s CD 4 PVRIG vsPD -1 CD 8 PVRIG vs PD -1 CD 4 PD -1 vsTIGIT · Background: TIGIT is a coinhibitory...
Transcript of s CD 4 PVRIG vsPD -1 CD 8 PVRIG vs PD -1 CD 4 PD -1 vsTIGIT · Background: TIGIT is a coinhibitory...
Background: TIGIT is a coinhibitory receptor that is highly expressed on tumor infiltrating
lymphocytes (TILs), including effector and regulatory (Treg) CD4+ T cells, effector CD8+ Tcells, and NK cells. Engagement of TIGIT with its cognate ligand PVR directly suppresseslymphocyte activation. TIGIT and PVR are broadly expressed in different types of solidtumors, suggesting that TIGIT-PVR signaling may be a dominant immune escape mechanismfor cancer. Utilizing COM902, a therapeutic antibody targeting TIGIT, we demonstrate thatco-blockade of TIGIT and a new checkpoint inhibitor, PVRIG, augments T cell responses invitro and in vivo.Results: COM902 is a mouse/cyno cross-reactive fully human antibody that binds TIGIT
with high affinity and specificity and disrupts the binding of TIGIT to PVR. This antibodybinds to TIGIT on human CD8+ T cells with higher affinity than tested benchmark antibodies.In dissociated tumor samples, TIGIT expression was highest on TILs in endometrial, headand neck, kidney and lung tumors, and directly correlated with PVRIG expression. Except forbreast tumors, PVR was moderately to highly expressed in all tumor types examined, whilePVRL2 expression was highest in prostate, ovarian, liver and endometrial tumors.Combination of COM902 and COM701 resulted in enhanced CD3+ TIL activity in vitro.Furthermore, the combination of chimeric COM902 and anti-PVRIG resulted in significantCT26 tumor growth inhibition and enhanced overall survival, which was comparable to thecombination of chimeric COM902 and anti-PD-L1.Conclusion: COM902 is a high affinity antagonistic TIGIT antibody, that is currently in
preclinical development. Co-expression of TIGIT with PVRIG in TILs and their non-redundantinhibitory effects on T cell activation suggest a potential therapeutic advantage in clinicalcombinations targeting both pathways. Towards this end we are planning a trial that willeventually incorporate combinations of COM902 with the anti-PVRIG antibody, COM701.
0 5 0 1 0 0 1 5 0
0
2 0 0 0 0
4 0 0 0 0
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8 0 0 0 0
[C O M 9 0 2 ] (B in d in g S ite , n M )
gM
FI
H u m a n T IG IT
P a r e n ta l
K D = 0 .3 0 n M 0 .1 1 n M
0 5 0 1 0 0 1 5 0
0
2 0 0 0 0
4 0 0 0 0
6 0 0 0 0
8 0 0 0 0
[C O M 9 0 2 ] (B in d in g S ite , n M )
gM
FI
C y n o T IG IT
P a r e n ta l
K D = 0 .3 5 n M 0 .0 2 n M
0 5 0 1 0 0 1 5 0
0
5 0 0 0
1 0 0 0 0
1 5 0 0 0
2 0 0 0 0
2 5 0 0 0
[C O M 9 0 2 ] (B in d in g S ite , n M )
gM
FI
M o u s e T IG IT
P a r e n ta l
K D = 9 .2 0 n M 4 .4 2 n M
Human TIGIT Cyno TIGIT Mouse TIGIT
Human TIGIT Cyno TIGIT Mouse TIGIT
0.1 1 10 100 10000
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[mAb] (Binding Site, nM)
% In
hib
itio
n o
f
hu
man
PV
R b
ind
ing
COM902
Isotype
IC50 = 0.18nM
0.02nM
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% In
hib
itio
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cy
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PV
R b
ind
ing
COM902
Isotype
IC50 = 0.55nM
0.06nM
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[mAb] (Binding Site, nM)
% In
hib
itio
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f
mo
use
PV
R b
ind
ing
Chimeric COM902
Isotype
IC50 = 0.16nM
0.03nM
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[mAb] (Binding Site, nM)
gM
FI
A. Human CD8+ TEM Cell Binding(From Peripheral Blood)
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[mAb] (Binding Site, nM)
% In
hib
itio
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f P
VR
-Fc B
ind
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BM1BM2
hIgG4 isotypeCOM902
BM3
B. Inhibition of TIGIT/PVR InteractionIn Cell-Based Assay
hIgG4 isotype
COM902BM1
BM2BM3
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50
100
150
IFN
(pg
/mL
)
C. Increased IFN- Secretion In CMV CD8+ T Cell Assay
Suboptimal antibody concentration of 0.67 nM was utilized in vitro
T cells alone
Isotype Control
COM701
COM902
COM701 + COM902
Pembrolizumab
0
500
1000
1500
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2500
Kidney CD3+ TIL
IFN (
pg
/mL
)
+43%
+68% +50%
+83%
T cells alone
Isotype Control
COM701
COM902
COM701 + COM902
Pembrolizumab
0
500
1000
1500
Lung CD3+ TIL
IFN (
pg
/mL
)
+14%+12% +21%
+43%
T cells alone
Isotype Control
COM701
COM902
COM701 + COM902
Pembrolizumab
0
50
100
150
Ovarian CD3+ TIL
IFN (
pg
/mL
)
+27%
+74%
+36%
+341%
Tumor resection Dissociation &T cell Isolation
No further expansion
Anti-CD3
Modified Mel-624 (prior to co-culture)
