Conditionally Active Antibodies for Immuno-oncology NOVEMBER 2022 | Nasdaq: SNSE Exhibit 99.2
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Engineered Selectivity to Extend the Reach of Immuno-oncology Agents THE CHALLENGE Systemically delivered I/O drugs often fail in the clinic due to on-target/off-tumor effects (TMDD, CRS) OUR FINANCIAL POSITION Ended 3Q 2022: $116.6M* Cash runway into Q1 2025 OUR STRATEGY Conditionally active antibodies engineered to enable druggability of promising oncology targets OUR LEAD PROGRAM SNS-101 is a pH-sensitive antibody targeting the VISTA receptor with IND expected H1 2023 *Consists of cash, cash equivalents and marketable securities
Innovative Pipeline of IO Drugs with Broad Commercial Potential Program (Target) Indication Discovery IND-enabling Phase 1 / 2 Clinical SNS-101 (VISTA) SNS-102 (VSIG4) SNS-103 (ENTPDase1/CD39) Solid Tumors Solid Tumors Solid Tumors
The Modern-Day Challenge in Immuno-Oncology The PD-1/PD-L1 market is big and growing fast1 PD-1/PD-L1 monotherapy does not benefit 70% of patients2 2020 2026 Survival Benefit 20-30% No Survival 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
Lack of Selectivity is a Major Obstacle to CI Innovation Industry Problem Sensei’s Solution Conventional antibodies target immune checkpoints that are highly expressed in normal tissues, resulting in: Dose-limiting toxicities due to on-target/off-tumor action Pharmacological sink effect requires higher and more frequent dosing Suboptimal activity due to poor PK and dose-limiting toxicities Conditionally active antibodies are selectively targeted to the tumor microenvironment, potentially providing: Little or no toxicity due to selective on-target/on-tumor action Lower and less frequent doses by avoiding normal tissue binding Powerful activity selectively focused on the tumor microenvironment Only one new checkpoint inhibitor has been approved since the original CTLA-4 and PD-1/PD-L1 group Ipilimumab (anti-CTLA-4) Pembrolizumab (anti-PD-1) Relatlimab (anti-LAG-3) 2011 2014 2022
pH-sensitive Antibodies Have Potential to Selectively Bind Their Targets in the Low-pH Tumor Microenvironment Exploits the tumor microenvironment using pH-selective properties Intended to alleviate undesirable properties: Dose-limiting toxicities due to on-target/off-tumor binding Higher and more frequent dosing due to poor pharmacokinetics (Target-mediated Drug Disposition (TMDD)) Bolsters specific activities Goal is to unlock previously undruggable immune targets TMAb Platform Sensei’s technology identifies pH-sensitive antibodies designed to bind only at the tumor The tumor microenvironment of pH ~6 is lower than physiological pH of 7.4
SNS-101
VISTA: A Potent T cell Checkpoint Extensively Expressed on Myeloid Cells1 1. Lines et al. Cancer research vol. 74,7 (2014) VISTA is a B7 family member that suppresses T cell function T-cell proliferation & activation
The VISTA:PSGL-1 Interaction is Selective for low pH Data are based on in vitro assay.
VISTA Checkpoint is Activated at the Low pH of the Tumor Microenvironment 1. Johnston et al., Nature 2019 VISTA extracellular domain is uniquely rich in histidines¹ Protonated VISTA histidines are required for PSGL-1 binding1
SNS-101: Selectively Targeting VISTA with a pH-sensitive Antibody pH 6.0 pH 7.4 Monovalent Affinity (KD) [nM] 0.218 132 (~No binding) Key features Selectivity for Active VISTApH6 over VISTApH7.4 Designed to block VISTA’s interaction with PSGL-1 and all other T-cell receptors at pH 6.0 IgG1 format Active Fc Development milestones Preclinical PK, safety and efficacy data presented at conferences throughout 2022 IND submission planned for 1H23
SNS-101 Is a Fully Differentiated Anti-VISTA Antibody Preclinical Phase 1 Phase 1 Phase 1 Preclinical Preclinical Preclinical (IgG1) (IgG1) (IgG1) (IgG4) (IgG1) Johnston et al., Nature 2019; Kineta website; Snyder et al, AACR Annual Meeting 2016; Pierre Fabre website; Hummingbird website; Thakkar et al, J of Immunother Cancer, 2022; PharmAbcine website
SNS-101 Strongly Inhibits the VISTA:PSGL-1 Interaction And All Other Potential Binding Partners at pH 6.0 in In Vitro Assay Receptor IC50 [nM] PSGL-1 7 VSIG3 6 VSIG8 6 Syndecan-2 6 LRIG1 6
