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

AACR-Abstract # 3720 - June 2020 – Do Not Post 2 Multiple Mechanisms of Action of EOS-448 to Restore Antitumor Immunity

MECHANISM 1: MECHANISM 2: EOS-448 blocks the TIGIT receptor, enhancing anti-tumor activity, EOS-448 depletes immunosuppressive Treg cells, and EOS-448 stimulates and the death of tumor cells further augments the immune response. cytokines to activate more immune cells.

2

Dead 3 NK cell NK tumor T EOS-448 cells TUMOR FCɣR T NK TIGIT Treg NK - TIGIT EOS-448 CD155 CD226 Presenting T Cells (APCs) FCɣR T CELL 4 ACTIVATION 1 Tumor- Tumor T cells or T specific ENHANCED IMMUNE cell NK cells T cells RESPONSE

1 EOS-448 blocks TIGIT, increasing the availability of CD155/CD112 to bind to 3 Regulatory T cells (Tregs) inhibit the anti-tumor function of cytotoxic T cells. CD226 receptor, without competition. This blocks the activation of TIGIT’s EOS-448 binds to TIGIT which is highly expressed on the surface of Tregs immunosuppressive function and activates anti-tumor immune cells. and stimulates NK cells and mediated cytotoxicity via FcɣR engagement. 2 Tumor destruction can lead to cross presentation of antigens by Antigen Presenting Cells (APCs) to T cells and augmentation of the immune 4 NK and macrophage activation stimulates the release inflammatory response. cytokines that signal and activate other immune cells to further augment the anti-tumor response. AACR-Abstract # 3720 - June 2020 – Do Not Post 3 EOS-448 has a Competitive Profile with Potential for Benefit in a Broad Range of Cancer Indications

Expression of TIGIT mRNA in solid and heme cancers CD155 protein is highly CD226 protein is expressed expressed in solid tumors on immune-infiltrating cells Blood Cancers Solid Cancers 100 8 n=284 80 n=307 6

Members of TIGIT cells area

high 60 pathway are highly + expressed in many 4 40 cancer indications

% CD226 2 20 % of CD155

0 0

Colon Lung Lung Renal KidneyGastric BreastCervix UterusBreast Prostate Bladder HNSCC Gastric Bladder Pancreas Prostate Pancreas Head/neck

IL2 promoter activation CD155 competition EOS884448 4000 EOS-448 Sequences from : Mereo • Mereo = 313M32 from Mereo US2016/0376365 A1 3000 Genentech Genentech • Genentech = 4.1D3 from Immunomodulatory WO2017/053748 A2 activity of EOS-448: 2000 Merck BMS • BMS = 22G2 from Potent competitive BMS Merck US2016/0176963 A1 • Merck = Clone 31C6 profile 1000 Arcus Arcus from WO2016/028656vA1 0 • Arcus = TIG1 from

Mean Fluorescence Intensity WO2017/152088 A1 CD155 binding to Jurkat hTIGIT MeanFluorescence Intensity

CD155 binding to Jurkat hTIGIT Jurkat to binding CD155 -6 -4 -2 0 2 4 LogLog inhibitor Inhibitor concentration concentration (nM) (nM) 4 AACR-Abstract # 3720 - June 2020 – Do Not Post Tregs, Particularly TILs, Express the Highest Level of TIGIT, Making Tregs a Preferred Target for Depletion by EOS-448

Increased frequency of TIGIT+ T cells in cancer patients Highest number of TIGIT molecules on Treg from TME

150 HD PBMCs (n=9) HD PBMCs PBMCs (n=10) (n=10) TIGIT is expressed in Cancer pt PBMCs (n=9) Cancer pt PBMCs pt PBMCs (n=12) (n=12) high proportion of Cancer TILs (n=9) DTC TILs TILs (n=12) (n=12) circulating CD8+ & 100 Treg cells in cancer patients, with Positive Cells Positive - highest density on 50 Tregs TILs % of TIGIT positive cells TIGIT Molecules / Cell / Molecules TIGIT % TIGIT %

0 cell / Receptors TIGIT

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

Preferred Treg cytotoxicity of EOS-448 TIGIT-expressing TILs are dysfunctional

EOS-448 shows CD4+ TIGIT+ CD8+ TIGIT+ IFN� IL-2 TNF� CD4+ TIGIT+ CD8+ TIGIT- preferred + + + + + - cytotoxicity on Fill le + - + Tregs and TIGIT+ ve - + + TILs are l 1 + - - dysfunctional - + - - - +

% ofspecific% lysis - - -

(ongated immune population) 5 AACR-Abstract # 3720 - June 2020 – Do Not Post FcɣR Engagement is Critical for Anti-Tumor Activity of a-TIGIT Ab in CT26 Colon Cancer Model

High FcɣR-engaging isotype Low FcɣR-engaging isotype High FcɣR-engaging isotype in WT mice in WT mice in FcɣR KO mice ) ) 3 3 ) 3 EOS-448 demonstrates strong antitumor activity as single agent & in combination with anti-PD-1 Ab, that is COMPLETE fully dependent on RESPONSE FcɣR engagement (7 out of 8 mice) Median Tumor Volume (mm Median Tumor Volume (mm Median Tumor Volume (mm

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

EOS-448 efficacy correlates with Antitumor activity correlates with: increased proportion of IFNɣ+ TILs and • increased in IFNɣ CD4+ and CD8+ T cells Treg depletion in the within TME TME • decreased proportion of Treg within TME p<0.001 • Long-term memory response Ctrl Low FcɣR- High FcɣR- Ctrl Low FcɣR- High FcɣR- engaging engaging engaging engaging a-TIGIT a-TIGIT a-TIGIT a-TIGIT 6 AACR-Abstract # 3720 - June 2020 – Do Not Post Cyno GLP Tox Shows Classical hIgG1 PK Profile for EOS-448 and Clean Safety Profile with NOAEL* at Highest Tested Dose (10mg/kg)

st PK (after 1 dose) ReceptorCD8 receptor occupancy occupancy assay st 1000 Male(after individuals 1 (Meandose) ± SEM) Single Agent 100 Dose Escalation

+ Untreated (n=3) 100

+ 80 10mg/kg 0.1mg/ml (n=3) to Define RP2D CD8b + CD8b 10 + 60 1mg/kg (n=3)

448 (ug/ml) 448 1mg/kg Advanced solid tumor - 10mg/kg (n=5) 40 patients (n=30)

EOS884448 (ug/ml) 1 EOS 0.1mg/kg (NCT04335253):

LLOQ % RO on TIGIT 20

0.1 ROon% TIGIT • Multicenter, open 0 0 50 100 150 200 label 0 1 2 24 48 72 96 120 144 168 192 TimepointTimepoint (h) (h) TimeTime post post 1 1stst dosingdosing (h) (h) • Flat dose infusion

Clean GLP toxicity profile in cynomolgus • Mandatory pre- & on- *NOAEL = No Observed ü Well tolerated at all tested doses Adverse Effect Level treatment biopsy ü No abnormalities during dosing phase and recovery examinations °HNSTD = highest non ü Classical IgG1 PK profile à NOAEL* =HNSTD° = 10mg/kg severely toxic dose

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

Presenter: G. Driessens Info: G. Driessens, iTeos Belgium SA, Gosselies, Belgium - [email protected] 7 AACR-Abstract # 3720 - June 2020 – Do Not Post