Overcoming Downstream Purification Challenges for Viral Vector Manufacturing: Enabling Advancement of Gene Therapies in the Clinic

Terova, Orjana; Soltys, Stephen M.; Hermans, Pim; Rooij, Jessica D. de; Detmers, Frank

doi:10.18609/cgti.2018.017

Cited by 20 publications

(25 citation statements)

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“…Chromatography matrix References Affinity A20 Grimm et al (1998) Heparin (POROS HE) Anderson et al (2000) Mucin Auricchio et al (2001) AVB Sepharose HP Dismuke and Kotin (2017), Gu et al (2018), Hebben (2018), Nass et al (2018), J. Smith, Grieger, and Samulski (2018), R. H. Smith, Levy, and Kotin (2009), Terova et al (2018), Toueille (2018) POROS AAVX Hebben (2018), Terova et al (2018), Toueille (2018) Anion exchange POROS 50 HQ Urabe et al (2006) Q sepharose FF Tomono et al (2018) Cation exchange Fractogel® EMD SO 3 − Chahal, Aucoin, and Kamen (2007) Mustang S Davidoff et al (2004) POROS 50 HS Heldt 2019Hydrophobic interaction CIMmultus OH Leskovec et al (2018) and full capsid quantity due the difference in DNA present in full capsids based on the predictable manner in which empty capsids reduce the absorbance A 260 /A 280 ratio (Sommer et al, 2003). Charge detection mass spectrometry can be used by measuring the mass charge ratio and the individual ion charge (Pierson, Keifer, Asokan, & Jarrold, 2016).…”

Section: Capture Methodsmentioning

confidence: 99%

“…These ligands have high avidity to the AAV capsids whilst allowing impurities to flow through the column, achieving a high purity after a single step. The potential of this technology was aptly illustrated in a study where comparable purity of material (as measured by sodium dodecyl sulfate polyacrylamide gel electrophoresis) was achieved with a single affinity capture step as compared to a three step ion exchange process (Terova, Soltys, Hermans, De Rooij, & Detmers, 2018).…”

Section: Purification Of Aav Vectors Through Capture Chromatographymentioning

confidence: 99%

“…In a recent study (Terova et al, 2018), POROS CaptureSelect AAVX was demonstrated to have high static binding recovery (>95%) for a broad range of natural and synthetic serotypes tested. This data shows the potential for POROS CaptureSelect AAVX to be a platform resin for various AAV serotypes.…”

Section: Purification Of Aav Vectors Through Capture Chromatographymentioning

confidence: 99%

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Moving from the bench towards a large scale, industrial platform process for adeno‐associated viral vector purification

Adams

Bak

Tustian

2020

Biotech & Bioengineering

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In recent years, there has been a strong interest in the development and production of gene therapy products, especially those utilizing adeno‐associated virus (AAV) particles. This is evident with the growing number of clinical successes and agency approvals for AAV therapeutics. Due to this increased investment in this technology, a need exists for scalable commercial production methods to ensure adequate product supply as research in AAV shifts from bench‐scale development to clinical production. The purpose of this review is to summarize current scalable purification techniques that can be employed during the commercial manufacturing of AAV as well as highlight certain development considerations, such as adventitious agent removal and process development using the principals of quality by design.

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Section: Capture Methodsmentioning

confidence: 99%

Section: Purification Of Aav Vectors Through Capture Chromatographymentioning

confidence: 99%

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Moving from the bench towards a large scale, industrial platform process for adeno‐associated viral vector purification

Adams

Bak

Tustian

2020

Biotech & Bioengineering

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“…, HEK293T cell) is used for viral vector production, but this method has a limitation of production capacity ( 57 ). Scaling-up can be achieved by applying a suspension expression system culturing in a bioreactor to replace the adherent cells grown in cell stacks ( 54 , 58 ). However, the suspension systems in which cells and virus particles are mixed in the liquid together may generate more challenges to downstream processing where the virus particles are purified from the media.…”

Section: Delivery Systems Of New-generation Vaccinesmentioning

confidence: 99%

The COVID-19 Vaccine Race: Challenges and Opportunities in Vaccine Formulation

et al. 2020

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In the race for a safe and effective vaccine against coronavirus disease (COVID)-19, pharmaceutical formulation science plays a critical role throughout the development, manufacturing, distribution, and vaccination phases. The proper choice of the type of vaccine, carrier or vector, adjuvant, excipients, dosage form, and route of administration can directly impact not only the immune responses induced and the resultant efficacy against COVID-19, but also the logistics of manufacturing, storing and distributing the vaccine, and mass vaccination. In this review, we described the COVID-19 vaccines that are currently tested in clinical trials and provided in-depth insight into the various types of vaccines, their compositions, advantages, and potential limitations. We also addressed how challenges in vaccine distribution and administration may be alleviated by applying vaccinestabilization strategies and the use of specific mucosal immune response-inducing, noninvasive routes of administration, which must be considered early in the development process.

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“…On the other hand, the vast majority of pharmaceutical products that require a high degree of purity are isolated by a series of downstream processing techniques which are affecting protein final yield [27]. Expression of intact and properly folded proteins favorably improves productivity by reducing the number of purification steps [28]. Therefore, the aim of this study was to determine the optimal condition for enhancement the correctly folded Fc-fusion protein production while improving protein yield.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Fc fusion protein misfolding: A three-phasic cultivation experimental design

Aghdam¹,

Moradhaseli²,

Jafari³

et al. 2019

PLoS ONE

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Cell culture process optimization is a critical solution to most of the challenges faced by the pharmaceutical manufacturing. One of the major problems encountered in large-scale production of therapeutic proteins is misfolded protein production. The accumulation of misfolded therapeutic proteins is an immunogenic signal and a risk factor for immunogenicity of the final product. The aim of this study was the statistical optimization of three-phasic temperature shift and timing for enhanced production of correctly folded Fc-fusion protein. The effect of culture temperatures were investigated using the biphasic culture system. Box–Behnken design was then used to compute temperature and time of shifting optimum. Response surface methodology revealed that maximum production with low level of misfolded protein was achieved at two-step temperature shift from 37°C to 30°C during the late logarithmic phase and 30°C to 28°C in the mid-stationary phase. The optimized condition gave the best results of 1860 mg L−1 protein titer with 24.5% misfolding level. The validation experiments were carried out under optimal conditions with three replicates and the protein misfolding level was decreased by two times while productivity increased by ~ 1.3-fold. Large-scale production in 250 L bioreactor under the optimum conditions was also verified the effectiveness and the accuracy of the model. The results showed that by utilizing two-step temperature shift, productivity and the quality of target protein have been improved simultaneously. This model could be successfully applied to other products.

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Overcoming Downstream Purification Challenges for Viral Vector Manufacturing: Enabling Advancement of Gene Therapies in the Clinic

Cited by 20 publications

References 0 publications

Moving from the bench towards a large scale, industrial platform process for adeno‐associated viral vector purification

Moving from the bench towards a large scale, industrial platform process for adeno‐associated viral vector purification

The COVID-19 Vaccine Race: Challenges and Opportunities in Vaccine Formulation

Therapeutic Fc fusion protein misfolding: A three-phasic cultivation experimental design

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