Prof. Sir Marc Feldmann
Kennedy Institute of Rheumatology Nuffield Department of Orthopaedics, Rheumatology
and Musculoskeletal Sciences, University of Oxford
IMI SYMPOSIUM - MILAN – 26th August 2013
HOW ANTI-TNF THERAPY WAS DISCOVERED
BY A PUBLIC-PRIVATE PARTNERSHIP
Supported by
• Chronic immune inflammatory disease
• Sex : F:M 3:1, ~1%
• Progressive joint damage & disability, reduced quality of life
• Structural damage early & progressive
• 50% severely impaired by 10 yrs (not working)
• Pathology: leucocyte recruitment inflammation, tissue destruction and repair
RHEUMATOID ARTHRITIS (RA)
Pannus
Tissue destruction
Inflammation
PLAN OF TALK
A. IDENTIFYING & VALIDATING TNF
AS A THERAPEUTIC TARGET
B. TRANSLATING INTO CLINICAL PRACTICE
C. HOW WAS ANTI-TNF DISCOVERY A
PUBLIC-PRIVATE PARTNERSHIP?
D. FUTURE OF PUBLIC-PRIVATE PARTNERS
e.g. STRUCTURAL GENOMICS CONSORTIUM
WHY LOOK FOR CYTOKINES IN RHEUMATOID ARTHRITIS?
Upregulation of HLA-DR in rheumatoid synovium
(Klareskog, Wigzell, Panayi, Janossy etc. 1981/82)
Rheumatoid Arthritis Osteoarthritis
Expression of HLA-DR on cells usually negative
indicates presence of inducers = cytokines
Londei et al., 1984, Nature Epithelial cells expressing aberrant
MHC class II determinants can
present antigen to cloned
human T cells.
Pujol-Borrell et al.,
1987, Nature HLA class II induction in human
islet cells by interferon-g
plus TNF or lymphotoxin
1983: A NEW HYPOTHESIS FOR AUTOIMMUNITY
Autoantibodies
and
tissue damage
TISSUE DAMAGE
VIRUSES
CYTOKINES
CYTOKINES
T Upregulation of
HLA class II and
antigen presentation
T
B
APC
Non tolerant
autoantigen
reactive
T cells
CYTOKINES &
INTERFERONS
Londei et al., 1985, Science Human T-cell clones from autoimmune
thyroid glands: specific recognition of
autologous thyroid cells.
Bottazzo et al, 1983, Lancet Hypothesis: Role of aberrant
HLA-DR expression and antigen
presentation in the induction of
endocrine autoimmunity.
Marco Londei
MANY CYTOKINES ARE PRODUCED IN
RHEUMATOID SYNOVIUM
ARE ANY THERAPEUTIC TARGETS?
Pro-inflammatory e.g. IL-1, IL-6, TNFa, IL-12, IL-15, IL-17, IL-18, IFNg, IL-2, OncoM, GM-CSF Anti-inflammatory e.g. IL-10, IL-1Ra, TGFb, IL-11, IL-13 Chemokines e.g. IL-8, MIP-1a, MCP-1, RANTES, ENA-78, GROa Growth Factors e.g. VEGF, PDGF, FGF
PRO-INFLAMMATORY
CHRONICITY
ANTI-INFLAMMATORY
Tiny Maini
ANALYSIS OF CYTOKINE REGULATION REVEALED IMPORTANCE OF TUMOUR NECROSIS FACTOR
APPROACH Operative sample RA synovium, cells
placed in ‘tissue culture’
OBSERVATION Spontaneous production of cytokines etc
EXPERIMENT Antibody to TNF
Brennan et al (1989) Lancet ii 244-247 Days of culture
6 3 1 0
10
20
30
control
anti LT
anti TNFa
IL-1
(U
/ml)
Rheumatoid Arthritis
Days of culture
Osteoarthritis
6 3 1 0.0
0.2
0.4
0.6
0.8
1.0
IL-1
(U
/ml)
Fionula Brennan
TNF DEPENDENT CYTOKINE CASCADE
IN RHEUMATOID ARTHRITIS
Immune system
TNFa
Anti-inflammatory
IL-10, IL-1ra, sTNF-R
Pro-inflammatory
IL-6, IL-8, GM-CSF etc
IL-1
Feldmann, Brennan and Maini (1996) Cell, 85: 307
A USEFUL OVERSIMPLIFICATION….