No Significant Binding of SNS-101 to Monocytes, Neutrophils, NK Cells and T-cells in Whole blood at Physiological pH T-cells NK cells FOB 1.57 FOB 2.0 FOB 1.0 FOB 8.75 FOB 12.4 FOB 1.36 Monocytes FOB 9.9 FOB 13.5 FOB 1.4 FOB 2.2 FOB 2.5 FOB 1.0 Neutrophils CYNO HUMAN FOB 7.4 FOB 8.8 FOB 1.0 Clinical mAb #1 Clinical mAb #2 SNS-101 Control FOB 2.0 FOB 2.0 FOB 0.5 Clinical mAb #1 Clinical mAb #2 SNS-101 Control FOB 1.66 FOB 1.9 FOB 0.95 FOB 9.7 FOB 10.7 FOB 1.31
SNS-101 Induced Substantially Lower Cytokine Release in Whole-blood Assay at Neutral pH Compared to pH-independent VISTA Antibody IFN-γ IL-8 TNF-α IL-6 IL-2 *** *** *** ** * ** ** ** ** ** ** ** ** ** ** Dose ranges: 1, 10, and 100 ug/ml #2
SNS-101 Has Displayed a Favorable Single-dose PK Profile in Preclinical Studies - No Significant TMDD in Human VISTA KI Mice or Cyno Monkeys Pharmacokinetics of Single Dose 5 mg/kg SNS-101 in VISTA Knock-in Mice Demonstrated a long mean residence time in the blood, indicating a lack of significant target-mediated drug disposition (TMDD) and clearance in non-malignant tissues Week 1 Week 2 Week 3 Week 4 Tumor (MB49) in VISTA KI mice VISTA KI mice No Target WT mice SNS-101 displays linear elimination kinetics unlike a pH-independent anti-VISTA mAb, which demonstrates TMDD and rapid clearance Pharmacokinetics of Single Dose SNS-101 in Cyno monkeys Clinical mAb #1 10 mg/kg
SNS-101 Demonstrated Strong Combinatorial Activity with Anti-PD-1 in MC38 Model in Human VISTA Knock-in Mice SNS-101 0/10 PD-1 Mono 1/10 Combo 5/10 Isotype Control 0/10 *** ** ** * P<0.05; ** P<0.01; *** P<0.001 *
SNS-101 Demonstrated Increased CD8 T-cells in Combination With Anti-PD-1 in MC38 Tumors In Vivo CTRL Anti-PD-1 1mg/kg 5mg/kg Anti-PD-1/SNS-101 3mg/kg 10mg/kg 30mg/kg Frequency of Live, CD45+ Population One-way ANOVA, Tukey Post-Hoc Analysis, * p<0.05; ** p<0.01, *** p<0.001, **** p<0.0001 with Anti-PD-1 with Anti-PD-1 α
SNS-101 Re-sensitized Anti-PD-1 Insensitive Sarcomas Tumors in 1956 Model in Human VISTA Knock-in Mice 5/8 CR 1/8 CR * p<0.05
Preliminary SNS-101 Phase 1/2 Study Schematic 2 Phase 1 Dose Escalation Monotherapy Projected Scheme * Phase 2 Cohort Expansion *** *** Tumor types, indication and samples size to be determined based on findings from dose-escalation phase and emerging scientific data; cohorts may run concurrently. Phase 1 Dose Escalation Combination Projected Scheme * Monotherapy RP2D** Combination RP2D** Expansion Cohort A Expansion Cohort B Expansion Cohort X . . . Mono Cohort A Mono Cohort B Mono Cohort X Combo Cohort A Combo Cohort B Combo Cohort C * Phase 1/2 study design is preliminary and subject to change, including based on feedback from the FDA following submission of IND. ** RP2D = Recommended Phase 2 Dose
VSIG-4
VSIG4 is an Immunosuppressive Receptor Expressed On- and Off-tumor See references in Appendix A B Tissue macrophages (Kupffer cells) in liver Tumor-associated macrophages in tumor and stroma (inset) In the liver, VSIG-4 … Is expressed on Kupffer cells Appears to drive significant target-mediated drug disposition (TMDD) and clearance In the tumor microenvironment, VSIG-4 … Correlates with immunosuppressive "M2" macrophage infiltration Inhibits T cell activation Promotes tumor growth based on data from a syngeneic Lewis lung carcinoma model in knockout mice
Sensei Has Identified pH-sensitive VSIG4 Antibodies pH-Sensitive VSIG4 Parental Antibodies Selected for Further Optimization Antibody Reference # Ratio of pH Selectivity (6.0 vs 7.4) Blockage of Immobilized VSIG4- T-cell Inhibition Blockage of Cellular VSIG4- T-cell Inhibition 1 1 + + 2 7 + + 3 1 + + 4 3 + + 5 3 +/- + 6 25 + + 7 1 + + 8 2 - + * Ratio assessed by flow cytometry on VSIG4 overexpressing cells As of August 2022, Sensei has: Identified 8 parental antibodies for further optimization; Identified novel VSIG4 receptors on primary T-cells by Hi-Res proteomics, which are currently in verification stage; Identified pH-sensitive antibodies highlighting the potential breadth of the TMAb platform Plan to select product candidate in 2023
