Building Bridges Between Discovery, Preclinical, And Clinical Research 2008
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Transcript of Building Bridges Between Discovery, Preclinical, And Clinical Research 2008
Cancer and Inflammatory Cancer and Inflammatory DiseasesDiseases
ImmunotherapyImmunotherapy
Building Bridges Between Discovery, Preclinical, and Clinical Research
Outline• B Cell Lymphoma Immunotherapy
Active immunotherpay following rituximab treatment: from nonclinical study to the clinic
Improving on rituximab immunotherapy: from discovery research to preclinical model
• Inflammatory Bowel Disease Analysis of gene expression profile in patient’s biopsies: from
clinical samples to basic research Identification of a clinical biomarker from mode of action studies:
from nonclinical research to clinical monitoring
• Asthma Analysis of anti-CD25 mAb mode of action in vitro: from nonclinical
research to expanded clinical indication
B Cell LymphomaImmunotherapy
B Cell Lymphoma
• Follicular Non-Hodgkin’s Lymphoma Clinical
Represents 25% of all cases of lymphoma in the US Indolent malignancy: slow progression Most patients will eventually relapse and will require more
aggressive treatment The duration of remission tends to decrease after each relapse
Pathology Mainly localized to lymph nodes and the bone marrow Malignant B cells preserve most of the features of mature B
cells• Expression of surface Ig, CD19, CD20, CD21, and CD22• Propensity to organize into follicles
Personalized Active Immunotherapy: concept
• IndicationIndication Follicular lymphomaFollicular lymphoma
• DrugDrug Unique vaccine for each Unique vaccine for each
patientpatient Based on unique Ig Based on unique Ig
(idiotype) expressed by (idiotype) expressed by tumortumor
Linked to KLH Linked to KLH immunogenicityimmunogenicity
• Clinical regimenClinical regimen1.1. ChemotherapyChemotherapy
2.2. Recovery (6 months)Recovery (6 months)
3.3. ImmunizationImmunization
• IndicationIndication Follicular lymphomaFollicular lymphoma
• DrugDrug Unique vaccine for each Unique vaccine for each
patientpatient Based on unique Ig Based on unique Ig
(idiotype) expressed by (idiotype) expressed by tumortumor
Linked to KLH Linked to KLH immunogenicityimmunogenicity
• Clinical regimenClinical regimen1.1. ChemotherapyChemotherapy
2.2. Recovery (6 months)Recovery (6 months)
3.3. ImmunizationImmunization
B CELL LYMPHOMA IMMUNOTHERAPY
Active immunotherapy following rituximab treatment: from
nonclinical study to the clinic
Clinical Study DesignImmunization efficiency following rituximab
Rituximab4 Doses(N=90)*
Restage at8 Weeks:
CR, CRu, PR
Follow-up
6-month Rest Period(N=23)
8 Immunizations Q 2 weeks
Patients who failed
chemotherapy
Study 2002-09
Sampling times for T and B cells and immune response
*Third cohort (N=16) of immunized patients were not eligible for either 3M or 6M Rest groups. Screen failures (N=33) not eligible for immunization.
Follow-up
3-month Rest Period(N=18)
8 Immunizations Q 2 weeks
Leonard J.P. et al., ASCO 2006
Patients treated with rituximab have dramatically reduced B cell numbers
Pre-R Imm1 Imm4 Imm8 8 Wks Post
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Pre-R Imm1 Imm4 Imm8 8 Wks Post
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B Cells (CD19+)
T Cells (CD3+)
3M rest period
3M rest period
6M rest period
6M rest period
Post-R Post-R
Leonard J.P. et al., ASCO 2006
Analysis of variance (treatment effect)
9902B 2002-09 3M Rest p < 0.0001
9902B 2002-09 6M Rest p < 0.0001
2002-09 3M Rest 2002-09 6M Rest p < 0.05
Patients treated with rituximab have significantly lower humoral response against KLH
Mean Anti-KLH Level
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Control Study 3M Rest
Rit. Study 3M Rest
Rit. Study 6M Rest
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g/m
L)
Leonard J.P. et al., ASCO 2006
Conclusions
• Rituximab treatment dramatically reduces the number of patient B cells B cell numbers remained low up to 10 months after treatment
• Humoral response in patients treated with rituximab is significantly reduced 6-month recovery is not sufficient to restore a normal response Significant improvement in response between 3- and 6-month
recovery period
Adapt active immunotherapy clinical regimen Allow for longer recovery time (if possible) Schedule start of immunization in function of B cell recovery
Include nonclinical exploratory end points to clinical studies future clinical strategy
B CELL LYMPHOMA IMMUNOTHERAPY
Can we improve on rituximab?