x8 x3 x8 x16
OKT3 PD-L1 PVRL2 PVR
A. B.
A. COM902 binds with high affinity to human TIGIT and cross reacts with cynomolgus monkey and mouse TIGIT. B. COM902 blocks the interaction between TIGIT and PVR in a dose-dependent manner.
T/NK Cell
Tumor / APC
A. B. C.
COM902, a Novel Therapeutic Antibody Targeting TIGIT Augments T Cell Function and the Activity of PVRIG Pathway Blockade In Vitro and In VivoKathryn Logronio1, Samir Qurashi1, Sarah Whelan1, Kyle Hansen1, Sandeep Kumar1, Ling Leung1, Hsin-Yuan Cheng1, Zoya Alteber2, Rupashree Sen3, Michele Doucet3, Mark White1, Spencer Liang1, Eran Ophir2, Sudipto Ganguly3,
John Hunter1, Drew Pardoll3 and Maya Kotturi1 1Compugen USA, Inc, South San Francisco CA, 2Compugen Ltd, Holon Israel, 3Bloomberg Kimmel Institute for Cancer Immunotherapy, John Hopkins University, Baltimore, MD
ABSTRACT COMBINATION OF COM902 AND COM701 DEMONSRATES COMPARABLE OR GREATER POTENCY THAN ANTI-PD1
COM902: A HIGH AFFINITY, MOUSE/CYNO CROSS-REACTIVE TIGIT ANTAGONIST
REDUCED TUMOR GROWTH IN PVRIG-/- AND TIGIT-/- MICE AND SYNERGISTIC TGI IN DOUBLE KO MICE IN B16-F10 MELANOMA CANCER MODEL
COM902 INHIBITS TUMOR GROWTH & INCREASES SURVIVAL IN COMBINATION WITH ANTI-PVRIG OR ANTI-PDL1 IN CT26 COLON CANCER MODEL
Lung
Hea
d&Nec
k
Endom
etrium
Kid
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rine
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ast
Sto
mac
h
Bla
dder
Colo
rect
al
Pro
stat
e
Ova
ry
0
2
4
6
8
Cancer Type
TIG
IT E
xp
ressio
n
(TIG
IT/Iso
typ
e M
FI
SD
)
CD8+ T cells
Lung
Hea
d&Nec
k
Ute
rine
Endom
etrium
Kid
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Sto
mac
h
Bre
ast
Colo
rect
al
Bla
dder
Pro
stat
e
Ova
ry
0
2
4
6
Cancer Type
TIG
IT E
xp
ressio
n
(TIG
IT/Iso
typ
e M
FI
SD
)
CD4+ T cells
Lung
Endom
etrium
Ute
rine
Hea
d&Nec
k
Kid
ney
Bla
dder
Bre
ast
Ova
ry
Sto
mac
h
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stat
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al0
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Cancer Type
TIG
IT E
xp
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(TIG
IT/Iso
typ
e M
FI
SD
)
Treg CD4+ T cells
Lung
Endom
etrium
Kid
ney
Ute
rine
Ova
ry
Sto
mac
h
Colo
rect
al
Pro
stat
e
Bre
ast
Bla
dder
Hea
d&Nec
k
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2
4
6
Cancer Type
TIG
IT E
xp
ressio
n
(TIG
IT/Iso
typ
e M
FI
SD
)
NK cells
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CD8 PVRIG vs TIGIT
TIGIT CD8+
T cell
PV
RIG
CD
8+
T c
ell
r=0.6235p<0.0001
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CD8 PD-1 vs TIGIT
TIGIT CD8+
T cell
PD
-1 C
D8
+T
cell r=0.6383
p<0.0001
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4
6
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CD8 PVRIG vs PD-1
PD-1 CD8+
T cellP
VR
IG C
D8
+T
cell r=0.5233
p<0.0001
0 2 4 60
2
4
6
8
CD4 PVRIG vs TIGIT
TIGIT CD4+
T cell
PV
RIG
CD
4+
T c
ell r=0.5746
p<0.0001
0 2 4 60
10
20
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CD4 PD-1 vs TIGIT
TIGIT CD4+
T cell
PD
-1 C
D4
+T
cell
r=0.6763p<0.0001
0 10 20 300
2
4
6
8
CD4 PVRIG vs PD-1
PD-1 CD4+
T cell
PV
RIG
CD
4+
T c
ell r=0.5532
p<0.0001
A. TIGIT expression on CD8+, non-Treg CD4+, Treg CD4+ T cells, and NK cells is shown for indication.
B. Correlation analysis of TIGIT, PVRIG, and PD1 expression on CD8+ and CD4+ T cells from dissociated tumors.
A.