ENTPDase1 (CD39)
ENTPDase1 (CD39) is the Rate Limiting Enzyme in the Production of Immunosuppressive Adenosine Figure adapted from: Moesta et al, Nat Rev Immunol. 2020; 20 (12) Hypoxia/cell damage ATP AMP Adeno-sine Blocking CD39 leads to: Immune Activation Primary function is conversion of extracellular ATP / ADP to adenosine, which exerts immunosuppressive properties through binding to A2a/A2b receptors Expressed on various immune cells in both tumors and normal tissues Development of a TMAb antibody has potential for improved safety and PK profile compared to competitor CD39 mAbs First set of parental antibodies received September 2022
SNS-101 (anti-VISTA) 1H 2023: Multi-dose Non-Human Primate (NHP) PK & Toxicology data 1H 2023: IND filing SNS-102 (anti-VSIG4) 2023: Select product candidate SNS-103 (anti-ENTPDase1/CD39) 2023: Select product candidate Expected Program Milestones
Engineered Selectivity to Extend the Reach of Immuno-oncology Agents THE CHALLENGE Systemically delivered I/O drugs often fail in the clinic due to on-target/off-tumor effects (TMDD, CRS) OUR FINANCIAL POSITION Ended 3Q 2022: $116.6M* Cash runway into Q1 2025 OUR STRATEGY Conditionally active antibodies engineered to enable druggability of promising oncology targets OUR LEAD PROGRAM SNS-101 is a pH-sensitive antibody targeting the VISTA receptor with IND expected H1 2023 *Consists of cash, cash equivalents and marketable securities
Proven Team With Deep Experience John Celebi, MBA President and CEO Erin Colgan Chief Financial Officer Robert Pierce, M.D. Chief R&D Officer Patrick Gallagher Chief Business Officer Elisabeth Colunio VP, Human Resources Edward van der Horst, Ph.D. SVP, TMAb Antibodies Christopher Gerry, J.D. VP, General Counsel
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Appendix References for Slide 23 Zheng F, Devoogdt N, Sparkes A, Morias Y, Abels C, Stijlemans B, Lahoutte T, Muyldermans S, De Baetselier P, Schoonooghe S, Beschin A, Raes G. Monitoring liver macrophages using nanobodies targeting Vsig4: concanavalin A induced acute hepatitis as paradigm. Immunobiology. 2015 Feb;220(2):200-9. doi: 10.1016/j.imbio.2014.09.018. Epub 2014 Oct 2. PMID: 25440182. Reviewed in Zang X, Allison JP. To be or not to be B7. J Clin Invest. 2006 Oct;116(10):2590-3. doi: 10.1172/JCI30103. PMID: 17016555; PMCID: PMC1578606. Helmy KY, Katschke KJ Jr, Gorgani NN, Kljavin NM, Elliott JM, Diehl L, Scales SJ, Ghilardi N, van Lookeren Campagne M. CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell. 2006 Mar 10;124(5):915-27. doi: 10.1016/j.cell.2005.12.039. PMID: 16530040. Voillet V, Berger TR, McKenna KM, Paulson KG, Tan WH, Smythe KS, Hunter DS, Valente WJ, Weaver S, Campbell JS, Kim TS, Byrd DR, Bielas JH, Pierce RH, Chapuis AG, Gottardo R, Rongvaux A. An In Vivo Model of Human Macrophages in Metastatic Melanoma. J Immunol. 2022 Aug 1;209(3):606-620. doi: 10.4049/jimmunol.2101109. Epub 2022 Jul 11. PMID: 35817516; PMCID: PMC9377377. Reviewed in Small AG, Al-Baghdadi M, Quach A, Hii C, Ferrante A. Complement receptor immunoglobulin: a control point in infection and immunity, inflammation and cancer. Swiss Med Wkly. 2016 Apr 5;146:w14301. doi: 10.4414/smw.2016.14301. PMID: 27045607. Liu G, Fu Y, Yosri M, Chen Y, Sun P, Xu J, Zhang M, Sun D, Strickland AB, Mackey ZB, Shi M. CRIg plays an essential role in intravascular clearance of bloodborne parasites by interacting with complement. Proc Natl Acad Sci U S A. 2019 Nov 26;116(48):24214-24220. doi: 10.1073/pnas.1913443116. Epub 2019 Nov 13. PMID: 31723045; PMCID: PMC6883839. Vogt L, Schmitz N, Kurrer MO, Bauer M, Hinton HI, Behnke S, Gatto D, Sebbel P, Beerli RR, Sonderegger I, Kopf M, Saudan P, Bachmann MF. VSIG4, a B7 family-related protein, is a negative regulator of T cell activation. J Clin Invest. 2006 Oct;116(10):2817-26. doi: 10.1172/JCI25673. PMID: 17016562; PMCID: PMC1578631. Liao Y, Guo S, Chen Y, Cao D, Xu H, Yang C, Fei L, Ni B, Ruan Z. VSIG4 expression on macrophages facilitates lung cancer development. Lab Invest. 2014 Jul;94(7):706-15. doi: 10.1038/labinvest.2014.73. Epub 2014 May 26. PMID: 24862966.
