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

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

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

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

 
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

 
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 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 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
 
Title Recombinant protein production 
Description 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 and hence reliance on wobble for decoding; the modified cells have so improved recombinant protein expression. 
IP Reference WO2017121988 
Protection Patent application published
Year Protection Granted 2016
Licensed No
Impact Collaborations with industrial partners.
 
Title Recombinant protein production 
Description Enhanced productivity of therapeutic antibodies. 
IP Reference WO2017121988 
Protection Patent application published
Year Protection Granted 2017
Licensed No
Impact None yet.
 
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 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