Sophisticated Cloning, Fermentation, and Purification Technologies for an Enhanced Therapeutic Protein Production: A Review

The protein productions strategies are crucial towards the development of application based research and elucidating the novel purification strategies for industrial production. Currently, there are few innovative avenues are studies for cloning, upstream, and purification through efficient bioprocess development. Such strategies are beneficial for industries as well as proven to be vital for effectual therapeutic protein development. Though, these techniques are well documented, but, there is scope of addition to current knowledge with novel and new approaches and it will pave new avenues in production of recombinant microbial and non-microbial proteins including secondary metabolites. In this review, we have focussed on the recent development in clone selection, various modern fermentation and purification technologies and future directions in these emerging areas. Moreover, we have also highlighted notable perspectives and challenges involved in the bioengineering of such proteins, including quality by design, gene editing and pioneering ideas. The biopharmaceutical industries continue to shift towards more flexible, automated platforms and economical product development, which in turn can help in developing the cost effective processes and affordable drug development for a large community.

[1]  Marcel Ottens,et al.  pH-gradient ion-exchange chromatography: an analytical tool for design and optimization of protein separations. , 2007, Journal of chromatography. A.

[2]  Pete Gagnon,et al.  How to Choose an Industrial Cation Exchanger for IgG Purification , 2010 .

[3]  Sanchayita Ghose,et al.  Evaluation and comparison of alternatives to Protein A chromatography Mimetic and hydrophobic charge induction chromatographic stationary phases. , 2006, Journal of chromatography. A.

[4]  Holger Fröhlich,et al.  Membrane Technology in Bioprocess Science , 2012 .

[5]  Cristen B. Peterson,et al.  Efficient expression of full-length antibodies in the cytoplasm of engineered bacteria , 2015, Nature Communications.

[6]  Eric S. Langer,et al.  Single‐use technologies in biopharmaceutical manufacturing: A 10‐year review of trends and the future , 2014 .

[7]  John Hickey,et al.  Profiling of host cell proteins by two‐dimensional difference gel electrophoresis (2D‐DIGE): Implications for downstream process development , 2010, Biotechnology and bioengineering.

[8]  Shigeru Iida,et al.  Establishment of FUT8 knockout Chinese hamster ovary cells: An ideal host cell line for producing completely defucosylated antibodies with enhanced antibody‐dependent cellular cytotoxicity , 2004, Biotechnology and bioengineering.

[9]  Duncan Low,et al.  Future of antibody purification. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[10]  Thomas Ryll,et al.  Maximizing productivity of CHO cell‐based fed‐batch culture using chemically defined media conditions and typical manufacturing equipment , 2010, Biotechnology progress.

[11]  J. Beckwith,et al.  The DsbA Signal Sequence Directs Efficient, Cotranslational Export of Passenger Proteins to the Escherichia coli Periplasm via the Signal Recognition Particle Pathway , 2003, Journal of bacteriology.

[12]  Kazuya Yamano,et al.  Engineering Chinese hamster ovary cells to maximize effector function of produced antibodies using FUT8 siRNA. , 2004, Biotechnology and bioengineering.

[13]  S. Jana,et al.  Strategies for efficient production of heterologous proteins in Escherichia coli. , 2005, Applied microbiology and biotechnology.

[14]  Barry Byrne,et al.  Preparative Purification of Recombinant Proteins: Current Status and Future Trends , 2013, BioMed research international.

[15]  H. Orozco,et al.  Genetic manipulation of longevity-related genes as a tool to regulate yeast life span and metabolite production during winemaking , 2013, Microbial Cell Factories.

[16]  Steven Rose,et al.  Mammalian Cell Culture , 2002 .

[17]  Peter Neubauer,et al.  Harmonization and characterization of different single‐use bioreactors adopting a new sparger design , 2014 .

[18]  Pratyoosh Shukla,et al.  Characterization, cloning and functional expression of novel xylanase from Thermomyces lanuginosus SS-8 isolated from self-heating plant wreckage material , 2013, World journal of microbiology & biotechnology.

[19]  C. Szymanski,et al.  Campylobacter--a tale of two protein glycosylation systems. , 2003, Trends in microbiology.

[20]  Holger Fröhlich,et al.  Efficient Engineering and Production Concepts for Products in Regulated Environments – Dream or Nightmare? , 2014 .

[21]  A. Chowdhury,et al.  Critical Factors Affecting the Success of Cloning, Expression, and Mass Production of Enzymes by Recombinant E. coli , 2012, ISRN biotechnology.

[22]  Gyun Min Lee,et al.  Development of recombinant Chinese hamster ovary cell lines for therapeutic protein production , 2013 .

