development of anti-ap2 therapeutics against diabetes and ... · development of anti-ap2...
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Dr. Mehmet Furkan Burak
ACP Annual Scientific Meeting, MA 2016
Development of anti-aP2 therapeutics against diabetes and fatty liver disease
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Financial Disclosure
I don’t have any conflict of interest
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Rosen, Cell 2014
70 Trillion $
Obesity recognized as a disease
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Spiegelman, Nature 2006
aP2
Adipocyte Fatty Acid Binding Protein (FABP4-aP2)
Furuhashi, Nature Rev 2008
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Genetic deficiency of aP2 is protective in many diseases
aP2
aP2-/-aP2dele on
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aP2 & Diabetes
aP2
Deficiency of adipocyte FABPs protects against a
variety of metabolic diseases
Boord et al 2004
Maeda et al 2005
Makowski et al 2002 FABP-/- = dual aP2/FABP5 KO
Shum et al 2006
Evidence that aP2 is important in metabolic disease
Hotamisligil Confidential
Blood
Gluco
se (mg/
dl)
Maeda2005CellMetabolism
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aP2 & Atherosclerosis
aP2
Deficiency of adipocyte FABPs protects against a
variety of metabolic diseases
Boord et al 2004
Maeda et al 2005
Makowski et al 2002 FABP-/- = dual aP2/FABP5 KO
Shum et al 2006
Evidence that aP2 is important in metabolic disease
Hotamisligil Confidential
Ath
ero
sclero
sis
+/+ -/-
Deficiency of adipocyte FABPs protects against a
variety of metabolic diseases
Boord et al 2004
Maeda et al 2005
Makowski et al 2002 FABP-/- = dual aP2/FABP5 KO
Shum et al 2006
Evidence that aP2 is important in metabolic disease
Hotamisligil Confidential
Boord2004Circula on
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aP2 & Fatty Liver Disease
aP2
Deficiency of adipocyte FABPs protects against a
variety of metabolic diseases
Boord et al 2004
Maeda et al 2005
Makowski et al 2002 FABP-/- = dual aP2/FABP5 KO
Shum et al 2006
Evidence that aP2 is important in metabolic disease
Hotamisligil Confidential
Hepato
steato
sis
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aP2 ?
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Serum aP2 levels increased with obesity Serum aP2 increases with BMI and obesity
7
Serum aP2 in genetic obesity in
mouse and man
Serum aP2 and BMI
Cao & Hotamisligil, unpublished
Data suggest mouse may be a good model for human
Serum aP2 increases with BMI and obesity
Hotamisligil Confidential
0
0
0
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0
0
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Fast
ing
glu
cose
an
d in
sulin
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Promoter polymorphism results in decreased adipose aP2 expression n: 7899
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0
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1 2
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1 2
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1 2
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5
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1 2
GIR
(m
g/k
g/m
in)
RD
(m
g/k
g/m
in)
*
C-H
GP
(m
g/k
g/m
in)
B-H
GP
(m
g/k
g/m
in)
PI-IgG aP2 antibody
*
*
PI-IgG aP2 antibody PI-IgG aP2 antibody
PI-lgG aP2 antibody
A B C
D
Figure 6
E
Lipolysis
β-adrenergic stimulation
MVB
Other
Organs ?
Glucose Production
aP2
aP2
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Treatment & tests HFD – become obese 6 21 25
Birth
Week 0
HFD
Vehicle or anti-aP2 monoclonal antibody 33mg/kg, 2x/week
subQ injections
Study Design
- Weekly Fasting Blood glucose
Fed Body Weight
- Week 2 Glucose tolerance test
- Week 3 Insulin tolerance test
- Week 4-5 Clamp – SAC
- Histological and molecular tests
from week 4-5 tissues.
Give me the same!
Sorry! You are
in control group
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The monoclonal anti-aP2 antibody CA33 improved glucose metabolism
0
2
4
6
8
10
PBS CA33 CA13 CA15 CA23 H3
Insulin(n
g/ml)
*
*
* *
*
n.s
Vehicle
CA33
CA13
CA15
CA23
HA3
Week0 Week4
0
50
100
150
200
PBS CA33 CA13 CA15 CA23 H3
Glucose(mg/dl)
**
CA33
CA13
CA15
CA23
HA3
Vehicle
*
Week0 Week4
0
100
200
300
400
0 30 60 90 120
Vehicle
CA33
Timea erglucose(min)
Glucose(mg/dL)
**
Glucose(mg/dL)
Timea erinsulin(min)