B Cell Surface Targets
CD22CD22
CD20CD20
CD19CD19
BCRBCRIdiotypeIdiotype frequency ~1/10 frequency ~1/101010
V region framework V region framework frequency ~ 1/20 frequency ~ 1/20V region framework V region framework frequency ~ 1/20 frequency ~ 1/20
C region C region frequency ~ 1/2 frequency ~ 1/2
CD19, CD20, CD22CD19, CD20, CD22 frequency 1/1 frequency 1/1 In Human
• 45 Ig heavy chain V genes • 70 Ig light chain V genes• Ig V gene sub-families share common structures• Ig include 1 light and 1 heavy chain
Sornasse T. et al., ASH 2007
Concept of a selective mAb immunotherapy of B cell lymphomas
Sornasse T. et al., ASH 2007
mAbs specific for Ig variable region framework directly kill lymphoma cell line in
vitro
Anti-Ig VL mAb: Cell line A Anti-Ig VH mAb: Cell line B
Lymphoma cell lines were incubated for 48 hours in the presence of mAbs. Dead cells were identified by flow cytometry as 7-AAD-positive cells.
Main Hurdle in vivo: Soluble Antigen
Is it possible to deplete target B cells in vivo, in the presence of high level of soluble antigen?
Anti-Ig mAb
Serum Ig
Target B Cell
Sornasse T. et al., ASH 2007
Incorporate Hypothesis Testing to Preclinical Study
• Study type: Exploratory toxicology
• Test article: anti-human Ig VH 3.23
• Model: cynomolgus monkeys Similar to human regarding frequency of target cells, levels
of soluble antigen, and affinity for Ig sub-family
• Study design 3 Dose levels: 10, 40, and 100 mg/kg 4 animals / group: 2 Males / 2 Females Treatment regimen: 4 x q3-4 d
• Exploratory end points Frequency of target B cells and of total T and B cells
Sornasse T. et al., ASH 2007
Anti human Ig VH 3.23 mAb does not significantly affect the frequencies of B and T lymphocytes in vivo
Control Group
Dose Group: 10 mg/kg
Dose Group: 40 mg/kg
Dose Group: 100 mg/kg
Legend
100
T Lymphocytes
D -13 D 1 D 2 D 5 D 9 D 12 D 15
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25
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75
125
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Time Point
Re
lati
ve
Ce
ll F
req
eu
nc
y (
%)
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B Lymphocytes
D -13 D 1 D 2 D 5 D 9 D 12 D 15
0
25
50
75
125
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Time Point
Re
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Ce
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req
eu
nc
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%)
Study Days
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Infusions
Flow cytometry
Schedule of events
Sornasse T. et al., ASH 2007
100
Dose Group: 100 mg/kg
D -13 D 1 D 2 D 5 D 9 D 12 D 15
0
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75
125
100
Time Point
Re
lati
ve
Ce
ll F
req
eu
nc
y (
%)
100
Dose Group: 40 mg/kg
D -13 D 1 D 2 D 5 D 9 D 12 D 15
0
25
50
75
125
100
Time Point
Re
lati
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Ce
ll F
req
eu
nc
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%)
Anti human Ig VH 3.23 mAb depletes target B cells in vivo (Study 2)
100
Control Group
D -13 D 1 D 2 D 5 D 9 D 12 D 15
0
25
50
75
125
100
Time Point
Re
lati
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Ce
ll F
req
eu
nc
y (
%)
100
Dose Group: 10 mg/kg
D -13 D 1 D 2 D 5 D 9 D 12 D 15
0
25
50
75
125
100
Time Point
Re
lati
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Ce
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req
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nc
y (
%)
Sornasse T. et al., ASH 2007
Conclusion
• Monoclonal antibody specific for human Ig HV 3.23 can reach of target B cells despite the presence of soluble serum immunoglobulins Method used to track target B cells can not differentiate
between cell depletion and antigen down-modulation
• In vivo administration of a mAb specific for human Ig HV 3.23 does not significantly affect the frequencies of T and B lymphocytes
Challenge/verify original hypothesis throughout developmentRemain aware of model limitation and built-in assumptions
Inflammatory Diseases
INFLAMMATORY BOWEL DISEASE
Analysis of gene expression profile in patient’s biopsies
Inflammatory Bowel Disease
• Definition: Inflammation of the gastro-intestinal tract that is not due to specific
pathogens.