[23]  Fei Wang,et al.  Purification of an amide hydrolase DamH from Delftia sp. T3-6 and its gene cloning, expression, and biochemical characterization , 2014, Applied Microbiology and Biotechnology.

[24]  Pratyoosh Shukla,et al.  Microbial platform technology for recombinant antibody fragment production: A review , 2017, Critical reviews in microbiology.

[25]  Feng Li,et al.  Cell culture processes for monoclonal antibody production , 2010, mAbs.

[26]  Z. Olempska-Beer,et al.  Food-processing enzymes from recombinant microorganisms--a review. , 2006, Regulatory toxicology and pharmacology : RTP.

[27]  F. Wurm.  Production of recombinant protein therapeutics in cultivated mammalian cells , 2004, Nature Biotechnology.

[28]  Christian Hakemeyer,et al.  Complete clarification solution for processing high density cell culture harvests , 2015 .

[29]  Sandeep Nema,et al.  Process Development Considerations for Therapeutic Monoclonal Antibodies in Mammalian Cell Culture , 2007 .

[30]  S. Akira,et al.  Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. , 1999, Journal of immunology.

[31]  Andrew J Racher,et al.  Antibody production. , 2006, Advanced drug delivery reviews.

[32]  F. Collart,et al.  Small-scale expression of proteins in E. coli. , 2014, Methods in enzymology.

[33]  Vaibhav Upadhyay,et al.  Protein recovery from inclusion bodies of Escherichia coli using mild solubilization process , 2015, Microbial Cell Factories.

[34]  Jacques Monod,et al.  The genetic control and cytoplasmic expression of “Inducibility” in the synthesis of β-galactosidase by E. coli , 1959 .

[35]  M. Ladisch,et al.  Hydrophobic interaction chromatography. , 1989, Biotechnology advances.

[36]  Oliver Spadiut,et al.  Microbials for the production of monoclonal antibodies and antibody fragments , 2014, Trends in biotechnology.

[37]  Stefan Kol,et al.  One-step generation of triple knockout CHO cell lines using CRISPR/Cas9 and fluorescent enrichment. , 2015, Biotechnology journal.

[38]  W. E. Razzell,et al.  Purification and properties of a pyrimidine deoxyriboside phosphorylase from Escherichia coli. , 1958, Biochimica et biophysica acta.

[39]  Michael W Laird,et al.  Characterization of a Monoclonal Antibody Cell Culture Production Process Using a Quality by Design Approach , 2010, Molecular biotechnology.

[40]  M. Knörnschild,et al.  Corrigendum: Bats host major mammalian paramyxoviruses , 2014, Nature Communications.

[41]  Brian Kelley,et al.  Very Large Scale Monoclonal Antibody Purification: The Case for Conventional Unit Operations , 2007, Biotechnology progress.

[42]  Patrick Thompson,et al.  Defining process design space for monoclonal antibody cell culture , 2010, Biotechnology and bioengineering.

[43]  Gerhard Schembecker,et al.  Developing the biofacility of the future based on continuous processing and single-use technology. , 2015, Journal of biotechnology.

[44]  Anindya Basu,et al.  Refolding of proteins from inclusion bodies: rational design and recipes , 2011, Applied Microbiology and Biotechnology.

[45]  Rajiv Gandhi,et al.  Overview of Microbial Therapeutic Enzymes , 2015 .

[46]  Daniel G Bracewell,et al.  Host cell protein adsorption characteristics during protein a chromatography , 2012, Biotechnology progress.

[47]  Sanchayita Ghose,et al.  Defining process design space for a hydrophobic interaction chromatography (HIC) purification step: Application of quality by design (QbD) principles , 2010, Biotechnology and bioengineering.

[48]  R. Bayer,et al.  Recovery and purification process development for monoclonal antibody production , 2010, mAbs.

[49]  Jens Nielsen,et al.  Production of natural products through metabolic engineering of Saccharomyces cerevisiae. , 2015, Current opinion in biotechnology.

[50]  Pratyoosh Shukla,et al.  Advanced technologies for improved expression of recombinant proteins in bacteria: perspectives and applications , 2016, Critical reviews in biotechnology.

[51]  D. Maresch,et al.  Development of a fed-batch process for a recombinant Pichia pastoris Δoch1 strain expressing a plant peroxidase , 2015, Microbial Cell Factories.

[52]  Brian Kelley,et al.  Industrialization of mAb production technology: The bioprocessing industry at a crossroads , 2009, mAbs.