0
50
100
150
200
0 20 40 60 80 100
Vehicle
CA33
**
A. B.
C. D.
Burak et al. Science TM 2015
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The monoclonal anti-aP2 antibody CA33 improved glucose metabolism
0
50
100
150
200
250
Week 0 Week 1 Week 3 Week 5
PBS CA33
Glu
cose
(m
g/d
l) *
** **
6 hr fasting
Burak et al. Science TM 2015
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C
0
100
200
300
400
0 30 60 90 120
PBS
CA33
Glucose(mg/dl)
Timea erglucose(min)
HFD-aP2-/-
Vehicle
A B
Bodyweight(g)
Week0 Week3
HFD-aP2-/-
0
20
40
60
80
100
120
140
160
1 2Vehicle CA33
HFD-aP2-/-
Glucose(mg/dL)
Week0 Week3
0
10
20
30
40
50
1 2Vehicle CA33
E
0
100
200
300
400
500
600
700
0 30 60 90 120
VehicleCA33
Timea erglucose(min)
Glucose(mg/dl)
ob/ob
*
D
0
100
200
300
400
500
1 2Vehicle CA33
Glucose(mg/dL) **
Week0 Week3
F
0
2
4
6
8
10
12
PBS CA33
Insulin(ng/ml)
**
Vehicle CA33
CA33 effect is specific to aP2 and robust in different obesity models
Burak et al. Science TM 2015
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PEPCK Pck1
G6pc
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SAC
clamp Steady state basal acclimatization
Tissue collection
-5 0 5 45 10 15...
2 hr 2.5 hr 45 min
Clamp Settings
+++ Insulin + Glucose H-glucose C-glucose 3
14
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CA33 decreased liver glucose production and increased peripheral insulin sensitivity
Burak et al. Science TM 2015
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1 cm 1 cm
PBS CA33
0
1
2
3
4
5
6
Liver Weight(g)
Liver % Bodyweight
PBS
CA33
**
**
*
*
CA33 treatment improved lipid metabolism
and reversed hepatosteatosis in obese mice
Burak et al. Science TM 2015
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0
50
100
150
200
250
PBSCA33
Cholesterol(mg/dl)
VehicleCA33
*
mRNA/36B4
**
**
0
0.5
1
1.5
Scd1 Fasn Acc1
**
Scd1 Fasn Acc1
Vehicle CA33C D
CA33 treatment improved lipid metabolism
and reversed hepatosteatosis in obese mice
Burak et al. Science TM 2015
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0
5
10
15
20
25
30
35
40
45
50
0 1 2 3 4 5
PBS
CA33
Bo
dy
We
igh
ts (
g)
* * * *
CA33 prevented HFD induced weight gain and decreased BW
weeks
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CA33 decreased fat mass
B
PGWATWeight(g)
0
10
20
30
40
50
60
70
PBS CA33
Fatmass(g)
Leanmass(g)
Vehicle CA33
*
Bod
ycompo
sion
0
1
2
3
4
5
6
LiverWeight %Bodyweight
**
**
LiverWeight
%BodyWeight
Weight
Vehicle
CA33
DCA
0
0.5
1
1.5
2
2.5
Vehicle CA33VehicleCA330
0.1
0.2
0.3
0.4
0.5
BATWeight(g)
VehicleCA33
**
**
E
Vehicle CA33
Burak et al. Science TM 2015
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0
1
2
3
4
5
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9
PBS CA33
Totalfoodintake(g)
n.s.
VehicleCA33
Acvitycounts(AU)
n.s.
0
100
200
300
400
500
Light Dark
n.s.Vehicle
CA33
Light Dark0.70
0.75
0.80
Light Dark
PBS CA33
**
0
500
1,000
1,500
2,000
2,500
3,000
3,500
Light Dark
PBS CA33**
Light DarkVO2(ml/kg/hr)
RER
Light Dark
**
**
E F G H
CA33 accelerated oxidative metabolism and decreased fat mass
Burak et al. Science TM 2015
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- aP2 secretion increased with fasting.
- Serum aP2 levels increased with human obesity and contributes to hyperglycemia.
- Secreted aP2 can be effectively targeted by a monoclonal antibody to ameliorate diabetes and reduce fat mass and hepatic steatosis.
- CA33, as a potential preclinical molecule that lowered fasting blood glucose, improved glucose metabolism, increased systemic insulin sensitivity and reduced liver steatosis.
- These metabolic outcomes were; -reproducible in two independent models of obesity, genetic and dietary, -specific to aP2, -linked to the regulation of hepatic glucose output and peripheral glucose utilization.
- CA33 also decreased fat mass and increased oxidative capacity without any effect on physical
activity and food intake.
Summary
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Acknowledgement
DP2 transition aP2
8 November 2013 Dr. Gökhan Hotamisligil
Dr.Valerie Stone
Dr.Patrick Gordan Dr.Barbara Blair