Shattuck Labs, Inc. · NASDAQ:STTK
Shattuck Labs — TIGIT Therapies Digital Summit 2021
30 slides from Shattuck Labs's conference presentation, Dec 9, 2021
Slide 1: LIGHTing the Way for TIGIT Blockade in CPI Refractory Tumors
LIGHTing the Way for TIGIT Blockade in CPI Refractory Tumors NASDAQ: STTK TIGIT Therapies Digital Summit December 9, 2021
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains “forward-looking statements” within the meaning of the federal securities laws, which statements are subject to substantial risks and uncertainties and are based on our estimates and assumptions. All statements, other than statements of historica
Slide 3: ARC Platform Overview
ARC Platform Overview SSW ass SHATTUCK LABS
Slide 4: ARC Platform Technology
ARC Platform Technology Designed to Simultaneously Block Immune Checkpoints and Activate TNF Receptors 6 Checkpoint Binding Domains ARC Platform Structure and Mechanistic Design ✓ Checkpoint Inhibition Removes the "Brakes" From the Immune System Proprietary Engineered Fc Domain ✓ TNF Superfamily Ago
Slide 5: Shattuck's Development Pipeline
Shattuck’s Development Pipeline Deep Pipeline of Scientifically Validated and Novel Targets DOMAINS STAGE OF DEVELOPMENT PLATFORM PROGRAM DOMAIN 1 DOMAIN 2 INDICATIONS DISCOVERY PRECLINICAL PHASE 1 PHASE 2 PHASE 3 CLINICAL-STAGE PIPELINE Ovarian Cancer (1) SL-172154 SIRPα CD40L CSCC and HNSCC ARC (2
Slide 6: TIGIT Landscape and Mechanism of Action
TIGIT Landscape and Mechanism of Action TIGIT Axis Introduction & Pairing Rationale
Slide 7: Pre-Clinical and Clinical Validation of TIGIT
Pre-Clinical and Clinical Validation of TIGIT TIGIT Blockade Enables PVR Costimulation of DNAM-1 (CD226) Tumor Cell or Dendritic Cell PVR (CD155) Competes with 1 DNAM-1 for PVR ~100 nM ~1 nM DNAM (CD226) TIGIT (VSIG9) Disrupts CD226- 3 mediated costimulation Directly inhibits 2 T cells in cis T Cell
Slide 8: TIGIT is Likely a Sub-Dominant Checkpoint to PD-1
TIGIT is Likely a Sub-Dominant Checkpoint to PD-1 In human NSCLC samples ➔ TIGIT is upregulated on TIL ➔ All TIGIT positive TIL are PD-1 positive ➔ The density of TIGIT expression correlates with the density of PD-1 expression In human melanoma samples TOXlowPD-1low TOXlowPD-1low TOXlowPD-1low ➔ TIG
Slide 9: Inhibition of DNAM-1 by PD-1 Signaling
Inhibition of DNAM-1 by PD-1 Signaling TIGIT Requires Co-Blockade of PD-1 Because PD-1 Inhibits DNAM-1 Dendritic Cell • PD-1 mediated SHP-2 activation directly dephosphorylates CD80 / CD96 DNAM-1, in a similar PVR (CD155) manner to CD28 PD-L1 DNAM-1 • This mechanism explains why anti-tumor activity
Slide 10: Pre-Clinical and Clinical Validation of TIGIT
Pre-Clinical and Clinical Validation of TIGIT Potential Clinical Benefit Emerging in PD-1/L1 Naïve Low Expressing Tumors Anti-TIGIT + Anti-TIGIT mAb Anti-TIGIT + PD-1/L1 mAb Monotherapy PD-1/L1 mAb Combo Combo ANY TUMOR PD-1/L1 SETTING PD-1/L1 NAIVE EXPERIENCED PD-L1 <50% >50% NO NO YES NO 10 Data i
Slide 11: Why Doesn't TIGIT/PD-1 Blockade Work in PD-1 Experienced Patients?