[53]  Florian M Wurm,et al.  Manufacturing recombinant proteins in kg-ton quantities using animal cells in bioreactors. , 2011, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[54]  Jochen Strube,et al.  Challenges in biotechnology production—generic processes and process optimization for monoclonal antibodies , 2005 .

[55]  Michael W. Laird,et al.  Scalable purification of Bacillus anthracis protective antigen from Escherichia coli. , 2006, Protein expression and purification.

[56]  Ashok Kumar,et al.  Upstream processes in antibody production: evaluation of critical parameters. , 2008, Biotechnology advances.

[57]  J. Cregg,et al.  Structural comparison of the Pichia pastoris alcohol oxidase genes , 1989, Yeast.

[58]  Howard L. Levine,et al.  Efficient, Flexible Facilities for the 21st Century , 2012 .

[59]  A. Robinson,et al.  Cellular engineering for therapeutic protein production: product quality, host modification, and process improvement , 2017, Biotechnology journal.

[60]  Adam C. Fisher,et al.  Production of Secretory and Extracellular N-Linked Glycoproteins in Escherichia coli , 2010, Applied and Environmental Microbiology.

[61]  S. Singh,et al.  Solubilization and refolding of bacterial inclusion body proteins. , 2005, Journal of bioscience and bioengineering.

[62]  S. Jana,et al.  RETRACTED ARTICLE: Strategies for efficient production of heterologous proteins in Escherichia coli , 2005, Applied Microbiology and Biotechnology.

[63]  Jianwei Zhu,et al.  Mammalian cell protein expression for biopharmaceutical production. , 2012, Biotechnology advances.

[64]  Alavattam Sreedhara,et al.  A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design. , 2011, Journal of pharmaceutical sciences.

[65]  D. Petranovic,et al.  Impact of protein uptake and degradation on recombinant protein secretion in yeast , 2014, Applied Microbiology and Biotechnology.

[66]  Pratyoosh Shukla,et al.  Gene editing for cell engineering: trends and applications , 2017, Critical reviews in biotechnology.

[67]  Yolanda Santiago,et al.  BAK and BAX deletion using zinc‐finger nucleases yields apoptosis‐resistant CHO cells , 2010, Biotechnology and bioengineering.

[68]  Mudassar Ahmad,et al.  Protein expression in Pichia pastoris: recent achievements and perspectives for heterologous protein production , 2014, Applied Microbiology and Biotechnology.

[69]  Daniel Cummings,et al.  Integrated continuous production of recombinant therapeutic proteins , 2012, Biotechnology and bioengineering.

[70]  Abhinav A Shukla,et al.  Recent advances in large-scale production of monoclonal antibodies and related proteins. , 2010, Trends in biotechnology.

[71]  J. Cregg,et al.  Functional characterization of the two alcohol oxidase genes from the yeast Pichia pastoris , 1989, Molecular and cellular biology.

[72]  Anurag S Rathore,et al.  Roadmap for implementation of quality by design (QbD) for biotechnology products. , 2009, Trends in biotechnology.

[73]  C. von Wachenfeldt,et al.  A folded and immunogenic IgE-hyporeactive variant of the major allergen Phl p 1 produced in Escherichia coli , 2015, BMC Biotechnology.

[74]  S. Oscarsson,et al.  A strategic crossflow filtration methodology for the initial purification of promegapoietin from inclusion bodies. , 2009, Journal of biotechnology.

[75]  C. Kurtzman.  Biotechnological strains of Komagataella (Pichia) pastoris are Komagataellaphaffii as determined from multigene sequence analysis , 2009, Journal of Industrial Microbiology & Biotechnology.

[76]  K. Takegawa,et al.  Engineering of protein secretion in yeast: strategies and impact on protein production , 2010, Applied Microbiology and Biotechnology.

[77]  Alois Jungbauer,et al.  Harnessing Candida tenuis and Pichia stipitis in whole‐cell bioreductions of o‐chloroacetophenone: Stereoselectivity, cell activity, in situ substrate supply and product removal , 2013, Biotechnology journal.

[78]  Karan Sukhija,et al.  A Single-use Strategy to Enable Manufacturing of Affordable Biologics , 2016, Computational and structural biotechnology journal.

[79]  C. Yanofsky,et al.  Transduction and recombination study of linkage relationships among the genes controlling tryptophan synthesis in Escherichia coli. , 1959, Virology.

[80]  J. Cregg,et al.  Expression of Recombinant Genes in the Yeast Pichia pastoris , 2010 .

[81]  C. Szymanski,et al.  Evidence for a system of general protein glycosylation in Campylobacter jejuni , 1999, Molecular microbiology.

