Preparation of a clinical trial with a-TIGIT antagonist antibody EOS-448, which demonstrates potent preclinical activity and safe toxicology profile

Thi Lien-Anh Nguyen1, Julia Cuende1, Lucile Garnero1, Virginie Rabolli1, Noemie Wald, Julie Preillon1, Catherine Hoofd1, Patricia Chevron1, Marjorie Mercier1, Olivier De Henau1,

Veronique Bodo1, Gregory Driessens1

1. iTeos Belgium SA, Gosselies, Belgium

1

Author Disclosure Information

• All authors are (or were former) employee of iTeos Therapeutics SA

2AACR-Abstract # 3720 - June 2020 – Do Not Post

Multiple Mechanisms of Action of EOS-448 to Restore Antitumor Immunity

AACR-Abstract # 3720 - June 2020 – Do Not Post

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2

3

1 EOS-448 blocks TIGIT, increasing the availability of CD155/CD112 to bind to CD226 receptor, without competition. This blocks the activation of TIGIT’s immunosuppressive function and activates anti-tumor immune cells.

2 Tumor destruction can lead to cross presentation of antigens by Antigen Presenting Cells (APCs) to T cells and augmentation of the immune response.

T cells or NK cells

1Tumor

cell

EOS-448

CD155 CD226

TIGIT

FCɣR

Tregcell

NK cell

TUMOR ANTIGENS

Tumor-specificT cells

Macrophage

FCɣR

EOS-448TIGIT

3 Regulatory T cells (Tregs) inhibit the anti-tumor function of cytotoxic T cells. EOS-448 binds to TIGIT which is highly expressed on the surface of Tregsand stimulates NK cells and macrophages mediated cytotoxicity via FcɣRengagement.

4 NK and macrophage activation stimulates the release inflammatory cytokines that signal and activate other immune cells to further augmentthe anti-tumor response.

Dead tumor cells

Antigen-Presenting Cells (APCs)

T CELL ACTIVATION

ENHANCED IMMUNE RESPONSE

MECHANISM 1:EOS-448 blocks the TIGIT receptor, enhancing anti-tumor activity,and the death of tumor cells further augments the immune response.

MECHANISM 2:EOS-448 depletes immunosuppressive Treg cells, and EOS-448 stimulates cytokines to activate more immune cells.

T

T

NK

TNK

T

NK

T

3

Gastr

icLu

ngRe

nal

Pros

tate

Blad

der

Panc

reas

Uteru

s

Brea

st

Head

/neck

0

2

4

6

8

% C

D22

6+ a

rea n=307

Panc

reas

Pros

tate

Kidn

ey

Gastr

icCo

lon

Blad

derLu

ng

HNSC

C

Brea

st

Cervi

x0

20

40

60

80

100

% o

f CD

155h

igh

cells n=284

-6 -4 -2 0 2 4

0

1000

2000

3000

4000

Log Inhibitor concentration (nM)

Me

an

Fluo

resc

enc

e In

tens

ity

CD

155

bin

din

g to

Jur

kat h

TIG

IT

EOS884448

Mereo

Genentech

Merck

BMS

Arcus

Log inhibitor concentration (nM)

Mea

n Fl

uore

scen

ce In

tens

ity

CD

155

bind

ing

to J

urka

t hTI

GIT

EOS-448 has a Competitive Profile with Potential for Benefit in a Broad Range of Cancer Indications

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Expression of TIGIT mRNA in solid and heme cancers CD155 protein is highly expressed in solid tumors

CD226 protein is expressed on immune-infiltrating cells

AACR-Abstract # 3720 - June 2020 – Do Not Post

CD155 competition IL2 promoter activationSequences from :• Mereo = 313M32 from

US2016/0376365 A1• Genentech = 4.1D3 from

WO2017/053748 A2• BMS = 22G2 from

US2016/0176963 A1• Merck = Clone 31C6

from WO2016/028656vA1

• Arcus = TIG1 from WO2017/152088 A1

Members of TIGIT pathway are highly expressed in many cancer indications

Immunomodulatoryactivity of EOS-448:Potent competitive profile

Blood Cancers Solid Cancers

EOS-448MereoGenentechBMSMerckArcus

TIGIT is expressed in high proportion of circulating CD8+ & Treg cells in cancer patients, with highest density on Tregs TILs

EOS-448 shows preferred cytotoxicity on Tregs and TIGIT+ TILs are dysfunctional

Tregs, Particularly TILs, Express the Highest Level of TIGIT, Making Tregs a Preferred Target for Depletion by EOS-448

