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Article ; Online: Amino acid degradation pathway inhibitory by-products trigger apoptosis in CHO cells.

Martínez, Verónica S / Rodriguez, Karen / McCubbin, Timothy / Tong, Junjie / Mahler, Stephen / Shave, Evan / Baker, Kym / Munro, Trent P / Marcellin, Esteban

Biotechnology journal

2024 Volume 19, Issue 2, Page(s) e2300338

Abstract: Chinese hamster ovary (CHO) cells are widely used to produce complex biopharmaceuticals. Improving their productivity is necessary to fulfill the growing demand for such products. One way to enhance productivity is by cultivating cells at high densities, ...

Abstract	Chinese hamster ovary (CHO) cells are widely used to produce complex biopharmaceuticals. Improving their productivity is necessary to fulfill the growing demand for such products. One way to enhance productivity is by cultivating cells at high densities, but inhibitory by-products, such as metabolite derivatives from amino acid degradation, can hinder achieving high cell densities. This research examines the impact of these inhibitory by-products on high-density cultures. We cultured X1 and X2 CHO cell lines in a small-scale semi-perfusion system and introduced a mix of inhibitory by-products on day 10. The X1 and X2 cell lines were chosen for their varied responses to the by-products; X2 was susceptible, while X1 survived. Proteomics revealed that the X2 cell line presented changes in the proteins linked to apoptosis regulation, cell building block synthesis, cell growth, DNA repair, and energy metabolism. We later used the AB cell line, an apoptosis-resistant cell line, to validate the results. AB behaved similar to X1 under stress. We confirmed the activation of apoptosis in X2 using a caspase assay. This research provides insights into the mechanisms of cell death triggered by inhibitory by-products and can guide the optimization of CHO cell culture for biopharmaceutical manufacturing.
MeSH term(s)	Cricetinae ; Animals ; Cricetulus ; CHO Cells ; Apoptosis/genetics ; Cell Proliferation ; Amino Acids
Chemical Substances	Amino Acids
Language	English
Publishing date	2024-02-17
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2221885-3
ISSN	1860-7314 ; 1860-6768
ISSN (online)	1860-7314
ISSN	1860-6768
DOI	10.1002/biot.202300338
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Article ; Online: Strategies for developing a recombinant butyrylcholinesterase medical countermeasure for Organophosphorus poisoning.

Allard, Joanne L / Shields, Katherine A / Munro, Trent P / Lua, Linda H L

Chemico-biological interactions

2022 Volume 363, Page(s) 109996

Abstract: Organophosphorus nerve agents represent a serious chemical threat due to their ease of production and scale of impact. The recent use of the nerve agent Novichok has re-emphasised the need for broad-spectrum medical countermeasures (MCMs) to these agents. ...

Abstract	Organophosphorus nerve agents represent a serious chemical threat due to their ease of production and scale of impact. The recent use of the nerve agent Novichok has re-emphasised the need for broad-spectrum medical countermeasures (MCMs) to these agents. However, current MCMs are limited. Plasma derived human butyrylcholinesterase (huBChE) is a promising novel bioscavenger MCM strategy, but is prohibitively expensive to isolate from human plasma at scale. Efforts to produce recombinant huBChE (rBChE) in various protein expression platforms have failed to achieve key critical attributes of huBChE such as circulatory half-life. These proteins often lack critical features such as tetrameric structure and requisite post-translational modifications. This review evaluates previous attempts to generate rBChE and assesses recent advances in mammalian cell expression and protein engineering strategies that could be deployed to achieve the required half-life and yield for a viable rBChE MCM. This includes the addition of a proline-rich attachment domain, fusion proteins, post translational modifications, expression system selection and optimised downstream processes. Whilst challenges remain, a combinatorial application of these strategies demonstrates potential as a technically feasible approach to achieving a bioactive and cost effective bioscavenger MCM.
MeSH term(s)	Animals ; Butyrylcholinesterase/chemistry ; Humans ; Mammals/metabolism ; Medical Countermeasures ; Nerve Agents ; Organophosphate Poisoning/drug therapy ; Organophosphorus Compounds ; Recombinant Proteins/chemistry
Chemical Substances	Nerve Agents ; Organophosphorus Compounds ; Recombinant Proteins ; Butyrylcholinesterase (EC 3.1.1.8)
Language	English
Publishing date	2022-05-30
Publishing country	Ireland
Document type	Journal Article ; Review
ZDB-ID	218799-1
ISSN	1872-7786 ; 0009-2797
ISSN (online)	1872-7786
ISSN	0009-2797
DOI	10.1016/j.cbi.2022.109996
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Article: Working Hard or Hardly Working? Regulatory Bottlenecks in Developing a COVID-19 Vaccine

Pregelj, Lisette / Hine, Damian C / Oyola-Lozada, Maria G / Munro, Trent P

Trends in biotechnology. 2020 Sept., v. 38, no. 9

2020

Abstract: Vaccine solutions rarely reach the public until after an outbreak abates; an Ebola vaccine was approved 5 years after peak outbreak and SARS, MERS, and Zika vaccines are still in clinical development. Despite massive leaps forward in rapid science, other ...

