The DSTT, a model for collaboration between

academia and industry

Philip Cohen

MRC Protein Phosphorylation and Ubiquitylation Unit,

University of Dundee, Scotland

The attachment and removal of phosphate from proteins

is a simple mechanism for altering their function

protein kinase

proteinphospho-

protein

(modified

function)

protein

phosphatase

P

• Since the first kinase inhibitor (Gleevec) was approved for CML in

2001, 29 other kinase inhibitors, have been approved for clinical use,

nearly all in the field of cancer

• Kinases account for 50-70% of all the cancer drug discovery

programmes in the pharmaceutical industry.

• The global market for kinase therapies was $29 billion per annum in

2011 and is expected to reach $45 billion per annum by 2016

• Over 150 other drugs targeting kinases are undergoing clinical trials

of which about 25 are in Phase III

• Kinase inhibitors are being developed for the treatment of other

diseases. e.g. Tofacitinib approved in 2012 for the treatment of

rheumatoid arthritis.

Clinically approved protein kinase inhibitors

The DSTT, a model collaboration between

academia and industry

History of the Division of Signal

Transduction Therapy (DSTT)

• Started in July 1998 as a collaboration in the

field of “mammalian kinases and phosphatases”

with Astra, NovoNordisk, Pfizer,

SmithKlineBeecham and Zeneca, who were

joined by Boehringer Ingelheim in 2001

• Renewed for a further five years in July 2003 at

a greatly expanded level with AstraZeneca,

Boehringer Ingelheim, GlaxoSmithKline, Merck

& Co, Merck KGaA and Pfizer

The Financial Times – 18 March 2003

History of the Division of Signal

Transduction Therapy (DSTT)

• Renewed for a further four years from July 2008 with

AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline,

Merck-Serono and Pfizer

• Renewed for a further four years from July 2012 with the

same five companies plus Janssen Pharmaceutica. Field

changed from “kinases and phosphatases” to “kinases

and the ubiquitin system.”

• Europe’s largest and longest running collaboration

between academia and the pharmaceutical industry

How can so many companies

collaborate under a single agreement?

• The companies supporting the DSTT share all

the unpublished research, reagents, technology

and know-how generated by the participating

Dundee laboratories and have the first right to

licence the intellectual property that is generated

• In contrast, information obtained using a

compound or technology that a company has

introduced into the DSTT is not shared, and only

sent to that one company

How is DSTT support used?

75% of the funding is used for fundamental

research on “mammalian kinases and

phosphatases” (1998-2012) or “kinases and

the ubiquitin system” (2012-2016)

The projects chosen and driven by the

academic researchers in areas of relevance

to human disease in consultation with the

pharmaceutical partners

How is DSTT support used?

25% of the funding is used to support a service

facility, of which the major components are a DNA

cloning team, a protein production and assay

development team, an antibody production team

and a kinase profiling service.

The service facility cloned, expressed and purified

gram quantities of the B-Raf[V600E] mutant,

which was used by GSK for the high-throughput

screens that identified the compound that led to the

development of Dabrafenib for the treatment of

malignant melanoma.

Reagents delivered by the DSTT to the

participating companies 1998-2015

• The DSTT has delivered the huge amounts of kinases needed to launch new drug discovery programmes on 267 occasions

• The DSTT has also delivered pilot amounts of kinases, phosphatases and ubiquitin system components (sufficient for up to 5000 measurements) on 2135 occasions

• 1104 antibodies and 1173 DNA constructs have been delivered to the companies

Unexpected commercial benefits of the DSTT

• The DSTT set up the world’s first protein kinase profiling service in

1998 to enable the collaborating pharmaceutical companies to assess

the specificities of the kinase inhibitors they were generating. A

similar lipid kinase profiling service was developed subsequently

• Led to the creation of the European Division of Upstate Inc in

Dundee which commercialized kinase profiling. Upstate Dundee

employed 125 people in 2004 when it was sold to Serologicals.The

MRC-PPU and College of Life sciences at Dundee received £10

million in royalties from Upstate/Serologicals

• Protein kinase profiling has been commercialized by many

companies and become a $US200 million per annum industry

• The DSTT has more recently set up analogous profiling services for

xomponents of the ubiquitin system, such as E2 conjugating

enzymes and deubiquitylases.

