An interdisciplinary research team from the University of Leeds and MedImmune, the global biologics research and development arm of AstraZeneca, developed a device that was able to apply extensional flow in the laboratory and used it to study the activity of proteins held in the fluid.
The team found the method can lead to an increased likelihood that a wide range of proteins including biopharmaceuticals would become less effective.
Dr Brockwell said: “There are very few existing protein tests available to industry which actually examine how aggregation levels are related to manufacturing conditions. What we now have is a much more accurate way of predicting which proteins can be used in biopharmaceutical drug development and how processes could also be changed to improve their quality.”
Outside manufacturing, common examples of extensional flow include syringes administering liquefied drugs or the effect on water seen when gardeners put their finger over the end of a hosepipe.
Proteins naturally fold into specific shapes in order to operate correctly, but extensional flow can cause them to stretch and unfold, making them less useful.
Once they begin to unfold, proteins stick together, or aggregate, which can block sensitive factory equipment and decrease the effectiveness of the medicines they are contained in, and can even pose a danger to people. Preventing aggregation is thus an important criterion in the development and licensing of a new biopharmaceutical product.
To test the effects of extensional flow, Professor Nik Kapur and PhD student John Dobson from the Faculty of Engineering developed a bench-top device able to very precisely control the strain exerted on proteins in fluid and the extent to which they unfolded.
Using the new device to gather evidence, researchers (Dr Amit Kumar and Mr Leon Willis, led by Professor Sheena Radford and Dr Brockwell) were able to calculate exactly the extent of the protein aggregation, creating a new evidence base for industry. Dr Brockwell and his colleagues found the extent of aggregation was dependent on:
The team also found that aggregation in a range of proteins was diverse and was particularly damaging to therapeutic proteins such as biopharmaceutical antibodies under conditions similar to those found in standard manufacturing processes.
Dr Brockwell and his colleagues say that with their new evidence, companies could consider re-designing manufacturing techniques to reduce the pressures exerted on proteins through extensional flow, if they want to make their products reach market faster. Alternatively, rather than changing embedded production methods, the device could instead be used to identify individual protein groups which are resistant to the rigours of manufacture.
“Biopharmaceutical drugs are a growing area of medical innovation, because of their success in treating a number of illnesses, but are very expensive to produce, so any innovation which drug companies can make to improve their costs will have a significant effect,” he said.
Researchers on the project are funded by the Engineering and Physical Sciences Research Council, European Research Council, GSK, MedImmune and the Royal Academy of Engineering.
The team’s research also found that shear flow, another type of manufacturing process, did not cause proteins to unfold and lose their effectiveness.
Ralf Richter, David Brockwell, Eric Hewitt, Jessica Kwok, Emanuele Paci and MAPS/FMH, BBSRC (Jun 2017), £600,000
Eric Blair, Adrian Whitehouse, Nicola Stonehouse, Alison Baker, Richard Bayliss, Joan Boyes, Ryan Seipke, Sally Boxall and MAPS/FMH, BBSRC (Jun 2017), £376,000
Stefan Kepinski, Yoselin Benitez-Alfonso, Tom Bennett, Michelle Peckham, BBSRC (Jun 2017), £331,000
Roman Tuma, Lars Jeuken, Paul Millner, Sheena Radford, Peter Stockley and MAPS/FMH, BBSRC (Jun 2017), £222,000
Vas Ponnambalam, Darren Tomlinson, Stephen Wheatcroft, BHF (May 2017), £107,878
Graham Askew in collaboration with Bangor University, BBSRC (Mar 2017), £477,383
Stephen Muench, BBSRC (Mar 2017), £132,945
Nic Stonehouse, MRC (Mar 2017), £906,341
Bill Kunin, Steve Sait, BBSRC (Mar 2017), £602,831
Adrian Goldman, EU (Mar 2017), £546,576
Sheena Radford, Wellcome Trust (Mar 2017), £1,836,482
Tom Bennett, Royal Society (Mar 2017), £15,000
Jamie Johnston, Royal Society (Mar 2017), £15,000
Beatrice Filippi, Royal Society (Mar 2017), £15,000
Ryan Seipke, BBSRC (Feb 2017), £52,116
Mary O'Connell, BBSRC (Feb 2017), £46,986
Hannah Dugdale, NERC (Feb 2017), £504,138
Anastasia Zhuravleva, EPSRC (Jan 2017), £100,792
Richard Bayliss, Cancer Research UK (Jan 2017), £1,600,000
John Barr, EU (Jan 2017), £339,000
Mark Harris, Royal Society (Jan 2017), £250,000
Alison Dunn, NERC (Jan 2017), £105,000
Alex Breeze, Pancreatic Cancer Research Fund (Jan 2017), £180,000
Alison Dunn, NERC (Dec 2016), £18,000
Lisa Collins, BBSRC (Dec 2016), £1,681,835
Brendan Davies, Leverhulme Trust (Dec 2016), £247,555
Alan Benson, Mark Drinkhill, Ed White, British Heart Foundaion (Dec 2016), £217,223
Adrian Goldman, Royal Society (Dec 2016), £82,999
Lisa Roberts, Alex Breeze, Brendan Davies, Timothy Devinney, Oliver Harlen, Joseph Holden, Anthea Hucklesby, Pamela Jones, Philip Mellor, RCUK (Nov 2016), £484,172
Lisa Roberts, Alex Breeze, Brendan Davies, Timothy Devinney, Oliver Harlen, Joseph Holden, Anthea Hucklesby, Pamela Jones, Philip Mellor, Wellcome Trust (Nov 2016), £119,343
Katie Field, Rank Prize Funds (Nov 2016), £20,000
Jessica Kwok, Royal Society (Nov 2016), £14,948
John Ladbury, Cancer Research UK (Oct 2016), £4,250
Miriam Wittmann, Martin Stacey, Edward Vital, Lupus UK
(Oct 2016), £34,010
Valerie Speirs, NC3Rs
(Oct 2016), £90,000
Nicola Stonehouse, Morgan Herod, David Rowlands, BBSRC
(Sep 2016), £436,424
Joseph Cockburn, Wellcome Trust
(Sep 2016), £100,000
John Barr, Public Health England
(Sep 2016), £94,471
Helen Miller, DSM Nutritional Products A/S
(Sep 2016), £54,680
Steven Clapcote, Vitaflo International Ltd
(Sep 2016), £39,285
Juan Fontana Jordan De Urries
, Royal Society
(Sep 2016), £21,793
Jing Li, Sarah Calaghan, Mark Drinkhill, British Heart Foundation
(Sep 2016), £117,585
Sheena Radford, Alison Ashcroft, BBSRC (Sep 2016), £457,216
Patricija Van Oosten-Hawle, An-Jung Chen, David Westhead, NC3Rs
(Sep 2016), £354,456
Glyn Hemsworth, BBSRC (Sep 2016), £1,024,034
David Jayne, Paul Millner, MRC (Aug 2016), £207,860
Sheena Radford, Alison Ashcroft, BBSRC (Aug 2016), £457,215
Patricija Van Oosten-Hawle, Dave Westhead, An-Jung Chen, NC3Rs (Aug 2016), £354,456
Peter Henderson, EU - European Union
EU - European Union
(Jul 2016), £123,897
Adrian Goldman, EU - European Union
(Jul 2016), £116,290
Urwin, Howard Atkinson, NERC
(Jul 2016), £105,053
Eileen Ingham and colleagues in Engineering and M&H, EPSRC (Jul 2016), £3,867,449
Michael Colman, MRC (Jul 2016), £200,956
Tim Benton, Fresca Group Ltd
(Jul 2016), £52,082