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.
Graham Askew, Simon Walker, BBSRC (Jan 2018), £699,781
Jennifer Tomlinson, Royal Society (Jan 2018), £512,801
Jennifer Tomlinson, Royal Society-Research Fellows Enhancement Award (Dec 2017), £94,681
Helen Miller, AB AGri Grant (Dec 2017), £73,600
Simon Walker, Royal Society Enhancement Award (Dec 2017), £10,000
Carrie Ferguson, Bryan Taylor, Harry Rossiter, The Physiological Society (Dec 2017), £7,392
Ralf Richter, Royal Society (Dec 2017), £6,000
Christine Foyer, British Council Newton Fund (Dec 2017), £49,840
Adrian Whitehouse and colleagues in School of Chemistry and University of Liverpool, MRC (Nov 2017), £622,319
Michelle Peckham, Neil Ransom, MRC (Nov 2017), £495,159
Dave Lewis, British Council India (Nov 2017), £22,540
Elton Zeqiraj, Royal Society (Nov 2017), £15,000
Hannah Dugdale, Royal Society (Nov 2017), £15,000
Shaunna Burke, Cancer Research UK Innovation Grant (Nov 2017), £20,000
Alex O'Neill and colleagues in Chemistry, BBSRC (Nov 2017), £431,865
Jessica Kwok, Wings for Life (Nov 2017), £87,365
Tom Bennett, BBSRC (Oct 2017), £523,679
Neil Ranson, Darren Tomlinson, BBSRC (Oct 2017), £494,318
Nikita Gamper, BBSRC (Oct 2017), £490,426
Amanda Bretman and colleagues from UEA, NERC (Oct 2017), £430,886
Juan Fontana, Rosetrees Trust consumables grant (Oct 2017), £22,500
Helen Miller, DSM Nutritional Products AG (Sep 2017), £69,988
Neil Ranson, Juan Fontana, Mark Harris, Michelle Peckham, Ralf Richter, Peter Stockley, Patricija Van Oosten-Hawle and colleagues in Engineering, FMH and MAPS, Wellcome Trust Equipment Call (Sep 2017), £418,000
Jamie Johnston, Physiological Society (Sep 2017), £10,000
Frank Sobott, Adrian Goldman, Mark Harris, Andrew Macdonald, Stephen Muench, Sheena Radford and colleagues in FMH and MAPS, Wellcome Trust Equipment Call (Aug 2017), £415,000
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
Beatrice Filippi, Royal Society (Mar 2017), £15,000
Tom Bennett, Royal Society (Mar 2017), £15,000
Jamie Johnston, 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