2. Centre of Excellence in
Biopharmaceuticals
Biopharmaceutical Research
This presentation lists a number of research projects
which are potentially relevant to companies that
discover, develop or manufacture protein
biopharmaceuticals.
Some are projects already underway or completed.
Others are ideas which require further industry input
before seeking funding.
The Centre‟s Research is grouped into two themes
underpinning industry research:
Product characterisation and formulation
Cell line development
3. University of Manchester Biopharmaceutical Technologies
Mechanisms of Protein Aggregation
• Develop improved methods for
predicting and controlling aggregation
during processing and in liquid
formulations using a combination of
numerical and experimental studies
• Delineate effects of partial unfolding
and protein self association on
aggregation kinetics
• Partial unfolding probed with
intrinsic/extrinsic fluorescence. Static
and dynamic light scattering used for
probing protein-protein interactions in
terms of osmotic second virial
coefficient, B22
• Examine link between protein-protein
interactions and protein phase
separation/opalescence
Dr Robin Curtis
r.curtis@manchester.ac.uk
Phone +441613064401
4. University of Manchester Biopharmaceutical Technologies
Concentrated Protein Solutions
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Method for solubilisation of
proteins, with increased stability
during bioprocessing and storage
50mM L-Arg + L-Glu; solubility of
many proteins increased (up to 8
times)
Further work in progress
Golovanov AP, Hautbergue GM, Wilson
SA, Lian LY. (2004). A simple method for
improving protein solubility and long-term
stability. Journal of the American
Chemical Society, 126(29), 8933-9
Dr Alexander “Sasha” Golov
a.golovanov@manchester.a
Phone +44161 306 5813
5. University of Manchester Biopharmaceutical Technologies
Protein Solution Rheology
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Rheological characterisation of high
concentration protein solutions
Modular design micro-rheometer
system
Suitable for cost-effective mass
production
High sensitivity
Small sample required
Potential for high throughput
Dr Xue-feng Yuan
XueFeng.Yuan@manchester.ac
.uk
Phone +44161 306 4887
6. University of Manchester Biopharmaceutical Technologies
Applications of RICS to
Formulation and Delivery of
Biologics
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Raster Image Correlation Spectroscopy
Detects and counts protein molecules,
reversible self aggregates, irreversible
aggregates, sub-visible particles in same
sample
Determines hydrodynamic size
No need to dilute or filter sample
Small sample
Potential for high throughput
characterisation
Raster image correlation spectroscopy as
a novel tool for the quantitative
assessment of protein diffusional
behaviour in solution, Hamrang Z, Pluen
A, Zindy E, Clarke D, Journal of
Pharmaceutical Sciences, 2012
Dr Alain Pluen
alain.pluen@manchester.ac
Phone +44 (0)161 275
1792
7. University of Manchester Biopharmaceutical Technologies
PK/PD Modelling for Biologics
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Adapt existing models for small molecule
PKPD simulations
Simulate different technologies eg
– Half life extension (PEGylation, fusion
proteins)
– Bispecifics
– Antibody Drug Conjugates
IV, subcutaneous, oral, inhaled biologics
Tissue penetration and microscopic
distribution
Potential use in improved biologics
molecular design, dosage, trial design
Dr David Berk
David.berk@manchester.ac
Phone +44 (0) 161 275
2375
8. University of Manchester Biopharmaceutical Technologies
Predictive Modeling of Protein
Solubility
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The aim is to predict the solubility of
biopharmaceuticals based on
knowledge of primary sequence and
structure
There are currently three approaches to
modelling protein solubility from
sequence and structure:
– partial unfolding
– beta-strand/amyloid-forming
propensity
– protein surface properties
In preliminary studies, the best
correlation between surface properties
and solubility was for a mixture of nonpolar and polar features that takes into
account detailed surface geometry.
Dr Jim Warwicker
jim.warwicker@manchester.