[82]  A. Dalton,et al.  Over-expression of secreted proteins from mammalian cell lines , 2014, Protein science : a publication of the Protein Society.

[83]  Massimo Morbidelli,et al.  Twin-column CaptureSMB: a novel cyclic process for protein A affinity chromatography. , 2015, Journal of chromatography. A.

[84]  S. Wildt,et al.  The humanization of N-glycosylation pathways in yeast , 2005, Nature Reviews Microbiology.

[85]  Per Hagander,et al.  Probing control of fed-batch cultivations: analysis and tuning , 2001 .

[86]  修 龍治,et al.  Recombinant Protein , 1987, Definitions.

[87]  Yu Shen,et al.  Engineering protein folding and translocation improves heterologous protein secretion in Saccharomyces cerevisiae , 2015, Biotechnology and bioengineering.

[88]  F. Szoka,et al.  Periplasmic production via the pET expression system of soluble, bioactive human growth hormone. , 2013, Protein expression and purification.

[89]  Brian Hubbard,et al.  Downstream processing of monoclonal antibodies--application of platform approaches. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[90]  J. Chon,et al.  Advances in the production and downstream processing of antibodies. , 2011, New biotechnology.

[91]  N. Aksöz,et al.  Effect of carbon and nitrogen sources on xylanase production by Trichoderma harzianum 1073 D3 , 2005 .

[92]  S. Iida,et al.  Establishment of FUT 8 Knockout Chinese Hamster Ovary Cells : An Ideal Host Cell Line for Producing Completely Defucosylated Antibodies With Enhanced Antibody-Dependent Cellular Cytotoxicity , 2004 .

[93]  Eric T. Boder,et al.  Yeast surface display for screening combinatorial polypeptide libraries , 1997, Nature Biotechnology.

[94]  Cleo Kontoravdi,et al.  Towards the implementation of quality by design to the production of therapeutic monoclonal antibodies with desired glycosylation patterns , 2010, Biotechnology progress.

[95]  M. Inan,et al.  Non-repressing carbon sources for alcohol oxidase (AOX1) promoter of Pichia pastoris. , 2001, Journal of bioscience and bioengineering.

[96]  K Rumbold,et al.  High-level intracellular expression of hydroxynitrile lyase from the tropical rubber tree Hevea brasiliensis in microbial hosts. , 1997, Protein expression and purification.

[97]  Y. Chao,et al.  Enhanced integration of large DNA into E. coli chromosome by CRISPR/Cas9 , 2017, Biotechnology and bioengineering.

[98]  R. Zubarev,et al.  Optimizing heterologous protein production in the periplasm of E. coli by regulating gene expression levels , 2013, Microbial Cell Factories.

[99]  Mariana Henriques,et al.  Guidelines to cell engineering for monoclonal antibody production. , 2010, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[100]  C. F. van der Walle,et al.  Therapeutic antibodies: market considerations, disease targets and bioprocessing. , 2013, International journal of pharmaceutics.

[101]  M. Butler,et al.  Recent advances in technology supporting biopharmaceutical production from mammalian cells , 2012, Applied Microbiology and Biotechnology.

[102]  David A Michels,et al.  Quantitative impurity analysis of monoclonal antibody size heterogeneity by CE‐LIF: Example of development and validation through a quality‐by‐design framework , 2012, Electrophoresis.

[103]  Regine Eibl,et al.  Bioengineering Parameters for Single‐Use Bioreactors: Overview and Evaluation of Suitable Methods , 2013 .

[104]  Yu Chen,et al.  Genome editing of CXCR4 by CRISPR/cas9 confers cells resistant to HIV-1 infection , 2015, Scientific Reports.

[105]  P. Ricciardi-Castagnoli,et al.  Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. , 1998, Science.

[106]  Maria Raquel Aires-Barros,et al.  Purification of a , 1999 .

[107]  Kathleen A. Curran,et al.  Design of synthetic yeast promoters via tuning of nucleosome architecture , 2014, Nature Communications.

[108]  Chaozhan Wang,et al.  High Recovery Refolding of rhG‐CSF from Escherichia coli, Using Urea Gradient Size Exclusion Chromatography , 2008, Biotechnology progress.

[109]  C. Emrich,et al.  SHuffle, a novel Escherichia coli protein expression strain capable of correctly folding disulfide bonded proteins in its cytoplasm , 2012, Microbial Cell Factories.

[110]  J. Corchero,et al.  Detoxifying Escherichia coli for endotoxin-free production of recombinant proteins , 2015, Microbial Cell Factories.

[111]  S. Padmanabhan,et al.  Expression and Purification of SAK-fused Human Interferon Alpha in Escherichia coli , 2009 .

