Arcus Biosciences, Inc. · NYSE:RCUS
Arcus Biosciences — Technical Presentation (March 2024)
20 slides from Arcus Biosciences's technical presentation, Mar 18, 2024
Slide 1: Fc-silent Anti-TIGIT Antibodies Offer Best-in-Class Potential
Fc-silent Anti-TIGIT Antibodies Offer Best-in-Class Potential By Potentiating Robust CD8+ T Cell-Mediated Anti-tumor Immunity Without Peripheral Regulatory T Cell Depletion Kelsey E. Sivick Gauthier, PhD Director, Biology March 18th, 2024
Slide 2: Co-blockade of TIGIT and PD-1 is Required for Full Activation of the CD226 Axis
Co-blockade of TIGIT and PD-1 is Required for Full Activation of the CD226 Axis Inhibited State Activated State Does adding TIGIT blockade enhance tumor control by anti- PD-1? 2 Jin et al (2020) Cancer Immunol Res; Worboys et al (2023) Nat Comm; Wang et al (2018) Sci Immunol; Banta et al (2022) Immu
Slide 3: Fc-silent Anti-TIGIT Promotes Anti-tumor Immunity Without Treg Depletion
Fc-silent Anti-TIGIT Promotes Anti-tumor Immunity Without Regulatory T Cell (Treg) Depletion αPD-1 αTIGIT MC38 αPD-1 αTIGIT MC38 tumor 3d Fc- Fc- Fc- Fc- silent enabled silent enabled Tumor Volume (mm3) 1500 iso αPD-1 **** ✱✱ 1000 ✱✱ αTIGIT Fce αPD-1 + αTIGIT Fc e 500 αTIGIT Fcs **** * αPD-1 + αTIGI
Slide 4: Treg and Exhausted CD8+ T Cell Subsets in Human NSCLC Tumors Co-express PD-1, TIGIT, CD226
Treg and Exhausted CD8+ T Cell Subsets in Human NSCLC Tumors Co-express PD-1, TIGIT, and CD226 Exhausted T Cell Differentiation Circulating and Resident Terminally Intermediate (Tex) precursor exhausted (Tpex) Differentiated (Ttex) cTpex rTpex Int Ttex Self-Renewal Proliferation Cytokine Secretion %
Slide 5: Fc-silent Anti-TIGIT Potentiates Precursor Exhausted Tumor-specific T Cell Activation
Fc-silent Anti-TIGIT Potentiates Precursor Exhausted Tumor-specific T Cell Activation and Differentiation Fc-silent αPD-1 αTIGIT MC38 tumor Tpex Tpex 3d Terminal Ttex + TCF-1-CD69+ TCF-1 Cytotoxic Tex TCF-1-CD69- Int Ttex Precursor Tpex 6 TCF-1+CD69-/+ % p15E+ (of CD8+) ✱✱✱✱ iso CD69 (FC vs iso) 4 ✱
Slide 6: AB154 (or dom) and AB308 are Potent Anti-TIGIT Antibodies in Clinical Development
AB154 (or dom) and AB308 are Potent Anti-TIGIT Antibodies in Clinical Development AB154 Phase 3 Domvanalimab (dom) AB308 Phase 1 Blocking Blocking & Effector Function Silent Enabled (‘LALA’ mutated hIgG1) (wild type hIgG1) 0.42 nM 0.36 nM Binding EC50 0.69 nM 0.68 nM Blocking IC50 6
Slide 7: In Contrast to Fc-enabled AB308, Dom Does Not Promote ADCC Against Peripheral Human Treg
In Contrast to Fc-enabled AB308, Dom Does Not Promote ADCC Against Peripheral Human Treg in vitro Fc-enabled Fc-silent Fc- Fc- Fc- AB308 dom enabled silent enhanced ✱✱ 2.0 ✱✱✱ % Dead Target (fold change) 1.5 Can Fc-enabled anti-TIGIT deplete 1.0 peripheral Treg in humans? 0.5 iso Fcee Fabdom + Fcee
Slide 8: Dom Does Not Deplete Peripheral Treg in Phase 1 Patients
In Contrast to Fc-enabled AB308, Dom Does Not Deplete Peripheral Treg in Phase 1 Patients with Advanced Solid Cancer Fc-enabled Fc-silent AB308 dom AB308: NCT04772989, n = 14 dom: NCT03628677, n = 10 AB308 domvanalimab Are certain (fold change vs baseline) (fold change vs baseline) # Treg/μL whole b
Slide 9: Peripheral eTreg Have Higher TIGIT and are Preferentially Targeted by ADCC
Peripheral eTreg Have Higher Levels of TIGIT and are Preferentially Targeted by NK Cell-mediated ADCC eTreg nTreg Naïve Peripheral Effector (most Treg Treg Treg Helios suppressive) Fc- Fc- Fc- Fc- Fc- Fc- % Live Counts (vs iso) pTreg enabled silent enabled silent enabled silent 20 ✱ gMFI TIGIT (x 10
Slide 10: Fc-silent Anti-TIGIT Potentiates Anti-tumor Immunity While Avoiding Depletion of Peripheral Treg
