Insulinlike Growth Factor Type 1 Receptor IGFIR Inhibition with Human Monoclonal AB A12 in Prostate

1
Insulin-like Growth Factor Type 1 Receptor
(IGF-IR)Inhibition with Human Monoclonal AB A12
in Prostate Cancer Combination Studies with
Docetaxel

• Stephen R. Plymate
• University of Washington

2
A.
pIGF-IRb
50
ng
/ml
50
ng
/ml
0
IGF-I
IGF-IAB
B.
kD for IGF-IR A12 kd0.04x10-9M IGF-I
kd0.1x10-9M
1.2
1
.8
Cell Mean O.D.
.6
.4
.2
0
0
1
10
50
0
1
10
50
IGF-1
A12
- - - -



3
M12 P69
60
50
40
Cell migrated
30




20
10
0
Serum
Serum
Serum
Serum
IGF-I RPMI
IGF-I RPMI
IGF-I RPMI
IGF-I RPMI
IGF-IR ab - -
- -
4
LuCap35 LuCaP35v
5
IGF-IR Human Monoclonal Studies
LuCaP 35 - AD
LuCaP 35v -AI
6
1000




800
control tv

Tumor Volume mm3
600
LuCaP 35-AD
A12 tv
400
200
0
0
2
4
6
8
Weeks



1250
Control
1000
Tumor Volume mm3
750
LuCaP 35v-AI
A12
500
250
0
0
2
4
6
8
Weeks
7
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Control
A12 -apoptosis
A12 -G1 arrest
G1 S G2
G1 S G2
Apoptosis
LuCaP 35
0
50
100
150
200
250
DNA content
DNA content
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G2
G1
0
50
100
150
200
250
0
50
100
150
200
250
250

200

150
increase / cas
100

50
0
Cas Cas A12 NC
NCA12
14
PSA ng/mk
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Kaplan-Meier Estimates of the Probability of
Overall Survival in the Three Groups
Tannock, I. F. et al. N Engl J Med
20043511502-1512
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Purpose To determine if inhibition of IGF-IR
signaling with the human monoclonal antibody,
A12, in combination with the current most
effective therapy for metastatic
androgen independent prostate cancer, docetaxel,
enhances survival in a human xenograft model of
prostate cancer.
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Docetaxel / IGF-IR AB study
Four Groups of SCID Mice -15 mice/group
Group 1 Docetaxel 20 mg/kg i.p. week 1 then 10
mg/kg q week x 3 Group 2 Docetaxel 10 mg/kg
i.p. week 1 then 5 mg/kg q week x 3 Group 3
Docetaxel 10 mg/kg i.p. week 1 then 5 mg/kg q
week x 3 plus IGF-IR AB (A12) 40 mg/kg 3 x week
x 4 weeks Group 4 Docetaxel 10 mg/kg i.p. week
1 then 5 mg/kg q week x 3 plus IGF-IR AB (A12)
40 mg/kg 3 x week x 4 weeks
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• Docetaxel/IGF-IR AB study (continued)
• Mice castrated.
• 2. LuCap 35v human prostate cancer xenograft
• implanted sc 2 weeks post castration.
• Treatment begun when tumor volume reached 100mm3
• All treatment stopped at 4 weeks
• 5. Mice sacrificed when all tumors in both
  docetaxel groups showed evidence of progression
  or when they met IACUC criteria e.g. tumor
  volume gt 1000mm3.

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Measurements Tumor volume twice weekly Weight
twice weekly Serum PSA q week At sacrifice 1.
BRDU 2. Flow cytometry for cell cycle and
apoptosis 3. Histology 4. Serum AB and IGF-I
measurements 5. cDNA microarray between groups
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Tumor cell cycle and survival activities at the
time of sacrifice.
Normal cycle ()
G2 arrest ()
G1 arrest ()
Apoptosis ()
Treatment
100
0
0
0
None
100
0
0
0
Doc (20)
0
0
33.3
66.7
Doc (20) A12
88
12
0
0
Doc (10)
12.2
0
77.8
Doc(10) A12
Data are obtained at the time of sacrifice that
is four weeks after treatment termination. Cell
cycle was measured by PI staining. Apoptosis was
assayed by TUNEL analysis.
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Conclusion 1. The combination of docetaxel and
IGF-IR inhibition is more effective than either
treatment alone. 2. The mechanism of action
of docetaxel and IGF-IR inhibition of prostate
cancer is different than either agent alone.
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Proposal Phase 1B Clinical Trial of IGF-IR
Human Monoclonal AB in Combination with Docetaxel
in AI Prostate Cancer Bone Metastases