[112]  Uwe Gottschalk,et al.  Single-use disposable technologies for biopharmaceutical manufacturing. , 2013, Trends in biotechnology.

[113]  C. Arunkumar,et al.  Production and single-step purification of Brugia malayi abundant larval transcript (ALT-2) using hydrophobic interaction chromatography , 2010, Journal of Industrial Microbiology & Biotechnology.

[114]  M. Aebi,et al.  A Combined System for Engineering Glycosylation Efficiency and Glycan Structure in Saccharomyces cerevisiae , 2012, Applied and Environmental Microbiology.

[115]  Michael Butler,et al.  Expression systems for therapeutic glycoprotein production. , 2009, Current opinion in biotechnology.

[116]  Anurag Rathore,et al.  Analytical QbD: Development of a native gel electrophoresis method for measurement of monoclonal antibody aggregates , 2014, Electrophoresis.

[117]  Mohamed Farhat,et al.  Surface wave dynamics in orbital shaken cylindrical containers , 2014, 1412.0919.

[118]  Enrico Drioli,et al.  Membrane engineering in process intensificationAn overview , 2011 .

[119]  Zhiwei Song,et al.  RNAi suppression of Bax and Bak enhances viability in fed-batch cultures of CHO cells. , 2006, Metabolic engineering.

[120]  T. Gingeras,et al.  Isolation of alcohol oxidase and two other methanol regulatable genes from the yeast Pichia pastoris , 1985, Molecular and cellular biology.

[121]  Hans Hummel,et al.  Paradigm shift for vaccine manufacturing facilities: The next generation of flexible, modular facilities , 2014 .

[122]  Shang-Tian Yang,et al.  Cell culture processes for biologics manufacturing: recent developments and trends , 2013 .

[123]  P. Gagnon.  Technology trends in antibody purification. , 2012, Journal of chromatography. A.

[124]  Oliver Kaltenbrunner,et al.  Continuous bind‐and‐elute protein A capture chromatography: Optimization under process scale column constraints and comparison to batch operation , 2016, Biotechnology progress.

[125]  Simon J North,et al.  N-linked glycosylation in Campylobacter jejuni and its functional transfer into E. coli. , 2002, Science.

[126]  Ashraf Amanullah,et al.  Novel micro‐bioreactor high throughput technology for cell culture process development: Reproducibility and scalability assessment of fed‐batch CHO cultures , 2010, Biotechnology and bioengineering.

[127]  Beatrix Fahnert,et al.  Inclusion bodies: formation and utilisation. , 2004, Advances in biochemical engineering/biotechnology.

[128]  T. Gingeras,et al.  Expression of the lacZ gene from two methanol-regulated promoters in Pichia pastoris. , 1987, Nucleic acids research.

[129]  Gerald Schwank,et al.  Advances in therapeutic CRISPR/Cas9 genome editing. , 2016, Translational research : the journal of laboratory and clinical medicine.

[130]  Joni Tsukuda,et al.  A clone screening method using mRNA levels to determine specific productivity and product quality for monoclonal antibodies , 2009, Biotechnology and bioengineering.

[131]  William G. Whitford.  Single-Use Systems As Principal Components in Bioproduction , 2010 .

[132]  Chris Morrison.  Fresh from the biotech pipeline—2015 , 2016, Nature Biotechnology.

[133]  Chung-Jr Huang,et al.  Industrial production of recombinant therapeutics in Escherichia coli and its recent advancements , 2012, Journal of Industrial Microbiology & Biotechnology.

[134]  P. Hinckley,et al.  Host cell protein clearance during protein a chromatography: Development of an improved column wash step , 2008, Biotechnology progress.

[135]  Varsha Joshi,et al.  Refolding of biotech therapeutic proteins expressed in bacteria: review , 2013 .

[136]  Katie F Wlaschin,et al.  Recombinant protein therapeutics from CHO cells : 20 years and counting , 2007 .

[137]  Xiangyang Wang,et al.  Defining Process Design Space for Biotech Products: Case Study of Pichia pastoris Fermentation , 2008, Biotechnology progress.

[138]  S. Hober,et al.  Protein A chromatography for antibody purification. , 2007, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[139]  Melissa A. Holstein,et al.  Downstream bioprocessing: recent advances and future promise , 2011 .

[140]  Kaushal Kumar,et al.  High-throughput process development for biopharmaceutical drug substances. , 2011, Trends in biotechnology.

[141]  J. K. Deb,et al.  Retraction Note: Strategies for efficient production of heterologous proteins in Escherichia coli , 2014, Applied Microbiology and Biotechnology.