Fc-silent Anti-TIGIT Potentiates Anti-tumor Immunity While Avoiding Depletion of Peripheral Treg • TIGIT blockade potentiates activation, differentiation, and effector function of tumor-specific CD8+ T cells • Silencing the Fc domain of anti-TIGIT prevents depletion of peripheral Treg, potentially c
Slide 11: The Team at Arcus Biosciences
The Team at Arcus Biosciences 2023 Research and Non-clinical Development Retreat • Gilead colleagues 11 Some images made with BioRender
Slide 12: Appendix
APPENDIX INGLES) BIOSCIENCES
Slide 13: TIGIT is an Inhibitory Receptor that Outcompetes CD226 for Shared Ligand CD155
TIGIT is an Inhibitory Receptor that Outcompetes the CD226 Activating Receptor for Shared Ligand CD155 APC or cancer cell Thickness = Strength Inhibitory Activating T and NK 13
Slide 14: Treg and Exhausted CD8+ T Cell Subsets in Human NSCLC Tumors Co-express PD-1, TIGIT, CD226
Treg and Exhausted CD8+ T Cell Subsets in Human NSCLC Tumors Co-express PD-1, TIGIT, and CD226 Exhausted T Cell Phenotyping Circulating pre-exhausted (Tpex) Terminally Intermediate Tex and Resident Tpex Differentiated (Ttex) cTpex rTpex Int Ttex TCF-1+ TCF-1- TIM-3- TIM-3+ % PD-1+TIGIT+CD226+ 80 ✱✱
Slide 15: Exhausted T Cell Subsets in Human NSCLC Tumors Express PD-1, TIGIT, and CD226
Exhausted T Cell Subsets in Human NSCLC Tumors Express PD-1, TIGIT, and CD226 NSCLC Gastro-esophageal CD103- CD103+ CD103- CD103+ Residency 80 30 % of CD8+ % of CD8+ 60 Exhausted 20 40 PD-1hi CD103+ 20 10 CD103- 0 0 PD-1 PD-1+ CD103+ PD-1: PD-1: CD103- 100 % TIGIT+CD226+ CD103+ % TIGIT+CD226+ 100 PD
Slide 16: MC38 is an Ideal Experimental Model to Evaluate Anti-PD-1 Combination Partners
MC38 is an Ideal Experimental Model to Evaluate Anti-PD-1 Combination Partners • Model: The MC38 colon carcinoma Anti-PD-1 model is T cell infiltrated and anti-PD-1 responsive • Readouts: Tools exist to monitor MHC class I tetramer endogenous MC38 cancer cell-specific p15E CD8+ T cell responses • Su
Slide 17: Fc-silent Anti-TIGIT Potentiates Expansion of Tumor-specific CD8+ T Cells and Tumor Control
Fc-silent Anti-TIGIT Potentiates Expansion of Tumor-specific CD8+ T Cells and Tumor Control FTY720 Tumor Volume (mm3) FTY720 ✱✱ 2500 6 αPD-1 ✱✱✱✱ ✱✱✱✱ 2000 0/10 CR Fold change in % p15E+ (of CD8+) Tumor 4 1500 1000 αPD-1 + αTIGIT Fcs 2 4/10 CR 500 p15E+ 0 0 (tumor-specific) 4 8 12 16 20 24 28 CD8+ T
Slide 18: Addition of Dom to Zimberelimab Resulted in a 33% Reduction in Risk of Progression or Death
Addition of Dom to Anti-PD-1 Zimberelimab (Zim) Resulted in a 33% Reduction in Risk of Progression or Death as Compared to Zim Alone in PD-L1 High Metastatic NSCLC CI: confidence interval; HR: hazard ratio; Mos: months; NE: not evaluable • Addition of dom to zim does not appear to add any meaningful
Slide 19: In Contrast to Fc-enabled Anti-TIGIT, Dom Does Not Promote ADCC Against TIGIT Expressing Cell Lines
In Contrast to Fc-enabled Anti-TIGIT, Dom Does Not Promote ADCC Against TIGIT Expressing Cell Lines Killing Correlates Target: CHO ± TIGIT Killing is Fc Dependent with TIGIT Expression ✱✱✱✱ 2.5 15 ✱✱✱✱ % Dead Target % Dead Target (fold change) (fold change) 2.0 10 1.5 5 1.0 0.5 0 TIGIT: - + - + TIGI
Slide 20: Three Subsets of Treg Can Be Identified in Human Peripheral Blood
Based on FoxP3 and Helios Expression, Three Subsets of Treg Can Be Identified in Human Peripheral Blood Self antigen specificity nTreg eTreg Helios pTreg FoxP3 Non-self antigen specificity Among thymic-derived subsets, effector Treg are more suppressive than naïve Treg 20 Sakaguchi et al (2020) Ann
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