Abstract	Vaccine solutions rarely reach the public until after an outbreak abates; an Ebola vaccine was approved 5 years after peak outbreak and SARS, MERS, and Zika vaccines are still in clinical development. Despite massive leaps forward in rapid science, other regulatory bottlenecks are hamstringing the global effort for pandemic vaccines.
Keywords	COVID-19 infection ; biotechnology ; pandemic ; vaccines
Language	English
Dates of publication	2020-09
Size	p. 943-947.
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-AP-2-clean
ZDB-ID	47474-5
ISSN	1879-3096 ; 0167-7799
ISSN (online)	1879-3096
ISSN	0167-7799
DOI	10.1016/j.tibtech.2020.06.004
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Working Hard or Hardly Working? Regulatory Bottlenecks in Developing a COVID-19 Vaccine.

Pregelj, Lisette / Hine, Damian C / Oyola-Lozada, Maria G / Munro, Trent P

Trends in biotechnology

2020 Volume 38, Issue 9, Page(s) 943–947

Abstract	Vaccine solutions rarely reach the public until after an outbreak abates; an Ebola vaccine was approved 5 years after peak outbreak and SARS, MERS, and Zika vaccines are still in clinical development. Despite massive leaps forward in rapid science, other regulatory bottlenecks are hamstringing the global effort for pandemic vaccines.
MeSH term(s)	Betacoronavirus/drug effects ; Betacoronavirus/immunology ; Betacoronavirus/pathogenicity ; COVID-19 ; COVID-19 Vaccines ; Coronavirus Infections/epidemiology ; Coronavirus Infections/immunology ; Coronavirus Infections/prevention & control ; Coronavirus Infections/virology ; Drug Approval/organization & administration ; Ebola Vaccines/administration & dosage ; Ebola Vaccines/biosynthesis ; Ebolavirus/drug effects ; Ebolavirus/immunology ; Ebolavirus/pathogenicity ; Europe/epidemiology ; Global Health/trends ; Government Regulation ; Hemorrhagic Fever, Ebola/epidemiology ; Hemorrhagic Fever, Ebola/immunology ; Hemorrhagic Fever, Ebola/prevention & control ; Hemorrhagic Fever, Ebola/virology ; Humans ; Influenza A Virus, H1N1 Subtype/genetics ; Influenza A Virus, H1N1 Subtype/immunology ; Influenza Vaccines/administration & dosage ; Influenza Vaccines/biosynthesis ; Influenza, Human/epidemiology ; Influenza, Human/immunology ; Influenza, Human/prevention & control ; Influenza, Human/virology ; Middle East Respiratory Syndrome Coronavirus/drug effects ; Middle East Respiratory Syndrome Coronavirus/immunology ; Middle East Respiratory Syndrome Coronavirus/pathogenicity ; Pandemics/prevention & control ; Pneumonia, Viral/epidemiology ; Pneumonia, Viral/immunology ; Pneumonia, Viral/prevention & control ; Pneumonia, Viral/virology ; SARS Virus/drug effects ; SARS Virus/immunology ; SARS Virus/pathogenicity ; SARS-CoV-2 ; Severe Acute Respiratory Syndrome/epidemiology ; Severe Acute Respiratory Syndrome/immunology ; Severe Acute Respiratory Syndrome/prevention & control ; Severe Acute Respiratory Syndrome/virology ; United States/epidemiology ; Viral Vaccines/administration & dosage ; Viral Vaccines/biosynthesis ; Zika Virus/drug effects ; Zika Virus/immunology ; Zika Virus/pathogenicity ; Zika Virus Infection/epidemiology ; Zika Virus Infection/immunology ; Zika Virus Infection/prevention & control ; Zika Virus Infection/virology
Chemical Substances	COVID-19 Vaccines ; Ebola Vaccines ; Influenza Vaccines ; Viral Vaccines
Keywords	covid19
Language	English
Publishing date	2020-06-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	47474-5
ISSN	1879-3096 ; 0167-7799
ISSN (online)	1879-3096
ISSN	0167-7799
DOI	10.1016/j.tibtech.2020.06.004
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Article ; Online: Working Hard or Hardly Working? Regulatory Bottlenecks in Developing a COVID-19 Vaccine

Pregelj, Lisette / Hine, Damian C. / Oyola-Lozada, Maria G. / Munro, Trent P.

