Surface-tethered IL-12 improves tumor-specific T cell

Confidential | © 2017 Torque

TITLE:

Surface-tethered IL-12 improves tumor-specific T cell therapy and enhances inflammatory activity in tumors without inducing systemic toxicities

AUTHORS: Douglas Jones1, De-Kuan Chang1, Gulzar Ahmad1, Jonathan Nardozzi1, Kate Sackton1, PengpengCao1, Lars Peterson2, Ditte Jaegher2, Esben Christensen2, Jesse Lyons1, Karsten Sauer1, Thomas Andresen1

1Torque Therapeutics, Cambridge, MA USA 2Technical University of Denmark, Copenhagen, Denmark

PRESENTING AUTHOR: Douglas Jones, PhD IL-12 Scientific Program Lead Torque Therapeutics

March 31, 2019

CONFIDENTIALJonathan FitzgeraldTorque Therapeutics



Torque platform is designed to overcome key cell therapy limitationsDeep-Priming harnesses natural T cell biology

surface-anchoredimmunomodulators

natural t cell receptors primed for tumor antigens

Torque Deep-PrimedTM T Cell

T cell

Multi-target, antigen-primed T CellsFor efficacy against heterogeneous tumors

Surface-anchored cytokines / ImmunomodulatorsTo overcome immunosuppression in the tumor microenvironment

High margin of safety • Outpatient, without myeloablative chemotherapy• Enables repeat dosing




D DM T

Torque platform harnesses natural T cell biology with ex vivo process

Antigen cassettes

Isolate cells

Dendritic cellMonocyte

Multi-Target Deep Primed T Cell

1

T cells trained by dendritic cells

Apheresis

2

Surface anchoring

Cytokines/Immunomodulators

T

T

T cell

• Deep IL-15• Deep IL-12• Deep TLR

“Primed”

18 Days




Deep IL-12 delivers controlled dose loading on the T cell surface

Controlled, uniform IL-12 loadingDeep IL-12

VH

CC

H1

VLC

Ck

IL-12B

IL-12A

Deep IL-12 Primed T cell

Humanized anti-CD45 Fab

T cell

TRQ12-01

CD45

IL-12p70

(-) control

Deep IL-12

500 nM

100 nM

20 nM

4 nM

0.8 nM

0.16 nM

Anti-IL-12 MFI

0 nM




Cell-tethered Deep IL-12 delivers superior efficacy Deeper and more durable response than systemic recombinant IL-12

PMEL / B16 melanoma tumor model

In vivo tumor growth inhibition

0 5 10 15 20 25 30 350

500

1000

1500

Days after ACT

Tum

or v

olum

e (m

m3 ) HBSS

PMEL

PMEL / IL12 TF (Preloaded)PMEL + 3.575pmole (250ng) sol rIL12Vehicle

control

PMEL T cells

Deep IL-12 Primed PMEL~150ng IL-12

PMEL + Systemic IL-12250ng IL-12

In vitro cytotoxicity

In vitro B16 melanoma cell killing at 48 hr

Effector:Target ratio

0.1 1 10

% T

um

or

cell

surv

ival

PMEL T cells

Deep IL-12 Primed PMEL

B16-F10

CD8 T cells

Activate

Deep IL-12 tethering

PMEL-1




Deep IL-12 delivers favorable systemic profile

Systemic IL-12IFNg elevation and systemic toxicities

Deep IL-12 Primed T cellsTransient circulating IFNg

Daily systemic IL-12 C57BL6

Day

1

Day

3

Day

7

24h

afte

r 1s

t dos

e

24h

afte

r 3r

d do

se

24h

afte

r 7t

h do

se

0

5000

10000

15000

20000

Pla

msa

IFNγ

(pg/

mL)

Circulating IFNg from 5ug Daily IL-12

Daily IL-12 - 5ug i.p.

Day

1

Day

3

Day

7 0 4 7

80

85

90

95

100

Time (days post ACT)

Bod

y w

eigh

t (%

)

Transform of Mouse weight change - Day 0,4,7

CD45Fab-IL12: 1 dose

Day

0

Day

4

Day

0

Day

4

Day

7

CD

45Fa

b-IL

12: 1

dos

e

CD

45Fa

b-IL

12: 1

dos

e

0500

1000

5000

10000

15000

20000

Pla

sma

IFNγ

(pg/

ml)

P48 Plasma_Day1,4_IFN - update y-ax - Deep only, noCTX

Day 1 Day 4

C57BL6




Deep IL-12 induces immune activation in the tumorUpregulates IFNg, co-stimulation, and MHC expression