0161-306 4490
9. University of Manchester Biopharmaceutical Technologies
Immunogenicity of Protein Aggregates
and Sub Visible Particles
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Aim to determine the
influence of aggregates of
well-defined reference
protein(s) on
vigour of T lymphocyte
and IgG and IgE
antibody responses in
mice
development of
functional
subpopulations on CD4+
T lymphocytes (Th1, Th2
and Treg cells) in mice
phenotype and function
of dendritic antigen
presenting cells
Prof Jeremy Derrick
jeremy.derrick@mancheste
Phone +44161 306 4207
Prof Ian Kimber
ian.kimber@manchester.ac
Phone +44161 275 1587
10. University of Manchester Biopharmaceutical Technologies
Spectroscopic Detection of Protein
Contaminants
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Ability to detect protein
contaminants at low levels in
protein solutions using FT-IR,
Raman spectroscopy
Apply chemometrics to the
comparison of spectroscopic data
Preliminary data with FT-IR on
spiked proteins eg RNAse A spike
with 1% RNAse B
Prof Roy Goodacre
Roy.Goodacre@manchester.ac
Phone +44161 306 4480
11. University of Manchester Biopharmaceutical Technologies
Higher Order Structure of Proteins
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Characterize and quantify protein higher order
structure (secondary and tertiary) using
Raman and FT-IR spectroscopies (already 3
times more accurate than CD)
Apply bioinformatics and chemometrics to
spectroscopic data to study structural changes
Detection of flow-induced aggregation and
correlating protein structural changes with the
shear forces applied (with a colleague at
Mechanical Engineering, UCL)
Structural characterization of glycoproteins
and carbohydrates
Dr Ewan Blanch
e.blanch@manchester.ac
Phone +44161 306 5819
12. University of Manchester Biopharmaceutical Technologies
NMR Investigations of Protein Structure
and Dynamics
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Structure, dynamics and energetics of
near transition-state complexes of
enzymes
Characterisation of conformational
transitions within partially folded
states of proteins
Intermediate species involved in the
assembly of prion particles, and the
inhibition of assembly processes by
small molecules
Fundamentals of instability within
protein therapeutics
Prof Jon Waltho
j.waltho@manchester.ac.uk
Phone +441613064191
13. University of Manchester Biopharmaceutical Technologies
RiboTite Controllable Protein
Expression Technology
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Controls expression in bacteria
using synthetic compounds
Regulates translation initiation
Tight control prior to induction
Affords true cellular level titratable
control
Controlled co-expression of two or
more proteins
Dixon N, Duncan JN, Geerlings T,
Dunstan MS, McCarthy JE, Leys D,
Micklefield J. Proc Natl Acad Sci U S A.
2010 Feb 16;107(7):2830-5
Dr Neil Dixon
Neil.Dixon@manchester.a
Phone +44161 306 4537
14. University of Manchester Biopharmaceutical Technologies
Transcription in response to small molecules
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Protein production in yeast
Structural biology of transcriptional complexes
Understanding how small molecules and
metabolites can influence protein-protein
interactions to affect transcription
Determining how changes in cellular location
of a protein can influence its function
Protein expression and purification facility
Prof Richard Reece
Richard.Reece@manchester.
Phone +441612755317
15. University of Manchester Biopharmaceutical Technologies
Yeast expression technologies
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Transcriptional/translational control mechanisms
Environmental signaling and stress responses
Small molecule intervention with regulatory
processes
Yeast genetics and physiology
Yeast genetic engineering
Dr Graham Pavitt
Graham.Pavitt@manchester.ac.u
Phone +441613064477
Prof Richard Reece
Richard.Reece@manchester.ac
Phone +441612755317
16. University of Manchester Biopharmaceutical Technologies
Protein quality control in the ER
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Understanding the mechanisms of,
and regulation of protein folding
reactions in the ER and secretory
pathways
Consequences for secreted protein
yield and quality
Application of molecular and cellular
biology toolkit to dissect regulatory
networks
Dr Lisa Swanton
Lisa.Swanton@manchester.a
Phone +441612751554
17. University of Manchester Biopharmaceutical Technologies
CHO Cell Line Research
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Optimisation of CHO platforms via
„omics approaches, including
metabolic flux balance models and
rationalised feeding regimes
CHO clonal variation analysis at
molecular and cellular level –
realtionship between phenotype and
clonal utilisation for defined product
portfolios
CHO cell line stability at molecular
(genomic and wider cellular) level
Early predictability of CHO cell lines in
relation to biomass
attainment, productivity and product
quality
Prof Alan Dickson
Alan.Dickson@manchester.a
Phone +441612755077
18. University of Manchester Biopharmaceutical Technologies
Differentiation of Single Stem Cells
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metabolic profiling studies
of a model stem cell
differentiation system
(pancreatic cells) at a
single cell level
metabolic profile within
populations undergoing
differentiation
follow metabolic profiles
from single cells during
differentiation
to follow the metabolic
profile at single cell level
for cells that maintain an
undifferentiated phenotype
Dr Karen Cosgrove
Karen.Cosgrove@manchester.ac
Phone +441612755462
Prof Mark Dunne
Mark.J.Dunne@manch
ester.ac.uk
Phone+44 (0)161 275
3921
19. University of Manchester Biopharmaceutical Technologies
Protein Biochemistry & Expression
• Protein biochemist with experience of
low and high resolution structural
analysis of proteins and protein-ligand
complexes
• Expertise in the analysis of proteinligand interactions by a wide range of
methodologies (Academic Lead for
BioMolecular Analysis Core Facility)
• Expression of proteins in E. coli. and
refolding/purification methodologies
• Ongoing development of protein
biological for the treatment of
osteoporosis and other disorders
Prof. Tony Day
anthony.day@manchester.ac.uk
Phone +44 161 2751495
20. If you are interested in any of these projects
please contact
University of Manchester
Centre of Excellence in Biopharmaceuticals
malcolm.rhodes@manchester.ac.uk
joanne.flannelly@manchester.ac.uk
alan.dickson@manchester.ac.uk
www.coebp.ls.manchester.ac.uk