Why has the collaboration continued for so long?

• The MRC-PPU and College of Life Sciences at Dundee, is the world’s largest

centre for the study of protein phosphorylation and ubiquitylation; Over 20

Programme Leaders and 200 scientific and support staff

• The companies can therefore obtain much of what they need in this area from a

single research centre

• The DSTT is considered to be good value for money. By contributing 6

positions, each company obtains the output of 200 scientific and support staff.

The reagents and services provided by the DSTT would be far more expensive to

purchase from commercial sources and many are not available commercially

• The DSTT works to industrial standards, nearly always deliver what they say

they can and on time, and the Dundee scientists have proved they can maintain

confidentiality

• Trust is created in a long collaboration, which increases its value to both parties

• The participating labs wish it to continue since it has greatly benefitted their

research (over Euro100 million of research funding so far). Proprietary

compounds from the companies have advanced our research projects. Our

students and postdocs have learned how the pharmaceutical industry works

The DSTT model should be widely applicable

The key ingredients needed to make it work are a critical

mass of leading researchers operating under a single

agreement in an area of interest to industry

How could pharmaceutical companies enhance

the value of the collaboration?

• The pharmaceutical companies need to ensure that the person they

appoint to coordinate the collaboration is of sufficient seniority to

see an important opportunity when it arises, and ensure that the

new information is relayed to the appropriate scientist(s) in every

division of the company worldwide.

• The companies need to send more scientists to the academic labs to

make sure that opportunities are not being lost, and especially to

senior scientists who are able to take decisions quickly. In recent

years some companies have cut travel budgets drastically, which has

resulted in fewer staff coming to the acdemic labs which has

resulted in lost opportunities.

How could pharmaceutical companies enhance

the value of the collaboration?

• The companies should invite the Principal Investigators to visit their

research Divisions more frequently and take advantage of the free

consultancies that are offered as part of the collaboration.

• The companies should act on the advice of their Academic

collaborators when the latter have, for example, cast iron evidence

that the information on which a drug discovery programme is based

is seriously flawed. The pharmaceutical companies have admitted

on a number of occasions that they have lost a lot of time and money

by not acting for years on such advice.

MRC-PPU

MRC-PPU

The College of Life Sciences at the University of Dundee

DRUG KINASE TARGETS COMPANY APPROVED FOR CLINICAL USE

Imatinib

(Gleevec)

Bcr-Abl, c-Kit receptor, PDGFR Novartis 2001 chronic myelogenous leukaemia

Gefitinib EGFR AstraZeneca 2005 lung cancer

Erlotinib ErbB1 Genentech/Roche 2005 lung, pancreatic and other cancers

Sorafenib Multiple tyrosine kinases targeted Onyx/Bayer 2005 renal cancer

Dasatinib Multiple tyrosine kinases targeted BristolMyersSquibb 2006 chronic myeloenous leukaemia,

acute lymphoblastic leukaemia

Sunitinib Multiple tyrosine kinases targeted SUGEN/Pfizer 2006 renal cancer and GIST

Nilotinib Bcr-Abl Novartis 2007 chronic myelogenous leukaemia

Lapatinib Her2/EGFR GlaxoSmithKline 2007 HER2-positive breast cancer

Temsirolimus mTOR Wyeth/Pfizer 2007 advanced renal cell carcinoma

Everolimus mTOR Novartis 2009 several cancers

Pazopanib VEGFR2/PDGFR/c-kit GlaxoSmithKline 2009 renal cancer

Toceranib Multiple Tyrosine kinases targeted Pfizer 2009 canine mastocytoma

Masivet/Kinav

et

cKIT/PDGFR AB Science 2010 canine mastocytoma

Ruxolitinib JAKs Incyte 2011 myelofibrosis

Crizotinib ALK/Met Pfizer 2011 NSCLC with Alk mutation

Vemurafenib BRAF Roche 2011 melanoma

Vandetanib Multiple tyrosine kinases targeted IPR Pharms 2011 medullary thyroid cancer

