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.
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
Bagdonas H
(2020)
Leveraging glycomics data in glycoprotein 3D structure validation with Privateer.
in Beilstein journal of organic chemistry
Fisher P
(2019)
Modeling Glycan Processing Reveals Golgi-Enzyme Homeostasis upon Trafficking Defects and Cellular Differentiation.
in Cell reports
Fisher P
(2019)
The N-Glycosylation Processing Potential of the Mammalian Golgi Apparatus.
in Frontiers in cell and developmental biology
Fisher P
(2016)
Bridging the Gap between Glycosylation and Vesicle Traffic.
in Frontiers in cell and developmental biology
Ha JY
(2016)
Molecular architecture of the complete COG tethering complex.
in Nature structural & molecular biology
Kleinjan DA
(2017)
Drug-tunable multidimensional synthetic gene control using inducible degron-tagged dCas9 effectors.
in Nature communications
Merrick CA
(2018)
Serine Integrases: Advancing Synthetic Biology.
in ACS synthetic biology
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 |