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Orally Bioavailable Small Molecule CD73 Inhibitor Reverses
Immunosuppression by Reduction of Adenosine Production
(Abstract #1242)
Xiaohui Du ORIC PharmaceuticalsAACR Annual Meeting 4/2020
Disclosure
• Xiaohui Du is an employee of ORIC Pharmaceuticals
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CD73 is required for adenosine production and linked to therapy resistance
3
T cell priming
T cell expansion
T cell activation / cytolytic activity
DC maturation / activation
Macrophage M1 polarization
NK degranulation
Therapeutic Hypothesis
• CD73 inhibition may enhance activity of chemotherapy and immunotherapy
• Small molecule approach may differentiate in dosing regimen and tumor penetration
• Overexpressed across cancer
types driving local elevation of
adenosine
• Overexpression correlated with
poor prognosis
• Mediates immunosuppression
and chemoresistance via
adenosine production
CD73
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Surveying linker region towards exo phosphonate led to novel starting point
4
Biochem IC50 :
Rat PO :
0.52 nM Biochem IC50 :
Rat PO Cmax :Rat PO AUCinf :
25 nM
0.12 µM
0.56 µM*hrNo oral exposure
Biochem IC50 :
Rat PO Cmax :
Rat PO AUCinf :
328 nM
ND
ND
Biochem IC50 :
Rat PO Cmax :
Rat PO AUCinf :
88 nM
ND
ND
Biochem IC50 :
Rat PO Cmax :
Rat PO AUCinf :
29 nM
0.11 µM
0.66 µM*hr
• Replace bisphosphonate motif to reduce overall polar surface area and charge
• Internal-capped phosphonate tolerated; linker length to exo phosphonate important
• Ether-linked phosphonic acid shows early signs of oral bioavailability
Muller J. Med. Chem. 2015, 58, 6248.
Biochem IC50 :
Rat PO :
2996 nM
No oral exposure
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Co-crystal structure of 5 with CD73 provided possible directions for potency
improvement
5
• Can a-substitution further improve potency?
5: IC50 = 29 nM
substitution?
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a-Substitution identified key functional groups to increase potency
6
• The oxygen in CH2OR possibly interacts with CD73
• Disubstituted analogs 21 and 22 are more potent than mono-substituted 8 and 9
10 11 12 13 14
28 559 108 193 387
Compound 6 7 8 9
CD73 IC50
(nM) 11 18 2.4 0.96
H
Compound 15 16 17
CD73 IC50
(nM) 1.3 >5000 97
18 19 20 21 22
10 23 31 0.57 0.53
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Discovery of potent and orally bioavailable CD73 Inhibitor OP-5244
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Compound Structure
Biochem H1568 EMT6 Mouse PO (200mg/kg)
IC50
(nM)
EC50
(nM)
EC50
(nM)
AUCinf
(µM*h)
Cmax
(µM)t1/2 (hr)
1 0.52 - - no oral exposure
AB680* 0.86 3.3 198Clinical trial (IV
formulation)
23
OP-52440.25 0.79 14 45.1 42.2 3.3
24 1.0 10.4 - -
*Bowman C.E. et al, Biochemistry
2019, 58, 3331-3334.
• OP-5244 has comparable potency to bisphosphonic acid series
• OP-5244 shows good oral bioavailability in mouse
Co-crystal structures confirmed key interactions for potency
improvement of OP-5244
8
• CH2OH/CH2OMe H-bonds with Arg 354/395
• Replaced the phosphonate H-bond interactions
OP-5244: IC50 = 0.25 nM
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OP-5244 fully suppresses ADO Production
9
• OP-5244 inhibited ADO production from AMP in tumor cells & CD8+ T Cell (EC50 = 0.22 nM)
• A CD73-targeted antibody incompletely inhibits AMP conversion to ADO
10 -2 100 102 104
0
20
40
60
80
100
CD73-driven Adenosine Production
Concentration (nM)
% m
ax A
den
osin
e
H1568
EMT6
CD8+
T cells
H1568
OP
-52
44
anti-C
D73
mA
b
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OP-5244 rescues immunosuppressive effects of AMP on T cells
10
acti
vate
d
25u
M A
MP
1000
nM
333
nM
111n
M
37
nM
12.3
nM
4.1
nM
0
10
20
30
40
50
60
70
80
90
100
% T
Ce
lls
Pro
life
rati
ng
OP-5244+AMP
OP-5244 rescued CD8+ T cell proliferation and cytokine (IFNg and TNFa) production
in the presence of AMP
T cell proliferation
ac
tiv
ate
d
25
uM
AM
P
10
00
nM
33
3.3
nM
11
1.1
nM
37
.0n
M
12
.3n
M
4.1
nM
0
1000
2000
3000
4000
5000
IFNg
pg
/ml
ac
tiv
ate
d
25
uM
AM
P
10
00
nM
33
3.3
nM
11
1.1
nM
37
.0n
M
12.3
nM
4.1
nM
0
50
100
150
200
250
300
TNFa
pg
/ml
OP-5244+AMP OP-5244+AMP
Cytokines
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OP-5244 reduces tumor size, ADO/AMP ratio and reverses immunosuppression
in vivo
11
Veh
icle
OP-5
244
0
100
200
300
Tu
mo
r V
olu
me (
mm
3)
✱
Veh
icle
OP-5
244
0
5
10
15
20
25
Ra
tio
of
Ad
en
os
ine
/AM
P ✱✱✱✱
Pla
sma
Tumor
0.01
0.1
1
10
Un
bo
un
d C
on
c.