• Clinical forms: Crohn’s Disease: can affect any part of the digestive tract. Ulcerative Colitis: limited to lower part of large intestine.
• Environmental factors: Disease of industrialized countries. Smoking reduces risk of UC but increases risks of CD.
• Treatments: Symptom control.
Basic Differences Between CD and UC
Ulcerative Colitis Crohn’s Disease
Lesion characteristics:- Strictly mucosal.- Continuous and diffuse.- Progress from distal portion of GI tract.
Lesion characteristics:- Transmural (may involve layers as deep as adventitia).- Scattered and focal.- May appear anywhere along lower GI tract.
Study Design
• Patients Pediatric patients (LSU) 8 Controls, 8 Crohn’s disease patients, 3 colitis patients
• Tissue samples ~ 500 – 750 mg / biopsy (estimated) Snap frozen upon collection
• Sample analysis Ratiometric RNA microarrays (2 channels) All samples compared to a common reference sample (total
colon) processed in parallel.
FUNCTION GSYM NAME
Probability
Dn9968-Ileum
-Norm
al (BS
27185)
Dn10122-C
olon-Norm
al (BS
27737&27738)
Dn9969-C
olon-Norm
al (BS
27187)
Dn9964-C
olon-Norm
al-Constipation (B
S 27181)
Dn9962-C
olon-Norm
al-AbP
ain (BS
27175)
Dn9960-C
olon-Norm
al-Inflam.P
olyp (BS
27171)
Dn9958-R
ectum-N
ormal-P
etechiae (BS
27167)
Dn9957-C
ecum-N
ormal-M
ild Edem
a (BS
27165)
Dn9955-C
olon-Colitis-P
sMbr (B
S 27161&
27162)
Dn10130-C
olon-Colitis-E
osinophilic (BS
27757)
Dn10367 C
olon-Colitis (B
S 29347)
Dn10367 C
olon-Colitis (B
S 29346)
Dn9954-C
olon-CD
p (BS
27159)
Dn9953-C
olon-CD
p (BS
27156)
Dn9953-C
olon-CD
p (BS
27157)
Dn9952-C
olon-CD
p (BS
27154)
Dn9952-C
olon-CD
p (BS
27155)
Dn9951-C
olon-CD
(BS
27152)
Dn9951-C
olon-CD
(BS
27153)
Dn1036-Ileum
-CD
(BS
29344)
Dn10366-C
olon-CD
BS
(29343)
Dn9950-C
olon-IBD
(BS
27151)
Dn10365-C
olon-IBD
(BS
29341)
STRESS HSP5 heat shock 70kD protein 5 8.E-06STRESS HIF1A hypoxia-inducible factor 1, alpha 1.E-05MHC II (Expression regulation) XBP1 X-box binding protein 1 2.E-05APOPTOSIS (Inhibitor) ETS2 v-ets 3.E-05STRESS DNAJA1 DnaJ A1 6.E-05UNKNOWN FLJ20073 FLJ20073 6.E-05APOPTOSIS (Inhibitor) BIRC3 BIRC3 6.E-05UNKNOWN ALEX2 (KIAA512) 7.E-05IFN-g GBP2 GBP1 7.E-05MACROPHAGE PSME2 proteasome activator subunit 2 8.E-05APOPTOSIS (Inhibitor) BIRC3 BIRC3 9.E-05CHEMOKINE SCYA2 MCP-1 1.E-04UNKNOWN C8orf4 1.E-04CHEMOKINE GRO2 GRO2 oncogene 1.E-04UNKNOWN neural precursor