Trends in Biotechnology

2020 Volume 38, Issue 9, Page(s) 943–947

Keywords	Biotechnology ; Bioengineering ; covid19
Language	English
Publisher	Elsevier BV
Publishing country	us
Document type	Article ; Online
ZDB-ID	47474-5
ISSN	1879-3096 ; 0167-7799
ISSN (online)	1879-3096
ISSN	0167-7799
DOI	10.1016/j.tibtech.2020.06.004
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Engineering death resistance in CHO cells for improved perfusion culture.

MacDonald, Michael A / Nöbel, Matthias / Martínez, Verónica S / Baker, Kym / Shave, Evan / Gray, Peter P / Mahler, Stephen / Munro, Trent / Nielsen, Lars K / Marcellin, Esteban

mAbs

2022 Volume 14, Issue 1, Page(s) 2083465

Abstract: The reliable and cost-efficient manufacturing of monoclonal antibodies (mAbs) is essential to fulfil their ever-growing demand. Cell death in bioreactors reduces productivity and product quality, and is largely attributed to apoptosis. In perfusion ... ...

Abstract	The reliable and cost-efficient manufacturing of monoclonal antibodies (mAbs) is essential to fulfil their ever-growing demand. Cell death in bioreactors reduces productivity and product quality, and is largely attributed to apoptosis. In perfusion bioreactors, this leads to the necessity of a bleed stream, which negatively affects the overall process economy. To combat this limitation, death-resistant Chinese hamster ovary cell lines were developed by simultaneously knocking out the apoptosis effector proteins Bak1, Bax, and Bok with CRISPR technology. These cell lines were cultured in fed-batch and perfusion bioreactors and compared to an unmodified control cell line. In fed-batch, the death-resistant cell lines showed higher cell densities and longer culture durations, lasting nearly a month under standard culture conditions. In perfusion, the death-resistant cell lines showed slower drops in viability and displayed an arrest in cell division after which cell size increased instead. Pertinently, the death-resistant cell lines demonstrated the ability to be cultured for several weeks without bleed, and achieved similar volumetric productivities at lower cell densities than that of the control cell line. Perfusion culture reduced fragmentation of the mAb produced, and the death-resistant cell lines showed increased glycosylation in the light chain in both bioreactor modes. These data demonstrate that rationally engineered death-resistant cell lines are ideal for mAb production in perfusion culture, negating the need to bleed the bioreactor whilst maintaining product quantity and quality.
MeSH term(s)	Animals ; Antibodies, Monoclonal/pharmacology ; Batch Cell Culture Techniques ; Bioreactors ; CHO Cells ; Cricetinae ; Cricetulus ; Perfusion
Chemical Substances	Antibodies, Monoclonal
Language	English
Publishing date	2022-06-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2537838-7
ISSN	1942-0870 ; 1942-0870
ISSN (online)	1942-0870
ISSN	1942-0870
DOI	10.1080/19420862.2022.2083465
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Modeling apoptosis resistance in CHO cells with CRISPR-mediated knockouts of Bak1, Bax, and Bok.

MacDonald, Michael A / Barry, Craig / Groves, Teddy / Martínez, Verónica S / Gray, Peter P / Baker, Kym / Shave, Evan / Mahler, Stephen / Munro, Trent / Marcellin, Esteban / Nielsen, Lars K

Biotechnology and bioengineering

2022 Volume 119, Issue 6, Page(s) 1380–1391

Abstract: Chinese hamster ovary (CHO) cells are the primary platform for the production of biopharmaceuticals. To increase yields, many CHO cell lines have been genetically engineered to resist cell death. However, the kinetics that governs cell fate in ... ...

Abstract	Chinese hamster ovary (CHO) cells are the primary platform for the production of biopharmaceuticals. To increase yields, many CHO cell lines have been genetically engineered to resist cell death. However, the kinetics that governs cell fate in bioreactors are confounded by many variables associated with batch processes. Here, we used CRISPR-Cas9 to create combinatorial knockouts of the three known BCL-2 family effector proteins: Bak1, Bax, and Bok. To assess the response to apoptotic stimuli, cell lines were cultured in the presence of four cytotoxic compounds with different mechanisms of action. A population-based model was developed to describe the behavior of the resulting viable cell dynamics as a function of genotype and treatment. Our results validated the synergistic antiapoptotic nature of Bak1 and Bax, while the deletion of Bok had no significant impact. Importantly, the uniform application of apoptotic stresses permitted direct observation and quantification of a delay in the onset of cell death through Bayesian inference of meaningful model parameters. In addition to the classical death rate, a delay function was found to be essential in the accurate modeling of the cell death response. These findings represent an important bridge between cell line engineering strategies and biological modeling in a bioprocess context.
MeSH term(s)	Animals ; Apoptosis/genetics ; Bayes Theorem ; CHO Cells ; Cricetinae ; Cricetulus ; Proto-Oncogene Proteins c-bcl-2/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; bcl-2-Associated X Protein/genetics ; bcl-2-Associated X Protein/metabolism
Chemical Substances	Proto-Oncogene Proteins c-bcl-2 ; bcl-2-Associated X Protein
Language	English
Publishing date	2022-03-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	280318-5
ISSN	1097-0290 ; 0006-3592
ISSN (online)	1097-0290
ISSN	0006-3592
DOI	10.1002/bit.28062
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Article: Working Hard or Hardly Working? Regulatory Bottlenecks in Developing a COVID-19 Vaccine

