Development of the spin-out company PolyTherics, a major provider of conjugate therapy and protein modification technology to the pharmaceutical and biotechnology industries
Submitting InstitutionUniversity College London
Unit of AssessmentAllied Health Professions, Dentistry, Nursing and Pharmacy
Summary Impact TypeTechnological
Research Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology
Medical and Health Sciences: Medical Biochemistry and Metabolomics, Pharmacology and Pharmaceutical Sciences
Summary of the impact
Protein modification represents a highly significant and growing source
of new products for the biopharmaceuticals market. This case study
outlines the development of PolyTherics, a highly successful spin-out
company from the UCL School of Pharmacy, and the impact that their
enabling technology has had on the pharmaceutical and biotechnology
industries. The company was developed as a direct result of new conjugate
technology developed by Professor Steve Brocchini and coworkers at the
School. The company moved to independent premises in 2006 and now manages
a portfolio of over 100 granted and pending patents. Several licensing
agreements are in place, including with Celtic Pharma Holdings for
haemophilia treatments and Nuron for a multiple sclerosis treatment based
on PEGylation conjugation technology. Revenue is expected to be £8m in
2013. The impact of Polytherics is therefore as a significant and
effective technology provider to the pharmaceutical and biotechnology
Conjugate technology is an approach to medicines development whereby a
bioactive molecule (typically a protein such as a cytokine, an antibody or
a low molecular weight drug) is synthetically altered so as to incorporate
a second molecule (typically a polymer such as poly(ethylene glycol)
(PEG)) which significantly improves the pharmacokinetics or stability of
the bioactive agent. Initial research in this area at the School of
Pharmacy formed the basis of spin-out company Polytherics, with further
underpinning research and the development of the patent portfolio
continuing in close collaboration between Polytherics and the School over
the following years, in parallel with the development of the company.
PolyTherics was founded in 2001 by Steve Brocchini from the School of
Pharmacy and Sunil Shaunak, a clinician then based at the Hammersmith
Hospital and who is currently Professor of Infectious Diseases at Imperial
College London. Anthony Godwin, who was a PhD student supervised by
Brocchini at the School of Pharmacy, was also a co-founder and remains
with the company as VP of Chemistry. The contribution of the School lay in
the management of IP and the development of the conjugation, synthetic,
purification, characterisation and modelling technologies, with the animal
testing and in vitro work being conducted at the aforementioned
partner institutions. Initially, the research strategy was based on a
portfolio of work derived from the development of polyvalent medicines ,
although this aspect of the portfolio is now being developed by a separate
spin-out company. In brief, this work examined systems such as anionic
dendrimers (hyperbranched macromolecules that can be chemically
synthesised to have precise structural characteristics). Water-soluble
conjugates of these molecules with D(+)-glucosamine and D(+)-glucosamine
6-sulfate were found to have significant immunomodulatory and
anti-angiogenic properties respectively, with highly encouraging results
found for the prevention of scar tissue formation after glaucoma surgery
using a rabbit model.
However, around this time the group also identified a significant
limitation within the protein conjugate therapy field, namely the need to
site-specifically modify proteins efficiently to provide homogeneous
products. Prior to their initial work, it was necessary to re-engineer
most proteins to have a free cysteine thiol to achieve site-selective
modification. This is usually not scalable because during production a
protein will misfold and/or aggregate, hence the re-engineering process
would render the system unusable as a clinically viable product. The team
hypothesised that if it were possible to exploit the innate reactivity of
the two cysteine thiols in a disulphide bond (which would be already
present within the protein) then such proteins could be site-specifically
conjugated with the added benefit of increased stability. If achievable,
then such a solution would effectively remove a key barrier to
commercialise many classes of protein-based therapeutics.
A grant from the BBSRC was obtained in 2004/5 and the associated work was
published in 2006 . One key insight of this research was that
most therapeutic proteins do indeed have accessible disulphides and that
the two cysteine thiols from a native disulphide could be used to achieve
site- specific conjugation, while maintaining the biological activity of
the protein. It was nevertheless surprising that a disulphide in a
therapeutic protein such as a cytokine could be modified and the protein
still remain active. The views of most experts at the time were that
proteins would be expected to lose activity when their cysteine disulphide
bonds had been altered in any way. This was therefore a ground-breaking
insight and led directly to the patented TheraPEG™ technology 
which enables the disulphide bond approach to be used to attach PEG
molecules via a three carbon bridge reagent. Although initial work was
focused on the development of "C-3" bridging technologies, a "C-1"
re-bridging technology has also been developed, thereby extending the
range of opportunity for conjugation .