(M
)
EMT6 Cell ADO EC90,unb
Veh
icle
OP-5
244
0
500
1000
1500
Tu
mo
r V
olu
me (
mm
3)
Veh
icle
OP-5
244
0
5
10
1530
35
% C
D8
+ o
f to
tal
CD
45
+
✱
Veh
icle
OP-5
244
0
2
4
6
15
20
25
CD
8 /
Tre
g r
ati
o
✱✱
EMT-6 Murine Breast Cancer Model
in BALB/c Mice
E.G7-OVA Murine T Cell Lymphoma Model
in C57BL6 Mice
• OP-5244 exhibits anti-tumor effects as a single agent
• OP-5244 modulates intra-tumoral adenosine pathway
• OP-5244 activates tumor-mediated immune response
Tumor Size ADO/AMP Modulation Exposure of OP-5244 Tumor Size CD8+/Treg RatioCD8+ Cytotoxic T cells
• OP-5244: 150 mg/kg, BID x 16, PO
• Tumor measurement on Day 15
• TIL analysis on Day 16
• *, p<0.05: **, p<0.01 by t-test
• OP-5244: 15 mg/kg/day mini pump infusion
• Tumor measurement on Day 13
• Tumor adenosine, exposure measurement on Day 13
• *, p<0.05: ****, p<0.0001 by t-test
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Upcoming AACR presentations featuring ORIC-533 development candidate
12
• Poster #10268: An orally bioavailable inhibitor of CD73 reverts intratumoral immunosuppression and
promotes anti-tumor responses
– Significant single agent anti-tumor activity of ORIC-533 associates with reversed immunosuppression
• Poster #4317: CD73 inhibition with a novel orally bioavailable small molecule blocks adenosine production
and rescues T-cells activation in high AMP conditions
0 5 10 15 20
0
500
1000
1500
2000
days post implantation
Tu
mo
r V
olu
me
(m
m3) Vehicle
ORIC-533 150 mg/kg, QD, PO
Tumor Adenosine
Veh
icle
150
mg/k
g
0
100
200
300
400
AD
O C
on
c.
(µM
)
Tumor Growth Inhibition Tumor T Cell Modulation
Veh
icle
150
mg/k
g
0
5
10
15
%CD8+ of CD45+
% o
f C
D45
+
*
Veh
icle
150
mg/k
g
20
40
60
80
100
%Mem/Eff of CD8+
% C
D62L
- of
CD
8+ T
*****
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Conclusions
13
• Designed novel orally bioavailable mono-phosphonic acid CD73 inhibitors
• Ether phosphonic acids with a,a-disubstitution gained additional interactions with CD73
and further potency enhancement
– equipotent relative to the bisphosphonic acid series
• Small molecule CD73 inhibitor represents a potential therapeutic approach to reverse
immunosuppression within the tumor microenvironment
– OP-5244 fully rescues T cell proliferation and cytokine production from ADO-mediated
suppression in vitro
– OP-5244 reduces tumor size, modulates intra-tumoral ADO pathway and reverses
immunosuppression in vivo
– OP-5244 is a prototype for further optimization/clinical candidate identification
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Acknowledgements of the ORIC CD73 team
14
Wayne Kong
Xi Chen
Xiaohui Du
Yuping Chen
Zhensheng Wang
PepTech
Proteros biostructures Gmbh
Jessica Sun
John Eksterowicz
Lori Friedman
Melissa R. Junttila
Natalie Yuen
Qiuping Ye
Tatiana Zavorotinskaya
Todd Metzger
Tom Huang
Valeria Fantin
Bob Warne
Brenda Chan
Brian Blank
Chudi Ndubaku
Daqing Sun
Dena Sutimantanapi
Erica Jackson
Frank Duong
Jae Chang
Jared Moore
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