A Combinatorial Approach to Enhance Production of Monoclonal Antibodies

Lead Research Organisation: University of York
Department Name: Biology

Abstract

Biopharmaceuticals, also known as biologic medical products (biologics for short) are medicinal products manufactured in or extracted from biological systems and are distinct from synthesized pharmaceutical products. Examples include vaccines against diseases such as polio and therapeutics used to treat numerous diseases, such as cancer and arthritis. These therapeutics are often molecules called monoclonal antibodies that are made by the immune system, our inbuilt anti-disease defense mechanism. Perhaps one the best known examples of this is Trastuzumab (trade name; Herceptin), a monoclonal antibody that is used to treat certain breast cancers. Production of these biologics is expensive and this translates into a high financial cost to health care providers.

This project aims to alter the cells that make monoclonal antibodies for therapeutic use, so that they make larger amounts with reduced production costs. This should increase the availability of these powerful therapeutics.

Technical Summary

CHO cells are the most widely used industrial system for producing recombinant therapeutic proteins, but can struggle to express and secrete large biologics such as monoclonal antibodies (mAbs) at sustained high levels. We will address this with a systematic programme of synthetic cell bioengineering that combines innovative approaches to concomitantly increase CHO cells' capacities to express and secrete mAbs. Our team combines complementary skill sets to enhance successive steps that are potentially rate-limiting for mAb production, including transgene expression, mRNA translation, intracellular trafficking, post-translational modification and secretion. We will combine a series of novel improvements in a holistic manner to generate CHO cell lines optimised to produce mAbs of great economic and therapeutic value. In so doing, the project will establish a robust, flexible and adaptable UK platform for optimisation and manufacture of therapeutic biologics.

Planned Impact

As described in proposal submitted to TSB

Publications

10 25 50
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Bagdonas H (2020) Leveraging glycomics data in glycoprotein 3D structure validation with Privateer. in Beilstein journal of organic chemistry

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Fisher P (2016) Bridging the Gap between Glycosylation and Vesicle Traffic. in Frontiers in cell and developmental biology

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Fisher P (2019) The N-Glycosylation Processing Potential of the Mammalian Golgi Apparatus. in Frontiers in cell and developmental biology

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Ha JY (2016) Molecular architecture of the complete COG tethering complex. in Nature structural & molecular biology

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Merrick CA (2018) Serine Integrases: Advancing Synthetic Biology. in ACS synthetic biology

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Petrie JL (2019) Effects on prostate cancer cells of targeting RNA polymerase III. in Nucleic acids research

 
Description We have discovered genetic manipulations that enhance therapeutic antibody production.
Exploitation Route Adoption by industrial partners engaged in production of therapeutic antibodies.
Sectors Healthcare,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology

 
Description University of York has Formed a Strategic Partnership with Industrial Collaborator Fujifilm Diosynth Biotechnologies
First Year Of Impact 2019
Sector Manufacturing, including Industrial Biotechology
Impact Types Economic

 
Description Development of a computational glycan engineering tool for biologics manufacturers
Amount £198,765 (GBP)
Funding ID BB/T016965/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 07/2020 
End 12/2021
 
Description Manipulation of tRNA to Enhance Biologic Production
Amount £194,925 (GBP)
Funding ID BB/S018727/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 09/2019 
End 03/2021
 
Description Optimisation of CHO for Biotherapeutic Manufacture
Amount £3,608,961 (GBP)
Funding ID EP/V038095/1 
Organisation Engineering and Physical Sciences Research Council (EPSRC) 
Sector Public
Country United Kingdom
Start 09/2021 
End 09/2026
 
Title Modified expression constructs 
Description Vectors with enhanced expression properties to produce therapeutic monoclonal antibodies 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? No  
Impact Enhanced expression of antibody products of high economic and societal value 
 
Title Transgenic CHO lines 
Description Novel CHO cell lines have been constructed that carry transgenes intended to enhance expression of therapeutic antibodies. 
Type Of Material Cell line 
Provided To Others? No  
Impact Patent filed. Collaborations underway with industrial partners. 
 
Description Collaborative Training Partnership Studentship Project 
Organisation Croda International
Department Croda Chemicals Europe Ltd
Country United Kingdom 
Sector Private 
PI Contribution PhD student will be based in my laboratory at University of York & supervised by me & my team.
Collaborator Contribution Studentship was awarded to Croda as a Collaborative Training Partnership.
Impact None yet. Student began work in October 2017.
Start Year 2017
 
Description FDBK studentships 
Organisation Fujifilm
Department Fujifilm Diosynth Biotechnologies, UK
Country United Kingdom 
Sector Private 
PI Contribution White, Bryant & Ungar as supervisors and co-supervisors
Collaborator Contribution Studentships awarded to FDBK as a Collaborative Training Partnership.
Impact No outputs yet
Start Year 2020
 
