Monoclonal
Monoclonal Antibodies
An
tibodies in
in The Tr
T ea
r tmen
ea
t
tmen of
of
Multiple
Multiple Myeloma
My
Sundar Jagannath, MD
Professor of Medicine
Mt. Sinai School of Medicine
New York, NY
The Tisch Cancer Institute
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Disclosure
Honorarium:
Celgene
Millennium Takeda
Merck
Onyx
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Milestones in the development of MCAB for therapy
1975 George Kohler and Cesar Milstein develop
Hybridoma technology The Nobel Prize in Physiology or
Medicine 1984
1982 The first report of successful use of a MCAB to treat
lymphoma (patient specific antiidiotype antibody therapy)
1986 First MCAB, muromonabCD3 (OKT3) approved by
FDA
1997 First MCAB to treat cancer (rituximab) approved
However NO APPROVED MCAB for Multiple Myeloma
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Mechanisms of MAB Mediated Cytotoxicity
Effector cells:
NK cell
monocyte
macrophage
neutrophil
Target cell
Target cell
Target cell
Antibodydependent
Complementdependent
Apoptosis/growth arrest
Cellular cytotoxicity
Cytotoxicity (CDC)
via intracellular
(ADCC)
signaling pathways
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Targets for MCAB Therapy in MM
C56
Cell Surface Targets
CD40
AntiCD56
antiCD40
PRO001 or Chir258 CS1
HuLuc63
antiCD138DM1
CD138
Growth Factors AntiIGF1R
IL6, RANKL
Bevacizumab
IGF1R
VEGF
VEGFR
IGF1
MM cell
SDF1
CD38
BAFF, APRIL
Adhesion
ICAM1
LFA1
MUC1
VCAM1
Fibronectin
VLA4
BMSC
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Target
Antibody
Company
Type
CS1
Elotuzumab
Abbot/BMS
Humanized
IL6
Siltuximab
Orthobiotec
Chimeric
CD138
BT062
Biotest
Chimeric; conjugated to
Maytansinoid
AntiKIR
IPH2101
Innate Pharma
Fully Human
CD40
SGN40, HCD122
Seattle Genetics
Humanized
Dacetuzumab, Lucatumumab
Novartis
Fully Human
CD56
IMGN901,
ImmunoGen
Humanized; conjugated to
Lorvotuzumab Meransine
Maytansinoid
CD74
Immu110
Immunomedics
Humanized; conjugated to
Doxorubicin
IGF1R
CP751,871
Pfizer
Fully Human
RANKL
Denosumab
Amgen
Fully Human
DKK1
BHQ880
Novartis
Fully Human
FGFR3
PRO001
Prochon Biotech
Humanized
Genetech
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CS1 in Multiple Myeloma
· Universal gene expression in multiple myeloma
· Confirmed CS1 protein expression by flow cytometry and
IHC with antiCS1 antibodies
· Normal tissue staining shows exclusive expression only in
tissue plasma cells
Plasma cells in normal gut
Multiple myeloma cells
in a plasmacytoma
Staining was performed with HuLuc63 humanized antiCS1 monoclonal antibody
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Conclusion for Elotuzumab Therapy in MM
Elotuzumab + lenalidomide and dexamethasone is well
tolerated
High response rate that is durable
Phase III trial is ongoing:
LenalidomideDexamethasone +/ Elotuzumab
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Role of IL6 in Myeloma
Bone Marrow Micro Environment
Osteoblast
Myeloma Cell
Osteoclast
WNT/ßCat
Runx2/Cbfa1
NFkB
IL6
sFRP2
DKK1
IL6
IL6
SDF1
IGF
MIP1/
VLA4/VCAM1
RANKL
Mesenchymal
Stem Cell
NFkB
VEGF
Bone Marrow Stromal Cell
Angiogenesis
Bernard Klein
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Phase II Study of Siltuximab in
Relapsed/Refractory Multiple Myeloma
· Relapsed myeloma after Bortezomib (100%), IMiDs 87% and Transplant 59%
· Siltuximab 6 mg/kg IV every 2 weeks + Dexamethasone
·Treatment Responses (N = 44 evaluable patients )
·Duration of therapy = 3.0 months (range 0.5 to 24.3 months)
Best
Number of
Duration of Response
Response*
Patients
(median)
CR
0
PR+MR
20%
PR
9
5.5 months (2.8 19.8)
30%
MR
4
3.2 months (1.6 6.4)
SD
23
PD
8
*EMBT criteria, 44 patients evaluable for response
Voorhees, et al. J Clin Oncol 2009; 27. Abstract 8527.
