VISTA Science Symposium

Presenters: Guest Speaker: John Celebi Prof. Robert Schreiber Chief Executive Officer Andrew M. Bursky and Jane M. Bursky Distinguished Professor of Pathology and Immunology, Professor of Molecular Microbiology and co-leader of the tumor Dr. Robert

Pierce immunology program at the Siteman Comprehensive Chief Scientific Officer Cancer Center, Founding Director of the Center for Human Immunology and Immunotherapy Programs at Dr. Edward van der Horst The Washington University School of Medicine

SVP, TMAb Antibody Development Sensei IOAB member

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AGENDA Speaker Topics John Celebi Welcome/TMAb Mission President

& CEO Professor, Robert Schreiber, Ph.D. VISTA biology Washington University School of Medicine Sensei IOAB member Robert Pierce, M.D. SNS-101 preclinical data Chief Scientific Officer highlights from SITC Edward van der Horst,

Ph.D. Join for Q&A SVP, TMAb Antibody Development 3

Our TMAb (Tumor Microenvironment Activated biologics) Platform Mission

Leverage unique features of the tumor microenvironment to selectively activate biologics that unleash clinically meaningful anti-cancer immune responses 4

The Modern-Day Challenge in Immuno-Oncology Majority of patients

don't respond to PD- 2 Global PD-1/PD-L1 Market 1 1/PD-L1 monotherapy 2026 2020 Survival Benefit 20-30% No Survival ~$90B ~$30B Benefit 70% 1. Gerber et al., Biochemical Pharmacology 2016 2. Market estimates from PD-1 and PDL-1 Inhibitors

Market Size in 2021 - MarketWatch, 360 Research

Two Major Types of Non-Responders to PD-1 Blockade Responders

Non-Responders T-cells Inactive or T-cells Inside Tumor T-cells Absent Outside Tumor Green = T-cells Purple = tumor 6 Adapted from Van der Woulde-LL, et al, Trends in Cancer, 2017

Two Platforms to Unleash Anti-Cancer T-cell Activity TODAY'S

DISCUSSION TMAb (Tumor ImmunoPhage Platform Microenvironment Activated Biologics) Platform Powerfully self-adjuvanted nanoparticle vaccine that drive Next-generation tumor activated tumor-specific T cell mAbs

VISTA (V-domain Ig suppressor of T cell activation) Target Overview:

Established immune checkpoint target to overcome checkpoint resistance Large market opportunity Extensive expression on normal myeloid cells Low pH tumor Sensei's Competitive Advantage: microenvironment Leverage

extensive understanding of VISTA biology to deliver a differentiated approach SNS-101: A fully human monoclonal antibody that selectively binds active (low pH) VISTA, but not inactive VISTA in the blood Potent inhibitor of PSGL-1

binding to VISTA Fc-competent framework to deliver positive "kick" to suppressive myeloid cells in the tumor microenvironment 8

Leveraging a Team with Decades of Experience 9

Dr. Schreiber VISTA Biology VISTA (B7-H5) is recognized an important

immune checkpoint and B7 family member that is expressed on myeloid cells, a hub of immunosuppressive activity, and is activated via binding to its receptor on T-cells (PSGL-1) at sub-physiologic pH

The Promise and Challenge of Immunotherapy Targeting Immunosuppressive

myeloid cells is a promising strategy to overcome resistance to checkpoint Inhibitor therapy THE PROMISE THE CHALLENGE Using the body's own immune system to 70-80% of patients do not achieve increased 1 attack cancer survival

with CPI monotherapy Capitalizing on immunological specificity and The immunosuppressive tumor long-term memory microenvironment (TME) influences response to immune checkpoint blockade Achieving durable cures with minimal

toxicity Innate immune cells such as myeloid cells are a key driver of immunosuppressive TME 11 1 Gerber, et al Biochemical Pharmacology 2016

VISTA Has Emerged as an Important Checkpoint Regulator Target Gao. J.,

et al Yuan, L., et.al

Patients with High Circulating Myeloid Cells Have Shown Lower Overall

Survival When Treated with Checkpoint Blockade Ipilimumab-treated Melanoma Patients Nivolumab-treated Melanoma Patients MDSC 12.65 MDSC low MDSC > 12.65 MDSC high Kitano et al., Cancer Immunol Res. 2012 13 Weber et al., Cancer Immunol

VISTA may be a Compensatory Pathway Following Checkpoint Therapy Can

targeting VISTA augment T-cell checkpoint blockade in refractory tumors? VISTA Increases on Prostate Tumor Cell Prostate Tumor Cell Infiltrates Increase Infiltrates Following Ipilumimab Treatment Following Ipilumimab Treatment Gao et al., Nat Med.