Why Doesn’t TIGIT/PD-1 Blockade Work in PD-1 Experienced Patients? Newly Diagnosed Established Established Multiple Myeloma Multiple Myeloma Lung Cancer ➔ Intratumoral CD8+ T cells express DNAM-1 at reasonable levels immediately following diagnosis; however, DNAM-1 is rapidly downregulated as tumors
Slide 12: HVEM & LTβR Are Highly Expressed in TIL Across Tumor Types
HVEM & LTβR Are Highly Expressed in TIL Across Tumor Types A. 12 Yoo KJ, 2021, Under Review
Slide 13: HVEM & LTβR Are Highly Expressed in TIL Across Tumor Types
HVEM & LTβR Are Highly Expressed in TIL Across Tumor Types A. B. 13 Yoo KJ, 2021, Under Review
Slide 14: HVEM & LTβR Are Highly Expressed in TIL Across Tumor Types
HVEM & LTβR Are Highly Expressed in TIL Across Tumor Types A. B. C. 14 Yoo KJ, 2021, Under Review
Slide 15: Co-Expression of TIGIT, DNAM-1 & HVEM on T and NK Cells
Co-Expression of TIGIT, DNAM-1 & HVEM on T and NK Cells TIGIT DNAM-1 HVEM • Murine T cells were activated with CD3+ CD3/28 beads, and Cells the relative induction of TIGIT & DNAM-1 was assessed • Freshly isolated murine NK cells express low levels of NK TIGIT, moderate Cells DNAM-1, and high levels
Slide 16: SL-9258 (TIGIT-Fc-LIGHT): Characterization & Anti-Tumor Activity
SL-9258 (TIGIT-Fc-LIGHT) Characterization & Anti-Tumor Activity
Slide 17: SL-9258: Novel TIGIT Inhibitor + LTβR/HVEM Agonist
SL-9258: Novel TIGIT Inhibitor + LTβR/HVEM Agonist Rationally Designed to Increase Efficacy of TIGIT Blockade SL-9258 (TIGIT-Fc-LIGHT) Highly Differentiated PVR/PVRL2/PVRL3 & 6 TIGIT Binding Domains: Nectin-4 Inhibitor Blocks All TIGIT Ligands Potential First-In-Class LTβR & HVEM Agonist Inert IgG4
Slide 18: Fc Domain Considerations
Fc Domain Considerations Advantages to Fc Silent ARC Paired with LIGHT Costimulation Enhance activation of Silent Fc Competent Fc myeloid lineage cells Prevent depletion of Enhance depletion of TIGIT+ effector T cells TIGIT + regulatory T cells No valid explanation as to why these wouldn’t go hand-i
Slide 19: Activation of LTβR on Myeloid Cells Supersedes Role of Fc Domain in TIGIT Blockade
Activation of LTβR on Myeloid Cells Supersedes Role of Fc Domain in TIGIT Blockade Activation of antigen-presenting cells (from mice) MHC Class II CD86 CD40 ➔ TIGIT-Fc-LIGHT induces the up- regulation of MHC Class II and other Merck myeloid cell activation genes. ➔ Fold-induction is greater than wha
Slide 20: In vivo: Immune Activation and Anti-Tumor Efficacy
In vivo: Immune Activation and Anti-Tumor Efficacy 24 Hours Following a Single Intravenous Injection Myeloid Cells 24 hrs after 1st dose 24 hrs after 1st dose Day 1 CD11b+CD80+ Day 1 CD11b+CD86+ CD11b+CD80+ CD11b+CD86+ 4 6 **** **** % of Total CD45+CD3- Peripheral Cells % of Total CD45+CD3- Peripher
Slide 21: Activation of LTβR on Myeloid Cells Supersedes Role of Fc Domain in TIGIT Blockade
