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CONFIDENTIAL| © 2019CONFIDENTIAL| © 2019
A Novel Class of NK-Cell Engagers Targeting NKp30
Monia Draghi, PhDCompass Therapeutics, Cambridge, MA-USA
1
CONFIDENTIAL| © 2019
Compass Therapeutics’ NK Cell Engager Platform
2
§ Rapid, first responders§ Highly potent§ Versatile target killing ability§ Critical immune system mediators
Functions of NK cells
Green: live Multiple Myelomatumor cells
Compass’ lead NK cell engager demonstrates highly
efficient tumor cell killing
E:T ratio (2:1)
Effectors = primary NK cellsTargets = MM1R cells
Time 0
CONFIDENTIAL| © 2019
Components of Optimized NK Engagers
3
NK
Tumor
CD16
NK-RNK-R
LigandTAA
1
23
4
NK-R
TAA
IgG1
1. Specifically target 1 or more tumor associated antigens (TAA’s) to localize activity and reduce toxicity
2. Optimally engage CD16a through Fc to drive effective ADCC response
3. Trigger signaling of additional NK activating receptors to synergistically amplify CD16a response or maintain activity after CD16a downregulation
4. Inhibit checkpoint pathways to prevent NK cell suppression
CONFIDENTIAL| © 2019
Compass’ Novel Anti-NKp30 Bispecific Platform
4
Comprehensive antibody discovery
NK-R
BCMA
IgG1
Panel of StitchMabs™ and CLC bispecifics Ø Better activity than anti-BCMA monoclonal
Ø Activity does not require CD16a engagement
Anti-NKp30 bispecific identified as superior
Empirical Discovery of Optimal Bispecific NK Engagers
CTX-4419
BCMA [B cell maturation antigen]
§ Restricted expression in plasma cells
§ Expressed in malignant cells from untreated and relapsed
multiple myeloma (MM) patients
§ Despite several drugs have improved patient survival, MM
remains an unmet medical need
TAA
NK-R
CONFIDENTIAL| © 2019 5
NKp30 is a Potent Activating Receptor Expressed on NK cells and Other Effector Cells
Moretta A. et al., Ann Rev Immunol, 2011
• NKp30 is a potent activating receptor on NK cells
• Expressed on NK cells and subsets of effector T-cell populations such as γδ T cells
• Known roles in tumor control and pathogen clearance
Compass NK cells engagers activate CD16+ and CD16- NK cells
CD3
TCR gd
27%19%
FSC
NKp30
NKp30 is expressed on gd T cells in the bone marrow of MM patients
0 . 0 0 0 1 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0
0
2 0
4 0
6 0
8 0
1 0 0
t a r g e t s : R P M I - 8 2 2 6
C o n c e n t r a t i o n ( n M )
% s
pe
cif
ic l
ys
is
C T X 4 4 1 9
B C M A - I g G 1 ( m A b )
H e r 2 - I g G 1
CD16neg NK cells (KHYG-1) tested towards BCMApos tumor cellsBCMA
NKp30
IgG1
IgG1
BCMA
NKp46 NKp30 NKp44
NKp30
CD16
A
NK cells from BM of MM patient
CONFIDENTIAL| © 2019
In vitro potency of CTX-4419
6
CTX-4419 Induces Potent NK Cell Killing of Target Cells%
mye
lom
a ce
ll ki
lling
N K p 3 0 N K G 2 D C D 1 6 A
0
2 0
4 0
6 0
8 0
1 0 0
% p
os
NK
ce
lls
H929 MM.1S RPMI-8226
<100,000 ~100-30,000 >30,000
n/a Targets: RPMI-8226
NK cells in bone marrow of MM patients
0 . 0 0 0 1 0 . 0 0 1 0 . 0 1 0 . 1 1 1 0 1 0 0
0
2 0 0
4 0 0
6 0 0
8 0 0
C o n c e n t r a t i o n ( n M )
IFN
g (
pg
/mL
)
C T X - 4 4 1 9
B C M A - I g G 1 m A b
I s o t y p e