RATIONALE FOR ANTI-TNFa THERAPY IN
RHEUMATOID ARTHRITIS
1. Disregulated cytokine network in RA
synovium is dependent on TNFa
Tiny Maini
2. TNFa/TNF-Receptor upregulated in
synovium
3. Animal model of RA responds
very well to anti TNFa
administered after disease
onset.
FORMAL PROOF:
RANDOMISED, PLACEBO-CONTROLLED TRIAL
OF INFLIXIMAB IN RHEUMATOID ARTHRITIS
Elliott, Maini, Feldmann et al, Lancet 1994; 344: 1105-10
Design
Placebo
1 mg/kg cA2
10 mg/kg cA2
4 3 2 1 0 0 0
10
20
30
40
50
60
70
80
Week
normal range
p<0.001
p<0.01
CRP
4 3 2 1 0 0 0
10
20
30
Week
Swollen Joint Count
p<0.001 p<0.001
3, 10 or 20 mg/kg 1 or 10 mg/kg
or HSA
Week -4 0 4
washout
cA2:
44%
8%
79%
1 mg/kg
Placebo
10 mg/kg
responders
non-responders
p=0.0083
p<0.0001
Paulus 20% responses at week 4
Ferry Breedveld
Jochen Kalden
Josef Smolen
Results
well-tolerated
good clinical responses
in cA2 groups
dose-response
relationship
Used in >70% patients
ENHANCED EFFICACY OF ANTI-TNF WITH
METHOTREXATE: ACR 50 (50% Paulus response)
% P
atie
nts
re
sp
on
din
g 1 mg/kg cA2 3 mg/kg cA2 10 mg/kg cA2
Week
60
80
40
20
0
20
60
80
40
0
0 4 8 12 16 26 0 4 8 12 16 26 Week 0 4 8 12 16 26
100 100
Placebo MTX+ cA2 MTX- cA2 MTX+
Maini RN et al. (1998) Arthritis Rheum.; 41:1552-1563.
Kennedy Institute gets royalties on USE patent
Charles et al (1999) J Immunol; 163: 1521-28
Day 28 21 7 0 14 1 3
0
100
200
150
50
Se
rum
IL
-6 (
pg
/ml
Placebo
1 mg/kg
10 mg/kg
MECHANISM OF ACTION:
TNFa DEPENDENT CYTOKINE CASCADE
IS OPERATIVE IN VIVO
Also IL-1, GM-CSF, IL-8, VEGF etc
Knees Hands
Pre
-tre
atm
en
t
2 w
ee
ks
post-
treatm
ent
MECHANISM OF ACTION:
REDUCED LEUCOCYTE TRAFFICKING
AFTER INFLIXIMAB THERAPY
Taylor et al (2000)Arthritis Rheum 43:38-47
R knee L Hand R hand L knee
Pe
rce
nta
ge
ch
an
ge
cp
m /p
ixe
l /M
Bq
5
-5
-15
-25
-35
-45
-55
-65
111 Indium labelled polymorphs
Peter Taylor
TNF BLOCKADE IN OTHER DISEASE:
1. CLINICAL STUDIES IN MANY DISEASES
2. APPROVAL ALSO IN: Juvenile RA
Ankylosing spondylitis
Psoriatic arthritis
Psoriasis
Crohn’s disease
Ulcerative colitis
3. ROUTINE USE IN: Behcet’s
Amyloidosis
etc
4. FUTURE USE: Fibrosis-Dupuytren’s
Post-Operative Cognitive Decline
CURRENT PROBLEMS OF
ANTI-TNF THERAPY
1. Not all patients respond
2. Degree of response inadequate
3. Side effect profile ● Infection
4. Cost of therapy ($20-30K)
UNEXPECTED: ACCELERATING A THERAPEUTIC REVOLUTION
1977 Kohler and Milstein:
mouse Mab by fusion
- problem immunogenicity
1980’s Molecular engineering
Chimeric Ab
- Infliximab, Rituximab
approved 1999/2002
1990’s Humanization & Human Antibodies - Adalimumab
Phage Display, Engineered Mice
SALES OF MONOCLONAL ANTIBODIES
2012 5 of top 10 drugs Mabs
anti-TNF biggest drug class
Mab revolution driven by
