A Phase I, Multi-Dose Study of
SGN-40 (anti-huCD40 mAb) in
Patients with Multiple Myeloma
Mohamad Hussein, M.D.
Director, Myeloma Research Program
Cleveland Clinic
December 6, 2004

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
>90% express CD40
Solid tumors
NSCLC, ovarian, renal cell, transitional cell
Variable expression levels

SGN-40
CD40 Expression in Hematologic
Malignancies
Percent CD40 positivity
Tumor Type
Percent CD40 positivity
specimens
Diffuse Large Cel
90 (n=52)
Lymphoma
90 (n=52
Fol icular Lymphoma
100 (n=44)
Multiple Myeloma/
94 (n=62)
Plasmacytoma
Smal Lymphocytic
94 (n=16)
Lymphoma
94 (n=16

SGN-40: Preclinical Summary
In vitro antitumor activity in multiple CD40-
expressing tumor cell lines
Tumor growth inhibition
Apoptosis
Antibody Dependent Cell-Mediated Cytotoxicity (ADCC)
Enhanced survival and decreased tumor growth
using xenograft SCID mouse models and cell lines
Synergy with IMiDs for primary myeloma cells in
vitro
Tested by repeated dosing in non-human primates
up to 100 mg/kg/week

Xenograft of Ramos Lymphoma
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
1.6 104
15
15
SGN-40
Control Ab
3 1.2 10
1.2 104
4 mice for
m
pathology
10
m
10

e
m
SGN-40
u
l
Control Ab
o
v
8000
80
r
(total # mice)
o
m
u
5
5
T
4000
SURVIVAL
0
0
0
50
100
150
200
250
40 60 80 100 120 140 160
12
19
23
29
DAYS POST TUMOR INJECTION

SGN-40 in Myeloma
Phase I Trial
Single-agent dose escalation study
Planned cohorts at 0.5, 1, 2, 4, 8, 16 mg/kg/week
Four weekly doses
Six weeks follow-up/observation
Patients with progressive or refractory disease
Open at four clinical sites

Patient Demographics
Male (6) Female (4)
Median number of prior
Median age of 58 (range
therapies 5 (range 3-10)
40-73)
Bortezomib
4/10
Race and Ethnicity
Thalomide
9/10
Caucasian (7)
RevimidTM
2/10
Black (1)
Melphalan
4/10
Hispanic (1)
Combo Chemo 9/10
Other (1)
Auto transplant 2/10
Median time from initial
diagnosis 6.9 years
(range 2.8-14.1)

Adverse Events: Hematologic
Grade 3
# of
Dose
Dose
Dose
Relationship
Lab Event
Events
Relationshi
0.5 mg/kg
1 mg/kg 2 mg/kg
Neutropenia
1/10
0
0
1
Possibly
Decreased
3/10
1
2
0
Unlikely
Hemoglobin
3/10
Unlikel
Hypercalcemia
2/10
0
1
2
Unrelated
All hematologic disorders are likely to be due to
progressive disease

Lymphocyte Subset Analysis:
B-cells Decreased
Most patients
0.5 mg/kg
1.0 mg/kg
demonstrated
2.0 mg/kg
200
significant decreases
in B-cells during
L
150
µ
treatment
lls
100
f
Ce
B-cells were quite low # o
at baseline, reflecting
50
extensive disease
and/or prior cytotoxic
-7
1
8
15
22
29
43
64
Study Days
therapies
CD19: B-cells

Lymphocyte Subset Analysis-II
900
0.5 mg/kg
800
1.0 mg/kg
Monocytes (CD14), NK
700
2.0 mg/kg
L 600
cells (CD16/CD56), T-cells
µ
CD14
500
(CD-3) not significantly
400
f

C
e
lls
affected by SGN-40
#
o 300
200
100
-7
1
8
15
22
29
43
64
Study Days
CD16/56
CD3
600
2000
500
L
µ
L 1500
400
µ
e
lls 300
f
C
1000
f

C
e
l
s
#
o 200
# o
500
100
-7
1
8
15
22
29
43
64
-7
1
8
15
22
29
43
64
Study Days
Study Days

Antitumor Activity
First 10 patients all demonstrated disease progression
by day 64
Two patients had stable M-protein during therapy
1.
16
500
50
5.0
5.
8000
450
45
4.5
4.
1.
14
7000
400
40
4.0
4.
1.
12
6000
350
35
3.5
3.
1.
10
5000
300
30
3.0
3.
0.
08
250
25
2.5
2.
4000
r
o
t
e
i
n
Ig
G
r
o
t
e
i
n
r
o
t
e
i
n
Ig
G
4000
r
o
t
e
i
n
P
M Pr
M P o
r t
o e
t i
en
P
M Pr
M P o
r t
o ei
t n
ei
200
20
2.0
M-
2.
M- 0.06
M-
3000
IgG
Ig
IgG
Ig
150
15
1.5
1.
0.
04
2000
100
10
1.0
1.
0.
02
1000
50
0.5
0.
0.
00
0
0.0
0.
0
-5
15
30
44
4
65
-7
15
29
43
57
Tr
T eat
r m
eat e
m n
e t
n D
t a
D y
a s
y
Tr
T e
r a
e tm
a e
tm n
e t D
n a
t D y
a s
y

Conclusions
Safety:
SGN-40 appears safe and well tolerated at 4
weekly doses up to 2 mg/kg
Dose escalation is currently ongoing
Antitumor activity:
Two patients showed stable M-protein during
therapy
Lymphocyte subset analysis:
B-cells declined significantly during therapy
T-cells, NK cells, monocytes were not significantly
affected by SGN-40

SGN-40 Future Directions
Phase I dose escalation trial initiated in NHL
Clinical studies planned in CLL (starting
mid-2005)
Potential trials in autoimmune diseases
under consideration

Document Outline