CTX-4419 induces potent killing of autologous myeloma cells from
MM patients
§ Better potency than BCMA-IgG1 mAb§ Potent activity towards targets cells with high, medium
& low BCMA
CT
X- 4
41
9
BC
MA
- I gG
1 m
Ab
CT
X- 4
41
9
BC
MA
- I gG
1 m
Ab
CT
X- 4
41
9
BC
MA
- I gG
1 m
Ab
- 1 0 0
0
1 0 0
2 0 0
3 0 0
4 0 0
EC
50
(p
M)
CONFIDENTIAL| © 2019 7
CTX-4419 Does Not Activate NK Cells in the Absence of BCMA Expressing Target Cells
Primary NK cells, H929 target cells, 10 nM antibody
NK
+ H
92
9
NK
al o
ne
0
1 5 0
3 0 0
4 5 0
6 0 0
7 5 0
9 0 0
IFN
g (
pg
/mL
)
C T X 4 4 1 9
B C M A - I g G 1 ( m A b )
0. 0
00
1
0. 0
01
0. 0
10
. 1 11
0
0
1 0
2 0
3 0
4 0
5 0
6 0
C o n c e n t r a t i o n o f C T X 4 4 1 9 ( n M )
% p
os
itiv
e N
K c
ell
s
C D 1 3 7
C D 6 9
N K + H 9 2 9
N K i n t h e a b s e n c e
o f t u m o r
0. 0
00
00
1
0. 0
00
1
0. 0
1 11
00
0
1 0
2 0
3 0
4 0
5 0
A n t i b o d y C o n c e n t r a t i o n ( n M )
tu
mo
r l
ys
is (
%)
Targets: JeKo-1~5,000 BCMA copies/cell
Targets: HL-60BCMA negative
Opportunity for Better Safety Profile Compared to Other Cell Engagers
CONFIDENTIAL| © 2019
Single Dose of CTX-4419 Potently Depletes Immunoglobulin-Secreting Cells in Bone Marrow of Cynomolgus Monkeys and Decreases Serum IgM levels
8
- 1 6 1 3 2 0 2 7 3 4 4 1 4 8 5 5
0
2 0
4 0
6 0
8 0
1 0 0
1 2 0
1 4 0
1 6 0
D a y s
Se
ru
m I
gM
(%
)
A K 7 4 9 J
B 6 0 1 6
0 1 0 2 0 3 0 4 0
0
2 5 0
5 0 0
7 5 0
1 0 0 0
5 0 0 0
1 0 0 0 0
D a y s p o s t t r e a t m e n t
Ig
s
ec
re
tin
g
ce
lls
pe
r
1
mil
lio
n
to
ta
l c
ell
s T o t a l I g
I g G
I g M
I g A
0 1 0 2 0 3 0 4 0
0
2 5 0
5 0 0
7 5 0
1 0 0 0
5 0 0 0
1 0 0 0 0
D a y s p o s t t r e a t m e n t
Ig s
ec
re
tin
g c
ell
s
pe
r 1
mil
lio
n t
ota
l c
ell
s
CTX-4419 displays IgG-like PK in cynomolgus monkey
Animal #AK749J Animal #B6016
CONFIDENTIAL| © 2019
Compass’ NK Engager Platform Summary
9
Ø Key properties of CTX-4419, a first-in-class NKp30xBCMA bispecific§ Potent - Enhances ADCC, cytokine production, and NK-cell proliferation compared to monoclonal antibodies§ Large therapeutic window - Active against target cells with wide range of antigen expression, but no activity in the
absence of target§ Resistant to CD16a downregulation - Activates NK cells in the absence of CD16a engagement § Highly manufacturable - Monoclonal-like drug-like properties and pharmacokinetics§ Flexible format – Common-LC format amenable to multi-TAA or multi-NKR targeting§ Potential to target additional effector cell types
Ø CTX-4419 induces potent depletion of plasma cells in cynomolgus monkeys
Ø Compass’ highly modular platform has the potential to tailor TAA and NK cell receptors to target multiple indications
CONFIDENTIAL| © 2019
Acknowledgments
10
William McConaughyBeata BobrowiczSujan LamaNiharika KuraDalton Markrush
Jason E. GoetzmannKenneth RogersFrancois Villinger
Thank you !
Immunology-Immunopharmacology
Allison NelsonJamie SchaferNaomi MaymanRobert Tighe
Antibody Discovery & Engineering-Protein Sciences
Jennifer Watkins-YoonSara HaserlatAmanda OliphantJason LajoieMichael SchmidtPiotr Bobrowicz
Poster # 1010- Monday -March 25, 2019
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