Since this initial work, numerous significant advances have been made and
published. In particular, PolyTherics developed new site-specific reagents
such as CyPEG™, which allow selective binding to thiols on a
free cysteine for proteins which have stable folds such as fibronectins.
Recent work has led to the development of the HiPEG™ technology to allow
conjugation to two histidines close together . This new HiPEG™
technology is `site-selective' rather than just `site-specific' as it
allows the conjugation site to be engineered at an optimal position on the
protein. Histidines are easier to engineer into proteins than non-native
amino acids, which have been the best way to achieve site-selective
conjugation. Histidines are also easier than cysteines to engineer into
proteins that already have existing native disulphide bonds. In parallel,
the team has ensure the technology was described in detail to the academic
community  and they developed a computational approach whereby
public protein databases and molecular modelling programs may be used to
select a protein rationally and to identify the optimum disulphide bond
for experimental studies. This approach allows identification of
accessible disulphide bridges in merely two hours, which can be of
significant use for more complex proteins with multiple disulfide bonds .
The company was therefore founded on the development of novel conjugation
technologies and continues to innovate based on these early approaches.
Much of PolyTherics' ongoing commercial activity is underpinned by the
PEGylation (e.g. TheraPEG™) technologies outlined here to optimise protein
pharmacokinetics and recently developed reagents (ThioBridge™) now being
used to develop antibody drug conjugates (ADCs).
References to the research
 Shaunak S, Thomas S, Gianasi E, Godwin A, Jones E, Teo I,
Mireskandari K, Luthert P, Duncan R, Patterson S, Khaw P, Brocchini S.
Polyvalent dendrimer glucosamine conjugates prevent scar tissue formation.
Nat Biotechnol. 2004 Aug;22(8):977-84. http://doi.org/c3jsmz
 Shaunak S, Godwin A, Choi JW, Balan S, Pedone E, Vijayarangam D,
Heidelberger S, Teo I, Zloh M, Brocchini S. Site-specific PEGylation of
native disulfide bonds in therapeutic proteins. Nat Chem Biol. 2006
 Godwin A, Pedone E, Choi J, Shuanak S, Brocchini S. Conjugated
biological molecules and their preparation. WO/2005/007197 (54 pp). EP
1648518, 2133099, 2253330 and 2277550; US 7595292 and 7939630. Also
granted in China and India. Several additional patents have subsequently
been filed by PolyTherics based on this initial patent.
 Godwin A, Brocchini S. Conjugated proteins and peptides.
WO/2010/100430 (36 pp). https://www.google.com/patents/WO2010100430A1
 Godwin A. Novel reagents and method for conjugating biological
molecules. WO/2010/010324 (70 pp). https://www.google.com/patents/WO2010010324A1
 Cong Y, Pawlisz E, Bryant P, Balan S, Laurine E, Tommasi R, Singh R,
Dubey S, Peciak K, Bird M, Sivasankar A, Swierkosz J, Muroni M,
Heidelberger S, Farys M, Khayrzad F, Edwards J, Badescu G, Hodgson I,
Heise C, Somavarapu S, Liddell J, Powell K, Zloh M, Choi JW, Godwin A,
Brocchini S. Site-specific PEGylation at histidine tags. Bioconjug Chem.
2012 Feb 15;23(2):248-63. http://dx.doi.org/10.1021/bc200530x
 Zloh M, Shaunak S, Balan S, Brocchini S. Identification and insertion
of 3-carbon bridges in protein disulfide bonds: a computational approach.
Nat Protoc. 2007;2(5):1070-83.
Details of the impact
Polytherics was founded in 2001 with funding from the Wellcome Trust
Catalyst Biomedica, the Bloomsbury Bioseed Fund (of which the School was a
shareholder) and Imperial Innovations [a]. PolyTherics moved in
2006 to the London Biotechnology Innovation Centre. The company currently
employs about 80 staff at three sites: London, Cambridge (following
acquisition of Antitope) and Coventry (following acquisition of Warwick
Effect Polymers). It manages a patent portfolio of over 100 granted and
pending patents. Annual revenue has grown to over £8m for the combined
businesses for the 2013 calendar year. Brocchini is now a consultant to
the company, having stepped down from the board to address new projects
and commitments, but remains very closely aligned to the development of
the patent and licencing portfolio.
