Antibody Based
-
Therapies in
Multiple My
pyeloma
Yu-
Yu Tzu Tai
Tai, Ph D
. .
Harvard Medical School
The Jerome Lipper Multiple Myeloma Center,
Dana Farber Cancer Institute,
Boston, Massachusetts, USA
Feb 26, 2009
XII IMW Multiple Myeloma Immune and Antibody Targets Session
Mechanisms of MAb-
MAb Mediated Cell Killing
Effector cells:
NK cell
macrophage
neutrophil
Target cell
Target cell
Target cell
Antibody-dependent
Complement-dependent
Apoptosis/growth arrest
arrest
Cellular gytotoxicity
Cytotoxicity
via intracellular
(ADCC)
(CDC)
signaling pathways
Obstacles to Effective Antibody
Antibody Therapy
· Immunogenicity of xenogeneic Abs
Abs
· Shedding of antigen into circulation
· Heterogeneity of antigen on tumor surface
surface
· Limited numbers of effector cells at tumor site
· Immunosuppressive tumor microenvironment
microenvironment
· Disordered vasculature in tumors
· Expression of CD55, CD59, CD46 that
that interfere
with CDC and allow tumor cells to escape
complement attack
Studies on MAb-
MAb Based Therapies
Therapies for MM
M
MM
· Despite
p
anti-CD20 mAb Rituximab is widely used for the
treatment of B cell malignancies, no mAb-based therapy is
approved for MM treatment.
· In early 2000, only mi i
n mal activity f
o irtit i
ux
b
ma
d
an
ti
an -
CD38 Abs were reported in MM.
· However, > 10 potential mAb
mAb candidates have entered
clinical development in recent years.
· Specifically, these mAbs are directly
yy against
g
MM cell surface
antigens (CD40, HM1.24, IGF-1R, CD56, CS1, CD138,
CD74, IL-6R, CD38, TRAIL-R1, 2-microglobulin) or target
cytokines, growth
yg
factors, and interaction of the MM cell with
the BM microenvironment (IL-6, RANKL, DKK1, VEGF,
BAFF).
Growth of MM Cells in the BM
BM Milieu
Milieu
CS1
Cell surface
CD40
MM
CD138
migration
Targets
GSK-3
SC
CD38
FKHR
PKC
Caspase-9
Survival
BCMA
Akt
NF-B
Anti-apoptosis
Cell cycle
mTOR
cy
PI3-K
Bad
Survival
IGF-1R
JAK/STAT3
Bcl-xL
Cytokines
Mcl-1
Anti-apoptosis
IL-6R
Raf
MEK/ERK
proliferation
IL-6, VEGF
FGFR3
Bcl-xL
Survival
IGF-1, SDF-1
NF-B
IAP
Anti-apoptosis
TRAIL-R
Cyclin-D
Cell cycle
BAFF, APRIL
Apoptosis
Proliferation
MEK/ERK
Anti-apoptosis
pp
Smad, ERK
Adhesion
NF-B
cytokines
adhesion
NF-B
molecules
ICAM-1
LFA-1
MUC-1
BMSC
VCAM-1
Fibronectin
VLA-4
Adopted from Nature Reviews Cancer 2007
MAbs for MM
MM in
in Preclinical
Preclinical Testing
Target
Brand name
Company/Sponsor
type of mAb (conjugate)
CD138
B-B4-DM1
ImmunoGen
the maytansinoid
immunoconjugate mouse IgG1
mAb B-B4
CD138
nBT062
ImmunoGen; Biotest
chimeric (B-B4-maytansinoids)
HM1.24
humanized HM1.24
Chugai Pharmaceutical
humanized
HLA-DR
1D09C3
GPC Biotech, AG
human
CD74
IMMU-110
Immunomedics, Inc.
humanized; doxorubicin
conjugated
kininogen
C11C1
Temple University School mouse
of Medicine
HLA class I 2D7 DB
-
Ch gai
u
Pharmace tical
u
con erted
v
from mo se
u
IgG2b
Co. Ltd.