cell expressed 1.E-04CYTOKINE IL1B IL-1b 1.E-04COLON LMAN1 lectin, mannose-binding, 1 1.E-04UNKNOWN 1.E-04CHEMOKINE GRO1 GRO1 oncogene 1.E-04NEUTROPHIL ACTIVATION ? ERP70 Ca-binding protein, intestinal-related 2.E-04COMPLEMENT PATHWAY C2 complement component 2 2.E-04MATRIX REMODELING MMP12 MMP12 2.E-04TISSUE STRUCTURE (Growth) GCG glucagon 2.E-04MATRIX REMODELING CTSB Cathepsin B 2.E-04MACROPHAGE DMBT1 deleted in malignant brain tumors 1 2.E-04CYTOKINE MDK Midkine 3.E-04TISSUE STRUCTURE (Repair) NID Nidogen 3.E-04CYTOKINE MDK Midkine 3.E-04MATRIX REMODELING MMP12 MMP12 3.E-04UNKNOWN x ADP-ribosylation factor 4 3.E-04
SLC21A3 Organic anion transporter 4.E-04TISSUE STRUCTURE (?) IGFBP5 IGF Binding Protein 5 4.E-04PATHOGEN INTERACTION PLS3 Plastin 3 4.E-04MHC II HLA-DOA MHC II, DOA 4.E-04STRESS HSPCB HSP90, 1 4.E-04APOPTOSIS (Inducer) HRASLS3 HREV107 4.E-04IFN-g & PATHOGEN INTERACTION (Defense) NOS2A nitric oxide synthase 2A 4.E-04IFN-g IFITM3 IFN induced transmembrane protein 3 4.E-04STRESS HSPA8 HSP70, 8 4.E-04CHEMOKINE SCYA20 MIP3a 5.E-04UNKNOWN DOC1 5.E-04PATHOGEN INTERACTION (Defense) PLA2G2A PLA2 IIA 6.E-04UNKNOWN GS3786 6.E-04TISSUE STRUCTURE (Repair) TFF1 Trefoil Factor 1 6.E-04PATHOGEN INTERACTION (Defense) PLA2G2A PLA2 IIA 6.E-04STRESS NCL Nucleolin 6.E-04MATRIX REMODELING (Inhibition) SERPINA1 Serpin A1 7.E-04
SEC24B SEC24 7.E-04APOPTOSIS (Inhibitor) BIRC3 BIRC3 7.E-04APOPTOSIS (Inducer) CASP5 Caspase 5 7.E-04
LegendApoptosisIFN- pathwayChemokinesCytokinesTissue remodeling
Summary of Observations
Tissue repair(Nidogen, IGFBP-5)
Proteases(MMP-12, Serpin)
TissueTissueRemodelingRemodeling
CellularCellularRecruitmentRecruitment
MCP-1, MIP3-
InflammationInflammation
IFN-, IL-1
Caspases
ApoptosisApoptosis
Inhibitors(Ets-2, BIRC3)
IBD Pathology
Collaborate with clinical research to obtain critical resources for discovery research
Visilizumab in ulcerative colitis
• Humanized anti-Human CD3 mAb
• Pharmacology in Steroid Refractory UC patients Rapid and sustained clinical response Rapid and reversible decrease of T cells
• In vitro mode of action Does not bind to Fc Receptor (engineered Fc portion: IgG2M3) Weak induction of proliferation and cytokine production in PBMC Rapid induction of apoptosis of activated T cells but not of resting T
cells
What is the mechanism of rapid decrease in peripheral T cells in vivo?
