Compugen Ltd. · NASDAQ:CGEN
Compugen — TIGIT Axis Therapies Digital Summit 2022
31 slides from Compugen's conference presentation, Dec 8, 2022
Slide 1: Unlocking the potential of PVRIG & TIGIT pathways to deliver the next transformational cancer immunotherapy drugs
Unlocking the potential of PVRIG & TIGIT pathways to deliver the next transformational cancer immunotherapy drugs TIGIT Axis Therapies Summit Eran Ophir, SVP Research & Drug Discovery December, 2022
Slide 2: Safe Harbor Statement
Safe Harbor Statement This presentation contains “forward-looking statements” within the meaning of the the Securities Act of 1933 and the Securities Exchange Act of 1934, as amended, and the safe-harbor provisions of the Private Securities Litigation Reform Act of 1995. Forward-looking statements c
Slide 3: DNAM-1 axis plays essential role in tumor immunology
DNAM-1 axis plays essential role in tumor immunology • PVRIG binds PVRL2 as a functional ligand and TIGIT TUMOR CELL / APC binds PVR PVRL2 PVR • DNAM-1 axis – two parallel dominant complementary inhibitory pathways (PVRIG & TIGIT) • TIGIT and PVRIG deliver direct inhibitory signals into T DNAM PVRIG
Slide 4: PVRIG, TIGIT and PD-1 are players in the DNAM-1 axis
PVRIG, TIGIT and PD -1 are players in the DNAM -1 axis Modified from Alteber et al. Cancer Discov. 2021 4
Slide 5: Potential intersection between PVRIG/TIGIT/PD-1 pathways supports combination approach
P o t e n t i a l i n t e r s e c t i o n b e t w e e n P V R I G / T I G I T/ P D - 1 p a t h w a y s s u p p o r t combination approach to overcome immunotherapy resistance Adapted from Alteber et al. Cancer Discov. 2021 5 Different tumor types may respond to different combinations depending on do
Slide 6: Synergistic T Cell activation with PVRIG, PD-1 and TIGIT blockade
Synergistic T Cell activation with PVRIG, PD -1 and TIGIT blockade COM701 +/- anti-TIGIT COM701 +/- anti-PD-1 Triple combination 400 200 500 +144% +467% +340% 400 300 150 +340% IFNγ (pg/mL) IFNγ (pg/mL) IFNγ (pg/mL) +41% +293% +136% +57% 300 200 100 +144% +57% +41% 200 100 50 100 0 0 0 Isotope COM70
Slide 7: Potent immune activation with COM701, nivolumab and BMS-986207 triple blockade
Potent activation of the immune system with COM701, nivolumab and BMS- 986207 (anti-TIGIT) triple blockade in patients with advanced cancer Increased T and NK cell activation, memory T Cell proliferation and IFNg induction in blood at all COM 701 doses A Avr. Fold Change=2.7 P=<0.0001 IFNγ B Avr. Fo
Slide 8: Early differentiated T stem-like cells are potent inducers of anti-tumor activity
E a r l y d i f f e r e n t i a t e d T s t e m - l i ke c e l l s a r e p o t e n t i n d u c e r s o f anti-tumor activity following adoptive T cell transfer Klebbanoff et al., 2005, PNAS. Gatiinoni et al., 2009, Nat Med Xu et al., 2015, J. of Hem and Onc. Krishna et al., 2020, Science 8
Slide 9: Growing evidence of Tscm importance in response to checkpoint blockade
G r o w i n g e v i d e n c e o f e a r l y d i f f e r e n t i a t e d T s t e m - l i ke m e m o r y c e l l s ( Ts c m ) i m p o r t a n c e i n r e s p o n s e t o c h e c k p o i n t b l o c k a d e The fraction of Tscm cells is predictive of Anti-PD-(L)1 expands a key population of PD-1-positi
Slide 10: PVRIG uniquely clusters with early differentiated/Tscm genes
P V R I G u n i q u e l y c l u s t e r s w i t h e a r l y d i f f e r e n t i a t e d / Ts c m g e n e s PCA Analysis of scRNA of CD8+ T cell genes, NSCLC Unsupervised correlation analysis of scRNA, CRC TRM ZNF683 (HOBIT) IL7R Naïve ITGAE SELL (CD103) TCF7 ENTPD1 (CD39) CCR7 CD28 LAYN PVRIG HAVCR2
Slide 11: Gene model correction for PVRIG in single cell data