2-
anti-2M mAbs
MD Anderson Cancer
mouse
microglobulin
Center
CD38
C38
MOR20
O02MorphoSys AG
huma
uan
CD32B
MGA321
MacroGenics
humanized
FGFR3
PRO-001
Prochon Biotech Ltd.
human
ICAM-1
UV3
Abiogen
mouse
BLyS
BLyS/rGel
Targa Therap
gpeutics
Fusion protein of an antibody
py
tethered to a toxin
TACI
Atacicept (TACI-Ig)
ZymoGenetics Inc.
fusion protein
CD70
SGN-70
Seatle Genetics
humanized
BCMA
SG1
Seatle Genetics
Auristatin- BCMA mAb
MAbs for MM
MM in
in Clinical
Clinical Trials
Target
Brand name
Company/Sponsor
type of mAb (conjugate) Phase
CD20
Rituxan
NCI & Memorial Sloan-
chimeric
II
Kettering Cancer Center
CD20
Zevalin (yttrium Y 90
NCI
mouse IgG1 antibody
I
ibritumomab tiuxetan)
CD40
SGN-40 (Dacetuzumab) Seatle Genetics
humanized
I
CD40
HCD122
Norvatis
human
I
CD20
Bexxar (131-
GlaxoSmithKline
radioactive iodine 131
II
tositumomab)
attaching to anti-
CD20;muIgG2a (131)
CD56
IMGN901(huN901-DM1) ImmunoGen
humanized (maytansine DM1) I
RANKL
AMG162 Denosumab
Amgen
human
II
VEGF
Avastin becacizumab
Genentech
humanized
II
CD52
Campath-1H
NCI; Fred Hutchinson
humanized
II
(alemtuzumab)
Cancer Research Institute
IL-
IL 6
CNTO 328
Centocor
chimerized
I/II
IL-6R
MRA (Tocilizumab)
Roche Pharmaceuticals
humanized
II
TRAIL-R1 Mapatumumab(TRM-1) Human Genome Sciences human
II
EGFR
Erbitux(EMMA-1)
Imclone; Bristol Meyers-
chimerized
II
Squibb
CS1
elotuzumab/HuLuc63
PDL Biopharma
humanized
I /II
CD38
HuMax-CD38
Genmab
human
I/II
DKK
BHQ880
Novartis
human
I/II
Anti CD40
-
MAbs
MAbs for
for Novel Therapies
Therapies
··SGN
SGN--40
40 is composed of the human IgG class constant region, as in
1
Rituximab, coupled with humanized murine variable regions against CD40
· 10% mouse protein
· Weak agonistic
· Induces ADCC against CD40+ MM cells
· Phase Ib clinical trial, with lenalidomide or bortezomib, in MM
· HCD122 is generated in Xenomice and selected based upon its inhibition
of CD40L-induced biological seq
gquelae
· 100% human protein
· Antagonistic and block CD40 activation in MM
· Induces ADCC to lyse CD40+ MM cells
· Phase 1 clinical trial in MM, CLL
Cancer Res 2005 65:11712
Cancer Res 2005 65:5898
Anti-
Anti MM Activity by
bby Anti-
Anti CD56 mAb
m
mAb
huN901
huN901--DM1
DM1
Tassone et al Cancer Res 2004, 64:4629
Anti-CS1 mAb Elotuzumab Triggers ADCC
& I hibit
n
s M l
ye oma Growth
th In vivo
A
C
MM1R
OPM2
OPM1
12PE
INA6
MCCAR
Solid symbol:
HuLuc63
CS1
Open symbol:
-tubulin
iso control
B
g
80
Killin
60
40
D
pecific
20
pS 0
treatment
%
0
1
25
10
20
(ng/ml)
iso controll
0.0001
0.001
0.01
0.1
15
HuLuc63
L-6R 10
HuLuc63, g/ml
5
U266
shuI
MM1R
CD19+B cells
0
MM1S
07
14
CD19+B cells
Days from treatment
Tai Blood 2008,112:1329
Elotuzumab Mediates ADCC Against MM
Cells and Activates NK and Monocytes
IFN-