INFLAMMATORY BOWEL DISEASE
Identification of a clinical biomarker from mode of action studies of
visilizumab (humanized anti-CD3 mAb)
In vitro mode of action: experiment design
OKT3: anti-CD3 mAb that binds to FcR strong activator of T cell proliferation and cytokine release
Microarray
Results: Cytokines
RN
A L
eve
ls (
Arb
itra
ry U
nits
)
Time
Results: CXC Chemokines
RN
A L
eve
ls (
Arb
itra
ry U
nits
)
Time
Observations and Hypothesis
• Visilizumab is a weak inducer of cytokine production by T cells
• Visilizumab is a strong inducer of CXCR3 ligands (IP10, MIG, I-TACK) production by T cells
Is this in vitro observation can be confirmed in patients?
Is there any association between CXC chemokine production and clinical outcome?
Study Design• Patients: Steroid refractory UC
• Unresponsive to IV steroids (minimum 5 days of 40 to 60 mg IV)• Composite score Modified Truelove and Witts’ Severity Index (MTWSI) was ≥11.
• Treatment:• Bolus infusions of visilizumab on days 1 and 2 at either 5, 7.5, 10 or 12.5 μg/kg.
• End Points:• Clinical response• Peripheral lymphocyte counts• Serum IP-10 levels
Woo J. et al., DDW 2006
Rapid increase in serum IP-10 levels in patients treated with visilizumab
Woo J. et al., DDW 2006
Conclusions• Strong correlation between the increase in serum IP-10 levels
and reduction in circulating T cells
• Significant association between elevated serum IP-10 levels and improved clinical outcome new working model
Active disease Disease “reset”
Maintain a two-way flow of information between clinical and discovery research
ASTHMA
Analysis of anti-CD25 mAb mode of action in vitro: from nonclinical
research to expanded clinical indication
Immunopathology of Asthma
Sornasse T. et al., AAAAI 2005
Allergic component•IgE-mediated activation•Mast cells and eosinophils
Metaplasia
Airway remodeling
Daclizumab
• Humanized anti-Human CD25 mAb
• Clinical indication Prophylaxis of acute organ rejection in patients receiving
renal transplant Initial positive phase II results in chronic asthma
• In vitro mode of action: Inhibition of T cell immune functions Inhibition of IL-2 signaling by blocking the binding of IL-2 to
the high affinity IL-2 receptor (IL-2 R) Inhibition of IL-2 dependent T-cell proliferation
Effect of daclizumab in vitro on the production of cytokines associated with the immunopathology of
asthma
• System Peripheral Blood Mononuclear Cells from
healthy volunteers
• Activation Anti-CD3 / anti-CD28 coated beads
APC independent
• Test article Daclizumab: 20 to 0.01 µg/mL
Sornasse T. et al., AAAAI 2005
Daclizumab does not significantly affect CD3/CD28-induced proliferation of human PBMC
The PBMC of adult volunteers were stimulated with CD3/CD28 beads for 72 hours in the presence of graded doses of daclizumab. Results are presented as the Average of the relative proliferation to no-daclizumab control ± SEM
Proliferation
0
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10 -3 10 -2 10 -1 10 0 10 1 10 2
Daclizumab Concentration (µg/mL)
Rel
ativ
e P
roli
fera
tio
n (
% o
f M
ediu
m A
lon
e)
Sornasse T. et al., AAAAI 2005
Potential effect on cytokine production is not affected by T cell number
Daclizumab strongly inhibits the secretion of pro-asthmatic Th2 cytokines
The PBMC of healthy adult volunteers were stimulated with CD3/CD28 beads for 72 hours in the presence of graded doses of daclizumab. Results are presented as the Average of the relative cytokine levels to no-daclizumab control ± SEM
IL-4 (N=8)
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Daclizumab Concentration (µg/mL)
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e C
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evel
(%
Med
ium
alo
ne)
IL-5 (N=8)
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Daclizumab Concentration (µg/mL)
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alo
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IL-13 (N=8)
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Daclizumab Concentration (µg/mL)
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lati
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ine
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ve
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diu
m a
lon
e)
IL-9 (N=8)
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ium
alo
ne)
Sornasse T. et al., AAAAI 2005
Daclizumab inhibits the secretion of pro-asthmatic Th0 cytokines