G e n e m o d e l c o r re c t i o n fo r P V R I G i n s i n g l e c e l l d ata e n a b l e s a c c u rate d ete c t i o n o f i t s f u n c t i o n a l re l e va n c e 11 https://www.biorxiv.org/content/10.1101/2022.11.02.514879v1
Slide 12: PVRL2 has a dominant expression on dendritic cells
PVRL2 has a dominant expression on dendritic cells T cell DC Population in SCC/BCC Multiple scRNA cancer datasets Ovarian cancer DC1 DC2 Total DCs Internal FLOW cytometry Data PVRL2 GSE123814 Dataset internally analyzed Alteber et al , Poster presentation SITC 2021 12 PVRIG blockade may enhance Tscm
Slide 13: Spatial transcriptomic analysis of TLS regions shows enrichment of Tscm and DCs
Spatial transcriptomic analysis of TLS regions shows enrichment o f Ts c m a n d D C s w h i l e e x h a u s t e d c e l l s l o c a l i z e t o t h e t u m o r In-situ MERFISH analysis of tertiary lymphoid structures (TLS) in TME of CRC patients Annotated cells in-situ TLS TLS region Fraction of ce
Slide 14: PVRIG and other DNAM-1 axis genes dominantly expressed in TLS region
PVRIG and other genes of the DNAM -1 axis are dominantly expressed in TLS region In-situ MERFISH analysis of tertiary lymphoid structures (TLS) in TME of CRC patients Expression in CD8+ T-cells TLS Expression in TLS vs Tumor Alteber et al, Oral presentation SITC 2022 14
Slide 15: COM701 may turn less inflamed tumors into hot tumors
CO M 7 0 1 m ay t u r n l e s s i n f l a m e d t u m o rs i nto h o t t u m o rs Alteber et al, Oral presentation SITC 2022 COM701 might play a dominant role controlling T cells expansion 15
Slide 16: COM701 shows clinical activity in platinum resistant ovarian cancer
CO M 7 0 1 s h o w s c l i n i c a l a c t i v i t y i n p l at i n u m re s i sta nt o va r i a n cancer Strong preliminary (and ongoing) signal in an indication with high unmet need and typically immunologically unresponsive SOC 2L+ ORR % mPFS (months) mOS (months) COM701 COM701 + COM701 + Mono’*
Slide 17: Confirmed PR in patient with primary peritoneal PD-L1 negative ovarian cancer treated with COM701 monotherapy
C o n f i r m e d P R i n p a t i e n t w i t h p r i m a r y p e r i t o n e a l P D - L 1 neg ovarian cancer treated with COM701 monotherapy Patient received 3 prior lines of anti-cancer therapy Increase in IFNγ induction and immune PVRL2 PDL1 activation in peripheral blood Prim peritoneal 20 mg/k
Slide 18: COM701 monotherapy induces TME immune modulation in patients with ovarian cancer
COM701 monotherapy induces TME immune modulation in patients with ovarian cancer PD-L1 expression CD8 expression (IF) Pre On 40 20 30 15 PDL1 CPS % of CD8 PD-L1 IHC 20 10 10 5 0 0 pre on pre on Alteber et al, Oral presentation SITC 2022 • 3 out of 4 patients showed an increase in CPS PD-L1 • 2 out o
Slide 19: COM701 monotherapy induced immune activation in the TME of patient with ovarian cancer
COM701 monotherapy induced immune activation in the TME of patient with ovarian cancer CD8 distribution in TME Protein expression in CD8 regions (NanoString, DSP) CD8 distribution in TME Pre On PRE ON p<0.05 CD8 CD8 PanCK nuclei 0 cell >5cel l ✱✱ ✱✱ ✱ 6 ✱✱ Protein Expression (Log2) 10 15 12 Protein
Slide 20: Platinum resistant ovarian cancer: COM701 combinations swimmer plot
P l at i n u m re s i sta nt ova r i a n c a n c e r CO M 7 0 1 C o m b i n at i o n s – s w i m m e r p l o t COM701+Nivolumab COM701+ BMS-986207 (a-TIGIT)+ nivolumab Pre PDL1 CPS<1 Pre PDL1 CPS 3 Yeku et al, Poster presentation ESMO-IO 2022 Moroney et al, Poster presentation ESMO-IO 2022 20 All 4
Slide 21: Platinum resistant ovarian cancer: COM701 combinations waterfall plots