TIGIT IS EXPRESSED ON LYMPHOCYTES IN THE TME IN CORRELATION TO PVRIG AND PD1
A.
Tissue TypeTotal
Samples
% PVRL2 Low
(score 1)
% PVRL2 Moderate
(score 2)
% PVRL2 High
(score 3)
Prostate 21 71 19 10
Ovarian 10 80 10 10
Liver 10 60 40 0
Endometrial 14 71 21 0
Bladder 11 73 18 0
Head and Neck 24 54 13 0
Skin 8 75 0 0
Stomach 25 72 0 0
Colon 20 50 0 0
Breast 21 67 0 0
Pancreatic 11 73 0 0
Lung 17 47 0 0
Thyroid 10 30 0 0
Kidney 25 0 0 0
Brain 10 0 0 0
Tissue TypeTotal
Samples
% PVR Low
(score 1)
% PVR Moderate
(score 2)
% PVR High
(score 3)
Colon 20 0 5 95
Prostate 21 0 14 86
Liver 10 0 10 90
Skin 8 13 25 63
Stomach 9 33 11 56
Brain 10 30 10 60
Head and Neck 24 33 21 46
Bladder 11 18 27 55
Endometrial 14 0 50 50
Lung 19 37 26 37
Pancreatic 11 27 36 36
Thyroid 10 60 20 20
Ovarian 10 20 50 30
Kidney 25 32 40 28
Breast 19 84 11 5
The expression of PVR (A.) and PVRL2 (B.) in 16 different types of tumor tissues with n=10-20 patients per indication is shown. A polyclonalanti-PVRL2 antibody (HPA012759, Sigma-Aldrich) and a monoclonal anti-PVR antibody (Clone D8A5G, Cell Signaling Technology) were used.
B.
PVR AND PVRL2 ARE EXPRESSED IN MULTIPLE TUMOR TISSUES
A.
TIGIT AND PVRIG ARE PARALLEL, NON-REDUNDANT IMMUNE CHECKPOINTS IN THE PVR/NECTIN FAMILY
COM902 HAVE SUPERIOR BINDING CAPACITY & SIMILAR OR GREATER FUNCTION COMPARED TO CLINICAL ANTI-TIGIT BMs
Martinet & Smyth, Nat Rev Immunol, 2015 (modified)
7 10 14 17
0
1000
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Wild-type
Days post-tumor implantation
Tu
mo
r V
olu
me (
mm
3)
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0
1000
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4000
Pvrig-/-
Days post-tumor implantation
Tu
mo
r V
olu
me (
mm
3)
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Days post-tumor implantation
Tu
mo
r V
olu
me (
mm
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Tigit-/-
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Days post-tumor implantation
Tu
mo
r V
olu
me (
mm
3)
Pvrig-/-Tigit-/-
7 10 14 170
500
1000
1500
2000
2500
Days post-tumor implantation
Mean
Tu
mo
r V
olu
me (
mm
3)
Wild-type
Pvrig-/-
Tigit-/-
Pvrig-/-Tigit-/-
p<0.03
p<0.01
0 1 0 2 0 3 0
0
2 0
4 0
6 0
8 0
1 0 0
D a y s p o s t - t u m o r i m p l a n t a t i o n
Pe
rc
en
t
su
rv
iv
al
W i l d T y p e P V R I G- / -
T I G I T- / -
P V R I G- / -
T I G I T- / -
A. B16-F10 tumor volume in PVRIG-/-, TIGIT-/- or PVRIG-/-TIGIT-/- double KO mice are represented as the mean volume ± SEM. B. Kaplan-Meier survival curves. C. Individual tumors measurements for each mouse
P=0.0003
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500
1000
1500
2000
Days Post Inoculation
Tu
mo
r V
olu
me (
mm
3)
Isotype mIgG1
-PD-L1 mIgG1
Chimeric COM902
Chimeric COM902 +
-PD-L1 mIgG1
Vehicle (1x PBS)
p = 0.0144
10 15 20 25 300
500
1000
1500
2000
Days Post InoculationT
um
or
Vo
lum
e (
mm
3)
p = 0.032
Vehicle (1x PBS)
Isotype mIgG1
-PVRIG mIgG1
Chimeric COM902
Chimeric COM902 +
-PVRIG mIgG1
0 10 20 300
20
40
60
80
100
Days post when TV >1500 mm3
% S
urv
iva
l
p = 0.012
70%
0 10 20 300
20
40
60
80
100
Days post when TV >1500 mm3
% S
urv
ival
p = 0.0092
80%
A. Tumor volume for the chimeric COM902 (10 mg/kg ) & anti-PD-L1 (3 mg/kg ) combination, or the chimeric COM902 & anti-PVRIG (10mg/kg ) combination are represented as the mean volume ± SEM. B. Kaplan-Meier survival curves for the monotherapy treatments andcombinations (n=10).
B.
B.