Study T05
Phase II Study of Siltuximab and Bortezomib in
Relapsed/Refractory Multiple Myeloma
· Patient Disposition (Part 1 Safety Group): N = 21 patients
· Bortezomib naive
Response
Number of Patients
CR
3
29%
VGPR*
3
ORR 57%
PR
6
SD
6
PD
3
*VGPR = Very Good Partial Response (>90% reduction in serum Mspike)
· Median time to progression = 8.7 months (1.2 22.4+)
Rossi, et al., Blood 2008:112. Abstract 867
Study T06
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Phase II Study of Siltuximab and Bortezomib in
Relapsed/Refractory Multiple Myeloma
Conclusions
Preliminary efficacy encouraging in Part 1 results
57% response (CR + VGPR + PR)
29% response (CR + VGPR)
No unexpected toxicity
Part 2 of the study completed enrollment and is
ongoing
Phase III Trial: MPV +/ Siltuximab
Rossi, et al., Blood 2008:112. Abstract 867
Study T06
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BT062: MCABdrug Conjugate
Maytansinoid linked to CD138
Targeted Antibody Payload (TAP) Technology
Chimeric antibody conjugate is stable and inactive in blood plasma
Binding to CD138 expressing cells and internalization of BT062 into the target cell
Processing and release of active DM4 inside the target cell killing of dividing
target cells
Jagannath et al. ASH Abs#3010, 2010
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BT062: MCABdrug Conjugate
Maytansinoid linked to CD138
Xenograft model
SCIDhu model
lm
g/
chain
Human
Days post inoculation
Tassone et al Blood 2004;104:3688
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BT062: Phase I Results
Objective
Clinical
Number of patients
Total Percentage
response
benefit
rate
rate
treated with BT-062
32
Number of pts. evaluable for
27
100%
response*
- disease progression after < 9
13
48%
weeks
- stable disease for 9 weeks**
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41%
52%
- minor response
2
7%
11%
- partial response
1
4%
* Patients who received only 1 treatment (3 DLTs; 1 withdrawal, 1 not eligible for further treatment) were defined as not evaluable for response
* * 4th treatment was only allowed if stable disease was confirmed by MProtein or sFLC data
BT-061 iv once every 3 weeks; dose range 10 to 200 mg/msq
A few adverse events have also been observed involving skin and/or mucosa
(tissues of epithelial origin with CD138 expressing cells),
All patients had relapsed after bortezomib and Lenalidomide/Thalidomide
About 50% of the patients achieve clinical benefit
Jagannath et al. ASH Abs#3010, 2010
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Principle of antiKIR: release inhibition of NK cells
NK cell
Tumor cell
Anti- KIR
No lysis
Lysis
NK cell activation is controlled by balanced activation and inhibitory signals
Recognition by NK cells of activating antigens is absolutely required for
their activation
Such activating antigens are electively expressed by tumor (or infected)
cells and not by healthy cells
KIR blockade promotes NK mediated cytotoxicity against tumor
IPH 2101 Phase II Trial
Two doses leading to intermittent or sustained KIR
2 doses leading to intermittent or sustained KIR occupancy
Smoldering Multiple Myeloma
203 Kirmono
n =30 (4
treated)
PI: N Munshi DFCI, Boston
Maintenance after any first line therapy
201 Remykir
n=28 (24
treated)
PI: M Attal Purpan's Hosp, Toulouse
Randomization between the 2 doses
A combination of IPH 2101 + lenalidomide
Upfront treatment of MM: first relapse
202 Kirimid
n= 12+19
PI: D Benson OSU, OH
2 sequential phases beginning by a dose escalation
To assess the impact of these function on NK cell phenotype and function
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Conclusion for MCAB Therapy in MM
Several promising MCAB are in advanced clinical testing in
myeloma
However single agent antitumor activity of these agents
appears to be modest
One of the challenges for application of MCAB in
myeloma may relate to underlying immunoparesis
Combination approaches with immunomodulatory drugs
as in case of elotuzumab appears promising
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