P l at i n u m re s i sta nt ova r i a n c a n c e r CO M 7 0 1 C o m b i n at i o n s – w ate r fa l l p l o t s COM701 + nivolumab COM701 + BMS-986207 (anti-TIGIT) + nivolumab Yeku et al, Poster presentation ESMO-IO 2022 Moroney et al, Poster presentation ESMO-IO 2022 21
Slide 22: Clinical vignette: COM701 + nivolumab
C L I N I C A L V I G N E T T E - CO M 7 0 1 + n i vo l u m a b 53yr old female, histology - high grade serous adenocarcinoma . Received 7 prior lines including 4th line: nivolumab/+lucitanib (TKI) [best response PD] Reduction in target lesion Increased CD8+ T cell infiltration post-treatment PR – 3
Slide 23: Clinical vignette: COM701 + BMS-986207 (anti-TIGIT) + nivolumab
CLINICAL VIGNETTE - CO M 7 0 1 + B M S - 9 8 6 2 0 7 ( a nt i - T I G I T ) + n i vo l u m a b 68yr old female, histology: high grade serous ovarian carcinoma with a history of 3 prior lines of non-maintenance therapy: carboplatin/paclitaxel, Y90 hepatic radioembolization, carboplatin/pegylated lipo
Slide 24: COM701 with nivolumab induce clinical response in patients with MSS CRC and liver metastasis
CO M 7 0 1 w i t h n i vo l u m a b i n d u c e c l i n i c a l re s p o n s e i n p at i e nt s w i t h M S S C RC a n d l i ve r m eta sta s i s MSS CRC Benchmark Last Line SoC ORR PFS OS Regorafenib 1% 2m 6.4m 17/22 patients with liver mets 2 PR with liver mets Difficult to treat MSS-CRC + liver
Slide 25: COM701 + nivolumab combination induces TME immune modulation in patients with MSS-CRC
COM701+ nivolumab combination induces TME immune modulation in patients with MSS-CRC PD-L1 expression CD8 IHC IFNγ signature Pre On Avg. fold change=3.5 Avg. fold change=7.9 Avg. fold change =7.8 0.0852 0.1271 100 0.0403 60 500 PR PR 80 PR 400 40 IFNg signature PR PDL1 CPS 60 % of CD8 300 PD-L1 IHC
Slide 26: Extensive TME modulation in MSS-CRC patients partially responding to COM701 + nivolumab
Extensive TME modulation in MSS-CRC patients partially responding to COM701+ nivolumab Increased CD8 infiltration and immune modulation Increased TCR clonality and clonal expansion Responder 1 Pre On Responder 1 Most dominant IFNg Clone count 128 64 clone on CD8+ Tcm Responder 1 treatment pre- Ratio
Slide 27: PVRIG highly expressed on Tscm and PVRL2 on DCs in liver metastases of MSS CRC patients
P V R I G i s h i g h l y ex p re s s e d o n Ts c m a n d P V R L 2 o n D C s i n l i ve r m eta sta s e s o f p at i e nt s w i t h M S S C RC High PVRIG on Tscm CD8+ T-cells Dominant PVRL2 on Dendritic cells Fraction of cells in group (%) Fraction of cells in group (%) DC1 185 2.6k 5 1015202530 T
Slide 28: COM701 + nivolumab induced markers of activated DCs in serum of responding patients
C o m b i n a t i o n o f C O M 7 0 1 + n i v o l u m a b i n d u c e d m a r ke r s o f activated DCs in serum of 3 responding patients Responders (R) vs non-responders (NR) differential gene expression NR R HLA-DR LAMP3 CD83 5 3 0.0029 4 0.0151 0.0004 to Pre-Treatment to Pre-Treatment to Pre-Treat
Slide 29: Summary
Summary • PVRIG has a unique dominant expression on Tscm, its ligand, PVRL2, is expressed also on dendritic cells (DCs) • Spatial transcriptomic analysis showed that Tscm and DCs preferentially localize to TLS regions while exhausted T cells localize to the tumor • PVRIG is dominantly expressed on C
Slide 30: Thank you!
Acknowledgments: Zoya Alteber, Roy Granit, Gady Cojocaru, Danae Hudson, Amanda Harp, Amit Novik, Compugen Ltd. Niv Sabath, Assaf Wool, Yossef Kliger, Yu Holon, Israel Natalia Petrenko, Rob Foreman, Liang, Inbal Barbiro, Athalia Markiewitz, Predictive Target Discovery & Experimental Validation Pierre
Slide 31: Our Vision
Our Vision Transforming patient lives by developing first-in-class therapeutics based on Compugen’s computational target discovery platform From Code to Cure® 31