VISTA Expression Increases in PBMC Subsets of Patients with Non-Small

Cell Lung Cancer (NSCLC) 15 Cairns B et al, AACR Annual Meeting 2016.

VISTA Blockade Synergizes With PD-1/L-1 Pathway Inhibition CT26

Syngeneic Tumor Model Liu J. et al. PNAS 2015 16

VISTA is An Emerging Target on Myeloid Cells and Key Resistance

Mechanism for PD-1/PD-L1 Blockade VISTA is a B7 family (e.g., same protein VISTA is a Negative Regulator of T cell family as PD-L1) ligand expressed on Function at Low pH myeloid cells, a hub of immunosuppressive 1 activity T-cell

VISTA is a key player in controlling Myeloid cell checkpoint blockade VISTA has been implicated in resistance to Low pH interaction 2 PD-1/PD-L1 inhibitors 1 Lines et al. Cancer research vol. 74,7 (2014) 17 2 Gao et al. Nature medicine vol.

VISTA is an Emerging Target on Myeloid Cells and Key Resistance

Mechanism for PD-1/PD-L1 Blockade Tumors are typically lower in pH than Tumors are typically lower in pH than normal tissues normal tissues At low pH, key amino acids in VISTA become protonated, changing its Tumor pH ~6-6.5 charge,

and likely, its shape Normal physiological pH This change activates VISTA enabling 7.4 VISTA to bind to PSGL-1 on T cells, engaging its checkpoint function 1 Lines et al. Cancer research vol. 74,7 (2014) 18 2 Gao et al. Nature medicine vol.

The Binding of VISTA to PSGL-1 is pH Dependent Active VISTA Inactive

VISTA 19 Adapted from Gao et al. Nature medicine vol. 23,5 (2017)

Dr. Schreiber VISTA has been difficult to drug due to its unique

VISTA is Expressed at High Levels on Human Monocytes and Neutrophils

Flow Cytometry Analysis of VISTA Expression on Normal Human Peripheral Immune Cells 21 Snyder et al, 2016 AACR Annual Meeting, Oral Presentation

High VISTA Expression on Monocytes and Neutrophils Results in

Sub-Optimal PK and may Decrease the Therapeutic Window Case Study + Antibodies binding VISTA cells CI-8993 Clinical Ongoing Clinical Study (e.g. monocytes) at physiological Phase 1 Dose Escalation Study pH result in rapid elimination

from 12 patients enrolled with advanced refractory solid circulation through targeted- tumors mediated drug disposition Initial dose of 0.005 mg/kg and above Low-grade transient Cytokine Release Syndrome (TMDD) (CRS) seen at

0.15 mg/kg and above Study halted after 1 DLT at sub-therapeutic dose level Efficacious drug occupancy levels may be difficult to reach and potentially narrow the therapeutic window Adapted from Curis Corporate presentation 2021

The VISTA Checkpoint Itself is Only ON Under Low pH Conditions 1

Antibodies that block VISTA histidines H153, H154 and H155 interrupt PSGL-1 binding VISTA's extracellular domain is uniquely 1 rich in histidines PSGL-1 Histidines are protonated at low pH enabling VISTA to distinguish the active (acidic pH)

and inactive (neutral pH) PSGL-1 interface 23 1. Johnston et al., Nature 2019

Engagement of Fc R may be Required for Optimal Activity of

Anti-VISTA Monoclonal Antibodies JNJ-61610588 VSTB140 Fc competent IgG1 Fc silent IgG2 24 Snyder et al., AACR Annual Meeting 2016

Summary Reasons Why VISTA Has Been Difficult to Drug Historically

VISTA is expressed at high levels on monocytes and neutrophils For non-pH-dependent blocking antibodies, high expression on monocytes and neutrophils results in a sub-optimal PK due to target-mediated clearance and may decrease the

therapeutic window The VISTA checkpoint itself is only ON under low pH conditions VISTA's immune checkpoint function is only active (i.e. capable of binding PSGL-1 at low pH) Other receptors for VISTA are active at

physiologic pH but do not appear to function as immune checkpoints Engagement of Fc R may be a prerequisite for optimal activity of anti-VISTA antibodies Fc silent antibodies are not effective at T cell proliferation ex vivo or

anti-tumor activity in vivo despite picomolar binding affinity to VISTA Engagement in the blood may result in untoward "off tumor" activation (i.e. CRS) 25