Activation of LTβR on Myeloid Cells Supersedes Role of Fc Domain in TIGIT Blockade Cxcl10 IP-10 ➔ TIGIT-Fc-LIGHT increases 250000 chemokine/cytokine 200000 production in vivo, in both mice and NHP Merck 150000 ➔ The kinetics of chemokine pg/mL 100000 induction by TIGIT-Fc- LIGHT translates from 5000
Slide 22: Assessing in vivo Activity & Combinations with Anti-PD(L)1
Assessing in vivo Activity & Combinations with Anti-PD(L)1 PD-1 Sensitive CT26 Tumor Model Internally Derived Shattuck Data CT26 Colorectal Carcinoma (mean STV = 84.09 mm3) • CT26 colorectal carcinoma tumors are usually responsive to checkpoint blockade of PD1 and PD-L1/ • Pre-clinical mouse models
Slide 23: Development of Anti-PD1 Acquired Resistant CT26 Tumor Model
Development of Anti-PD1 Acquired Resistant CT26 Tumor Model Acquired Established Initial response resistance to CT26 tumor to PD1 mAb PD1 mAb Excision and in vitro culture of PD1-resistant tumor Cycle repeated 4+ times ➔ The CT26-AR model pheno-copies CPI acquired resistant NSCLC tumors, and may be
Slide 24: Assessing in vivo Activity & Combinations with Anti-PD(L)1
Assessing in vivo Activity & Combinations with Anti-PD(L)1 PD-1 Acquired Resistant Tumor Model Group Comparator Mantel Cox p-value anti-TIGIT + Fc-LIGHT + anti-PD1 TIGIT-Fc-LIGHT 0.0082 TIGIT-Fc-LIGHT + anti-PD1 <0.0001 anti-TIGIT + Fc-LIGHT + anti-PD-L1 TIGIT-Fc-LIGHT 0.2502 TIGIT-Fc-LIGHT + anti-P
Slide 25: TIGIT-Fc-LIGHT Activates Both Innate and Adaptive Immunity in Tumors
TIGIT-Fc-LIGHT Activates Both Innate and Adaptive Immunity in Tumors Vehicle anti-PD1 Anti-PD-L1 mTIGIT-Fc-LIGHT mTIGIT-Fc-LIGHT + anti-PD1 mTIGIT-Fc-LIGHT + anti-PD-L1 ➔ Anti-tumor activity is accompanied by the tumor infiltration of antigen-specific CD8+ T cells and NK cells ➔ Activity of TIGIT-Fc
Slide 26: SL-9258 (TIGIT-Fc-LIGHT): Differentiated Mechanism of Action
SL-9258 (TIGIT-Fc-LIGHT) Differentiated Mechanism of Action
Slide 27: SL-9258 Stimulated Dose-Dependent Lymphocyte Migration and Cytokine Production in NHP
SL-9258 Stimulated Dose-Dependent Lymphocyte Migration and Cytokine Production in Non-Human Primates Lymphocyte Margination Fold Induction of IL-2 Fold Induction of IP-10 (TIGIT-Fc-LIGHT) mg/kg (Dose 3 pre-dose to 24 hours post-dose) % Change in Peripheral Lymphocytes Max (FC IP0-10) Max (FC IL-2) V
Slide 28: SL-9258 (TIGIT-Fc-LIGHT): Dual Mechanism of Action
SL-9258 (TIGIT-Fc-LIGHT): Dual Mechanism of Action Differentiated TIGIT Inhibitor and LIGHT Costimulation HVEM Co-Stimulation LTbR Activation ✓ TIGIT / PVR checkpoint blockade ✓ LIGHT costimulation of HVEM on T and NK Cells ✓ LIGHT activation of LTbR + stromal, tumor, and myeloid cells to chemo-attr
Slide 29: SL-9258 (TIGIT-Fc-LIGHT) has Potential to be Highly Differentiated
SL-9258 (TIGIT-Fc-LIGHT) has Potential to be Highly Differentiated Triple MOA ✓ Checkpoint blockade (PVR) differentiates from ✓ T/NK cell activation (HVEM) other in-class agents ✓ Myeloid cell activation and pro-inflammatory signaling in TME (LTbR) ✓ Pre-clinical development demonstrates monotherapy
Slide 30: Thank you
LABS Thank you SHATTUCK