The impact of the company has been on the pharmaceutical and biotech
industries as a result of the development of technologies which overcome
significant technical and clinical challenges that are needed to develop
new biopharmaceutical medicines. It is also worth noting that Brocchini is
a key member of the EPSRC Centre for Innovative Engineering in
Macromolecular Therapies, based at UCL which was set up to provide
practical solutions to the issues associated with the commercial
production of macromolecular medicines such as conjugate therapies. The
impact of Polytherics has been derived through the new technologies based
on academic research (e.g. TheraPEG™, CyPEG, HiPEG, ThioBridge) [b].
These technologies have additionally been combined with those obtained
through the purchases of Warwick Effect Polymers in 2012 [c] and
Antitope in 2013 [d].
The net effect is an innovative and growing company that is demonstrating
significant impact via the licensing of new technologies to the
pharmaceutical industry. This is corroborated by the development of
associated products into clinical trials. While exemplar projects are
specified here, PolyTherics and its affiliate companies have collaborative
agreements and/or relationships with approximately 40 pharmaceutical and
biotech companies. The conjugation technologies are being used
commercially to (i) increase protein circulation half-life (TheraPEG™,
CyPEG™, HiPEG™), (ii) develop ADCs (ThioBridge™) and other protein-drug
conjugates and (iii) to develop new product formats (e.g. bispecific
antibodies). Other technologies within the subsidiary company Antitope are
focused on protein de-immunisation and protein engineering which is being
used to produce better conjugates and modified protein-therapeutics. These
technologies are being merged to provide new platforms to innovate in the
development of new biopharmaceuticals.
Examples are given here of projects whereby the PolyTherics' TheraPEG™
technology is being used to develop products with partner companies,
inevitably representing considerable investment by those organisations.
Programs in development utilising TheraPEG technology include:
- Licence agreement for a long-acting interferon β for the treatment
of relapsing-remitting multiple sclerosis with Nuron Biotech Inc (US),
with a view to reducing dosing frequency for interferon β-1b products
from every two days to potentially fortnightly injections [e].
- Licence agreement with Celtic Pharma Holdings for long-acting forms of
blood-clotting factors VIIA, VIII and IX for the treatment of
haemophilia A & B. These products have the potential to be
administered via subcutaneous rather than intravenous injection, thus
providing a viable option for self-administered prophylactic therapy [f].
In addition, the ThioBridge antibody-drug conjugate technology is being
developed in a research collaboration with several partners including
[text removed for publication]
- Spirogen (another UCL spin-out company) and Polytherics are
collaborating to conjugate Spirogen's pyrrolobenzodiazepine (PBD)
cytotoxic agents to antibodies and antibody fragments [g].
- PolyTherics is working with Biotecnol to attach cytotoxic payloads to
Tribodies (multi-specific antibody products generated via
heterodimerisation of Fab fragments) for the development of targeted
cancer therapies [h].
With the successful development of the TheraPEG™, HiPEG™, CyPEG™ and
ThioBridge™ technologies and their commercialisation, PolyTherics is now
leveraging this success by integrating other services and technologies
into its offering. PolyTherics position as a leading UK life sciences
company has been pursued through the acquisition of University of Warwick
spin-out company [c], Warwick Effect Polymers (where Brocchini's
expertise with polymer technologies has enabled the further development
and utilisation of their technologies) and in July 2013 the acquisition of
Antitope [d], the leading provider in the field of assessment of
immunogenicity potential for protein and antibody therapeutics and protein
re-engineering in an agreement that was secured with further investment of
£13.5m, with a substantial investment from Invesco.
Polytherics continues to benefit from the close connections with UCL
School of Pharmacy and the venture capital arm of Imperial Innovations.
The company now has a valuation of [text removed for publication], a clear
indication that it is a major provider of expertise and technology
relating to conjugate therapies and protein modification approaches to the
pharmaceutical and biotechnology industries.
Sources to corroborate the impact
[a] Details about the spin-out from SoP can be corroborated by the
appropriate Business Manager at UCLB. Contact details provided.
[b] PolyTherics website:www.polytherics.com. See in particular the Jan 2013 company fact
sheet: http://www.polytherics.com/uploads/default/files/polytherics-corporate-fact-sheet-final-14jan13.pdf. Details about PolyTherics can be corroborated by the
CEO. Contact details provided.