chromatography setup.

Update: 2020/11/17

Congratulation to Caijuan Zhan and Hubert Schwarz for the publication of "Low Shear Stress Increases Recombinant Protein Production and High Shear Stress Increases Apoptosis in Human Cells", in iScience.

This is a collaboration of Veronique Chotteau's group (CETEG) with Johan Rockberg's group, Adil Mardinoglu's group and AstraZeneca, UK. Caijuan, Hubert and Veronique are members of AdBIOPRO.

The paper is about Fluid dynamics, transcriptomics and phenotype study used to understand the impact of perfusion process on the cells. It reveals that mild shear stress has favourable effects on protein transcription and phosphorylation, high shear stress provokes apoptosis by three different pathways, and average shear rate in hollow filter cell separation device ATF is lower than in TFF (ATF and TFF are both cell separation devices highly used in perfusion processes).

More information: doi.org/10.1016/j.isci.2020.101653

Update: 2020/11/17

Congratulation to Liang Zhang and Hubert Schwarz for the publication of "Control of IgG glycosylation in CHO cell perfusion cultures by GReBA mathematical model supported by a novel targeted feed, TAFE", by Liang Zhang, Hubert Schwarz, Mingliang Wang, Andreas Castan, Håkan Hjalmarsson, Veronique Chotteau, in Metabolic Engineering.

This is a collaboration with Div. Decision and Control Systems and Cytiva within AdBIOPRO. 

The paper is about a novel targeted feeding, TAFE, for perfusion culture forces the cells to consume the substrates according to selected targets. Different antibody glycosylation is obtained by feeding glucose, mannose and/or galactose in perfusion cultures of CHO cells. TAFE enables larger cellular consumption of non-glucose sugar than glucose in presence of both substrates. The model GReBA of N-link glycosylation can be used for the design of the targeted feeding TAFE to obtain a desired glycosylation. For more information:

doi.org/10.1016/j.ymben.2020.11.004

Update: 2020/06/08

Welcome to the Half time seminar of Hubert Schwarz, AdBIOPRO, Cell Technology Group, Industrial Biotechnology Dept., CBH, KTH.

Title: Tools for the development of intensified perfusion processes using mammalian cells
Time: June 12 2PM
ZOOM: webinar

Registratrion link:
kth-se.zoom.us/webinar/register/WN__QEprPqZSkKtuuyldsr89Q

Abstract
Perfusion processes for biopharmaceutical production regained strong interest within the past years. Although this operation mode has existed for around 30 years for the production of labile recombinant proteins, recent advances in this technology has made perfusion an attractive alternative to legacy fed-batch processes for the production of other biotherapeutics, such as monoclonal antibodies (mAbs). This is in particular due to the intensified production in a perfusion bioreactor, i.e. the maintenance of very high densities of mammalian cells (>100 x 106 cells/mL) in long term steady-state cultures in a constant environment that is favorable for the cells, which ultimately allows for higher productivities and better product quality.

The thesis will provide tools for the development of such intensified perfusion processes. Firstly, a small-scale parallel perfusion bioreactor system was developed to support the cultivation of mammalian cells at very high cell densities with continuous medium exchange and cell separation capacity. Such a scale-down model is an efficient tool for rapid perfusion process development. It has the advantage of a smaller footprint and working volume (200 mL), hence it significantly reduces media consumption and labor time compared to traditional 1-10 L lab-scale bioreactors. This novel scale-down model based on alternating tangential flow filtration (ATF) for cell separation was validated with a human embryonic kidney cell line (HEK293) producing recombinant human Erythropoietin (rhEPO) and confirmed its applicability for long term steady-state cultures with cell densities of 100 x 106 viable cells/mL.

The scale-down perfusion model from the first study was further utilized in a small-scale integrated continuous end-to-end mAb process. Here the perfusion bioreactor was integrated with a whole purification process for the continuous capture, polishing and virus inactivation of the product. MAbs produced by Chinese Hamster Ovary cells (CHO) showed a consistent product quality through the steady-state operation of the process and successful removal of host cell proteins (HCPs). A mathematical model of the chromatography provided a digital twin of the downstream process in order to implement advanced control strategies to facilitate process automatization. A scale-up study of an integrated continuous end-to-end bioprocess for mAb production will be performed in a future project.

Current research activities for this thesis are centered around perfusion process monitoring using spectroscopic tools (Raman). Multivariate data analysis is employed to generate models for the predictions of nutrients, metabolites and product concentrations and critical quality attributes. Furthermore, mathematical models of the cell metabolism and mAb glycosylation have been developed and currently investigated for the rational design of experiments in perfusion process development. In particular, the use of alternative sugars and amino acid cocktails that are optimal for the CHO cell metabolism and mAb glycosylation are investigated for the optimization of perfusion medium.

The different methods and strategies that have been developed for this thesis will contribute to more efficient development of continuous bioprocesses that are more sustainable and economically profitable.

