Slide 1: Inhibiting TIGIT to Promote Anti-Tumor Immunity
INHIBITING TIGIT TO PROMOTE ANTI-TUMOR IMMUNITY DANA PIOVESAN, MSc June 23rd, 2022
Slide 2: Disclosures and Forward-Looking Statements/Safe Harbor
Disclosures and Forward-Looking Statements/Safe Harbor This presentation contains forward-looking statements about Arcus Biosciences, Inc. (“we,” ”Arcus” or the “Company”) made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. All statements other than s
Slide 3: Molecular Suppression of T Cells in the Tumor Microenvironment
Molecular Suppression of T Cells in the Tumor Microenvironment: T Cell Inhibitory Receptors (Checkpoints) Antigen- presenting cell (APC) T cell (CD4+, CD8+) Cancer cell TIGIT/CD226 Pathway 3 CONFIDENTIAL © Arcus Biosciences 2022
Slide 4: TIGIT is an Inhibitory Receptor That Out-Competes CD226 for CD155 Binding
TIGIT is an Inhibitory Receptor That Out-Competes CD226 Activating Receptor for CD155 Binding, Resulting in Immunosuppression Cancer cells APC (DCs) TIGIT out-competes CD226 for CD155 binding CD8+ T cells CD4+ T cells Tregs NK cells Reduced activation / functionality 4 CONFIDENTIAL © Arcus Bioscienc
Slide 5: PD-1 Has Also Been Shown to Restrict CD226 Signaling
Similar to the PD-1/CD28 Interaction, PD-1 Has Also Been Shown to Restrict CD226 Signaling Cancer cells APC (DCs) TIGIT out-competes CD226 for CD155 binding CD8+ T cells CD4+ T cells Tregs NK cells Reduced activation / functionality 5 Banta et al. (2022) Immunity, DOI: 10.1016/j.immuni.2022.02.005 C
Slide 6: CD226 Signaling Can be Enhanced Through Co-blockade of PD-1 and TIGIT
CD226 Signaling Can be Enhanced Through Co-blockade of PD-1 and TIGIT Cancer cells APC (DCs) Anti-PD-1 Anti-TIGIT CD8+ T cells CD4+ T cells Tregs NK cells Increased activation / functionality 6 Banta et al. (2022) Immunity, DOI: 10.1016/j.immuni.2022.02.005 CONFIDENTIAL © Arcus Biosciences 2022
Slide 7: Domvanalimab and AB308 are Potent Anti-TIGIT Antibodies
Domvanalimab (Fc-silent) and AB308 (Fc-enabled) are Potent Anti-TIGIT Antibodies Currently Being Evaluated in Cancer Patients Blocking Blocking & potential effector function1-3 (domvanalimab) (AB308) TIGIT TIGIT FcγR NK cells DCs 1 Macrophages Han et al. (2020) Frontiers in Immun. DOI: 10.3389/fimmu
Slide 8: In Mice, Combination of α-PD-1 with α-TIGIT Enhances Tumor Control
In Mice, Combination of α-PD-1 with Either Fc-Silent (FcS) or Fc- Enabled (WT) α-TIGIT Enhances Tumor Control α-TIGIT-WT Associated With Intratumoral Treg Depletion Tumor Spleen (Fold-change over isotype) 5 MC38 4 TIGIT gMFI TIGIT 3 1600 Isotype Tumor Volume (mm3) expression levels 2 αPD-1 1 1200 αT
Slide 9: In Human, Fc-enabled AB308 and tiragolumab Promote NK-mediated ADCC
In Human, Fc-enabled AB308 and tiragolumab Induce FcγR- mediated Signaling and Promote NK-mediated ADCC Against TIGIT-Expressing Target Cells FcγRIIIa V158 (high affinity) NK-mediated ADCC 8×10 5 AB308 pCHO hTIGIT-CHO Relative Light Units 30 ✱ ✱✱ 6×10 5 tiragolumab 25 25 Isotype domvanalimab 20 20 A
Slide 10: Identity of TIGIT-expressing T cells Modulated by Anti-TIGIT Antibodies
What is the Identity of TIGIT-expressing T cells Modulated by Treatment with Anti-TIGIT Antibodies? Increased pool of T cells capable of differentiating into cells with enhanced cytotoxic/effector potential Pre-dysfunctional/Stem-like CD8+ T cells activated by anti-PDx are also probable targets for
Slide 11: Stem-like and Terminally Differentiated CD8+ T Cells in NSCLC Tumors
Stem-like (TCF-1+) and Terminally Differentiated (TIM-3+) CD8+ T Cells are Present in NSCLC Tumors Gated on CD8+ T cells Terminally Stem-like differentiated Stem-like TCF-1 Terminally CD39 differentiated TIM-3 PD-1 100 % of CD8+ T cells ✱✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱✱ ✱✱✱✱ 80 % of CD8+ T cell subset 60 100 40 80
Slide 12: PD-1, TIGIT, and CD226 Expressed on Stem-like and Terminally Differentiated CD8+ T Cells
In NSCLC Tumors, PD-1, TIGIT, and CD226 are Expressed on a High Proportion of Both Stem-like and Terminally Differentiated CD8+ T Cells PD-1 TIGIT CD226 ✱✱✱ ✱✱✱ ✱✱ % of CD8+ T cell subset Isotype 100 80 Stem-like 60 40 Terminally 20 differentiated 0 PD-1+ TIGIT+ CD226+ 12 CONFIDENTIAL © Arcus Biosci
Slide 13: PD-1+TIGIT+CD226+ Stem-like are Probable Targets for Co-blockade
PD-1+TIGIT+CD226+ Stem-like CD8+ T cells are Probable Targets for Co-blockade of PD-1 and TIGIT Terminally Stem-like differentiated TIGIT CD226 % of CD8+ T cell subset ✱✱✱ 80 60 40 20 0 13 PD-1+ TIGIT+ CD226+ CONFIDENTIAL © Arcus Biosciences 2022
Slide 14: Conclusions and Future Directions
Conclusions and Future Directions • Fc-enabled AB308, but not Fc-silent domvanalimab, has the capacity to bind Fcγ receptors and promote NK-mediated ADCC • PD-1, TIGIT, and CD226 are co-expressed on both stem-like and terminally differentiated intratumoral CD8+ T cell subsets in NSCLC subjects • Aki
Slide 15: Arcus is Hiring!
Arcus is Hiring! • https://arcusbio.com/careers/#careers Annual Research Retreat Napa, CA (Circa 2019) 15 CONFIDENTIAL © Arcus Biosciences 2022
Slide 16: Arcus Biosciences
ARCUS BIOSCIENCES