Highest number of TIGIT molecules on Treg from TME

Preferred Treg cytotoxicity of EOS-448

TIGIT

Rece

ptor

s / c

ell

Increased frequency of TIGIT+ T cells in cancer patients

TIGIT-expressing TILs are dysfunctional

AACR-Abstract # 3720 - June 2020 – Do Not Post5

CD3+CD4+ non-Treg cells Treg cells CD3+CD8+ T cells

0

50

100

150

% o

f TIG

IT p

ositi

ve c

ells

HD PBMCs (n=10)

Cancer pt PBMCs (n=12)

DTC TILs (n=12)

% T

IGIT

-Pos

itive

Cel

ls

HD PBMCs (n=10)Cancer pt PBMCs (n=12)DTC TILs (n=12)

TIG

IT M

olec

ules

/ C

ell

HD PBMCs (n=9)Cancer pt PBMCs (n=9)Cancer TILs (n=9)

% o

f spe

cific

lysi

s(o

n ga

ted

imm

une

popu

latio

n)

Fill level 1

CD4+ TIGIT+ CD8+ TIGIT+ CD4+ TIGIT+ CD8+ TIGIT-+++

+-

---

++-+

+--

-

+

+-

+

-

-

+-

IFN𝜸 IL-2 TNF𝜶

FcɣR Engagement is Critical for Anti-Tumor Activity of a-TIGIT Ab in CT26 Colon Cancer Model

Antitumor activity correlates with:• increased in IFNɣ CD4+ and CD8+ T cells

within TME• decreased proportion of Treg within TME• Long-term memory response

High FcɣR-engaging isotype in WT mice

High FcɣR-engaging isotype in FcɣR KO mice

Low FcɣR-engaging isotype in WT mice

High FcɣR-engaginga-TIGIT

Low FcɣR-engaging a-TIGIT

CtrlHigh FcɣR-engaginga-TIGIT

Low FcɣR-engaginga-TIGIT

Ctrl

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EOS-448 demonstrates strong antitumor activity as single agent & in combination with anti-PD-1 Ab, that is fully dependent on FcɣR engagement

EOS-448 efficacy correlates with increased proportion of IFNɣ+ TILs and Treg depletion in the TME

AACR-Abstract # 3720 - June 2020 – Do Not Post

COMPLETE RESPONSE(7 out of 8 mice) M

edia

n Tu

mor

Vol

ume

(mm3 )

Time (days)Time (days)Time (days)

Med

ian

Tum

or V

olum

e (m

m3 )

Med

ian

Tum

or V

olum

e (m

m3 )

p

Clean GLP toxicity profile in cynomolgus ü Well tolerated at all tested dosesü No abnormalities during dosing phase and recovery examinationsü Classical IgG1 PK profile à NOAEL* =HNSTD° = 10mg/kg

Ongoing Phase 1/2 Trial & ongoing preparation of Phase 2 expansions

Cyno GLP Tox Shows Classical hIgG1 PK Profile for EOS-448 and Clean Safety Profile with NOAEL* at Highest Tested Dose (10mg/kg)

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PK (after 1st dose)

Single AgentDose Escalationto Define RP2D

Advanced solid tumor patients (n=30) (NCT04335253):

• Multicenter, open label

• Flat dose infusion

• Mandatory pre- & on-treatment biopsy

Presenter: G. DriessensInfo: G. Driessens, iTeos Belgium SA, Gosselies, Belgium - gregory.driessens@iteostherapeutics.com

*NOAEL = No Observed Adverse Effect Level

°HNSTD = highest non severely toxic dose

AACR-Abstract # 3720 - June 2020 – Do Not Post

0 50 100 150 200

0.1

1

10

100

1000

Timepoint (h)

EOS8

8444

8 (u

g/m

l)

LLOQ

10mg/kg

1mg/kg

0.1mg/kgEO

S-44

8 (u

g/m

l)

Timepoint (h)0 1 2 24 48 72 96 120 144 168 192

0

20

40

60

80

100

Time post 1st dosing (h)

% R

O o

n TI

GIT

+ CD8

b+

CD8 receptor occupancy Male individuals (Mean ± SEM)

Untreated (n=3)

0.1mg/ml (n=3)

1mg/kg (n=3)

10mg/kg (n=5)

% R

O o

n TI

GIT

+ CD

8b+

Time post 1st dosing (h)

Receptor occupancy assay (after 1st dose)

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