Refer:
Schwarz, H., Zhang, Y., Zhan, C., Malm, M., Field, R., Turner, R., Sellick, C., Varley, P., Rockberg, J. and Chotteau, V., 2020. Small-scale bioreactor supports high density HEK293 cell perfusion culture for the production of recombinant Erythropoietin. Journal of Biotechnology, 309, pp.44-52.

Gomis‐Fons, J.*, Schwarz, H.*, Zhang, L., Andersson, N., Nilsson, B., Castan, A., Solbrand, A., Stevenson, J. and Chotteau, V., 2020. Model‐based design and control of a small‐scale integrated continuous end‐to‐end mAb platform. Biotechnology Progress, p.e2995. *1st authors

Update: 2020/05/27

Welcome to the public PhD defence of Liang Zhang "Development of mathematical modelling for the glycosylation of IgG in CHO cell cultures". Liang has been working in SmartFD project and in the AdBIOPRO Competence Centre.

The defence will be open for public at KTH main campus and also accessible via ZOOM. 

Time: Thursday 2020-June-04, 15:00 (3 PM CEST)
Videoconf.: kth-se.zoom.us/j/67302879470  , Stockholm (English)
 

Doctoral student: Liang Zhang, Dept. Industrial Biotechnology/Cell Technology group CETEG, AdBIOPRO, VINNOVA Competence Centre for Advanced Bioproduction by Continuous Processing

Link to the thesis

urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-273343

Opponent:
Professor Michael J. Betenbaugh, Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore
 

Chairwoman of the Public Defence
Assoc. Prof. Ines Ezcurra, Dept. Industrial Biotechnology, CBH School, KTH

Members of the Committee Evaluation (Jury):
Professor Sara Lindén, Department of Medical Biochemistry and Cell biology at Institute of Biomedicine, Göteborg University, Sweden
Professor Carl-Fredrik Mandenius, Division of Biotechnology, Department of Physics, Chemistry and Biology (IFM), Linköping University, Sweden
Professor Erik Fransén, Div Computational Science and Technology, KTH, Sweden

Update: 2020/04/14

Joaquin Gomis Fons (Lund Univeristy) has recenetly published another article about the Optimization of a periodic counter-current chromatography (PCC) integrated in a downstream process for the purification of monoclonal antibodies  in Jornal of Chromatography A

Highlights:

- Optimal values of capture productivity and resin utilization were obtained from a model-based optimization.

- This is the first (to our knowledge) study of the integration alternatives of multi-column continuous chromatography in a downstream process. 

- Integration approaches with higher cycle time leads to lower productivity.

- The integrated downstream process was validated experimentally at lab scale with two ÄKTA pure systems.

Update: 2020/04/08

Joaquin Gomis Fons (Lund Univeristy) and Hubert Schwarz (KTH) have have published their article about the Model‐based design and control of a small‐scale integrated continuous end‐to‐end mAb platform  in Biotechnology progress.

Highlights:

- A 200 mL ATF perfusion bioreactor and a single chromatography system were integrated in a compact design.

- Real-time model-based control strategies in the downstream process were implemented to achieve an automated and optimal operation.

- A maximum productivity of 0.8 mg/mL day of purified product was obtained, with a recovery time of less than 4 hours.

Update: 2020/01/17

Mingliang Wang (Post-Doc at AdBIOPRO) has published his article about the Identification of nonlinear kinetics of macroscopic bio-reactions using multilinear Gussian processes  in Computers & Chemical Engineering. 

Update: 2020/01/13

Hubert Schwarz (PhD student at AdBIOPRO) has now published his article about very high cell density perfusion process in small-scale bioreactor perfusion system in J. of Biotechnology. The article is available at the link below (free of access until Feb 18, 2020).

www.sciencedirect.com/science/article/pii/S0168165619309538

Highlights:

- Cell densities of HEK293 cells and CHO cells maintained at 80 and 100 x 10^6 cells/mL 

- Novel small-scale perfusion bioreactor system for animal/human cells with working volumes < 250 mL

- Very low cell specific perfusion rate down to 10 pL/cell/day

- HEK293 cell expressing Erythropoietin cultured in high cell density perfusion process more than 75 days

Update: 2019/12/24

The AdBIOPRO centre wishes everyone a Merry Christmas and a Happy New Year

Update: 2019/11/04

Welcome to the PhD defence of Erika Hagrot on Nov 13 at 10:00, room FB54.

Title: "Macroscopic models of Chinese hamster ovary cell cultures" 

Opponent: Assoc. Prof. Nathan Lewis, UCSD, San Diego, CA, USA

Evaluation Committee:
Assoc. Prof. Carl Johan Franzén, Chalmers Univ., Sweden
Dr. Anna Maria Sandén, Octapharma, Sweden
CNRS Researcher Emmanuel Guedon, Université de Lorraine, France

Supervisor: Veronique Chotteau

Co-Supervisor: Prof. Andres Forsgren, Dept. Mathematics, KTH 

Update: 2019/11/04

Guest lecture 

Nathan Lewis will give a seminar at 15:00 on Nov 13

Page responsible:Johan Sven Erik Rockberg
Belongs to: Advanced BioProduction by Continuous Processing
Last changed: Mar 16, 2021