Dr. Rob Pierce SITC 2021: SNS-101 Preclinical Data Poster

pH-sensitive Antibodies Primarily Bind Their Antibodies in the Low pH

Tumor Microenvironment TMAb Platform The tumor microenvironment of pH 6.0 is lower than Sensei's technology identifies pH-sensitive antibodies physiological pH of 7.4 that bind primarily at the tumor pH 7.4 Antibodies that bind

at physiological pH may encounter a "sink" Prevents effective binding at the tumor and may lead to toxicity pH 6.0 Sensei's technology selectively targets pH-sensitive antibodies to bypass tissue compartments other

than the low-pH tumor microenvironment: pH 6.0 Potential for improved safety and pH 6.0 clinical activity profile 27

SNS-101 Inhibited Interaction of VISTA to its Receptor, PSGL-1, in

CD4/CD8 T-Cells at Low pH 6.0 PSGL-1: VISTA Interaction on primary T-cells at pH 6.0 T-cell PE PSGL-1 VISTA-Bio SA 28 SITC 2021: Poster titled: Antagonistic pH-selective VISTA antibody SNS-101 potentiates anti-PD-1/PD-L1-induced anti-tumor immunity.

CD8 T-cells CD4 T-cells

SNS-101 Identified Based on Stringent Cell-Based Assay Candidate

profile: no significant binding at pH 7.4 pH6.0 29

pH6 SNS-101 Has >600-Fold Selectivity for VISTA Biophysical

characterization demonstrates pH 6.0 pH 7.4 >600-fold selectivity for VISTA at pH 6.0 132 Picomolar binding at low pH Monovalent Affinity (K ) [nM] 0.218 (~No D binding) No significant binding observed at

physiological pH (7.4) pH7.4 pH 6.0 pH-independent pH-dependent pH-dependent pH-independent SNS-101 SNS-101 "benchmark" "benchmark" "benchmark" "benchmark" -1 -1 -1 -1 -1 -1 -1 -1 k = 4.59E+06 M s k =

1.45E+06 M S k = 7.11E+05 M s k = 4.162E+05 M S a a a a -1 -1 -1 -1 K = 1.00E-03 s K = 2.25E-03 S K = 1.78E-04 s K = 9.27E-05 S d d d d K = 2.18E-10 M K = 1.55E-09 M D K = 2.5E-10 M K = 2.23E-10 M D D D [Vista] - 7.5 nmol - 0.2 nmol

[Vista] - 7.5 nmol - 0.2 nmol [Vista] - 15 nmol - 0.2 nmol [Vista] - 15 nmol - 0.2 nmol [Vista] - 15 nmol - 0.2 nmol [Vista] - 15 nmol - 0.47 nmol 30 SITC 2021: Poster titled: Antagonistic

pH-selective VISTA antibody SNS-101 potentiates anti-PD-1/PD-L1-induced anti-tumor immunity. R [RU] R [RU]

+ SNS-101 Does Not Significantly Bind to VISTA Monocytes at pH 7.4

VISTA+ monocytes are one of the main causes of TMDD Non-pH sensitive VISTA mAbs bind to monocytes at pH 7.4 thus allowing TMDD and have potential for on-target/off-tumor toxicity VISTA Copy Number: Kasumi-3: 70,202 CD14+ Monocytes:

Proposed Mechanism of Action for SNS-101 Fc-competent framework is

required for optimal activity, but Fc R engagement in the blood may result in untoward "off tumor" activation (i.e. CRS) Non-pH dependent pH-dependent Monocyte Macrophage Blood Monocyte Peripheral Sink and Activation No Activation

CRS? No CRS Pro-inflammatory Pro-inflammatory Cytokines Cytokines T-cell Macrophage T-cell Macrophage Macrophage Same Macrophage Tumor Macrophage Macrophage Activation Activation Non-pH VISTA PSGL-1 Fc R SNS-101 sensitive mAb 32

High-bar' In Vivo Screening Test of SNS-101 Activity