Axitinib VEGFR1/VEGFR2/VEGFR3/PDGFRB/c-

KIT

Pfizer 2012 renal cell carcinoma

Bosutinib BcrAbi/SRC Pfizer 2012 chronic myelogenous leukaemia

Tofacitinib JAKs Pfizer 2012 rheumatoid arthritis

Regorafenib VEGFR2, TIE2 and other PTKs Bayer 2012 colorectal cancer, GIST

Cabozantinib VEGFR2, RET, MET Exelixis Inc 2012 medullary thyroid cancer

Ponatinib Src and Abl Ariad Pharma 2012 CML and ALL

Lenvatinib VEGFR2/VEGFR2 Eisai 2013 thyroid cancer

Trametinib MEK1/2 GlaxoSmithKline 2013 skin cancer

Dabrafenib BRaf GlaxoSmithKline 2013 skin cancer

Afatinib Her2/EGFR Boehringer Ingelheim 2013 NSCLC

Ibrutinib BTK Pharmacyclics, J&J 2013 mantle cell lymphoma and CLL

The kinase inhibitors that have been approved for clinical use

Will kinase inhibitors have an impact on

other global diseases, such as chronic

inflammatory and autoimmune diseases?

DRUG KINASE TARGETS COMPANY APPROVED FOR CLINICAL USE

Imatinib

(Gleevec)

Bcr-Abl, c-Kit receptor, PDGFR Novartis 2001 chronic myelogenous leukaemia

Gefitinib EGFR AstraZeneca 2005 lung cancer

Erlotinib ErbB1 Genentech/Roche 2005 lung, pancreatic and other cancers

Sorafenib Multiple tyrosine kinases targeted Onyx/Bayer 2005 renal cancer

Dasatinib Multiple tyrosine kinases targeted BristolMyersSquibb 2006 chronic myeloenous leukaemia,

acute lymphoblastic leukaemia

Sunitinib Multiple tyrosine kinases targeted SUGEN/Pfizer 2006 renal cancer and GIST

Nilotinib Bcr-Abl Novartis 2007 chronic myelogenous leukaemia

Lapatinib Her2/EGFR GlaxoSmithKline 2007 HER2-positive breast cancer

Temsirolimus mTOR Wyeth/Pfizer 2007 advanced renal cell carcinoma

Everolimus mTOR Novartis 2009 several cancers

Pazopanib VEGFR2/PDGFR/c-kit GlaxoSmithKline 2009 renal cancer

Toceranib Multiple Tyrosine kinases targeted Pfizer 2009 canine mastocytoma

Masivet/Kinavet cKIT/PDGFR AB Science 2010 canine mastocytoma

Ruxolitinib JAKs Incyte 2011 myelofibrosis

Crizotinib ALK/Met Pfizer 2011 NSCLC with Alk mutation

Vemurafenib BRAF Roche 2011 melanoma

Vandetanib Multiple tyrosine kinases targeted IPR Pharms 2011 medullary thyroid cancer

Axitinib VEGFR1/VEGFR2/VEGFR3/PDGFRB/c-

KIT

Pfizer 2012 renal cell carcinoma

Bosutinib BcrAbi/SRC Pfizer 2012 chronic myelogenous leukaemia

Tofacitinib JAKs Pfizer 2012 rheumatoid arthritis

Regorafenib VEGFR2, TIE2 and other PTKs Bayer 2012 colorectal cancer, GIST

Cabozantinib VEGFR2, RET, MET Exelixis Inc 2012 medullary thyroid cancer

Ponatinib Src and Abl Ariad Pharma 2012 CML and ALL

Lenvatinib VEGFR2/VEGFR2 Eisai 2013 thyroid cancer

Trametinib MEK1/2 GlaxoSmithKline 2013 skin cancer

Dabrafenib BRaf GlaxoSmithKline 2013 skin cancer

Afatinib Her2/EGFR Boehringer Ingelheim 2013 NSCLC

Ibrutinib BTK Pharmacyclics, J&J 2013 mantle cell lymphoma and CLL

Ceritinib ALK Novartis 2014 late stage NSCLC

Tofacitinib was approved for the treatment of rheumatoid arthritis in 2012,

the 1st kinase inhibitor approved for the treatment of any inflammatory disease