- anti TNFs - $25bn
- anti cancer - >$20bn
Georges Köhler
Cesar Milstein
Greg Winter
ANTI-TNF THERAPY: PRIME EXAMPLE
OF BENEFIT OF OPEN RESEARCH
1. Hypothesis Rationale Proof of Principle 1983-1992
2. Public Disclosure - Sept 1992
- Publication Dec 1993
● Grant by Centocor did not prevent early
disclosure for common good
● Other companies joined fray post hearing of clinical success
e.g. Celltech, Roche, Immunex, BASF (Abbott)
Public disclosure is a fundamental principle of science:
credit for discovery depends on disclosure
- first to disclose is discoverer (Royal Society 1660’s)
- reproducibility is key to science
TIMELINE: DISCOVERY AND
DEVELOPMENT OF ANTI-TNF THERAPY
1983 Hypothesis
1985-90’s Cytokine analysis in RA and Joints
1989 TNF dependent cytokine cascade (Brennan)
1991 Anti-TNF ameliorates mouse arthritis (Williams)
1992 Proof-of-Principle open trial London }
1992/3 Re-treatment }
SEPT 1992 DISCLOSURE IN ARAD, ISRAEL
DEC 1993 PUBLICATION
1993 Randomized, placebo-controlled
1994-5 Dose ranging and combination
1996 Mechanism Action
1997-8 Phase III
1998/9 Registration Etanercept/Infiliximab
2002 Approval NICE
2003- Safety by patient registers
2002 ONWARDS Commercial and Patent Disputes
ACADEMIC
COMMERCIAL
GRANT
PUBLIC-PRIVATE PARTNERSHIPS example in Toronto/Oxford -
Structural Genomics Consortium
SGC-Oxford: human proteins/ structures to
facilitate therapeutics development
• World leader in human protein structural biology
– Nearly 700 novel structures
– 8% of all structures solved per annum
• Generating freely available novel epigenetic inhibitors
– 10 so far
– 5 more per annum
– In partnership with 8 companies (GSK, Pfizer, Novartis, Lilly,
Abbvie, Boehringer-Ingelheim, Janssen, Takeda)
• Now working closely with Kennedy Institute,
to help discover a cure for RA
FUTURE: EVOLUTION OF SGC
• Working closely with Kennedy Institute to develop new
therapeutics on new targets
e.g. DDR1
CCR4-CAF1
• Use of human disease cells to improve target validation
- increase throughput
• Taking new targets and drugs into proof-of- principle
clinical trials
KEY POINTS
• Academic researchers far outnumber Industrial
• Certain specialized skills only in academia due to
restricted resources e.g. human blood/tissue
• Avoiding needless duplication reduces costs, improves quality
• i.p. on targets difficult to sustain
• Commerical use of targets leads to new drugs with solid i.p.
CONCLUSIONS
• Private-Public partnerships are a very
efficient way of conducting research
with major human impact
Sir Ravinder Maini
FUNDING: ARUK, KTRR, MRC, Wellcome Trust,
Centocor, Inc., Nuffield Foundation, etc
Peter Taylor
Richard Williams
Fionula Brennan
ACKNOWLEDGEMENTS
Claudia Monaco