Vehi

cle

cont

rol -

tum

or

Pm

el -

tum

or

Pm

el +

250

ng

i.v. I

L12

- tum

or

Pm

el /

chM

1Fab

-IL12

- tu

mor

0

5000

10000

15000

pg /

g tu

mor

Tumor IFNg

Dee

p IL

-12

/ PM

EL~

250n

g IL

-12

Syst

. IL-

12 +

PM

EL50

0ng

IL-1

2

PMEL

Vehi

cle

IFNg

(pg/

mL)

Increased IFNgproduction in the tumor

Activating myeloid-derived suppressor cells(Mo-MDSC) in the tumor

Deep IL-12Primed PMEL

CD86

MC

HII

PMEL Syst. IL-12 + PMEL

9%

54%36%

1% 17%

46%34%

3% 37%

13%27%

23%

Day 4 Mo-MDSC: CD11b+/CD11c-/Ly6GLow/Ly6Chi




Cell-tethered Deep IL-12 drives activity specifically in the tumor

Increased PMEL T cell expansion and activity in tumor No activity in spleen

Day 4 Day 4

HB

SS

5M P

mel

5M P

mel

/125

nM C

D45

Fab-

IL12

0

2000

4000

6000

8000

10000

Pmel

/g tu

mor

p = 0.013

Dee

p IL

-12

/ PM

EL

PMEL

Veh.

con

trol

PMEL

/ g

tum

or

HB

SS

5M P

mel

5M P

mel

/125

nM C

D45

Fab-

IL12

0

5

10

15

% o

f IFN

g+ P

mel

in tu

mor p = 0.002

Dee

p IL

-12

/ PM

EL

PMEL

Veh.

con

trol

%IF

Ng +

of P

MEL

in tu

mor

Dee

p IL

-12

/ PM

EL

PMEL

Veh.

con

trol

%IF

Ng +

of P

MEL

in s

plee

n

HB

SS

5M P

mel

5M P

mel

/125

nM C

D45

Fab-

IL12

0

5

10

15

% o

f IFN

g+ P

mel

in s

plee

n




Memory cell expansionDay 5 cytotoxicity

Deep IL-12 and Deep IL-15 combination further enhance T cell activityLeveraging complementary biology of Deep IL-15 and Deep IL-12

CD62L

CD

44

Eff Naive

EM CM

Dee

p IL

-15

/ PM

EL

PMEL

Dee

p IL

-12

/ PM

EL

Com

bina

tion

Dee

p IL

-15

/ PM

EL

PMEL

Dee

p IL

-12

/ PM

EL

Com

bina

tion

Pm

el

Pm

el+D

eep

IL15

Pm

el+D

eep

IL12

Pm

el+c

o-lo

ad

Pm

el

Pm

el+D

eep

IL15

Pm

el+D

eep

IL12

Pm

el+c

o-lo

ad

0

50

100

150

200

Rel

ativ

e tu

mor

cel

l sur

viva

l

Transpose of MTT-Day5-5000cells per well - rmv 10:1 grp

E:T 1:1

E:T 1:10

% B

16 c

ell s

urvi

val

0 1 2 3 4 50

2

4

6

8

10

Time (days)

T ce

ll fo

ld e

xpan

sion

Fold-expansion of PMEL

Pmel+Deep IL12

Pmel+co-load

Time (days)

Combination

Deep IL-12/PMEL




Torque’s Deep Primed T Cell PipelineThree Phase 1 Programs in 2019

PRODUCTIND

FILINGANTIGEN

TARGETING IMMUNOMODULATORCHECKPOINT

INHIBITORLEAD

OPTIMIZATIONIND-

ENABLING PHASE 1UPCOMING

MILESTONES

TRQ-1501 ✓ Antigen Cassette #1

Deep IL-15Phase 1

underwayDeep IL-15 ✓

TRQ-1502 2019 Antigen Cassette #2

Deep IL-15Phase 1:

4Q19Deep IL-15 ✓

TRQ-1201 2019 Antigen Cassette #1

Deep IL-12

Phase 1:4Q19

Deep IL-12Deep IL-15

Deep IL-12Deep IL-15 ✓

TRQ-TLR 2020 TBD Deep TLR Candidate:2019

Solid & hematologic

tumors

Solid &hematologic

tumors

Solidtumors

ANTIGEN & IMMUNOMODULATORCOMBINATIONS

è è

Combo

Combo




Torque Therapeutics • Gulzar Ahmad, PhD • De-Kuan Chang, PhD• Jonathan Nardozzi, PhD • Kate Sackton, PhD • Pengpeng Cao, PhD • Jesse Lyons, PhD • Karsten Sauer, PhD • Thomas Andresen, PhD

Technical University of DenmarkAPC profiling in TME• Lars Peterson, PhD • Ditte Jaegher• Esben Christensen

AcknowledgementsCONFIDENTIAL

Jonathan FitzgeraldTorque Therapeutics



Surface-tethered IL-12 for T cell cancer immunotherapy

AACR Annual Meeting 2019



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Surface-tethered IL-12 improves tumor-specific T cell