A Phase I, Multi-Dose Study of
SGN-40 (anti-huCD40 mAb) in
Patients with Multiple Myeloma
10th International Multiple Myeloma Congress
April 14, 2005
SGN-40
Antigen
Binding Site
Light
Chain
Heavy
Chain
Fully humanized monoclonal antibody
Neither agonistic nor blocking
Allows CD40 Ligand interaction
CD40: The Target
TNF receptor family
CD40 ligand (CD154) on T-cells
Expressed on B-cells, dendritic cells, monocytes
Hematologic malignancies of B-cell origin
Myeloma, NHL, CLL, Hodgkin's Disease
>90% express CD40
SGN-40: Mechanisms of Action
Present:
Antibody Dependent Cellular Cytotoxicity (ADCC)
Antibody induced Cell Death (AICD)
Not present:
Complement Dependent Cytotoxicity (CDC)
Potent Activity in Xenograft Models
Start on d3
Start on d13
s.c. model
2mg/kg/2x/wk (5 doses)
4mg/kg/3 x/wk (5 doses)
1.6 10
104
15
15
3 1.2 10
104
4 mice for
m
pathology
m
10
10
em
mice)
u
#
lov 8000
SGN-40
r
(total
o
SGN-40
Control Ab
mu
Control Ab
5
5
T
4000
SURVIVAL
SGN-40
Control Ab
Ab
0
0
0
12
19
23
29
50
100
150
200
250
40 60 80 100 120 140 160
DAYS POST TUMOR INJECTION
SGN-40 in Myeloma
Phase I Trial
Single-agent dose escalation study
Multiple cohorts at 0.5 - 8 mg/kg/week
Weekly doses
Six weeks follow-up/observation
Patients with progressive or refractory disease
Open at four clinical sites
Patient Demographics
Male (8) Female (5)
Median number of prior
Median age of 63 (range
therapies 5 (range 3-10)
40-77)
Bortezomib
4/13
Race and Ethnicity
Thalidomide
12/13
Caucasian (10)
RevlimidTM
3/13
Black (1)
Melphalan
5/13
Hispanic (1)
Combo Chemo 11/13
Other (1)
Auto transplant 3/13
Median time from initial
diagnosis 6.4 years
(range 2.8-14.1)
Adverse Events: Grade 3/4
Dose
Dose
Dose
Grade 3
# of
0.5 mg/kg
1 mg/kg
2 mg/kg
Relationship
Adverse Event
Events
(n=3)
(n=4)
(n=6)
Neutropenia
1/13
0
0
1
Possibly
Thrombocytopenia
1/13
0
0
1
Unlikely
Decreased
3/13
1
2
0
Unlikely
Hemoglobin
Hypercalcemia
3/13
0
1
2
Unrelated
Renal Insufficiency
1/13
0
0
1
Unrelated
Lymphocyte Subset Analysis:
B-cells Decreased
CD19: B-cells
200
CD19
0.5 mg/kg
1.0 mg/kg
2.0 mg/kg
150
Lµ
llse
C
100
fo#
50
-7
1
8
15
22
29
43
64
Study Days
Patient 065-0001: 0.5 mg/kg
SGN-40
EOT
1.6
100 CD19+
+8%
1.4
dl
80
SPEP
g/ 1.2
0%
60
cells/uL
-8%
1
40
-23%
SPEP 0.8
20
CD19+ cells
0.6
0
-5
1
8
5
2
0
4
5
1
2
3
4
6
ay
ay
ay
D
D
D
ay
ay
ay
ay
ay
D
D
D
D
D
Patient 065-0006: 2 mg/kg
5
80
SGN-40
EOT
+25%70
4.5
r
+16%
60
L
h
4
/u
UPEP
50
ls
+3%
/24 3.5
g
40
-6%
cel
PEP
30
19+
3
U
D
20
C
CD19+ cells
2.5
10
2
0
1
3
6
8
y -7
15
22
29
64
78
ay
y 8
y 4
10
14
Da
D
Da
ay
ay
ay
ay
ay
D
D
D
Da
D
D
ay
ay
D
D
Patient 065-0008: 4 mg/kg/wk
SGN-40
2.5
ms)
rag
2
(
rsh 1.5
-41%
/24n
-50%
1
tei
rop 0.5
e
rinU
0
Baseline
Day 9
Day 21
Conclusions
Safety:
SGN-40 appears safe and well tolerated at 4 weekly
doses up to 2 mg/kg
Antitumor activity:
Several patients have decreased serum or urine protein
during therapy
Higher dose and/or prolonged treatment might be
necessary for sustained response
Lymphocyte subset analysis:
B-cells declined significantly during therapy
T-cells, NK cells, monocytes were not significantly
affected by SGN-40
B-cell depletion appears to correlate with clinical response
Acknowledgements
Study sites and P.I.s
Cleveland Clinic
Mohamad Hussein
Dana Farber Cancer Institute
Nikhil Munshi
James R. Berenson MD, Inc.
James Berenson
Weill Medical College/
Ruben Niesvizky
Cornell University
Sponsor: Seattle Genetics