IFN-
Balasa ASH 2008 Abstract #108
Elotuzumab Clinical Trials in MM
· A Phase 1 Multi-Center, Open-Label
,p
, Dose Escalation
Study in Advanced Multiple Myeloma
· A Phase 1/2, Multi-Center, Open-Label, Dose-Escalation
Study of HuLuc63 and Bortezomib in Multiple Myeloma
Following One
One to Three Prior
Prior Therapies (HuLuc63-1702)
· Phase 1B Study Of Elotuzumab Monoclonal Antibody In
Combination With REVLIMID and Dexamethasone
Zonder ASH 2008 Abstract #2773
http://clinicaltrials.gov
Lenalidomide Augments Anti-
Anti MM Immunity
T Cell
NK Cell
NFAT
IL-2
IL-2
PKC
IFN
Dendritic Cell
PI3K
CD28
Apoptotic MM
MM Cell
Cells
VEGF
IMiDs
IL-6
Bone Marrow Stromal Cells
LeBlanc Blood 2004; Hayashi Brit J Hematol 2005
Lenalidomide Augments SGN
SGN-40
- -
40 mediated
-
Lysis of Autologous MM Cells
A
medium
60
Target: 12BM
Target: 28BM
lysis
lysis 60
control IgG1
45
45
SGN-40
ecific
30
e
pecific 30
p
lenalidomide
Sp
15
S 15
0
%
SGN-40 +
%
0
lenalidomide
25
10
40
25
10
40
E/T ratio
E/T ratio
B
Patient 1
Patient 2
Patient 3
60
50
25
**
lysis
50
**
**
40
** **
20
fic
40
30
30
30
*
15
*
20
20
10
10
*
*
10
5
Speci
0
0
0
%
dcon
nIgG
N-40
N-40
N-40
n
d
n
d
n
omide
S+L
G
omide
S+L
dcon
nIgG
o
G
omide
S+L
dcon
nIgG
o
G
me
co
S
me
co
S
me
co
S
lenalid
lenalid
lenalid
Tai Cancer Res 2005 65:11712
Lenalidomide Augments Elotuzumab-
I d
n
d
uce ADCC
ADCC A i
ga nst MM
MM
l
cells
80
MM1S
MM1R
80
lysis
60
60
40
40
ecific
20
20
sp% 0
0
mAb, g/ml
MM patient cells
s
50
40
iso IgG1 + Lenalidomide
lysi
30
HuLuc63 + Lenalidomide
20
iso IgG1
pecific
10
s
0
HuLuc63
%
01
10
mAb, g/ml
Tai Blood 2008 112:1329
Anti-CD138 (B-B4
(
)-DM1
)
Blocks MM Cell
Growth in vivo
Xenograft model
model
SCID-hu model
g/ml
ainch
umanH
Days post inoculation
Tassone et al Blood 2004;104:3688
Anti-CD138 nBT062-SPDB-DM4 Induces
P t
o
t
en Toxiciti
ities against CD138+ MM
ll
ce s
A
B
Time (h)
Dose (ng/ml)
2.5
12
024 36 48 72
0 55 111 221 442 885
G1
2.0
PARP FL
S
CL
G
1.5
2/M
Caspase 3 FL
anges
CL
ch
1.0
Caspase 8 FL
CL
Fold
0.5
Caspase 9 FL
CL
0
-Tubulin
0h
12h
24h
C
Xenograft model
10
SCID
SCID--hu
hu model
2000
1750
PBS
PBS
olume
8
o
1500
100 g/ml
0
100
g/ml
BT062
n
-SPDB
v
-
1250
250 g/ml
n
6
DM4 (250ug/ml)
1000
450 g/ml
tumor
4
750
500
sIL-6R
2
dian 3
d
m
250
Me
m
0
0
10
20
30
40
50
714
21
27
35 42
49
Day s p os t in oculation
Days post treatment
Ikeda et al Clin Cancer Res 2009
Antibodies Targeting MM Cells in the
Bone Marrow Microenvironment
MM-
MM induced bone lesion
· Targeting RANK/RANKL/OPG axis using denosumab for MM-
associated bone destruction
Denosumab (AMG 162,
(, Amgen
g
Inc., Thousand Oaks, CA)
· Targeting the Wnt inhibitor Dickkopf-1 (DKK-1)
BHQ880 (Norvatis)
Targeting angiogenesis
VEGF inhibitor Becacizumab (Avastin, Genentech Inc.)