Pregelj, Lisette / Hine, Damian C / Oyola-Lozada, Maria G / Munro, Trent P

Trends Biotechnol

Abstract	Vaccine solutions rarely reach the public until after an outbreak abates; an Ebola vaccine was approved 5 years after peak outbreak and SARS, MERS, and Zika vaccines are still in clinical development. Despite massive leaps forward in rapid science, other regulatory bottlenecks are hamstringing the global effort for pandemic vaccines.
Keywords	covid19
Publisher	WHO
Document type	Article
Note	WHO #Covidence: #597298
Database	COVID19

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Article ; Online: Working hard or hardly working? Regulatory bottlenecks in developing a COVID-19 vaccine

Pregelj, Lisette / Hine, Damian C. / Oyola-Lozada, Maria G. / Munro, Trent P.

2020

Abstract	Vaccine solutions rarely reach the public until after an outbreak abates; an Ebola vaccine was approved 5 years after peak outbreak and SARS, MERS, and Zika vaccines are still in clinical development. Despite massive leaps forward in rapid science, other regulatory bottlenecks are hamstringing the global effort for pandemic vaccines.
Keywords	COVID-19 ; innovation speed ; regulation ; vaccine development ; 1305 Biotechnology ; 1502 Bioengineering ; covid19
Language	English
Publishing date	2020-01-01
Publisher	Elsevier
Publishing country	au
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Long-term safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2 in adults aged 18-55 years or ≥56 years: 12-month results from a randomised, double-blind, placebo-controlled, phase 1 trial.

EBioMedicine

2023 Volume 97, Page(s) 104842

Abstract: Background: We previously demonstrated the safety and immunogenicity of an MF59-adjuvanted COVID-19 vaccine based on the SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a molecular clamp using HIV-1 glycoprotein 41 sequences. ... ...

Abstract	Background: We previously demonstrated the safety and immunogenicity of an MF59-adjuvanted COVID-19 vaccine based on the SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a molecular clamp using HIV-1 glycoprotein 41 sequences. Here, we describe 12-month results in adults aged 18-55 years and ≥56 years. Methods: Phase 1, double-blind, placebo-controlled trial conducted in Australia (July 2020-December 2021; ClinicalTrials.govNCT04495933; active, not recruiting). Healthy adults (Part 1: 18-55 years; Part 2: ≥56 years) received two doses of placebo, 5 μg, 15 μg, or 45 μg vaccine, or one 45 μg dose of vaccine followed by placebo (Part 1 only), 28 days apart (n = 216; 24 per group). Safety, humoral immunogenicity (including against virus variants), and cellular immunogenicity were assessed to day 394 (12 months after second dose). Effects of subsequent COVID-19 vaccination on humoral responses were examined. Findings: All two-dose vaccine regimens were well tolerated and elicited strong antigen-specific and neutralising humoral responses, and CD4 Interpretation: The SARS-CoV-2 molecular clamp vaccine is well tolerated and evokes robust immune responses in adults of all ages. Although the HIV glycoprotein 41-based molecular clamp is not being progressed, the clamp concept represents a viable platform for vaccine development. Funding: This study was funded by the Coalition for Epidemic Preparedness Innovations, the National Health and Medical Research Council of Australia, and the Queensland Government.
MeSH term(s)	Humans ; Aged ; SARS-CoV-2 ; COVID-19 Vaccines/adverse effects ; COVID-19/prevention & control ; Spike Glycoprotein, Coronavirus ; Vaccines ; Adjuvants, Immunologic ; HIV Infections/prevention & control ; Glycoproteins ; Double-Blind Method ; Antibodies, Viral ; Antibodies, Neutralizing
Chemical Substances	COVID-19 Vaccines ; spike protein, SARS-CoV-2 ; Spike Glycoprotein, Coronavirus ; MF59 oil emulsion ; Vaccines ; Adjuvants, Immunologic ; Glycoproteins ; Antibodies, Viral ; Antibodies, Neutralizing
Language	English
Publishing date	2023-10-20
Publishing country	Netherlands
Document type	Randomized Controlled Trial ; Clinical Trial, Phase I ; Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2023.104842
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