The PBMC of healthy adult volunteers were stimulated with CD3/CD28 beads for 72 hours in the presence of graded doses of daclizumab. Results are presented as the Average of the relative cytokine levels to no-daclizumab control ± SEM
IL-3 (N=7)
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Daclizumab Concentration (µg/mL)
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evel
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alo
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GM-CSF (N=8)
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Daclizumab Concentration (µg/mL)
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e C
yto
kin
e L
evel
(%
Med
ium
alo
ne)
TNF- (N=8)
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10 -3 10 -2 10 -1 10 0 10 1 10 2
Daclizumab Concentration (µg/mL)
Rel
ativ
e C
yto
kin
e L
evel
(%
Med
ium
alo
ne)
Sornasse T. et al., AAAAI 2005
Daclizumab partially inhibits the secretion of pro-inflammatory Th1 cytokines
The PBMC of healthy adult volunteers were stimulated with CD3/CD28 beads for 72 hours in the presence of graded doses of daclizumab. Results are presented as the Average of the relative cytokine levels to no-daclizumab control ± SEM
IFN- (n=7)
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Daclizumab Concentration (µg/mL)
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e C
yto
kin
e L
evel
(%
Med
ium
alo
ne)
TNF- (N=8)
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10 -3 10 -2 10 -1 10 0 10 1 10 2
Daclizumab Concentration (µg/mL)
Rel
ativ
e C
yto
kin
e L
evel
(%
Med
ium
alo
ne)
IL-1 (N=8)
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10 -3 10 -2 10 -1 10 0 10 1 10 2
Daclizumab Concentration (µg/mL)
Rel
ativ
e C
yto
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e L
evel
(%
Med
ium
alo
ne)
IL-6 (N=8)
0
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10 -3 10 -2 10 -1 10 0 10 1 10 2
Daclizumab Concentration (µg/mL)
Rel
ativ
e C
yto
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e L
evel
(%
Med
ium
alo
ne)
Sornasse T. et al., AAAAI 2005
Conclusions
• Effect of daclizumab on cytokine production by T cells supports: Pursuing clinical research in allergic
asthma Expanding clinical research to non-
allergic asthma
Sornasse T. et al., AAAAI 2005
Discovery and nonclinical research remain essential to articulate a coherent clinical research strategy
Building Bridges Between Discovery, Preclinical, and Clinical Research
• Include nonclinical exploratory end points to clinical studiesInclude nonclinical exploratory end points to clinical studies
• Collaborate with clinical research to obtain critical resources for Collaborate with clinical research to obtain critical resources for discovery researchdiscovery research
• Challenge/verify original hypothesis throughout developmentChallenge/verify original hypothesis throughout development
• Remain aware of model limitation and built-in assumptionsRemain aware of model limitation and built-in assumptions
• Maintain a two-way flow of information between clinical and Maintain a two-way flow of information between clinical and discovery researchdiscovery research
• Discovery and nonclinical research remain essential to Discovery and nonclinical research remain essential to articulate a coherent clinical research strategyarticulate a coherent clinical research strategy
• Include nonclinical exploratory end points to clinical studiesInclude nonclinical exploratory end points to clinical studies
• Collaborate with clinical research to obtain critical resources for Collaborate with clinical research to obtain critical resources for discovery researchdiscovery research
• Challenge/verify original hypothesis throughout developmentChallenge/verify original hypothesis throughout development
• Remain aware of model limitation and built-in assumptionsRemain aware of model limitation and built-in assumptions
• Maintain a two-way flow of information between clinical and Maintain a two-way flow of information between clinical and discovery researchdiscovery research
• Discovery and nonclinical research remain essential to Discovery and nonclinical research remain essential to articulate a coherent clinical research strategyarticulate a coherent clinical research strategy
Flow of information in Flow of information in researchresearch
The old viewThe old view
Flow of information in Flow of information in researchresearch
The old viewThe old view
Flow of information in Flow of information in researchresearch
The new viewThe new view
Flow of information in Flow of information in researchresearch
The new viewThe new view