Description Formal Collaboration with Industrial Partner 
Organisation Fujifilm
Country Japan 
Sector Private 
PI Contribution Formal Collaboration with Fujifilm Diosynth Biotechnologies, involving CDA & MTA agreements & conference calls every month. My team is testing our innovations in systems developed by Fujifilm.
Collaborator Contribution A range of reagents have been provided. Conference calls every month.
Impact None yet.
Start Year 2017
 
Description Fujifilm Diosynth Biotechnologies Centre of Excellence in Bioprocessing 2.0 
Organisation Fujifilm
Department Fujifilm Diosynth Biotechnologies
Country United States 
Sector Private 
PI Contribution I lead the bid from University of York to join this partnership
Collaborator Contribution My staff have been conducting tests in FDB laboratories, using their equipment and reagents
Impact Ongoing.
Start Year 2019
 
Description Lonza Collaboration 
Organisation Lonza Group
Country Global 
Sector Private 
PI Contribution Exchange of reagents & expertise
Collaborator Contribution Exchange of reagents & expertise
Impact No outputs yet
Start Year 2020
 
Description NPIF studentship with GSK 
Organisation GlaxoSmithKline (GSK)
Country Global 
Sector Private 
PI Contribution Studentship based at UoY with UoY supervisors (Ungar & Thomas-Oates). White to supervise training & progression.
Collaborator Contribution Placement & co-supervision.
Impact None yet.
Start Year 2017
 
Description Prosperity Partnership 
Organisation Fujifilm
Department Fujifilm Diosynth Biotechnologies, UK
Country United Kingdom 
Sector Private 
PI Contribution We are actively contributing to four of the five work packages.
Collaborator Contribution FDBK are the Industrial partners. Additional academic partners are the universities of Edinburgh (lead) and Manchester.
Impact No outputs yet.
Start Year 2021
 
Title Chinese Hamster Ovary (CHO) cell lines and their identified genome hotspots for stable recombinant protein production 
Description Genomic sites identified to allow optimal production of recombinant proteins. 
IP Reference UK Patent Application No.2019484.1 filed on10th December 2020 
Protection Patent application published
Year Protection Granted 2020
Licensed No
Impact None yet.
 
Title Glycosylation Method 
Description A novel method to manipulate glycosylation of secreted proteins 
IP Reference 2107057.8 
Protection Patent application published
Year Protection Granted 2021
Licensed No
Impact Interest from industrial partners leading to funding of studentships
 
Title RECOMBINANT PROTEIN PRODUCTION 
Description The disclosure relates to recombinant protein expression systems comprising genetically modified cells wherein the cells are transformed or transfected with tRNA genes to reduce base mismatch due to genetic degeneracy in the genetic code. 
IP Reference WO2017121988 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact None yet.
 
Title Recombinant Protein Production 
Description Enhanced production of recombinant proteins. 
IP Reference Japanese patent application 4543P JPPJ1957SYM filed 29.06.2018 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact None yet.
 
Title Recombinant Protein Production 
Description Enhanced productivity of therapeutic antibodies. 
IP Reference U.S. application 16/0645421 
Protection Patent application published
Year Protection Granted 2018
Licensed No
Impact None yet.
 
Description 4th Glycobiology World Congress 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited speaker, 4th Glycobiology World Congress, Rome, Italy
Year(s) Of Engagement Activity 2018
 
Description Fujifilm Diosynth Biotechnologies Centre of Excellence in Bioprocessing 2.0 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Ongoing collaboration involving industrial partner Fujifilm Diosynth Biotechnologies UK and the Universities of Edinburgh, Manchester and York.
Year(s) Of Engagement Activity 2019,2021,2022
 
Description MedImmune Visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Visit by MedImmune to University of Edinburgh to discuss opportunities for collaboration.
Year(s) Of Engagement Activity 2017
 
Description Presentation at GSK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Presentation by Dani Ungar at GSK.
Year(s) Of Engagement Activity 2017
 
Description Presentation at UCB 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Presentation at UCB Slough concerning our technology advancements & potential collaboration.
Year(s) Of Engagement Activity 2016
 
Description Presentation to Fujifilm 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact Presentation of our technology innovations to staff from Fujifilm Diosynth Biotechnologies.
Year(s) Of Engagement Activity 2017
 
Description STEM for Britain poster at Westminster 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact Poster describing our research presented to MPs at Westminster at a STEM for Britain event.
Year(s) Of Engagement Activity 2019
 
Description Society for Glycobiology 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Society for Glycobiology, USA, virtual meeting
Talk title: "A computational model linking the organization of the mammalian glycosylation machinery with glycan processing
Year(s) Of Engagement Activity 2020
 
Description Sun Pharmaceuticals 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Industry/Business
Results and Impact Meeting at University of oYork with Anil Kumar Jain, CEO Global API Business, Sun Pharmaceutical Industries Ltd.
Year(s) Of Engagement Activity 2017
 
Description University of Delhi 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Professional Practitioners
Results and Impact Invited talk at University of Delhi
Year(s) Of Engagement Activity 2019