Targeting BAFF/ARPIL growth and survival pathway (preclinical stage)
Atacicept/TACI-Ig (ZymoGenetics; Serono)
Anti-
Anti BAFF (Eli
(Eli Lily)
Lily)
AMG523 (Amgen)
Anti-DKK-1 BHQ880 Reverses the Inhibitory
Effect of MM Cells on Osteoblastogenesis
A
Isotype control BHQ880, 1 g/ml
-BHQ880
+BHQ880
no
150
P=0.08
MM cells
P= 0.0001
eposition
ntrol) 100
ed coof
with
50
(%
P= 0.0001
MM cells
Calcium
0
no MM cells
with MM cells
B
P=0.002
ml
8
ng/
6
P=0.0002
-BHQ880
4
+BHQ880
huIL-6
P=0.0003
2
0
no MM cells
with MM cells
Fulciniti et al Blood 2009
Anti-DKK-1 BHQ880 Improves
OS
Osteoblastogenesis in C
SCID-hu Model
Control
Treated
10
1 0
0
0
p= 0
. 0
0 0
0 1
0
15
1
p=0.01
husIL-6
OB
80
OB
10
60
1(ng/ml)
R(pg/ml)
Bone
40
MM
Bone
5
h-DKK 20
0
0
60
0
cells
d
0
1 2 3 4 5 6 7 8
4 5 6 7 8
+
40
p=0.001
weeks from INA-6 MM cel s injection
fiel
20
ALP
per
0
Control
Treated
15
lcin
Control
Treated
10
B
p=0.003
o
l)
anosteoca
5
m
n
m
e
hum
(ng/
0
MM
Co n tr o l
T r e a te d
Fulciniti et al Blood 2009
Neutralizing Anti-BAFF Antibody Improves
S&
Survival & Inhibits Osteoclastogenesis
control
Anti-BAFF
control
At
An iti-BAFF
Neri Clin Cancer Res. 2007 13:5903
Future Direction
Direction
· Studies in GEP
GEP & oncogenomics will allow the
identification of new therapeutic MM targets.
· Engineering Ab structures to facilitate selective
interaction with host immune effectors.
· A better understanding of the immune defects
that prevent MM patients from mounting a strong
response against their tumor cells.
· Incorporation of
of mAbs
mAbs into
into MM
MM treatment
treatment
paradigm
ACHKNOWLEDGEMENTS
Mariateresa Fulciniti
Laurence Catley
Hiroshi Ikeda
Klaus Podar
Weihua Song
Teru Hideshima
Kihyun Kim
Dharmindar Chauhan
Xianfeng Li
Peter Burger
Robert Schlossman
Mathew Rumizen
Nikhil Munshi
Sabikun Nahar
Paul Richardson
Rory Coffey
Noopur Raje
Pierfrancesco Tassone
The LeBow Institute for Myeloma Therapeutics
& Jerome Lipper Multiple Myeloma Center, DFCI
Paola Neri
Neri
Kenneth C Anderson
Grant support: Multiple Myeloma Research Foundation (Y.T.Tai); National Institutes of Health Grants RO-1
50947, PO1-78378 and SPORE P50CA100707; and the Lebow Fund to Cure Myeloma (K
(K.C.A.).